A Study of Poziotinib in Combination With T-DM1 in HER2-Positive Breast Cancer

In Part 1, the dose of poziotinib, in combination with the standard dose of T-DM1 (3.6 mg/kg IV) on Day 1 of each cycle will be determined using a "3+3" design with up to 3 dose levels tested beginning with 8 mg/day.

Poziotinib dose escalation/de-escalation for the next dose cohort will proceed based on the occurrence of dose-limiting toxicities (DLTs) during Cycle 1 of the dose cohort. Patients in the dose cohort, if not discontinued, will continue treatment until discontinuation.

In Part 2 of the study, approximately 10 patients will be treated at the MTD/MAD to confirm dose for safety of the combination and to evaluate preliminary efficacy. Treatment for all patients will continue until disease progression, unacceptable toxicity, or continuation of study treatment is not in the best interest of the patient.

The Screening period (Day -30 to Day -1) will last up to 30 days prior to Cycle 1, Day 1.

During each 21-day cycle, eligible patients will receive poziotinib at the assigned dose, orally, once daily. T-DM1 3.6 mg/kg IV will be administered on Day 1 of each treatment cycle.

All treated patients will be followed for response until disease progression or the start of new treatment and then for survival (3 year study duration).

• Poziotinib (Drug): Poziotinib is a tablet for oral administration.
• T-DM1 (Drug), also known as ado-trastuzumab emtansine: T-DM1 (ado-trastuzumab emtansine) is a HER2-targeted therapy for I.V. administration.

Primary outcomes

• Objective Response Rate (ORR) [3 Years]: Evaluate the Objective Response Rate (ORR) in patients treated with daily poziotinib in combination with T-DM1 (every 3 weeks) in women with advanced or metastatic HER2 positive breast cancer.

Secondary outcomes

• Disease Control Rate (DCR) [27 weeks]: Evaluate the Disease Control Rate (DCR) at 9, 18, and 27 weeks in patients treated at the MTD/MAD.
• Progression-free Survival (PFS) [3 years]: Evaluate Progression-free Survival (PFS) in patients treated with MTD/MAD.

Sex: Female, ages: 18 Years to 90 Years

Inclusion Criteria:

* Patient must be female, at least 18 years of age, but not older than 90 years, with advanced or metastatic HER2+ breast cancer and a life expectancy of more than 6 months
* Patient must have confirmed HER2 overexpression or gene-amplified tumor via immunohistochemistry \[IHC\] with IHC 3+ or IHC 2+ with confirmatory fluorescence in situ hybridization \[FISH\]+ or \[ISH\]+
* Patients must have had at least 1 line of anti-HER2 directed therapy either in the metastatic or early-stage disease setting
* Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1

Exclusion Criteria:

* Patient has had previous treatment with poziotinib.
* Patient has received anticancer chemotherapy, TKIs, biologics, immunotherapy, radiotherapy, or investigational treatment within 15 days. (There is no washout for hormonal therapy for breast cancer).
* Patient has a life expectancy less than 3 years due to other malignancies.
* Patient is pregnant or breast-feeding.