A Phase I Study of the Combination of Pexidartinib and Sirolimus to Target Tumor-Associated Macrophages in Unresectable Sarcoma and Malignant Peripheral Nerve Sheath Tumors.

Abstract

PURPOSE:

To evaluate the safety and tolerability in phase I first-in-human combination therapy with pexidartinib, an inhibitor of colony-stimulating factor-1 receptor, and sirolimus, an mTOR inhibitor, to target tumor-associated macrophage (TAM) polarization in soft tissue sarcomas (STS).

PATIENTS AND METHODS:

This multicenter phase I study used the time-to-event continual reassessment method (TITE-CRM) to study the combination of sirolimus, doses ranging from 2 to 6 mg, with pexidartinib, doses ranging from 600 to 1,000 mg, both provided continuously on a 28-day cycle, in patients with advanced sarcoma. A total of 24 patients [8 malignant peripheral nerve sheath tumor, 3 tenosynovial giant cell tumor (TGCT), 5 leiomyosarcoma, and 8 with other sarcoma subtypes] were enrolled. The median age was 46 years, 56% were male, and 61% had >2 prior lines of therapy.

RESULTS:

The recommended phase II dose was 2 mg of sirolimus combined with 1,000 mg of pexidartinib daily. Of the 18 evaluable subjects, 5 experienced dose-limiting toxicities (2 elevated aspartate aminotransferase/alanine aminotransferase, 2 elevated sirolimus trough levels, and 1 grade 5 dehydration). Most common grade 2 or higher treatment-related adverse events included anemia, fatigue, neutropenia, and lymphopenia. Clinical benefit was observed in 12 of 18 (67%) evaluable subjects with 3 partial responses (all in TGCT) and 9 stable disease. Tissue staining indicated a decreased proportion of activated M2 macrophages within tumor samples with treatment.

CONCLUSIONS:

Pexidartinib can be safely administered with sirolimus. These findings support further investigation of this combination to determine clinical efficacy. Clinicaltrials.gov identifier NCT02584647.

• Authors: Gulam A Manji, Brian A Van Tine, Shing M Lee, Alexander G Raufi, Ilenia Pellicciotta, Angela C Hirbe, Jaya Pradhan, Andrew Chen, Raul Rabadan, Gary K Schwartz
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 27 Issue 20 Pg. 5519-5527 (10 15 2021) ISSN: 1557-3265 [Electronic] United States
• PMID: 34321280 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S., Comment)
• Copyright: ©2021 The Authors; Published by the American Association for Cancer Research.

Chemical References

• Aminopyridines
• Pyrroles
• pexidartinib
• Sirolimus

Topics

• Aminopyridines
• Humans
• Male
• Middle Aged
• Neurofibrosarcoma
• Pyrroles
• Sarcoma (drug therapy)
• Sirolimus (adverse effects)
• Tumor-Associated Macrophages