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A Study to Evaluate the Efficacy and Safety of Bintrafusp Alfa (M7824) Monotherapy in Metastatic or Locally Advanced Urothelial Cancer

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT04349280
Recruitment Status : Recruiting
First Posted : April 16, 2020
Last Update Posted : November 26, 2020
Sponsor:
Collaborator:
Merck KGaA, Darmstadt, Germany
Information provided by (Responsible Party):
GlaxoSmithKline

Brief Summary:
The purpose of this study is to evaluate bintrafusp alfa in participants with metastatic or locally advanced urothelial cancer. This trial provides the first evaluation of bintrafusp alfa in participants with urothelial cancer that has progressed following platinum therapy

Condition or disease Intervention/treatment Phase
Neoplasms Drug: Bintrafusp alfa Phase 1

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 40 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Intervention Model Description: This is a single arm study.
Masking: None (Open Label)
Masking Description: This is an open label study.
Primary Purpose: Treatment
Official Title: A Phase Ib Trial to Evaluate the Efficacy and Safety of Bintrafusp Alfa Monotherapy in Metastatic or Locally Advanced/Unresectable Urothelial Cancer With Disease Progression or Recurrence Following Treatment With a Platinum Agent
Actual Study Start Date : October 15, 2020
Estimated Primary Completion Date : September 8, 2022
Estimated Study Completion Date : September 8, 2022

Arm Intervention/treatment
Experimental: Participants receiving bintrafusp alfa
Participants will receive bintrafusp alfa 1200 milligram (mg), intravenous (IV) infusion, once every 2 weeks (Q2W) until progressive disease (PD), death, unacceptable toxicity, study withdrawal or up to 2 years.
Drug: Bintrafusp alfa
Participants will receive bintrafusp alfa 1200 mg, IV infusion, Q2W until PD, death, unacceptable toxicity, study withdrawal or up to 2 years.




Primary Outcome Measures :
  1. Confirmed overall response rate (ORR) - Investigator assessment [ Time Frame: From 6 month after Day 1 of treatment through 3 years maximum ]
    The ORR is defined as the percentage of participants with a partial response (PR) or complete response (CR) as assessed by Investigator using Response Evaluation Criteria in Solid Tumors (RECIST) version (v) 1.1.


Secondary Outcome Measures :
  1. Duration of Response (DOR) - Investigator assessment [ Time Frame: From start of treatment up to 3 years ]
    DOR is defined as the time from first documentation of an objective response (CR or PR) according to RECIST v 1.1 assessed by the investigator to the date of first documentation of objective response of disease progression or death due to any cause whichever occurs first.

  2. Progression-free Survival (PFS) - Investigator assessment [ Time Frame: From start of treatment up to 3 years ]
    PFS according to RECIST v 1.1 assessed by investigator is defined as the time from first administration of study intervention until date of the first documentation of PD or death due to any cause in the absence of documented PD, whichever occurs first.

  3. Confirmed overall response rate- Independent Review Committee (IRC) [ Time Frame: From start of treatment up to 3 years ]
    ORR is defined as the percentage (%) of participants with a PR or CR as assessed by IRC using RECIST v 1.1.

  4. Duration of Response - IRC [ Time Frame: From start of treatment up to 3 years ]
    DOR is defined as the time from first documentation of an objective response (CR or PR) according to RECIST v 1.1 assessed by IRC to the date of first documentation of objective response of disease progression or death due to any cause whichever occurs first.

  5. Progression free survival - IRC [ Time Frame: From start of treatment up to 3 years ]
    PFS according to RECIST v 1.1 assessed by IRC, is defined as the time from first administration of study intervention until date of the first documentation of PD or death due to any cause in the absence of documented PD, whichever occurs first.

  6. Overall survival (OS) [ Time Frame: From start of treatment up to 3 years ]
    OS is defined as the time from first administration of study intervention to the date of death due to any cause.

  7. Number of participants with adverse events (AEs) and serious adverse events (SAEs) [ Time Frame: From start of treatment up to 3 years ]
    An AE is any untoward medical occurrence in a clinical study participant, temporally associated with the use of a study intervention, whether considered related to the study intervention. A SAE is defined as any untoward medical occurrence that, at any dose: results in death, is life-threatening, requires hospitalization or prolongation of existing hospitalization, results in persistent or significant disability/incapacity, is a congenital anomaly/birth defect, other situations which involve medical or scientific judgment.

  8. Number of participants with AEs by their severity [ Time Frame: From start of treatment up to 3 years ]
    The severity of AEs will be graded utilizing the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE), v 5.0.

