Evaluation of Bintrafusp Alfa and Doxorubicin Hydrochloride in Advanced Soft-Tissue Sarcoma: A Phase II Clinical Trial
- Trial ID
- 2023-509497-30-00
- Protocol
- IB 2020-05
- Sponsor
- Institut Bergonie
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this study is to evaluate the **antitumor activity** of the combined administration of standard doxorubicin and double immune modulation with Bintrafusp alfa in patients with advanced soft-tissue sarcomas (STS). This will be assessed in terms of the 6-month progression-free rate according to RECIST v1.1 criteria, following a blinded centralized radiological review. The evaluation will be conducted independently for two distinct subgroups of patients, based on the presence (TLS+) or absence (TLS-) of mature tertiary lymphoid structures. This objective is clinically relevant as it aims to determine the efficacy of this combination therapy in prolonging progression-free survival in a challenging patient population with limited treatment options.
Secondary objectives include:
- Evaluating the antitumor activity of the combination in terms of 6-month objective response, best overall response, 1-year progression-free survival (PFS), and 1-year overall survival (OS) as per RECIST v1.1 criteria.
- Assessing the antitumor activity in terms of immune response using iRECIST criteria.
- Evaluating the safety profile of the combination using NCI-CTC v5 criteria, with a safety run-in for tolerability to ensure the absence of safety signals.
- Conducting a mandatory biomarker study to analyze pharmacodynamic/mechanism of action biomarkers and predictive biomarkers on pre-treatment and on-treatment tumor biopsies.
Participants
The clinical trial involves **adult patients** with locally advanced, unresectable, and/or metastatic **soft-tissue sarcomas**. The study population includes both male and female participants aged 18 years and older. Participants are required to have a histologically confirmed diagnosis of soft-tissue sarcoma, with adequate hematological, renal, metabolic, and hepatic function. The trial does not include a vulnerable population. Participants must have a life expectancy greater than three months and an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. The trial population was selected based on specific inclusion criteria, including the absence of prior systemic treatment for advanced or metastatic disease and the availability of tumor tissue samples for TLS status confirmation. Lifestyle considerations such as diet and physical activity are not specified. The sponsor has not provided information on the total number of participants in the trial.
Plans and Procedures
The clinical trial is designed to evaluate the **antitumor activity** of a combined administration of standard **doxorubicin hydrochloride** and double immune modulation with **bintrafusp alfa** in patients with advanced soft-tissue sarcomas. This is a Phase II, randomized, double-blind, controlled trial. The trial aims to assess the 6-month progression-free rate as per the Response Evaluation Criteria in Solid Tumors (RECIST v1.1) after a blinded centralized radiological review. The trial is expected to run from March 2022 to June 2026, with an estimated participant involvement of up to 24 months.
Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as histologically confirmed soft-tissue sarcoma, adequate organ function, and measurable disease. Following the screening, participants will be randomized to receive either the investigational treatment or a comparator. The treatment period will include regular follow-up visits to monitor safety, efficacy, and any adverse events. The end-of-study visit will occur after the completion of the treatment period or upon early termination.
Participants are expected to remain in the study for the full duration unless they experience disease progression, unacceptable toxicity, or withdraw consent. The trial will also assess secondary endpoints, including objective response rate, duration of overall response, progression-free survival, overall survival, and immune response. Safety will be evaluated using the common toxicity criteria from the NCI CTC-AE v5.0. The trial is not categorized as low intervention and is conducted under the sponsorship of Merck KGaA and Accord Healthcare France SAS.
Treatment
The clinical trial involves the administration of **Bintrafusp alfa**, a **concentrate for solution for infusion**. This experimental medication is designed as an **anti-PD-L1/TGFβ Trap** and is provided by Merck KGaA. The active substance, **bintrafusp alfa**, is a protein-based therapeutic agent. The medication is administered via **intravenous use**. The dosing regimen includes a maximum daily dose of 2400 mg, with a total maximum dose of 43200 mg over a treatment period of up to 24 weeks. The trial aims to evaluate the antitumor activity of this agent in combination with standard treatments.
In addition to the experimental treatment, the trial includes the administration of **Doxorubicin Hydrochloride**, marketed as **DOXORUBICINE ACCORD 2 mg/ml, solution for infusion**. This non-experimental treatment is a standard chemotherapeutic agent provided by Accord Healthcare France SAS. The active substance, **doxorubicin hydrochloride**, is a chemical compound used in cancer therapy. The medication is administered through **intravenous infusion**. The dosing schedule allows for a maximum daily dose of 75 mg/m², with a total maximum dose of 450 mg/m² over a treatment period of up to 18 weeks. This agent serves as a comparator in the study, providing a standard-of-care reference for evaluating the efficacy of the experimental treatment.
Efficacy
Efficacy in the clinical trial titled "TRUST: Bintrafusp Alfa and Doxorubicin Hydrochloride in Treating Patients with Advanced Sarcoma" will be assessed primarily through the **6-month progression-free rate**. This will be evaluated according to the Response Evaluation Criteria in Solid Tumors (RECIST v1.1). Non-progression is defined as complete or partial response (CR, PR) or stable disease (SD) as per RECIST v1.1. Disease status at 6 months will undergo a centralized review by an expert radiologist who is blinded to the treatment, and the reviewed data will be utilized for the primary efficacy analysis.
