Feasibility of Total Neoadjuvant Treatment With HYPErthermia in Patients With High-risk Extremity and Trunk Soft Tissue Sarcoma (TNT-HYPE)

Phase 2

Not yet recruiting

• Conditions: Sarcoma,Soft Tissue
• Interventions: Drug: Doxorubicin; Drug: Ifosfamide; Drug: Dacarbazine; Other: Hyperthermia; Radiation: Radiotherapy; Procedure: Surgery

• Registration Number: NCT06835049
• Lead Sponsor: Swiss Group for Clinical Cancer Research

Brief Summary

Soft tissue sarcomas (STSs) are rare cancers with a 5-year survival rate of 60%, and there is no standard treatment for high-risk extremity and trunk STSs (eSTS). A phase III trial suggests that adding moderate regional hyperthermia (HT) to anthracycline-based chemotherapy, followed by surgery and radiotherapy (RT), can improve 10-year overall survival by 10%. This trial aims to optimize treatment by combining the most effective regimens from chemotherapy, HT, RT, and surgery, and will evaluate the feasibility of this new total neoadjuvant treatment (TNT) approach.

Detailed Description

Soft tissue sarcomas (STSs) are rare cancers with a 5-year survival rate of only 60%. There is no international standard treatment for high-risk extremity and trunk STSs (eSTS). Current evidence from a phase III trial suggests that adding moderate regional hyperthermia (HT) to anthracycline-based chemotherapy followed by surgery and radiotherapy (RT) can improve survival rates, showing a 10% improvement in 10-year overall survival.

The aim of this trial is to optimize the treatment for this high-risk group. To achieve this, the assumed most effective treatment regimens from each treatment modality (chemotherapy, HT, RT, and surgery) were identified and combined into an optimized treatment protocol. Neoadjuvant chemotherapy in this population is not yet broadly accepted as standard of care. Furthermore, this new total neoadjuvant treatment (TNT) approach has not yet been investigated prospectively and in addition, the patients have to get their HT treatment potentially in a hospital distant from their domicile. Therefore, we will evaluate in this trial the feasibility of this new treatment schedule as primary endpoint.

Trial treatment consists of 3 neoadjuvant cycles of doxorubicin with either ifosfamide or dacarbazine (the latter only in case of leiomyosarcoma) combined with HT, followed by RT and surgery. Each chemotherapy cycle will last 3 weeks. Trial treatment will last approximately 20 weeks. After surgery, a follow-up period of 36 months per patient is foreseen.

Study Timeline

• Status Verified: 2025-02
• Study First Submitted: 2025-02-13
• Study First Submitted QC: 2025-02-13
• Study First Posted: 2025-02-19
• Last Update Submitted: 2025-02-25
• Last Update Posted: 2025-02-28
• Study Start: 2025-05-15
• Primary Completion: 2028-03-31
• Study Completion: 2031-03-31

Recruitment & Eligibility

• Status: NOT_YET_RECRUITING
• Sex: All
• Target Recruitment: 24

Inclusion Criteria

• Histologically confirmed primary high-risk Soft tissue sarcoma (STS) of extremity or trunk.
• High-risk according to the prognostic Sarculator tool: 10-year OS probability < 60%5.
• Resectable tumor: resectability is based on pre-operative imaging and has to be defined by the local treating sarcoma team. A patient is not considered resectable when the expectation is that only a R2 resection is feasible.
• Measurable disease per RECIST v1.1.
• Diagnostic biopsy is available for the central pathology review.
• Candidate for chemotherapy regimen according to protocol.
• Candidate for loco-regional HT.
• Adequate bone marrow function, hepatic function, renal function, cardiac function and coagulation function.

Main

Exclusion Criteria

• Metastatic disease.
• Previous Whoops resection.
• Ex-ulcerating tumors or tumors infiltrating the skin.
• Other invasive malignancy within 5 years, with the exception of adequately treated non melanoma skin cancer, localized cervical cancer, localized and Gleason ≤ 6 prostate cancer.
• Any previous radiotherapy (RT) or systemic therapy for the present tumor.
• Previous treatment with maximum cumulative doses (450 mg/m² doxorubicin or equivalent 900 mg/m² epirubicin) of doxorubicin, daunorubicin, epirubicin, idarubicin, and/or other anthracyclines and anthracenediones.
• Concomitant or recent (within 30 days of registration) treatment with any other experimental drug.
• Concomitant use of other anti-cancer drugs or RT.
• No metal implants in the region of tumor or cardiac implant electronic devices (CIEDs).
• Severe or uncontrolled cardiovascular disease (congestive heart failure NYHA III or IV), unstable angina pectoris, history of myocardial infarction within the last 12 months, serious arrhythmias requiring medication (with exception of atrial fibrillation or paroxysmal supraventricular tachycardia), significant QT-prolongation, uncontrolled hypertension.
• Active and uncontrolled infections, in particular urinary tract infections.
• Inflammation of the urinary bladder (interstitial cystitis).
• History of cerebrovascular accident or intracranial hemorrhage within 6 months prior to registration.
• Vaccination with live vaccines within 30 days prior to registration.
• Known hypersensitivity to trial drug(s) or to any component of the trial drug(s).

