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

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

This study was 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.

Study Overview

• Status: Completed
• Conditions: Cervical Cancer
• Intervention / Treatment: Drug: M7824; Drug: Carboplatin; Drug: Paclitaxel; Drug: Bevacizumab; Drug: Cisplatin; Radiation: Radiotherapy

• Study Type: Interventional
• Enrollment (Actual): 25
• Phase: Phase 1

Contacts and Locations

Study Locations

• Japan
  • Chuo-ku, Japan
    • National Cancer Center Hospital
  • Hidaka-shi, Japan
    • Saitama Medical University International Medical Center
  • Koto-ku, Japan
    • Cancer Institute Hospital of Jfcr
  • Osaka-shi, Japan
    • Osaka International Cancer Institute
  • Sunto-gun, Japan
    • Shizuoka Cancer Center
• Spain
  • Barcelona, Spain
    • Hospital Clinic i Provincial de Barcelona - Servicio de Oncologia
  • Barcelona, Spain
    • Hospital Universitari Vall d'Hebron - Dept of Oncology
  • Barcelona, Spain
    • ICO l´Hospitalet - Hospital Duran i Reynals - Servicio de Oncologia
• United States
  • California
    • Stanford, California, United States, 94305
      • Stanford Health Care Hospital & Clinics
  • Georgia
    • Augusta, Georgia, United States, 30912
      • Augusta University - formerly Georgia Regents University
  • Nevada
    • Henderson, Nevada, United States, 89074
      • Comprehensive Cancer Centers of Nevada
  • Ohio
    • Cincinnati, Ohio, United States, 45206
      • University of Cincinnati Physicians Group, LLC - Pharmatech Oncology, Inc
  • Texas
    • Dallas, Texas, United States, 75390
      • UT Southwestern Medical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Inclusion Criteria for participants enrolling into Cohort 1:
• Study participants had documented persistent, recurrent, or metastatic squamous cell carcinoma, adenosquamous carcinoma, or adenocarcinoma of the cervix
• Study participants had not been treated with systemic chemotherapy and were not amenable to curative treatment
• Prior radiation with or without radio-sensitizing chemotherapy was allowed
• Inclusion Criteria for participants enrolling into Cohort 2:
• Participants had documented evidence of cervical adenocarcinoma, squamous cell carcinoma, or adenosquamous carcinoma International Federation of Gynecology and Obstetrics (FIGO) 2018 Stages 1B2 to 4A
• Participants had 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 was required
• Participants who had Eastern Cooperative Oncology Group (ECOG) Performance status (PS) of 0 to 1 were eligible
• Participants had a life expectancy greater than or equal to 12 weeks
• Participants had adequate hematological, hepatic, renal, and coagulation function as defined in the protocol
• Participants with known Human immunodeficiency virus (HIV) infections were eligible if the criteria described in the protocol were met
• Participants with Hepatitis B virus (HBV) and/or Hepatitis C virus (HCV) infections were eligible if the criteria described in the protocol were met
• Other protocol defined inclusion criteria could apply

Exclusion Criteria:

