Bintrafusp Alfa Monotherapy in Platinum-Experienced Cervical Cancer

Uterine Cervical Neoplasms Clinical Trial

Official title:

A Phase II, Multicenter, Open Label Study of Bintrafusp Alfa (M7824) Monotherapy in Participants With Advanced, Unresectable Cervical Cancer With Disease Progression During or After Platinum-Containing Chemotherapy

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT04246489
• Other study ID #: MS200647_0017
• Secondary ID: 2019-003583-40
• Status: Completed
• Phase: Phase 2
• Start date: March 30, 2020
• Est. completion date: December 14, 2022

Study information

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

Clinical Trial Summary

The main purpose of this study was to evaluate clinical efficacy and safety of bintrafusp alfa in participants with advanced, unresectable cervical cancer with disease progression during or after platinum-containing chemotherapy.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 146
• Est. completion date: December 14, 2022
• Est. primary completion date: April 5, 2022
• Accepts healthy volunteers: No
• Gender: Female
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

• Participants who had advanced unresectable and/or metastatic cervical cancer (squamous cell carcinoma, adenocarcinoma, adenosquamous cell carcinoma) with disease progression during or after the prior platinum-containing chemotherapy:

1. The prior platinum-containing chemotherapy may be a systemic treatment for advanced unresectable, recurrent, persistent or metastatic disease or treatment in the adjuvant or neo-adjuvant setting with disease progression or recurrence within 6 months of completion of platinum-containing chemotherapy

2. Participants who previously only received platinum as a radiosensitizer are not eligible

3. Participants must be naïve to checkpoint inhibitors

• Participants who had measurable disease

• Participants who provide a tumor tissue sample, either from archival tissue or newly obtained core or excisional biopsy. If the participant received local therapy (For example: radiation therapy or chemoradiotherapy) after the archival tissue was taken, a new biopsy was required

• Participants who had Eastern Cooperative Oncology Group (ECOG) PS of 0 to 1

• Life expectancy greater than or equals to (>=) 12 weeks as judged by the Investigator

• Adequate hematological, hepatic and renal function as defined in the protocol

• Participants with known Human Immunodeficiency Virus (HIV) infections were in general eligible if the following criteria are met:

1. Clinically indicated participants must be stable on antiretroviral therapy (ART) for at least 4 weeks and agree to adhere to ART

2. had no evidence of documented multi-drug resistance that would prevent effective ART

3. had an HIV viral load of < 400 copies per milliliter (/mL) at Screening

4. had CD4+ T-cell (CD4+) counts >= 350 cells/microliter

5. For participants with a history of an Acquired immunodeficiency syndrome (AIDS)-defining opportunistic infection within the last 12 months, participants may be eligible only after consultation and agreement with the study Medical Monitor

6. If prophylactic antimicrobial drugs were indicated, participants would still be considered eligible upon agreement with the study Medical Monitor

• Participants with hepatitis B virus (HBV) and/or hepatitis C virus (HCV) infections were in general eligible if the following criteria are met:

1. HBV viral load below the limit of quantification. If medically indicated, participants infected with HBV must be treated and on a stable dose of antivirals at study entry and with planned monitoring and management according to appropriate labeling guidance

2. Participants with a history of HCV infection should have completed curative antiviral treatment and require HCV viral load below the limit of quantification

3. Participants on concurrent HCV treatment should have HCV below the limit of quantification

• Other protocol defined inclusion criteria could apply

Exclusion Criteria:

• Participants with active central nervous system (CNS) metastases causing clinical symptoms or 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 treatment

• Participants with interstitial lung disease or has had a history of pneumonitis that has required oral or intravenous (IV) steroids

• Participants with significant acute or chronic infections

• Participants with active autoimmune disease that might deteriorate when receiving an immunostimulatory agent

• Participants with clinically significant cardiovascular/cerebrovascular disease including: cerebral vascular accident/stroke, myocardial infarction, unstable angina, congestive heart failure, or serious cardiac arrhythmia

• Other protocol defined exclusion criteria could apply

Related Conditions & MeSH terms

• Uterine Cervical Neoplasms

Intervention

Drug:
• Bintrafusp alfa
Participants received an intravenous infusion of 1200 milligrams (mg) bintrafusp alfa once every 2 weeks until confirmed disease progression, death, unacceptable toxicity and study withdrawal.

