Metastatic Breast Cancer
Conditions
Keywords
Breast Cancer, HER2 Negative, Hormone receptor positive
Brief summary
This study is a multi-center, randomized, double-blind, placebo-controlled, Phase 2 study in postmenopausal women with heregulin positive, hormone receptor positive, HER2 negative metastatic, unresectable breast cancer.
Detailed description
This study is a randomized, double-blind, placebo-controlled international phase 2 trial in patients with HRG+, HR+, HER2- metastatic breast cancer that has progressed following treatment with no more than 2 prior therapies, one of which must have been a CDK inhibitor. All patients will be screened for heregulin using central testing, and eligible patients will be randomized to receive either seribantumab + fulvestrant or placebo + fulvestrant. Disease status will be assessed according to RECIST v 1.1 to support the primary endpoint.
Interventions
DRUGSeribantumab
Seribantumab is a human monoclonal antibody that inhibits ErbB3 signalling
DRUGFulvestrant
Fulvestrant is an estrogen receptor antagonist with no agonist effects
DRUGPlacebo
Placebo
Sponsors
Elevation Oncology
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Caregiver, Investigator)
Masking description
This is a multi-center, randomized, double-blind, placebo-controlled Phase 2 Study.
Intervention model description
Patients will be randomized in a 1:1 ratio (experimental arm versus active comparator arm) using an Interactive Web Response System (IWRS). Randomization will be stratified based on bone-only disease (yes, no) and geographic region (US, non-US).
Eligibility
Sex/Gender
FEMALE
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
To be eligible for participation in the study, patients must meet the following criteria. Patients who are HRG negative do not need to complete screening procedures beyond HRG assessment. 1. Patients must have histologically or cytologically confirmed ER+ and/or PR+ (with staining of \>1% cells) breast cancer. 2. Patients with confirmed postmenopausal status due to either surgical/natural menopause or ovarian suppression. 3. Patients must be HER2 negative. 4. Patient must have at least one lesion amenable to either core needle biopsy or fine needle aspiration. 5. Patient must have a positive in-situ hybridization (ISH) test for heregulin, as determined by centralized testing of unstained tumor tissue. 6. Patients that have progressed following at least one but no more than two prior systemic therapies in the locally advanced or metastatic disease setting. 7. Patients with documented progression of locally advanced or metastatic disease as defined by RECISTv1.1 (Exception: patients with bone-only metastatic disease are eligible if they have at least 2 lytic lesions visible on a CT or MRI and have documented disease progression on prior therapy based on the appearance of new lesions). 8. Patients with bone-only lesions who have received radiation to those lesions must have documented progression following radiation therapy. 9. ECOG Performance Score (PS) of 0 or 1. 10. Patients with adequate bone marrow reserves. 11. Adequate hepatic function. 12. Adequate renal function. 13. Patient has recovered from clinically significant effects of any prior, surgery, radiosurgery, or other antineoplastic therapy. 14. Patients who have experienced a venous thromboembolic event within 60 days of signing the main consent form should have been treated with anti-coagulants for at least 7 days prior to beginning treatment and for the duration of treatment on this study.
Exclusion criteria
Patients must meet all the inclusion criteria listed above and none of the following
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Progression Free Survival | Randomization until progression of disease or death due to any cause up to 13 months (The study terminated prematurely) . The primary analysis was planned to be initiated when 58 PFS events have occurred | Progression Free Survival is defined as the time from randomization to the first documented radiographical progression of disease using RECIST v1.1 or death from any cause, whichever comes first as assessed by the investigator. The tumor assessment (i.e., scan dates) was used for progression/censor date not the date corresponding to the determination of overall response. Progression-free survival time distribution and median survival for each treatment group were analyzed using the Kaplan-Meier method. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Objective Response Rate | Randomization through end of study up to 13 months (The study terminated prematurely) | Objective Response Rate (ORR) is defined as the proportion of patients with a RECIST v1.1 response recorded from randomization until disease progression characterized as either a Complete Response (CR) or Partial Response (PR) relative to the total number of evaluable patients. |
| Time to Progression | Randomization to date of objective tumor progression up to 13 months (The study terminated prematurely) | Time to Progression (TTP) is defined as the time from the date of randomization to the date of objective tumor progression. |