Secondary efficacy endpoints include objective response, duration of overall response, best overall response under treatment, progression-free survival (PFS), overall survival (OS), and immune response. Objective response is defined as CR or PR, confirmed at least 4 weeks later. Duration of overall response is measured from the time CR or PR criteria are met until recurrence or progression is documented. Best overall response is determined from the start of treatment until its end, based on RECIST v1.1 criteria. PFS is defined as the time from randomization to disease progression or death, with median PFS and 1-year PFS reported. OS is the time from randomization to death, with median OS and 1-year OS reported. Immune response will be analyzed following iRECIST guidelines, based on blinded central radiological review data.
Inclusion and Exclusion Criteria
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 or on site by a pathologist specifically trained by a representative of Biopathological platform at Bergonié Institute, presence or absence of TLS should be confirmed by central review based on FFPE (Formalin-Fixed ParaffinEmbedded) tumor tissue sample (archived or newly obtained by biopsy for research purpose),
- Age ≥ 18 years,
- Eastern Cooperative Oncology Group (ECOG) performance status (PS) ≤ 1,
- Life expectancy > 3 months,
- Patients must have measurable disease (lesion in previously irradiated filed can be considered as measurable if progressive at inclusion according to RECIST v1.1) defined as per RECIST v1.1 with at least one lesion that can be measured in at least one dimension (longest diameter to be recorded) 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: a) Hemoglobin ≥ 9 g/dl (patients may not have received prior red blood cell [RBC] transfusion in the last 30 days); absolute neutrophil count (ANC) ≥ 1.5 G/l, and platelet count ≥ 100 G/l. b) Alkaline phosphatase (AP), alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 2.5 x upper limit of normality (ULN) (≤ 5 in case of extensive skeletal involvement and/or liver metastasis for AP and ≤ 5 x ULN in case of liver metastasis for AST and ALT) c) Total bilirubin ≤ ULN (≤ 3 in case of liver involvement) d) Albumin ≥ 30 g/l e) Creatinine level ≤ 1.5 x ULN or calculated creatinine clearance (CrCl) ≥ 40 ml/min (according to Cockroft Gault formula) f) Normal international normalized ratio (INR), PT ≤ 1.5 x ULN and activated partial thromboplastine time (aPTT) ≤ 1.5 x ULN.
- 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 seven months after discontinuation of treatment for women and four months for men. Acceptable methods of contraception will be described in the full protocol.
- 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, 14.
- .Recovery to grade ≤ 1 from any adverse event (AE) derived from previous treatment (excluding alopecia and vitiligo of any grade and non-painful peripheral neuropathy grade ≤ 2) according to the National Cancer Institute Common Terminology Criteria for Adverse Events (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: a) Mean resting corrected QT interval (QTcF) ≥ 470 msec, obtained from three consecutive ECGs, b) Any clinically important abnormalities in rhythm, conduction or morphology of resting ECG, c) LVEF ≤ 50% per CTCAE v5 by MUGA or echocardiogram) d) 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, e) 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: a) Subjects with diabetes type I, vitiligo, psoriasis, hypo- or hyperthyroid disease not requiring immunosuppressive treatment are eligible b) Subjects requiring hormone replacement with corticosteroids are eligible if the steroids are administered only for the purpose of hormonal replacement and at doses ≤ 10 mg or 10 mg equivalent prednisone per day c) Administration of steroids through a route known to result in a minimal systemic exposure (intranasal, topical, local (e.g., intro-ocular, inhalation or intra-articular) are acceptable. d) Steroids as premedication for hypersensitivity reactions (e;g;, CT scan premedication) are allowed.
- History of bleeding diathesis or recent major bleeding event (i.e. Grade ≥ 2 bleeding events within 30 days prior to treatment,
- 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 (ILD) 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 (clinical evaluation that includes clinical history, physical examination and radiographic findings, and TB testing in line with local practice),
- Has known active hepatitis B or hepatitis C,
- Has a known history of Human Immunodeficiency Virus (HIV) infection (HIV1/2 antibodies),
- 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. Low molecular weight heparin and heparin are allowed.
- Prior mediastinal radiation.
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 France | Not Recruiting | 22 Mar 2022 | 80 |
Sites & Investigators
Investigational Products
Details about the medicinal products being studied in this clinical trial.
| Product Name | Role in Trial | Formulation | Administration | Max Daily Dose | Treatment Duration | EU MP Number |
|---|---|---|---|---|---|---|
DOXORUBICINE ACCORD 2 mg/ml, solution pour perfusion | Comparator | SOLUTION POUR PERFUSION | INTRAVENOUS INFUSION | 75 | 18 | PRD379852 |
Bintrafusp alfaanti-PD-L1/TGFβ Trap | Test | CONCENTRATE FOR SOLUTION FOR INFUSION | INTRAVENOUS USE | 2400 | 24 | PRD8936145 |