A Phase 1/2 Study to Evaluate the Safety, Tolerability, and Preliminary Efficacy of KW-2450 in Combination With Lapatinib and Letrozole in Subjects With Advanced or Metastatic Breast Cancer Whose Tumors Overexpress HER2

Inclusion Criteria

Inclusion Criteria

1. Histopathologically or cytologically confirmed, advanced or metastatic breast cancer
(stage IIIb, IIIc or IV disease) including inflammatory breast cancer or inoperable
locally advanced disease.

2. Documented ErbB2 overexpression

3. Estrogen receptor positive (ER+) and/or progesterone positive (PgR+) tumors

4. Measurable or non-measurable disease according to Response Evaluation Criteria in
Solid Tumors (RECIST) 1.1 Criteria

5. A life expectancy of > 3 months for Phase 1 and > 6 months for Phase 2

6. Eastern Cooperative Oncology Group (ECOG) performance status score of ≤ 2 at study
entry in Phase 1 and ≤ 1 in Phase 2;

7. Normal cardiac ejection fraction

8. Adequate hematologic, hepatic and renal function

9. Post-menopausal female (defined as the absence of a menstrual cycle for at least 12
consecutive months) or male subjects ≥ 18 years of age.

10. Sign an IRB or EC approved informed consent

Exclusion Criteria

1. Type 1 diabetes or uncontrolled Type 2 diabetes

2. Subjects showing clinical evidence or with a history of cataract(s), proliferate
retinopathy or significant macular edema

3. Subjects with abnormal free T4 values and a history or evidence of thyroid disease

4. Subjects who are unable or unwilling to take metformin

5. Uncontrolled intercurrent illness

6. Known or suspected human immunodeficiency virus (HIV) infection or hepatitis B or C

7. Subjects with inflammatory diseases of the gastrointestinal tract

8. History of other malignancy. Subjects who have been disease free for 5 years, or
subjects with a history of completely resected non-melanoma skin cancer or
successfully treated in situ carcinoma are eligible;

9. Subjects with extensive symptomatic visceral disease including hepatic involvement
and pulmonary lymphangitic spread of tumor

10. A history of prior treatment with other agents specifically targeting IGFRs

11. Subjects who require pharmacological doses of glucocorticoids beyond replacement
doses. The use of topical, intra-ocular or inhalation glucocorticoids is permitted