Phase I/II Trial of IMC-A12 in Combination With Temsirolimus in Patients With Metastatic Breast Cancer

Inclusion Criteria:

- Histologically confirmed diagnosis of breast cancer

- Metastatic or locally recurrent disease (locally recurrent disease should be
stage IV [e.g, chest wall involvement])

- Measurable disease, defined as at least one lesion that can be accurately measured in
at least one dimension (longest diameter to be recorded) as ≥ 20 mm by conventional
techniques or as ≥ 10 mm by spiral CT scan (phase II only)

- Must have received at least 1, but no more than 2, prior chemotherapy regimens in the
setting of metastatic or locally recurrent (stage IV chest wall involvement) disease
(phase II only)

- No uncontrolled brain metastases

- Brain metastases are not permitted on study unless the metastases have been
treated by surgery or radiotherapy, and the patient has been neurologically
stable and off of steroids for ≥ 12 weeks

- ECOG performance status (PS) 0-1 OR Karnofsky PS 80-100%

- Life expectancy > 12 weeks

- Not pregnant or nursing

- Negative pregnancy test

- Fertile patients must use effective contraception during and for 3 months after
completion of study treatment

- Absolute neutrophil count ≥ 1,500/μL

- Hemoglobin ≥ 8.5 g/dL

- Platelets ≥ 100,000/μL

- Total bilirubin ≤ 1.5 times upper limit of normal (ULN)

- AST and ALT ≤ 3 times ULN (5 times ULN if LFT elevations due to liver metastases)

- Creatinine ≤ 1.5 times ULN OR creatinine clearance ≥ 60 mL/min

- Fasting serum cholesterol ≤ 350 mg/dL (9.0 mmol/L)

- Fasting triglycerides ≤ 400 mg/dL (4.56 mmol/L)

- Albumin ≥ 3.4 mg/dL

- Fasting serum glucose < 120 mg/dL

- No baseline diabetes requiring oral hypoglycemics or insulin (phase I only)

- No poorly controlled diabetes mellitus (phase II only)

- Patients with a history of diabetes mellitus on oral hypoglycemics or insulin
are allowed to participate, provided that their fasting blood glucose is < 120
mg/dL and that they are on a stable dietary or therapeutic regimen for this
condition

- No prior invasive non-breast malignancy, except for adequately treated basal cell or
squamous cell carcinoma of the skin or other cancer from which the patient has been
disease free for ≥ 5 years

- No known hypersensitivity reactions to macrolide antibiotics (such as erythromycin,
clarithromycin, and azithromycin)

- No allergic reactions attributed to compounds of similar chemical or biologic
composition toanti-IGF-1R recombinant monoclonal antibody IMC-A12 or temsirolimus

- Known HIV-positive patients who have CD4 counts below the normal range are not
eligible

- No uncontrolled intercurrent illness including, but not limited to:

- Ongoing or active infection

- Symptomatic congestive heart failure

- Unstable angina pectoris

- Uncontrolled symptomatic cardiac arrhythmia

- Psychiatric illness/social situations that would limit compliance with study
requirements

- No systemic anticancer therapy within the past 3 weeks

- No radiotherapy within the past 2 weeks

- No prior treatment with agents targeting the IGF-IR/IGFs or PI3K/Akt/mT OR pathway

- Any number of prior therapy regimens allowed (phase I only)

- No concurrent hormonal agents used for the treatment of breast cancer with the
exception that premenopausal women who have been on a gonadotrophin-releasing hormone
(GnRH)agonist and subsequently progressed may, at the discretion of the treating
physician, continue on the GnRH agonist

- No other concurrent investigational agents or herbal preparations

- No concurrent oral corticosteroids except for replacement for adrenal insufficiency

- No concurrent combination antiretroviral therapy for HIV-positive patients

- No concurrent enzyme-inducing antiepileptic drugs (EIAEDs) (e.g., phenytoin,
carbamazepine, phenobarbital) or any other CYP3A4 inducer such as rifampin or
Hypericum perforatum (St. John's wort)

- No other concurrent chemotherapy or radiotherapy