Locations

Country	Name	City	State
Argentina	Centro Oncologico Riojano Integral (CORI)	La Rioja
Argentina	Sanatorio El Parque	Salta
Argentina	Centro Medico San Roque S.R.L.	San Miguel de Tucuman
Australia	Peter MacCallum Cancer Centre-East Melbourne	Melbourne
Australia	Linear Clinical Research Limited	Nedlands
Australia	Calvary Mater Newcastle	Waratah
Belgium	Cliniques Universitaires Saint-Luc	Bruxelles
Belgium	Institut Jules Bordet	Bruxelles
Belgium	Universitair Ziekenhuis Gent - Pneumology	Gent
Belgium	AZ Groeninge - Campus Kennedylaan - account 2	Kortrijk
Belgium	CHU de Liège - PARENT	Liège
Belgium	CHU Sart Tilman	Liège
Belgium	UZ Leuven	Pellenberg
Belgium	GZA Ziekenhuizen - Campus Sint-Augustinus	Wilrijk
Brazil	HGB - Hospital Giovanni Battista - Mãe de Deus Center - Centro de Pesquisa Clínica - Instituto do Câncer	Porto Alegre
Brazil	Clínica de Pesquisas e Centro de Estudos em Oncologia Ginecológica e Mamária Ltda.	São Paulo
Brazil	IBCC - Instituto Brasileiro de Controle do Câncer	São Paulo
China	Chongqing Cancer Hospital	Chongqing
China	Sun Yat-sen University, Cancer Center	Guangzhou
China	Zhejiang Cancer Hospital	Hangzhou
China	Anhui Provincial Hospital	Hefei
China	Shanghai Cancer Hospital, Fudan University	Shanghai
China	Union Hospital Tongji Medical College Huazhong University of Science and Technology	Wuhan
China	Henan Cancer Hospital	Zhengzhou
France	Institut Bergonié	Bordeaux cedex
France	Centre Oscar lambret - Service d'Oncologie medicale	Lille cedex
France	Centre Léon Bérard	Lyon
France	Centre Antoine Lacassagne	Nice
France	Hôpital Cochin - Hematologie et Oncologie Médicale	Paris
France	Centre Hospitalier Lyon Sud - service d'oncologie medicale	Pierre Benite cedex
France	CARIO - Centre Armoricain de Radiothérapie, Imagerie médicale et Oncologie	Plérin
France	Institut Jean Godinot - Service d'hématologie et Oncologie Médicale	Reims cedex
France	ICO - Site René Gauducheau	Saint Herblain
France	Institut de Cancérologie de Strasbourg Europe - ICANS - Service d'oncologie médicale	Strasbourg
Hungary	Orszagos Onkologiai Intezet - Nogyogyaszati Osztaly	Budapest
Hungary	SzSzB Megyei Korhazak es Egyetemi Oktatokorhaz - Onkoradiologia	Nyiregyhaza
Japan	National Cancer Center Hospital - Dept of Mammary Gland/Oncology	Chuo-ku
Japan	NHO Kyushu Cancer Center - Dept of Gynecology	Fukuoka-shi
Japan	Saitama Medical University International Medical Center - Dept of Gynecology/Oncology	Hidaka-shi
Japan	Cancer Institute Hospital of JFCR - Dept of Gynecology	Koto-ku
Japan	Kurume University Hospital - Dept of Gynecology	Kurume-shi
Japan	Jikei University Hospital - Dept of Gynecology	Minato-ku
Japan	University Hospital, University of the Ryukyus - Dept of Obstetrics/Gynecology	Nakagami-gun
Japan	Osaka International Cancer Institute - Dept of Gynecology	Osaka-shi
Japan	NHO Hokkaido Cancer Center - Dept of Gynecology	Sapporo-shi
Japan	Kanagawa Cancer Center - Dept of Gynecology	Yokohama-shi
Korea, Republic of	National Cancer Center	Goyang-si
Korea, Republic of	Asan Medical Center	Seoul
Korea, Republic of	Samsung Medical Center	Seoul
Korea, Republic of	Seoul National University Hospital	Seoul
Korea, Republic of	Severance Hospital, Yonsei University Health System	Seoul
Korea, Republic of	Ajou University Hospital	Suwon
Russian Federation	BHI of Omsk region "Clinical Oncology Dispensary"	Omsk
Russian Federation	LLC "ClinicaUZI4D"	Pyatigorsk
Spain	Hospital Clinic i Provincial de Barcelona - Servicio de Oncologia	Barcelona
Spain	Hospital Universitari Vall d'Hebron - Dept of Oncology	Barcelona
Spain	ICO Girona - Hospital Doctor Josep Trueta - Servicio de Oncologia Medica	Girona
Spain	Clinica Universidad de Navarra (MAD) - Oncology Service	Madrid
Spain	Hospital Universitario 12 de Octubre - Servicio de Oncologia	Madrid
Spain	Hospital Universitario Ramon y Cajal - Servicio de Oncologia	Madrid
Spain	Hospital Regional Universitario de Malaga	Málaga
Spain	Hospital Clinico Universitario de Valencia - Servicio de Hematologia y Oncologia Medica	Valencia
United States	UC Health Clinical Trials Office	Cincinnati	Ohio
United States	Karmanos Cancer Institute	Farmington Hills	Michigan
United States	Highlands Oncology Group	Fayetteville	Arkansas
United States	The West Clinic	Germantown	Tennessee
United States	Comprehensive Cancer Centers of Nevada	Henderson	Nevada
United States	University of Arkansas Medical Sciences	Little Rock	Arkansas
United States	SCRI - Tennessee Oncology	Nashville	Tennessee
United States	Oregon Health & Science University	Portland	Oregon
United States	Washington University in St. Louis	Saint Louis	Missouri
United States	The Stamford Hospital	Stamford	Connecticut
United States	Stanford University Hospital and Clinics - Stanford Cancer Center	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,  Argentina,  Australia,  Belgium,  Brazil,  China,  France,  Hungary,  Japan,  Korea, Republic of,  Russian Federation,  Spain, 

