| Exclusion Criteria: | 1) Type 1 diabetes or uncontrolled Type 2 diabetes as defined as: Fasting plasma glucose (FPG) >/=160 mg/dL; or HbA1c >/= 8 % or: albuminuria < 300 mg/g; or foot ulcer > 3 mm diameter or chronic osteomyelitis of lower extremity, or claudication that prevents walking or; requiring the routine use of insulin;
2) Subjects showing clinical evidence or with a history of cataract(s), proliferate retinopathy or significant macular edema, history of vitreous hemorrhage, photocoagulation or vitrectomy;
3) Abnormal free T4 values. Abnormal thyroid stimulating hormone (TSH) values at enrollment will be further evaluated by free T4. Subjects with abnormal free T4 values and a history or evidence of thyroid disease will be excluded.
4) Subjects who are unable or unwilling to take metformin;
5) Uncontrolled intercurrent illness including, but not limited to: Ongoing or active infection requiring parenteral antibiotics; A serious or nonhealing active wound, ulcer, or bone fracture; Uncontrolled hypertension (systolic blood pressure > 160 mmHg, diastolic blood pressure > 100 mmHg, found on two consecutive measurements separated by a 1week period despite treatment with two antihypertensive agents);
6) Unstable cardiovascular disease (i.e., uncontrolled ischemic heart disease, congestive heart failure, arrhythmia or hypertension; New York Heart Association [NYHA, Appendix 2] >/= class III; or myocardial infarction or acute coronary syndrome within 6 months);
7) Known or suspected human immunodeficiency virus (HIV) infection or hepatitis B or C;
8) Subjects with inflammatory diseases of the gastrointestinal tract or malabsorption syndrome, or resection of the stomach or small bowel. Subjects with ulcerative colitis are also excluded
9) Major surgery within 4 weeks prior to the administration of study medication;
10) 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;
11) Subjects with extensive symptomatic visceral disease including hepatic involvement and pulmonary lymphangitic spread of tumor;
12) Evidence of organ dysfunction or any clinically significant deviation in physical examination, vital signs, or clinical laboratory determination;
13) QTcF of >450 msec or any clinically significant abnormalities on ECG;
14) Prior treatment with lapatinib (for the Phase 1 portion, it is permitted that subjects may have received prior lapatinib treatment up to 3 months prior to study enrollment) and letrozole (For the Phase 1 portion, it is permitted that subjects may have received prior aromatase inhibitors as a single agent for up to 4 weeks prior to study enrollment)
15) A history of prior treatment with other agents specifically targeting IGFRs;(i.e. ganitumab, AVE1642, BIIB022, BMS-754807, figitumumab, cixutumumab, dalotuzumab, linsitinib)
16) Subjects who require pharmacological doses of glucocorticoids beyond replacement doses. The use of topical, intra-ocular or inhalation glucocorticoids is permitted;
17) Strong inhibitors/inducers of CYP3A4/5, herbal medications (within 1 week of administration of study medication), or drugs for prevention of graft versus host disease or transplant rejection (within 2 months prior to the administration of study medication);
18) Hematopoietic growth factors and erythropoiesis-stimulating agents within 3 weeks prior to the administration of study medication. |