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A Phase II Multicenter Trial of Trabectedin in Combination with Olaparib in Patients with Advanced Unresectable or
Brittany L Siontis1, John D Rice2, Scott M Schuetze3
1Division of Medical Oncology, Mayo Clinic, Rochester, Minnesota.
Purpose:
Soft-tissue sarcomas 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.
Patients And Methods:
Patients with soft-tissue sarcoma 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 twice daily continuously). The study was conducted using a Simon minimax two-stage design with a primary endpoint of objective response (OR) rate per RECIST 1.1.
Results:
Twenty-nine (cohort 1, 16; cohort 2, 13) patients enrolled; one patient in cohort 2 was not evaluable. There were no confirmed ORs in cohort 1; the best response was stable disease in 12 (75%) patients and progressive disease in four (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%). The median progression-free survival and overall survival for all patients were 3.5 (95% confidence interval, 3.3-8.2) and 13.2 months (95% confidence interval, 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 ORs 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.
Insights
Trabectedin plus olaparib showed significant toxicity and no response in soft tissue sarcoma (STS) subtypes leiomyosarcoma and liposarcoma. However, it demonstrated potential benefit in other STS types, warranting further investigation.
Area of Science:
- Oncology
- Medical Oncology
- Sarcoma Research
Background:
- Soft tissue sarcomas (STS) are rare cancers with limited treatment options.
- Trabectedin and olaparib are systemic agents with potential activity in STS.
Purpose of the Study:
- To evaluate the efficacy and safety of combining trabectedin and olaparib in advanced STS.
- To assess response rates in specific STS subtypes: leiomyosarcoma/liposarcoma (Cohort 1) and other histologies (Cohort 2).
Main Methods:
- A Phase II study using a Simon Minimax two-stage design.
- 29 patients with advanced STS received trabectedin (1.1 mg/m2 IV infusion q21 days) and olaparib (150 mg BID continuous).
- Primary endpoint was objective response rate (ORR) per RECIST 1.1.
Main Results:
- No objective responses were observed in Cohort 1 (leiomyosarcoma/liposarcoma); 75% had stable disease.
- Two partial responses (16.7%) were noted in Cohort 2 (other histologies).
- Common toxicities included fatigue, neutropenia, anemia, and thrombocytopenia. Median progression-free survival was 3.5 months.
Conclusions:
- Trabectedin plus olaparib demonstrated high toxicity without efficacy in leiomyosarcoma and liposarcoma.
- Preliminary efficacy in other STS subtypes suggests potential value for these agents in specific sarcoma contexts.
- Further research is needed to explore the role of trabectedin and olaparib in non-liposarcoma/leiomyosarcoma STS.
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