  9. Concentration observed immediately at the end of infusion (Ceoi) for bintrafusp alfa [ Time Frame: Up to 2 years maximum ]
    Blood sample will be collected for measurement of serum concentrations of bintrafusp alfa for Ceoi analysis at indicated time points.

  10. Concentration observed immediately before next dosing (corresponding to pre-dose or trough concentration for multiple dosing) (Ctrough) for bintrafusp alfa. [ Time Frame: Up to 2 years maximum ]
    Blood sample will be collected for measurement of serum concentrations of bintrafusp alfa for Ctrough analysis at indicated time points.

  11. Number of participants with positive anti-drug antibodies (ADAs) against bintrafusp alfa [ Time Frame: Up to 2 years maximum ]
    Serum samples will be collected at indicated time points for analysis of ADAs by using tiered testing with validated immunoassay.

  12. Percentage of participants with positive ADAs against bintrafusp alfa [ Time Frame: Up to 2 years maximum ]
    Serum samples will be collected at indicated time points for analysis of ADAs.



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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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:

  • Participants can give signed informed consent/assent which includes compliance with the requirements and restrictions listed in the informed consent form (ICF).
  • At least eighteen years of age at the time of signing the informed consent.
  • Participants with histologically confirmed locally advanced or metastatic or locally advanced/unresectable urothelial carcinoma (including renal, pelvis, ureter, urinary bladder, urethra). Mixed histologies are acceptable provided transitional cell carcinoma is the predominant histology. 1. Measurable disease per RECIST v 1.1 criteria; and 2. Experienced PD or recurrence either following platinum containing chemotherapy for metastatic or locally advanced/unresectable urothelial cancer or within 12 months from completion of neo-adjuvant or adjuvant platinum-containing chemotherapy for localized muscle-invasive urothelial cancer.
  • Able to provide, a tumor tissue sample collected during screening and prior to administration of bintrafusp alfa.
  • Able to provide an archival tumor sample (preferably from the most recent biopsy). Archival material is formalin fixed tumor tissue sample from a biopsy of a tumor lesion.
  • Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0-1.
  • Participants with adequate organ system functions as defined follows: Absolute neutrophil count (ANC) >=1.5*10^9 cells per liter (cells/L); Hemoglobin >=9.0 grams per deciliter (g/dL); Platelets >=100*10^9 cells/L; international normalized ratio (INR) or prothrombin time (PT) <=1.5*Upper limit of normal (ULN); Albumin >=2.5 g/dL; Alanine aminotransferase (ALT) and Aspartate aminotransferase (AST) <=2.5*ULN or <=5*ULN for participants with documented liver metastases; Total bilirubin <=1.5*ULN (Isolated bilirubin >1.5*ULN is acceptable if bilirubin is fractionated and direct bilirubin <35 percent); calculated creatinine clearance (CrCI) >=30 milliliter per minute (mL/min) and Ejection Fraction >=50 percent.
  • Life expectancy of at least 12 weeks.
  • A female is eligible if she is not pregnant or breastfeeding, and at least one of the following conditions applies: Not a woman of childbearing potential (WOCBP) or If a WOCBP, use a highly effective contraceptive method (i.e., with a failure rate of <1% per year), preferably with low user dependency, for the following time periods: Before the first dose of the study interventions, if using hormonal contraception: has completed at least one 4-week cycle of an oral contraception pill and either had or has begun her menses or has used a depot contraceptive or extended-cycle oral contraceptive for least 28 days and has a documented negative pregnancy test using a highly sensitive assay; during the intervention period; and after the study intervention period (i.e., after the last dose of study intervention is administered) for at least 2 months.
  • The Investigator evaluates the effectiveness of the contraceptive method in relationship to the first dose of study intervention.
  • Participant has a negative serum or highly sensitive urine pregnancy test, as required by local regulations, within 24 hours before the first dose of study intervention. If a urine test cannot be confirmed as negative (e.g., an ambiguous result), a serum pregnancy test is required.
  • The Investigator reviews the medical history, menstrual history, and recent sexual activity to decrease the risk for inclusion of a female with an early undetected pregnancy.
  • Male participants: Contraceptive use by men should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies. Male participants are eligible to participate if they agree to the following from the time of first dose of study until 125 days after the last dose of study treatment to allow for clearance of any altered sperm: Refrain from donating sperm; Be abstinent from heterosexual intercourse as their preferred and usual lifestyle (abstinent on long term and persistent basis) and agree to remain abstinent or agree to use a male condom and female partner to use an additional highly effective contraceptive method with a failure rate of <1% per year when having sexual intercourse with a woman of childbearing potential who is not currently pregnant.
  • Archival tumor sample high for Programmed Death-Ligand 1 (PD-L1) by central assay.

