Abstract OT-35-01: Solti-1507 A phase ib study of ipatasertib and anti-her2 therapy in her2-positive advanced breast cancer with pik3ca mutation (ipather)
Authors: Oliveira Mafalda , Villagrasa Patricia , Ciruelos Eva , Gavilá Joaquín , Cortegoso Alexandra , Henao Fernando , Vega Estela , Bofill Javier S. , Quiroga Vanesa , García-Estevez Laura , Morales Serafín , Tolosa Pablo , Céliz Pamela , Farré Xavier Gonzalez , Saura Cristina 
Published: February 2021

Background The combination of trastuzumab, pertuzumab (HP) and a taxane increases progression-free survival (PFS) and overall survival (OS) in patients with HER2-positive (HER2+) advanced breast cancer (BC). PIK3CA mutations can occur in 30-35% of HER2+ tumors, independently of hormone receptor (HR) status. In an exploratory analysis from CLEOPATRA, patients with a tumor harboring a PIK3CA mutation (mut) had a shorter PFS. The AKT inhibitor ipatasertib (IPAT) blocks the PI3K/AKT pathway and has activity in PI3K/AKT-altered tumors. We hypothesize that ipatasertib + HP is safe and can be beneficial in patients with PIK3CAmut HER2+ BC. Trial design This is an open-label, single arm, phase Ib study to evaluate the safety and preliminary efficacy of IPAT plus HP (+/- endocrine therapy [ET]) in patients with PIK3CA mut HER2+ BC. Key inclusion criteria include the presence of locally advanced/unresectable or metastatic HER2+ BC with a PIK3CA mut (detected in tissue or plasma ctDNA); candidates to receive maintenance HP (+/- ET) after taxane discontinuation in first line setting for a reason different to progressive disease; male and female (pre and postmenopausal status); adequate performance status (ECOG 0-1); and adequate bone marrow, cardiac and hepatic function. Key exclusion criteria include: active or progressive brain metastases; diabetes mellitus requiring insulin, and prior exposure to an AKT inhibitor. The primary endpoint is to define the maximum tolerated dose (MTD) and the recommended phase 2 dose of the combination. MTD is defined as the highest dose level at which ≤1 of 6 subjects experience a dose-limiting toxicity (DLT) during the first 28 days of treatment. Grade ≥3 diarrhea for more than 72 hours or Grade ≥2 diarrhea for more than 5 days are considered DLTs amongst others. Secondary endpoints include objective response rate, duration of response, clinical benefit rate and PFS. Exploratory objectives include identification of molecular biomarkers of response to treatment both in ctDNA (Amplicon-seq) and tumor tissue (Breast Cancer 360 panel), as well as to characterize the pharmacokinetics of study drugs. Given the low risk for overlapping toxicities, full doses of IPAT (400mg orally once daily D1-21 q28d) and standard dose HP will be used in the first cohort. Dose reductions of IPAT (300mg and 200mg) are allowed if the full dose exceeds MTD. Loperamide is given as prophylaxis for diarrhea. In HR-positive tumors, ET may be started after the DLT period. Approximately 25 evaluable patients in a given dose level will be required to assess the safety of the combination of IPAT plus HP. Patients are currently being screened for PIK3CA mutations at 7 sites in Spain. The first patient was enrolled in March 2020 and the recruitment is ongoing. This study is sponsored by SOLTI and financially supported by Roche. For further information on this trial, visit ClinicalTrials.gov (NCT04253561)

Citation Format: Mafalda Oliveira, Patricia Villagrasa, Eva Ciruelos, Joaquín Gavilá, Alexandra Cortegoso, Fernando Henao, Estela Vega, Javier S. Bofill, Vanesa Quiroga, Laura García-Estevez, Serafín Morales, Pablo Tolosa, Pamela Céliz, Xavier Gonzalez Farré, Cristina Saura. Solti-1507 A phase ib study of ipatasertib and anti-her2 therapy in her2-positive advanced breast cancer with pik3ca mutation (ipather) [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-35-01.