A Phase 1/2 study of ontorpacept (TTI-621) in combination with doxorubicin in patients with unresectable or metastatic high-grade leiomyosarcoma

BACKGROUND: Ontorpacept, a recombinant signal regulatory protein alpha (SIRPα)-blocking fusion protein, has antitumour activity by disrupting CD47-SIRPα signalling. This Phase 1/2 study examined ontorpacept with doxorubicin in patients with leiomyosarcoma. METHODS: Eligible patients were ≥18 years with metastatic or locally advanced high-grade soft-tissue sarcomas (high-grade leiomyosarcoma in Phase 2). In Phase 1, patients received escalating doses of ontorpacept plus doxorubicin. Phase 2 dose expansion evaluated ontorpacept doses 0.2, 1.0, and 2.0 mg/kg plus doxorubicin. The primary endpoints were safety (Phase 1); and objective response rate (ORR) (Phase 1/2). RESULTS: Seventy-six patients were enrolled (Phase 1, n = 9; Phase 2, n = 67). No dose-limiting toxicities occurred in Phase 1. The most common treatment-related adverse events were neutrophil count decreased/neutropenia (grade ≥3 in 66% of patients). In Phase 1, one patient receiving ontorpacept 2.0 mg/kg had a confirmed partial response. In Phase 2, six patients receiving ontorpacept 0.2 mg/kg (ORR, 18.8%; 95% CI, 7.2-36.4) and one patient receiving 2.0 mg/kg (ORR, 4.5%; 95% CI, 0.1-22.8) had confirmed partial responses. CONCLUSIONS: This first study of CD47 inhibition with chemotherapy in leiomyosarcomas shows manageable safety, supporting further investigation of ontorpacept dosing and schedule, in combination with doxorubicin and as monotherapy.