A Phase II Multi-Center Trial of Trabectedin in Combination with Olaparib in Patients with Advanced Unresectable or Metastatic Sarcoma.

Objective: Soft tissue sarcoma (STS) are rare malignancies with poor prognosis and limited systemic treatment options. We conducted a phase II study to assess the efficacy and safety of trabectedin and olaparib in patients with advanced disease.

Methods: Patients with STS who received ≥ 1 prior therapy were recruited into two cohorts. Cohort 1 included leiomyosarcoma and liposarcoma; Cohort 2 included other histologies. All patients received trabectedin (1.1 mg/m2 24-hour infusion every 21 days) and olaparib (150 mg BID continuously). The study was conducted using a Simon Minimax two-stage design with a primary endpoint of objective response rate per RECIST 1.1.

Results: Twenty-nine patients enrolled (Cohort 1:16, Cohort 2:13); one patient in Cohort 2 was not evaluable. There were no confirmed objective responses in Cohort 1; best response was stable disease in 12 patients (75%) and progressive disease in 4 (25%). Two partial responses were observed in Cohort 2 (n=12). The most common adverse events were fatigue (75%), neutropenia (75%), anemia (68%), and thrombocytopenia (68%). Median progression free survival and overall survival for all patients was 3.5 (95% CI 3.3-8.2) and 13.2 months (95% CI 10.3-20.9), respectively. Next generation sequencing of 17 tumors revealed multiple abnormalities, most commonly in TP53, RB1, and ATRX.

Conclusions: Trabectedin plus olaparib conferred high rates of toxicity and failed to demonstrate objective responses in leiomyosarcoma and liposarcoma. Preliminary evidence of clinical benefit in two patients in cohort 2 suggests potential value of either or both drugs in other sarcomas.