Phase I study of intravenous PI3K inhibitor BAY 80-6946: Activity in patients (pts) with advanced solid tumors and non-Hodgkin lymphoma treated in MTD expansion cohorts.

Abstract

3019 Background: BAY 80-6946 (BAY) is a potent and highly selective reversible pan-Class I PI3K inhibitor, previously reported to be tolerated as a 1-hr infusion at a dose of 0.8 mg/kg on days 1, 8 and 15 every 28 days (MTD). Additional pts were treated in MTD expansion cohorts to assess safety, PK, biomarkers and clinical benefit in selected tumor types, as well as safety in Type 2 diabetics. Methods: To date, 23 nondiabetic pts with solid tumors and 5 with follicular lymphoma (FL) received BAY at the MTD, until disease progression or unacceptable toxicity. Tumor types were selected for high frequency of PIK3CA mutation, including breast cancer (BC; 16), endometrial (3), gastric (2), GU transitional cell (1) and ovarian clear cell (1). Partial enrichment for PIK3CA mutation was achieved by analysis of plasma DNA. 3 diabetic pts have been enrolled, at starting dose of 0.4 mg/kg. PK was done after the 1st and 3rd doses. FDG-PET/CT scans were done at baseline and 48 hrs after the 1st dose for pharmacodynamic assessment. Results: Safety and tolerability assessments confirmed MTD. There were no 1st cycle DLTs. Almost all nondiabetic pts had acute Grade 2/3 hyperglycemia (HG) following each dose; at least 10 of them received insulin for 1-3 days post dose. Hypertension (HTN) lasting < 24 hrs was common in pts with preexisting HTN, and manageable. 2 FL pts developed interstitial pneumonitis (IP) after cycles 2 and 3, both responsive to steroids. Diabetic pts tolerated 0.4 mg/kg. Tumor SUVmax consistently fell at 48 hrs. 3 of 4 FL pts had partial response (PR) after 2 cycles, with 2 confirmed PR pts on BAY for 10+ and 8+ mos. 2 BC pts showed PR , 1 confirmed. PIK3CA mutation (n=7) does not appear to correlate with response. Average T1/2 was 36 hrs. Observation of high Cmax in very obese pts led to recommended maximum dose of 65 mg. Conclusions: BAY induced PRs in pts with BC and FL. The acute toxicities of HG in most pts and HTN in some are manageable, and IP has been limited to 2 lymphoma pts and is responsive to steroids. The observed clinical activity of BAY, along with its acceptable safety profile, provide a rationale for the ongoing development of BAY in combination with cytotoxic and targeted agents.