• Exclusion Criteria for All Participants were:
• Participants with active central nervous system (CNS) metastases causing clinical symptoms or metastases that required therapeutic intervention were excluded. Participants with a history of treated CNS metastases (by surgery or radiation therapy) were not eligible unless they had fully recovered from treatment, demonstrated no progression for at least 4 weeks, and were 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 did not require immuno-suppression
• Participants with significant acute or chronic infections
• Participants with active autoimmune disease that might have deteriorated when receiving an immuno-stimulatory agent
• Participants with clinically significant cardiovascular/cerebrovascular disease including: a cerebral vascular accident/stroke, myocardial infarction, unstable angina, congestive heart failure, or serious cardiac arrhythmia
• Participants with a history of bleeding diathesis or recent major bleeding events
• Participant that had 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 were:
• 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 a 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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Cohort 1A:M7824+Cisplatin/Carboplatin+Paclitaxel+Bevacizumab	Drug: M7824; Participants received bintrafusp alfa until confirmed disease progression, death, unacceptable toxicity and study withdrawal maximum of 2 years (at the discretion of the Investigator).; Other Names: Bintrafusp alfa; Drug: Carboplatin; Carboplatin was administered intravenously as per standard of care.; Drug: Paclitaxel; Paclitaxel was administered intravenously as per standard of care.; Drug: Bevacizumab; Bevacizumab was administrated as indicated for standard of care.; Drug: Cisplatin; Cisplatin was administered intravenously as per standard of care.
Experimental: Cohort1B:M7824+Cisplatin or Carboplatin+Paclitaxel	Drug: M7824; Participants received bintrafusp alfa until confirmed disease progression, death, unacceptable toxicity and study withdrawal maximum of 2 years (at the discretion of the Investigator).; Other Names: Bintrafusp alfa; Drug: Carboplatin; Carboplatin was administered intravenously as per standard of care.; Drug: Paclitaxel; Paclitaxel was administered intravenously as per standard of care.; Drug: Cisplatin; Cisplatin was administered intravenously as per standard of care.
Experimental: Cohort 2: M7824+Cisplatin+ Radiotherapy	Drug: M7824; Participants received bintrafusp alfa until confirmed disease progression, death, unacceptable toxicity and study withdrawal maximum of 2 years (at the discretion of the Investigator).; Other Names: Bintrafusp alfa; Drug: Cisplatin; Cisplatin was administered intravenously as per standard of care.; Radiation: Radiotherapy; Participants received radiotherapy as per standard of care.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants With Dose-Limiting Toxicities (DLTs)	DLT was defined as Adverse Events (AEs) with any of following toxicities: Grade 4 nonhematologic toxicity or hematologic toxicity lasting more than equal to (>=) 7 days despite medical intervention; Grade 3 nausea, vomiting, and diarrhea lasting >= 3 days despite supportive care; Any Grade 3 or Grade 4 nonhematologic lab value leading to hospitalization or persisting for >= 7 days; Grade 3 or Grade 4: grade 3 is defined as absolute neutrophil count (ANC) less than (<) 1,000/mm3 with a temperature of > 38.3 degree Celsius (°C); grade 4 is defined as ANC < 1,000/mm3 with a temperature of > 38.3°C, with life-threatening consequences; Thrombocytopenia < 25,000/mm3 associated with bleeding not resulting in hemodynamic instability or a life-threatening bleeding resulting in urgent intervention; Bleeding events >= Grade 3 occurring within 5 days of bintrafusp alfa treatment; Prolonged delay (> 3 weeks) in initiating Cycle 2 due to treatment-related toxicity; Grade 5 toxicity.	Up to 4 weeks after first administration of study intervention
Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs)	Adverse Event (AE) was defined any untoward medical occurrence in a participant administered with a study drug, which does not necessarily had a causal relationship with this treatment. Treatment-Emergent Adverse Events (TEAEs) were defined as events with onset date or worsening during the on-treatment period. A serious adverse event (SAE) was an AE that resulted in any of the following outcomes: death; life threatening; persistent/significant disability/incapacity; initial or prolonged inpatient hospitalization; congenital anomaly/birth defect or was otherwise considered medically important. TEAEs included serious TEAEs and non-serious TEAEs.	Time from first treatment assessed up to approximately 20 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Immediate Observed Serum Concentration at End of Infusion (Ceoi) of Bintrafusp Alfa	Ceoi was the observed concentration at the end of the infusion period. This was taken directly from the observed Bintrafusp Alfa concentration-time data.	Pre-dose Up to 20 months
Serum Trough Concentration Levels (Ctrough) of Bintrafusp Alfa	Ctrough was the serum concentration observed immediately before next dosing.	Pre-dose Up to 20 months
Area Under the Serum Concentration-Time Curve From Time Zero to Last Measurable Concentration (AUC0-t) of Bintrafusp Alfa	The area under the concentration-time curve (AUC) from time zero (= dosing time) to the last sampling time (tlast) at which the concentration is at or above the lower limit of quantification. Calculated using the mixed log-linear trapezoidal rule (linear up, log down).	Pre-dose Up to 20 months
Area Under the Serum Concentration-time Curve From Time Zero Extrapolated to Infinity (AUC0-inf) of Bintrafusp Alfa	AUC0-inf was calculated by combining AUC0-t and AUCextra. AUCextra represents an extrapolated value obtained by Clast pred/Lambda z, where Clast pred was the calculated serum concentration at the last sampling time point at which the measured serum concentration is at or above the Lower Limit of quantification (LLQ) and Lambda z was the apparent terminal rate constant determined by log-linear regression analysis of the measured serum concentrations of the terminal log-linear phase.	Pre-dose Up to 20 months
Maximum Observed Serum Concentration (Cmax) of Bintrafusp Alfa	Cmax was obtained directly from the concentration versus time curve.	Pre-dose Up to 20 months
Time to Reach Maximum Serum Concentration (Tmax) of Bintrafusp Alfa	The time to reach the maximum observed concentration collected during a dosing interval. Tmax was obtained directly from the concentration versus time curve.	Pre-dose Up to 20 months
Terminal Elimination Half-Life (T1/2) of Bintrafusp Alfa	Elimination Half Life (T1/2) was defined as the time required for the concentration or amount of drug in the body to be reduced by one-half. Elimination half-life determined as 0.693/ Lamda z(λz), λz=terminal first order (elimination) rate constant.	Pre-dose Up to 20 months
Number of Participants With Positive Anti-Drug Antibody (ADA) of Bintrafusp Alfa	A validated method was applied to detect ADAs in the presence of drug in human serum. The ADA titers of positive samples were determined.	Pre-dose Up to 20 months
Number of Japanese Participants With Dose-Limiting Toxicities (DLTs)	DLT was defined as Adverse Events (AEs) with any of following toxicities: Grade 4 nonhematologic toxicity or hematologic toxicity lasting more than equal to (>=) 7 days despite medical intervention; Grade 3 nausea, vomiting, and diarrhea lasting >= 3 days despite supportive care; Any Grade 3 or Grade 4 nonhematologic lab value leading to hospitalization or persisting for >= 7 days; Grade 3 or Grade 4: grade 3 is defined as absolute neutrophil count (ANC) less than (<) 1,000/mm3 with a temperature of > 38.3 degree Celsius (°C); grade 4 is defined as ANC < 1,000/mm3 with a temperature of > 38.3°C, with life-threatening consequences; Thrombocytopenia < 25,000/mm3 associated with bleeding not resulting in hemodynamic instability or a life-threatening bleeding resulting in urgent intervention; Bleeding events >= Grade 3 occurring within 5 days of bintrafusp alfa treatment; Prolonged delay (> 3 weeks) in initiating Cycle 2 due to treatment-related toxicity; Grade 5 toxicity.	Up to 4 weeks after first administration of study intervention
Number of Japanese Participants With Treatment Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs)	Adverse Event (AE) was defined any untoward medical occurrence in a participant administered with a study drug, which does not necessarily had a causal relationship with this treatment. Treatment-Emergent Adverse Events (TEAEs) were defined as events with onset date or worsening during the on-treatment period. A serious adverse event (SAE) was an AE that resulted in any of the following outcomes: death; life threatening; persistent/significant disability/incapacity; initial or prolonged inpatient hospitalization; congenital anomaly/birth defect or was otherwise considered medically important.	Time from first treatment assessed up to approximately 20 months

