Background: The PI3K signaling pathway regulates proliferation, differentiation, and cell death in human cancers. ZSTK474 is a novel and selective pan-Class I PI3K inhibitor that has demonstrated antitumor activity against a broad range of tumors in preclinical models.

Methods: This was an open label, serial cohort, 3 + 3 dose escalation study to determine the safety, tolerability, pharmacokinetics (PK) and the maximal tolerated dose and/or recommended Phase II dose (MTD/RP2D) in patients with advanced solid malignancies. ZSTK474 was administered orally once daily in 28-day cycles (21 daily doses followed by 7 days off). PK sampling was performed on Days 1, 8, 15, and 21 of Cycle 1.

Results: Twenty-four patients were treated with daily doses of 75, 125, 150, or 175 mg/day (n=3, 3, 10, 8 patients at each dose level respectively) during the dose-finding phase of the study. Once the tentative MTD was identified as 150 mg/day, an additional fifteen patients were treated at that dose to obtain additional safety, PK, and biomarker data in this expanded MTD cohort. For all subjects, median age was 57.0 years (range 22-82). Tumor types included 8 colorectal, 8 gynecological, 5 non-small cell lung (NSCLC), 4 soft tissue sarcoma, 3 anal, 2 pancreatic, 2 cholangio and 7 others. Drug-related adverse events (AEs) occurring in more than 2 patients were diarrhea (46%), nausea (23%), vomiting (18%), anorexia (13%), fatigue (10%), rash (10%), fever (8%), dizziness (5%), hypokalemia (5%), and elevated aspartate aminotransferase (5%). The majority of AEs were mild to moderate (Grade 1/2) and responsive to appropriate supportive medication. Grade 3 diarrhea was observed as a dose-limiting toxicity (DLT) in two of six evaluable patients at 175 mg/day and three of twenty-one evaluable patients at 150 mg/day; thus 150 mg/day was defined as the MTD/RP2D of ZSTK474. There was a tendency for plasma ZSTK474 levels to show higher AUC (0-24) and Cmax on Day 21 compared to Day 1 in several subjects; three active metabolites were also detected in patients’ plasma. There were no partial or complete responses; however, nine patients had stable disease lasting for >8 weeks, and four of those nine patients had stable disease lasting for >16 weeks (1 NSCLC, 1 anal, and 2 soft tissue sarcoma).

Conclusions: The MTD/RP2D of ZSTK474 was 150 mg/day. The most prominent AE at this dose, diarrhea, was controlled with anti-motility agents. Other PI3K inhibition class-like side effects have been manageable. Prolonged stable disease was observed in some subjects.

Citation Information: Mol Cancer Ther 2013;12(11 Suppl):B271.

Citation Format: Albert C. Lockhart, Anthony J. Olszanski, Robin L. Allgren, Shinichi Yaguchi, Steven J. Cohen, John F. Hilton, Andrea Wang-Gillam, Geoffrey I. Shapiro. A first-in-human Phase I study of ZSTK474, an oral pan-PI3K inhibitor, in patients with advanced solid malignancies. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr B271.