Phase 1 combination therapy with pexidartinib (PEX) and sirolimus (S) to target tumor-associated macrophages in pigmented villonodular synovitis, malignant peripheral nerve sheath tumors, and other soft tissue sarcomas.

Abstract

11055 Background: No effective therapy exists for unresectable malignant peripheral nerve sheath tumors (MPNSTs). We previously reported that the combination of PEX and the mTOR inhibitor S synergistically inhibited MPNST growth (CCR 20: 3146, 2014) by depleting M2 TAMs and by inhibiting receptor tyrosine kinases (RTKs), including c-KIT, PDGFR, CSF1R. We characterized the safety, tolerability, recommended phase 2 dose (RP2D) of PEX plus S in all sarcoma sub-types. Methods: Patients (pts) received PEX plus S orally in 28 days cycle as per Table. The RP2D was determined using the time-to-event continual reassessment method (TITE-CRM) in advanced sarcoma who have progressed on standard therapy. DLT was defined as any need for a dose reduction. Results: 24 pts were accrued (Acr) of which 18 were evaluable (MPNST – 6, pigmented villonodular synovitis (PVNS) – 3, leiomyosarcoma – 5, and other – 9). The mean age was 46y, 56% were male, and 67% had greater than 2 prior therapies. Most common ( > 20%) grade 2 or higher TEAEs were anemia (33%), WBC count decrease (28%), fatigue, neutropenia, and lymphopenia (22% each). There were 5 dose limiting toxicities (DLT): 2 for elevated LFTs both of which resolved with dose reduction, 2 for supra-therapeutic S trough levels, and 1 for grade 5 dehydration at dose level (DL) 3. Four subjects experienced a partial response (PR; -44% to -77% by RECIST, 18 – 61 wks on therapy). Seven subjects experienced stable disease (SD; +19.7% to -20.7% by RECIST; 9.4 – 30 wks on therapy). Five subjects progressed on therapy and two subjects experienced early DLTs and did not undergo tumor assessment. The RP2D is DL 3 (S 2mg/PEX 1000mg) with an estimated probability of DLT of 26.7% as determined by TITE-CRM. This recommendation is based on a target DLT rate of 25%. TAMs and immune subtypes from available tissue specimens and historical controls will be presented. Conclusions: 1000mg of PEX in combination with 2mg of S daily has an acceptable safety profile. Objective responses and durable SD was observed in PNVS and MPNST patients justifying proceeding with a multi-center single arm phase 2 study in advanced MPNST. Clinical trial information: NCT02584647. [Table: see text]