Table 1 Key inclusion and exclusion criteria for the Phase 2 HERMIONE study

Inclusion criteria

 Disease-specific

• Histologically or cytologically confirmed invasive cancer of the breast, with documented locally advanced/metastatic disease that is not amenable to resection with curative intent. Cancer must be HER2-positive, as defined by ASCO/CAP 2013 guidelines [37].

• Documented disease progression (via RECIST or clinical progression) or intolerance during or after the most recent treatment for locally advanced/metastatic breast cancer.

• Refractory or intolerant to pertuzumab (refractory to pertuzumab is defined as progression on pertuzumab in the locally advanced or metastatic setting, or development of disease recurrence during or within 12 months of completing pertuzumab-containing neoadjuvant and/or adjuvant therapy).

• Disease progression on, or intolerant to, T-DM1 in the locally advanced/metastatic breast cancer setting.

• Previously treated with trastuzumab in any setting (trastuzumab could have been previously administered with or without pertuzumab).

 General

• Age ≥18 years.

• Eastern Cooperative Oncology Group performance status 0 or 1.

 Hematologic, biochemical, and organ function

• Eligible to receive at least one of gemcitabine, capecitabine, or vinorelbine.

• Adequate bone marrow reserves (absolute neutrophil count ≥1500/μL; platelet count ≥100 000/μL; hemoglobin ≥9 g/dL [transfusions allowed]), coagulation function (INR and aPTT ≤1.5 ULN, unless on therapeutic coagulants), hepatic function (serum total bilirubin within normal limits; AST and ALT up to 3x ULN; serum albumin ≥2.5 g/dL), renal function (serum creatinine ≤1.5x ULN), and cardiac function (LVEF ≥50 % by MUGA or ECHO).

Exclusion criteria

 Disease-specific

• Previous treatment with doxorubicin, liposomal doxorubicin, epirubicin, mitoxantrone, or any other anthracycline derivative.

• CNS metastases, unless patients 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.

• Active other malignancy or history of other malignancy within the last 5 years except appropriately treated carcinoma of the cervix, non-melanoma skin carcinoma, stage 1 uterine cancer, or cancers with a similar curative outcome as those previously mentioned.

• Known hypersensitivity to any of the components of MM-302 or hypersensitivity reactions to fully humanized monoclonal antibodies.

• History of intolerance to trastuzumab. Patients who have been successfully re-challenged with trastuzumab after a mild infusion reaction are allowed.

• Investigational therapy administered <28 days (or <5 half-lives; whichever is the longest) prior to the first scheduled day of study drug dosing.

• Any standard anticancer therapy <14 days prior to the first scheduled day of study drug dosing (except trastuzumab).

 Cardiac

• Any class of NYHA congestive heart failure, or heart failure with preserved ejection fraction.

• History of known coronary artery disease or a myocardial infarction within the last 12 months.

• Uncontrolled hypertension (SBP >160 mmHg or DBP >100 mmHg).

• Unstable angina pectoris.

• Known history of serious cardiac arrhythmias requiring treatment (exception: atrial fibrillation and paroxysmal supraventricular tachycardia).

• Prolonged QTc interval (≥450 ms).

• Previous discontinuation of trastuzumab due to unacceptable cardiac toxicity or infusion-related reactions.

• History of LVEF decline to <50 % during or after HER2-directed therapy.

• Current dyspnea at rest that requires continuous oxygen therapy.

 General

• Pregnant or breast feeding.

• Active infection or unexplained fever >38.5 °C during screening visits.

• History of allogeneic transplant (patients with a history of autologous bone marrow or stem cell transplant may be enrolled).