| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Locally Advanced/Metastatic HER2-Positive Breast Cancer |
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| E.1.1.1 | Medical condition in easily understood language |
| Locally Advanced/Metastatic HER2-Positive Breast Cancer |
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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 | 19.0 |
| 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 |
To determine whether the combination of MM-302 plus trastuzumab is more effective than chemotherapy of physician’s choice (CPC) plus trastuzumab based on progression free survival (PFS) as assessed by an independent blinded review of tumor assessments.
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| E.2.2 | Secondary objectives of the trial |
• 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:
o Overall survival (OS)
o Landmark overall survival rate (6 months and 1 year)
o Time to treatment failure (TTF)
o Objective response rate (ORR) based on both independent and investigator review of tumor assessments
o Duration of response (DoR) based on both independent and investigator review of tumor assessments
• To compare the safety and toxicity profile of the two treatment arms
• To describe the pharmacokinetic exposure of MM-302 and trastuzumab at the protocol specified time-points |
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Disease Specific Inclusion Criteria
1. Patients must have histologically or cytologically confirmed invasive cancer of the breast
2. Patients must have documented locally advanced/metastatic disease, defined by the investigator, which is not amenable to resection with curative intent
3. 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
4. Patients must have archived tissue available to submit for analysis or be willing to undergo a biopsy for HER2 evaluation
5. Patients must be candidates for systemic chemotherapy
6. Patients must have documentation of disease progression (via RECIST or clinical progression) or intolerance during or after the most recent treatment for LABC/MBC
7. 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
8. Patients must have progressed on, or be intolerant to adotrastuzumab emtansine in the LABC/MBC setting
9. Patients must have been previously treated with trastuzumab in any setting (which may have been previously administered with or without pertuzumab)
General Inclusion Criteria
10. Patients must be ≥ 18 years of age
11. Patients or their legal representatives must be able to understand and sign an informed consent
12. Patients must have Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) of 0 or 1
13. 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
Hematologic, Biochemical and Organ Function
14. 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
15. Patients must have adequate bone marrow reserves as evidenced by:
a. Absolute neutrophil count (ANC) ≥ 1,500/µL
b. Platelet count ≥ 100,000/µL
c. Hemoglobin ≥ 9 g/dL (transfusions allowed)
16. Patients must have adequate coagulation function as evidenced by
a. International normalized ratio (INR) and activated partial thromboplastin time (aPTT) ≤1.5 Upper Limit of Normal (ULN; unless on therapeutic coagulants)
17. Patients must have adequate hepatic function as evidenced by:
a. Serum total bilirubin within normal limits
b. Aspartate aminotransferase (AST), Alanine aminotransferase (ALT) up to 3x upper limit of normal (ULN (≤ 5 x ULN is acceptable if liver metastases are present)
c. Serum Albumin ≥ 2.5 g/dL
18. Patients must have adequate renal function as evidenced by a serum creatinine ≤ 1.5 x upper limit of normal
19. 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
20. 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.
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| E.4 | Principal exclusion criteria |
Disease Specific Exclusion Criteria:
1. Patients who have previously been treated with doxorubicin, liposomal doxorubicin, epirubicin, mitoxantrone or any other anthracycline derivative
2. 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.
3. 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
4. Patients with known hypersensitivity to any of the components of MM 302 or who have had hypersensitivity reactions to fully humanized monoclonal antibodies
5. 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
6. Patients who have received other recent antitumor therapy prior to the first scheduled day of dosing with study drug defined as:
a. Investigational therapy administered within the 28 days (or 5 half-lives; whichever is the longest) prior to the first scheduled day of dosing
b. Any standard anti-cancer therapy within 14 days prior to the first scheduled day of dosing (excluding trastuzumab)
Cardiac Exclusion Criteria:
7. Patients with any class of NYHA congestive heart failure (CHF) including heart failure with preserved ejection fraction (HFPEF)
8. Patients with a history of known coronary artery disease or a myocardial infarction within the last 12 months
9. Patients with hypertension (systolic BP > 150 mm Hg or diastolic BP > 100 mm Hg) that is not controlled by adequate standard anti-hypertensive treatment
10. Patients with known unstable angina pectoris
11. Patients with a known history of serious cardiac arrhythmias requiring treatment (exception: atrial fibrillation and paroxysmal supraventricular tachycardia)
12. Patients with a prolonged QTc interval (≥ 450 ms)
13. Patients who previously discontinued trastuzumab due to unacceptable cardiac toxicity or infusion related reactions
14. Patients with a history of LVEF decline to below 50% during or after prior trastuzumab/lapatinib or other HER2 directed therapy
15. Patients with current dyspnea at rest due to complications of advanced malignancy or other disease that requires continuous oxygen therapy
General Exclusion Criteria:
16. Patients who are pregnant or breast feeding
17. Patients with an active infection or with an unexplained fever > 38.5°C during screening visits (at the discretion of the investigator, patients with tumor fever may be enrolled)
18. Patients with a history of 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)
19. 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 |
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| E.5 End points |
| E.5.1 | Primary end point(s) |
| The primary endpoint is progression free survival (PFS) based on blinded independent review. PFS is defined as the time from randomization to the first documented progressive disease, as determined by the independent review using modified RECIST 1.1, or death from any cause, whichever comes first. |
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Tumor assessments will be made using RECIST 1.1 and recorded every 6 weeks (±7 days) from randomization, regardless of dose delays or dose interruptions, until a final scan completed 6 weeks after investigator-assessed PD. Images should be sent for central review within 2 weeks. |
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| E.5.2 | Secondary end point(s) |
The secondary endpoints are:
- Investigator-assessed PFS
- Overall Survival (OS)
- Time to Treatment Failure (TTF)
- Objective Response Rate (ORR)
- Duration of Objective Response (DoR)
- Patient Reported Outcomes (PRO) |
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
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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 | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | No |
| 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) | Yes |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | Yes |
| E.8.2.3.1 | Comparator description |
| gemcitabine, capecitabine, vinorelbine |
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| 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 | 3 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 20 |
| 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 |
| Czech Republic |
| France |
| Germany |
| Italy |
| Spain |
| United States |
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| E.8.7 | Trial has a data monitoring committee | No |
| 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
|
| The study will terminate 1 year following the primary PFS analysis cut-off date. Patients who are still receiving MM-302 at the end of study will continue receiving study drug and discontinue all other study related procedures. However, SAE data will continue to be collected until 30 days post treatment discontinuation. |
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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 | 2 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 3 |
| E.8.9.2 | In all countries concerned by the trial months | 0 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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