Abstract OT-24-01: Phase I study combining ipatasertib with chemotherapy and atezolizumab in patients with metastatic triple negative breast cancer
Authors: Yuan Yuan , Yost Susan E. , Lee Jin Sun , Frankel Paul H. , Ruel Christopher , Murga Mireya , Tang Aileen , Martinez Norma , Waisman James , Patel Niki , Sedrak Mina , Stewart Daphne , Lavasani Sayeh , Mortimer Joanne 
Published: February 2021

Abstract
Background: The PI3K-ATK pathway is one of the most common cancer drivers in breast cancer, and the AKT inhibitor ipatasertib (ipat) has shown great efficacy in patients (pts) with metastatic triple negative breast cancer (mTNBC). The current phase I trial is designed to test the safety and efficacy of the following ipat combinations: ipat + carboplatin (C) + paclitaxel (T); ipat + C; ipat + capecitabine (cape) + atezolizumab (atezo). Trial Design: This is a Phase I open-label study for pts with mTNBC. Eligible pts receive one of three regimens: A) weekly carbo AUC 2 plus taxol 80 mg/m2 days 1, 8, 15 and daily ipat 300 mg every 28 days; B) weekly carbo AUC 2, days 1, 8, 15 and daily ipat 400 mg every 28 days; C) cape 750 mg bid 1 week on 1 week off, ipat 300 mg daily and atezo 840 mg iv days 1, 15 every 28 days. Eligibility Criteria: Eligible patients must have histologically confirmed mTNBC (ER/PR ≤ 10%, HER2- per ASCO/CAP); RECIST 1.1 measurable disease; 0-2 lines of chemotherapy prior for mTNBC; AEs recovered to ≤ Gr 2 per CTCAE 5.0; adequate bone marrow, hepatic and renal function. Prior exposure to AKT targeted therapy is excluded.Specific Aims: Primary objectives are to evaluate the safety and tolerability of the combinations and determine the recommended Phase II dose (RP2D) of the combinations. Secondary objectives are to evaluate response rate, clinical benefit rate, progression free survival, and overall survival. Statistical Design: For the safety-lead in, a “3 at risk design” will be utilized to assess toxicity for the combination therapy. The DLT period is 1-cycle (28 days). Each participant will remain on the dosing level according to the escalation dose level they were enrolled in, and intra-dose level escalations will not be allowed, even if the MTD is defined at a higher dose level. Rules for escalation are as follows: if escalating from Level 1, two dose levels will be open, Level 2A, and Level 2B. Only if both 2A and 2B result in a decision to escalate will dose level 3 for this triplet be open. When both 2A and 2B are both open, slots will be given to the arm with the most open slots (starting with 2A if there are ties). When a maximum tolerable dose level has been defined by the dose escalation portion of the study, and the recommended phase 2 dose (RP2D not to exceed the MTD) has been selected, additional patients will be accrued to confirm the tolerability of the regimen. For Arm C, at least 12 patients will be treated at the RP2D to confirm tolerability. Additional patients can be accrued if the total number of patients accrued does not exceed 21 patients (e.g. if the RP2D is dose level 1, with 2A and 2B not well-tolerated based on 3 patients on each 2A and 2B, the total at RP2D could be 15). If one agent is discontinued due to toxicity, then the participant may continue to receive the remaining single agent or doublet agent therapy on protocol. With 12 patients, any specific severe toxicity with 20% incidence will be observed with 93% probability.
Citation Format: Yuan Yuan, Susan E. Yost, Jin Sun Lee, Paul H. Frankel, Christopher Ruel, Mireya Murga, Aileen Tang, Norma Martinez, James Waisman, Niki Patel, Mina Sedrak, Daphne Stewart, Sayeh Lavasani, Joanne Mortimer. Phase I study combining ipatasertib with chemotherapy and atezolizumab in patients with metastatic triple negative 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-24-01.