A Phase II Study of CCI-779 in Combination With Bevacizumab in Stage III or IV Melanoma

Inclusion Criteria:

- Histologically or cytologically confirmed melanoma

- Stage III or IV disease

- Recurrent disease allowed

- Measurable disease defined as ≥ 1 lesion that can be accurately measured in ≥ 1
dimension as ≥ 20 mm with conventional techniques OR ≥ 10 mm with spiral CT scan

- Tumor lesions in previously irradiated areas are not considered measurable
disease

- Prior brain metastases allowed provided all of the following criteria are met:

- No more than a total of 5 brain metastases

- All metastases are no more than 2.5 cm

- Surgically resected or have been treated with gamma-knife or stereotactic
radiosurgery

- More than 30 days since prior disease progression

- More than 30 days since prior steroids for managing brain metastases

- Concurrent steroids for other reasons allowed provided the dose is < that
required for managing brain metastases

- Disease accessible for core needle biopsy, incisional biopsy, and/or surgical
resection and meets one of the following criteria:

- One large tumor deposit ≥ 5 cm³ from which biopsies can be harvested multiple
times

- Multiple deposits that can be biopsied or excised individually on different
dates, measured as follows:

- One lesion ≥ 5 cm^3

- Two lesions ≥ 3 cm^3

- Three lesions ≥ 2 cm^3

- ECOG performance status 0-1

- Weight ≥ 110 pounds (without clothes)

- WBC ≥ 3,000 mm³

- Absolute neutrophil count ≥ 1,500/mm³

- Platelet count ≥ 100,000/mm³

- Bilirubin normal

- AST and ALT ≤ 2.5 times upper limit of normal

- Creatinine normal OR creatinine clearance ≥ 60 mL/min

- Urine protein: creatinine ratio < 1.0 OR 24-hour urine protein < 1,000 mg

- Fasting cholesterol < 350 mg/dL (cholesterol medications are allowed)

- Fasting triglycerides < 400 mg/dL

- PT INR ≤ 1.5 (unless on full-dose anticoagulants)

- Hematocrit < 41% (for males) or < 38% (for females)

- None of the following within the past 4 weeks:

- Uncontrolled intercurrent illness

- Ongoing or active acute (CTCAE v.3 grade 3 or 4) infection

- Abdominal fistula

- Gastrointestinal perforation

- Intra-abdominal abscess

- Serious or nonhealing wound, ulcer, or bone fracture

- No psychiatric illness or social situations that would preclude study compliance

- No clinically significant cardiovascular disease, including the following:

- Cerebrovascular accident within the past 6 months

- Transient ischemic attack within the past 6 months

- Myocardial ischemia within the past 6 months

- Myocardial infarction within the past 6 months

- Other thromboembolic event within the past 6 months

- Unstable angina within the past 6 months

- Uncontrolled hypertension (i.e., hypertension despite maximal therapy)

- New York Heart Association class II-IV heart disease

- Congestive heart failure

- Serious cardiac arrhythmia requiring medication

- Clinically significant peripheral vascular disease

- History of stroke

- Artificial valve, pacemaker, or similar device

- No uncontrolled diabetes

- Hemoglobin A1c < 7%

- No significant traumatic injury within the past 28 days

- No history of allergic reactions to compounds of similar chemical or biological
composition to temsirolimus or bevacizumab

- No hypersensitivity to Chinese hamster ovary cell products or other recombinant human
antibodies (e.g., infliximab)

- Not pregnant or nursing

- Negative pregnancy test

- Fertile patients must use effective contraception during and for ≥ 6 months after
completion of study treatment

- HIV negative

- Hepatitis C negative

- See Disease Characteristics

- More than 4 weeks since any of the following prior treatments and recovered:

- Chemotherapy (6 weeks for nitrosoureas or mitomycin C)

- Radiotherapy to nontarget lesions or lesions that are not to be biopsied

- Immunotherapy

- Cytokine therapy

- Enzyme-inducing antiepileptic drugs (EIAEDs) or other CYP3A4 inducers

- Investigational agents

- More than 4 weeks since prior major surgery or open biopsy and recovered

- No prior temsirolimus, rapamycin, bevacizumab, or systemic therapies targeted
primarily to vascular endothelial growth factor (VEGF), VEGF receptors, or to mTOR
inhibition

- Concurrent full-dose anticoagulants (e.g., warfarin/low molecular weight heparin)
with PT INR > 1.5 are allowed provided the following criteria are met:

- In-range INR (usually between 2 and 3.5) on a stable dose of oral anticoagulant
or on a stable dose of low molecular weight heparin

- No active, clinically significant bleeding or pathological condition that
carries a high risk of bleeding (e.g., tumor involving major vessels or known
varices)

- Minimal tumor bleeding of the skin allowed at the clinician's discretion

- No concurrent medications or substances known to affect or with the potential to
affect the activity or pharmacokinetics of the following:

- Temsirolimus

- Bevacizumab

- CYP450 isoenzymes

- No concurrent nonstudy-related surgical procedures

- No other concurrent anticancer agents or therapies