A phase I/II study of safety/efficacy using lurbinectedin, combined with ipilimumab, and nivolumab, for advanced soft tissue sarcomas (NCT05876715).

TPS11599 Background: Soft tissue sarcoma (STS) cells exhibit heightened immunogenicity during the early stages of the disease. Therefore, immunotherapies such as ipilimumab (ipi) and nivolumab (nivo), which enhance sustained T-cell activation by suppressing regulatory T cells, are potentially more effective when administered as first-line therapy in combination with lurbinectedin—a synthetic analog of the marine alkaloid trabectedin—that not only induces apoptosis in cancer cells and exposes tumor neoantigens for immune recognition but also depletes tumor-associated macrophages, thereby restoring immune surveillance and potentially enhancing the efficacy of immunotherapy. Methods: This Phase I/II open-label single-site study will evaluate the safety and efficacy of lurbinectedin in combination with ipi and nivo in patients with advanced STS. Phase I patients will be previously treated, whereas phase II patients will be untreated. Objectives: Primary: Evaluate MTD of lurbinectedin in combination with fixed doses of ipi and nivo. Secondary: Evaluate objective response rate by RECIST v1.1 via CT/MRI/PET q 6w until end of treatment (EOT); determine progression-free survival (PFS); determine overall survival (OS). Exploratory: correlate response with amount of ctDNA via Signatera testing q 6w until EOT. Schedule: IV lurbinectedin q 3w (Phase I: escalating doses as per standard “cohort of three” design, 2.6 - 3.2mg/m2, Phase 2: determined MTD), IV ipi 1 mg/kg q 12w, and IV nivo 3 mg/kg q 2w. Participants may continue treatment until significant disease progression or unacceptable toxicity occurs. Key Criteria: Inclusion: pathologic diagnosis of locally advanced unresectable or metastatic STS; measurable disease by RECIST v1.1; ECOG ≤ 1; life expectancy of ≥ 3 months; acceptable hematological status and liver/renal function. Exclusion: untreated CNS metastases; radiation therapy, targeted therapy, other antitumor treatment, or investigational drug or device study, within 2 weeks prior to study entry; chemotherapy within 21 days prior to study entry; prior exposure to anti-CTLA4 or anti-PD-1 inhibitors; pregnancy or breastfeeding; autoimmune disease, carcinomatous meningitis, systemic immunosuppression, skin rash affecting > 25% of body surface area, or inflammatory bowel disease. Analysis: The Intention-To-Treat population (all patients who received at least one dose of study drug) will be used for OS analysis and adverse event analysis. The Modified Intention-To-Treat population (patients who completed the first two 3-week cycles and follow-up imaging) will be used for analysis of PFS. PFS and OS will be estimated by Kaplan Meir method with two-sided 95% confidence interval. Status: This study has enrolled 40 patients. Clinical trial information: NCT05876715 .