Abstract OT-27-01: PALVEN: A phase 1b study of palbociclib, letrozole and venetoclax in estrogen receptor, BCL2-positive metastatic breast cancer

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 >2 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;81(4 Suppl):Abstract nr OT-27-01.