Gemcitabine Plus Cisplatin With or Without Bintrafusp Alfa (M7824) in Participants With 1L BTC
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| ClinicalTrials.gov Identifier: NCT04066491 |
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Recruitment Status :
Completed
First Posted : August 26, 2019
Results First Posted : June 13, 2022
Last Update Posted : December 9, 2022
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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. )
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Brief Summary:
Study consisted of an open-label, safety run-in part and a randomized, double-blind, placebo-controlled Phase 2/3 part. In the Phase 2/3 part, the study was evaluated whether bintrafusp alfa in combination with the current standard of care (SoC) (gemcitabine plus cisplatin) improves overall survival (OS) in chemotherapy and immunotherapy-naïve participants with locally advanced or metastatic Biliary Tract Cancer (BTC) compared to placebo, gemcitabine and cisplatin.
| Condition or disease | Intervention/treatment | Phase |
|---|---|---|
| Biliary Tract Cancer Cholangiocarcinoma Gallbladder Cancer | Drug: M7824 Drug: Placebo Drug: Gemcitabine Drug: Cisplatin | Phase 2 Phase 3 |
| Study Type : | Interventional (Clinical Trial) |
| Actual Enrollment : | 309 participants |
| Allocation: | Randomized |
| Intervention Model: | Parallel Assignment |
| Masking: | Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor) |
| Primary Purpose: | Treatment |
| Official Title: | A Phase II/III, Multicenter, Randomized, Placebo-controlled Study of Gemcitabine Plus Cisplatin With or Without Bintrafusp Alfa (M7824) as First-line Treatment of Biliary Tract Cancer |
| Actual Study Start Date : | September 20, 2019 |
| Actual Primary Completion Date : | May 20, 2021 |
| Actual Study Completion Date : | November 10, 2022 |
Resource links provided by the National Library of Medicine
MedlinePlus Genetics related topics:
Cholangiocarcinoma
| Arm | Intervention/treatment |
|---|---|
| Experimental: Safety Run-In Part: M7824 + Gemcitabine + Cisplatin |
Drug: M7824
Participants received intravenous infusion of M7824 at a dose of 2400 milligrams (mg), once every 3 weeks (Q3W) 2 years (in case of Complete Response), otherwise until criterion pre-sepcified in protocol for discontinuation is met, in combination with intravenous infusion of Gemcitabine and Cisplatin at a dose of 1000 milligram per meter square (mg/m^2) and 25 mg/m^2 respectively on Day 1 and Day 8 of 21- day cycle, for 8 cycles every 3 weeks. Drug: Gemcitabine Gemcitabine was received intravenously at a dose of 1000 milligram per meter square (mg/m^2) on Day 1 and Day 8 of 21- day cycle, for 8 cycles every 3 weeks (Q3W). Drug: Cisplatin Cisplatin was received intravenously at a dose of 25 mg/m^2 on Day 1 and Day 8 of 21-day cycle, for 8 cycles every 3 weeks (Q3W). |
| Experimental: Double-blinded Part: M7824 + Gemcitabine + Cisplatin |
Drug: Gemcitabine
Gemcitabine was received intravenously at a dose of 1000 milligram per meter square (mg/m^2) on Day 1 and Day 8 of 21- day cycle, for 8 cycles every 3 weeks (Q3W). Drug: Cisplatin Cisplatin was received intravenously at a dose of 25 mg/m^2 on Day 1 and Day 8 of 21-day cycle, for 8 cycles every 3 weeks (Q3W). |
| Placebo Comparator: Double-blinded Part: Placebo + Gemcitabine + Cisplatin |
Drug: Placebo
Participants received intravenous infusion of M7824 matched placebo, once every 3 weeks (Q3W) until 2 years (in case of CR), otherwise until crtiterion pre-sepcified in protocol for discontinuation is met. Drug: Gemcitabine Gemcitabine was received intravenously at a dose of 1000 milligram per meter square (mg/m^2) on Day 1 and Day 8 of 21- day cycle, for 8 cycles every 3 weeks (Q3W). Drug: Cisplatin Cisplatin was received intravenously at a dose of 25 mg/m^2 on Day 1 and Day 8 of 21-day cycle, for 8 cycles every 3 weeks (Q3W). |
Primary Outcome Measures :
- Safety Run-in Part: Number of Participants Who Experienced Dose Limiting Toxicities (DLTs) [ Time Frame: Day 1 up to Day 21 of Cycle 1 (each Cycle is of 21 days) ]A DLT is a toxicity related to the study intervention that meets the following criteria as evaluated in the open-label, safety run-in: Grade 3 or 4 Immune-related adverse event (irAE) that needs permanent discontinuation of M7824 treatment; a malignant skin lesion induced by M7824 that is local and can be resected with a negative resection margin is not a DLT; Grade 3 or 4 nonhematologic toxicity other than irAE, A life threatening hematological toxicity (unless clearly attributable to chemotherapy alone), which is hardly medically manageable, including a bleeding event resulting in urgent intervention and admission to an intensive care unit and Grade 5 toxicity.
