ATREUS Trial: A Phase II Study On The Activity Of Trabectedin In Pretreated Epithelioid Or Biphasic/Sarcomatoid Malignant Pleural Mesothelioma (MPM)

Abstract

Background: Treatment options for patients (pts) with relapsing MPM are scarce. Moreover, the sarcomatoid and biphasic histotypes are generally resistant to treatment and outcome is poor. A viable regimen for 1st and 2nd line treatments is an unmet medical need. Trabectedin (T) is a natural marine compound that binds to the minor groove of DNA. It acts both directly on cancer cells and on tumor microenvironment, reducing the production of cytokines and chemokines and the number of tumor-associated macrophages. These features suggest a therapeutic potential for inflammation-related tumors, such as MPM. This study evaluates the activity and safety of T in pts with MPM. Methods: ATREUS is an Italian multicenter single arm phase II not for profit trial of T as 2nd line treatment in pts with epithelioid MPM and as 1st or 2nd line in sarco/ biphasic pts. The study aims to assess T's activity (in terms of progression free survival at 12 weeks (12w-PFS)) and its safety. The effect on several biological features of MPM, including miR profile, HMGB1 levels and monocyte/macrophage number and function, and on cancer related pain are also evaluated. Eligible pts receive T (1.3 mg/m 2 over 3 hours) every 21 days until progression or unacceptable toxicity. Treatment response is evaluated every 6 weeks using the Modified RECIST for MPM. Simon's optimal two-stage design was used for the epithelioid cohort. The first stage foresaw enrolment of 24 pts, and accrual extension in case of >6 responses. In the second stage, 12w-PFS should be observed in >19 of 62 pts to reject, with a one-sided alpha error of 10%, the null hypothesis that 12w-PFS is ≤25% and an 85% power to show a 12w-PFS of ≥40%. In the sarcomatoid/biphasic cohort, adopting the Fleming design with A'Hern's approach, >5 of 17 pts should report PFS ≥12w to reject, with a one-sided alpha error of 10%, the null hypothesis that 12w-PFS is ≤15% and to have 85% power to show 12w-PFS in ≥40% pts. To date, 64 patients were enrolled (41 epithelioid and 23 sarco/biphasic). Analysis of the first 24 epithelioid pts confirmed achievement of the first stage activity goal and enrolment continues. The sarcomatoid/biphasic cohort has completed accrual. ClinicalTrials.gov Identifier: NCT02194231).