Bintrafusp Alfa Combination Therapy in Participants With Cervical Cancer (INTR@PID 046)

Study Overview
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Brief Summary
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This study is to evaluate the safety and tolerability of bintrafusp alfa in combination with other anti-cancer therapies in participants with locally advanced or advanced cervical cancer.

Official Title
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Safety Study of Bintrafusp Alfa in Combination With Other Anti-cancer Therapies in Participants With Locally Advanced or Advanced Cervical Cancer (INTR@PID 046)

Conditions
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Cervical Cancer

Intervention / Treatment
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* Drug: M7824
* Drug: Carboplatin
* Drug: Paclitaxel
* Drug: Bevacizumab
* Drug: Cisplatin
* Radiation: Radiotherapy


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Inclusion Criteria for participants enrolling into Cohort 1: Study participants have documented persistent, recurrent, or metastatic squamous cell carcinoma, adenosquamous carcinoma, or adenocarcinoma of the cervix Study participants have not been treated with systemic chemotherapy and are not amenable to curative treatment Prior radiation with or without radio-sensitizing chemotherapy is allowed Inclusion Criteria for participants enrolling into Cohort 2: Participants have documented evidence of cervical adenocarcinoma, squamous cell carcinoma, or adenosquamous carcinoma International Federation of Gynecology and Obstetrics (FIGO) 2018 Stages 1B2 to 4A Participants have not received prior chemotherapy or radiotherapy for cervical cancer Inclusion Criteria for all participants: Archival tumor tissue sample or newly obtained core or excisional biopsy is required Participants who have Eastern Cooperative Oncology Group (ECOG) Performance status (PS) of 0 to 1 Participants have a life expectancy greater than or equal to 12 weeks Participants have adequate hematological, hepatic, renal and coagulation function as defined in the protocol Participants with known Human immunodeficiency virus (HIV) infections are eligible if the criteria described in the protocol are met Participants with Hepatitis B virus (HBV) and/or Hepatitis C virus (HCV) infections are eligible if the criteria described in the protocol are met Other protocol defined inclusion criteria could apply Exclusion Criteria: Exclusion Criteria for All Participants: Participants with active central nervous system (CNS) metastases causing clinical symptoms or metastases that require therapeutic intervention are excluded.Participants with a history of treated CNS metastases (by surgery or radiation therapy) are not eligible unless they have fully recovered from treatment, demonstrated no progression for at least 4 weeks, and are not using steroids for at least 7 days prior to the start of study intervention Participants that received any organ transplantation, including allogeneic stem-cell transplantation, but with the exception of transplants that do not require immuno-suppression Participants with significant acute or chronic infections Participants with active autoimmune disease that might deteriorate when receiving an immuno-stimulatory agent Participants with clinically significant cardiovascular/cerebrovascular disease including: cerebral vascular accident/stroke, myocardial infarction, unstable angina, congestive heart failure, or serious cardiac arrhythmia Participants with history of bleeding diathesis or recent major bleeding events Participant that has received prior cancer treatment with any other immunotherapy or checkpoint inhibitors or any other immune-modulating monoclonal antibody (mAb) Exclusion Criteria for Participants in Cohort 1A related to use of bevacizumab: Participants with inadequately controlled hypertension Prior history of hypertensive crisis or hypertensive encephalopathy Participants with significant vascular disease within 6 months prior to Screening Participants with history of hemoptysis within 1 month prior to Screening Current use of full-dose oral or parenteral anticoagulants or thrombolytic agents for therapeutic purposes Core biopsy or other minor surgical procedure, excluding placement of a vascular access device, within 7 days prior to the first dose of bevacizumab Participants with a history of abdominal or trache-oesophageal fistula or gastrointestinal (GI) perforation within 6 months prior to Screening Participants with clinical signs of GI obstruction or requirement for routine parenteral hydration, parenteral nutrition, or tube feeding Participants with evidence of abdominal free air not explained by paracentesis or recent surgical procedure Participants with serious, non-healing wound, active ulcer, or untreated bone fracture Participants with proteinuria Other protocol defined exclusion criteria could apply

