A Phase Ib/II Dose-Escalation Study Evaluating the Combination of Trastuzumab Emtansine (T-DM1) With Neratinib in Women With Metastatic HER2-Positive Breast Cancer
A Phase Ib/II Dose-Escalation Study Evaluating the Combination of Trastuzumab Emtansine (T-DM1) With Neratinib in Women With Metastatic HER2-Positive Breast Cancer
This study is being done for the following reasons:
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:
The following criteria for evidence of adequate hepatic function performed within 4 weeks prior to study entry must be met:
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:
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.
Oklahoma City, Oklahoma 73104, United States