Phase 2 Trial of Seribantumab Plus Fulvestrant in Postmenopausal Women With Metastatic Breast Cancer (SHERBOC)

• ClinicalTrials.gov Identifier: NCT03241810
• Recruitment Status: Terminated
• First Posted: August 8, 2017
• Results First Posted: September 2, 2020
• Last Update Posted: September 2, 2020
• Sponsor: Elevation Oncology
• Information provided by (Responsible Party): Elevation Oncology

Tracking Information

• First Submitted Date: August 2, 2017
• First Posted Date: August 8, 2017
• Results First Submitted Date: July 20, 2020
• Results First Posted Date: September 2, 2020
• Last Update Posted Date: September 2, 2020
• Actual Study Start Date: August 15, 2017
• Actual Primary Completion Date: November 30, 2018 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: August 7, 2020)

Progression Free Survival [ 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 ]

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.

Original Primary Outcome Measures (submitted: August 7, 2017)

Progression Free Survival [ Time Frame: A total study duration of approximately 20 months is expected. The primary analysis will be initiated when 58 PFS events have occurred ]

Time from randomization to disease progression according to RECIST v 1.1 as assessed by the Investigator

Current Secondary Outcome Measures (submitted: August 20, 2020)

• Overall Survival [ Time Frame: 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.
• Objective Response Rate [ Time Frame: 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 [ Time Frame: 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.
• Number of Participants With Treatment-emergent Adverse Events Reported With the Combinations of Seribantumab Plus Fulvestrant Versus Fulvestrant Alone [ 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 ]
  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.
• Percentage of Treatment-emergent Adverse Events Reported With the Combinations of Seribantumab Plus Fulvestrant Versus Fulvestrant Alone [ 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 ]
  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. [ 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 ]
  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).

Original Secondary Outcome Measures (submitted: August 7, 2017)

• Overall Survival [ Time Frame: A total study duration of approximately 20 months is expected. ]
  Time from randomization to death
• Objective Response Rate [ Time Frame: A total study duration of approximately 20 months is expected. ]
  Based on RECIST v 1.1
• Time to Progression [ Time Frame: A total study duration of approximately 20 months is expected. ]
• Rate of Treatment-emergent Adverse Events Reported With the Combinations of Seribantumab Plus Fulvestrant Versus Fulvestrant Alone [ Time Frame: A total study duration of approximately 20 months is expected. ]
• Pharmacokinetic (PK) Profile of Seribantumab When Given in Combination With Fulvestrant and of Fulvestrant When Given in Combination With Serbantumab. [ Time Frame: A total study duration of approximately 20 months is expected. ]
  Pharmacokinetic (PK) evaluation will be 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) will be presented and will be calculated usig Non-compartmental analysis (NCA). Serum levels of MM-121 will be measured at a central lab using an enzyme-linked immunosorbent assay (ELISA).

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Phase 2 Trial of Seribantumab Plus Fulvestrant in Postmenopausal Women With Metastatic Breast Cancer
• Official Title: Randomized Phase 2 Trial of Seribantumab Plus Fulvestrant in Postmenopausal Women With Hormone Receptor-positive, Heregulin Positive (HRG+), HER2 Negative Metastatic Breast Cancer (Merrimack Pharmaceuticals Inc.)
• 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.
• Study Type: Interventional
• Study Phase: Phase 2

Study Design

Allocation: Randomized
Intervention Model: Parallel Assignment
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).

Masking: Triple (Participant, Care Provider, Investigator)
Masking Description:

This is a multi-center, randomized, double-blind, placebo-controlled Phase 2 Study.

Primary Purpose: Treatment

• Condition: Metastatic Breast Cancer

Intervention

• Drug: Seribantumab
  Seribantumab is a human monoclonal antibody that inhibits ErbB3 signalling
  Other Name: MM-121
• Drug: Fulvestrant
  Fulvestrant is an estrogen receptor antagonist with no agonist effects
  Other Name: Faslodex
• Drug: Placebo
  Placebo
  Other Name: Solution containing 20 mM histidine, 150 mM sodium chloride, at a pH of 6.5

Study Arms

• Experimental: Arm A

  Seribantumab

  Fulvestrant

  Interventions:

  • Drug: Seribantumab
  • Drug: Fulvestrant
• Active Comparator: Arm B

  Placebo

  Fulvestrant

  Interventions:

  • Drug: Fulvestrant
  • Drug: Placebo

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Terminated
• Actual Enrollment (submitted: November 5, 2019): 22
• Original Estimated Enrollment (submitted: August 7, 2017): 80
• Actual Study Completion Date: November 30, 2018
• Actual Primary Completion Date: November 30, 2018 (Final data collection date for primary outcome measure)

Eligibility Criteria

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 exclusion criteria.

1. Prior treatment with an anti-ErbB3 antibody.
2. Prior treatment with a chemotherapy in the locally advanced or metastatic disease setting.
3. Patients cannot have received prior treatment with fulvestrant or other SERDs in the locally advanced or metastatic setting.
4. Uncontrolled CNS disease or presence of leptomeningeal disease.
5. Inflammatory breast cancer.
6. History of another active malignancy that required systemic therapy in the last 2 years. Patients with prior history of in-situ cancer, basal, or squamous cell skin cancer are eligible.
7. Patients with an active infection, or unexplained fever > 38.5 C during screening visits or on the first scheduled day of dosing, which in the investigator's opinion might compromise the patients participation in the trial or affect the study outcome. At the discretion of the investigator, patients with tumor fever may be enrolled.
8. Known hypersensitivity to any of the components of seribantumab, fulvestrant, or who have had hypersensitivity reactions to fully human monoclonal antibodies.
9. NYHA Class III or IV congestive heart failure.
10. Patients with a significant history of cardiac disease (i.e. uncontrolled blood pressure, unstable angina, myocardial infarction within 1 year or ventricular arrhythmias requiring medication) are also excluded.
11. Uncontrolled infection requiring IV antibiotics, antivirals, or antifungals; or active human immunodeficiency virus (HIV) infection, active hepatitis B infection or active hepatitis C infection.

Sex/Gender

• Sexes Eligible for Study: Female
• Gender Based Eligibility: Yes
• Gender Eligibility Description: Confirmed postmenopausal status due to either surgical/natural menopause or ovarian suppression (initiated at least 28 days prior to Day 1 of Cycle 1).

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Austria, Belgium, Canada, Germany, Spain, United States

Administrative Information

• NCT Number: NCT03241810
• Other Study ID Numbers: MM-121-02-02-10; 2017-000565-76 ( EudraCT Number )
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

• IPD Sharing Statement: Not Provided
• Responsible Party: Elevation Oncology
• Study Sponsor: Elevation Oncology
• Collaborators: Not Provided

Investigators

• Study Director: Marc Pipas, MD; Merrimack Pharmaceuticals Inc.

• PRS Account: Elevation Oncology
• Verification Date: November 2019