Abstract OT2-08-01: A phase 1b trial to evaluate safety and anti-tumor activity of the AKT inhibitor, ipatasertib, in combination with endocrine therapy with/without CDK 4/6 inhibitor for patients with hormone receptor positive (HR+)/HER2 negative metastatic breast cancer (MBC) (TAKTIC)
Authors: Wander Seth A. , Juric Dejan , Spring Laura M. , Vidula Neelima , Beeler Maureen , Habin Karleen , Viscosi Elene , Scarpetti Lauren , Tripp Elizabeth , Hepp Rachel , Moy Beverly , Isakoff Steven J. , Ellisen Leif W. , Bardia Aditya 
Published: March 2020

Abstract
Background: The cyclin-dependent 4/6 inhibitors (CDK4/6i), in combination with an anti-estrogen, have emerged as the standard of care for patients with HR+/HER2- MBC. While only limited insight exists into the molecular factors that drive progression, emerging evidence suggests that activation of AKT1 may provoke resistance in a subset of patients. Overexpression of AKT1 also conveys resistance in HR+/HER2- breast cancer cells in vitro. AKT1 plays a well-established role in promoting tumor progression and metastasis. Targeting AKT1 following progression on CDK4/6i may provide durable clinical benefit in HR+/HER2- MBC.
Trial Design: This is an open-label phase Ib trial with three arms - Arm A includes fulvestrant + ipatasertib and Arm B includes an aromatase inhibitor (AI) + ipatasertib. Arm C includes fulvestrant + ipatasertib + palbociclib. Arm A and B are dose-expansion cohorts while Arm C is a dose-escalation (standard 3+3 design) followed by subsequent dose-expansion.
Eligibility Criteria: Key inclusion criteria include the presence of locally advanced/unresectable and metastatic HR+/HER2- breast cancer; postmenopausal status or pre/peri-menopausal status s/p oophrectomy or GNRH agonist; at least one prior therapy for MBC including any CDK4/6i; adequate performance status (ECOG 0-2); and adequate bone marrow and hepatic function. Stable CNS metastatic disease and up to two prior lines of chemotherapy for MBC are allowed (no limit on number of prior lines of endocrine therapy). Key exclusion criteria include prior use of fulvestrant (for Arm A); any prior intolerable toxicity with CDK4/6i (for Arm C); prior exposure to an AKT inhibitor in any setting; active CNS disease; concurrent use of specific CYP3A4 inhibitors or inducers; poorly controlled intercurrent illness; and pregnancy or active child-bearing potential.
Specific Aims: The primary objective of this study is to evaluate the safety and tolerability of ipatasertib in combination with endocrine therapy (aromatase inhibitor or fulvestrant) with or without CDK4/6i in patients with HR+/HER2- MBC who have received prior CDK 4/6i. Secondary objectives include assessment of objective response rate (ORR), clinical benefit rate (CBR), and progression free survival (PFS). Exploratory objectives include next generation sequencing of solid tumor biopsies and cfDNA along with immunohistochemical analysis of tumor biopsies to identify genomic and protein-based predictors of response and resistance.
Statistical Methods: Arms A and B constitute dose-expansion cohorts to confirm the safety/tolerability of ipatasertib use with anti-estrogens and evaluate preliminary efficacy. A dose-limiting toxicity (DLT) rate of &lt;33% will constitute success for future doublet development. There will be an initial enrollment phase (n=6); if ≤ 2 DLTs occur, total enrollment will be pursued (n=15 for each arm). Arm C is a standard 3+3 phase I trial design to establish a recommended phase II dose (RP2D) and maximum tolerated dose (MTD). Once the doses are established, an expansion cohort will be pursued (n=15) to confirm safety of the triplet and evaluate preliminary evidence of efficacy.
Present and Target Accrual: Anticipated accrual for Arms A+B will be n=15 (each). Arm C enrollment will be n=15-30 pending establishment of RP2D/MTD prior to dose expansion. Current enrollment n=4, since study activation in May 2019.
Citation Format: Seth A. Wander, Dejan Juric, Laura M. Spring, Neelima Vidula, Maureen Beeler, Karleen Habin, Elene Viscosi, Lauren Scarpetti, Elizabeth Tripp, Rachel Hepp, Beverly Moy, Steven J. Isakoff, Leif W. Ellisen, Aditya Bardia. A phase 1b trial to evaluate safety and anti-tumor activity of the AKT inhibitor, ipatasertib, in combination with endocrine therapy with/without CDK 4/6 inhibitor for patients with hormone receptor positive (HR+)/HER2 negative metastatic breast cancer (MBC) (TAKTIC) [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 OT2-08-01.