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

• ClinicalTrials.gov Identifier: NCT04551950
• Recruitment Status: Completed
• First Posted: September 16, 2020
• Results First Posted: March 8, 2024
• Last Update Posted: March 8, 2024
• Sponsor: EMD Serono Research & Development Institute, Inc.
• Collaborator: Merck KGaA, Darmstadt, Germany
• Information provided by (Responsible Party): EMD Serono ( EMD Serono Research & Development Institute, Inc. )

Tracking Information

• First Submitted Date: September 7, 2020
• First Posted Date: September 16, 2020
• Results First Submitted Date: July 31, 2023
• Results First Posted Date: March 8, 2024
• Last Update Posted Date: March 8, 2024
• Actual Study Start Date: October 19, 2020
• Actual Primary Completion Date: June 15, 2022 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: July 31, 2023)

• Number of Participants With Dose-Limiting Toxicities (DLTs) [ Time Frame: Up to 4 weeks after first administration of study intervention ]
  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.
• Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) [ Time Frame: Time from first treatment assessed up to approximately 20 months ]
  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.

Original Primary Outcome Measures (submitted: September 10, 2020)

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

Current Secondary Outcome Measures (submitted: July 31, 2023)

• Immediate Observed Serum Concentration at End of Infusion (Ceoi) of Bintrafusp Alfa [ Time Frame: Pre-dose Up to 20 months ]
  Ceoi was the observed concentration at the end of the infusion period. This was taken directly from the observed Bintrafusp Alfa concentration-time data.
• Serum Trough Concentration Levels (Ctrough) of Bintrafusp Alfa [ Time Frame: Pre-dose Up to 20 months ]
  Ctrough was the serum concentration observed immediately before next dosing.
• Area Under the Serum Concentration-Time Curve From Time Zero to Last Measurable Concentration (AUC0-t) of Bintrafusp Alfa [ Time Frame: Pre-dose Up to 20 months ]
  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).
• Area Under the Serum Concentration-time Curve From Time Zero Extrapolated to Infinity (AUC0-inf) of Bintrafusp Alfa [ Time Frame: Pre-dose Up to 20 months ]
  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.
• Maximum Observed Serum Concentration (Cmax) of Bintrafusp Alfa [ Time Frame: Pre-dose Up to 20 months ]
  Cmax was obtained directly from the concentration versus time curve.
• Time to Reach Maximum Serum Concentration (Tmax) of Bintrafusp Alfa [ Time Frame: Pre-dose Up to 20 months ]
  The time to reach the maximum observed concentration collected during a dosing interval. Tmax was obtained directly from the concentration versus time curve.
• Terminal Elimination Half-Life (T1/2) of Bintrafusp Alfa [ Time Frame: Pre-dose Up to 20 months ]
  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.
• Number of Participants With Positive Anti-Drug Antibody (ADA) of Bintrafusp Alfa [ Time Frame: Pre-dose Up to 20 months ]
  A validated method was applied to detect ADAs in the presence of drug in human serum. The ADA titers of positive samples were determined.
• Number of Japanese Participants With Dose-Limiting Toxicities (DLTs) [ Time Frame: Up to 4 weeks after first administration of study intervention ]
  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.
• Number of Japanese Participants With Treatment Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) [ Time Frame: Time from first treatment assessed up to approximately 20 months ]
  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.

Original Secondary Outcome Measures (submitted: September 10, 2020)

• Concentration of Bintrafusp alfa Immediately at the End of Infusion (Ceoi) [ Time Frame: 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) [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: Before the first infusion up to 28 days after the last treatment, assessed up to 2 years ]
• Elimination Half-life (t½) of Bintrafusp alfa [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: Week 1 Day 1 up to Week 4 ]
• Number of Japanese Participants With Adverse Events (AE) [ Time Frame: Time from first treatment to planned final assessment at approximately 2 years ]

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Bintrafusp Alfa Combination Therapy in Participants With Cervical Cancer (INTR@PID 046)
• Official Title: Safety Study of Bintrafusp Alfa in Combination With Other Anti-cancer Therapies in Participants With Locally Advanced or Advanced Cervical Cancer (INTR@PID 046)
• Brief Summary: 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.
• Detailed Description: Not Provided
• Study Type: Interventional
• Study Phase: Phase 1
• Study Design: Allocation: Non-Randomized; Intervention Model: Parallel Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Condition: Cervical Cancer

Intervention

• 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 Name: 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.
• Radiation: Radiotherapy
  Participants received radiotherapy as per standard of care.

Study Arms

• Experimental: Cohort 1A:M7824+Cisplatin/Carboplatin+Paclitaxel+Bevacizumab
  Interventions:

  • Drug: M7824
  • Drug: Carboplatin
  • Drug: Paclitaxel
  • Drug: Bevacizumab
  • Drug: Cisplatin
• Experimental: Cohort1B:M7824+Cisplatin or Carboplatin+Paclitaxel
  Interventions:

  • Drug: M7824
  • Drug: Carboplatin
  • Drug: Paclitaxel
  • Drug: Cisplatin
• Experimental: Cohort 2: M7824+Cisplatin+ Radiotherapy
  Interventions:

  • Drug: M7824
  • Drug: Cisplatin
  • Radiation: Radiotherapy

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: April 26, 2021): 25
• Original Estimated Enrollment (submitted: September 10, 2020): 24
• Actual Study Completion Date: June 30, 2022
• Actual Primary Completion Date: June 15, 2022 (Final data collection date for primary outcome measure)

Eligibility Criteria

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

Sex/Gender

• Sexes Eligible for Study: Female

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Japan, Spain, United States

Administrative Information

• NCT Number: NCT04551950
• Other Study ID Numbers: MS200647_0046; 2020-001561-36 ( EudraCT Number )
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

IPD Sharing Statement

• Plan to Share IPD: No
• 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

• Current Responsible Party: EMD Serono ( EMD Serono Research & Development Institute, Inc. )
• Original Responsible Party: Same as current
• Current Study Sponsor: EMD Serono Research & Development Institute, Inc.
• Original Study Sponsor: Same as current
• Collaborators: Merck KGaA, Darmstadt, Germany

Investigators

• Study Director: Medical Responsible; Merck Healthcare KGaA, Darmstadt, Germany, an affiliate of Merck KGaA, Darmstadt, Germany

• PRS Account: EMD Serono
• Verification Date: July 2023