Bintrafusp Alfa and Doxorubicin Hydrochloride in Treating Patients With Advanced Sarcoma

Study Overview
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Brief Summary
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This study encompasses two multicenter, prospective, open-labeled, 2-arm, non-comparative randomized phase II trials to assess the antitumor activity of bintrafusp alfa in association with doxorubicin

Detailed Description
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This is a two multicenter, prospective, open-labeled, 2-arm, non-comparative randomized (2:1) phase II trials. Patients satisfying eligibility criteria will first be stratified into 2 strata / subgroups: Soft-tissue sarcoma (STS) patients with an inflamed tumor (i.e. TLS+, defined as presence of mature tertiary lymphoid structures, as per IHC). Soft-tissue sarcoma patients with a cold tumor (i.e. TLS-, defined as absence of mature tertiary lymphoid structures, as per IHC). Note: TLS+ and TLS- account for 20% and 80% of STS patients, respectively. STS patients with TLS+ will be randomized between arm A (bintrafusp alfa combined with doxorubicin for 6 cycles, followed by bintrafusp alfa maintenance) and arm B (doxorubicin for 6 cycles) with two patients randomized in arm A for one patient randomized in arm B. STS patients with TLS- will be randomized between arm C (bintrafusp alfa combined with doxorubicin for 6 cycles, followed by bintrafusp alfa maintenance) and arm D (doxorubicin for 6 cycles) with two patients randomized in arm C for one patient randomized in arm D.

Official Title
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Bintrafusp Alfa and Doxorubicin Hydrochloride in Treating Patients With Advanced Sarcoma. TRUST Study

Conditions
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Advanced Soft-tissue Sarcoma, Metastatic Soft-tissue Sarcoma

Intervention / Treatment
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* Drug: Bintrafusp alfa
* Drug: Doxorubicin