Exclusion Criteria:

  • Active brain and/or leptomeningeal disease that is symptomatic or requires therapeutic intervention. Participants with asymptomatic central nervous system (CNS) metastases who are clinically stable as demonstrated by serial brain images and have no requirement for corticosteroids for at least 14 days prior to enrollment are eligible.
  • History of malignancy other than urothelial cancer within the last 3 years except for localized tumors that have been treated with curative intent or have not required therapy in the past 2 years. (e.g., resected non-melanoma skin cancer).
  • No more than 2 lines of systemic therapy for the treatment of metastastic disease. If the most recent therapy was not a platinum-based regimen, the participant must have progressed on or after that therapy.
  • Cirrhosis or current unstable liver or biliary disease per investigator assessment defined by the presence of ascites, encephalopathy, coagulopathy, hypoalbuminemia, esophageal or gastric varices, or persistent jaundice.
  • Current pneumonitis or history of non-infectious pneumonitis that required systemic immunosuppressive treatment.
  • Active autoimmune disease that required systemic immunosuppressive treatment within the past 2 years.
  • Received prior allogeneic/autologous bone marrow or solid organ transplant.
  • Receiving systemic corticosteroids (>10 mg daily oral prednisone or equivalent) or other immunosuppressive agent within 7 days prior to study treatment. Inhaled or topical steroids are permitted.
  • Known severe hypersensitivity reactions to monoclonal antibodies or any ingredient used in the study treatment formulation (Grade >=3 NCI-CTCAE v 5.0).
  • Active infection requiring systemic therapy.
  • Received any live vaccine within 30 days prior first dose of intervention.
  • Known history of positive test for human immunodeficiency virus (HIV) with the exception of participants with cluster of differentiation 4 (CD4) + T-cell (CD4+) counts >=350 cells per microliter (cells /uL) and no history of acquired immunodeficiency syndrome (AIDS)-defining opportunistic infections.
  • Active hepatitis B virus (HBV) (HBV surface antigen-positive).
  • Active hepatitis C virus (HCV) infection, or positive HCV antibody, with the exception of participants that 1. Have HCV viral load below the limits of quantitation and 2. Completed curative antiviral therapy or are receiving and compliant with antiviral therapy.
  • History or evidence of cardiac abnormalities within the 6 months prior to first dose of intervention which include: a. Serious, uncontrolled cardiac arrhythmia or clinically significant electrocardiogram abnormalities including second degree (Type II) or third-degree atrioventricular block or QTcF interval >450 millisecond (msec) (or QTcF >480 msec for participants with bundle branch block); b. Cardiomyopathy, myocardial infarction, acute coronary syndromes (including unstable angina pectoris), coronary angioplasty, stenting or bypass grafting; c. Congestive heart failure (Class II, III, or IV) as defined by the New York Heart Association functional classification system; and d. Symptomatic pericarditis.
  • Participants with history of bleeding diathesis or recent major bleeding events considered by the Investigator as high risk for investigational drug treatment are also excluded.
  • Any other serious or uncontrolled medical disorder that, in the opinion of the investigator, may increase the risk associated with study participation or study drug administration, impair the ability of the participant to receive protocol therapy, or interfere with the interpretation of study results.
  • Received prior systemic anti-cancer therapy within 2 weeks prior to study treatment.
  • Received prior therapy with an anti- programmed death 1 (PD-1), anti-PD-L1, anti-PD-L2, anti-CD137, or anti-Cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) antibody (including ipilimumab or any other antibody or drug specifically targeting T-cell co-stimulation or checkpoint pathways).
  • Received prior therapy targeting transforming growth factor (TGF) beta - (e.g., Galunistertib).
  • Received radiation therapy (or other non-systemic disease therapy) within 2 weeks prior to study treatment.
  • Undergone major surgery within 4 weeks prior to administration of study treatment.
  • Residual toxicities attributed to prior anti-cancer therapy that are clinically significant or unmanaged and >Grade 1 or previous baseline other than neuropathy (<=Grade 2), alopecia, and fatigue.
  • The participant has participated in a clinical trial and has received an investigational product within the following time period prior to the first dosing day in the current study: 30 days, 5 half-lives or twice the duration of the biological effect of the investigational product (whichever is longer).
  • Exposure to more than 2 investigational anti-cancer medicinal products within 12 months prior to the first dosing day.
  • Is known to abuse alcohol or drugs.
  • Has any psychiatric condition that would prohibit the understanding or rendering of informed consent or consistent participation in study procedures.
  • Has legal incapacity or limited legal capacity.

