Triple Negative Breast Neoplasms
Conditions
Keywords
M7824, Bintrafusp alfa, Programmed death-ligand 1, Transforming growth factor-β (TGF-β), Breast Cancer, MS200647
Brief summary
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.
Interventions
DRUGBintrafusp alfa
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.
Sponsors
Merck Healthcare KGaA, Darmstadt, Germany, an affiliate of Merck KGaA, Darmstadt, Germany
EMD Serono Research & Development Institute, Inc.
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Objective Response Rate (ORR) According to Response Evaluation Criteria in Solid Tumors (RECIST Version 1.1) Assessed by an Independent Review Committee (IRC) | Time from first study intervention up to 321 days | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Durable Response Rate (DRR) of at Least 6 Months Assessed by an Independent Review Committee (IRC) | Time from first study intervention up to 321 days | DRR was defined as the number of participants having a DOR of at least 6 months, out of the total number of participants. |
| Progression-Free Survival (PFS) According to RECIST Version 1.1 Assessed by the IRC | Time from first study intervention up to until the first documentation of PD or death, assessed up to 321 days | 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. |
| Duration of Response (DOR) According to Response Evaluation Criteria in Solid Tumors (RECIST Version 1.1) Assessed by the Investigator | From first documented objective response to PD or death due to any cause, assessed up to 321 days | 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. |
| Objective Response Rate (ORR) According to Response Evaluation Criteria in Solid Tumors (RECIST Version 1.1) Assessed by the Investigator | Time from first study intervention up to 321 days | 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. |
| Durable Response Rate (DRR) According to Response Evaluation Criteria in Solid Tumors (RECIST Version 1.1) Assessed by Investigator | Time from first study intervention up to 321 days | DRR was defined as the number of participants having a DOR of at least 6 months, out of the total number of participants. |
| Duration of Response (DOR) According to RECIST Version 1.1 | From first documented objective response to PD or death due to any cause, assessed up to 321 days | 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. |
| Overall Survival (OS) | Time from the first dose of study drug until occurrence of death due to any cause, assessed up to 321 days | 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. |
| Number of Participants With Treatment-Emergent Adverse Events (TEAEs), Treatment-Related AEs, and Adverse Events of Special Interest (AESIs) | Time from first study intervention up to 321 days | 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. |
| Immediate Observed Serum Concentration at End of Infusion (Ceoi) of Bintrafusp Alfa | Pre-dose, End of Infusion from Day 1 to 321 | Ceoi was the serum concentration observed immediately at the end of infusion. This was taken directly from the observed bintrafusp alfa concentration-time data. |
| Serum Trough Concentration Levels (Ctrough) of Bintrafusp Alfa | Pre-dose, End of Infusion from Day 1 to 321 | Ctrough was the serum concentration observed immediately before next dosing. |
| Number of Participants With Positive Anti-Drug Antibody (ADA) of Bintrafusp Alfa | Pre-dose, End of Infusion from Day 1 to 321 | The detection of antibodies to bintrafusp alfa was performed using a validated ADA assay method with tiered testing of screening, confirmatory and titration. |
| Progression-Free Survival (PFS) According to Response Evaluation Criteria in Solid Tumors (RECIST Version 1.1) Assessed by Investigator | Time from first study intervention up to the first documentation of PD or death, assessed up to 321 days | 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. |
Countries
Belgium, France, Italy, Russia, Spain, United States
Participant flow
Pre-assignment details
A total of 15 participants were screened, of which 11 participants received bintrafusp alfa monotherapy.
Participants by arm
| Arm | Count |
|---|---|
| Bintrafusp Alfa 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. | 11 |
| Total | 11 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Death | 5 |
| Overall Study | Lost to Follow-up | 1 |
| Overall Study | Other | 2 |
| Overall Study | Withdrawal by Subject | 2 |
Baseline characteristics
| Characteristic | Bintrafusp Alfa |
|---|---|
| Age, Continuous | 59 Years STANDARD_DEVIATION 11.3 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 9 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 2 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 2 Participants |
| Race (NIH/OMB) White | 9 Participants |
| Sex: Female, Male Female | 11 Participants |
| Sex: Female, Male Male | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 6 / 11 |
| other Total, other adverse events | 9 / 11 |
| serious Total, serious adverse events | 7 / 11 |
Outcome results
Primary
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 frame: Time from first study intervention up to 321 days
Population: As per changes in planned analysis, the outcome measure related to efficacy were not assessed.
Secondary
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 frame: Time from first study intervention up to 321 days
Population: As per changes in planned analysis, the outcome measure related to efficacy were not assessed.
Secondary
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 frame: Time from first study intervention up to 321 days
Population: As per changes in planned analysis, the outcome measure related to efficacy were not assessed.
Secondary
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.
Time frame: From first documented objective response to PD or death due to any cause, assessed up to 321 days
Population: As per changes in planned analysis, the outcome measure related to efficacy were not assessed.
Secondary
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.
Time frame: From first documented objective response to PD or death due to any cause, assessed up to 321 days
Population: As per changes in planned analysis, the outcome measure related to efficacy were not assessed.
Secondary
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.
Time frame: Pre-dose, End of Infusion from Day 1 to 321
Population: As per changes in planned analysis, the outcome measure related to pharmacokinetics were not assessed.
Secondary
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.
Time frame: Pre-dose, End of Infusion from Day 1 to 321
Population: As per changes in planned analysis, the outcome measure related to pharmacokinetics were not assessed.
Secondary
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 frame: Time from first study intervention up to 321 days
Population: The Safety Analysis Set (SAF) analysis set included all participants who received at least 1 dose of study intervention.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Bintrafusp Alfa | Number of Participants With Treatment-Emergent Adverse Events (TEAEs), Treatment-Related AEs, and Adverse Events of Special Interest (AESIs) | Participants with TEAEs | 10 Count of Participants |
| Bintrafusp Alfa | Number of Participants With Treatment-Emergent Adverse Events (TEAEs), Treatment-Related AEs, and Adverse Events of Special Interest (AESIs) | Participants with Treatment-Related TEAEs | 5 Count of Participants |
| Bintrafusp Alfa | Number of Participants With Treatment-Emergent Adverse Events (TEAEs), Treatment-Related AEs, and Adverse Events of Special Interest (AESIs) | Participants with AESIs | 4 Count of Participants |
Secondary
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 frame: Time from first study intervention up to 321 days
Population: As per changes in planned analysis, the outcome measure related to efficacy were not assessed.
Secondary
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 frame: Time from the first dose of study drug until occurrence of death due to any cause, assessed up to 321 days
Population: As per changes in planned analysis, the outcome measure related to efficacy were not assessed.
Secondary
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 frame: Time from first study intervention up to until the first documentation of PD or death, assessed up to 321 days
Population: As per changes in planned analysis, the outcome measure related to efficacy were not assessed.
Secondary
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 frame: Time from first study intervention up to the first documentation of PD or death, assessed up to 321 days
Population: As per changes in planned analysis, the outcome measure related to efficacy were not assessed.
Secondary
Serum Trough Concentration Levels (Ctrough) of Bintrafusp Alfa
Ctrough was the serum concentration observed immediately before next dosing.
Time frame: Pre-dose, End of Infusion from Day 1 to 321
Population: As per changes in planned analysis, the outcome measure related to pharmacokinetics were not assessed.