Abstract
BACKGROUND: Nab-sirolimus (ABI-009, nab-rapamycin; Aadi Bioscience Inc. [Aadi]) is a human albumin-bound form of sirolimus nanoparticles, a potent mTOR inhibitor. This phase I trial was conducted to define dose-limiting toxicities (DLT), maximum tolerated or recommended phase II dose (MTD/RP2D), and pharmacokinetics of Nab-sirolimus in combination with temozolomide and irinotecan. METHODS: Using a rolling 6 design, Nab-sirolimus was administered intravenously (IV) on days (D) 1 and 8 of cycle (C) 1. In subsequent cycles, Nab-sirolimus was administered D1 and D8 in combination with temozolomide (125 mg/m(2)/dose, maximum 250 mg/dose) and irinotecan (90 mg/m(2)/dose) orally, daily on D1-5. Cycle duration was 21 days. Three dose levels (DL) of Nab-sirolimus were investigated (DL1: 35 mg/m(2)/dose, DL-1: 20 mg/m(2)/dose, and DL-2: 15 mg/m(2)/dose). The observation period for estimating the MTD/RP2D was defined by cycles 1 and 2. RESULTS: Thirty-three patients were enrolled, 32 were eligible. Dose determination included 17 evaluable patients, median (range) age 12 (2-20) years and six additional patients were enrolled (four evaluable for toxicity) on a pharmacokinetic cohort. C1 or C2 DLTs were primarily thrombocytopenia including 2/5 patients at DL1, 2/6 patients at DL-1, and 1/6 patients at DL-2. One patient (DL1) with Ewing Sarcoma had a partial response and remained on study for 35 cycles. Rapamycin clearance was dose dependent. Irinotecan clearance and its active metabolite SN-38 exposure were not affected by coadministration with Nab-sirolimus. CONCLUSION: The MTD for Nab-sirolimus was 15 mg/m(2)/dose IV on D1 and D8 in combination with temozolomide 125 mg/m(2)/dose and oral irinotecan 90 mg/m(2)/dose daily for 5 days during 21D cycles. TRIAL REGISTRATION: ClinicalTrials.gov identifier NCT02975882.