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histologically confirmed soft-tissue sarcoma with unknown translocation (including the following histologies but not limited to undifferentiated pleomorphic sarcomas, dedifferentiated liposaromas or leiomyosarcomas). Diagnosis must be reviewed or confirmed by the RRePS Network (Réseau de référence en pathologie des sarcomes et des viscères) as recommended by the French NCI (Institut National du Cancer, Inca). Metastatic or unresectable locally advanced disease, No previous systemic treatment for advanced/metastatic disease, For TLS status: available archived FFPE (Formalin-Fixed Paraffin-Embedded) tumor tissue sample or tumor material newly obtained by biopsy. Except if TLS analysis have been already performed by Biopathological platform at Bergonié Institute, presence or absence of TLS should be confirmed by central review based on FFPE tumor tissue sample (archived or newly obtained by biopsy for research purpose), Age ≥ 18 years, ECOG ≤ 1, Life expectancy > 3 months, Patients must have measurable disease defined as per RECIST v1.1 with at least one lesion that can be measured in at least one dimension as > 10 mm with spiral CT scan., Patient must comply with the collection of tumor biopsies and biomarkers study. Tumors must be accessible for biopsy, Adequate hematological, renal, metabolic and hepatic function Female subjects of childbearing potential must have a negative serum pregnancy test within 7 days prior to randomization. Serum or urine pregnancy test must be repeated within 72 hours prior to receiving the first dose of study medication, Both women and men must agree to use a highly effective method of contraception throughout the treatment period and for at least two months after discontinuation of treatment for women and four months for men. No prior or concurrent malignant disease diagnosed or treated in the last 3 years except for superficial/non-invasive bladder cancer, or basal or squamous cell carcinoma in situ treated with curative intent; b. endoscopically resected GI cancers limited to the mucosal layer without recurrence in > 1 year, Recovery to grade ≤ 1 from any adverse event derived from previous treatment (excluding alopecia and vitiligo of any grade and non-painful peripheral neuropathy grade ≤ 2) according to to NCI-CTCAE, version 5.0, Voluntarily signed and dated written informed consent prior to any study specific procedure, Patients with a social security in compliance with the French law. Exclusion Criteria: Previous treatment with doxorubicin, daunorubicin, epirubicin, idarubicin and/or any other anthracyclines or anthracediones at the maximum cumulative dose or any approved or investigational treatment targeting PD1, PD-L1 or TGFB1, Known central nervous system malignancy (CNS), Men or women of childbearing potential who are not using an effective method of contraception as previously described; women who are pregnant or breast feeding, Participation to a study involving a medical or therapeutic intervention in the last 30 days, Previous enrolment in the present study, Patient unable to follow and comply with the study procedures because of any geographical, social or psychological reasons, Known hypersensitivity to any involved study drug or any of its formulation components, Any history of anaphylaxis, or recent, within 5 months, history of uncontrollable asthma, Individuals deprived of liberty or placed under legal guardianship, Any of the following cardiac criteria: Mean resting corrected QT interval (QTcF) ≥ 470 msec, obtained from three consecutive ECGs, Any clinically important abnormalities in rhythm, conduction or morphology of resting ECG, LVEF ≤ 50% per CTCAE v5 by MUGA or echocardiogram Any factors increasing the risk of QTc prolongation or arrhythmic events such as heart failure, hypokalaemia, potential for torsades de pointes, congenital long QT syndrome, family history of long QT syndrome or unexplained sudden death under 40 years old or any concomitant medication known to prolong the QT interval, Experience of any of the following procedures or conditions in the preceding 6 months: coronary artery bypass graft, angioplasty, vascular stent, myocardial infarction, unstable angina pectoris, uncontrolled hypertension, congestive heart failure NYHA Grade ≥2, ventricular arrhythmias requiring continuous therapy, supraventricular arrhythmias including atrial fibrillation, which are uncontrolled, haemorrhagic or thrombotic stroke, including transient ischaemic attacks, cerebral vascular accident/stroke or any other central nervous system bleeding Active autoimmune disease that might deteriorate when receiving an immunostimulatory agent: History of bleeding diathesis or recent major bleeding event , Prior organ transplantation including allogenic stem-cell transplantation, except transplants that do not require immunosuppression, Uncontrolled intercurrent illness, including but not limited to, ongoing or active infection requiring systemic therapy, drug-induced interstitial lung disease or subject has had a history of drug-induced pneumonitis that has required oral or IV steroids, and/or other diseases, which in the opinion of the investigator might impair the subject's tolerance for the study or ability to consistently participate in study procedures, Active infection including tuberculosis , Has known active hepatitis B or hepatitis C, Has a known history of Human Immunodeficiency Virus infection, Receipt of live attenuated vaccine within 30 days prior to the first dose of treatment. Note: Patients, if enrolled, should not receive live vaccine within 30 days prior to the first dose of treatment, whilst receiving study treatments and up to 30 days after the last dose. Seasonal flu vaccines that do not contain a live virus are permitted, Patients with current or history of deep vein thrombosis within 6 months prior to randomization, Any contraindication to biopsy for the research, Any other contraindication to Doxorubicin administration,. Patients with oral anticoagulation therapy based on Vitamin K antagonist. Prior mediastinal radiation.

