Assessment of Safety and Efficacy of Combined Trabectedin and Low-Dose Radiotherapy for Patients With Metastatic Soft-Tissue Sarcomas: A Nonrandomized Phase 1/2 Clinical Trial

Abstract

Importance: Active therapeutic combinations, such as trabectedin and radiotherapy, offer potentially higher dimensional response in second-line treatment of advanced soft-tissue sarcomas. Dimensional response can be relevant both for symptom relief and for survival.

Objective: To assess the combined use of trabectedin and radiotherapy in treating patients with progressing metastatic soft-tissue sarcomas.

Design, setting, and participants: Phase 1 of this nonrandomized clinical trial followed the classic 3 + 3 design, with planned radiotherapy at a fixed dose of 30 Gy (3 Gy/d for 10 days) and infusion of trabectedin at 1.3 mg/m2 as the starting dose, 1.5 mg/m2 as dose level +1, and 1.1 mg/m2 as dose level -1. Phase 2 followed the Simon optimal 2-stage design. Allowing for type I and II errors of 10%, treatment success was defined as an overall response rate of 35%. This study was conducted in 9 sarcoma referral centers in Spain, France, and Italy from April 13, 2015, to November 20, 2018. Adult patients with progressing metastatic soft-tissue sarcoma and having undergone at least 1 previous line of systemic therapy were enrolled. In phase 2, patients fitting inclusion criteria and receiving at least 1 cycle of trabectedin and the radiotherapy regimen constituted the per-protocol population; those receiving at least 1 cycle of trabectedin, the safety population.

Interventions: Trabectedin was administered every 3 weeks in a 24-hour infusion. Radiotherapy was required to start within 1 hour after completion of the first trabectedin infusion (cycle 1, day 2).

Main outcomes and measures: The dose-limiting toxic effects of trabectedin (phase 1) and the overall response rate (phase 2) with use of trabectedin plus irradiation in metastatic soft-tissue sarcomas.

Results: Eighteen patients (11 of whom were male) were enrolled in phase 1, and 27 other patients (14 of whom were female) were enrolled in phase 2. The median ages of those enrolled in phases 1 and 2 were 42 (range, 23-74) years and 51 (range, 27-73) years, respectively. In phase 1, dose-limiting toxic effects included grade 4 neutropenia lasting more than 5 days in 1 patient at the starting dose level and a grade 4 alanine aminotransferase level increase in 1 of 6 patients at the +1 dose level. In phase 2, among 25 patients with evaluable data, the overall response rate was 72% (95% CI, 53%-91%) for local assessment and 60% (95% CI, 39%-81%) for central assessment.

Conclusions and relevance: The findings of this study suggest that the recommended dose of trabectedin for use in combination with this irradiation regimen is 1.5 mg/m2. The trial met its primary end point, with a high overall response rate that indicates the potential of this combination therapy for achieving substantial tumor shrinkage beyond first-line systemic therapy in patients with metastatic, progressing soft-tissue sarcomas.

Trial registration: ClinicalTrials.gov Identifier: NCT02275286.

Conflict of interest statement

Conflict of Interest Disclosures: Dr Martin-Broto reported receiving research grants from PharmaMar, Eisai, and Novartis outside the submitted work; honoraria for advisory board participation and expert testimony from PharmaMar; honoraria for advisory board participation from Eli Lilly and Company, Bayer, and Eisai; and research funding for clinical studies (institutional) from PharmaMar, Eli Lilly and Company, Bayer, Eisai, Lixte, Karyopharm, Deciphera, Blueprint, Nektar, Forma, Amgen, and Daichii-Sankyo. Dr Hindi reported receiving travel support from PharmaMar; honoraria from PharmaMar and Eli Lilly and Company; and institutional research grants from PharmaMar, Eisai, and Novartis. Dr Alvarez reported receiving honoraria from Boehringer-Ingelheim, Roche/Genentech, Bristol-Myers Squibb, Eli Eli Lilly and Company and Company, Novartis, and PharmaMar, and travel support from Roche and PharmaMar. Dr Italiano reported receiving a research grant and travel support from PharmaMar. Dr Sargos reported receiving research support and honoraria from Nanobiotix. Dr Cruz-Jurado reported receiving speaker fees, and honoraria for service as a consultant/advisor, from Glaxo, AstraZeneca, Roche, Novartis, PharmaMar, Eisai, Eli Lilly and Company, Celgene, Astellas, Amgen, and Pfizer. Ms Sanchez-Bustos reported receiving institutional research grants from PharmaMar, Eisai, and Novartis outside the submitted work. Dr Romagosa reported receiving travel support and grants from PharmaMar outside the submitted work and grants from Grupo Español de Investigación de Sarcomas (GEIS) during the conduct of the study. Dr Grignani reported receiving research grants, travel support, and honoraria for advisory board participation from PharmaMar, Eisai, and Pfizer, and grants and honoraria for advisory board participation from Bayer and Novartis outside the submitted work. Dr Redondo reported receiving grants and honoraria for advisory board participation from PharmaMar and Roche; honoraria for advisory board participation from Eli Lilly and Company, Novartis, Amgen, AstraZeneca, and Tesaro; and grants from Eisai outside the submitted work. Dr Luna reported receiving travel support from PharmaMar and honoraria for advisory board participation from PharmaMar and Eli Lilly and Company. Dr Dei Tos reported serving on a PharmaMar advisory board and receiving a research grant and travel support from PharmaMar. Dr Romero reported receiving honoraria from Celgene and Roche. Dr Gronchi reported receiving honoraria from Novartis, Pfizer, Bayer, Eli Lilly and Company, PharmaMar, SpringWorks, and Nanobiotix outside the submitted work, and an institutional research grant from PharmaMar. Dr Blay reported receiving grants and honoraria for advisory board participation from PharmaMar during the conduct of the study; research support and honoraria for work on sarcoma with LyriCan (INCa–INSERM–DGOS project 12563), NetSarc+, EuroSarc (FP7 grant), and EuraCan (EC grant 739521); and grants and honoraria from GSK, Novartis, and Bayer. Dr Moura reported receiving institutional research grants from PharmaMar, Eisai, and Novartis outside the submitted work, and travel support from PharmaMar, Eisai, and Celgene. No other disclosures were reported.

Figures

Figure 1.. CONSORT Diagram

CONSORT indicates Consolidated Standards of Reporting Trials; ECOG, Eastern Cooperative Oncology Group. To convert gray to rad, multiply by 100.

Figure 2.. Waterfall Plot of Phase 2 Trabectedin and Radiotherapy in Soft-Tissue Sarcoma Trial Results

Plot shows dimensional change in target lesions as a percentage of the baseline measurement. Among 25 patients with evaluable data, the overall response rate defined by Response Evaluation Criteria in Solid Tumors, version 1.1, was 72%. Lower and upper dashed lines represent the cutoffs for progressive disease (20% increase in the sum of diameters of target lesions) and for partial response (30% decrease in the sum of diameters of target lesions), respectively. aIndicates disease progression due to new lesions.