ORCID Profile
0000-0002-2363-8707
Current Organisation
Princess Margaret Cancer Centre
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Publisher: Springer International Publishing
Date: 2016
Publisher: American Society of Clinical Oncology (ASCO)
Date: 11-2018
DOI: 10.1200/PO.17.00248
Abstract: Fine-needle biopsy (FNB) and liquid biopsy are minimally invasive methods of tumor s ling that provide feasible means to assess tumor genotypes in real time. However, more data are needed to establish the strength of these methods by benchmarking against the current gold standard methods, core-needle biopsy (CNB) or surgical excision of the tumor. Eligible patients with advanced solid tumors were prospectively recruited. We performed mutation profiling using matched tumor DNA obtained by CNB, FNB and liquid biopsy, and matrix-assisted laser desorption/ionization time-of-flight custom mass-spectrometry or targeted next-generation DNA sequencing. The actionability of detected mutations was determined using the OncoKB Web tool. Agreement between mutations detected in CNBs, FNBs, and circulating tumor DNA (ctDNA) was examined. Forty-one patients underwent tumor biopsy. Thirty CNBs (73%) and 34 FNBs (83%) had sufficient tumor and DNA for mutation profiling. Median DNA yield from CNB and FNB were 775 ng (interquartile range, 240 to 347 4ng) and 649 ng (interquartile range, 180 to1350 ng), respectively. Of 29 CNB/FNB pairs available for comparison, actionable mutation results were concordant in 28 (96%). Six of nine actionable mutations (67%) that were found by CNB, FNB, or both were detectable in ctDNA. Two additional actionable mutations were found exclusively in ctDNA. Optimally processed FNB and liquid biopsy can be used routinely for tumor mutation profiling to identify actionable mutations.
Publisher: American Society of Clinical Oncology (ASCO)
Date: 04-2023
DOI: 10.1200/PO.22.00509
Abstract: To evaluate early circulating tumor DNA (ctDNA) kinetics using a tumor-naïve assay and correlate it with clinical outcomes in early phase immunotherapy (IO) trials. Plasma s les were analyzed using a 425-gene next-generation sequencing panel at baseline and before cycle 2 (3-4 weeks) in patients with advanced solid tumors treated with investigational IO agents. Variant allele frequency (VAF) for mutations in each gene, mean VAF (mVAF) from all mutations, and change in mVAF between both time points were calculated. Hyperprogression (HyperPD) was measured using Matos and Caramella criteria. A total of 162 plasma s les were collected from 81 patients with 27 different tumor types. Patients were treated in 37 different IO phase I/II trials, 72% of which involved a PD-1/PD-L1 inhibitor. ctDNA was detected in 122 plasma s les (75.3%). A decrease in mVAF from baseline to precycle 2 was observed in 24 patients (37.5%) and was associated with longer progression-free survival (hazard ratio [HR], 0.43 95% CI, 0.24 to 0.77 P .01) and overall survival (HR, 0.54 95% CI, 0.3 to 0.96 P = .03) compared with an increase. These differences were more marked if there was a % decrease in mVAF for both progression-free survival (HR, 0.29 95% CI, 0.13 to 0.62 P .001) and overall survival (HR, 0.23 95% CI, 0.09 to 0.6 P = .001). No differences in mVAF changes were observed between the HyperPD and progressive disease patients. A decrease in ctDNA within 4 weeks of treatment was associated with treatment outcomes in patients in early phase IO trials. Tumor-naïve ctDNA assays may be useful for identifying early treatment benefits in phase I/II IO trials.
Publisher: Public Library of Science (PLoS)
Date: 12-2021
DOI: 10.1371/JOURNAL.PONE.0259272
Abstract: Non-schistosomiasis related-squamous cell carcinoma of urinary bladder (NSR-SCCUB) is a rare tumor subtype distinct from urothelial carcinoma (UC). Studies assessing molecular biomarkers in bladder cancer have generally focused on UC, and genomic data of NSR-SCCUB is limited. We aim to provide additional insight into the molecular underpinnings of this rare entity. NSR-SCCUB patients were identified retrospectively at Princess Margaret Cancer Centre between 2002 and 2017. Demographics, disease characteristics, therapeutic approaches, and outcomes were collected. Tissue s les were interrogated using the Oncomine Comprehensive Assay v3 (ThermoFisher). Kaplan-Meier method was used to estimate the disease-free survival and overall survival (OS). Overall, 11 patients with NSR-SCCUB were identified between 2002 and 2017 with adequate tissue s les. Median age was 71 years (45–86), predominantly male (63.6%). At time of diagnosis, 9 patients (81.8%) had muscle-invasive disease, 1 (9.1%) had non-muscle invasive, and 1 (9.1%) had advanced disease. Nine (81.8%) patients had radical cystectomy and pelvic lymph nodes dissection. Eight (72.7%) patients had pT3 or pT4 with N0, and 5 (45.5%) were grade 3. Median OS was 12.5 months (95% CI 7.7–17.2 months). Single nucleotide variants or insertion/deletions were identified in TP53 , TERT , PIK3CA , PTEN , CREBBP , FBXW 7 , and FGFR3 . Amplifications were found in CCND1 , and EGFR . NSR-SCCUB has potentially actionable genomic alterations with anticancer agents and many of these aberrations are also seen in UC. The recruitment of NSR-SCCUB patients harboring such mutations should be considered in biomarker driven urinary bladder cancer studies.
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/1078-0432.22487037.V1
Abstract: Supplementary Table from A Randomized Phase II Study of MEDI0680 in Combination with Durvalumab versus Nivolumab Monotherapy in Patients with Advanced or Metastatic Clear-cell Renal Cell Carcinoma
Publisher: Springer Science and Business Media LLC
Date: 15-11-2016
DOI: 10.1007/S40259-016-0204-3
Abstract: Immune checkpoint inhibitors (ICIs), including antibodies targeting cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) and programmed cell death protein-1 (PD-1), have shown durable treatment responses in multiple tumor types by enhancing antitumor immunity. However, removal of self-tolerance can induce autoimmunity and produce a unique immune-driven toxicity profile, termed immune-related adverse events (irAEs). As ICIs gain approval for a growing number of indications, it is imperative clinicians increase their knowledge of and ability to manage irAEs. This review examines the etiology, presentation, kinetics, and treatment of irAEs and aims to provide practical guidance for clinicians.
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/1078-0432.22487043.V1
Abstract: Supplementary Figure from A Randomized Phase II Study of MEDI0680 in Combination with Durvalumab versus Nivolumab Monotherapy in Patients with Advanced or Metastatic Clear-cell Renal Cell Carcinoma
Publisher: MDPI AG
Date: 08-2016
DOI: 10.3747/CO.23.3242
Abstract: Population-based datasets can provide observational insights into cancer incidence, [...]
Publisher: Elsevier BV
Date: 04-2015
Publisher: Elsevier BV
Date: 10-2016
Publisher: Wiley
Date: 30-06-2020
DOI: 10.1002/CNCR.33032
Publisher: Oxford University Press (OUP)
Date: 04-03-2019
DOI: 10.1634/THEONCOLOGIST.2018-0808
Abstract: Enrichment of patients based on molecular biomarkers is increasingly used in early phase clinical trials. Molecular profiling of patients with advanced cancers can identify specific genomic alterations to inform decisions about investigational treatment(s). Our aim was to evaluate the outcomes of new patient referrals to a large academic solid tumor phase I clinical trial program after the implementation of molecular profiling. Retrospective chart review of all new referrals to the Princess Margaret Cancer Centre (PM) phase I clinic from May 2012 to December 2014. Molecular profiling using either MALDI-TOF hotspot mutation genotyping or targeted panel DNA sequencing was performed for patients at PM or community hospitals through the institutional IMPACT/COMPACT trials. A total of 971 new patient referrals were included for this analysis. Twenty-seven percent of referrals assessed in clinic were subsequently enrolled in phase I trials. Of all new referrals, 41% had prior molecular profiling, of whom 11% (n = 42) were enrolled in genotype-matched trials. Patients with prior molecular profiling were younger, more heavily pretreated, and had more favorable Princess Margaret Hospital Index (PMHI) scores. Eastern Cooperative Oncology Group (ECOG) performance status 0–1 (p = .002), internal referrals within PM (p = .002), and PMHI (p ≤ .001) were independently associated with successful trial enrollment in multivariable analysis. Although nearly half of new patients referred to a phase I clinic had prior molecular profiling, the proportion subsequently enrolled into clinical trials was low. Prior molecular profiling was not an independent predictor of clinical trial enrollment.
Publisher: Elsevier BV
Date: 08-2019
DOI: 10.1016/J.IJROBP.2019.03.047
Abstract: To identify adverse radiologic nodal features in cN+ TNM-8 stage I human papillomavirus-related (HPV+) oropharyngeal cancer (OPC). All patients with HPV+ cT1-T2cN1 OPC treated with definitive intensity modulated radiation therapy from 2008 to 2015 were included. Radiologically involved lymph node number (LN), radiologic extranodal extension (rENE), retropharyngeal LN (RPLN), and lower neck (level 4 or 5b) LN involvement were assessed on pre-treatment computed tomography/magnetic resonance imaging by a specialized head and neck neuroradiologist. Disease-free survival (DFS), locoregional control, and distant control were compared between those with versus without rENE. Univariable and multivariable analysis with stepwise modal selection were applied to identify prognostic factors for DFS. A total of 45 rENE+ and 234 rENE- were identified. The rENE+ cohort had a higher number of LNs per patient (median: 6 vs 2, P < .001) and was more likely to have necrotic LNs (33 [73%] vs 132 [56%], P = .046). Median follow-up was 4.8 years. Although locoregional control was high in both cohorts (93% vs 97%, P = .34), the rENE+ group had inferior 5-year distant control (78% [59-88] vs 95% [91-97], P < .001) and DFS (58% [43-77] vs 90% [86-94], P < .001). In multivariable analysis, rENE+ (HR [hazard ratio] 4.3 [2.3-8.1], P < .001], T2 (vs T1) category (HR 2.1 [1.0-4.2], P = .039), smoking pack-years (HR 1.02 [1.0-1.03], P = .013), and the addition of systemic agents (HR 0.4 [0.2-0.8], P = .005) were prognostic for DFS. RPLN was prognostic for distant metastasis (HR 3.2, P = .013) but not for DFS after adjusting for rENE. Data from this contemporaneously treated cT1-T2N1 HPV+ OPC cohort suggest that the presence of rENE is an independent prognostic factor within stage I HPV+ OPC. RPLN is also associated with DM risk but not with DFS.
Publisher: American Association for Cancer Research (AACR)
Date: 13-10-2023
Publisher: Elsevier BV
Date: 10-2018
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/1078-0432.22487780.V1
Abstract: Supplementary Figure from A Phase I Study Investigating AZD8186, a Potent and Selective Inhibitor of PI3Kβ/δ, in Patients with Advanced Solid Tumors
Publisher: BMJ
Date: 13-03-2019
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/1078-0432.22487049
Abstract: Supplementary Figure from A Randomized Phase II Study of MEDI0680 in Combination with Durvalumab versus Nivolumab Monotherapy in Patients with Advanced or Metastatic Clear-cell Renal Cell Carcinoma
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/1078-0432.22487046
Abstract: Supplementary Figure from A Randomized Phase II Study of MEDI0680 in Combination with Durvalumab versus Nivolumab Monotherapy in Patients with Advanced or Metastatic Clear-cell Renal Cell Carcinoma
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/1078-0432.C.6532443.V1
Abstract: AbstractPurpose: MEDI0680 is a humanized anti–programmed cell death-1 (PD-1) antibody, and durvalumab is an anti-PD-L1 antibody. Combining treatment using these antibodies may improve efficacy versus blockade of PD-1 alone. This phase II study evaluated antitumor activity and safety of MEDI0680 plus durvalumab versus nivolumab monotherapy in immunotherapy-naïve patients with advanced clear-cell renal cell carcinoma who received at least one prior line of antiangiogenic therapy. Patients and Methods: Patients received either MEDI0680 (20 mg/kg) with durvalumab (750 mg) or nivolumab (240 mg), all intravenous, every 2 weeks. The primary endpoint was investigator-assessed objective response rate (ORR). Secondary endpoints included best overall response, progression-free survival (PFS), safety, overall survival (OS), and immunogenicity. Exploratory endpoints included changes in circulating tumor DNA (ctDNA), baseline tumor mutational burden, and tumor-infiltrated immune cell profiles. Results: Sixty-three patients were randomized (combination, i n /i = 42 nivolumab, i n /i = 21). ORR was 16.7% [7/42 95% confidence interval (CI), 7.0–31.4] with combination treatment and 23.8% (5/21 95% CI, 8.2–47.2) with nivolumab. Median PFS was 3.6 months in both arms median OS was not reached in either arm. Because of adverse events, 23.8% of patients discontinued MEDI0680 and durvalumab and 14.3% of patients discontinued nivolumab. In the combination arm, reduction in ctDNA fraction was associated with longer PFS. ctDNA mutational analysis did not demonstrate an association with response in either arm. Tumor-infiltrated immune profiles showed an association between immune cell activation and response in the combination arm. Conclusions: MEDI0680 combined with durvalumab was safe and tolerable however, it did not improve efficacy versus nivolumab monotherapy. /
Publisher: Wiley
Date: 02-03-2020
DOI: 10.1002/CAM4.2940
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/1078-0432.22487043
Abstract: Supplementary Figure from A Randomized Phase II Study of MEDI0680 in Combination with Durvalumab versus Nivolumab Monotherapy in Patients with Advanced or Metastatic Clear-cell Renal Cell Carcinoma
Publisher: Elsevier BV
Date: 10-2018
Publisher: Wiley
Date: 14-08-2014
Publisher: Elsevier BV
Date: 2018
DOI: 10.1016/J.EJCA.2018.10.017
Abstract: Immunotherapy (IO) agents can cause late-onset immune-related adverse events (irAEs). In phase I trials, observation for dose-limiting toxicities (DLTs) is typically limited to the first cycle. The incidence of delayed-onset DLTs and their potential impact on dose determination have not been fully elucidated. Consecutive patients enrolled in early phase IO trials at Princess Margaret Cancer Centre between August 2012 and September 2016 were retrospectively reviewed, applying trial-specific definitions for DLTs. A clinically significant AE (csAE) was defined as a treatment-related adverse event requiring corticosteroids, hormone replacement, IO delay or discontinuation. A total of 352 consecutive trial enrolments in 21 early phase clinical trials were included. Two-hundred seventy-eight patients (79%) received monotherapy and 74 (21%) received combination IO. Two hundred sixty (74%) patients experienced irAEs. There were two protocol-defined DLTs. Twenty (5.7%) patients had 24 csAEs qualifying as DLTs except for occurrence after the protocol-specified DLT period. One-hundred and six (10%) of irAEs were csAEs, including endocrine (26%), respiratory (14%), gastrointestinal (11%), general (10%), dermatological (8%), hepatic (8%), musculoskeletal (6%), pancreatic (6%), haematological, metabolic, neurological, cardiac (each 2%), infective and ocular (each 1%) events. The highest risk of first-onset csAE was during the first 4 weeks compared with the period from 4 weeks to end of treatment (odds ratio 3.13, 95% confidence interval 1.95-5.02). The median time to first onset csAE was significantly shorter with combination than monotherapy IO (32 vs. 146 days, P < 0.001). In our series of early phase IO trials, the risk of csAE was highest during the initial 4 weeks on IO treatment, supporting the use of the conventional DLT period for dose escalation decision. However, there were 24 clinically significant late-onset DLTs in 5.7% of patients. Combination IO was associated with greater risk of and also earlier onset for csAE, which may need to be considered for early phase trial design.
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/1078-0432.22487040
Abstract: Supplementary Figure from A Randomized Phase II Study of MEDI0680 in Combination with Durvalumab versus Nivolumab Monotherapy in Patients with Advanced or Metastatic Clear-cell Renal Cell Carcinoma
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/1078-0432.22487052.V1
Abstract: Supplementary Figure from A Randomized Phase II Study of MEDI0680 in Combination with Durvalumab versus Nivolumab Monotherapy in Patients with Advanced or Metastatic Clear-cell Renal Cell Carcinoma
Publisher: American Association for Cancer Research (AACR)
Date: 13-10-2023
Publisher: Elsevier BV
Date: 10-2016
Publisher: Elsevier BV
Date: 10-2018
Publisher: American Association for Cancer Research (AACR)
Date: 03-2022
DOI: 10.1158/1078-0432.CCR-21-3087
Abstract: To characterize safety and tolerability of the selective PI3Kβ inhibitor AZD8186, identify a recommended phase II dose (RP2D), and assess preliminary efficacy in combination with abiraterone acetate or vistusertib. This phase I open-label study included patients with advanced solid tumors, particularly prostate cancer, triple-negative breast cancer, and squamous non–small cell lung cancer. The study comprised four arms: (i) AZD8186 monotherapy dose finding (ii) monotherapy dose expansion (iii) AZD8186/abiraterone acetate (with prednisone) and (iv) AZD8186/vistusertib. The primary endpoints were safety, tolerability, and identification of the RP2D of AZD8186 monotherapy and in combination. Secondary endpoints included pharmacokinetics (PK), pharmacodynamics, and tumor and prostate-specific antigen (PSA) responses. In total, 161 patients were enrolled. AZD8186 was well tolerated across all study arms, the most common adverse events being gastrointestinal symptoms. In the monotherapy dose-finding arm, four patients experienced dose-limiting toxicities (mainly rash). AZD8186 doses of 60-mg twice daily [BID 5 days on, 2 days off (5:2)] and 120-mg BID (continuous and 5:2 dosing) were taken into subsequent arms. The PKs of AZD8186 were dose proportional, without interactions with abiraterone acetate or vistusertib, and target inhibition was observed in plasma and tumor tissue. Monotherapy and combination therapy showed preliminary evidence of limited antitumor activity by imaging and, in prostate cancer, PSA reduction. AZD8186 monotherapy had an acceptable safety and tolerability profile, and combination with abiraterone acetate rednisone or vistusertib was also tolerated. There was preliminary evidence of antitumor activity, meriting further exploration of AZD8186 in subsequent studies in PI3Kβ pathway–dependent cancers.
