E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Hormone Receptor-positive, Heregulin Positive (HRG+), HER2 Negative Metastatic Breast Cancer |
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E.1.1.1 | Medical condition in easily understood language |
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E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10027475 |
E.1.2 | Term | Metastatic breast cancer |
E.1.2 | System Organ Class | 100000004864 |
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E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
The primary objective of this study is to determine whether the combination of seribantumab + fulvestrant is more effective than placebo + fulvestrant based on investigator assessed Progression Free Survival (PFS) in HRG positive patients (defined as HRG ISH score of > 1+) |
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E.2.2 | Secondary objectives of the trial |
To determine whether the combination of seribantumab + fulvestrant is more effective than placebo + fulvestrant in HRG positive patients for the following clinical outcome parameters: -Time to Progression (TTP) -Overall Survival (OS) -Objective Response Rate (ORR) based on RECISTv1.1 • To describe the safety profile of seribantumab in combination with fulvestrant • To characterize the pharmacokinetic (PK) profile of seribantumab when given in combination with fulvestrant and of fulvestrant when given in combination with seribantumab |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
In order for inclusion, patients must have/be: • Histologically or cytologically confirmed ER+ and/or PR+ (with staining of > 1% cells) breast cancer • Confirmed postmenopausal status due to either surgical/natural menopause or ovarian suppression (initiated at least 28 days prior to Day 1 of Cycle 1) with a gonadotropin-releasing hormone (GnRH) agonist, such as goserelin • HER2 negative per ASCO/CAP guidelines • A positive in-situ hybridization (ISH) test for heregulin with a score of ≥1+, as determined by centralized testing of unstained tumor tissue • Must have at least one lesion amenable to either fresh tissue biopsy • Progressed following at least one but no more than two prior systemic therapies in the locally advanced or metastatic disease setting o Received prior CDK inhibitor based therapy for locally advanced or metastatic disease • Documented progression of locally advanced or metastatic disease as defined by RECIST v1.1. 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 RECIST v1.1 criteria. o Patients with bone-only lesions who have received radiation to those lesions must have documented progression following radiation therapy. • Able to understand and sign an informed consent (or have a legal representative who is able to do so) • ECOG Performance Score (PS) of 0 or 1 • Adequate bone marrow reserves as evidenced by: -ANC > 1500/μl -Platelet count > 100,000/μl; and -Hemoglobin > 9 g/dL • Adequate hepatic function as evidenced by: -Serum total bilirubin ≤ 1.5 x ULN except for patients with Morbus Gilbert -Aspartate aminotransferase (AST), Alanine aminotransferase (ALT) and Alkaline Phosphatase ≤ 2.5 x ULN (≤ 5 x ULN is acceptable if liver metastases are present, and ≤ 5 x ULN of Alkaline Phosphatase is acceptable if bone metastases are present) • Adequate renal function as evidenced by a serum creatinine ≤ 1.5 x ULN • Recovered from clinically significant effects of any prior surgery, radiotherapy, or other antineoplastic therapy. • Patients may be treated with bone modifying agents such as bisphosphonates or receptor activator of nuclear factor kappa-B (RANK)-ligand agents (e.g. denosumab) per American Society of Clinical Oncology (ASCO) guidelines; whenever possible, patients requiring bone modifying agents should start treatment > 7 days prior to study therapy and should continue the same agent throughout study unless clinically compelled to change • ≥ 18 years of age • 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. |
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E.4 | Principal exclusion criteria |
Patients must meet all the inclusion criteria listed above and none of the following exclusion criteria: • Prior treatment with an anti-ErbB3 antibody • Prior treatment with a chemotherapy in the locally advanced or metastatic disease setting • Patients cannot have received prior fulvestrant or other SERDs in the locally advanced or metastatic setting • Uncontrolled CNS disease or presence of leptomeningeal disease • Inflammatory breast cancer • History of another active malignancy that required systemic therapy in the last 2 years. Patients with prior history of in-situ cancer or basal or squamous cell skin cancer are eligible. • Active infection, or an 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 patient’s participation in the trial or affect the study outcome. At the discretion of the investigator, patients with tumor fever may be enrolled • Known hypersensitivity to any of the components of seribantumab, fulvestrant, or who have had hypersensitivity reactions to fully human monoclonal antibodies • Received other recent antitumor therapy including: -Investigational therapy administered within the 28 days or 5 half-lives, whichever is shorter, prior to the first scheduled day of dosing in this study -Radiation or other standard systemic therapy within 14 days prior to the first scheduled dose in this study, including, in addition (if necessary), the timeframe for resolution of any actual or anticipated toxicities from such radiation • NYHA Class III or IV congestive heart failure • 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 • Uncontrolled infection requiring IV antibiotics, antivirals, or antifungals; or active human immunodeficiency virus (HIV) infection, active hepatitis B infection or active hepatitis C infection • Any other medical condition deemed by the Investigator to be likely to interfere with a patient’s ability to sign informed consent, interfere with a patient’s ability to cooperate and participate in the study, or interfere with the interpretation of the results |
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E.5 End points |
E.5.1 | Primary end point(s) |
The primary endpoint of this study is Progression Free Survival (PFS) |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
Progression Free Survival (PFS) 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. |
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E.5.2 | Secondary end point(s) |
Overall Survival (OS) Objective Response Rate (ORR) Time to Progression (TTP) |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
Overall Survival (OS) is defined as the time from the date of randomization to the date of death from any cause. Patients who are alive or lost to follow-up at the time of the analysis will be censored at the last known alive date.
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 (TTP) is defined as the time from the date of randomization to the date of objective tumor progression. |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | Yes |
E.8.1.5 | Parallel group | Yes |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | Yes |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 2 |
E.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 5 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 26 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
Austria |
Belgium |
Canada |
Germany |
Italy |
Spain |
United States |
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E.8.7 | Trial has a data monitoring committee | Yes |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 2 |
E.8.9.1 | In the Member State concerned months | 0 |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial years | 2 |
E.8.9.2 | In all countries concerned by the trial months | 5 |