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Original Investigation
February 20, 2020

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

Author Affiliations
  • 1Department of Medical Oncology, University Hospital Virgen del Rocío, Sevilla, Spain
  • 2TERABIS Group, IBiS (Instituto de Biomedicina de Sevilla), Sevilla, Spain
  • 3Department of Medical Oncology, Santa Creu i Sant Pau Hospital, Barcelona, Spain
  • 4CIBERONC (Centro de Investigación Biomédica en Red de Cáncer), Instituto de Salud Carlos III, Madrid, Spain
  • 5Department of Radiation Oncology, University Hospital Virgen del Rocío, Sevilla, Spain
  • 6Department of Medical Oncology, Gregorio Marañon University Hospital, Madrid, Spain
  • 7Radiotherapy Department, Gregorio Marañon University Hospital, Madrid, Spain
  • 8Department of Medical Oncology, Institut Bergonié, Bordeaux, France
  • 9Department of Radiotherapy, Institut Bergonié, Bordeaux, France
  • 10Department of Medical Oncology, University Hospital of the Canary Islands, Tenerife, Spain
  • 11Radiation Department, Santa Creu i Sant Pau Hospital, Barcelona, Spain
  • 12Department of Radiation Oncology, University Hospital of the Canary Islands, Tenerife, Spain
  • 13Department of Hematology, University Hospital Son Espases, Mallorca, Spain
  • 14Department of Pathology, Vall d’Hebron University Hospital, Barcelona, Spain
  • 15Department of Radiology, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
  • 16Division of Medical Oncology, Candiolo Cancer Institute, Candiolo, Italy
  • 17Department of Radiotherapy, Candiolo Cancer Institute, Candiolo, Italy
  • 18Department of Medical Oncology, University Hospital Son Espases, Mallorca, Spain
  • 19Radiotherapy Department, University Hospital Son Espases, Mallorca, Spain
  • 20Medical Oncology Department, University Hospital La Paz, Madrid, Spain
  • 21Health Research Institute of La Paz Hospital (IdiPAZ), Madrid, Spain
  • 22Department of Radiotherapy, University Hospital La Paz, Madrid, Spain
  • 23Department of Radiotherapy, Centre Léon Bérard, Lyon, France
  • 24Department of Biopathology, Institut Bergonié, Bordeaux, France
  • 25Department of Biopathology, Bordeaux University, Talence, France
  • 26Department of Medicine, University of Padua School of Medicine, Padua, Italy
  • 27Department of Radiation Oncology, University Hospital Puerta de Hierro, Madrid, Spain
  • 28Department of Surgery, Fondazione IRCCS, Istituto Nazionale dei Tumori, Milan, Italy
  • 29Medical Oncology Department, Centre Léon Bérard, Lyon, France
  • 30Département of Medicine, Université Claude Bernard Lyon I, Lyon, France
JAMA Oncol. Published online February 20, 2020. doi:10.1001/jamaoncol.2019.6584
Key Points

Questions  What is the recommended dose of trabectedin in combination with radiotherapy at a dose of 30 Gy with fractionation of 3 Gy/d for 10 days, and does this combination offer an enhancement of activity in terms of tumor reduction that cannot be achieved with systemic therapy alone?

Findings  In this nonrandomized phase 1/2 clinical trial of 45 patients, the maximum tolerated dose of trabectedin when combined with the specified radiotherapy regimen in phase 1 was 1.5 mg/m2, which was the recommended dose used in phase 2. The overall response rate in the 25 patients with evaluable data was 72% and 60% in local and central assessments, respectively.

Meaning  The higher response rate seen with the combination therapy, in comparison with the response rate with systemic therapy alone, suggests potential for greater relief in cases where symptoms are related to tumor volume in second-line treatment of advanced soft-tissue sarcomas.

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

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