Publisher: American Association for Cancer Research (AACR)
Date: 11-08-2023
DOI: 10.1158/1078-0432.CCR-23-1137
Abstract: Purpose: Non-inflamed (cold) tumors such as leiomyosarcoma (LMS) do not benefit from immune checkpoint blockade (ICB) monotherapy. Combining ICB with angiogenesis-, or poly-ADP ribose polymerase (PARP) inhibitors may increase tumor immunogenicity by altering the immune cell composition of the tumor microenvironment (TME). The DAPPER phase II study evaluated the safety, immunologic, and clinical activity of ICB-based combinations in pre-treated LMS patients. Patients and Methods: Patients were randomized to receive durvalumab 1500mg IV q4w with either Olaparib 300mg bid PO (Arm A) or Cediranib 20mg qd PO on 5 days/week (Arm B) until unacceptable toxicity or disease progression. Paired tumor biopsies, serial radiological assessments and stool collections were performed. Primary endpoints were safety, and immune cell changes in the TME. Objective responses and survival were correlated with transcriptomic, radiomic and microbiome parameters. Results: Among 30 heavily pre-treated patients (15 on each arm), grade ≥ 3 toxicity occurred in 3 (20%) and 2 (13%) on Arms A and B, respectively. On arm A, 1 patient achieved partial response (PR) with increase in CD8 T-cells and macrophages in the TME during treatment, while 4 had stable disease ≥ 6 months (SD-6m). No patients on Arm B achieved PR or SD-6m. Transcriptome analysis showed that baseline M1-macrophage and B-cell activity were associated with overall survival. Conclusions: Durvalumab plus olaparib increased immune cell infiltration of TME with clinical benefit in some LMS patients. Baseline M1-macrophage and B-cell activity may identify LMS patients with favorable outcomes on immunotherapy and should be further evaluated.
Publisher: American Society of Clinical Oncology (ASCO)
Date: 10-05-2021
DOI: 10.1200/JCO.20.03296
Abstract: The classification of the International Germ Cell Cancer Collaborative Group (IGCCCG) plays a pivotal role in the management of metastatic germ cell tumors but relies on data of patients treated between 1975 and 1990. Data on 9,728 men with metastatic nonseminomatous germ cell tumors treated with cisplatin- and etoposide-based first-line chemotherapy between 1990 and 2013 were collected from 30 institutions or collaborative groups in Europe, North America, and Australia. Clinical trial and registry data were included. Primary end points were progression-free survival (PFS) and overall survival (OS). The survival estimates were updated for the current era. Additionally, a novel prognostic model for PFS was developed in 3,542 patients with complete information on potentially relevant variables. The results were validated in an independent data set. Compared with the original IGCCCG publication, 5-year PFS remained similar in patients with good prognosis with 89% (87%-91%) versus 90% (95% CI, 89 to 91), but the 5-year OS increased from 92% (90%-94%) to 96% (95%-96%). In patients with intermediate prognosis, PFS remained similar with 75% (71%-79%) versus 78% (76%-80%) and the OS increased from 80% (76%-84%) to 89% (88%-91%). In patients with poor prognosis, the PFS increased from 41% (95% CI, 35 to 47) to 54% (95% CI, 52 to 56) and the OS from 48% (95% CI, 42 to 54) to 67% (95% CI, 65 to 69). A more granular prognostic model was developed and independently validated. This model identified a new cutoff of lactate dehydrogenase at a 2.5 upper limit of normal and increasing age and presence of lung metastases as additional adverse prognostic factors. An online calculator is provided ( www.eortc.org/IGCCCG-Update ). The IGCCCG Update model improves in idual prognostication in metastatic nonseminomatous germ cell tumors. Increasing age and lung metastases add granularity to the original IGCCCG classification as adverse prognostic factors.
Publisher: Elsevier BV
Date: 08-2020
DOI: 10.1016/J.CLGC.2019.12.007
Abstract: The present retrospective, longitudinal cohort study assessed the association between the first-line sunitinib treatment duration and clinical outcomes with second-line immuno-oncology (IO) therapy among patients with metastatic renal cell carcinoma (mRCC). A total of 161 patients with mRCC who had been treated with first-line sunitinib and subsequent IO therapy from select International mRCC Database Consortium centers were included. The overall survival, time to next therapy, time to treatment discontinuation, and real-world physician-assessed best response measured from IO therapy initiation were analyzed and compared between patients treated with first-line sunitinib for ≥ 6 months and those treated for < 6 months. The 116 patients treated with sunitinib for ≥ 6 months tended to be older and to have a better International mRCC Database Consortium risk than the 45 patients treated for < 6 months (favorable, 36% vs. 8%, P = .001 intermediate, 59% vs. 70%, P = .21 poor, 5% vs. 22%, P = .007). The receipt of sunitinib for ≥ 6 months versus < 6 months was associated with longer survival (hazard ratio [HR], 0.42 95% confidence interval [CI], 0.21-0.87 P = .02). No significant association was observed between the first-line sunitinib duration and second-line IO outcomes, including the time to next therapy (HR, 0.89 95% CI, 0.52-1.51 P = .66), time to treatment discontinuation (HR, 0.85 95% CI, 0.54-1.34 P = .49), and tumor response (odds ratio, 0.73 95% CI, 0.22-2.49 P = .62). We found no statistically significant association between the first-line sunitinib duration and clinical outcomes with second-line IO therapy. Patients receiving first-line sunitinib for ≥ 6 months compared with < 6 months was associated with better overall survival, although potential unadjusted confounders could have been present. These findings support the paradigm that previous therapy will not dictate the effectiveness of subsequent immunotherapy.
Publisher: Elsevier BV
Date: 03-2017
DOI: 10.1016/J.IJROBP.2016.11.029
Abstract: The objective of this study was to compare the cost-effectiveness of transoral robotic surgery (TORS) versus the standard treatment modality for oropharyngeal squamous cell carcinoma (OPSCC), radiation therapy (RT), in a subset of patients with early-stage OPSCC. We developed a microsimulation state-transition model associated with RT and TORS for patients with clinically staged T1N0M0 to T2N1M0 OPSCC. Transition probabilities, utilities, and costs for each health state were estimated from recently published data and discounted by 3% annually over a lifetime time horizon. Model outcomes included lifetime costs (in 2014 US dollars), health benefits (quality-adjusted life-years [QALYs]), and cost-effectiveness ratios from a societal perspective. Under base-case assumptions, TORS was associated with modest gains in QALYs. RT yielded 10.43 QALYs at a cost of $123,410 per patient, whereas TORS yielded 11.10 QALYs at a cost of $178,480. This resulted in an incremental cost-effectiveness ratio of $82,190/QALY gained. The incremental cost-effectiveness ratio was most sensitive to the need for adjuvant therapy, cost of late toxicity, age at diagnosis, disease state utilities, and discount rate. Accounting for joint parameter uncertainty, RT had a higher probability of demonstrating a cost-effective profile compared with TORS, at 54% compared with 46%. By use of standard benchmarks for cost-effectiveness in the United States, TORS may be a cost-effective alternative for the subset of patients with early-stage OPSCC but demonstrates considerable sensitivity to assumptions around quality of life.
Publisher: American Society of Clinical Oncology (ASCO)
Date: 2020
DOI: 10.1200/JCO.19.02105
Abstract: Genomes of tumors that are deficient in DNA mismatch repair (dMMR) have high microsatellite instability (MSI-H) and harbor hundreds to thousands of somatic mutations that encode potential neoantigens. Such tumors are therefore likely to be immunogenic, triggering upregulation of immune checkpoint proteins. Pembrolizumab, an anti‒programmed death-1 monoclonal antibody, has antitumor activity against MSI-H/dMMR cancer. We report data from the phase II KEYNOTE-158 study of pembrolizumab in patients with previously treated, advanced noncolorectal MSI-H/dMMR cancer. Eligible patients with histologically/cytologically confirmed MSI-H/dMMR advanced noncolorectal cancer who experienced failure with prior therapy received pembrolizumab 200 mg once every 3 weeks for 2 years or until disease progression, unacceptable toxicity, or patient withdrawal. Radiologic imaging was performed every 9 weeks for the first year of therapy and every 12 weeks thereafter. The primary end point was objective response rate per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1, as assessed by independent central radiologic review. Among 233 enrolled patients, 27 tumor types were represented, with endometrial, gastric, cholangiocarcinoma, and pancreatic cancers being the most common. Median follow up was 13.4 months. Objective response rate was 34.3% (95% CI, 28.3% to 40.8%). Median progression-free survival was 4.1 months (95% CI, 2.4 to 4.9 months) and median overall survival was 23.5 months (95% CI, 13.5 months to not reached). Treatment-related adverse events occurred in 151 patients (64.8%). Thirty-four patients (14.6%) had grade 3 to 5 treatment-related adverse events. Grade 5 pneumonia occurred in one patient there were no other treatment-related fatal adverse events. Our study demonstrates the clinical benefit of anti–programmed death-1 therapy with pembrolizumab among patients with previously treated unresectable or metastatic MSI-H/dMMR noncolorectal cancer. Toxicity was consistent with previous experience of pembrolizumab monotherapy.
Publisher: Springer Science and Business Media LLC
Date: 17-04-2020
Publisher: Impact Journals, LLC
Date: 22-03-2017
Publisher: Elsevier BV
Date: 12-2019
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/1078-0432.22487040.V1
Abstract: Supplementary Figure from A Randomized Phase II Study of MEDI0680 in Combination with Durvalumab versus Nivolumab Monotherapy in Patients with Advanced or Metastatic Clear-cell Renal Cell Carcinoma
Publisher: Wiley
Date: 08-01-2020
DOI: 10.1002/CNCR.32692
Abstract: Patients with cancer who are treated with immune checkpoint modulators (ICMs) have their health-related quality of life (HRQOL) measured using general patient-reported outcome (PRO) tools. To the authors' knowledge, no instrument has been developed to date specifically for patients treated with ICMs. The objective of the current study was to develop a toxicity subscale PRO instrument for patients treated with ICMs to assess HRQOL. Input was collected from a systematic review as well as patients and physicians experienced with ICM treatment. Descriptive thematic analysis was used to evaluate the qualitative data obtained from patient focus groups and interviews, which informed an initial list of items that described ICM side effects and their impact on HRQOL. These inputs informed item generation and/or reduction to develop a toxicity subscale. Focus groups and in idual interviews with 37 ICM-treated patients generated an initial list of 176 items. After a first round of item reduction that produced a shortened list of 76 items, 16 physicians who care for patients who are treated with ICMs were surveyed with a list of 49 patient-reported side effects and 11 physicians participated in follow-up interviews. A second round of item reduction was informed by the physician responses to produce a list of 25 items. To the authors' knowledge, this 25-item list is the first HRQOL-focused toxicity subscale for patients treated with ICMs and was developed in accordance with US Food and Drug Administration guidelines, which prioritize patient input in developing PRO tools. The subscale will be combined with the Functional Assessment of Cancer Therapy-General (FACT-G) to form the FACT-ICM. Prior to recommending the formal use of this PRO instrument, the authors will evaluate its validity and reliability in longitudinal studies involving substantially more patients.
Publisher: Springer Science and Business Media LLC
Date: 03-2023
DOI: 10.1038/S41416-023-02166-5
Abstract: Outcomes for patients with metastatic renal cell carcinoma (mRCC) and tumour thrombus remain poor. Recent data suggest limited role for cytoreductive nephrectomy (CN) and data on thrombus response to systemic therapy (ST) is scarce. Here, we describe response and survival of patients with de novo mRCC and thrombi treated with ST with or without CN. Demographics, disease characteristics and survival of patients with de novo mRCC were collected. Progression-free survival (PFS) and overall survival (OS) in months (m) was calculated using the Kaplan–Meier method (log-rank). Between 2002 and 2019, 226 patients with mRCC were identified, 64 (28.3%) had tumour thrombus out of which 18 (28.1%) received only ST. Among 12 evaluable patients, thrombus response, stability and progression were seen in 3 (25%), 6 (50%) and 3 (25%) patients, respectively. Median OS was similar for patients with and without tumour thrombus treated with systemic therapy alone [OS: 12.1 m (8.8–27.7) vs. 13.9 m (7.9–21.5), p = 0.87]. CN predicted for better OS in patients with tumour thrombus [OS: 29.4 m (17.4–48.9) vs. 12.1 m (8.8–27.7), p = 0.01]. In this retrospective series of patients with mRCC and tumour thrombus, addition of CN to ST improved outcomes. Validation of these findings with contemporary regimens is needed.
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/1078-0432.22487789
Abstract: Supplementary Figure from A Phase I Study Investigating AZD8186, a Potent and Selective Inhibitor of PI3Kβ/δ, in Patients with Advanced Solid Tumors
Publisher: American Association for Cancer Research (AACR)
Date: 13-10-2023
Publisher: Wiley
Date: 10-2021
DOI: 10.1002/CNCR.33936
Abstract: This study examined long‐term health utility and symptom‐toxicity trajectories among patients with head and neck cancer (HNC). For patients diagnosed with HNC (2014‐2019), Health Utility Index 3 (HUI‐3), Edmonton Symptom Assessment Scale (ESAS), and MD Anderson Symptom Inventory (MDASI) surveys (including both the core and head and neck cancer modules) were prospectively collected at multiple time points (at the baseline, after surgery, during radiotherapy, and 3, 6, 12, and 24 months after treatment). Locally estimated scatterplot smoothing plots were generated to describe HUI‐3, ESAS, and MDASI trajectories over time by clinicodemographic factors, treatment modality, and tumor subsite. Contributions of clinical factors were assessed with univariable and multivariable analyses. In 800 patients, the treatment modality and the tumor subsite produced unique HUI‐3, ESAS, and MDASI trajectories. Patients treated with surgery alone experienced rapid improvements in HUI‐3, ESAS, and MDASI scores postoperatively. Among patients treated with chemoradiotherapy, patients with nasopharyngeal carcinoma had greater declines in HUI‐3 during treatment in comparison with patients with oropharyngeal carcinoma, but they had similar ESAS/MDASI scores. Among patients treated with radiotherapy, patients with laryngeal carcinoma had better HUI‐3/ESAS/MDASI scores than those with oropharyngeal carcinoma during treatment, but they slowly converged after treatment. Female sex, an age 75 years, a household income $40,000, a Charlson comorbidity score 1, an Eastern Cooperative Oncology Group performance status 0 (at the baseline), and current smoking were independently associated with worse HUI‐3 trajectories. HUI‐3 had mild to moderate correlations (ρ = 0.2‐0.5) with in idual symptom‐toxicity trajectories. Long‐term HUI‐3 trajectories are associated with tumor subsite, clinicodemographic, and treatment factors, and this may be partly explained by relationships with symptoms/toxicities. Separate evaluations by subsite and treatment should occur in health utility and symptom‐toxicity studies of HNC. This study indicates that the long‐term health utility and symptoms/toxicities of patients with the most common head and neck cancers (ie, squamous cell carcinomas and nasopharyngeal carcinomas) differ over time with a variety of factors, including the tumor anatomic site, treatment volume, clinicodemographic characteristics (eg, age, human papillomavirus status, tumor stage, gender, smoking status, alcohol status, education, and comorbidities), and treatment modalities. Generalizations across all head and neck cancers should be strongly discouraged. Future studies should evaluate health utility, symptoms and toxicities, and patient need assessments separately for each anatomic site and treatment modality.
Publisher: American Association for Cancer Research (AACR)
Date: 02-10-2023
Publisher: Wiley
Date: 06-2020
DOI: 10.1002/CNCR.32968
Abstract: The objective of this study was to identify a subgroup of patients with head and neck squamous cell carcinoma (HNSCC) who might be suitable for hypofractionated radiotherapy (RT‐hypo) during the COVID‐19 pandemic. HNSCC cases (oropharynx/larynx/hypopharynx) treated with definitive RT‐hypo (60 Gy in 25 fractions over 5 weeks), moderately accelerated radiotherapy (RT‐acc) alone (70 Gy in 35 fractions over 6 weeks), or concurrent chemoradiotherapy (CCRT) during 2005‐2017 were included. Locoregional control (LRC) and distant control (DC) after RT‐hypo, RT‐acc, and CCRT were compared for various subgroups. The study identified 994 human papillomavirus–positive (HPV+) oropharyngeal squamous cell carcinoma cases (with 61, 254, and 679 receiving RT‐hypo, RT‐acc, and CCRT, respectively) and 1045 HPV– HNSCC cases (with 263, 451, and 331 receiving RT‐hypo, RT‐acc, and CCRT, respectively). The CCRT cohort had higher T/N categories, whereas the radiotherapy‐alone patients were older. The median follow‐up was 4.6 years. RT‐hypo, RT‐acc, and CCRT produced comparable 3‐year LRC and DC for HPV+ T1‐2N0‐N2a disease (seventh edition of the TNM system [TNM‐7] LRC, 94%, 100%, and 94% P = .769 DC, 94%, 100%, and 94% P = .272), T1‐T2N2b disease (LRC, 90%, 94%, and 97% P = .445 DC, 100%, 96%, and 95% P = .697), and T1‐2N2c/T3N0‐N2c disease (LRC, 89%, 93%, and 95% P = .494 DC, 89%, 90%, and 87% P = .838). Although LRC was also similar for T4/N3 disease (78%, 84%, and 88% P = .677), DC was significantly lower with RT‐hypo or RT‐acc versus CCRT (67%, 65%, and 87% P = .005). For HPV– HNSCC, 3‐year LRC and DC were similar with RT‐hypo, RT‐acc, and CCRT in stages I and II (LRC, 85%, 89%, and 100% P = .320 DC, 99%, 98%, and 100% P = .446) however, RT‐hypo and RT‐acc had significantly lower LRC in stage III (76%, 69%, and 91% P = .006), whereas DC rates were similar (92%, 85%, and 90% P = .410). Lower LRC in stage III predominated in patients with laryngeal squamous cell carcinoma receiving RT‐acc (62%) but not RT‐hypo (80%) or CCRT (92% RT‐hypo vs CCRT: P = .270 RT‐acc vs CCRT: P = .004). CCRT had numerically higher LRC in comparison with RT‐hypo or RT‐acc in stage IV (73%, 65%, and 66% P = .336). It is proposed that RT‐hypo be considered in place of CCRT for HPV+ T1‐T3N0‐N2c (TNM‐7) HNSCCs, HPV– T1‐T2N0 HNSCCs, and select stage III HNSCCs during the COVID‐19 outbreak.
