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.

©2021 The Authors; Published by the American Association for Cancer Research.

Figures

Figure 1.

TITE-CRM and antitumor activity. A, TITE-CRM was used to estimate the RP2D with the probability of DLT of 0.25. Treatment was initiated at dose level 2. Total daily doses of sirolimus (S) and pexidartinib (P) are indicated on the y-axis in milligrams. Evaluable (blue circle) and nonevaluable patients (gray circle) enrolled sequentially are depicted. Patients who experienced a DLT are depicted separately at the time of the event (red circle). B, Maximal change of tumor size from baseline assessed by an independent radiologist per RECIST version 1.1 (N = 16). Percent change from baseline represents the maximal decrease or minimal increase in target lesion(s). C, Change in individual tumor burden over time from baseline as assessed by RECIST 1.1 (N = 16). D, Exposure and duration of response per RECIST 1.1 (N = 16). Patients with reduction of target lesion(s) of greater than 30% ( ), or those between 30% reduction and 20% increase ( ), or those with equal or greater than 20% ( ) are depicted. DL, dose level.

Figure 2.

PFS and overall survival. Kaplan–Meier curves by RECIST version 1.1 for PFS and overall survival of 18 evaluable patients with advanced sarcoma who were previously treated (A and B); 9 patients at dose level 3 (C and D); and 5 patients with MPNST treated at dose level 3 (E and F). Probability of survival is shown at indicated time points and number of patients at risk at indicated time points are shown below the x-axis. NC, noncalculable.

Figure 3.

Activated M2 macrophages in tumor tissue. Treatment with pexidartinib and sirolimus resulted in a decrease in both CD206 expressing cells and CD206 and HLA-DR coexpressing cells. A, Pretreatment (top row) and on-treatment (bottom row) sections obtained from a patient with TGCT stained with H&E (left column), antisera against CD206 (middle column), and qmIF staining of both CD206 and HLA-DR (right column), with pexidartinib plus sirolimus. B, Scoring of pre- and on-treatment tumor tissue from a patient with TGCT for CD206 and HLA-DR using inForm (Perkin-Elmer) scoring of CD206 (red) and HLA-DR (green). C, Graphs depict non-statistically significant trends in total and activated macrophages (left column) and total and activated M2 macrophages (right column).