ORCID Profile
0000-0002-4955-7745
Current Organisations
University of Melbourne
,
Peter MacCallum Cancer Centre
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Publisher: American Association for Cancer Research (AACR)
Date: 15-02-2021
DOI: 10.1158/1538-7445.SABCS20-OT-27-01
Abstract: Background: CDK4/6 inhibitors are integral to the treatment of Estrogen Receptor (ER) positive metastatic breast cancer (MBC). Although they are potent inhibitors of proliferation, tumor cell death (by apoptosis) may be curtailed. Venetoclax, an inhibitor of the pro-survival protein BCL2, has shown promise in an early phase clinical trial in ER+ MBC1. Moreover, preclinical studies suggest that venetoclax could improve tumor response to endocrine therapy and a CDK4/6 inhibitor by triggering apoptosis, including in growth arrested/senescent cells2. PALVEN is a phase 1b study (NCT NCT03900884), aiming to combine venetoclax with letrozole and the CDK4/6 inhibitor palbociclib. Trial Design: Eligible patients will be treated with letrozole (2.5 mg), palbociclib (75-125 mg) and venetoclax (100-800 mg) using a 3+3 dose escalation study design, with a maximum of 6 patients per dose cohort. Both palbociclib and venetoclax will be administered on day 1-21 of a 28 day cycle. Dose limiting toxicity (DLT) will be evaluated in the first 4 weeks of treatment. Tumor assessment will be performed every 8 weeks for 24 weeks and then every 12 weeks until progression. The primary endpoint is to describe DLTs reported within the first 4 weeks of treatment and determine the maximum tolerated dose (MTD), in order to define a recommended phase 2 dose (RP2D). Secondary endpoints include type and worst grade adverse events per patient (CTCAE v5.0), tumor response (RECIST v1.1), clinical benefit rate (CBR), progression free and overall survival (PFS, OS) as well as patient reported outcomes. Exploratory endpoints include metabolic response (using FDG-PET), changes in circulating tumor DNA (ctDNA), peripheral blood leukocyte subsets, and tumor phenotype in paired and progression biopsies. Eligibility Women with ER+ (≥10% positively stained carcinoma cells) and BCL2+ (≥50% cells with at least moderate cytoplasmic staining intensity 2-3 on a 0-3 scale), unresectable locally advanced or MBC are eligible. Patients must have measurable or evaluable disease as per RECIST v1.1 and ECOG performance score of 0-1. Participants must not have had & prior lines of treatment in the metastatic setting and no previous treatment with CDK4/6 inhibitor or venetoclax in the adjuvant or metastatic setting. Statistical methods This is a proof-of-concept, dose escalation study and any statistical analysis of responses will be exploratory. Analysis will be focused primarily on adverse events, particularly DLTs reported in the DLT observation period. All secondary endpoints will be analysed separately combining all dosing cohorts. The response rate and CBR will be estimated with 95% confidence intervals calculated using exact methods based on the binomial distribution. Time-to-event endpoints (PFS and OS) will be described using Kaplan-Meier methods to calculate the median survival. Response rate, CBR and time-to-event endpoints (PFS and OS) will also be described for patients treated in the 1st versus 2nd and 3rd line setting. Accrual Target accrual is 6-36, depending on the number of dose cohorts required to reach DLT. Recruitment is active at 2 sites in Australia. References 1 Lok, S.W., et al. (2019). Cancer Discov 9, 354-369. 2 Whittle, J.R., et al. (2020). Clin Cancer Res Advance online. Citation Format: Christine Muttiah, Avraham Travers, James R Whittle, Sarah-Jane Dawson, Belinda Yeo, Jane E Visvader, Catherine Oakman, Geoffrey J Lindeman. PALVEN: A phase 1b study of palbociclib, letrozole and venetoclax in estrogen receptor, BCL2-positive metastatic breast cancer [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium 2020 Dec 8-11 San Antonio, TX. Philadelphia (PA): AACR Cancer Res 2021 (4 Suppl):Abstract nr OT-27-01.