- Double-blind Part: Overall Survival [ Time Frame: Time from study day 1 up to data cutoff (assessed up to 609 days) ]Overall Survival was defined as the time from study day 1 to the date of death due to any cause. The overall survival was analyzed by using the Kaplan-Meier method.
Secondary Outcome Measures :
- Safety Run-in Part: Number of Participants With Treatment-Emergent Adverse Events (TEAEs), Serious TEAEs (SAEs) and Treatment Related TEAEs According to National Cancer Institute-Common Terminology Criteria for Adverse Events (NCI-CTCAE) Version 5.0 [ Time Frame: Time from first treatment to up to data cutoff (assessed up to 609 days) ]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. TEAE was defined as events with onset date or worsening during the on treatment period. TEAEs included serious TEAEs and non-serious TEAEs.
- Safety Run-in Part: Number of Participants With Grade Greater Than or Equal (>=) 3 Laboratory Abnormalities [ Time Frame: Time from first treatment to up to data cutoff (assessed up to 609 days) ]Laboratory investigation included hematology and biochemistry. The number of participants with Grade >=3 laboratory abnormalities were reported. Severity of grade 3 or higher TEAEs were graded using NCI-CTCAE v5.0 toxicity grades, as follows: Grade 3 = Severe; Grade 4 = Life-threatening and Grade 5 = Death.
- Double-blind Part: Progression-Free Survival (PFS) According to Response Evaluation Criteria in Solid Tumors (RECIST Version 1.1) Assessed by Independent Review Committee (IRC) [ Time Frame: Time from randomization of study drug until the first documentation of PD or death, assessed approximately up to 609 days ]Progression free survival was defined as the time from randomization of study intervention until the first documentation of disease progression (PD) or death due to any cause in the absence of documented PD, whichever occurred first. PD: At least a 20 percent (%) increase in the sum of the longest diameter (SLD) taking as reference the smallest SLD recorded from baseline or the appearance of 1 or more new lesions.
- Double-blind Part: 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) [ Time Frame: Time from randomization of study drug up to data cut off (assessed up to 609 days) ]Percentage of participants with confirmed objective response that is at least one overall assessment of complete response (CR) or partial response (PR) reported here. 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.
- Double-blind Part: 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) [ Time Frame: From first documented objective response to PD or death due to any cause, assessed approximately up to 609 days ]DOR was defined for participants with objective response, as the time from first documentation of objective response (confirmed Complete Response [CR] or Partial Response [PR]) 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.
- Durable Response of at Least 6 Months According to Response Evaluation Criteria In Solid Tumors (RECIST) Version 1.1 [ Time Frame: Time from first treatment assessed up to 1199 days ]
- Double-blind Part: Number of Participants With Treatment-Emergent Adverse Events (TEAEs), Serious TEAEs (SAEs), Treatment Related TEAEs and Adverse Events of Special Interest (AESIs) According to NCI-CTCAE Version 5.0 [ Time Frame: Time from first treatment to up to data cutoff (assessed up to 609 days) ]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. TEAE was defined as events with onset date or worsening during the on treatment period. TEAEs included serious TEAEs and non-serious TEAEs. Adverse events of special interest (AESI) are serious or non-serious AEs that are of clinical interest and should be closely followed. For this study, AESIs include the following: Infusion-related reactions including immediate hypersensitivity; Immune-related AEs; Transforming growth factor beta (TGFβ) inhibition mediated skin reactions; Anemia; Bleeding AEs.
