Abstract OT2-06-02: Phase 2 trial with safety-run in of gedatolisib plus talazoparib in advanced triple negative or BRCA1/2 positive HER2 negative breast cancer
Authors: Phadke Sneha , Yu Menggang , Miller Kathy , Shah Ami , Danciu Oana , Wisinski Kari 
Published: March 2020

Abstract
Background: Advanced triple negative breast cancer (TNBC) has a poor prognosis, with a median survival of approximately 12 months. Due to a lack of receptor targets, chemotherapy remains the mainstay of treatment. A subset of TNBC has defects in homologous recombination (HR) DNA repair due to germline BRCA mutations. Poly(ADP-ribose) polymerase (PARP) inhibitors have been shown to be an effective therapy in this subgroup. The phosphoinositide-3-kinase (PI3K) pathway inhibitors are also active in some breast cancers, lowering nucleotide pools required for DNA synthesis and S-phase progression. Preclinical studies suggest that PI3K stabilizes and preserves double strand break repair by interacting with the HR complex. Inhibition of PI3K/mTOR could impede PI3K interaction with the HR complex, thereby increasing dependency on PARP enzymes for DNA repair, and making this dual inhibition a rational combination. This trial is studying the safety and efficacy of combining the PI3K/mTOR inhibitor, gedatolisib, and the PARP inhibitor, talazoparib. Single-agent talazoparib is currently approved in advanced HER2 negative breast cancer with a germline BRCA 1/2 mutation. Trial design: This trial is designed with a safety run-in to determine the recommended phase 2 doses (RP2D) of the talazoparib and gedatolisib combination. The safety run-in will be followed by a phase II single-arm study of the combination, with 2 patient cohorts. Cohort A will be comprised of patients with advanced TNBC with negative or unknown germline BRCA1/2 status. Cohort B will be used for an exploratory analysis, comprised of patients with advanced HER2 negative breast cancer and a germline BRCA1/2 mutation. Eligibility Criteria: For the safety run-in phase, patients ≥18 of age with advanced breast cancer (defined as metastatic or unresectable) are eligible if they meet criteria for either cohort A or cohort B. For cohort A, all patients are required to have at least one line of prior systemic therapy for advanced breast cancer but no more than 2 lines of prior chemotherapy are allowed. For cohort B, no more than 2 lines of prior chemotherapy are allowed, with no limit on prior endocrine or targeted therapies. Patients with type I or poorly controlled diabetes are excluded due to the common side effect of hyperglycemia with gedatolisib.
Specific aims: Primary objective of the safety run-in: Determine the RP2D of talazoparib in combination with gedatolisib in patients with advanced HER2 negative (triple negative or BRCA1/2 deficient) breast cancer. Primary objective of the phase II study: Estimate the objective response rate (ORR) in patients with BRCA1/2 negative, or unknown, advanced TNBC - Cohort A. Correlative analysis will include correlating the HR deficiency (HRD) score with clinical response in patients with TNBC. Statistical Methods: In the safety run-in, a 3+3 design will be used for dose escalation. Maximum tolerated dose (MTD) is decided when 6 patients are treated at a dose level with &lt; 2 DLTs. The MTD will be the RP2D. The safety run-in (dose escalation) component will require 9-18 subjects. In the Phase II study, the primary endpoint for sample size justification is ORR for cohort A (TNBC). The null response rate of 5% will be compared to the alternative hypothesis of 20% ORR with a 1-sided alpha level of 0.1. Based on the exact binomial test, we propose 21 subjects to target a power level of 80%. ORR in cohort B is a secondary endpoint. Target Accrual: Our target accrual for the safety run-in is 9-18 participants. Assuming 10% of subjects will be not be evaluable for the primary outcomes, then the number of patients accrued to cohort A will be 24. Cohort B will remain at 12 since it is exploratory. Contact information: The study is being administered through the Big Ten Cancer Research Consortium and can be identified as BTCRC-BRE18-337.
Citation Format: Sneha Phadke, Menggang Yu, Kathy Miller, Ami Shah, Oana Danciu, Kari Wisinski. Phase 2 trial with safety-run in of gedatolisib plus talazoparib in advanced triple negative or BRCA1/2 positive HER2 negative breast cancer [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr OT2-06-02.