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/1078-0432.22487798
Abstract: Supplementary Data from A Phase I Study Investigating AZD8186, a Potent and Selective Inhibitor of PI3Kβ/δ, in Patients with Advanced Solid Tumors
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/1078-0432.22487037
Abstract: Supplementary Table from A Randomized Phase II Study of MEDI0680 in Combination with Durvalumab versus Nivolumab Monotherapy in Patients with Advanced or Metastatic Clear-cell Renal Cell Carcinoma
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/1078-0432.22487795
Abstract: Supplementary Data from A Phase I Study Investigating AZD8186, a Potent and Selective Inhibitor of PI3Kβ/δ, in Patients with Advanced Solid Tumors
Publisher: Elsevier BV
Date: 10-2017
Abstract: Immune checkpoint inhibitor (ICI) monoclonal antibodies (mAbs) targeting cytotoxic T-lymphocyte antigen 4 (CTLA-4), programmed cell death protein 1 (PD-1) or its ligand (PD-L1) produce unique toxicity profiles. The objective of this review was to identify patterns and incidence of immune-related adverse events (irAE) based on tumour type and ICI class. Medline, EMBASE and COCHRANE databases were searched to identify prospective monotherapy trials of ICIs from 2003 to November 2015. Paired reviewers selected studies for inclusion and extracted data. Odds ratio (OR), χ2 tests and multivariable regression models were used to analyse for effect size and associations. We identified 48 trials (6938 patients), including 26 CTLA-4, 17 PD-1, 2 PD-L1 trials, and 3 studies tested both CTLA-4 and PD-1. Grade 3/4 irAE were more common with CTLA-4 mAbs compared with PD-1 (31% versus 10%). All grades colitis (OR 8.7, 95% CI 5.8-12.9), hypophysitis (OR 6.5, 95% CI 3.0-14.3) and rash (OR 2.0, 95% CI 1.8-2.3) were more frequent with CTLA-4 mAbs whereas pneumonitis (OR 6.4, 95% CI 3.2-12.7), hypothyroidism (OR 4.3, 95% CI 2.9-6.3), arthralgia (OR 3.5, 95% CI 2.6-4.8) and vitiligo (OR 3.5, 95% CI 2.3-5.3) were more common with PD-1 mAbs. Comparison of irAE from the three most studied tumour types in PD-1 mAbs trials [melanoma (n = 2048), non-small-cell lung cancer (n = 1030) and renal cell carcinoma (n = 573)] showed melanoma patients had a higher frequency of gastrointestinal and skin irAE and lower frequency of pneumonitis. CTLA-4 and PD-1 mAbs have distinct irAE profiles. Different immune microenvironments may drive histology-specific irAE patterns. Other tumour-dependent irAE profiles may be identified as data emerge from ICI trials.
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/1078-0432.22487034
Abstract: Supplementary Table from A Randomized Phase II Study of MEDI0680 in Combination with Durvalumab versus Nivolumab Monotherapy in Patients with Advanced or Metastatic Clear-cell Renal Cell Carcinoma
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/1078-0432.22487792
Abstract: Supplementary Figure from A Phase I Study Investigating AZD8186, a Potent and Selective Inhibitor of PI3Kβ/δ, in Patients with Advanced Solid Tumors
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/1078-0432.22487055.V1
Abstract: Supplementary Data from A Randomized Phase II Study of MEDI0680 in Combination with Durvalumab versus Nivolumab Monotherapy in Patients with Advanced or Metastatic Clear-cell Renal Cell Carcinoma
Publisher: American Society of Clinical Oncology (ASCO)
Date: 10-05-2021
DOI: 10.1200/JCO.20.03292
Abstract: The classification of the International Germ-Cell Cancer Collaborative Group (IGCCCG) has been a major advance in the management of germ-cell tumors, but relies on data of only 660 patients with seminoma treated between 1975 and 1990. We re-evaluated this classification in a database from a large international consortium. Data on 2,451 men with metastatic seminoma treated with cisplatin- and etoposide-based first-line chemotherapy between 1990 and 2013 were collected from 30 institutions or collaborative groups in Australia, Europe, and North America. Clinical trial and registry data were included. Primary end points were progression-free survival (PFS) and overall survival (OS) calculated from day 1 of treatment. Variables at initial presentation were evaluated for their prognostic impact. Results were validated in an independent validation set of 764 additional patients. Compared with the initial IGCCCG classification, in our modern series, 5-year PFS improved from 82% to 89% (95% CI, 87 to 90) and 5-year OS from 86% to 95% (95% CI, 94 to 96) in good prognosis, and from 67% to 79% (95% CI, 70 to 85) and 72% to 88% (95% CI, 80 to 93) in intermediate prognosis patients. Lactate dehydrogenase (LDH) proved to be an additional adverse prognostic factor. Good prognosis patients with LDH above 2.5× upper limit of normal had a 3-year PFS of 80% (95% CI, 75 to 84) and a 3-year OS of 92% (95% CI, 88 to 95) versus 92% (95% CI, 90 to 94) and 97% (95% CI, 96 to 98) in the group with lower LDH. PFS and OS in metastatic seminoma significantly improved in our modern series compared with the original data. The original IGCCCG classification retains its relevance, but can be further refined by adding LDH at a cutoff of 2.5× upper limit of normal as an additional adverse prognostic factor.
Publisher: MDPI AG
Date: 04-2019
DOI: 10.3747/CO.26.4595
Abstract: Objectives: In the present study, we explored the real-world efficacy of the immuno-oncology checkpoint inhibitor nivolumab and the tyrosine kinase inhibitor cabozantinib in the second-line setting. Methods: Using the International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) dataset, a retrospective analysis of patients with metastatic renal cell carcinoma (MRCC) treated with nivolumab or cabozantinib in the second line after prior therapy targeted to the vascular endothelial growth factor receptor (VEGFR) was performed. Baseline characteristics and imdc risk factors were collected. Overall survival (OS) and time to treatment failure (TTF) were calculated using Kaplan–Meier curves. Overall response rates (ORRS) were determined for each therapy. Multivariable Cox regression analysis was performed to determine survival differences between cabozantinib and nivolumab treatment. Results: The analysis included 225 patients treated with nivolumab and 53 treated with cabozantinib. No significant difference in median OS was observed: 22.10 months [95% confidence interval (CI): 17.18 months to not reached] with nivolumab and 23.70 months (95% CI: 15.52 months to not reached) with cabozantinib (p = 0.61). The TTF was also similar at 6.90 months (95% CI: 4.60 months to 9.20 months) with nivolumab and 7.39 months (95% CI: 5.52 months to 12.85 months) with cabozantinib (p = 0.20). The adjusted hazard ratio (HR) for nivolumab compared with cabozantinib was 1.30 (95% CI: 0.73 to 2.3), p = 0.38. When adjusted by IMDC criteria and age, the HR was 1.32 (95% CI: 0.74 to 2.38), p = 0.35. Conclusions: Real-world IMDC data indicate comparable OS and TTF for nivolumab and cabozantinib. Both agents are reasonable therapeutic options for patients progressing after initial first-line VEGFR-targeted therapy.
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/1078-0432.22487031
Abstract: Supplementary Table from A Randomized Phase II Study of MEDI0680 in Combination with Durvalumab versus Nivolumab Monotherapy in Patients with Advanced or Metastatic Clear-cell Renal Cell Carcinoma
Publisher: Elsevier BV
Date: 10-2018
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/1078-0432.22487774.V1
Abstract: Supplementary Figure from A Phase I Study Investigating AZD8186, a Potent and Selective Inhibitor of PI3Kβ/δ, in Patients with Advanced Solid Tumors
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/1078-0432.22487034.V1
Abstract: Supplementary Table from A Randomized Phase II Study of MEDI0680 in Combination with Durvalumab versus Nivolumab Monotherapy in Patients with Advanced or Metastatic Clear-cell Renal Cell Carcinoma
Publisher: Elsevier BV
Date: 11-2019
Publisher: Springer Science and Business Media LLC
Date: 21-11-2016
Abstract: Profiling the heterogeneous phenotypes of rare circulating tumour cells (CTCs) in whole blood is critical to unravelling the complex and dynamic properties of these potential clinical markers. This task is challenging because these cells are present at parts per billion levels among normal blood cells. Here we report a new nanoparticle-enabled method for CTC characterization, called magnetic ranking cytometry, which profiles CTCs on the basis of their surface expression phenotype. We achieve this using a microfluidic chip that successfully processes whole blood s les. The approach classifies CTCs with single-cell resolution in accordance with their expression of phenotypic surface markers, which is read out using magnetic nanoparticles. We deploy this new technique to reveal the dynamic phenotypes of CTCs in unprocessed blood from mice as a function of tumour growth and aggressiveness. We also test magnetic ranking cytometry using blood s les collected from cancer patients.
Publisher: Elsevier BV
Date: 12-2019
DOI: 10.1016/J.EJCA.2019.10.002
Abstract: Treatment options are limited for recurrent nasopharyngeal carcinoma (NPC). We report results from a phase II study of CC-486 (oral azacitidine) in advanced NPC. Patients with locally advanced or metastatic NPC and 1-2 prior treatment regimens received CC-486 300 mg daily on days 1-14 of 21-day cycles until disease progression or unacceptable toxicity. The first 6 patients of Asian-Pacific Islander (API) ethnicity received a reduced dose of 200 mg to preserve safety and tolerability if well tolerated, subsequent API patients received CC-486 300 mg. The study could advance to stage 2 if > 4 patients achieved a response. Co-primary end-points were overall response rate (ORR) and progression-free survival (independent review). Key secondary end-points were overall survival and safety. Owing to faster-than-anticipated enrolment, 36 patients, including 13 of API ethnicity, were enrolled the median age was 54.0 years. Most patients were male (81%) and had an Eastern Cooperative Oncology Group performance status ≤ 1 (97%). Among 25 efficacy-evaluable patients, the ORR was 12% the median progression-free and overall survival were 4.7 and 18.0 months, respectively. The most common grade III/IV treatment-emergent adverse events were neutropenia (33%) and febrile neutropenia (11%). Twenty-one posttreatment deaths, primarily due to progressive disease or disease complications, and 1 on-treatment death (epistaxis, unrelated to study drug) occurred. The study did not advance to stage 2. CC-486 did not show sufficient clinical activity to support further development as monotherapy in this patient population. The safety profile of CC-486 in NPC was consistent with that in other solid tumours.
Publisher: American Society of Clinical Oncology (ASCO)
Date: 03-2022
DOI: 10.1200/JCO.21.01874
Abstract: Pembrolizumab demonstrated durable antitumor activity in patients with previously treated, advanced microsatellite instability–high or mismatch repair–deficient (MSI-H/dMMR) tumors, including endometrial cancer, in the nonrandomized, open-label, multicohort, phase II KEYNOTE-158 study ( NCT02628067 ). We report efficacy and safety outcomes for patients with MSI-H/dMMR endometrial cancer enrolled in KEYNOTE-158. Eligible patients from cohorts D (endometrial cancer, regardless of MSI-H/dMMR status) and K (any MSI-H/dMMR solid tumor, except colorectal) with previously treated, advanced MSI-H/dMMR endometrial cancer received pembrolizumab 200 mg once every 3 weeks for 35 cycles. The primary end point was objective response rate per RECIST version 1.1 by independent central radiologic review. Secondary end points included duration of response, progression-free survival, overall survival, and safety. As of October 5, 2020, 18 of 90 treated patients (20%) had completed 35 cycles of pembrolizumab and 52 (58%) had discontinued treatment. In the efficacy population (patients who received ≥ 1 dose of pembrolizumab and had ≥ 26 weeks of follow-up N = 79), the median time from first dose to data cutoff was 42.6 (range, 6.4-56.1) months. The objective response rate was 48% (95% CI, 37 to 60), and median duration of response was not reached (2.9-49.7+ months). Median progression-free survival was 13.1 (95% CI, 4.3 to 34.4) months, and median overall survival was not reached (95% CI, 27.2 months to not reached). Among all treated patients, 76% had ≥ 1 treatment-related adverse event (grades 3-4, 12%). There were no fatal treatment-related events. Immune-mediated adverse events or infusion reactions occurred in 28% of patients (grades 3-4, 7% no fatal events). Pembrolizumab demonstrated robust and durable antitumor activity and encouraging survival outcomes with manageable toxicity in patients with previously treated, advanced MSI-H/dMMR endometrial cancer.
Publisher: American Society of Clinical Oncology (ASCO)
Date: 12-2018
DOI: 10.1200/CCI.18.00004
Abstract: After chemotherapy, approximately 50% of patients with metastatic testicular germ cell tumors (GCTs) who undergo retroperitoneal lymph node dissections (RPNLDs) for residual masses have fibrosis. Radiomics uses image processing techniques to extract quantitative textures/features from regions of interest (ROIs) to train a classifier that predicts outcomes. We hypothesized that radiomics would identify patients with a high likelihood of fibrosis who may avoid RPLND. Patients with GCT who had an RPLND for nodal masses 1 cm after first-line platinum chemotherapy were included. Preoperative contrast-enhanced axial computed tomography images of retroperitoneal ROIs were manually contoured. Radiomics features (n = 153) were used to train a radial basis function support vector machine classifier to discriminate between viable GCT/mature teratoma versus fibrosis. A nested 10-fold cross-validation protocol was used to determine classifier accuracy. Clinical variables/restricted size criteria were used to optimize the classifier. Seventy-seven patients with 102 ROIs were analyzed (GCT, 21 teratoma, 41 fibrosis, 40). The discriminative accuracy of radiomics to identify GCT/teratoma versus fibrosis was 72 ± 2.2% (area under the curve [AUC], 0.74 ± 0.028) sensitivity was 56.2 ± 15.0%, and specificity was 81.9 ± 9.0% ( P = .001). No major predictive differences were identified when data were restricted by varying maximal axial diameters (AUC range, 0.58 ± 0.05 to 0.74 ± 0.03). The prediction algorithm using clinical variables alone identified an AUC of 0.76. When these variables were added to the radiomics signature, the best performing classifier was identified when axial masses were limited to diameter 2 cm (accuracy, 88.2 ± 4.4 AUC, 0.80 ± 0.05 P = .02). A predictive radiomics algorithm had a discriminative accuracy of 72% that improved to 88% when combined with clinical predictors. Additional independent validation is required to assess whether radiomics allows patients with a high predicted likelihood of fibrosis to avoid RPLND.
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/1078-0432.C.6532583.V1
Abstract: AbstractPurpose: To characterize safety and tolerability of the selective PI3Kβ inhibitor AZD8186, identify a recommended phase II dose (RP2D), and assess preliminary efficacy in combination with abiraterone acetate or vistusertib. Patients and Methods: This phase I open-label study included patients with advanced solid tumors, particularly prostate cancer, triple-negative breast cancer, and squamous non–small cell lung cancer. The study comprised four arms: (i) AZD8186 monotherapy dose finding (ii) monotherapy dose expansion (iii) AZD8186/abiraterone acetate (with prednisone) and (iv) AZD8186/vistusertib. The primary endpoints were safety, tolerability, and identification of the RP2D of AZD8186 monotherapy and in combination. Secondary endpoints included pharmacokinetics (PK), pharmacodynamics, and tumor and prostate-specific antigen (PSA) responses. Results: In total, 161 patients were enrolled. AZD8186 was well tolerated across all study arms, the most common adverse events being gastrointestinal symptoms. In the monotherapy dose-finding arm, four patients experienced dose-limiting toxicities (mainly rash). AZD8186 doses of 60-mg twice daily [BID 5 days on, 2 days off (5:2)] and 120-mg BID (continuous and 5:2 dosing) were taken into subsequent arms. The PKs of AZD8186 were dose proportional, without interactions with abiraterone acetate or vistusertib, and target inhibition was observed in plasma and tumor tissue. Monotherapy and combination therapy showed preliminary evidence of limited antitumor activity by imaging and, in prostate cancer, PSA reduction. Conclusions: AZD8186 monotherapy had an acceptable safety and tolerability profile, and combination with abiraterone acetate rednisone or vistusertib was also tolerated. There was preliminary evidence of antitumor activity, meriting further exploration of AZD8186 in subsequent studies in PI3Kβ pathway–dependent cancers. /
Publisher: Wiley
Date: 20-02-2014
DOI: 10.1111/AJCO.12167
Abstract: Perioperative chemotherapy has improved the prognosis for patients with operable osteosarcoma. The literature is conflicting about which regimen is optimal. The aim of this study was to evaluate the survival outcomes of two cohorts of patients with operable osteosarcoma treated with different perioperative chemotherapy regimens. This was a retrospective review of patients diagnosed with operable osteosarcoma treated at the Princess Alexandra Hospital from 1986 to 2009. The standard perioperative chemotherapy regimen changed from the modified T10 Rosen protocol to cisplatin/doxorubicin in 1997. Using the Kaplan-Meier method, overall survival (OS) and disease-free survival (DFS) curves were generated for the cisplatin/doxorubicin and the modified T10 Rosen cohorts. Seventy-one patients were identified of whom 63 had potentially curable disease. Of these, 24 received the modified T10 Rosen regimen and 39 received cisplatin/doxorubicin. There was a non-significant trend toward better OS and DFS in the patients who received the modified T10 Rosen protocol. The trend toward poorer survival in the cisplatin/doxorubicin cohort, in combination with current evidence, has prompted our institution to change its practice.