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| Ages Eligible for Study: | 18 Years and older (Adult, Older Adult) |
| Sexes Eligible for Study: | All |
| Accepts Healthy Volunteers: | No |
Criteria
Inclusion Criteria:
- Are participants with histologically or cytologically confirmed locally advanced or metastatic BTC
- Participants must have available tumor tissue (primary or metastatic) (archival or fresh biopsies) before the first administration of study treatment
- At least 1 measurable lesion according to RECIST 1.1
- Eastern Cooperative Oncology Group Performance Status (ECOG PS) of 0 or 1 at study entry and at Week 1, Day 1 prior to dosing
- Life expectancy of >= 12 weeks, as judged by the Investigator
- Adequate hematological function, hepatic function, renal function, coagulation function as defined in the protocol
- Hepatitis B virus (HBV) deoxyribonucleic acid (DNA) positive participants must be treated and on a stable dose of antivirals
- Other protocol defined inclusion criteria could apply
Exclusion Criteria:
- Previous and/or intercurrent cancers
- Receipt of any organ transplantation, including allogeneic stem-cell transplantation, but with the exception of transplants that do not require immunosuppression
- Participants with symptomatic central nervous system (CNS) metastases
- Significant acute or chronic infection including known history of positive test for human immunodeficiency virus (HIV), active tuberculosis, uncontrolled biliary infection and active bacterial or fungal infection requiring systemic therapy (with the exception of hepatitis B and hepatitis C) requiring systemic therapy at study entry and at Week 1 Day 1 prior to dosing.
- Active autoimmune disease that might deteriorate when receiving an immunostimulatory agent
- History of or concurrent interstitial lung disease
- History of hypersensitivity reactions to bintrafusp alfa, anaphylaxis, or recent (within 5 months) uncontrolled asthma, cardiovascular/cerebrovascular disease
- Chronic obstructive pulmonary disease exacerbation or other respiratory illness requiring hospitalization or precluding study therapy within 30 days before randomization
- Prior therapy with any antibody/drug targeting T-cell coregulatory proteins (immune checkpoints)
- Other protocol defined exclusion criteria could apply
Information from the National Library of Medicine
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04066491
Locations
Show 94 study locations
Sponsors and Collaborators
EMD Serono Research & Development Institute, Inc.
Merck KGaA, Darmstadt, Germany
Investigators
| Study Director: | Medical Responsible | Merck Healthcare KGaA, Darmstadt, Germany, an affiliate of Merck KGaA, Darmstadt, Germany |
Study Documents (Full-Text)
Documents provided by EMD Serono ( EMD Serono Research & Development Institute, Inc. ):
Documents provided by EMD Serono ( EMD Serono Research & Development Institute, Inc. ):
Study Protocol [PDF] July 14, 2021
Statistical Analysis Plan [PDF] February 1, 2022
Additional Information:
Publications of Results:
Publications of Results:
| Responsible Party: | EMD Serono Research & Development Institute, Inc. |
| ClinicalTrials.gov Identifier: | NCT04066491 |
| Other Study ID Numbers: |
MS200647_0055 2019-001992-35 ( EudraCT Number ) |
| First Posted: | August 26, 2019 Key Record Dates |
| Results First Posted: | June 13, 2022 |
| Last Update Posted: | December 9, 2022 |
| Last Verified: | November 2022 |
| Individual Participant Data (IPD) Sharing Statement: | |
| Plan to Share IPD: | Yes |
| Plan Description: | We are committed to enhancing public health through responsible sharing of clinical trial data. Following approval of a new product or a new indication for an approved product in both the US and European Union, the study sponsor and/or its affiliated companies will share study protocols, anonymized patient data and study level data, and redacted clinical study reports 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 bit.ly/IPD21 |
| Supporting Materials: |
Study Protocol Statistical Analysis Plan (SAP) Clinical Study Report (CSR) |
| Time Frame: | Within six months after the approval of a new product or a new indication for an approved product in both the United States and the European Union. |
| Access Criteria: | Qualified scientific and medical researchers can request the data. Such requests must be submitted in writing to the company's portal and will be internally reviewed regarding criteria for researchers' qualification and legitimacy of the research proposal. |
| URL: | http://bit.ly/IPD21 |
| Studies a U.S. FDA-regulated Drug Product: | Yes |
| Studies a U.S. FDA-regulated Device Product: | No |
Keywords provided by EMD Serono ( EMD Serono Research & Development Institute, Inc. ):
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Metastatic Biliary Tract Cancer Cholangiocarcinoma Gallbladder Cancer Ampullary cancer M7824 |
Bintrafusp alfa Transforming growth factor-beta Programmed death-ligand 1 INTR@PID |
Additional relevant MeSH terms:
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Cholangiocarcinoma Biliary Tract Neoplasms Gallbladder Neoplasms Adenocarcinoma Carcinoma Neoplasms, Glandular and Epithelial Neoplasms by Histologic Type Neoplasms Digestive System Neoplasms Neoplasms by Site Biliary Tract Diseases Digestive System Diseases |
Gallbladder Diseases Gemcitabine Antineoplastic Agents Antimetabolites, Antineoplastic Antimetabolites Molecular Mechanisms of Pharmacological Action Antiviral Agents Anti-Infective Agents Enzyme Inhibitors Immunosuppressive Agents Immunologic Factors Physiological Effects of Drugs |