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: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Experimental Arm A: treatment by bintrafusp alfa combined with doxorubicin<br>Soft-tissue sarcoma patients with an inflammed tumor will be treated with bintrafusp alfa combined with doxorubicin for 6 cycles, followed by bintrafusp alfa maintenance | Drug: Bintrafusp alfa<br>* Bintrafusp alfa will be administered by intravenous infusion on day 1 every 3 weeks at a fixed dose of 2400 mg.<br>Drug: Doxorubicin<br>* Doxorubicin will be administered by intravenous infusion on day 1 every 3 weeks at a fixed dose of 75 mg/m² for a maximum of 6 cycles<br>|
| Other: Standard Arm B: treatment by doxorubicin<br>Soft-tissue sarcoma patients with an inflammed tumor will be treated with doxorubicin for 6 cycles | Drug: Doxorubicin<br>* Doxorubicin will be administered by intravenous infusion on day 1 every 3 weeks at a fixed dose of 75 mg/m² for a maximum of 6 cycles<br>|
| Experimental: Experimental Arm C: treatment by bintrafusp alfa combined with doxorubicin<br>Soft-tissue sarcoma patients with a cold tumor will be treated with bintrafusp alfa combined with doxorubicin for 6 cycles, followed by bintrafusp alfa maintenance | Drug: Bintrafusp alfa<br>* Bintrafusp alfa will be administered by intravenous infusion on day 1 every 3 weeks at a fixed dose of 2400 mg.<br>Drug: Doxorubicin<br>* Doxorubicin will be administered by intravenous infusion on day 1 every 3 weeks at a fixed dose of 75 mg/m² for a maximum of 6 cycles<br>|
| Other: Standard Arm D: treatment by doxorubicin<br>Soft-tissue sarcoma patients with a cold tumor will be treated with doxorubicin for 6 cycles | Drug: Doxorubicin<br>* Doxorubicin will be administered by intravenous infusion on day 1 every 3 weeks at a fixed dose of 75 mg/m² for a maximum of 6 cycles<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Assessment of the antitumor activity of combined administration of standard doxorubicin and double immune modulation with Bintrafusp alfa in terms of 6-month progression-free rate, in STS patients with an inflammed tumor | Antitumor activity will be assessed in terms of 6-month progression-free rate and is defined as the rate of complete or partial response (CR, PR) or stable disease (SD), as per RECIST v1.1. | 6 months | 
| Assessment of the antitumor activity of combined administration of standard doxorubicin and double immune modulation with Bintrafusp alfa in terms of 6-month progression-free rate, in STS patients with a cold tumor | Antitumor activity will be assessed in terms of 6-month progression-free rate and is defined as the rate of complete or partial response (CR, PR) or stable disease (SD), as per RECIST v1.1. | 6 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 6-month objective response rate (ORR) independently for patients with an inflammed tumor | Objective response is defined as complete response (CR) or partial response (PR) as per adapted RECIST v1.1. | 6 months | 
| 6-month objective response rate (ORR) independently for patients with a cold tumor | Objective response is defined as complete response (CR) or partial response (PR) as per adapted RECIST v1.1. | 6 months | 
| Best overall response for patients with an inflammed tumor | Best overall response is defined as the best reponse across all time points (RECIST v1.1). The best overall response rate is determined once all the data for the patient is known | throughout the treatment period, an expected average of 6 months | 
| Best overall response for patients with a cold tumor | Best overall response is defined as the best reponse across all time points (RECIST v1.1). The best overall response rate is determined once all the data for the patient is known | throughout the treatment period, an expected average of 6 months | 
| 1-year progression-free survival for patients with an inflammed tumor | Progression-free survival is defined as the delay between the date of randomization and the date of progression (as per RECIST v1.1) or death (from any cause), whichever occurs first | 1 year | 
| 1-year progression-free survival for patients with a cold tumor | Progression-free survival is defined as the delay between the date of randomization and the date of progression (as per RECIST v1.1) or death (from any cause), whichever occurs first | 1 year | 
| 1-year overall survival for patients with an inflammed tumor | Overall survival is defined as the delay between the date of randomization and the date of death (from any cause) | 1 year | 
| 1-year overall survival for patients with a cold tumor | Overall survival is defined as the delay between the date of randomization and the date of death (from any cause) | 1 year | 
| Assessment of the antitumor activity of combined administration of standard doxorubicin and double immune modulation with Bintrafusp alfa in terms of immune response, in STS patients with an inflammed tumor | Immune response is defined following (iRECIST - Seymour et al. 2017). | Throughout the treatment period, an expected average of 6 months | 
| Assessment of the antitumor activity of combined administration of standard doxorubicin and double immune modulation with Bintrafusp alfa in terms of immune response, in STS patients with a cold tumor | Immune response is defined following (iRECIST - Seymour et al. 2017). | Throughout the treatment period, an expected average of 6 months | 
| Safety profile independently for each population: Common Terminology Criteria for Adverse Event version 5 | Toxicity graded using the Common Terminology Criteria for Adverse Events version 5 | Throughout the treatment period, an expected average of 6 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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advanced/metastatic, tertiary lymphoid structure, soft-tissue sarcoma, immunotherapy