A Phase I study of the dual, intravenous (IV) phosphatidylinositol 3-kinase (PI3K)/mammalian target of rapamycin (mTOR) inhibitor PF-05212384 in combination with irinotecan in patients (pts) with colorectal cancer (CRC) and other advanced solid tumors

Background: Signaling through the PI3K-AKT-mTOR pathway plays an important role in cell survival, proliferation, and metabolism. In preclinical studies, combining the PI3K/mTOR inhibitor PF-05212384 (PF-384) with irinotecan demonstrated enhanced anti-tumor activity, suggesting a potential benefit from this combination in cancer pts. Patients and Methods: Adult pts with advanced solid tumors were enrolled in the dose-escalation part (stage 1 [S1], based on a standard 3+3 design) in arm C of a multi-arm Phase I study or in an expansion cohort (stage 2 [S2]). In arm C, pts received biweekly irinotecan 180 mg/m2 in combination with IV PF-384 administered at 95, 110, or 130 mg on days 2, 9, 16, and 23 of each 28-day cycle. Study endpoints included safety, antitumor activity, pharmacokinetics (PK), and pharmacodynamic (PD) effects on circulating biomarkers. Results: In arm C, 13 pts were enrolled in S1 and 27 pts in S2. Median age was 64 yrs (range 43-77) and 57 yrs (range 33-78), respectively. CRC was the most frequent diagnosis. S2 included CRC pts with disease progression on irinotecan-based regimens (n = 17) and pancreatic cancer (PC) pts who progressed on front-line therapy (n = 10). Two patients, receiving PF-384 130 mg plus irinotecan, experienced DLTs: grade 4 (G4) febrile neutropenia and G3 fatigue (n = 1 each). Median duration of treatment was 7.3 (PF-384 95 mg), 9.9 (110 mg), and 19.3 (130 mg) weeks in S1, and 7.4 weeks in S2 (110 mg). Treatment-related adverse events (AEs) were mostly G1 or G2 in severity; the most frequent were nausea and diarrhea. G3/G4 AEs noted in S2 included G3 asthenia, hyperglycemia, and leukopenia (3.7% each); G3 (14.8%) and G4 (11.1%) neutropenia. No treatment-related deaths were reported in S1 or S2. In S1 (n = 13), 1/10 pts with CRC had a partial response, 6 pts (4/10 with CRC, 2/2 with PC) had stable disease (SD). In S2 (n = 27), 13 pts had SD (9/17 with CRC, 4/10 with PC). In S1, 2/6 pts with mt-KRAS CRC and 1/2 pts with wt-KRAS CRC had SD. In S2, 3/4 pts with mt-KRAS CRC and 4/11 pts with wt-KRAS CRC had SD. Conclusions: Treatment with weekly IV PF-384 in combination with irinotecan waswell tolerated and demonstrated antitumor activity in patients with advanced, irinotecan-refractory, mt- and wt-KRAS CRC or with advanced, pretreated PC. The MTD for this combination was determined to be PF-384 110 mg. The most relevant AEs were fatigue and gastrointestinal AEs. Updated safety, antitumor activity, PK, and PD results will be presented. Randomized trials with irinotecan and PF-384 are ongoing in pts with mCRC.