References & Publications (3)

Lan Y, Zhang D, Xu C, Hance KW, Marelli B, Qi J, Yu H, Qin G, Sircar A, Hernandez VM, Jenkins MH, Fontana RE, Deshpande A, Locke G, Sabzevari H, Radvanyi L, Lo KM. Enhanced preclinical antitumor activity of M7824, a bifunctional fusion protein simultaneously targeting PD-L1 and TGF-beta. Sci Transl Med. 2018 Jan 17;10(424):eaan5488. doi: 10.1126/scitranslmed.aan5488. — View Citation

Strauss J, Heery CR, Schlom J, Madan RA, Cao L, Kang Z, Lamping E, Marte JL, Donahue RN, Grenga I, Cordes L, Christensen O, Mahnke L, Helwig C, Gulley JL. Phase I Trial of M7824 (MSB0011359C), a Bifunctional Fusion Protein Targeting PD-L1 and TGFbeta, in Advanced Solid Tumors. Clin Cancer Res. 2018 Mar 15;24(6):1287-1295. doi: 10.1158/1078-0432.CCR-17-2653. Epub 2018 Jan 3. — View Citation

Vugmeyster Y, Grisic AM, Wilkins JJ, Loos AH, Hallwachs R, Osada M, Venkatakrishnan K, Khandelwal A. Model-informed approach for risk management of bleeding toxicities for bintrafusp alfa, a bifunctional fusion protein targeting TGF-beta and PD-L1. Cancer Chemother Pharmacol. 2022 Oct;90(4):369-379. doi: 10.1007/s00280-022-04468-6. Epub 2022 Sep 6. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Number of Participants With Confirmed Objective Response According to Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1) as Assessed by Independent Review Committee (IRC)	Confirmed objective response was defined as the number of participants with a confirmed objective response of complete response (CR) or partial response (PR). CR: Disappearance of all evidence of target and non-target lesions. PR: At least 30% reduction from baseline in the sum of the longest diameter (SLD) of all lesions. Confirmed CR = at least 2 determinations of CR at least 4 weeks apart and before progression. Confirmed PR = at least 2 determinations of PR at least 4 weeks apart and before progression (and not qualifying for a CR). Confirmed objective response was determined according to RECIST v1.1 and as adjudicated by IRC.	Time from first treatment up to 688 days
Secondary	Duration of Response (DOR) According to Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1) as Assessed by Independent Review Committee (IRC)	DOR was defined for participants with confirmed response, as the time from first documentation of confirmed objective response (Complete Response [CR] or Partial Response [PR]) according to RECIST 1.1 to the date of first documentation of progression disease (PD) or death due to any cause, whichever occurred first. CR: Disappearance of all evidence of target and non-target lesions. PR: At least 30% reduction from baseline in the SLD of all lesions. PD: At least a 20 percent (%) increase in the SLD, taking as reference the smallest SLD recorded from baseline or the appearance of 1 or more new lesions. DOR was determined according to RECIST v1.1 and assessed by IRC. Results were calculated based on Kaplan-Meier estimates.	Time from first treatment up to 688 days
Secondary	Durable Response According to Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1) as Assessed by Independent Review Committee (IRC)	Durable Response was defined as the number of participants with confirmed objective response (CR or PR) according to RECIST 1.1, determined by IRC with duration of at least 6 months. CR: Disappearance of all evidence of target and non-target lesions. PR: At least 30% reduction from baseline in the SLD of all lesions. PD: At least a 20 percent (%) increase in the SLD, taking as reference the smallest SLD recorded from baseline or the appearance of 1 or more new lesions.	Time from first treatment up to 688 days
Secondary	Number of Participants With Treatment-Emergent Adverse Events (TEAEs) and Treatment-Related TEAEs, Including Adverse Event of Special Interests (AESIs)	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. Serious AE was defined AE that resulted in any of the following outcomes: death; life threatening; persistent/significant disability/incapacity; initial/prolonged inpatient hospitalization; congenital anomaly/birth defect. TEAEs: TEAEs was defined as events with onset date or worsening during the on-treatment period. TEAEs included serious AEs and non-serious AEs. Treatment-related TEAEs: reasonably related to the study intervention. AESIs included Infusion-related reactions, Immune-related AEs, Transforming growth factor- beta (TGF-ß) inhibition mediated skin AE, bleeding and anemia.	Time from first treatment up to 688 days