Collaborators and Investigators

• Sponsor: EMD Serono Research & Development Institute, Inc.
• Collaborators: Merck KGaA, Darmstadt, Germany
• Investigators: Study Director: Medical Responsible, Merck Healthcare KGaA, Darmstadt, Germany, an affiliate of Merck KGaA, Darmstadt, Germany

Publications and helpful links

Helpful Links

• Trial Awareness and Transparency website

Study record dates

Study Major Dates

• Study Start (Actual): October 19, 2020
• Primary Completion (Actual): June 15, 2022
• Study Completion (Actual): June 30, 2022

Study Registration Dates

• First Submitted: September 7, 2020
• First Submitted That Met QC Criteria: September 10, 2020
• First Posted (Actual): September 16, 2020

Study Record Updates

• Last Update Posted (Actual): March 8, 2024
• Last Update Submitted That Met QC Criteria: July 31, 2023
• Last Verified: July 1, 2023

More Information

Terms related to this study

• Keywords: M7824; Bintrafusp alfa; Transforming growth factor-beta; Programmed death-ligand 1; INTR@PID; Advanced cervical cancer
• Additional Relevant MeSH Terms: Neoplasms; Urogenital Neoplasms; Neoplasms by Site; Uterine Neoplasms; Genital Neoplasms, Female; Uterine Cervical Diseases; Uterine Diseases; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Genital Diseases; Genital Diseases, Female; Uterine Cervical Neoplasms; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Antineoplastic Agents; Tubulin Modulators; Antimitotic Agents; Mitosis Modulators; Antineoplastic Agents, Phytogenic; Antineoplastic Agents, Immunological; Angiogenesis Inhibitors; Angiogenesis Modulating Agents; Growth Substances; Growth Inhibitors; Carboplatin; Paclitaxel; Bevacizumab
• Other Study ID Numbers: MS200647_0046; 2020-001561-36 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO
• IPD Plan Description: Per company policy, following approval of a new product or a new indication for an approved product in both the EU and the US, EMD Serono will share study protocols, anonymized patient level and study level data and redacted clinical study reports from clinical trials in patients with qualified scientific and medical researchers, upon request, as necessary for conducting legitimate research. Further information on how to request data can be found on our website https://www.emdgroup.com/en/research/our-approach-to-research-and-development/healthcare/clinical-trials/commitment-responsible-data-sharing.html

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No