Columbia University Medical Center - New York Presbyterian Hospital, New York, NY
Gulam Abbas Manji , Parag Patwardhan , Shing Mirn Lee , Nanette Matos , Edward Bentlyewski , Brian Andrew Van Tine , Khanh Tu Do , Suzanne George , Gary K. Schwartz
Background: Malignant peripheral nerve sheath tumors (MPNSTs) are generally resistant to chemotherapy. Receptor tyrosine kinases (RTKs) play a role in MPNST growth and include c-KIT, PDGFR, and CSF1R, all of which are inhibited by pexidartinib (PLX3397, PEX). We reported that the combination of PEX and the mTOR inhibitor sirolimus (S) synergistically inhibited MPNST growth (Patwardhan P. et al CCR 20: 3146, 2014). Inhibiting CSF1R resulted in a marked depletion of tumor-associated macrophages (TAMs) in MPNST xenografts and a shift from M2 (tumor promoting) to M1 (tumor inhibiting) TAMs within tumors. This effect on TAMs was enhanced and sustained by mTOR inhibition with S. Therefore, this drug combination, by potently blocking RTKs and by altering tumor macrophage infiltration, represents a novel drug combination. The goal of this first-in-man trial is to prove safety and test efficacy of PEX and S in sarcomas and MPNST. Methods: This is an open label, multicenter, investigator-initiated study testing PEX in combination with S in patients with advanced sarcomas (phase 1, N = 24) and MPNST (phase 2, N = 25). The primary objective of the phase 1 component is to determine the safety, tolerability, and the recommended phase 2 dose (RP2D) using the time-to-event continual reassessment method. The phase 1 component enrolls patients with sarcoma who have progressed on standard of care therapy or for whom no standard treatment exists. The primary outcome for phase 2 is progression free survival (PFS). Assuming a median PFS of 6 weeks in patients treated with standard of care, we have 90% power to detect a difference of 12 weeks in median PFS given a 2-sided test with an alpha of 0.05. Secondary objectives include response rate and overall survival. Patients enrolled to the phase 2 component will undergo mandatory biopsies at baseline and at end of cycle 1 and an optional biopsy on progression. Exploratory studies include analysis of RTK activity and assessment of TAMs within the tumor samples. This trial has started in December 2015 and has enrolled 4 patients to the phase Ib (2 PVNS, 1 MPNST, and 1 Epithelioid sarcoma) as of January 2016. Clinical trial information: NCT02584647
Disclaimer
This material on this page is ©2024 American Society of Clinical Oncology, all rights reserved. Licensing available upon request. For more information, please contact licensing@asco.org
Abstract Disclosures
2019 ASCO Annual Meeting
First Author: Gulam Abbas Manji
2023 ASCO Annual Meeting
First Author: Neeta Somaiah
2024 ASCO Genitourinary Cancers Symposium
First Author: Christos Kyriakopoulos
2023 ASCO Gastrointestinal Cancers Symposium
First Author: Jessica Dreger McDermott