Abstract OT1-01-06: PIQHASSO: Open label, non-randomized, multicenter phase 1/2b study investigating safety and efficacy of PQR309 and eribulin combination in patients (pts) with locally advanced (LA) or metastatic HER2 (-) and triple-negative breast cancer (TNBC) (study PQR309-007)

BACKGROUND: The PI3K/AKT/mTOR (PAT) pathway alteration has been strongly implicated in breast cancer and may contribute to resistance to available therapy. PQR309 is an oral pan-PI3K and mTOR inhibitor that penetrates the blood-brain barrier. Experiments of eribulin in combination with PI3K inhibitors in luminal and TNBC pre-clinical models enhanced antitumor activity. TRIAL OBJECTIVES: The primary objectives of the study are: to identify the maximum tolerated dose (MTD), evaluate the efficacy, safety and tolerability as well as the pharmacokinetics (PK) of PQR309 in combination with eribulin. In addition, exploratory objectives include assessments of: PAT pathway alterations prior to treatment, pharmacodynamics (PD) activity of PQR309 in combination with eribulin and correlation of PAT pathway alterations and PD activity with PQR309 and eribulin PK. TRIAL DESIGN: This is an open label, non-randomized, multicenter phase 1/2b clinical trial (dose escalation followed by expansion part) of PQR309 p.o. in combination with the standard dose of eribulin mesylate (1.4 mg/m2) in patients with LAMBC until progression or unacceptable adverse events (AE). The dose escalation part of the study will first investigate PQR309 administered in a continuous daily (q.d.) and two intermittent treatment schedules in combination with standard administration of eribulin mesylate in patients with HER2 negative LAMBC following the “modified” 3 by 3 design. MTD is defined as the highest dose level at which ≤1 of 6 pts experiences dose-limiting toxicity (DLT) during the 1st cycle. After the MTD of PQR309 in combination with eribulin has been defined in all the three treatment schedules, one schedule will be selected, based on the overall evaluation of clinical data from the dose escalation part of the study, for further evaluation of efficacy in the expansion part of the study. The expansion part of the trial applies Simon9s MiniMax two-stage design. At the first stage, > 3 pts with TNBC with clinical benefit (CB) among 14 pts will be necessary to continue to the second stage. At the study end, > 9 pts with CB out of 28 pts are required to reject the null hypothesis. With this design, there is an 80% probability of a positive finding if the true clinical benefit rate (CBR) is ≥ 43% and a 5% probability of a positive finding if the true CBR is ≤ 21%. ELIGIBILITY: Women with HER2- LAMBC with two to 5 prior chemotherapy regimens in advanced disease. Adequate organ function and performance status. Phase II specific selection criteria are: triple negative LAMBC and RECIST v1.1 evaluable disease. ACCRUAL: Approximately 60 patients will be enrolled in approximately 10 sites Recruitment opened in March 2016. TRIAL REGISTRATION: NCT02723877. Date of registration: 21/12/2015. First patient included: 04/04/2016. Citation Format: Lopez-Miranda E, Gavila J, Pernas S, Saura C, Oliveira M, Serra V, Schmid P, Lord S, Paez D, Perez J, Llombart A, Petrovic K, Dimitrijevic S, Cortes J. PIQHASSO: Open label, non-randomized, multicenter phase 1/2b study investigating safety and efficacy of PQR309 and eribulin combination in patients (pts) with locally advanced (LA) or metastatic HER2 (-) and triple-negative breast cancer (TNBC) (study PQR309-007) [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr OT1-01-06.