Temsirolimus and Bevacizumab in Treating Patients With Stage III or Stage IV Malignant Melanoma

PRIMARY OBJECTIVES:

I. Determine the objective tumor response rate (complete response and partial response) in
patients with stage III or IV melanoma treated with temsirolimus and bevacizumab.

SECONDARY OBJECTIVES:

I. Describe the adverse event profile of this regimen in these patients. II. Determine the
efficacy of this regimen, in terms of progression-free survival, in these patients.

III. Compare pre- vs post-treatment measurements of biomarkers and vascular system/immune
system parameters in patients treated with this regimen.

IV. Correlate tumor and blood biomarkers with clinical response in these patients.

OUTLINE: This is a multicenter study.

Patients receive temsirolimus intravenously (IV) over 30 minutes on days 1 and 8 and
bevacizumab IV over 30-90 minutes on day 8. Treatment repeats every 14 days for a maximum of
26 courses in the absence of disease progression or unacceptable toxicity. Patients undergo
tumor resection on day 9 of course 2.Blood samples are collected during courses 1 and 2.
Samples are examined by flow cytometry to evaluate peripheral blood mononuclear cells for
molecular effects of study agents. Patients also undergo normal and tumor tissue biopsy (by
core needle biopsy, incisional biopsy, or surgical resection) during courses 1 and 2.
Samples are examined by immunohistochemistry, western blotting, protein array technology,
gene expression analyses, DNA mutation analyses, and genomic analyses for pre-and
post-treatment measurements of target molecules (epidermal growth factor receptor, B-Raf,
MEK, MAPK), downstream pathway components (PI-3 kinase, AKT, mTOR), markers of angiogenesis,
proliferation and apoptosis, markers that may modulate cell signaling or the response to
investigational agents, and vascular and immune system parameters.

After completion of study treatment, patients are followed at 1 month, every 3 months for up
to 2 years, and then periodically for up to 5 years.

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