Details
Description
Inclusion Criteria
Exclusion Criteria
Details
Title HERMIONE: A Randomized, Multicenter, Open Label Study of MM-302 plus Trastuzumab vs. Chemotherapy of Physician’s Choice plus Trastuzumab in Anthracycline Naive Patients with Locally Advanced/Metastatic HER2-Positive Breast Cancer
IRB MERR 1115
CC 16-417
Hospital Main Campus
Stage Advanced/Metastatic
Disease Breast
Drug MM-302 , Trastuzumab
Description
Primary Objective- To determine whether the combination of MM-302 plus trastuzumab is more effective than chemotherapy of physician's choice (CPC) plus trastuzumab based on PFS as assessed by a blinded independent review of tumor assessments
- To determine whether the combination of MM-302 plus trastuzumab is more effective than CPC plus trastuzumab based on PFS as assessed by local review of tumor assessments
- To compare the efficacy of the combination of MM-302 plus trastuzumab versus CPC plus trastuzumab using:
- Overall survival (OS)
- Landmark overall survival rate (6 months and 1 year)
- Time to treatment failure (TTF)
- Objective response rate (ORR) on both independent and investigator review of tumor assessments
- Duration of response (DoR) on both independent and investigator review of tumor assessments
- To compare the safety and toxicity profiles of the two treatment arms
- To describe the PK exposure of MM-302 and trastuzumab at the protocol specified timepoints
- To explore the correlation between biomarkers from tumor tissue and/or blood samples and clinical outcome
- To compare the time to symptom progression between the two arms, using FACT-Breast Treatment Outcome Index (FACT-B TOI)
- To compare PRO outcome changes between the two treatment arms as measured by the FACT-B and EQ-5D questionnaires
- To determine the population PK of MM-302 and to estimate the typical values for and inter-patient variability of PK parameters (including covariate effects on inter-patient variability) in this patient population
- To compare the rate of development/time to development of CNS progression and development of new CNS metastases
- To estimate the resources for hospitalizations and/or hospital visits that occur during the study and within 30 days of the last dose of study treatment (other than those required by the protocol)
- To assess the concordance between Independent Review and Investigator Review of tumor assessment
Inclusion Criteria
- Patients must have histologically or cytologically confirmed invasive cancer of the breast
- Patients must have documented locally advanced/metastatic disease, defined by the investigator, which is not amenable to resection with curative intent
- Patients must have HER2-positive breast cancer as defined by ASCO/CAP 2013 guidelines (Appendix 5) that is confirmed by a Sponsor-designated central laboratory
- Patients must have archived tissue available to submit for analysis or be willing to undergo a biopsy for HER2 evaluation
- Patients must be candidates for systemic chemotherapy
- Patients must have documentation of disease progression (via RECIST or clinical progression) or intolerance during or after the most recent treatment for LABC/MBC
- Patients must be refractory, or intolerant to pertuzumab; refractory to pertuzumab is defined as progression on pertuzumab in the LABC/MBC setting or development of disease recurrence during or within 12 months of completing pertuzumab-containing neoadjuvant and/or adjuvant therapy
- Patients must have progressed on, or be intolerant to ado-trastuzumab emtansine in the LABC/MBC setting
- Patients must have been previously treated with trastuzumab in any setting (which may have been previously administered with or without pertuzumab)
- Patients must be ≥ 18 years of age
- Patients or their legal representatives must be able to understand and sign an informed consent
- Patients must have Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) of 0 or 1
- Patients must agree to abstain from sexual intercourse or to use a reliable form of contraception during the study and for 6 months following the last dose of assigned study drug(s). Exceptions: women who are no longer of childbearing potential
- Patients must be eligible to receive at least one of the treatments constituting CPC according to the specific package insert or local practice guidelines for the given agent
- Patients must have adequate bone marrow reserves as evidenced by:
- Absolute neutrophil count (ANC) ≥ 1,500/μL
- Platelet count ≥ 100,000/μL
- Hemoglobin ≥ 9 g/dL (transfusions allowed)
- Patients must have adequate coagulation function as evidenced by
- International normalized ratio (INR) and activated partial thromboplastin time (aPTT) ≤1.5 Upper Limit of Normal (ULN; unless on therapeutic coagulants)
- Patients must have adequate hepatic function as evidenced by:
- Serum total bilirubin within normal limits
- Aspartate aminotransferase (AST), Alanine aminotransferase (ALT) up to 3x upper limit of normal (ULN (≤ 5 x ULN is acceptable if liver metastases are present)
- Serum Albumin ≥ 2.5 g/dL
- Patients must have adequate renal function as evidenced by a serum creatinine ≤ 1.5 x upper limit of normal
- Patients must have adequate cardiac function as evidenced by a measured left ventricular ejection fraction of ≥ 50% by MUGA or ECHO. Measurements by ECHO must be read as a single value and not as a range
- Patients must be recovered to at least CTCAE (v4.0) grade 1 from any clinically relevant toxic effects of any prior surgery, radiotherapy or other therapy intended for the treatment of breast cancer. For peripheral neuropathy, up to CTCAE (v4.0) Grade 2 is acceptable for patients with pre-existing condition. Patients with any grade of alopecia and/or fatigue may be enrolled.