Publisher: American Chemical Society (ACS)
Date: 02-07-2019
DOI: 10.1021/ACS.ANALCHEM.9B01697
Abstract: The analysis of circulating tumor cells (CTCs) provides a means to collect information about the evolving properties of a tumor during cancer progression and treatment. For patients with metastatic prostate cancer, noninvasive serial measurements of bloodborne cells may provide a means to tailor therapeutic decisions based on an in idual patient's response. Here, we used a high-sensitivity profiling approach to monitor CTCs in patients with metastatic castrate-resistant prostate cancer (mCRPC) undergoing treatment with abiraterone and enzalutamide, two drugs used to treat advanced prostate cancer. The capture and profiling approach uses antibody-functionalized magnetic nanoparticles to sort cells according to protein expression levels. CTCs are tagged with magnetic nanoparticles conjugated to an antibody specific for the epithelial cell adhesion molecule (EpCAM) and sorted into four zones of a microfluidic device based on EpCAM expression levels. Our approach was compared to the FDA-cleared CellSearch method, and we demonstrate significantly higher capture efficiency of low-EpCAM cells compared to the commercial method. The nanoparticle-based approach detected CTCs from 86% of patients at baseline, compared to CellSearch which only detected CTCs from 60% of patients. Patients were stratified as prostate specific antigen (PSA) progressive versus responsive based on clinically acceptable definitions, and it was observed that patients with a limited response to therapy had elevated levels of androgen receptor variant 7 (ARV7) and the mesenchymal marker, N-cadherin, expressed on their CTCs. In addition, these CTCs exhibited lower EpCAM expression. The results highlight features of CTCs associated with disease progression on abiraterone or enzalutamide, including mesenchymal phenotypes and increased expression levels of ARV7. The use of a high-sensitivity method to capture and profile CTCs provides more informative data concerning the phenotypic properties of these cells as patients undergo treatment relative to an FDA-cleared method.
Publisher: Elsevier BV
Date: 10-2018
Publisher: Elsevier BV
Date: 05-2017
DOI: 10.1016/J.CRITREVONC.2017.02.026
Abstract: Prostate cancer is the second most common malignant neoplasm in men worldwide and the fifth cause of cancer-related death. Although multiple new agents have been approved for metastatic castration resistant prostate cancer over the last decade, it is still an incurable disease. New strategies to improve cancer control are needed and agents targeting the immune system have shown encouraging results in many tumor types. Despite being attractive for immunotherapies due to the expression of various tumor associated antigens, the microenvironment in prostate cancer is relatively immunosuppressive and may be responsible for the failures of various agents targeting the immune system in this disease. To date, sipuleucel-T is the only immunotherapy that has shown significant clinical efficacy in this setting, although the high cost and potential trial flaws have precluded its widespread incorporation into clinical practice. Issues with patient selection and trial design may have contributed to the multiple failures of immunotherapy in prostate cancer and provides an opportunity to tailor future studies to evaluate these agents more accurately. We have reviewed all the completed immune therapy trials in prostate cancer and highlight important considerations for the next generation of clinical trials.
Publisher: Oxford University Press (OUP)
Date: 11-05-2015
DOI: 10.1634/THEONCOLOGIST.2015-0008
Abstract: First-in-human (FIH) trials of low-molecular-weight anticancer agents conventionally derive a safe start dose (SD) from one-tenth the severely toxic dose in 10% of rodents or one-sixth the highest nonseverely toxic dose (HNSTD) in nonrodent species. No consensus has been reached on whether this paradigm can be safely applied to biotechnology-derived products (BDPs). A comprehensive search was conducted to identify all BDPs (excluding immune checkpoint inhibitors and antibody drug conjugates) with sufficient nonclinical and clinical data to assess the safety of hypothetical use of one-sixth HNSTD in an advanced cancer FIH trial. The search identified 23 BDPs, of which 21 were monoclonal antibodies. The median ratio of the maximum tolerated or maximum administered dose (MTD or MAD) to the actual FIH SD was 36 (range, 8–500). Only 2 BDPs reached the MTD. Hypothetical use of one-sixth HNSTD (allometrically scaled to humans) would not have exceeded the MTD or MAD for all 23 BDPs and would have reduced the median ratio of the MTD or MAD to a SD to 6.1 (range, 3.5–55.3). Pharmacodynamic (PD) markers were included in some animal toxicology studies and were useful to confirm the hypothetical SD of one-sixth HNSTD. One-sixth HNSTD would not have resulted in unacceptable toxicities in the data available. Supporting its use could reduce the number of dose escalations needed to reach the recommended dose. A low incidence of toxicities in animals and humans underscores the need to identify the pharmacokinetic and PD parameters to guide SD selection of BDPs for FIH cancer trials. Start dose (SD) for biotechnology-derived products (BDPs) can be safely derived from one-sixth the highest nonseverely toxic dose in nonrodent species and may reduce the number of dose escalations needed to reach the recommended dose in first-in-human studies while limiting unnecessary exposure to high drug levels in humans. The use of this type of SD could improve the design of phase I studies of BDPs by making them more efficient. The role of preclinical pharmacodynamic markers was useful in confirming the hypothetical SD, and attempts should be explored in future animal studies to identify such parameters.
Publisher: Elsevier BV
Date: 08-2016
DOI: 10.1016/J.ORALONCOLOGY.2016.05.016
Abstract: To compare cumulative cisplatin dose and toxicity between patients who received 3-weekly versus weekly cisplatin during adjuvant radiotherapy for high-risk head and neck squamous cell carcinoma (HNSCC). Consecutive HNSCC patients with involved resection margins and/or extra-capsular extension in two tertiary cancer centers with different institutional practices were identified. Cumulative cisplatin dose was calculated and information on toxicity reviewed and compared between patients who received 3-weekly versus weekly cisplatin. Of 270 high risk patients, 60 received 3-weekly 100mg/m(2) and 48 received weekly 50mg/m(2) cisplatin during adjuvant radiotherapy (60-66Gy in 30-33 fractions). Fourteen patients received other chemotherapy schedules and 148 received no chemotherapy. Mean cumulative cisplatin dose was 199.4mg/m(2) (standard error (SE) 5.4) in 3-weekly versus 239.8mg/m(2) (SE 11.0, P=0.001) in weekly treated patients. Cumulative cisplatin ⩾200mg/m(2) was given to 67.7% of patients in the 3-weekly cohort and 85.2% (P=0.039) in the weekly cohort. The rate of feeding tube dependency 6months after treatment, osteoradionecrosis, neutropenic fever, and persistent renal function decline were not statistically different. About one half of high-risk HNSCC patients are not eligible for cisplatin during postoperative radiotherapy. Patients treated with weekly 50mg/m(2) cisplatin received a higher cumulative dose with comparable toxicity as patients who received 3-weekly 100mg/m(2) cisplatin. Efficacy and applicability to the frequently used weekly 40mg/m(2) schedule remains to be evaluated.
Publisher: American Association for Cancer Research (AACR)
Date: 08-2023
DOI: 10.1158/1078-0432.CCR-23-0092
Abstract: In this first-in-human, Phase 1, open-label, multicenter study, we evaluated JNJ-64619178, a selective and potent PRMT5 inhibitor, in patients with advanced malignant solid tumors or non-Hodgkin lymphomas (NHL). The primary objective was to evaluate the safety and to identify a recommended Phase 2 dose (RP2D) of JNJ-64619178. Adult patients with treatment-refractory advanced solid tumors or NHL and measurable disease received escalating doses of JNJ-64619178 following two schedules (Schedule A: 14 days on/7 days off Schedule B: every day on a 21-day cycle). Safety, pharmacokinetics (PK), pharmacodynamics (PD), and clinical activity were evaluated. Ninety patients received JNJ-64619178. Thrombocytopenia was identified as the only dose-limiting toxicity. JNJ-64619178 showed dose-proportional PK and robust target engagement, as measured by plasma symmetric dimethylarginine, across all dose levels. The objective response rate was 5.6% (5 of 90). Patients with adenoid cystic carcinoma (ACC) had an ORR of 11.5% (3 of 26) and a median progression-free survival of 19.1 months. JNJ-64619178 demonstrated manageable dose-dependent toxicity and preliminary evidence of antitumor activity in ACC and other tumor types. Plasma exposure was dose dependent, and target inhibition was maintained with intermittent and continuous dosing. On the basis of safety, clinical activity, PK, and PD findings, two provisional RP2Ds were selected: 1.5 mg intermittently and 1.0 mg once daily. Aside from ACC, clinical benefit was limited, and biomarkers to enrich for responsiveness to PRMT5 inhibition will be needed for further development.
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/1078-0432.22487049.V1
Abstract: Supplementary Figure from A Randomized Phase II Study of MEDI0680 in Combination with Durvalumab versus Nivolumab Monotherapy in Patients with Advanced or Metastatic Clear-cell Renal Cell Carcinoma
Publisher: Elsevier BV
Date: 09-2019
DOI: 10.1016/J.EJCA.2019.06.019
Abstract: To evaluate the impact of cisplatin cumulative dose (CDDP-D) and smoking pack-years (PYs) on cause-specific survival (CSS) and overall survival (OS) in human papillomavirus-positive (HPV+) oropharyngeal carcinoma (OPSCC) using the eighth edition tumour-node-metastasis (TNM) staging classification (TNM8). We reviewed patients with HPV+ OPSCC treated with high-dose CDDP and intensity-modulated radiotherapy between 2005 and 2015 at Princess Margaret Cancer Centre. CSS and OS were compared according to CDDP-D 200 mg/m A total of 482 consecutive patients were evaluated (stage I/II/III: N = 189/174/119 CDDP-D 200 mg/m CDDP-D correlated with neither survival nor disease-specific outcomes in this large and homogeneous HPV+ cohort, although reduced CSS was observed in stageIII HPV+ OPSCC receiving CDDP-D <200 mg/m
Publisher: Wiley
Date: 02-04-2021
DOI: 10.1002/CNCR.33523
Abstract: Because multiple treatments are available for metastatic castrate‐resistant prostate cancer (mCRPC) and most patients are elderly, the prediction of toxicity risk is important. The Cancer and Aging Research Group (CARG) tool predicts chemotherapy toxicity in older adults with mixed solid tumors, but has not been validated in mCRPC. In this study, its ability to predict toxicity risk with docetaxel chemotherapy (CHEMO) was validated, and its utility was examined in predicting toxicity risk with abiraterone or enzalutamide (A/E) among older adults with mCRPC. Men aged 65+ years were enrolled in a prospective observational study at 4 Canadian academic cancer centers. All clinically relevant grade 2 to 5 toxicities over the course of treatment were documented via structured interviews and chart review. Logistic regression was used to identify predictors of toxicity. Seventy‐one men starting CHEMO (mean age, 73 years) and 104 men starting A/E (mean age, 76 years) were included. Clinically relevant grade 3+ toxicities occurred in 56% and 37% of CHEMO and A/E patients, respectively. The CARG tool was predictive of grade 3+ toxicities with CHEMO, which occurred in 36%, 67%, and 91% of low, moderate, and high‐risk groups ( P = .003). Similarly, grade 3+ toxicities occurred among A/E users in 23%, 48%, and 86% with low, moderate, and high CARG risk ( P .001). However, it was not predictive of grade 2 toxicities with either treatment. There is external validation of the CARG tool in predicting grade 3+ toxicity in older men with mCRPC undergoing CHEMO and demonstrated utility during A/E therapy. This may aid with treatment decision‐making.
Publisher: Oxford University Press (OUP)
Date: 05-04-2019
DOI: 10.1634/THEONCOLOGIST.2018-0621
Abstract: Enhancing the effectiveness of docetaxel for men with metastatic castration-resistant prostate cancer (mCRPC) is an unmet clinical need. Preclinical studies demonstrated that high-dose pantoprazole can prevent or delay resistance to docetaxel via the inhibition of autophagy in several solid tumor xenografts. Men with chemotherapy-naive mCRPC with a prostate-specific antigen (PSA) & ng/mL were eligible for enrolment. Men received intravenous pantoprazole (240 mg) prior to docetaxel (75 mg/m2) every 21 days, with continuous prednisone 5 mg twice daily. Primary endpoint was a confirmed ≥50% decline of PSA. The trial used a Simon's two-stage design. Between November 2012 and March 2015, 21 men with a median age of 70 years (range, 58–81) were treated (median, 6 cycles range, 2–11). Men had received prior systemic therapies (median, 1 range, 0–3), and 14 had received abiraterone and/or enzalutamide. PSA response rate was 52% (11/21), which did not meet the prespecified criterion (≥13/21 responders) to proceed to stage 2 of the study. At interim analysis with a median follow-up of 17 months, 18 (86%) men were deceased (15 castration-resistant prostate cancer, 2 unknown, 1 radiation complication). Of the men with RECIST measurable disease, the radiographic partial response rate was 31% (4/13). The estimated median overall survival was 15.7 months (95% confidence interval [CI], 9.3–19.6) and median PFS was 5.3 months (95% CI, 2.6–12.9). There were no toxic deaths, and all adverse events were attributed to docetaxel. The combination of docetaxel and pantoprazole was tolerable, but the resultant clinical activity was not sufficient to meet the ambitious predefined target to warrant further testing. To date, no docetaxel combination regimen has reported superior efficacy over docetaxel alone in men with metastatic castration-resistant prostate cancer (mCRPC). The PANDORA trial has demonstrated that the combination of high dose pantoprazole with docetaxel is tolerable, but the clinical activity was not sufficient to warrant further testing. The chemotherapy standard of care for men with mCRPC remains docetaxel with prednisone. Future studies of autophagy inhibitors will need to measure autophagy inhibition accurately and determine the degree of autophagy inhibition required to produce a meaningful clinical response.
Publisher: Elsevier BV
Date: 02-2019
DOI: 10.1016/J.EJCA.2018.12.006
Abstract: Sunitinib is administered on a rigid schedule that may not be optimal for all patients. We hypothesised that toxicity-driven dose and schedule changes would optimise drug exposure and outcome for each patient. In a phase 2 trial, 117 patients with metastatic clear cell renal cell cancer were started on sunitinib 50 mg/day with the aim to treat for 28 days. Treatment breaks were reduced to 7 days. Sunitinib dose and the number of days on therapy were in idualised based on toxicity aiming for ≤ grade II toxicity with dose escalation in patients with minimal toxicity. The null hypothesis for the primary end-point was a progression-free survival (PFS) of 8.5 months based on a study with similar eligibility criteria. The null hypothesis was rejected (p < 0.001) with a median PFS of 12.5 months (95% confidence interval [CI]: 9.6-16.5). The median overall survival was 38.5 months (95% CI: 28.3-not reached). The objective response rate (46.1%) and stable disease rate (38.5%) translated into a clinical benefit for 84.6% of patients with no decline in quality of life scores during therapy. Fewer patients were dose reduced (26.5% vs. 50%) or discontinued due to toxicity (7.7 vs. 18-20%) compared to standard sunitinib dosing, and 20 (18.4%) patients were dose escalated to 62.5 mg (12) and 75 mg (8) with a wide in idual variation in the optimal dose and treatment duration. In idualised sunitinib therapy is feasible, safe and an effective method to manage toxicity with one of the best efficacy seen for oral vascular endothelial growth factor inhibitors in metastatic renal cell carcinoma. CLINICALTRIALS. NCT01499121.
Publisher: Elsevier BV
Date: 07-2019
DOI: 10.1016/J.EUO.2018.08.031
Abstract: Standard-dose computed tomography (SDCT) scans are associated with radiation exposure during stage I testicular cancer surveillance. To evaluate low-dose CT (LDCT) for clinical use. In this single-arm prospective study, patients on surveillance for stage I testicular germ cell tumour underwent SDCT and LDCT scans on their first visit after enrolment. The adequacy of LDCT image quality was assessed for subsequent use. Patients were followed with LDCT only and suspected relapse was confirmed by SDCT. We assessed whether initial LDCT scans were of sufficient quality for routine clinical use. We compared mean differences in nodal size at relapse between LDCT and SDCT using a one-s le paired t test. The relapse free-rate was calculated using the Kaplan-Meier method. Of 257 patients, one was excluded because of inadequate image quality. At median follow-up of 5.25 yr, 35 patients had relapsed, 33 with retroperitoneal lymphadenopathy. The 2- and 5-yr relapse-free rates were 89.5% and 85.3%, respectively. The mean size of retroperitoneal nodal relapse was 17.3 and 17.5mm on the short axis, 23.2 and 22.7mm on the long axis, and 26.1 and 26.7mm on craniocaudal length for LDCT and SDCT, respectively. The mean difference between LDCT and SDCT was 0.14mm (p=0.55) short axis, -0.54mm (p=0.092) long axis, and -0.51mm (p=0.086) length. A limitation was the lack of a control arm. LDCT image quality was adequate for clinical use, and retroperitoneal nodal relapse was detected with minimal differences seen between LD and SDCT. LDCT can be safely adopted and will decrease overall radiation exposure in stage I germ cell tumour surveillance. We studied the use of low-dose computed tomography scans for detecting testicular cancer recurrence in lymph nodes of the abdomen and pelvis and found that they were safe, effective and would potentially reduce overall X-ray exposure. This trial is registered at ClinicalTrials.gov as NCT03142802.
Publisher: American Society of Clinical Oncology (ASCO)
Date: 10-04-2013
Publisher: Springer Science and Business Media LLC
Date: 11-02-2019
DOI: 10.1007/S00262-019-02307-X
Abstract: Adoptive cell therapy using autologous tumor-infiltrating lymphocytes (TIL) has shown significant clinical benefit, but is limited by toxicities due to a requirement for post-infusion interleukin-2 (IL-2), for which high dose is standard. To assess a modified TIL protocol using lower dose IL-2, we performed a single institution phase II protocol in unresectable, metastatic melanoma. The primary endpoint was response rate. Secondary endpoints were safety and assessment of immune correlates following TIL infusion. Twelve metastatic melanoma patients were treated with non-myeloablative lymphodepleting chemotherapy, TIL, and low-dose subcutaneous IL-2 (125,000 IU/kg/day, maximum 9-10 doses over 2 weeks). All but one patient had previously progressed after treatment with immune checkpoint inhibitors. No unexpected adverse events were observed, and patients received an average of 6.8 doses of IL-2. By RECIST v1.1, two patients experienced a partial response, one patient had an unconfirmed partial response, and six had stable disease. Biomarker assessment confirmed an increase in IL-15 levels following lymphodepleting chemotherapy as expected and a lack of peripheral regulatory T-cell expansion following protocol treatment. Interrogation of the TIL infusion product and monitoring of the peripheral blood following infusion suggested engraftment of TIL. In one responding patient, a population of T cells expressing a T-cell receptor Vβ chain that was dominant in the infusion product was present at a high percentage in peripheral blood more than 2 years after TIL infusion. This study shows that this protocol of low-dose IL-2 following adoptive cell transfer of TIL is feasible and clinically active. (ClinicalTrials.gov identifier NCT01883323.).