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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Female

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: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Cohort 1A:M7824+cisplatin/carboplatin+paclitaxel+bevacizumab<br> | Drug: M7824<br>* Participants will receive bintrafusp alfa until confirmed disease progression, death, unacceptable toxicity and study withdrawal maximum of 2 years (at the discretion of the Investigator).<br>* Other names: Bintrafusp alfa;Drug: Carboplatin<br>* Carboplatin will be administered intravenously as per standard of care.<br>Drug: Paclitaxel<br>* Paclitaxel will be administered intravenously as per standard of care.<br>Drug: Bevacizumab<br>* Bevacizumab will be administrated as indicated for standard of care.<br>Drug: Cisplatin<br>* Cisplatin will be administered intravenously as per standard of care.<br>|
| Experimental: Cohort1B:M7824+cisplatin or carboplatin+paclitaxel<br> | Drug: M7824<br>* Participants will receive bintrafusp alfa until confirmed disease progression, death, unacceptable toxicity and study withdrawal maximum of 2 years (at the discretion of the Investigator).<br>* Other names: Bintrafusp alfa;Drug: Carboplatin<br>* Carboplatin will be administered intravenously as per standard of care.<br>Drug: Paclitaxel<br>* Paclitaxel will be administered intravenously as per standard of care.<br>Drug: Cisplatin<br>* Cisplatin will be administered intravenously as per standard of care.<br>|
| Experimental: Cohort 2: M7824+cisplatin+ radiotherapy<br> | Drug: M7824<br>* Participants will receive bintrafusp alfa until confirmed disease progression, death, unacceptable toxicity and study withdrawal maximum of 2 years (at the discretion of the Investigator).<br>* Other names: Bintrafusp alfa;Drug: Cisplatin<br>* Cisplatin will be administered intravenously as per standard of care.<br>Radiation: Radiotherapy<br>* Participants will receive radiotherapy as per standard of care.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of Dose-Limiting Toxicity (DLT) |  | Week 1 Day 1 up to Week 4 | 
| Number of Participants With Adverse Events (AEs) |  | Time from first treatment to planned final assessment at approximately 2 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Concentration of Bintrafusp alfa Immediately at the End of Infusion (Ceoi) |  | Before the first infusion up to 28 days after the last treatment, assessed up to 2 years | 
| Concentration of Bintrafusp alfa Immediately Before Next Dosing (Ctrough) |  | Before the first infusion up to 28 days after the last treatment, assessed up to 2 years | 
| Area Under the Concentration-Time Curve From Time Zero Extrapolated to Infinity (AUC0-inf) of Bintrafusp alfa |  | Before the first infusion up to 28 days after the last treatment, assessed up to 2 years | 
| Area Under the Serum Concentration-Time Curve From Time Zero to Last Sampling Time at Which the Concentration is at or Above the Lower Limit of Quantification (AUC0-t) of Bintrafusp alfa |  | Before the first infusion up to 28 days after the last treatment, assessed up to 2 years | 
| Maximum Serum Concentration Observed (Cmax) of Bintrafusp alfa |  | Before the first infusion up to 28 days after the last treatment, assessed up to 2 years | 
| Time at which Cmax Occurs (tmax) of Bintrafusp alfa |  | Before the first infusion up to 28 days after the last treatment, assessed up to 2 years | 
| Elimination Half-life (t½) of Bintrafusp alfa |  | Before the first infusion up to 28 days after the last treatment, assessed up to 2 years | 
| Immunogenicity of Bintrafusp alfa, as Assessed by Anti-drug Anti-body (ADA) Assay |  | Prior to the first infusion up to 28 days after the last treatment,assessed up to 2 years | 
| Incidence of Dose-Limiting Toxicity (DLT) in Japanese Participants |  | Week 1 Day 1 up to Week 4 | 
| Number of Japanese Participants With Adverse Events (AE) |  | Time from first treatment to planned final assessment at approximately 2 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Advanced cervical cancer, Bintrafusp alfa, M7824, INTR@PID, Transforming growth factor-beta, Programmed death-ligand 1