Exclusion Criteria
- Patients who have previously been treated with doxorubicin, liposomal doxorubicin, epirubicin, mitoxantrone or any other anthracycline derivative
- Subjects with known central nervous system (CNS) metastases, unless they have been treated and are stable without symptoms for 4 weeks after completion of treatment and they must be off steroids for at least 4 weeks prior to enrollment. Brain scan is not required at screening for patients who do not have symptoms/signs of CNS metastasis.
- Evidence of active malignancy or history of other malignancy within the last five years except for appropriately treated in situ carcinoma of the cervix, non-melanoma skin carcinoma, stage 1 uterine cancer, or cancers with a similar curative outcome as those previously mentioned
- Patients with known hypersensitivity to any of the components of MM-302 or who have had hypersensitivity reactions to fully humanized monoclonal antibodies
- Patients with a history of intolerance to trastuzumab (i.e. a grade 3 or 4 infusion reaction) are excluded. Patients with a history of mild infusion reaction to trastuzumab who have previously been successfully re-challenged after an infusion reaction with or without prophylactic medication are allowed
- Patients who have received other recent antitumor therapy prior to the first scheduled day of dosing with study drug defined as:
- Investigational therapy administered within the 28 days (or 5 half-lives; whichever is the longest) prior to the first scheduled day of dosing
- Any standard anti-cancer therapy within 14 days prior to the first scheduled day of dosing (excluding trastuzumab)
- Patients with any class of NYHA congestive heart failure (CHF) including heart failure with preserved ejection fraction (HFPEF)
- Patients with a history of known coronary artery disease or a myocardial infarction within the last 12 months
- Patients with hypertension (systolic BP > 150 mm Hg or diastolic BP > 100 mm Hg) that is not controlled by adequate standard anti-hypertensive treatment
- Patients with known unstable angina pectoris
- Patients with a known history of serious cardiac arrhythmias requiring treatment (exception: atrial fibrillation and paroxysmal supraventricular tachycardia)
- Patients with a prolonged QTc interval (≥ 450 ms)
- Patients who previously discontinued trastuzumab due to unacceptable cardiac toxicity or infusion related reactions
- Patients with a history of LVEF decline to below 50% during or after prior trastuzumab/lapatinib or other HER2 directed therapy
- Patients with current dyspnea at rest due to complications of advanced malignancy or other disease that requires continuous oxygen therapy
- Patients who are pregnant or breast feeding
- Patients with an active infection or with an unexplained fever > 38.5oC during screening visits (at the discretion of the investigator, patients with tumor fever may be enrolled)
- Patients with a history of allogeneic transplant (e.g. allogeneic stem cell transplant, kidney transplant etc.). Patients with a history of allogeneic bone graft transplant and those with a history of autologous bone marrow or stem cell transplant can be enrolled..
- Patients with any other medical or social condition, deemed by the Investigator to be likely to interfere with a patient's ability to sign informed consent, cooperate and participate in the study, or interfere with the interpretation of the results