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

Cervical Cancer Clinical Trial

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)

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT04551950
• Other study ID #: MS200647_0046
• Secondary ID: 2020-001561-36
• Status: Completed
• Phase: Phase 1
• Start date: October 19, 2020
• Est. completion date: June 30, 2022

Study information

• Verified date: July 2023
• Source: EMD Serono
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 25
• Est. completion date: June 30, 2022
• Est. primary completion date: June 15, 2022
• Accepts healthy volunteers: No
• Gender: Female
• Age group: 18 Years and older

Eligibility

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

Related Conditions & MeSH terms

• Cervical Cancer
• Uterine Cervical Neoplasms

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).
• Carboplatin
Carboplatin was administered intravenously as per standard of care.
• Paclitaxel
Paclitaxel was administered intravenously as per standard of care.
• Bevacizumab
Bevacizumab was administrated as indicated for standard of care.
• Cisplatin
Cisplatin was administered intravenously as per standard of care.

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

Locations

Country	Name	City	State
Japan	National Cancer Center Hospital	Chuo-ku
Japan	Saitama Medical University International Medical Center	Hidaka-shi
Japan	Cancer Institute Hospital of JFCR	Koto-ku
Japan	Osaka International Cancer Institute	Osaka-shi
Japan	Shizuoka Cancer Center	Sunto-gun
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	Barcelona
United States	Augusta University - formerly Georgia Regents University	Augusta	Georgia
United States	University of Cincinnati Physicians Group, LLC - Pharmatech Oncology, Inc	Cincinnati	Ohio
United States	UT Southwestern Medical Center	Dallas	Texas
United States	Comprehensive Cancer Centers of Nevada	Henderson	Nevada
United States	Stanford Health Care Hospital & Clinics	Stanford	California

Sponsors (2)

Lead Sponsor	Collaborator
EMD Serono Research & Development Institute, Inc.	Merck KGaA, Darmstadt, Germany

Countries where clinical trial is conducted

United States,  Japan,  Spain, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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
Primary	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	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
Secondary	Serum Trough Concentration Levels (Ctrough) of Bintrafusp Alfa	Ctrough was the serum concentration observed immediately before next dosing.	Pre-dose Up to 20 months
Secondary	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
Secondary	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
Secondary	Maximum Observed Serum Concentration (Cmax) of Bintrafusp Alfa	Cmax was obtained directly from the concentration versus time curve.	Pre-dose Up to 20 months
Secondary	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
Secondary	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(?z), ?z=terminal first order (elimination) rate constant.	Pre-dose Up to 20 months
Secondary	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
Secondary	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
Secondary	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

External Links

•   Trial Awareness and Transparency website