Publisher: Elsevier BV
Date: 11-2020
Publisher: Springer Science and Business Media LLC
Date: 07-07-2023
DOI: 10.1038/S41416-023-02307-W
Abstract: Patient perspectives are fundamental to defining tolerability of investigational anti-neoplastic therapies in clinical trials. Phase I trials present a unique challenge in designing tools for efficiently collecting patient-reported outcomes (PROs) given the difficulty of anticipating adverse events of relevance. However, phase I trials also offer an opportunity for investigators to optimize drug dosing based on tolerability for future larger-scale trials and in eventual clinical practice. Existing tools for comprehensively capturing PROs are generally cumbersome and are not routinely used in phase I trials. Here, we describe the creation of a tailored survey based on the National Cancer Institute’s PRO-CTCAE for collecting patients’ perspectives on symptomatic adverse events in phase I trials in oncology. We describe our stepwise approach to condensing the original 78-symptom library into a modified 30 term core list of symptoms which can be efficiently applied. We further show that our tailored survey aligns with phase I trialists’ perspectives on symptoms of relevance. This tailored survey represents the first PRO tool developed specifically for assessing tolerability in the phase I oncology population. We provide recommendations for future work aimed at integrating this survey into clinical practice.
Publisher: MDPI AG
Date: 21-12-2019
Abstract: With the advent of checkpoint inhibitor treatment for various cancer types, the optimization of drug selection, pharmacokinetics and biomarker assays is an urgent and as yet unresolved dilemma for clinicians, pharmaceutical companies and researchers. Drugs which inhibit cytotoxic T-lymphocyte associated protein-4 (CTLA-4), such as ipilimumab and tremelimumab, programmed cell death protein-1 (PD-1), such as nivolumab and pembrolizumab, and programmed cell death ligand-1 (PD-L1), such as atezolizumab, durvalumab and avelumab, each appear to have varying pharmacokinetics and clinical activity in different cancer types. Each drug differs in terms of dosing, which becomes an issue when drug comparisons are attempted. Here, we examine the various checkpoint inhibitors currently used and in development. We discuss the antibodies and their protein targets, their pharmacokinetics as measured in various tumor types, and their binding affinities to their respective antigens. We also examine the various dosing regimens for these drugs and how they differ. Finally, we examine new developments and methods to optimize delivery and efficacy in the field of checkpoint inhibitors, including non-fucosylation, prodrug formations, bispecific antibodies, and newer small molecule and peptide checkpoint inhibitors.
Publisher: American Association for Cancer Research (AACR)
Date: 13-10-2023
Publisher: American Medical Association (AMA)
Date: 2016
Publisher: American Association for Cancer Research (AACR)
Date: 14-09-2018
DOI: 10.1158/0008-5472.CAN-18-0316
Abstract: MEK inhibition is of interest in cancer drug development, but clinical activity in metastatic colorectal cancer (mCRC) has been limited. Preclinical studies demonstrated Wnt pathway overexpression in KRAS-mutant cell lines resistant to the MEK inhibitor, selumetinib. The combination of selumetinib and cyclosporin A, a noncanonical Wnt pathway modulator, demonstrated antitumor activity in mCRC patient-derived xenografts. To translate these results, we conducted a NCI Cancer Therapy Evaluation Program–approved multicenter phase I/IB trial (NCT02188264) of the combination of selumetinib and cyclosporin A. Patients with advanced solid malignancies were treated with the combination of oral selumetinib and cyclosporin A in the dose escalation phase, followed by an expansion cohort of irinotecan and oxaliplatin-refractory mCRC. The expansion cohort utilized a single-agent selumetinib “run-in” to evaluate FZD2 biomarker upregulation and KRAS-WT and KRAS-MT stratification to identify any potential predictors of efficacy. Twenty and 19 patients were enrolled in dose escalation and expansion phases, respectively. The most common adverse events and grade 3/4 toxicities were rash, hypertension, and edema. Three dose-limiting toxicities (grade 3 hypertension, rash, and increased creatinine) were reported. The MTD was selumetinib 75 mg twice daily and cyclosporin A 2 mg/kg twice daily on a 28-day cycle. KRAS stratification did not identify any differences in response between KRAS-WT and KRAS-MT cancers. Two partial responses, 18 stable disease, and 10 progressive disease responses were observed. Combination selumetinib and cyclosporin A is well tolerated, with evidence of activity in mCRC. Future strategies for concept development include identifying better predictors of efficacy and improved Wnt pathway modulation. Significance: These findings translate preclinical studies combining selumetinib and cyclosporin into a phase I first-in-human clinical trial of such a combination in patients with advanced solid malignancies. Cancer Res 78(18) 5398–407. ©2018 AACR.
Publisher: Springer Science and Business Media LLC
Date: 24-10-2017
DOI: 10.1038/BJC.2017.357
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/1078-0432.C.6532583
Abstract: AbstractPurpose: To characterize safety and tolerability of the selective PI3Kβ inhibitor AZD8186, identify a recommended phase II dose (RP2D), and assess preliminary efficacy in combination with abiraterone acetate or vistusertib. Patients and Methods: This phase I open-label study included patients with advanced solid tumors, particularly prostate cancer, triple-negative breast cancer, and squamous non–small cell lung cancer. The study comprised four arms: (i) AZD8186 monotherapy dose finding (ii) monotherapy dose expansion (iii) AZD8186/abiraterone acetate (with prednisone) and (iv) AZD8186/vistusertib. The primary endpoints were safety, tolerability, and identification of the RP2D of AZD8186 monotherapy and in combination. Secondary endpoints included pharmacokinetics (PK), pharmacodynamics, and tumor and prostate-specific antigen (PSA) responses. Results: In total, 161 patients were enrolled. AZD8186 was well tolerated across all study arms, the most common adverse events being gastrointestinal symptoms. In the monotherapy dose-finding arm, four patients experienced dose-limiting toxicities (mainly rash). AZD8186 doses of 60-mg twice daily [BID 5 days on, 2 days off (5:2)] and 120-mg BID (continuous and 5:2 dosing) were taken into subsequent arms. The PKs of AZD8186 were dose proportional, without interactions with abiraterone acetate or vistusertib, and target inhibition was observed in plasma and tumor tissue. Monotherapy and combination therapy showed preliminary evidence of limited antitumor activity by imaging and, in prostate cancer, PSA reduction. Conclusions: AZD8186 monotherapy had an acceptable safety and tolerability profile, and combination with abiraterone acetate rednisone or vistusertib was also tolerated. There was preliminary evidence of antitumor activity, meriting further exploration of AZD8186 in subsequent studies in PI3Kβ pathway–dependent cancers. /
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/1078-0432.22487046.V1
Abstract: Supplementary Figure from A Randomized Phase II Study of MEDI0680 in Combination with Durvalumab versus Nivolumab Monotherapy in Patients with Advanced or Metastatic Clear-cell Renal Cell Carcinoma
Publisher: Elsevier BV
Date: 10-2018
Publisher: Springer Science and Business Media LLC
Date: 20-05-2019
Publisher: American Association for Cancer Research (AACR)
Date: 15-09-2023
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/1078-0432.22487055
Abstract: Supplementary Data from A Randomized Phase II Study of MEDI0680 in Combination with Durvalumab versus Nivolumab Monotherapy in Patients with Advanced or Metastatic Clear-cell Renal Cell Carcinoma
Publisher: Elsevier BV
Date: 07-2019
Publisher: American Association for Cancer Research (AACR)
Date: 14-01-2015
DOI: 10.1158/1078-0432.CCR-14-1334
Abstract: Purpose: Tumor necrosis factor (TNF)–like weak inducer of apoptosis (TWEAK) and fibroblast growth factor-inducible molecule 14 (Fn14) are a ligand–receptor pair frequently overexpressed in solid tumors. TWEAK:Fn14 signaling regulates multiple oncogenic processes through MAPK, AKT, and NFκB pathway activation. A phase I study of RG7212, a humanized anti-TWEAK IgG1κ monoclonal antibody, was conducted in patients with advanced solid tumors expressing Fn14. Experimental Design: Dose escalations, over a 200- to 7,200-mg range, were performed with patients enrolled in weekly (QW), bi-weekly (Q2W), or every-three-week (Q3W) schedules. Primary objectives included determination of dose and safety profile. Secondary endpoints included assessments related to inhibition of TWEAK:Fn14 signaling, tumor proliferation, tumor immune cell infiltration, and pharmacokinetics. Results: In 192 treatment cycles administered to 54 patients, RG7212 was well-tolerated with no dose-limiting toxicities observed. More than 95% of related adverse events were limited to grade 1/2. Pharmacokinetics were dose proportional for all cohorts, with a t1/2 of 11 to 12 days. Pharmacodynamic changes included clearance of free and total TWEAK ligand and reductions in tumor Ki-67 and TRAF1. A patient with BRAF wild-type melanoma who received 36 weeks of RG7212 therapy had tumor regression and pharmacodynamic changes consistent with antitumor effects. Fifteen patients (28%) received 16 or more weeks of RG7212 treatment. Conclusion: RG7212 demonstrated excellent tolerability and favorable pharmacokinetics. Pharmacodynamic endpoints were consistent with reduced TWEAK:Fn14 signaling. Tumor regression was observed and prolonged stable disease was demonstrated in multiple heavily pretreated patients with solid tumors. These encouraging results support further study of RG7212. Clin Cancer Res 21(2) 258–66. ©2014 AACR.
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/1078-0432.22487052
Abstract: Supplementary Figure from A Randomized Phase II Study of MEDI0680 in Combination with Durvalumab versus Nivolumab Monotherapy in Patients with Advanced or Metastatic Clear-cell Renal Cell Carcinoma
Publisher: Oxford University Press (OUP)
Date: 22-02-2021
DOI: 10.1093/JNCI/DJAB015
Abstract: Clinician reporting of symptomatic adverse events (AEs) in phase I trials uses the Common Terminology Criteria for Adverse Events (CTCAE). The utility of the patient-reported outcomes (PROs) version of the CTCAE (PRO-CTCAE) in this setting is unknown. This prospective, observational study compared patient- and clinician-reported symptomatic AEs in phase I patients. Phase I study–eligible patients at Princess Margaret were surveyed with the PRO-CTCAE full-item library (78 symptomatic AEs) at baseline (BL), mid-cycle 1, and mid-cycle 2 (C2). Patient and trial characteristics, best response, and survival data were collected. Presence or absence of patient- (PRO-CTCAE) or clinician-reported symptomatic AEs were compared (kappa) at defined timepoints and overall (BL+ mid-cycle 1 + C2). Of 292 patients approached from May 2017 to January 2019, a total of 265 (90.8%) were consented, with 243 (91.7%) evaluable and 552 PRO-CTCAE surveys (completion rate = 98.7%) included in analyses. Evaluation of overall patient-reported symptomatic AEs identified 50 PRO-CTCAE and 11 CTCAE items with 10% or greater reporting frequency. Nineteen CTCAE items were reported as 1% or less despite matched PRO-CTCAE items reporting as 10% or greater. Underreported categories included sexual health, bodily emissions, and cognition. Clinician- relative to patient-reporting frequency (ratio) demonstrated 9 symptomatic AEs with a 50-fold or more lower clinician reporting rate. Overall patient–clinician agreement for in idual symptomatic AEs ranged from poor (κ = 0.00-0.19) to moderate (κ = 0.40-0.59), with discordance driven by lack of clinician reporting. Dyspnea (κ = 0.54) and peripheral neuropathy (κ = 0.63) at BL and limb edema (κ = 0.55) at C2 demonstrated the highest patient–clinician agreement. Poor to moderate patient–clinician agreement for symptomatic AEs suggests clinician underreporting in phase I trials. Analyses of severity and interference PRO categories are ongoing.
Publisher: Oxford University Press (OUP)
Date: 23-01-2020
DOI: 10.1634/THEONCOLOGIST.2019-0605
Abstract: International Metastatic Renal Cell Carcinoma (mRCC) Database Consortium (IMDC) risk groups are important when considering therapeutic options for first-line treatment. Adult patients with clear cell mRCC initiating first-line sunitinib between 2010 and 2018 were included in this retrospective database study. Median time to treatment discontinuation (TTD) and overall survival (OS) were estimated using Kaplan-Meier analysis. Outcomes were stratified by IMDC risk groups and evaluated for those in the combined intermediate and poor risk group and separately for those in the intermediate risk group with one versus two risk factors. Among 1,769 patients treated with first-line sunitinib, 318 (18%) had favorable, 1,031 (58%) had intermediate, and 420 (24%) had poor IMDC risk. Across the three risk groups, patients had similar age, gender, and sunitinib initiation year. Median TTD was 15.0, 8.5, and 4.2 months in the favorable, intermediate, and poor risk groups, respectively, and 7.1 months in the combined intermediate and poor risk group. Median OS was 52.1, 31.5, and 9.8 months in the favorable, intermediate, and poor risk groups, respectively, and 23.2 months in the combined intermediate and poor risk group. Median OS (35.1 vs. 21.9 months) and TTD (10.3 vs. 6.6 months) were significantly different between intermediate risk patients with one versus two risk factors. This real-world study found a median OS of 52 months for patients with favorable IMDC risk treated with first-line sunitinib, setting a new benchmark on clinical outcomes of clear cell mRCC. Analysis of intermediate risk group by one or two risk factors demonstrated distinct clinical outcomes. This analysis offers a contemporary benchmark for overall survival (median, 52.1 months 95% confidence interval, 43.4–61.2) among patients with clear cell metastatic renal cell carcinoma who were treated with sunitinib as first-line therapy in a real-world setting and classified as favorable risk according to International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) risk group classification. This study demonstrates that clinical outcomes differ between IMDC risk groups as well as within the intermediate risk group based on the number of risk factors, thus warranting further consideration of risk group when counseling patients about therapeutic options and designing clinical trials.
Publisher: American Association for Cancer Research (AACR)
Date: 13-10-2023
Publisher: Elsevier BV
Date: 09-2019
DOI: 10.1016/J.EUF.2019.05.003
Abstract: At Princess Margaret, we recommend active surveillance for all patients with clinical stage I nonseminomatous germ cell tumor. Here we refute common arguments against surveillance and urge clinicians to engage in a shared decision-making process that goes beyond merely citing relapse rates for the different options.
Publisher: Wiley
Date: 18-01-2021
DOI: 10.1002/CAM4.3717
Publisher: Springer Science and Business Media LLC
Date: 08-11-2019
DOI: 10.1007/S00280-019-03989-X
Abstract: Some patients who participate in early phase cancer trials enroll to more than one trial. Whether these patients have different characteristics or outcomes than patients who enroll to a single phase I trial is unknown. The study included all patients who participated in the solid tumor drug development program of the Princess Margaret Cancer Centre, a specialized academic cancer center, from July 2014 to January 2017. Patients sequentially enrolled to multiple phase I trials were compared to those enrolled in a single trial according to demographics, clinical characteristics, reported toxicities and prognosis. The study cohort included 328 patients, including 61 (19%) enrolled to multiple phase I trials and 267 (81%) enrolled to a single phase I trial. Demographics, comorbidities, performance status, cancer site and time between initial diagnosis and initial enrollment to the phase I program were comparable between both groups. Patients enrolled to multiple phase I trials received more previous non-trial treatment lines (median 3 versus 2, p < 0.001) and had a higher average response rate on phase I trials (18% versus 10%, p = 0.03). Toxicity data, including number of any adverse events (AEs), grade 3/4 AEs, serious AEs and dose-limiting toxicities were comparable between both groups. Time to disease progression and time to last documented follow-up were also comparable between both groups. Patients enrolled to multiple phase I trials and those enrolled to a single trial had similar toxicity and prognostic profiles. These patients do not introduce bias into early-phase cancer trials results.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 04-2015
Publisher: American Association for Cancer Research (AACR)
Date: 08-2023
DOI: 10.1158/1078-0432.23815995
Abstract: Supplementary Tables 1-3
Publisher: Wiley
Date: 29-06-2021
DOI: 10.1002/CAM4.4086
Abstract: There are limited data regarding the quality of patient‐reported outcome (PRO) data in immune checkpoint inhibitor (ICI) clinical trial publications. A systematic search of citations from various databases was conducted to identify prospective clinical trials involving ICI in advanced tumors from 2003 to 2020. A 30‐point score was adapted from the CONSORT PRO extension statement to assess adherence to CONSORT PRO reporting. Linear regression was used to identify factors associated with quality reporting. After the review of 8058 articles, 33 trials were included with ICIs as either monotherapy (91%) or part of a combination regimen (9%). The median score was 23.5 points (range 15–29). In the majority of cases (82%), PROs were reported in a separate publication from the original study. Most of the trials were conducted in the metastatic setting and predominantly in melanoma, lung, and renal cell carcinoma (RCC) (73%). Univariate analysis revealed that trials with greater than 250 patients were associated with a higher score. The score was more likely to be lower in disease sites other than melanoma, lung, and RCC and was higher in the KEYNOTE than in the CHECKMATE trial series. There was no significant correlation between the score and whether a trial met its primary end‐point or if the trial improved or worsened the quality of life. In the multivariate analysis, the number of patients enrolled to the trial, disease site, and trial series remained significant. The quality of reporting of PROs in ICI phase II and III clinical trials is heterogeneous across various cancer sites. As PRO data are increasingly used to counsel patients and complement clinical decision making, innovative and collaborative efforts are required to improve the reporting of these essential data.
