Bintrafusp Alfa in High Mobility Group AT-Hook 2 (HMGA2) Expressing Triple Negative Breast Cancer

Study Overview
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Brief Summary
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The main purpose of this study was to evaluate bintrafusp alfa monotherapy in participants with triple negative breast cancer (TNBC) who express high levels of HMGA2 as determined by a centralized reverse transcriptase-polymerase chain reaction (RT-PCR) test.

Official Title
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A Phase II, Multicenter, Open Label Study of Bintrafusp Alfa (M7824) Monotherapy in Participants With HMGA2-expressing Triple Negative Breast Cancer

Conditions
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Triple Negative Breast Neoplasms

Intervention / Treatment
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* Drug: Bintrafusp alfa


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Study participants have histologically or cytologically confirmed TNBC Absence of human epidermal growth factor receptor 2 (HER2), estrogen receptor, and progesterone receptor expression must be documented (criteria for defining TNBC are outlined in the protocol) Participants must have received at least one line of systemic therapy for metastatic disease and have progressed on the line of therapy immediately prior to study entry. There is no limit to the number of prior therapies Participants may prescreen for HMGA2 expression while on preceding treatment, however screening should only occur if in the opinion of the Investigator, the participant would likely be eligible for study within 6 months Participants must have measurable disease Availability of either archival tumor tissue or fresh core or excisional biopsy of a tumor lesion (primary or metastatic, excluding bone biopsies) is mandatory to determine HMGA2 expression level prior to enrollment HMGA2 high tumor expression is required and will be determined by a central lab Participants who have Eastern Cooperative Oncology Group (ECOG) PS of 0 to 1 Participants have a life expectancy greater than or equal to (>=) 12 weeks as judged by the Investigator at study start Participants have adequate hematological, hepatic and renal and coagulation function as defined in the protocol Participants with known Human Immunodeficiency Virus (HIV) infections are in general eligible if the criteria as defined in the protocol are met (Food and Drug Administration [FDA] Guidance on Cancer Clinical Trial Eligibility, March 2019) Participants with hepatitis B virus (HBV) and/or hepatitis C virus (HCV) infections are in general eligible if the criteria as defined in the protocol are met (FDA Guidance on Cancer Clinical Trial Eligibility, March 2019) Other protocol defined inclusion criteria could apply Exclusion Criteria: Participants with active central nervous system (CNS) metastases causing clinical symptoms or metastases that 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 intervention Participants must not have received prior cancer treatment with any other immunotherapy or checkpoint inhibitors, or any other immune-modulating monoclonal antibody Participants that received any organ transplantation, including stem-cell transplantation, but with the exception of transplants that do not require immunosuppression 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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Bintrafusp alfa<br> | Drug: Bintrafusp alfa<br>* Participants received an intravenous infusion of 1200 milligrams (mg) bintrafusp alfa once every 2 weeks until confirmed disease progression, unacceptable toxicity, study withdrawal or death.<br>* Other names: M7824;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Objective Response Rate (ORR) According to Response Evaluation Criteria in Solid Tumors (RECIST Version 1.1) Assessed by an Independent Review Committee (IRC) | The ORR was defined as the percentage of participants with a confirmed objective response of Complete Response (CR) or Partial Response (PR) according to RECIST v1.1 as assessed by IRC. CR: Disappearance of all evidence of target and non-target lesions. PR: At least 30 percent (%) reduction from baseline in sum of longest diameter (SLD) of all lesions. | Time from first study intervention up to 321 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Duration of Response (DOR) According to RECIST Version 1.1 | DOR was defined for participants with a confirmed objective response as the time from first documentation of a confirmed objective response (CR or PR) according to RECIST 1.1 to the date of first documentation of objective PD or death due to any cause, whichever occurs first. CR: Disappearance of all evidence of target and non-target lesions. PR: At least 30 percent (%) reduction from baseline in sum of longest diameter (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. | From first documented objective response to PD or death due to any cause, assessed up to 321 days | 
| Durable Response Rate (DRR) of at Least 6 Months Assessed by an Independent Review Committee (IRC) | DRR was defined as the number of participants having a DOR of at least 6 months, out of the total number of participants. | Time from first study intervention up to 321 days | 