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): NCT04349280


Contacts
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Contact: US GSK Clinical Trials Call Center 877-379-3718 GSKClinicalSupportHD@gsk.com
Contact: EU GSK Clinical Trials Call Center +44 (0) 20 89904466 GSKClinicalSupportHD@gsk.com

Locations
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United States, New York
GSK Investigational Site Recruiting
Lake Success, New York, United States, 11041
Contact: US GSK Clinical Trials Call Center    877-379-3718    GSKClinicalSupportHD@gsk.com   
Contact: EU GSK Clinical Trials Call Centre    +44 (0) 20 8990 4466    GSKClinicalSupportHD@gsk.com   
Principal Investigator: Matthew Galsky         
United States, Ohio
GSK Investigational Site Recruiting
Cincinnati, Ohio, United States, 45229
Contact: US GSK Clinical Trials Call Center    877-379-3718    GSKClinicalSupportHD@gsk.com   
Contact: EU GSK Clinical Trials Call Centre    +44 (0) 20 8990 4466    GSKClinicalSupportHD@gsk.com   
Principal Investigator: Shuchi Gulati         
United States, Washington
GSK Investigational Site Recruiting
Seattle, Washington, United States, 98109
Contact: US GSK Clinical Trials Call Center    877-379-3718    GSKClinicalSupportHD@gsk.com   
Contact: EU GSK Clinical Trials Call Centre    +44 (0) 20 8990 4466    GSKClinicalSupportHD@gsk.com   
Principal Investigator: Petros Grivas         
Netherlands
GSK Investigational Site Recruiting
Amsterdam, Netherlands, 1066 CX
Contact: US GSK Clinical Trials Call Center    877-379-3718    GSKClinicalSupportHD@gsk.com   
Contact: EU GSK Clinical Trials Call Centre    +44 (0) 20 8990 4466    GSKClinicalSupportHD@gsk.com   
Principal Investigator: Michiel S. van der Heijden         
Spain
GSK Investigational Site Recruiting
Madrid, Spain, 28040
Contact: US GSK Clinical Trials Call Center    877-379-3718    GSKClinicalSupportHD@gsk.com   
Contact: EU GSK Clinical Trials Call Centre    +44 (0) 20 8990 4466    GSKClinicalSupportHD@gsk.com   
Principal Investigator: Bernard Doger de Spéville         
GSK Investigational Site Recruiting
Madrid, Spain, 28041
Contact: US GSK Clinical Trials Call Center    877-379-3718    GSKClinicalSupportHD@gsk.com   
Contact: EU GSK Clinical Trials Call Centre    +44 (0) 20 8990 4466    GSKClinicalSupportHD@gsk.com   
Principal Investigator: Daniel Castellano Gauna         
GSK Investigational Site Recruiting
Sevilla, Spain, 41013
Contact: US GSK Clinical Trials Call Center    877-379-3718    GSKClinicalSupportHD@gsk.com   
Contact: EU GSK Clinical Trials Call Centre    +44 (0) 20 8990 4466    GSKClinicalSupportHD@gsk.com   
Principal Investigator: Begoña Pérez Valderrama         
United Kingdom
GSK Investigational Site Recruiting
London, United Kingdom, EC1A 7BE
Contact: US GSK Clinical Trials Call Center    877-379-3718    GSKClinicalSupportHD@gsk.com   
Contact: EU GSK Clinical Trials Call Centre    +44 (0) 20 8990 4466    GSKClinicalSupportHD@gsk.com   
Principal Investigator: Thomas Powles         
Sponsors and Collaborators
GlaxoSmithKline
Merck KGaA, Darmstadt, Germany
Investigators
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Study Director: GSK Clinical Trials GlaxoSmithKline
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Responsible Party: GlaxoSmithKline
ClinicalTrials.gov Identifier: NCT04349280    
Other Study ID Numbers: 213152
First Posted: April 16, 2020    Key Record Dates
Last Update Posted: November 26, 2020
Last Verified: November 2020
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description: IPD for this study will be made available via the Clinical Study Data Request site.
Supporting Materials: Study Protocol
Statistical Analysis Plan (SAP)
Informed Consent Form (ICF)
Clinical Study Report (CSR)
Time Frame: IPD will be made available within 6 months of publishing the results of the primary endpoints, key secondary endpoints and safety data of the study.
Access Criteria: Access is provided after a research proposal is submitted and has received approval from the Independent Review Panel and after a Data Sharing Agreement is in place. Access is provided for an initial period of 12 months but an extension can be granted, when justified, for up to another 12 months.
URL: http://clinicalstudydatarequest.com

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by GlaxoSmithKline:
Bintrafusp Alfa
Platinum Agent
Response Evaluation Criteria in Solid Tumors
Urothelial Cancer
M7824