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Neoadjuvant Treatment	Doxorubicin	Trial treatment consists of 3 neoadjuvant cycles of doxorubicin with either ifosfamide or dacarbazine (the latter only in case of leiomyosarcoma) combined with hyperthermia (HT), followed by radiotherapy (RT) and surgery. Each chemotherapy cycle will last 3 weeks. Trial treatment will last approximately 20 weeks. After surgery, a follow-up period of 36 months per patient is foreseen.
Neoadjuvant Treatment	Ifosfamide	Trial treatment consists of 3 neoadjuvant cycles of doxorubicin with either ifosfamide or dacarbazine (the latter only in case of leiomyosarcoma) combined with hyperthermia (HT), followed by radiotherapy (RT) and surgery. Each chemotherapy cycle will last 3 weeks. Trial treatment will last approximately 20 weeks. After surgery, a follow-up period of 36 months per patient is foreseen.
Neoadjuvant Treatment	Dacarbazine	Trial treatment consists of 3 neoadjuvant cycles of doxorubicin with either ifosfamide or dacarbazine (the latter only in case of leiomyosarcoma) combined with hyperthermia (HT), followed by radiotherapy (RT) and surgery. Each chemotherapy cycle will last 3 weeks. Trial treatment will last approximately 20 weeks. After surgery, a follow-up period of 36 months per patient is foreseen.
Neoadjuvant Treatment	Hyperthermia	Trial treatment consists of 3 neoadjuvant cycles of doxorubicin with either ifosfamide or dacarbazine (the latter only in case of leiomyosarcoma) combined with hyperthermia (HT), followed by radiotherapy (RT) and surgery. Each chemotherapy cycle will last 3 weeks. Trial treatment will last approximately 20 weeks. After surgery, a follow-up period of 36 months per patient is foreseen.
Neoadjuvant Treatment	Radiotherapy	Trial treatment consists of 3 neoadjuvant cycles of doxorubicin with either ifosfamide or dacarbazine (the latter only in case of leiomyosarcoma) combined with hyperthermia (HT), followed by radiotherapy (RT) and surgery. Each chemotherapy cycle will last 3 weeks. Trial treatment will last approximately 20 weeks. After surgery, a follow-up period of 36 months per patient is foreseen.
Neoadjuvant Treatment	Surgery	Trial treatment consists of 3 neoadjuvant cycles of doxorubicin with either ifosfamide or dacarbazine (the latter only in case of leiomyosarcoma) combined with hyperthermia (HT), followed by radiotherapy (RT) and surgery. Each chemotherapy cycle will last 3 weeks. Trial treatment will last approximately 20 weeks. After surgery, a follow-up period of 36 months per patient is foreseen.

Primary Outcome Measures

Name	Time	Method
Protocol feasibility rate	End of treatment approx. 20 weeks after registration	PFR defined as percentage of patients who are able to finish the following planned trial treatment parts according to protocol

Secondary Outcome Measures

Name	Time	Method
Disease-free survival (DFS)	From the date of registration until the date of local or distant relapse, progressive disease according to RECIST v1.1 or death, whichever occurs first, assessed up to 3 years after registration	DFS defined as; * time from registration until local or distant relapse,; * or, if tumor has not been operated, time from registration until progression according to RECIST v1.1,; * or death from any cause, whichever occurs first.

Trial Locations

Locations (8)

Kantonsspital Aarau; 🇨🇭 Aarau, Switzerland

Universitaetsspital Basel; 🇨🇭 Basel, Switzerland

EOC - Istituto Oncologico della Svizzera Italiana; 🇨🇭 Bellinzona, Switzerland

Inselspital Bern - Universitätsklinik für Radioonkologie; 🇨🇭 Bern, Switzerland

CHUV - Swiss Cancer Center Lausanne; 🇨🇭 Lausanne, Switzerland

hoch Health Ostschweiz - Kantonsspital St. Gallen; 🇨🇭 St. Gallen, Switzerland

Kantonsspital Winterthur; 🇨🇭 Winterthur, Switzerland

Universitätsspital Zürich; 🇨🇭 Zürich, Switzerland