| Overall Survival | Randomization until death due to any cause up to 13 months (The study terminated prematurely) | Overall Survival (OS) is defined as the time from the date of randomization to the date of death from any cause. The study was terminated on 30 Nov 2018 . Data represents outcomes up to 150 days of treatment. |
| Percentage of Treatment-emergent Adverse Events Reported With the Combinations of Seribantumab Plus Fulvestrant Versus Fulvestrant Alone | TEAEs were collected through the study completion (30 Nov 2018), up to 13 months. Frequency and percent summaries were presented for TEAE defined as adverse events that occur or worsen in severity following the first dose of seribantumab, or fulvestrant | Treatment-emergent adverse events (TEAEs) are defined as any event that occurred after the first dose of study drug and was not present prior to study drug administration or worsened in severity after study drug administration. |
| Pharmacokinetic (PK) Profile of Seribantumab When Given in Combination With Fulvestrant and of Fulvestrant When Given in Combination With Serbantumab. | The study terminated prematurely after 13 months. Were to be analyzed post-dose on Cycle 1,Week 1 & pre-dose for all subsequent seribantumab infusions until the completion of Cycle 2. Fulvestrant PK samples were to be collected prior to seribantumab dose | Pharmacokinetic (PK) evaluation are performed on samples obtained pre-dose on day 1 and 15 of each 28-day cycle to assess pre-treatment trough concentrations of MM-121. The maximum observed concentration (Cmax) is presented and calculated usig Non-compartmental analysis (NCA). Serum levels of MM-121 are measured at a central lab using an enzyme-linked immunosorbent assay (ELISA). |
| Number of Participants With Treatment-emergent Adverse Events Reported With the Combinations of Seribantumab Plus Fulvestrant Versus Fulvestrant Alone | TEAEs were collected through the study completion (30 Nov 2018), up to 13 months. Frequency and percent summaries were presented for TEAE defined as adverse events that occur or worsen in severity following the first dose of seribantumab, or fulvestrant | Treatment-emergent adverse events (TEAEs) are defined as any event that occurred after the first dose of study drug and was not present prior to study drug administration or worsened in severity after study drug administration. |
Countries
Austria, Belgium, Canada, Germany, Spain, United States
Participant flow
Recruitment details
At the time of the study termination by the prior Sponsor (Merrimack Pharmaceuticals), 62 sites participated in the study (27 in North America and 35 in Europe).
Participants by arm
| Arm | Count |
|---|---|
| Arm A (Experimental): Seribantumab and Fulvestrant Seribantumab (a human monoclonal antibody that targets ErbB3, a cell surface receptor that is activated by the ligand heregulin. Heregulin-driven ErbB3 signaling has been implicated as a mechanism of tumor growth and resistance to targeted, cytotoxic and anti-endocrine therapies. When used in the combination setting, seribantumab is designed to block ErbB3 signaling in order to enhance the anti-tumor effect of a combination therapy partner): fixed dose of 3000 mg intravenously (IV) on day 1 and 15 of each 28-day cycle
Fulvestrant (a drug treatment of hormone receptor-positive metastatic breast cancer in post-menopausal women with disease progression following anti-estrogen therapy. It is an estrogen receptor antagonist with no agonist effects, which works both by down-regulating and by degrading the estrogen receptor): 500 mg intramuscularly (IM) on Days 1 and 15 of Cycle 1, and then on Day 1 of each subsequent 28 day cycle | 11 |
| Arm B (Control): Placebo and Fulvestrant Placebo: intravenously (IV) on day 1 and 15 of each 28-day cycle
Fulvestrant: (a drug treatment of hormone receptor-positive metastatic breast cancer in post-menopausal women with disease progression following anti-estrogen therapy. It is an estrogen receptor antagonist with no agonist effects, which works both by down-regulating and by degrading the estrogen receptor): 500 mg intramuscularly (IM) on Days 1 and 15 of Cycle 1, and then on Day 1 of each subsequent 28 day cycle | 11 |
| Total | 22 |
Baseline characteristics
| Characteristic | Arm A (Experimental): Seribantumab and Fulvestrant | Total | Arm B (Control): Placebo and Fulvestrant |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 3 Participants | 7 Participants | 4 Participants |
| Age, Categorical Between 18 and 65 years | 8 Participants | 15 Participants | 7 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 11 Participants | 22 Participants | 11 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Heregulin positive status and staining in archival tissue | 11 Participants | 22 Participants | 11 Participants |
| Metastatic burden (TNM Stage at Initial Diagnosis) TNM Stage I | 0 Participants | 1 Participants | 1 Participants |
| Metastatic burden (TNM Stage at Initial Diagnosis) TNM Stage II | 0 Participants | 2 Participants | 2 Participants |
| Metastatic burden (TNM Stage at Initial Diagnosis) TNM Stage IIa | 4 Participants | 4 Participants | 0 Participants |
| Metastatic burden (TNM Stage at Initial Diagnosis) TNM Stage IIb | 1 Participants | 1 Participants | 0 Participants |