Publisher: Wiley
Date: 05-2021
DOI: 10.1111/IMJ.15217
Abstract: The COVID‐19 pandemic has challenged cancer care globally, introducing resource limitations and competing risks into clinical practice. To describe the COVID‐19 impact on medical oncology care provision in an Australian setting. Calvary Mater Newcastle and Newcastle Private Hospital medical oncology data from 1 February to 31 April 2019 versus 2020 were retrospectively analysed. Three hundred and sixty‐four inpatient admissions occurred in 2020, 21% less than in 2019. Total inpatient days decreased by 22% (2842 vs 2203). April was most impacted (36% and 44% fewer admissions and inpatient days respectively). Mean length of stay remained unchanged (6.4 vs 6.2 days, P = 0.7). In all, 5072 outpatient consultations were conducted, including 417 new‐patient consultations (4% and 6% increase on 2019 respectively). Telephone consultations (0 vs 1380) replaced one‐quarter of face‐to‐face consultations (4859 vs 3623, −25%), with minimal telehealth use (6 vs 69). Day Treatment Centre encounters remained stable (3751 vs 3444, −8%). The proportion of new patients planned for palliative treatment decreased (35% vs 28%, P = 0.04), observation increased (16% vs 23%, P = 0.04) and curative intent treatment was unchanged (both 41%). Recruiting clinical trials decreased by one‐third (45 vs 30), two trials were activated (vs 5 in 2019) and 45% fewer patients consented to trial participation (62 vs 34). Our medical oncology teams adapted rapidly to COVID‐19 with significant changes to care provision, including fewer hospital admissions, a notable transition to telephone‐based outpatient clinics and reduced clinical trial activity. The continuum of care was largely defended despite pandemic considerations and growing service volumes.
Publisher: Elsevier BV
Date: 03-2021
DOI: 10.1016/J.CLCC.2020.08.002
Abstract: The management of metastatic colorectal cancer patients with a poor performance status (PS) continues to be a clinical dilemma, with the potential activity and safety of treating this population remaining poorly understood. Few of these patients are enrolled onto clinical trials, and poor PS is often multifactorial. We analyzed the Treatment of Recurrent and Advanced Colorectal Cancer registry to describe treatment practices and outcomes in poor (Eastern Cooperative Oncology Group [ECOG] PS 2) and very poor PS (ECOG PS > 2) patients to explore the relationship between age, tumor burden, comorbidities, and PS, and to evaluate the benefit of systemic therapy. Standard descriptive statistical methods, Kaplan-Meier analysis, and a multivariate Cox regression model were used. Of 2769 registry patients (diagnosed January 2009 to June 2018), 329 (12%) and 182 (7%) patients had a poor and very poor PS, respectively. Good PS patients were more likely to receive systemic therapy than poor and very poor PS patients (85%, 55%, and 21.5%, P < .0001), but clinician assessed response was observed in all subsets (53%, 41%, and 29%, P = .0003). Treatment with chemotherapy was associated with longer median overall survival across PS groups. Exploratory analysis based on comorbidity score and tumor burden subgroups demonstrated a consistently positive overall survival association with treatment. Benefit was observed where poor overall survival was attributable to medical comorbidities and to tumor burden. In routine clinical care, a substantial proportion of poor and very poor PS patients receive active treatment, which is often associated with meaningful clinical benefit.
Publisher: American Association for Cancer Research (AACR)
Date: 03-2019
DOI: 10.1158/2159-8290.CD-18-1151
Abstract: In the first clinical study to evaluate venetoclax in a solid tumor, we demonstrate that combining venetoclax with endocrine therapy has a tolerable safety profile and elicits notable activity in ER and BCL2-positive metastatic breast cancer. These findings support further investigation of combination therapy for patients with BCL2-positive tumors. See related commentary by Drago et al., p. 323. This article is highlighted in the In This Issue feature, p. 305
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 09-2022
Start Date: 2022
End Date: End date not available
Funder: National Health and Medical Research Council
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