A Phase 1 Study of ABI-009 (Nab-sirolimus) in Combination With Temozolomide and Irinotecan in Pediatric Patients With Recurrent or Refractory Solid Tumors, Including CNS Tumors-A Children's Oncology Group Pediatric Early Phase Clinical Trial Network Study ADVL1514

Authors

Stuart L Cramer
Alyssa Terry Reddy
Charles Gene Minard
Stephan Voss
Elizabeth Fox
Xiaowei Liu
Kristina Denic
Joel M Reid
Brenda J Weigel

Publication Date

11-1-2024

Journal

Cancer Medicine

DOI

10.1002/cam4.70376

PMID

39487711

PMCID

PMC11533328

PubMedCentral® Posted Date

11-2-2024

PubMedCentral® Full Text Version

Post-Print

Published Open-Access

no

Keywords

Humans, Irinotecan, Temozolomide, Male, Antineoplastic Combined Chemotherapy Protocols, Child, Female, Adolescent, Child, Preschool, Sirolimus, Maximum Tolerated Dose, Central Nervous System Neoplasms, Neoplasms, Young Adult, Neoplasm Recurrence, Local, Treatment Outcome, ABI‐009, Clinical trial, nab‐rapamycin, Pediatrics, rapamycin

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

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/m2/dose IV on D1 and D8 in combination with temozolomide 125 mg/m2/dose and oral irinotecan 90 mg/m2/dose daily for 5 days during 21D cycles.

Comments

ClinicalTrials.gov identifier NCT02975882