| Metastatic burden (TNM Stage at Initial Diagnosis) TNM Stage III | 0 Participants | 2 Participants | 2 Participants |
| Metastatic burden (TNM Stage at Initial Diagnosis) TNM Stage IIIa | 1 Participants | 1 Participants | 0 Participants |
| Metastatic burden (TNM Stage at Initial Diagnosis) TNM Stage IIIc | 1 Participants | 1 Participants | 0 Participants |
| Metastatic burden (TNM Stage at Initial Diagnosis) TNM Stage IV | 4 Participants | 10 Participants | 6 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 1 Participants | 1 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) White | 10 Participants | 19 Participants | 9 Participants |
| Region of Enrollment Belgium | 2 Participants | 3 Participants | 1 Participants |
| Region of Enrollment Canada | 0 Participants | 1 Participants | 1 Participants |
| Region of Enrollment Spain | 4 Participants | 7 Participants | 3 Participants |
| Region of Enrollment United States | 5 Participants | 11 Participants | 6 Participants |
| Sex: Female, Male Female | 11 Participants | 22 Participants | 11 Participants |
| Sex: Female, Male Male | 0 Participants | 0 Participants | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 10 / 11 | 10 / 11 |
| other Total, other adverse events | 10 / 11 | 8 / 11 |
| serious Total, serious adverse events | 1 / 11 | 0 / 11 |
Outcome results
Primary
Progression Free Survival
Progression Free Survival is defined as the time from randomization to the first documented radiographical progression of disease using RECIST v1.1 or death from any cause, whichever comes first as assessed by the investigator. The tumor assessment (i.e., scan dates) was used for progression/censor date not the date corresponding to the determination of overall response. Progression-free survival time distribution and median survival for each treatment group were analyzed using the Kaplan-Meier method.
Time frame: Randomization until progression of disease or death due to any cause up to 13 months (The study terminated prematurely) . The primary analysis was planned to be initiated when 58 PFS events have occurred
Population: Intent-to-Treat (ITT) population treated up to 150 days
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Arm A (Experimental): Seribantumab and Fulvestrant | Progression Free Survival | 1 Participants |
| Arm B (Control): Placebo and Fulvestrant | Progression Free Survival | 1 Participants |
Secondary
Number of Participants With Treatment-emergent Adverse Events Reported With the Combinations of Seribantumab Plus Fulvestrant Versus Fulvestrant Alone
Treatment-emergent adverse events (TEAEs) are defined as any event that occurred after the first dose of study drug and was not present prior to study drug administration or worsened in severity after study drug administration.
Time frame: TEAEs were collected through the study completion (30 Nov 2018), up to 13 months. Frequency and percent summaries were presented for TEAE defined as adverse events that occur or worsen in severity following the first dose of seribantumab, or fulvestrant
Population: Safety Population: The safety population includes patients receiving at least one dose of study medication. All safety analyses were to be performed on this population.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Arm A (Experimental): Seribantumab and Fulvestrant | Number of Participants With Treatment-emergent Adverse Events Reported With the Combinations of Seribantumab Plus Fulvestrant Versus Fulvestrant Alone | Patients with any TEAE-Related | 7 participants |
| Arm A (Experimental): Seribantumab and Fulvestrant | Number of Participants With Treatment-emergent Adverse Events Reported With the Combinations of Seribantumab Plus Fulvestrant Versus Fulvestrant Alone | Patients with any TEAE-Serious Adverse event | 1 participants |
| Arm A (Experimental): Seribantumab and Fulvestrant | Number of Participants With Treatment-emergent Adverse Events Reported With the Combinations of Seribantumab Plus Fulvestrant Versus Fulvestrant Alone | NCI-CTCAE Grade 3 or Higher | 2 participants |
| Arm B (Control): Placebo and Fulvestrant | Number of Participants With Treatment-emergent Adverse Events Reported With the Combinations of Seribantumab Plus Fulvestrant Versus Fulvestrant Alone | Patients with any TEAE-Related | 4 participants |
| Arm B (Control): Placebo and Fulvestrant | Number of Participants With Treatment-emergent Adverse Events Reported With the Combinations of Seribantumab Plus Fulvestrant Versus Fulvestrant Alone | Patients with any TEAE-Serious Adverse event | 0 participants |
| Arm B (Control): Placebo and Fulvestrant | Number of Participants With Treatment-emergent Adverse Events Reported With the Combinations of Seribantumab Plus Fulvestrant Versus Fulvestrant Alone | NCI-CTCAE Grade 3 or Higher | 1 participants |
Secondary
Objective Response Rate
Objective Response Rate (ORR) is defined as the proportion of patients with a RECIST v1.1 response recorded from randomization until disease progression characterized as either a Complete Response (CR) or Partial Response (PR) relative to the total number of evaluable patients.
