A Phase 1/2 Study Of HKI-272 (Neratinib) in Combination With Trastuzumab (Herceptin) In Subjects With Advanced Breast Cancer

Open label phase 1/2 study of ascending multiple oral doses of HKI-272 in combination with IV
trastuzumab in subjects with advanced human epidermal growth factor receptor 2 positive
(HER2+) breast cancer. Three to six subjects will be enrolled in each dose group. Adverse
events and dose limiting toxicities will be assessed from the first dose of study drug though
day 21. When the maximum tolerated dose (MTD) of HKI-272 plus trastuzumab is determined, an
additional 30 subjects will be enrolled at that dose level, and followed for progression free
survival for approximately 1 year.

Inclusion Criteria:

- Pathologic diagnosis of breast cancer with current stage IIIB, IIIC or IV not curable
by available therapy

- Progression following at least one Herceptin-containing cytotoxic chemotherapy regimen
(neoadjuvant, adjuvant, or metastatic setting)

- HER2 positive breast cancer

- At least one measurable target lesion

- Adequate performance status

- Adequate cardiac, kidney, and liver function

- Adequate blood counts

- Willingness of all subjects who are not surgically sterile or post menopausal to use
acceptable methods of birth control

Exclusion Criteria:

- More than 3 prior cytotoxic chemotherapy regimens for locally advanced or metastatic
disease

- Major surgery, chemotherapy, radiotherapy, investigational agents, Herceptin or other
cancer therapy within 2 weeks of treatment day 1

- Prior treatment with anthracyclines with cumulative dose of >400 mg/m^2

- Extensive visceral disease

- Active central nervous system metastases

- Pregnant or breast feeding women

- Significant chronic or recent acute gastrointestinal disorder with diarrhea as a major
symptom

- Prior exposure to HKI-272 or other HER2 targeted agents (except Herceptin and Tykerb)

- Significant cardiac disease or dysfunction

- History of life-threatening hypersensitivity to Herceptin

- Inability or unwillingness to swallow HKI-272 capsules

- Any other cancer within 5 years with the exception of contralateral breast cancer,
adequately treated cervical carcinoma in situ, or adequately treated basal or squamous
cell carcinoma of the skin