Publisher: Wiley
Date: 17-12-2021
DOI: 10.1002/CAM4.4480
Abstract: Testicular cancer survivors often have impaired gonadal function possibly related to chemotherapy. Platinum is a heavy metal that can be detected at low levels in serum many years after treatment, it is not known whether platinum also persists in semen and if platinum persistence in semen is associated with impaired fertility. Adult cisplatin‐treated testicular cancer survivors were enrolled. High‐Performance Liquid Chromatography‐tandem mass spectrometry was used to measure semen and serum platinum levels. Semen quality and DNA Fragmentation Index (DFI) were assessed. From 11/2017 to 12/2019, 38 patients (median age 32 years range: 19–52) were enrolled. Median cumulative cisplatin dose was 301 mg/m 2 (range: 274–404). Platinum levels were higher in semen than in blood ( p = 0.03). Semen platinum levels were not significantly associated with time from last cisplatin dosing ( r = −0.34 p = 0.09) nor cumulative dose ( r = −0.10, p = 0.63). Sperm concentration was correlated with time from last cisplatin dosing ( r = 0.58, p 0.001) but not with semen platinum level ( r = −0.15, p = 0.46). DFI was not significantly associated with time from last cisplatin dosing ( r = 0.55, p = 0.08) or semen platinum level ( r = −0.32, p = 0.33). In four patients with serial semen s les, platinum level decreased and sperm concentration and motility increased over time. Platinum is detected in semen of testicular cancer survivors at higher levels than matched blood s les. These preliminary findings may have important implications for the reproductive health of survivors of advanced testicular cancer, further study is needed to assess the relationship between platinum persistence in semen and recovery of fertility postchemotherapy.
Publisher: Research Square Platform LLC
Date: 21-07-2023
DOI: 10.21203/RS.3.RS-3153100/V1
Abstract: Immune gene expression signatures are emerging as potential biomarkers for immunotherapy. Yet, their limited predictive performance and complexity limit routine clinical implementation. VIGex is a 12-gene expression classifier developed in both nCounter (Nanostring) and RNA-Seq assays and analytically validated across laboratories. VIGex classifies tumor s les into Hot, Intermediate-Cold (I-Cold) and Cold subgroups. VIGex-Hot has been associated with better immunotherapy (IO) treatment outcomes. Here we investigated the performance of VIGex and other IO biomarkers in an independent dataset of patients treated with Pembrolizumab in the INSPIRE phase 2 clinical trial (NCT02644369). Patients with advanced solid tumors were treated with Pembrolizumab 200 mg IV every 3 weeks. Tumor RNA-seq data from baseline tumor s les were classified by the VIGex algorithm. Circulating tumor DNA (ctDNA) was measured at baseline and start of cycle 3 using the bespoke Signatera™ assay. VIGex-Hot was compared to VIGex Intermediate-Cold + Cold and 4 groups were defined based on the combination of VIGex subgroups and the change in ctDNA at cycle 3 from baseline (ΔctDNA). Seventy-six patients were enrolled including 16 ovarian, 12 breast, 12 head and neck cancers, 10 melanoma and 26 other tumor types. Objective response rate was 24% in VIGex-Hot and 10% in I-Cold/Cold. VIGex-Hot subgroup was associated with higher OS (HR: 0.43 p = 0.009) and PFS (HR: 0.49 p = 0.036) when included in a multivariable model adjusted for tumor type, tumor mutational burden (TMB) and PD-L1 immunohistochemistry. The addition of ΔctDNA improved the predictive performance of the baseline VIGex classification for both OS and PFS. Our data indicate that the addition of ΔctDNA to baseline VIGex may refine prediction for IO.
Publisher: Springer Science and Business Media LLC
Date: 25-08-2022
Publisher: American Association for Cancer Research (AACR)
Date: 15-09-2023
DOI: 10.1158/1078-0432.C.6769722
Abstract: AbstractPurpose: In this first-in-human, Phase 1, open-label, multicenter study, we evaluated JNJ-64619178, a selective and potent PRMT5 inhibitor, in patients with advanced malignant solid tumors or non-Hodgkin lymphomas (NHL). The primary objective was to evaluate the safety and to identify a recommended Phase 2 dose (RP2D) of JNJ-64619178. Patients and Methods: Adult patients with treatment-refractory advanced solid tumors or NHL and measurable disease received escalating doses of JNJ-64619178 following two schedules (Schedule A: 14 days on/7 days off Schedule B: every day on a 21-day cycle). Safety, pharmacokinetics (PK), pharmacodynamics (PD), and clinical activity were evaluated. Results: Ninety patients received JNJ-64619178. Thrombocytopenia was identified as the only dose-limiting toxicity. JNJ-64619178 showed dose-proportional PK and robust target engagement, as measured by plasma symmetric dimethylarginine, across all dose levels. The objective response rate was 5.6% (5 of 90). Patients with adenoid cystic carcinoma (ACC) had an ORR of 11.5% (3 of 26) and a median progression-free survival of 19.1 months. Conclusions: JNJ-64619178 demonstrated manageable dose-dependent toxicity and preliminary evidence of antitumor activity in ACC and other tumor types. Plasma exposure was dose dependent, and target inhibition was maintained with intermittent and continuous dosing. On the basis of safety, clinical activity, PK, and PD findings, two provisional RP2Ds were selected: 1.5 mg intermittently and 1.0 mg once daily. Aside from ACC, clinical benefit was limited, and biomarkers to enrich for responsiveness to PRMT5 inhibition will be needed for further development. /
Publisher: Wiley
Date: 13-07-2021
DOI: 10.1002/CAM4.4125
Abstract: In men with metastatic castration‐resistant prostate cancer (mCRPC) with primarily bone metastases, radium‐223 ( 223 Ra) improves overall survival (OS). However, the selection of 223 Ra is not guided by specific validated clinicopathologic factors, and thus outcomes are heterogeneous. This retrospective survival analysis was performed in men with mCRPC treated with 223 Ra at our cancer center. Demographics and disease characteristics were collected. OS was calculated using the Kaplan–Meier method (log‐rank). The potential prognostic factors were determined using both univariable (UVA) and multivariable analysis (MVA) (Cox‐regression) methods. In total, 150 patients with a median age of 74 years (52–93) received 223 Ra between May 2015 and July 2018, and 58% had 6–20 bone metastases. Ninety‐four (63%) patients received 223 Ra doses, and 56 (37%) received ≤4. The following pre‐treatment factors were analyzed (median [range]): eastern cooperative oncology group performance status (ECOG PS), (1 [0–3]) Albumin (ALB), (39 g/L [24–47]) alkaline phosphatase (ALP), (110 U/L [35–1633]) and prostate‐specific antigen (PSA), (49 µg/L [0.83–7238]). The median OS for all patients was 14.5 months (95% CI: 11.2–18). These factors were associated with poor survival outcomes in UVA and MVA: ALB g/L, ALP U/L, ECOG PS 2–3, and PSA µg/L. By assigning one point for each of these factors, a prognostic model was developed, wherein three distinct risk groups were identified: good, 0–1 ( n = 103) intermediate, 2 ( n = 30) and poor risk, 3–4 points ( n = 17). The median OS was 19.4, 10.0, and 3.1 months, respectively ( p 0.001). Pre‐treatment ALB, ALP, ECOG, and PSA, were significantly correlated with OS and could guide treatment selection for men with mCRPC by identifying those who are most or least likely to benefit from 223 Ra. Validation in an independent dataset is required prior to widespread clinical utilization.
Publisher: American Society of Clinical Oncology (ASCO)
Date: 20-12-2017
Abstract: To establish the safety profile and antitumor activity of the anti–programmed death 1 receptor monoclonal antibody, pembrolizumab, in patients with recurrent or metastatic nasopharyngeal carcinoma (RM-NPC) that expressed programmed death-ligand 1 (PD-L1). KEYNOTE-028 (NCT02054806) is a nonrandomized, multicohort, phase Ib trial of pembrolizumab in patients with PD-L1–positive advanced solid tumors. Key eligibility criteria for the NPC cohort included unresectable or metastatic disease, failure on prior standard therapy, and PD-L1 expression in 1% or more of tumor cells or tumor-infiltrating lymphocytes. Patients received pembrolizumab 10 mg/kg every 2 weeks up to 2 years or until disease progression or unacceptable toxicity. Primary end point was objective response rate (ORR) per investigator review. Tumor response was assessed according to Response Evaluation Criteria in Solid Tumors (RECIST version 1.1) every 8 weeks for the first 6 months and every 12 weeks thereafter. Twenty-seven patients received pembrolizumab. Median age was 52.0 years (range, 18 to 68 years) 92.6% received prior therapies for RM-NPC 70.4% had received three or more therapies. Partial response and stable disease were observed in seven and 14 patients, respectively, for an ORR of 25.9% (95% CI, 11.1 to 46.3) over a median follow-up of 20 months. ORR by central review was similar (26.3%). Drug-related adverse events that occurred in 15% or more of patients included rash (25.9%), pruritus (25.9%), pain (22.2%), hypothyroidism (18.5%), and fatigue (18.5%). Grade ≥ 3 drug-related adverse events occurred in eight patients (29.6%), and there was one drug-related death (sepsis). As of the data cutoff (June 20, 2016), two patients remained on pembrolizumab treatment. Pembrolizumab demonstrated antitumor activity and a manageable safety profile in patients with RM-NPC.
Publisher: American Association for Cancer Research (AACR)
Date: 08-2023
DOI: 10.1158/1078-0432.23815998
Abstract: Supplementary Figure 1: Overall Response Over Time on JNJ-64619178 Treatment A. Dose Cohorts 0.5 mg - 1.5 mg (schedule A& B). B. Dose Cohorts 2.0 mg - 4.0 mg (schedule A& B)
Publisher: American Association for Cancer Research (AACR)
Date: 15-09-2023
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/1078-0432.22487798.V1
Abstract: Supplementary Data from A Phase I Study Investigating AZD8186, a Potent and Selective Inhibitor of PI3Kβ/δ, in Patients with Advanced Solid Tumors
Publisher: Public Library of Science (PLoS)
Date: 22-10-2019
Publisher: Elsevier BV
Date: 10-2018
Publisher: Elsevier BV
Date: 04-2020
DOI: 10.1016/J.UROLOGY.2019.12.032
Abstract: To compare a simultaneous vs sequential approach to residual post chemotherapy mass resections in metastatic testis cancer. A retrospective review was performed of patients who underwent retroperitoneal and thoracic/cervical resection of post chemotherapy residual masses between 2002 and 2018. Group 1: "Simultaneous" (Combined Retroperitoneal and Thoracic/Cervical resections on the same date) Group 2: "Sequential" (Retroperitoneal and Thoracic/Cervical resections at separate dates). During the study period, 35 simultaneous and 17 sequential resections were performed. The median age at surgery was 28 years (Range 16-61). The median follow-up from last surgical procedure was 62.7 months (Range 0.4-194). Histology revealed teratoma in 38 (73.1%) patients, necrosis in 8 (15.4%) and viable tumor in 6 (11.5%). Discordant pathology findings between thoracic/cervical and abdominal resections were noted in 16 (30.8%) patients. No differences were observed between the simultaneous vs sequential groups in median operating time (585 minutes vs 545 minutes, P = .64), blood loss (1300 vs 1300 mls, P = .42), or length of stay (9 vs 11 days, P = .14). There was no difference between the 5-year (65.7% vs 68.6%) relapse-free survival between the 2 groups (P = .84) or the 5-year (88.6% vs 100%) overall and disease-specific survival (P = .25). Simultaneous resection of retroperitoneal and thoracic/cervical post chemotherapy metastases is a feasible in some patients. It requires multidisciplinary collaboration and a longer primary procedure.
Publisher: American Society of Clinical Oncology (ASCO)
Date: 16-06-2023
DOI: 10.1200/OP.23.00191
Abstract: International guidelines advocate for active surveillance as the preferred treatment strategy for patients with stage 1 testicular cancer after orchidectomy although a personalized discussion is required. We conducted an analysis of in iduals registered in iTestis, Australia's testicular cancer registry, to describe the patterns of relapse and outcomes of patients treated in Australia where the Australian and New Zealand Urogenital and Prostate Cancer Trials Group Surveillance Recommendations are widely adopted. A total of 650 in iduals diagnosed between 2000 and 2020 were included, 63% (411 of 650) seminoma and 37% (239 of 650) nonseminoma. The median age was 34 years (range 14-74). 26% (106 of 411) with seminoma and 15% (36 of 239) nonseminoma received adjuvant chemotherapy. After a median follow-up of 43 months (range 0-267) postorchidectomy, relapse occurred in 10% (43 of 411) of seminoma and 18% (43 of 239) of nonseminoma. The two-year relapse-free survival was 92% (95% CI, 89 to 95) and 82% (95% CI, 78 to 87) in seminoma and nonseminoma, respectively. All relapses (86 of 86) were detected at a routine surveillance visit 98% (85 of 86) were asymptomatic and detected solely through imaging (62 of 86, 72%), tumor markers (6 of 86, 7%), or a combination (17 of 86, 20%). The most common relapse site was isolated retroperitoneal lymphadenopathy (53 of 86, 62%). No nonpulmonary visceral metastases occurred. At relapse, 98% (84 of 86) had International Germ Cell Cancer Collaborative Group (IGCCCG) good prognosis 2 of 86 intermediate prognosis (both nonseminoma). No deaths occurred. In our cohort of stage 1 testicular cancer, where national surveillance recommendations have been widely adopted, recurrences were detected at routine surveillance visits and, almost exclusively, asymptomatic with IGCCCG good-prognosis disease. This provides reassurance that active surveillance is safe.
Publisher: Elsevier BV
Date: 03-2019
DOI: 10.1016/J.CRITREVONC.2019.01.008
Abstract: Non-urothelial (NU) histologies represent less than 10% of bladder cancers, with squamous cell carcinoma (SCC) being the most common subtype (approximately 5%). Bladder SCCs are sub ided into Schistosoma-related or non-Schistosoma-related tumors, with the latter being the most frequent subtype in the western world. Typically, these patients have been excluded or under-represented in clinical trials and thus little is known about treatment efficacy in bladder SCC. To address this paucity of data, extrapolation from urothelial carcinoma (UC) trials can be performed but this approach has inherent limitations. In the era of precision medicine, efforts to characterize the genomic and molecular profiles of bladder tumors may yield evidence to support new targets for effective therapies. We reviewed the available data on biomarkers of bladder SCC and provide suggestions on how these may influence therapeutic testing and clinical trials in the future.
Publisher: Elsevier BV
Date: 06-2020
Publisher: American Association for Cancer Research (AACR)
Date: 02-10-2023
Publisher: American Association for Cancer Research (AACR)
Date: 02-10-2023
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/1078-0432.C.6532443
Abstract: AbstractPurpose: MEDI0680 is a humanized anti–programmed cell death-1 (PD-1) antibody, and durvalumab is an anti-PD-L1 antibody. Combining treatment using these antibodies may improve efficacy versus blockade of PD-1 alone. This phase II study evaluated antitumor activity and safety of MEDI0680 plus durvalumab versus nivolumab monotherapy in immunotherapy-naïve patients with advanced clear-cell renal cell carcinoma who received at least one prior line of antiangiogenic therapy. Patients and Methods: Patients received either MEDI0680 (20 mg/kg) with durvalumab (750 mg) or nivolumab (240 mg), all intravenous, every 2 weeks. The primary endpoint was investigator-assessed objective response rate (ORR). Secondary endpoints included best overall response, progression-free survival (PFS), safety, overall survival (OS), and immunogenicity. Exploratory endpoints included changes in circulating tumor DNA (ctDNA), baseline tumor mutational burden, and tumor-infiltrated immune cell profiles. Results: Sixty-three patients were randomized (combination, i n /i = 42 nivolumab, i n /i = 21). ORR was 16.7% [7/42 95% confidence interval (CI), 7.0–31.4] with combination treatment and 23.8% (5/21 95% CI, 8.2–47.2) with nivolumab. Median PFS was 3.6 months in both arms median OS was not reached in either arm. Because of adverse events, 23.8% of patients discontinued MEDI0680 and durvalumab and 14.3% of patients discontinued nivolumab. In the combination arm, reduction in ctDNA fraction was associated with longer PFS. ctDNA mutational analysis did not demonstrate an association with response in either arm. Tumor-infiltrated immune profiles showed an association between immune cell activation and response in the combination arm. Conclusions: MEDI0680 combined with durvalumab was safe and tolerable however, it did not improve efficacy versus nivolumab monotherapy. /
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/1078-0432.22487789.V1
Abstract: Supplementary Figure from A Phase I Study Investigating AZD8186, a Potent and Selective Inhibitor of PI3Kβ/δ, in Patients with Advanced Solid Tumors
Publisher: Elsevier BV
Date: 09-2015
Abstract: There are limited data about the quality of immune-related adverse event (irAE) reporting in immune checkpoint inhibitor (ICI) clinical trial publications. A systematic search of citations from Medline, EMBASE and Cochrane databases identified prospective clinical trials involving ICIs in advanced solid tumors from 2003 to 2013. A 21-point quality score (QS) was adapted from the CONSORT harms extension statement. Linear regression was used to identify factors associated with quality reporting. After a review of 2628 articles, 50 trial reports were included, with ICIs as either monotherapy (54%) or part of a combination regimen (46%). The mean QS was 11.21 points (range 3.50-17.50 points). The median grade 3/4 AE rate reported was 21% (range 0%-66%) and 29/50 (58%) trials concluded that irAEs were tolerable. Multivariate regression analysis revealed that year of publication (within last 5 years, P = 0.01) and journal impact factor >15 (P = 0.004) were associated with higher QS. Complete reporting of specific characteristics of irAEs including onset, management and reversibility were reported by 14%, 8% and 6% of studies, respectively. The incidence of grade 3/4 adverse events was higher for inhibitors against CTLA-4 compared with other immune checkpoints (P < 0.001). The reporting of irAEs is suboptimal. A standardized reporting method of irAEs that accounts for tolerability, management and reversibility is needed and would enable a more precise evaluation of the therapeutic risk benefit ratio of ICIs.
Publisher: Wiley
Date: 24-11-2019
DOI: 10.1002/HED.26031
Abstract: There is no mechanism to predict health utility (HU) values from the University of Washington Quality of Life Questionnaire (UWQoL) scores. We sought to develop a mapping algorithm capable of using UWQoL data to approximate HU scores. Outpatients with head and neck cancer completed the UWQoL, EQ-5D, and the Health Utilities Index-Mark 3 (HUI-3). Results of the UWQoL were mapped onto both EQ-5D and HUI-3 scores using ordinary least-squares regression models. Two-part models were explored. The predictive power of the model was assessed using 10-fold cross-validation. A total of 209 patients were recruited. The reduced model converting UWQoL data into EQ-5D scores performed best (adjusted R The abovementioned algorithms enable researchers to perform health economic evaluations with existing UWQoL data in cases where prospectively collected HU values are not available.
