This study is being done for the following reasons:

• The study has two parts. The purpose of the first part (Phase I) of the study is to find out the highest dose of neratinib that can be given safely with T-DM1.
• The purpose of the second part of the study (Phase II) is to find out whether the dose of neratinib with T-DM1 determined in Phase I will keep breast cancer from getting worse for a period of time.
• In order to learn more about study therapy levels in blood and discover genetic and protein changes associated with cancer, the study includes special research tests using samples from blood and from breast tumor. Blood samples will be collected before study treatment, once during treatment, and after study treatment stops.
• In the optional part of this study, three biopsies will be performed to obtain fresh tumor samples from an area where your cancer has spread.

The FB-10 study is designed as an open label, single arm, Phase Ib/II study with a dose-escalation phase and an expanded cohort (phase II) to evaluate the combination of trastuzumab emtansine (T-DM1) with neratinib in women with metastatic, HER2-positive breast cancer. The primary aim of the phase Ib portion of this study is to determine the safety and tolerability of the two-drug combination. The primary aim of the phase II portion is to demonstrate efficacy.

Patients will receive concurrent therapy with T-DM1 (3.6 mg/kg IV) on Day 1 of a 3-week (21 day) cycle and neratinib as a continuous daily oral dose. The neratinib dose-escalation will include 4 dose levels (120 mg, 160 mg, 200 mg, and 240 mg). At the recommended phase II dose (RP2D) of the T-DM1 and neratinib combination, up to 39 additional patients will be treated.

The sample size of the phase I portion of the study was 27 patients. The sample size of the Phase II portion will be 22 evaluable patients (and 4 replacement patients). The total study enrollment, phase Ib and II, will be a maximum of 50 patients.

Submission of diagnostic tumor samples and blood samples for FB-10 correlative science studies will be a study requirement for all patients. Blood samples for pharmacokinetics (PKs) and for future study will be collected prior to administration of study therapy on Cycle 1/Day 1, Cycle 1/Day 8, and Cycle 2/Day1.

A tumor biopsy will be procured from an accessible site of metastasis before study therapy is initiated (after the patient has signed the consent and has been screened for eligibility).

Inclusion Criteria:

• The ECOG performance status must be less than or equal to 2.

• Patients must have the ability to swallow oral medication.

• Patients must have histologic or cytologic confirmation of the diagnosis of invasive adenocarcinoma of the breast.

• Patients must have had anti-HER2 based therapy with pertuzumab and trastuzumab for neoadjuvant therapy, adjuvant therapy or with first line therapy for metastatic disease (which may include trastuzumab and pertuzumab either sequentially or in combination).

• There must be documentation that the patient has evidence of measurable metastatic breast cancer that is accessible to biopsy at study entry.

• Patients must have estrogen receptor (ER) analysis performed prior to study entry. If ER analysis is negative, then progesterone receptor (PgR) analysis must also be performed. (Patients are eligible with either hormone receptor-positive or hormone receptor-negative tumors.)

• Breast cancer must be determined by local testing to be human epidermal growth factor receptor 2 (HER2)-positive prior to study entry using American Society of Clinical Oncology (ASCO) - College of American Pathologists (CAP) HER2 test guidelines.

• At the time of study entry, blood counts performed within 4 weeks prior to study entry must meet the following criteria:

  • absolute neutrophil count (ANC) must be greater than or equal to 1000/mm3;
  • platelet count must be greater than or equal to 100,000/mm3; and
  • hemoglobin must be greater than or equal to 9 g/dL. (Note: Patient must have discontinued growth factors greater than or equal to two weeks prior to entry labs.)

• The following criteria for evidence of adequate hepatic function performed within 4 weeks prior to study entry must be met:

  • Total bilirubin must be less than or equal to 1.5 x upper limit of normal (ULN), and
  • aspartate aminotransferase (AST) and alanine aminotransferase (ALT) must be less than or equal to 1.5 x ULN for the lab or less than or equal to 5 x ULN if liver metastasis.

• Serum creatinine performed within 4 weeks prior to study entry must be less than or equal to 1.5 x ULN for the lab.

• The left ventricular ejection fraction (LVEF) assessment by 2-D echocardiogram or multi-gated acquisition (MUGA) scan performed within 90 days prior to study entry must be greater than or equal to 50% regardless of the facility's lower limit of normal (LLN).

• Patients with reproductive potential must agree to use an effective non-hormonal method of contraception during therapy, and for at least 7 months after the last dose of study therapy.

Exclusion Criteria

• Previous therapy with T-DM1 or any HER2 tyrosine kinase inhibitor (TKI) including neratinib for any malignancy.

• Symptomatic brain metastases or brain metastases requiring chronic steroids to control symptoms.

• Active hepatitis B or hepatitis C with abnormal liver function tests; HIV positive patients receiving antivirals.

• Lung disease resulting in dyspnea at rest.

• Active infection or chronic infection requiring chronic suppressive antibiotics.

• Malabsorption syndrome, ulcerative colitis, inflammatory bowel disease, resection of the stomach or small bowel, or other disease or condition significantly affecting gastrointestinal function.

• Persistent greater than or equal to grade 2 diarrhea regardless of etiology.

• Conditions that would prohibit intermittent administration of corticosteroids for T-DM1 premedication.

• Chronic daily treatment with corticosteroids with a dose of greater than or equal to 10 mg/day methylprednisolone equivalent (excluding inhaled steroids).

• Uncontrolled hypertension defined as a systolic BP greater than 150 mmHg or diastolic BP greater than 90 mmHg, with or without anti-hypertensive medications. (Patients with hypertension that is well controlled on medication are eligible.)

• Cardiac disease (history of and/or active disease) that would preclude the use of any of the drugs included in the treatment regimen. This includes but is not confined to:

  • Active cardiac disease: symptomatic angina pectoris within the past 90 days that required the initiation of or increase in anti-anginal medication or other intervention; ventricular arrhythmias except for benign premature ventricular contractions; supraventricular and nodal arrhythmias requiring a pacemaker or not controlled with medication; conduction abnormality requiring a pacemaker; valvular disease with documented compromise in cardiac function; and symptomatic pericarditis
  • History of cardiac disease: myocardial infarction documented by elevated cardiac enzymes or persistent regional wall abnormalities on assessment of left ventricular (LV) function; history of documented congestive heart failure (CHF); and documented cardiomyopathy

• Other nonmalignant systemic disease that would preclude the patient from receiving study treatment or would prevent required follow up.

• Pregnancy or lactation at the time of study entry. (Note: Pregnancy testing should be performed within 14 days prior to study entry according to institutional standards for women of childbearing potential.)

• The investigator should assess the patient to determine if she has any psychiatric or addictive disorder or other condition that, in the opinion of the investigator, would preclude her from meeting the study requirements.

• Use of any investigational agent within 4 weeks prior to study entry.