| Progression-Free Survival (PFS) According to RECIST Version 1.1 Assessed by the IRC | PFS was defined as the time from first study intervention until the first documentation of PD or death due to any cause in the absence of documented PD, whichever occurred first. PD: At least a 20% increase in the SLD, taking as reference the smallest SLD recorded from baseline or the appearance of 1 or more new lesions. The tumor response was determined according to RECIST version 1.1 and assessed by the IRC. | Time from first study intervention up to until the first documentation of PD or death, assessed up to 321 days | 
| Duration of Response (DOR) According to Response Evaluation Criteria in Solid Tumors (RECIST Version 1.1) Assessed by the Investigator | DOR was defined for participants with a confirmed objective response as the time from first documentation of a confirmed objective response (CR or PR) according to RECIST 1.1 to the date of first documentation of objective PD or death due to any cause, whichever occurs first. CR: Disappearance of all evidence of target and non-target lesions. PR: At least 30% reduction from baseline in sum of longest diameter (SLD) of all lesions. PD: At least a 20% 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 investigator. | From first documented objective response to PD or death due to any cause, assessed up to 321 days | 
| Objective Response Rate (ORR) According to Response Evaluation Criteria in Solid Tumors (RECIST Version 1.1) Assessed by the Investigator | The ORR was defined as the percentage of participants with a confirmed objective response of Complete Response (CR) or Partial Response (PR) according to RECIST v1.1 as assessed by investigator. CR: Disappearance of all evidence of target and non-target lesions. PR: At least 30 percent (%) reduction from baseline in sum of longest diameter (SLD) of all lesions. | Time from first study intervention up to 321 days | 
| Durable Response Rate (DRR) According to Response Evaluation Criteria in Solid Tumors (RECIST Version 1.1) Assessed by Investigator | DRR was defined as the number of participants having a DOR of at least 6 months, out of the total number of participants. | Time from first study intervention up to 321 days | 
| Progression-Free Survival (PFS) According to Response Evaluation Criteria in Solid Tumors (RECIST Version 1.1) Assessed by Investigator | PFS was defined as the time from first study intervention until the first documentation of PD or death due to any cause in the absence of documented PD, whichever occurred first. PD: At least a 20% increase in the SLD, taking as reference the smallest SLD recorded from baseline or the appearance of 1 or more new lesions. The tumor response was determined according to RECIST version 1.1 and assessed by the investigator. | Time from first study intervention up to the first documentation of PD or death, assessed up to 321 days | 
| Overall Survival (OS) | OS was defined as the time from first day of study treatment to death due to any cause. Participants without documented death at the time of analysis are censored at the date of the last follow-up. OS was summarized by Kaplan-Meier (KM) methods. | Time from the first dose of study drug until occurrence of death due to any cause, assessed up to 321 days | 
| Number of Participants With Treatment-Emergent Adverse Events (TEAEs), Treatment-Related AEs, and Adverse Events of Special Interest (AESIs) | An AE was defined as any untoward medical occurrence in a participant administered a pharmaceutical product and which did not necessarily have a causal relationship with this treatment. An AE could therefore be any unfavorable and unintended sign, symptom, or disease temporally associated with the use of a medicinal product or protocol-specified procedure, whether considered related to the medicinal product or protocol-specified procedure. 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. The AESIs considered in this study are infusion-related reactions including immediate hypersensitivity, immune-related adverse events, skin adverse events, bleeding events and anemia. | Time from first study intervention up to 321 days | 
| Immediate Observed Serum Concentration at End of Infusion (Ceoi) of Bintrafusp Alfa | Ceoi was the serum concentration observed immediately at the end of infusion. This was taken directly from the observed bintrafusp alfa concentration-time data. | Pre-dose, End of Infusion from Day 1 to 321 | 
| Serum Trough Concentration Levels (Ctrough) of Bintrafusp Alfa | Ctrough was the serum concentration observed immediately before next dosing. | Pre-dose, End of Infusion from Day 1 to 321 | 
| Number of Participants With Positive Anti-Drug Antibody (ADA) of Bintrafusp Alfa | The detection of antibodies to bintrafusp alfa was performed using a validated ADA assay method with tiered testing of screening, confirmatory and titration. | Pre-dose, End of Infusion from Day 1 to 321 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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M7824, Bintrafusp alfa, Programmed death-ligand 1, Transforming growth factor-β (TGF-β), Breast Cancer, MS200647