Publisher: Wiley
Date: 04-03-2021
DOI: 10.1002/CNCR.33457
Publisher: Oxford University Press (OUP)
Date: 06-02-2019
DOI: 10.1634/THEONCOLOGIST.2018-0332
Abstract: The patient-reported outcomes version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE) complements capture of symptomatic adverse events (AEs) by clinicians. Previous trials have typically used a limited subset of relevant symptomatic AEs to reduce patient burden. We aimed to determine the feasibility of administering all 80 AEs included in the PRO-CTCAE library by approaching consecutive patients enrolled in a large academic phase I program at three points in time. Here, we report a preplanned analysis after enrolling the first 20 patients. All items were answered on 51 of 56 potential visits (adherence 91%). Three (5%) additional PRO-CTCAE assessments were partially completed, and two (4%) were missed because of conflicting appointments. No patient withdrew consent or chose not to complete the assessments once enrolled on study. Future trials of experimental drugs that incorporate the PRO-CTCAE should consider using this unselected approach to identify adverse events more completely.
Publisher: American Society of Clinical Oncology (ASCO)
Date: 11-2021
DOI: 10.1200/PO.20.00370
Publisher: American Association for Cancer Research (AACR)
Date: 15-09-2023
Publisher: Elsevier BV
Date: 02-2018
Publisher: American Association for Cancer Research (AACR)
Date: 15-09-2023
Publisher: SAGE Publications
Date: 07-2014
DOI: 10.1177/107327481402100304
Abstract: Concerns have been recognized about the operating characteristics of the standard 3 + 3 dose-escalation design. Various innovative phase 1 trial designs have been proposed to address the issues and new challenges posed by molecularly targeted agents. However, in spite of these proposals, the conventional design is still the most widely utilized. A review of the literature of phase 1 trials and relevant statistical studies was performed. Beyond statistical simulations, sparse clinical data exist to support or refute many of the shortcomings ascribed to the 3 + 3 rule method. Data from phase 1 trials demonstrate that traditional designs identified the correct dose and relevant toxicities with an acceptable level of precision in some instances however, no single escalation method was proven superior in all circumstances. Design selection should be guided by the principle of slow escalation in the face of toxicity and rapid dose increases in the setting of minimal or no adverse events. When the toxicity of a drug is uncertain or a narrow therapeutic window is suggested from preclinical testing, then a conservative 3 + 3 method is generally appropriate. However, if the therapeutic window is wide and the expected toxicity is low, then rapid escalation with a novel rule- or model-based design should be employed.
Publisher: American Association for Cancer Research (AACR)
Date: 08-2023
DOI: 10.1158/1078-0432.C.6769722.V1
Abstract: AbstractPurpose: In this first-in-human, Phase 1, open-label, multicenter study, we evaluated JNJ-64619178, a selective and potent PRMT5 inhibitor, in patients with advanced malignant solid tumors or non-Hodgkin lymphomas (NHL). The primary objective was to evaluate the safety and to identify a recommended Phase 2 dose (RP2D) of JNJ-64619178. Patients and Methods: Adult patients with treatment-refractory advanced solid tumors or NHL and measurable disease received escalating doses of JNJ-64619178 following two schedules (Schedule A: 14 days on/7 days off Schedule B: every day on a 21-day cycle). Safety, pharmacokinetics (PK), pharmacodynamics (PD), and clinical activity were evaluated. Results: Ninety patients received JNJ-64619178. Thrombocytopenia was identified as the only dose-limiting toxicity. JNJ-64619178 showed dose-proportional PK and robust target engagement, as measured by plasma symmetric dimethylarginine, across all dose levels. The objective response rate was 5.6% (5 of 90). Patients with adenoid cystic carcinoma (ACC) had an ORR of 11.5% (3 of 26) and a median progression-free survival of 19.1 months. Conclusions: JNJ-64619178 demonstrated manageable dose-dependent toxicity and preliminary evidence of antitumor activity in ACC and other tumor types. Plasma exposure was dose dependent, and target inhibition was maintained with intermittent and continuous dosing. On the basis of safety, clinical activity, PK, and PD findings, two provisional RP2Ds were selected: 1.5 mg intermittently and 1.0 mg once daily. Aside from ACC, clinical benefit was limited, and biomarkers to enrich for responsiveness to PRMT5 inhibition will be needed for further development. /
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/1078-0432.22487795.V1
Abstract: Supplementary Data from A Phase I Study Investigating AZD8186, a Potent and Selective Inhibitor of PI3Kβ/δ, in Patients with Advanced Solid Tumors
Publisher: Springer Science and Business Media LLC
Date: 10-2013
DOI: 10.1186/BCR3558
Publisher: Wiley
Date: 19-02-2019
DOI: 10.1002/IJC.32164
Abstract: The prevalence of human papillomavirus (HPV) in squamous cell carcinoma of unknown primary in the head and neck (SCCUPHN), and prognosis by HPV status of SCCUPHN patients has been difficult to estimate because of the rarity of this subtype. In MEDLINE, Epub Ahead of Print, In-Process & Other Non-Indexed Citations, EMBASE, Cochrane library and Web of Science searches, observational studies and clinical trials that reported survival rates of patients with SCCUPHN by HPV status were identified. Meta-analysis estimated the prevalence and prognosis (overall survival, OS progression-free survival, PFS) of SCCUPHN by HPV status, and compared them to studies of oropharyngeal squamous cell carcinoma (OPSCC) from the same institutions and across continents. In 17 SCCUPHN studies (n = 1,149) and 17 institution-matched OPSCC studies (n = 6,522), the pooled HPV prevalence of SCCUPHN was 49%, which was only 10% (95%CI: 1-19%) lower than OPSCC prevalence in the underlying population. Estimated 5-year OS for HPV-negative SCCUPHN was 44% (95%CI: 36-51%) vs. HPV-positive SCCUPHN of 91% (95%CI: 86-96%) hazard ratio (HR) for OS was 3.25 (95%CI: 2.45-4.31) and PFS was 4.49 (95%CI: 2.88-7.02). HRs by HPV status for OPSCC were similar to that in SCCUPHN. While North American SCCUPHNs had higher HPV prevalence than European SCCUPHNs (OR = 2.68 (95%CI: 1.3-5.6)), HR of OS for HPV-negative vs. HPV-positive patients were similar in both continents (HRs of 3.78-4.09). Prevalence of HPV among SCCUPHN patients were lower than in OPSCC. The survival benefit conferred by being HPV-positive was similar in SCCUPHN as in OPSCCs, independent of continent.
Publisher: Springer Science and Business Media LLC
Date: 18-09-2013
DOI: 10.1038/NATURE12627
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/1078-0432.22487792.V1
Abstract: Supplementary Figure from A Phase I Study Investigating AZD8186, a Potent and Selective Inhibitor of PI3Kβ/δ, in Patients with Advanced Solid Tumors
Publisher: Elsevier BV
Date: 10-2018
Publisher: American Association for Cancer Research (AACR)
Date: 13-07-2023
DOI: 10.1158/1078-0432.CCR-23-0731
Abstract: Early treatment intensification with neoadjuvant therapy may improve outcomes in patients with high-risk, localized prostate cancer treated with radical prostatectomy. Our objective was to compare pathologic, oncologic, and safety outcomes of neoadjuvant abiraterone acetate plus leuprolide acetate with or without cabazitaxel prior to radical prostatectomy in patients with localized, high-risk prostate cancer. This open-label, multicenter, phase II trial randomized men with clinically localized, D'Amico high-risk prostate cancer to neoadjuvant abiraterone acetate (1,000 mg/day) and leuprolide acetate (22.5 mg every 3 months) with or without cabazitaxel (25 mg/m2) prior to radical prostatectomy. The primary outcome was pathologic complete response (pCR) or minimal residual disease (MRD). Secondary outcomes included surgical margins, lymph node involvement, pathologic stage, 12-month biochemical relapse-free survival (BRFS) rates, and safety profile. The per-protocol population consisted of 70 patients [cabazitaxel arm (Arm A): 37, no cabazitaxel arm (Arm B): 33]. Median patient age and prostate-specific antigen levels were 63.5 years [interquartile range (IQR), 58.0–68.0] and 21.9 ng/mL (IQR, 14.6–42.8), respectively. pCR/MRD occurred in 16 (43.2%) versus 15 patients (45.5%) in arms A and B, respectively (P = 0.85). pCR occurred in two (5.4%) versus three patients (9.1%) in arms A and B, respectively (P = 0.66). Patients with ≤ 25% total biopsy cores positive had increased odds of pCR/MRD (P = 0.04). Patients with pCR/MRD had superior 12-month BRFS rates (96.0% vs. 62.0%, P = 0.03). Grade 3+ adverse events occurred in 42.5% and 23.7% of patients in arms A and B, respectively (P = 0.078). Neoadjuvant cabazitaxel addition to abiraterone acetate/leuprolide acetate prior to radical prostatectomy did not improve pCR/MRD in clinically localized, high-risk prostate cancer.
Publisher: American Association for Cancer Research (AACR)
Date: 13-10-2023
Publisher: SAGE Publications
Date: 07-2019
Abstract: In epidemiologic studies, patients with head and neck squamous cell carcinoma (HNSCC) are classified mainly by the International Classification of Diseases (ICD) codes. However, some patients are of an unclear subsite, the “gray zone” cases, which could reflect ICD coding error, absence of primary subsite, or extensive primary tumors that cross over multiple subsites of the oral cavity and oropharynx. Patients with gray zone squamous cell carcinomas were compared with patients with oral cavity squamous cell carcinoma (OSCC) or oropharyngeal squamous cell carcinoma (OPSCC) and stratified by human papillomavirus (HPV) status that was determined by p16 immunostaining or HPV serology. Comparisons consisted of clinicodemographic features and prognostic outcomes presented by Kaplan-Meier curves and Cox proportional hazards regression models, reported as hazard ratios. There were 158 consecutive patients with gray zone HNSCC diagnosed at the Princess Margaret Cancer Center between 2006 and 2017: 66 had subsite coding discrepancies against the clinician’s documentation (“discrepant” cases e.g., the diagnosis by the clinician was OSCC, while the classification by ICD coding was OPSCC), while 92 were squamous cell carcinoma of unknown primary of the head and neck (SCCUPHN) after complete diagnostic workup. Comparators included 721 consecutive OSCC and 938 OPSCC adult cases. All HPV-positive cohorts (OPSCC, discrepant, and SCCUPHN) had similar clinicodemographic characteristics and better 3- and 5-y overall survival and disease-free survival than their HPV-negative counterparts. In contrast, HPV-negative discrepant cases had prognostic outcomes most similar to HPV-negative OPSCC cases, while HPV-negative SCCUPHN had survival outcomes most similar to those of patients with OSCC in this study. HPV-positive status can improve the classification of patients with unclear or discrepant oral/oropharyngeal subsite, an improvement over classification systems that are solely clinician defined or conducted through ICD coding. However, due to clinical practice, we could not make definitive reclassification for patients with HPV-negative gray zone HNSCC.
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/1078-0432.22487786.V1
Abstract: Supplementary Figure from A Phase I Study Investigating AZD8186, a Potent and Selective Inhibitor of PI3Kβ/δ, in Patients with Advanced Solid Tumors
Publisher: American Association for Cancer Research (AACR)
Date: 13-10-2023
Publisher: Wiley
Date: 09-02-2017
DOI: 10.1002/CNCR.30579
Abstract: The recommended phase 2 dose (RP2D) of anticancer agents is determined traditionally by dose-limiting toxicities. Nontoxicity or biological endpoints such as pharmacokinetics, pharmacodynamics, and efficacy can also be used to identify RP2D, which may be relevant to molecularly targeted agents (MTAs). A systematic review identified all monotherapy phase 1 studies of MTAs in solid tumors published between 2001 and 2013. Dose, dosing schedule, and determinants of RP2D were collected from each study. A supplementary search of the US Food and Drug Administration (FDA) website identified the licensed dose for drugs with regulatory approval. Logistic regression was used to explore predictors for the RP2D being consistent with the final approved dose. The search identified 4175 records, of which 250 studies evaluating 181 in idual MTAs were included. Of these MTAs, 161 (64%) determined an RP2D. Fifty-two trials (32%), used toxicity alone to specify an RP2D. The remaining trials used a nonclassical approach with either multiple endpoints that included toxicity (n = 87, 54%), multiple nontoxicity endpoints (n = 12, 7%), or a single nontoxicity endpoint (n = 10, 6%). Twenty-nine (16%) MTAs were approved by the FDA for solid tumor indications. The use of nonclassical definitions compared with toxicity alone was significantly associated with higher likelihood of FDA approval (odds ratio, 5.03 95% confidence interval, 1.11-22.73 P = .036). In the past decade, there has been a dominance of a nonclassical approach using multiple endpoints with or without toxicity or single nontoxicity endpoints to define RPTD in MTA monotherapy phase 1 trials. Nonclassically defined RP2Ds for MTAs appear to be associated with a higher rate of FDA drug approval. Cancer 2017 :1409-1415. © 2016 American Cancer Society.
Publisher: American Association for Cancer Research (AACR)
Date: 08-2023
DOI: 10.1158/1078-0432.23815995.V1
Abstract: Supplementary Tables 1-3
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/1078-0432.22487777.V1
Abstract: Supplementary Figure from A Phase I Study Investigating AZD8186, a Potent and Selective Inhibitor of PI3Kβ/δ, in Patients with Advanced Solid Tumors
Publisher: American Association for Cancer Research (AACR)
Date: 13-10-2023
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/1078-0432.22487786
Abstract: Supplementary Figure from A Phase I Study Investigating AZD8186, a Potent and Selective Inhibitor of PI3Kβ/δ, in Patients with Advanced Solid Tumors
Publisher: Elsevier BV
Date: 05-2017
DOI: 10.1016/J.IJROBP.2017.01.018
Abstract: To report the outcome of ipsilateral radiation therapy (RT) in human papillomavirus (HPV)-positive (HPV+) patients and HPV-negative (HPV-) patients with T1-T2N0-N2b tonsillar cancer treated 25 years after our initial historical cohort. Patients with T1-T2N0-N2b tonsillar cancer who received ipsilateral RT or bilateral RT between 1999 and 2014 were reviewed. Overall survival (OS), local control (LC), regional control (RC), and grade 3 to 4 late toxicity (LT) were compared between ipsilateral RT and bilateral RT within HPV+ and HPV- patients, separately. HPV status was ascertained in 379/427 (88%) consecutive patients (ipsilateral RT: 62 HPV+, 34 HPV- bilateral RT: 240 HPV+ 240, 41 HPV-). The proportion of ipsilateral RT by N category for HPV+ and HPV- patients were as follows: N0: 24/37 (65%) versus 28/48 (74%) N1: 21/49 (43%) versus 4/9 (44%) N2a: 10/39 (26%) versus 1/4 (25%) and N2b: 7/177 (4%) versus 1/24 (4%), respectively. Of the patients receiving ipsilateral RT, 94/96 (98%) were treated with RT alone. The median follow-up time was 5.03 years. The respective 5-year rates of OS, LC, RC, and LT were similar between ipsilateral RT and bilateral RT for the HPV+ patients (OS: 89% vs 87%, P=.55 LC: 97% vs 98%, P=.65 RC: 98% vs 97%, P=.27 LT: 17% vs 12%, P=.83) and HPV- patients (OS: 63% vs 48%, P=.27 LC: 90% vs 80%, P=.19 RC: 94% vs 83%, P=.14 LT: 15% vs 22%, P=.36). Of the 96 patients receiving ipsilateral RT, contralateral neck failure (CNF) occurred in 1/52 HPV+ patients and 1/34 HPV- patients. The 5-year CNF rates were 2% (95% CI: 1-9) (HPV+: 2% [0-14] HPV-: 3% [0-21], P=.66). Five local failures (2 HPV+ 3 HPV-) and no distant failures were seen. The 5-year rates of LC, RC, and LT were 97% versus 90% (P=.24), 98% versus 94% (P=.25), and 18% versus 15% (P=.75) for the HPV+ and HPV- cohorts, respectively. Osteoradionecrosis occurred in 9 patients: 6/47 (13%) treated with conventional RT and 3/49 (6%) with intensity modulated RT (P=.32). Ipsilateral radiation to selected patients with T1-T2N0-N2b tonsillar cancer results in equally excellent outcomes regardless of tumor HPV status.
Publisher: Elsevier BV
Date: 03-2017
DOI: 10.1016/J.CTRV.2017.01.003
Abstract: The identification of common molecular aberrations that drive cancer progression has led to targeted therapies that improve treatment efficacy in many tumor types. Epidermal growth factor receptor (EGFR) inhibitors have been used to treat both lung and head and neck cancers with squamous cell histology. These tumors often show high EGFR expression and/or increased gene copy number, but low incidence of the activating kinase domain mutations common to adenocarcinomas of the lung. In this manuscript, we review clinical trial data on EGFR-inhibitors in the treatment of squamous cell carcinoma (SqCC) of the lung and head and neck (SCCHN), including both efficacy and biomarker analyses. Although some efficacy with use of EGFR inhibitors is observed, the level of benefit varies within and across tumor types, and the predictive capacity of high EGFR protein expression and/or gene lification, if any, is limited. Due to the lack of candidate biomarkers that consistently predict response to EGFR-inhibitor therapy across treatment setting and class of agent in SqCC of the lung and SCCHN, we explore the biology, genomics and patterns of response to EGFR-inhibitors to inform identification of potential biomarkers, highlighting several key molecules that have shown promise in preclinical studies and clinical trials across multiple cancer sites.
