Hyper-Thermia Enhanced Anti-tumor Efficacy of Trabectedin (HyperTET)

Trabectedin Combined With Regional Hyperthermia as Second Line Treatment for Adult Patients With Advanced Soft-tissue Sarcoma

This trial compares trabectedin alone to trabectedin in combination with regional hyperthermia in patients with high-risk soft tissue sarcoma. The study is designed to demonstrate a significant benefit for sarcoma-therapy by adding regional hyperthermia.

Study Overview

• Status: Active, not recruiting
• Conditions: Sarcoma
• Intervention / Treatment: Drug: Trabectedin; Genetic: DNA double-strand breaks

• Study Type: Interventional
• Enrollment (Actual): 120
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Gesa Schuebbe; Phone Number: 74768 +49 89 4400-0; Email: sarkum@med.uni-muenchen.de
• Study Contact Backup: Name: Lars Lindner, MD; Phone Number: 74768 +49 89 4400-0; Email: sarkum@med.uni-muenchen.de

Study Locations

• Germany
  • Bad Saarow, Germany
    • Helios Klinikum Bad Saarow
  • Berlin, Germany
    • Charité - Universitätsmedizin Berlin
  • Berlin, Germany
    • Helios Klinikum Berlin-Buch
  • Erlangen, Germany
    • Universitätsklinikum Erlangen
  • Bavaria
    • Munich, Bavaria, Germany, 81377
      • Ludwig-Maximilians University of Munich, Klinikum Großhadern

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Age > 18 years
• Histologically confirmed STS (primary or recurrent), except: Ewing sarcoma, osteosarcoma, skeletal chondrosarcoma (extraskeletal chondrosacomas are included), GIST, dermatofibrosarcoma protuberans, malignant mesothelioma, rhabdomyosarcoma
• Patients after failure of first-line chemotherapy (anthracyclines with/without ifosfamide) with or without RHT
• Progressive or recurrent tumor which is unresectable or only resectable with adverse functional outcome
• After macroscopic incomplete resection or marginal resection (tumor-free margins < 1 cm)
• Prior chemotherapy, including anthracyclines with/without ifosfamide (with or without RHT) or patients who cannot be given these medicines
• At least one tumor manifestation which is eligible for hyperthermia
• Performance status (ECOG) 0,1 or 2
• More than 3 weeks from last treatment
• Neutrophil count ≥ 1,5 G/l, hemoglobin ≥ 9 g/dl, platelets ≥ 100 G/l
• Albumin ≥ 25 g/l, total bilirubin ≤ 1 x ULN, ALT/AST ≤ 2.5 x ULN, AP ≤ 2.5 x ULN, Cockroft and Gault's calculated creatinine clearance ≥ 30 ml/min, CPK ≤ 2.5 x ULN
• Patients with the ability to follow study instructions and likely to attend and complete all required visits
• Written informed consent of the subject

Exclusion Criteria:

• Uncontrolled infection (e.g. active viral hepatitis)
• Unstable cardiac status
• Peripheral neuropathy > grade 2
• Known or persistent abuse of medications, drugs or alcohol
• Other malignancy during the last 5 years (exclusion of basal cell carcinoma or adequately treated cervical carcinoma in situ)
• Prior therapy with Tr or known history of hypersensitivity to drugs with a similar chemical structure
• Pregnancy or breast-feeding
• Females of childbearing potential, who are not using and not willing to use medically reliable methods of contraception for the entire study duration
• Uncontrolled CNS-metastases
• Medical or technical impossibility for hyperthermia to heat the major target lesion

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Trabectedin with regional hyperthermia; Trabectedin 1.5 mg/m², 24 hrs continuous i.v. infusion, repetition after 21 days, until progress of disease. Additional treatment with regional hyperthermia (RHT): RHT treatment of the tumor area and the surrounding tissue (41-44°C for 60 min treatment time) is applied at the end of Trabectedin infusion (+/- 4 hrs).	Drug: Trabectedin; Other Names: Yondelis; Genetic: DNA double-strand breaks; The rationale for combining Tr and RHT is based on immune mechanisms induced by local heating of which are independent of the anti-tumor effects of Tr. Recent results demonstrate that an acute inflammation at the site of the heated tumor area and "danger signals" are responsible for immune reactions against tumor and metastases (Frey 2012). Abscopal effects after local radiation of tumors with response of distant metastases are induced by similar mechanisms like heat stress (Formenti 2013, Golden 2015). The long-term results for soft-tissue sarcoma are consistent with abscopal effects induced by RHT in a randomized trial compared to chemotherapy alone (Issels 2018).
Active Comparator: Trabectedin; Trabectedin 1.5 mg/m², 24 hrs continuous i.v. infusion, repetition after 21 days, until progress of disease.	Drug: Trabectedin; Other Names: Yondelis; Genetic: DNA double-strand breaks; The rationale for combining Tr and RHT is based on immune mechanisms induced by local heating of which are independent of the anti-tumor effects of Tr. Recent results demonstrate that an acute inflammation at the site of the heated tumor area and "danger signals" are responsible for immune reactions against tumor and metastases (Frey 2012). Abscopal effects after local radiation of tumors with response of distant metastases are induced by similar mechanisms like heat stress (Formenti 2013, Golden 2015). The long-term results for soft-tissue sarcoma are consistent with abscopal effects induced by RHT in a randomized trial compared to chemotherapy alone (Issels 2018).

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Progression-free Survival (PFS)	planned after 46 events after start of recruitment which are expected to occur after 27 month

Secondary Outcome Measures

Outcome Measure	Time Frame
Radiological response according to RECIST	planned after 46 events after start of recruitment which are expected to occur after 27 month
Overall Survival (OS)	planned after 46 events after start of recruitment which are expected to occur after 27 month
Treatment related toxicity (hematological, renal, hepatic, others)	planned after 46 events after start of recruitment which are expected to occur after 27 month

Collaborators and Investigators

• Sponsor: Ludwig-Maximilians - University of Munich

Study record dates

Study Major Dates

• Study Start (Actual): December 19, 2014
• Primary Completion (Anticipated): August 1, 2023
• Study Completion (Anticipated): August 1, 2023

Study Registration Dates

• First Submitted: November 10, 2014
• First Submitted That Met QC Criteria: February 4, 2015
• First Posted (Estimate): February 10, 2015

Study Record Updates

• Last Update Posted (Estimate): February 28, 2023
• Last Update Submitted That Met QC Criteria: February 27, 2023
• Last Verified: February 1, 2023

More Information

Terms related to this study

• Keywords: trabectedin; high-risk soft tissue sarcoma
• Additional Relevant MeSH Terms: Neoplasms, Connective and Soft Tissue; Neoplasms by Histologic Type; Neoplasms; Sarcoma; Molecular Mechanisms of Pharmacological Action; Antineoplastic Agents; Antineoplastic Agents, Alkylating; Alkylating Agents; Trabectedin
• Other Study ID Numbers: HyperTET