Hyper-Thermia Enhanced Anti-tumor Efficacy of Trabectedin

Study Overview
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Brief Summary
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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.

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

Conditions
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Sarcoma

Intervention / Treatment
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* Drug: Trabectedin
* Genetic: DNA double-strand breaks


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Trabectedin with regional hyperthermia<br>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<br> <br> * Other names: Yondelis;Genetic: DNA double-strand breaks<br>* 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).<br>|
| Active Comparator: Trabectedin<br>Trabectedin 1.5 mg/m², 24 hrs continuous i.v. infusion, repetition after 21 days, until progress of disease. | Drug: Trabectedin<br> <br> * Other names: Yondelis;Genetic: DNA double-strand breaks<br>* 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).<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | 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 | Measure Description | 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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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high-risk soft tissue sarcoma, trabectedin