Publisher: Wiley
Date: 13-06-2020
DOI: 10.1111/BCP.14355
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/1078-0432.22487783
Abstract: Supplementary Figure from A Phase I Study Investigating AZD8186, a Potent and Selective Inhibitor of PI3Kβ/δ, in Patients with Advanced Solid Tumors
Publisher: American Association for Cancer Research (AACR)
Date: 02-10-2023
Publisher: Wiley
Date: 24-08-2021
DOI: 10.1002/CNR2.1528
Abstract: Out‐of‐pocket costs (OOPC) associated with treatment have significant implications on quality of life and survival in cancer patients. Head and neck cancer patients face unique treatment‐related challenges, but to date OOPC have been understudied in this population. This study aims to identify and measure OOPC for patients with head and neck cancer (HNC) in Ontario. HNC patients between 2015 and 2018 at Princess Margaret Cancer Centre in Toronto were recruited. Participants completed OOPC questionnaires and lost income questions during radiation, post‐surgery, and 3, 6, 12, and 24 months after completion of treatment. Associations between OOPC and treatment modality and disease site were tested with multivariable hurdle regression. A total of 1545 questionnaires were completed by 657 patients. Median estimated OOPC for the total duration of treatment for participants undergoing chemoradiation was $1452 [$0–14 616], for surgery with adjuvant radiation or chemoradiation (C/RT) was $1626, for radiation therapy alone was $635, and for surgery alone was $360. The major expenses for participants at the mid‐treatment time‐point was travel (mean $424, standard error of the mean [SEM] $34) and meals, parking, and accommodations (mean $617, SEM $67). In multivariable analysis, chemoradiation, surgery with C/RT, and radiation were associated with significantly higher OOPC than surgery alone during treatment (791% higher, p .001 539% higher, p .001 370% higher, p .001 respectively) among patients with non‐zero OOPC. Participants with non‐zero OOPC in the laryngeal cancer group paid 49% lower OOPC than those with oropharyngeal cancers in adjusted analysis ( p = .025). Patients undergoing treatment for HNC pay significant OOPC. These costs are highest during treatment and gradually decrease over time. OOPC vary by patient demographics, clinical factors, and, in particular, treatment modality.
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/1078-0432.22487031.V1
Abstract: Supplementary Table from A Randomized Phase II Study of MEDI0680 in Combination with Durvalumab versus Nivolumab Monotherapy in Patients with Advanced or Metastatic Clear-cell Renal Cell Carcinoma
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/1078-0432.22487780
Abstract: Supplementary Figure from A Phase I Study Investigating AZD8186, a Potent and Selective Inhibitor of PI3Kβ/δ, in Patients with Advanced Solid Tumors
Publisher: Elsevier BV
Date: 10-2019
DOI: 10.1016/J.ORALONCOLOGY.2019.05.012
Abstract: To evaluate outcomes in oropharyngeal cancer (OPC) patients who did not complete their planned curative radiation therapy (RT). OPC Patients who received less than planned curative RT dose between 2002 and 2016 were identified for analysis. HPV status was assessed. Radiation dose was normalized for fractionation variations using biological effective doses assuming tumor α/β = 10 Gy [BED10]. Outcomes were compared using BED10. Multivariable and univariable analysis identified OS predictors. From a total of 80 patients who did not complete therapy, 64 patients were eligible for analysis. RT incompletion was due to: RT side effects (n = 23), patients' decision (n = 21), disease progression or metastases (n = 3), and other causes (n = 7). Median BED10 (Gy) was 56.2 for the HPV-positive and 58 for the HPV-negative. Three-year OS was 74% vs 13% (p < 0.001) for the HPV-positive (n = 29) and HPV-negative (n = 24), respectively. HPV-positive patients who received BED10 ≥55 had higher OS than those received BED10 <55 (94% vs 47%, p = 0.002) while no difference in OS by BED10 ≥55 vs <55 for the HPV-negative (12 vs 13%, p = NS). HPV-positive status was associated with a higher OS (HR 12.5, 95% CI, 4.54 to 33.3, p < 0.001). A total of 37 patients were available to estimate TD Overall, in patients with incomplete treatment, HPV-positive OPC patients demonstrated a better OS compared to HPV-negative patients. HPV-positive patients who received BED10 ≥55 have higher rates of OS.
Publisher: American Association for Cancer Research (AACR)
Date: 02-10-2023
Publisher: American Association for Cancer Research (AACR)
Date: 13-10-2023
Publisher: American Association for Cancer Research (AACR)
Date: 13-10-2023
Publisher: American Association for Cancer Research (AACR)
Date: 13-10-2023
Publisher: Elsevier BV
Date: 10-2018
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/1078-0432.22487783.V1
Abstract: Supplementary Figure from A Phase I Study Investigating AZD8186, a Potent and Selective Inhibitor of PI3Kβ/δ, in Patients with Advanced Solid Tumors
Publisher: Elsevier BV
Date: 09-2019
DOI: 10.1016/J.CRITREVONC.2019.06.004
Abstract: The human microbiome is an emerging target in cancer development and therapeutics. It may be directly oncogenic, through promotion of mucosal inflammation or systemic dysregulation, or may alter anti-cancer immunity/therapy. Microorganisms within, adjacent to and distant from tumors may affect cancer progression, and interactions and differences between these populations can influence the course of disease. Here we review the microbiome as it pertains to cancer for clinicians. The microbiota of cancers including colorectal, pancreas, breast and prostate are discussed. We examine "omics" technologies, microbiota associated with tumor tissue and tumor-site fluids such as feces and urine, as well as indirect effects of the gut microbiome. We describe roles of the microbiome in immunotherapy, and how it can be modulated to improve cancer therapeutics. While research is still at an early stage, there is potential to exploit the microbiome, as modulation may increase efficacy of treatments, reduce toxicities and prevent carcinogenesis.
Publisher: American Association for Cancer Research (AACR)
Date: 04-05-2022
DOI: 10.1158/1078-0432.CCR-21-4115
Abstract: MEDI0680 is a humanized anti–programmed cell death-1 (PD-1) antibody, and durvalumab is an anti-PD-L1 antibody. Combining treatment using these antibodies may improve efficacy versus blockade of PD-1 alone. This phase II study evaluated antitumor activity and safety of MEDI0680 plus durvalumab versus nivolumab monotherapy in immunotherapy-naïve patients with advanced clear-cell renal cell carcinoma who received at least one prior line of antiangiogenic therapy. Patients received either MEDI0680 (20 mg/kg) with durvalumab (750 mg) or nivolumab (240 mg), all intravenous, every 2 weeks. The primary endpoint was investigator-assessed objective response rate (ORR). Secondary endpoints included best overall response, progression-free survival (PFS), safety, overall survival (OS), and immunogenicity. Exploratory endpoints included changes in circulating tumor DNA (ctDNA), baseline tumor mutational burden, and tumor-infiltrated immune cell profiles. Sixty-three patients were randomized (combination, n = 42 nivolumab, n = 21). ORR was 16.7% [7/42 95% confidence interval (CI), 7.0–31.4] with combination treatment and 23.8% (5/21 95% CI, 8.2–47.2) with nivolumab. Median PFS was 3.6 months in both arms median OS was not reached in either arm. Because of adverse events, 23.8% of patients discontinued MEDI0680 and durvalumab and 14.3% of patients discontinued nivolumab. In the combination arm, reduction in ctDNA fraction was associated with longer PFS. ctDNA mutational analysis did not demonstrate an association with response in either arm. Tumor-infiltrated immune profiles showed an association between immune cell activation and response in the combination arm. MEDI0680 combined with durvalumab was safe and tolerable however, it did not improve efficacy versus nivolumab monotherapy.
Publisher: American Association for Cancer Research (AACR)
Date: 13-10-2023
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/1078-0432.22487777
Abstract: Supplementary Figure from A Phase I Study Investigating AZD8186, a Potent and Selective Inhibitor of PI3Kβ/δ, in Patients with Advanced Solid Tumors
Publisher: Elsevier BV
Date: 11-2019
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/1078-0432.22487774
Abstract: Supplementary Figure from A Phase I Study Investigating AZD8186, a Potent and Selective Inhibitor of PI3Kβ/δ, in Patients with Advanced Solid Tumors
Publisher: American Association for Cancer Research (AACR)
Date: 08-2023
DOI: 10.1158/1078-0432.23815998.V1
Abstract: Supplementary Figure 1: Overall Response Over Time on JNJ-64619178 Treatment A. Dose Cohorts 0.5 mg - 1.5 mg (schedule A& B). B. Dose Cohorts 2.0 mg - 4.0 mg (schedule A& B)
Publisher: Elsevier BV
Date: 08-2018
Abstract: Patients with castration-resistant prostate cancer derive only modest clinical benefit from available therapies. Blockade of the inhibitory programmed death 1 (PD-1) receptor by monoclonal antibodies has been effective in several malignancies. Results from the prostate adenocarcinoma cohort of the nonrandomized phase Ib KEYNOTE-028 trial of pembrolizumab in advanced solid tumors are presented. Key eligibility criteria included advanced prostate adenocarcinoma, unsuccessful standard therapy, measurable disease per Response Evaluation Criteria in Solid Tumors, version 1.1 (RECIST v1.1), and PD-1 ligand (PD-L1) expression in ≥1% of tumor or stromal cells. Patients received pembrolizumab 10 mg/kg every 2 weeks until disease progression or intolerable toxicity for up to 24 months. Primary end point was objective response rate (ORR) per RECIST v1.1 by investigator review. Median patient age in this cohort (n = 23) was 65 years 73.9% of patients received at least two prior therapies for metastatic disease. There were four confirmed partial responses, for an ORR of 17.4% [95% confidence interval (CI) 5.0%-38.8%] 8 of 23 (34.8%) patients had stable disease. Median duration of response was 13.5 months. Median progression-free survival (PFS) and overall survival (OS) were 3.5 and 7.9 months, respectively 6-month PFS and OS rates were 34.8% and 73.4%, respectively. One patient remained on treatment at data cutoff. After a median follow-up of 7.9 months, 14 (60.9%) patients experienced treatment-related adverse events (TRAEs), most commonly nausea (n = 3, 13.0%). Four (17.3%) experienced grade 3/4 TRAEs: grade 3 peripheral neuropathy, grade 3 asthenia, grade 3 fatigue, and grade 4 lipase increase. No pembrolizumab-related deaths or discontinuations occurred. Pembrolizumab resulted in durable objective response in a subset of patients with heavily pretreated, advanced PD-L1-positive prostate cancer, and its side effect profile was favorable. NCT02054806.
Publisher: American Association for Cancer Research (AACR)
Date: 31-08-2017
DOI: 10.1158/1078-0432.CCR-16-3065
Abstract: Immuno-oncology (I-O) has required a shift in the established paradigm of toxicity and response assessment in clinical research. The design and interpretation of cancer clinical trials has been primarily driven by conventional toxicity and efficacy patterns observed with chemotherapy and targeted agents, which are insufficient to fully inform clinical trial design and guide therapeutic decisions in I-O. Responses to immune-targeted agents follow nonlinear dose–response and dose–toxicity kinetics mandating the development of novel response evaluation criteria. Biomarker-driven surrogate endpoints may better capture the mechanism of action and biological response to I-O agents and could be incorporated prospectively in early-phase I-O clinical trials. While overall survival remains the gold standard for evaluation of clinical efficacy of I-O agents in late-phase clinical trials, exploration of potential novel surrogate endpoints such as objective response rate and milestone survival is to be encouraged. Patient-reported outcomes should also be assessed to help redefine endpoints for I-O clinical trials and drive more efficient drug development. This paper discusses endpoints used in I-O trials to date and potential optimal endpoints for future early- and late-phase clinical development of I-O therapies. Clin Cancer Res 23(17) 4959–69. ©2017 AACR. See all articles in this CCR Focus section, “Clinical Trial Design Considerations in the Immuno-oncology Era.”
Publisher: American Society of Clinical Oncology (ASCO)
Date: 08-2019
DOI: 10.1200/JCO.18.01250
Abstract: Active surveillance (AS) for testicular nonseminomatous germ cell tumors (NSGCT) is widely used. Although there is no consensus for optimal treatment at relapse on surveillance, globally patients typically receive chemotherapy. We describe treatment of relapses in our non–risk-adapted NSGCT AS cohort and highlight selective use of primary retroperitoneal lymph node dissection (RPLND). From December 1980 to December 2015, 580 patients with clinical stage I NSGCT were treated with AS, and 162 subsequently relapsed. First-line treatment was based on relapse site and extent. Logistic regression was used to explore factors associated with need for multimodal therapy on AS relapse. Median time to relapse was 7.4 months. The majority of relapses were confined to the retroperitoneum (66%). After relapse, first-line treatment was chemotherapy for 95 (58.6%) and RPLND for 62 (38.3%), and five patients (3.1%) underwent other therapy. In 103 (65.6%), only one modality of treatment was required: chemotherapy only in 58 of 95 (61%) and RPLND only in 45 of 62 (73%). Factors associated with multimodal relapse therapy were larger node size (odds ratio, 2.68 P = .045) in patients undergoing chemotherapy and elevated tumor markers (odds ratio, 6.05 P = .008) in patients undergoing RPLND. When RPLND was performed with normal markers, 82% required no further treatment. Second relapse occurred in 30 of 162 patients (18.5%). With median follow-up of 7.6 years, there were five deaths (3.1% of AS relapses, but 0.8% of whole AS cohort) from NSGCT or treatment complications. The retroperitoneum is the most common site of relapse in clinical stage I NSGCT on AS. Most are cured by single-modality treatment. RPLND should be considered for relapsed patients, especially those with disease limited to the retroperitoneum and normal markers, as an option to avoid chemotherapy.
Publisher: American Association for Cancer Research (AACR)
Date: 02-10-2023
Publisher: BMJ
Date: 12-2019
DOI: 10.1136/BMJOPEN-2019-035431
Abstract: Carcinomas of unknown primary site (CUP) of the head and neck have historically been worked up and managed heterogeneously. Failure to identify a primary site may result in large radiotherapy mucosal volumes. Transoral approaches such as Transoral Robotic Surgery (TORS) may improve the yield of identifying hidden primaries. We aim to assess the oncological and functional outcomes of a combined treatment approach with TORS and tailored radiotherapy. Twenty-five patients with metastatic squamous cell carcinoma to the neck without clinical or radiographic evidence of a primary site will be enrolled in a phase II trial. Patients will undergo a diagnostic or therapeutic approach with TORS based on specific algorithms incorporating tailored radiotherapy according to the location and laterality of the primary tumour. The primary outcome is to evaluate the out-of-field failure rate over a 2-year period. Secondary outcomes include identification rates, survival outcomes, patient reported outcomes and functional swallowing outcomes. The University Health Network Research Ethics Board approved this study (ID 15–9767). The results will be published in an open access journal. NCT03281499 .
Publisher: Elsevier BV
Date: 03-2020
DOI: 10.1016/J.RADONC.2019.10.011
Abstract: This study examines outcome heterogeneity and potential to refine the TNM-8 cN-classification using radiologic extranodal extension (rENE) in a contemporary HPV-positive (HPV+) oropharyngeal carcinoma (OPC) cohort. All HPV+ OPC treated with definitive IMRT from 2010-2015 were included. Pre-treatment CT/MR of cN+ cases were reviewed by a head-neck radiologist for rENE. Overall survival (OS) and disease-free survival (DFS) were compared between rENE-positive (rENE+) vs rENE-negative (rENE-). Multivariable analysis (MVA) for OS confirmed the prognostic value of rENE. Refined cN-classifications for new TNM staging proposals were evaluated against TNM-8 using established criteria. A total of 517 cN+ (rENE+: 97 rENE-: 420) and 41 cN0 cases were identified. The rENE+ proportion increased with rising N-category (N1/N2/N3: 11%/19%/84%, p < 0.001). Median follow-up was 5.1 years. Compared to rENE-, rENE+ patients had a lower 5-year OS (56% vs 85%) and DFS (46% vs 83%) overall, and in N1 (OS: 57% vs 89% DFS: 51% vs 87%) and N2 subsets (OS: 45% and 76% DFS: 33% vs 74%) (all p < 0.001). MVA confirmed the prognostic value of rENE for OS (HR = 3.86, p < 0.001) and DFS (HR = 3.89, p < 0.001). We proposed two new cN-classifications: Schema1 reclassified any N_rENE+ as New_N3 Schema2 reclassified N1_rENE+ as New_N2 and N2_rENE+ as New_N3. Stage incorporating either Schema1 (ranked 1st) or Schema2 (ranked 2nd) cN-categories outperformed TNM-8. This study confirms that rENE is prognostically important and facilitates understanding of known outcome heterogeneity within TNM-8 in HPV+ OPC patients. rENE is a promising parameter to refine the TNM-8 cN-classifications.
Publisher: American Association for Cancer Research (AACR)
Date: 15-09-2023
Publisher: American Association for Cancer Research (AACR)
Date: 14-02-2016
DOI: 10.1158/1078-0432.CCR-15-1506
Abstract: Purpose: The TWEAK–Fn14 pathway represents a novel anticancer target that is being actively investigated. Understanding the relationship between pharmacokinetics of anti-TWEAK therapeutics and tumor pharmacodynamics is critical. We investigated exposure-response relationships of RG7212, an anti-TWEAK mAb, in patients with Fn14-expressing tumors. Experimental Design: Patients with Fn14-positive tumors (IHC≥1+) treated in a phase I first-in-human study with ascending doses of RG7212 were the basis for this analysis. Pharmacokinetics of RG7212 and dynamics of TWEAK were determined, as were changes in tumor TWEAK–Fn14 signaling in paired pre- and posttreatment tumor biopsies. The objectives of the analysis were to define exposure-response relationships and the relationship between pretreatment tumor Fn14 expression and pharmacodynamic effect. Associations between changes in TWEAK–Fn14 signaling and clinical outcome were explored. Results: Thirty-six patients were included in the analysis. RG7212 reduced plasma TWEAK to undetectable levels at all observed RG7212 exposures. In contrast, reductions in tumor Fn14 and TRAF1 protein expression were observed only at higher exposure (≥300 mg*h/mL). Significant reductions in tumor Ki-67 expression and early changes in serum concentrations of CCL-2 and MMP-9 were observed exclusively in patients with higher drug exposure who had high pretreatment tumor Fn14 expression. Pretreatment tumor Fn14 expression was not associated with outcome, but a trend toward longer time on study was observed with high versus low RG7212 exposure. Conclusions: RG7212 reduced tumor TWEAK–Fn14 signaling in a systemic exposure-dependent manner. In addition to higher exposure, relatively high Fn14 expression might be required for pharmacodynamic effect of anti-TWEAK monoclonal antibodies. Clin Cancer Res 22(4) 858–67. ©2015 AACR.
No related grants have been discovered for Aaron Hansen.