This Phase 1/2 clinical study assessed ontorpacept (TTI-621), a recombinant signal regulatory protein alpha (SIRPα)–blocking fusion protein that antagonises CD47–SIRPα signalling, combined with doxorubicin for patients with unresectable or metastatic high-grade leiomyosarcoma. Preclinical rationale for ontorpacept is based on disrupting CD47-mediated “don’t eat me” signals to enhance antitumour activity. The study represents the first clinical evaluation of CD47 pathway inhibition combined with chemotherapy in leiomyosarcoma.
The trial comprised a Phase 1 dose-escalation portion followed by a Phase 2 dose-expansion cohort restricted to high-grade leiomyosarcoma. Eligible participants were adults (≥18 years) with metastatic or locally advanced high-grade soft-tissue sarcomas; Phase 2 enrolled patients specifically with high-grade leiomyosarcoma. Overall enrollment included 76 patients: nine in Phase 1 and 67 in Phase 2.
Phase 1 used escalating doses of ontorpacept given in combination with standard doxorubicin to assess tolerability and identify suitable doses for expansion. The Phase 2 expansion evaluated ontorpacept at three dose levels—0.2, 1.0, and 2.0 mg/kg—each administered with doxorubicin. The publication provides an illustration of study design and dose cohorts (Fig. 1 in the source). Details beyond the reported dose levels and combination with doxorubicin were not reported in the source abstract.
Primary endpoints differed by phase: safety was the primary endpoint in Phase 1, while objective response rate (ORR) served as the primary endpoint across Phase 1/2. Safety assessments included monitoring for dose-limiting toxicities (DLTs) and treatment-related adverse events (TRAEs). Tumour responses were assessed and confirmed per the study’s defined criteria; the abstract reports confirmed partial responses (PRs) observed in both phases.
No DLTs occurred during the Phase 1 dose-escalation portion. The most commonly reported treatment-related adverse events were decreases in neutrophil count and neutropenia; grade ≥3 neutropenia was reported in 66% of patients. The source abstract highlights neutropenia as the predominant high-grade toxicity but does not provide a comprehensive adverse-event table or additional frequency data within the abstract text. Cardiotoxicity risks associated with doxorubicin are noted in the reference list but specific cardiac adverse events in this study were not detailed in the abstract.
Overall, the study reported confirmed partial responses in both phases. In Phase 1, one patient treated at the ontorpacept 2.0 mg/kg dose experienced a confirmed PR. In Phase 2 dose-expansion cohorts, six patients receiving ontorpacept 0.2 mg/kg had confirmed PRs, yielding an ORR of 18.8% (95% CI, 7.2–36.4) for that cohort. One patient receiving ontorpacept 2.0 mg/kg in Phase 2 had a confirmed PR, yielding an ORR of 4.5% (95% CI, 0.1–22.8) for that cohort. The abstract does not report median progression-free survival, overall survival, duration of response, or response data for the 1.0 mg/kg cohort in the abstract text.
The article includes biomarker analyses and figures summarising those data (Fig. 3 in the source). The abstract notes that biomarker evaluation was performed but does not report biomarker results or their association with response in the abstract. Specific biomarker findings and their potential predictive value were not detailed in the provided source excerpt.
Authors conclude that combining CD47 pathway inhibition with chemotherapy in patients with leiomyosarcoma demonstrated a manageable safety profile, with neutropenia as the most frequent high-grade toxicity. The observed partial responses—particularly in the 0.2 mg/kg expansion cohort—support further investigation of ontorpacept dosing and scheduling, both in combination with doxorubicin and as monotherapy. The study represents an initial clinical signal for targeting the CD47–SIRPα axis in leiomyosarcoma, warranting additional trials to refine dose, schedule, and patient selection.
The publication states that, upon request and subject to review, Pfizer will provide the data supporting the study findings. Access to related individual de-identified participant data may be available under certain criteria, conditions and exceptions. The source directs interested parties to Pfizer’s clinical trial data and results page for more information on requesting data.