Abstract 568P
Background
Inhibition of the PI3K pathway may overcome resistance to chemotherapy. The PI3K/mTORC1/2 dual inhibitor Gedatolisib (G) has an acceptable safety profile as single agent. This phase I study aimed to define safety, recommended phase II dose (RP2D), pharmacokinetics and preliminary activity of G in combination with C and weekly P.
Methods
Adult pts with selected advanced solid tumours previously treated with 0-2 lines of palliative chemotherapy were eligible. G was administered intravenously on days (d) 1, 8, 15 and 22 at increasing doses (95, 110 and 130 mg/m2) following a 3+3 design. C was initially administered at AUC5 on d8 and P at 80 mg/m2 on d8, 15 and 22 and after a protocol amendment on d1 and d1, 8 and 15 respectively, in 28d cycles. Pts responding or on stable disease (SD) after cycle 6 continued on weekly G maintenance.
Results
Seventeen pts were enrolled (11 ovarian [10 clear cell, 1 low grade serous], 4 high grade endometrial and 2 non small cell lung cancer). Median number of previous therapies was 1 (range 0-2); 8 pts were chemotherapy naïve. Median age was 52 (range 34-71). Four pts were treated at G 95 mg/m2, 8 at 110 mg/m2 and 5 at 130 mg/m2. Median number of administered cycles was 6 (range 2-16). Dose limiting toxicities (DLT) occurred in 4/16 evaluable pts: 2 (delay in starting cycle 2 due to G2 and G3 neutropenia) at 110 mg/m2 (initial schedule), 2 at 130 mg/m2 (G2 and G3 mucositis) and no DLT at 110 mg/m2 at amended schedule. G >3 treatment-emergent adverse events were neutropenia (6 pts), anemia (3 pts), mucositis (2 pts) and fatigue, nausea, peripheral neuropathy, thrombocytopenia, hypokalemia, hypomagnesemia, infective colitis and aortic intramural hematoma (one pt each). All pts were evaluable for response: 11/17 (65%) achieved an objective response (8 partial and 3 complete) and 3 SD (17%). Among clear cell ovarian cancer (CCOC) pts, 8/10 had an objective response.
Conclusions
G has a tolerable safety profile when combined with C and weekly P. The RP2D is G 110 mg/m2 on d1, 8, 15 and 22 with C AUC 5 on d1 and P 80 mg/m2 on d1, 8 and 15 in 28d cycles. Preliminary antitumor activity was observed especially in the CCOC pts.
Clinical trial identification
NCT02069158.
Editorial acknowledgement
Legal entity responsible for the study
Oncology Institute of Southern Switzerland (IOSI).
Funding
Pfizer.
Disclosure
I. Colombo: Travel/Accommodation/Expenses: Tesaro. A. Stathis: Research grant/Funding (institution), Institutional funding for clinical trial serving as PI: Roche; Research grant/Funding (institution), Institutional funding for clinical trial serving as PI: Pfizer; Research grant/Funding (institution), Institutional funding for clinical trial serving as PI: Merck; Research grant/Funding (institution), Institutional funding for clinical trial serving as PI: Bayer; Research grant/Funding (institution), Institutional funding for clinical trial serving as PI: Novartis; Research grant/Funding (institution), Institutional funding for clinical trial serving as PI: MEI-Pharma; Research grant/Funding (institution), Institutional funding for clinical trial serving as PI: ADC Therapeutics; Research grant/Funding (institution), Institutional funding for clinical trial serving as PI: Cellestia; Travel/Accommodation/Expenses: PharMar; Travel/Accommodation/Expenses: AbbVie. All other authors have declared no conflicts of interest.