Time frame: Randomization through end of study up to 13 months (The study terminated prematurely)
Population: Incomplete data for all subjects due to length of time on study treatment and frequency of scanning. All patients analysed had progressive disease. Therefore, they did not meet the criteria for ORR and hence could not be evaluated for CR or PR
Secondary
Overall Survival
Overall Survival (OS) is defined as the time from the date of randomization to the date of death from any cause. The study was terminated on 30 Nov 2018 . Data represents outcomes up to 150 days of treatment.
Time frame: Randomization until death due to any cause up to 13 months (The study terminated prematurely)
Population: Intent-to-Treat (ITT) population treated up to 150 days
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Arm A (Experimental): Seribantumab and Fulvestrant | Overall Survival | 1 participants |
| Arm B (Control): Placebo and Fulvestrant | Overall Survival | 1 participants |
Secondary
Percentage of Treatment-emergent Adverse Events Reported With the Combinations of Seribantumab Plus Fulvestrant Versus Fulvestrant Alone
Treatment-emergent adverse events (TEAEs) are defined as any event that occurred after the first dose of study drug and was not present prior to study drug administration or worsened in severity after study drug administration.
Time frame: TEAEs were collected through the study completion (30 Nov 2018), up to 13 months. Frequency and percent summaries were presented for TEAE defined as adverse events that occur or worsen in severity following the first dose of seribantumab, or fulvestrant
Population: Safety Population: The safety population includes patients receiving at least one dose of study medication. All safety analyses were be performed on this population.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Arm A (Experimental): Seribantumab and Fulvestrant | Percentage of Treatment-emergent Adverse Events Reported With the Combinations of Seribantumab Plus Fulvestrant Versus Fulvestrant Alone | TEAE-Related | 63.6 percentage of adverse events |
| Arm A (Experimental): Seribantumab and Fulvestrant | Percentage of Treatment-emergent Adverse Events Reported With the Combinations of Seribantumab Plus Fulvestrant Versus Fulvestrant Alone | TEAE-Serious Adverse event | 9.1 percentage of adverse events |
| Arm A (Experimental): Seribantumab and Fulvestrant | Percentage of Treatment-emergent Adverse Events Reported With the Combinations of Seribantumab Plus Fulvestrant Versus Fulvestrant Alone | NCI-CTCAE Grade 3 or Higher | 18.2 percentage of adverse events |
| Arm B (Control): Placebo and Fulvestrant | Percentage of Treatment-emergent Adverse Events Reported With the Combinations of Seribantumab Plus Fulvestrant Versus Fulvestrant Alone | TEAE-Related | 36.4 percentage of adverse events |
| Arm B (Control): Placebo and Fulvestrant | Percentage of Treatment-emergent Adverse Events Reported With the Combinations of Seribantumab Plus Fulvestrant Versus Fulvestrant Alone | TEAE-Serious Adverse event | 0 percentage of adverse events |
| Arm B (Control): Placebo and Fulvestrant | Percentage of Treatment-emergent Adverse Events Reported With the Combinations of Seribantumab Plus Fulvestrant Versus Fulvestrant Alone | NCI-CTCAE Grade 3 or Higher | 9.1 percentage of adverse events |
Secondary
Pharmacokinetic (PK) Profile of Seribantumab When Given in Combination With Fulvestrant and of Fulvestrant When Given in Combination With Serbantumab.
Pharmacokinetic (PK) evaluation are performed on samples obtained pre-dose on day 1 and 15 of each 28-day cycle to assess pre-treatment trough concentrations of MM-121. The maximum observed concentration (Cmax) is presented and calculated usig Non-compartmental analysis (NCA). Serum levels of MM-121 are measured at a central lab using an enzyme-linked immunosorbent assay (ELISA).
Time frame: The study terminated prematurely after 13 months. Were to be analyzed post-dose on Cycle 1,Week 1 & pre-dose for all subsequent seribantumab infusions until the completion of Cycle 2. Fulvestrant PK samples were to be collected prior to seribantumab dose
Population: Due to the premature study termination, the PK data were not collected. There was no pharmacokinetic data feasible for the analysis, and as such, no related analyses were performed. Hence, data could not be reported in the data table.
Secondary
Time to Progression
Time to Progression (TTP) is defined as the time from the date of randomization to the date of objective tumor progression.
Time frame: Randomization to date of objective tumor progression up to 13 months (The study terminated prematurely)
Population: Intent-to-Treat (ITT) population consisted of all participants randomized to the study.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Arm A (Experimental): Seribantumab and Fulvestrant | Time to Progression | 52 days |
| Arm B (Control): Placebo and Fulvestrant | Time to Progression | 48 days |