Secondary	Progression-Free Survival (PFS) According to Response Evaluation Criteria in Solid Tumors (RECIST Version 1.1) Assessed by Independent Review Committee (IRC)	PFS was defined as the time from first administration of study intervention until date of the first documentation of disease progression (PD) or death due to any cause, whichever occurred first. PD: At least a 20 percent (%) increase in the SLD, taking as reference the smallest SLD recorded from baseline or the appearance of 1 or more new lesions. Kaplan-Meier estimates was used to calculate PFS.	Time from first administration of study drug until the first documentation of PD or death, assessed up to 688 days
Secondary	Number of Participants With Confirmed Objective Response According to Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1) as Assessed by the Investigator	Confirmed objective response was defined as the number of participants with a confirmed objective response of complete response (CR) or partial response (PR). CR: Disappearance of all evidence of target and non-target lesions. PR: At least 30% reduction from baseline in the sum of the longest diameter (SLD) of all lesions. Confirmed CR = at least 2 determinations of CR at least 4 weeks apart and before progression. Confirmed PR = at least 2 determinations of PR at least 4 weeks apart and before progression (and not qualifying for a CR). Confirmed objective response was determined according to RECIST v1.1 and as adjudicated by Investigator.	Time from first treatment up to 688 days
Secondary	Overall Survival (OS)	OS was defined as the time from first administration of study intervention to the date of death due to any cause. The OS was analyzed by using the Kaplan-Meier method.	Time from first administration of study drug up to data cutoff (assessed up to 688 days)
Secondary	Serum Pre-Dose Concentrations (Ctrough) of Bintrafusp Alfa	Ctrough was defined as the concentration observed immediately before next dosing (corresponding to pre-dose or trough concentration for multiple dosing).	At Day 15, Day 29, Day 43, Day 85, Day 127, Day 169, Day 253, Day 337, Day 421, Day 505 and Day 589
Secondary	Serum Concentration at End of Infusion (CEOI) of Bintrafusp Alfa	Serum Concentration at End of Infusion (CEOI) of bintrafusp alfa is reported.	At Day 1 and Day 29
Secondary	Number of Participants With Positive Antidrug Antibodies (ADA)	Serum samples were analyzed by a validated assay method to detect the presence of antidrug antibodies (ADA). Number of participants with positive ADA were reported.	Time from first treatment up to 688 days
Secondary	Percentage of Participants With Confirmed Objective Response According to Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1) as Assessed by Independent Review Committee (IRC) According to Programmed Death Ligand 1 (PD-L1) Expression	Confirmed objective response was defined as the percentage of participants with a confirmed objective response of complete response (CR) or partial response (PR). CR: Disappearance of all evidence of target and non-target lesions. PR: At least 30% reduction from baseline in the sum of the longest diameter (SLD) of all lesions. Confirmed CR = at least 2 determinations of CR at least 4 weeks apart and before progression. Confirmed PR = at least 2 determinations of PR at least 4 weeks apart and before progression (and not qualifying for a CR). Confirmed objective response was determined according to RECIST v1.1 and as adjudicated by IRC through PD-L1 Subgroup. Participants with PD-L1 positive tumors (Combined positive score (CPS) >=1) and PD-L1 negative tumors (CPS<1).	Time from first treatment up to 688 days
Secondary	PFS According to Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1) as Assessed by Independent Review Committee (IRC) According to Programmed Death Ligand 1 (PD-L1) Expression	PFS was defined as the time from first administration of study intervention until the first documentation of disease progression (PD) or death due to any cause, whichever occurred first. PD: At least a 20 percent (%) increase in the SLD, taking as reference the smallest SLD recorded from baseline or the appearance of 1 or more new lesions. PFS was determined according to RECIST v1.1 and as adjudicated by IRC through PD-L1 Subgroup. Participants with PD-L1 positive tumors (Combined positive score (CPS) >=1) and PD-L1 negative tumors (CPS<1).	Time from first administration of study drug until the first documentation of PD or death, assessed up to 688 days
Secondary	Overall Survival (OS) as Assessed According to Programmed Death Ligand 1 (PD-L1) Expression	OS was defined as the time from first administration of study intervention to the date of death due to any cause. The OS was analyzed by using the Kaplan-Meier method. Participants with PD-L1 positive tumors (Combined positive score (CPS) >=1) and PD-L1 negative tumors (CPS<1).	Time from first administration of study drug up to 688 days

External Links

•   Trial Awareness and Transparency website
•   US Medical Information website, Medical Resources