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

Official title

Feasibility of Total Neoadjuvant Treatment With HYPErthermia in Patients With High-risk Extremity and Trunk Soft Tissue Sarcoma (TNT-HYPE). A Multicenter, Single Arm, Open Label, Phase II Trial

Overview

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.

Interventions

• Drug Doxorubicin
  Trial treatment consists of 3 neoadjuvant cycles of doxorubicin with either ifosfamide or dacarbazine (the latter only in case of leiomyosarcoma). Doxorubicin will be given at a dose of 75 mg/m2 Body surface area (BSA) on day 1 of each cycle as a intravenous infusion over 15 minutes.
• Drug Ifosfamide
  Trial treatment consists of 3 neoadjuvant cycles of doxorubicin with either ifosfamide or dacarbazine (the latter only in case of leiomyosarcoma). Ifosfamide will be given at a dose of 3 g/m2 BSA on days 1 to 3 of each cycle, for a total dose per cycle of 9 g/m2 BSA, as an intravenous infusion of 3 g/m2 daily over 4 hours.
• Drug Dacarbazine
  Trial treatment consists of 3 neoadjuvant cycles of doxorubicin with either ifosfamide or dacarbazine (the latter only in case of leiomyosarcoma). Dacarbazine will be given at a daily dose of 300 mg/m2 BSA on days 1 to 3 of each cycle, for a total dose per cycle of 900 mg/m2 BSA, as an intravenous infusion over 30 minutes.
• Other Hyperthermia
  Hyperthermia (HT) sessions are scheduled on days 1 and 3 of each chemotherapy cycle. The duration of the preheating phase is always 30 minutes. Together with the treatment phase of 60 minutes, the duration of a HT session is uniformly 90 minutes (Total treatment time). On days 2, chemotherapy will be applied without HT.
• Radiation Radiotherapy
  Radiotherapy (RT) treatment should start ideally 19 days after last chemotherapy dose received (range -4 / +7), preferably on a Monday to omit that the last RT fractions will be applied directly after the weekend. Start of RT can be postponed up to 14 days due to medical reasons without violating treatment protocol. Patients will preferably receive normofractionated RT to a total dose of 50 Gy in 25 fractions of 2 Gy over 5 weeks23. Alternatively, patients can receive a moderate hypofractionat
• Procedure Surgery
  Standard of care surgical resection must be done by an experienced sarcoma surgeon. All lesions of the trunk and extremities will be resected after total neoadjuvant treatment with chemotherapy, HT and RT. Surgery will take place preferentially 6 weeks (+/- 2 weeks) after end of radiation.

Primary outcome measures

• Protocol feasibility rate [Time frame: End of treatment approx. 20 weeks after registration]

Secondary outcome measures (1)

• Disease-free survival (DFS) [Time frame: 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]

Eligibility criteria

Main 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).

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

N/A

Model

Single group

Masking

Open label

Primary purpose

Treatment

Study locations

Switzerland · 8 centers

• Kantonsspital Aarau — Aarau
• Universitaetsspital Basel — Basel
• EOC - Istituto Oncologico della Svizzera Italiana — Bellinzona
• Inselspital Bern - Universitätsklinik für Radioonkologie — Bern
• CHUV - Swiss Cancer Center Lausanne — Lausanne
• hoch Health Ostschweiz - Kantonsspital St. Gallen — Sankt Gallen
• Kantonsspital Winterthur — Winterthur
• Universitätsspital Zürich — Zurich

Identifiers

NCT: NCT06835049 · SAKK 57/24

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