Temozolomide and Everolimus in Treating Patients With Stage IV Melanoma That Cannot be Removed by Surgery

OBJECTIVES:

Primary

- Estimate the 9-week progression-free survival rate for patients with stage IV malignant
melanoma treated with everolimus and temozolomide.

Secondary

- Evaluate overall survival time.

- Evaluate time to disease progression.

- Assess the toxicity profile of the combination of everolimus and temozolomide in
patients with stage IV malignant melanoma.

- Assess the clinical benefit rate (i.e., stable disease, partial remission, and complete
response rates).

- Describe the impact of therapy on parameters of angiogenesis and immunity (systemic and
tumor microenvironment).

OUTLINE: This is a multicenter study.

Patients receive oral everolimus once a day on days 1-5, 8-12, 15-19, 22-26, and 29-33 and
oral temozolomide once a day on days 8-12 for course 1 only. For course 2 and all subsequent
courses, patients receive oral everolimus once a day on days 1-5, 8-12, 15-19, and 22-26 and
oral temozolomide once a day on days 1-5. Treatment repeats every 28 days in the absence of
disease progression or unacceptable toxicity.

All patients undergo blood sample collection periodically for correlative studies. Samples
are analyzed for relative numbers of T, B, and NK cells via flow cytometry, quantitative
immunoglobulin levels (IgG, IgM, and IgA), Tetramer/ELISPOT CTL frequencies to CMV/EBV
immunodominant antigens, V beta T cell spectratyping, and VEGF levels via ELISA.

After completion of study treatment, patients are followed every 8 weeks.

DISEASE CHARACTERISTICS:

- Histologically confirmed melanoma with manifestations of metastatic disease.

- Unresectable stage IV malignant melanoma with measurable disease

- Measurable disease defined as at least one lesion with the longest diameter
measured as ≥ 20 mm by CT scan or MRI scan OR ≥ 10 mm by spiral CT

- No previously untreated or unstable active brain metastases within the past 3 months

- No known standard therapy for this disease that is potentially curative or proven
capable of extending life expectancy

PATIENT CHARACTERISTICS:

- ECOG performance status 0-2

- Life expectancy ≥ 12 weeks

- ANC ≥ 1,500/μL

- Platelet count ≥ 100,000/μL

- Hemoglobin ≥ 9.0 g/dL

- Alkaline phosphatase ≤ 3 times institutional upper limit of normal (ULN)

- Creatinine ≤ 1.5 times ULN

- AST ≤ 3 times ULN

- INR ≤ 1.5

- Not pregnant or nursing

- Negative pregnancy test

- Fertile patients and their partners must use effective contraception during and for ≥
8 weeks after completion of study treatment

- Able to return to a NCCTG institution for follow-up

- Able to forego foods high in fat content 2 hours prior to and 2 hours after
administration of everolimus therapy

- Able to provide blood samples for research purposes

- No hypersensitivity to temozolomide, dacarbazine, or any analog of sirolimus

- No history of malignancy within the past 5 years except for basal cell or squamous
cell carcinoma of the skin treated with local resection only

- No immunosuppression from any cause, including known HIV infection or chronic
immunosuppressive therapy

- No impairment of gastrointestinal function or gastrointestinal disease that may
significantly alter the absorption of everolimus (e.g., ulcerative disease,
uncontrolled nausea, vomiting, diarrhea, or malabsorption syndrome)

- No serious medical condition that may make it unsafe for a patient to enroll in
study, including any of the following:

- Severely impaired lung function (FEV1 < 1 liter), unstable angina pectoris
(ongoing symptoms), ongoing symptomatic congestive heart failure (i.e., NYHA
class I-IV) refractory to appropriate therapy, or myocardial infarction within
the past 6 months, or serious uncontrolled cardiac arrhythmia

- Uncontrolled diabetes in spite of optimal therapy (i.e., a history of fasting
serum glucose > 150 mg/dL)

- Any active (acute or chronic) or uncontrolled infection/disorders

- Nonmalignant medical illnesses that are uncontrolled or whose control may be
jeopardized by the study treatment

- Liver disease (i.e., uncompensated cirrhosis or active hepatitis with elevated
liver enzymes)

- No bleeding diathesis

- No concurrent severe condition that would make it undesirable for the patient to
participate in this trial or that would jeopardize compliance with the trial

PRIOR CONCURRENT THERAPY:

- Must have recovered from effects of prior antineoplastic therapy

- At least 4 weeks since prior chemotherapy (6 weeks for mitomycin C or nitrosoureas)

- At least 4 weeks since prior immunotherapy

- At least 4 weeks since prior biologic therapy

- At least 4 weeks since prior radiosurgery

- At least 4 weeks since prior investigational therapy for melanoma

- No prior small bowel resection that may significantly alter the absorption of
everolimus

- No prior sirolimus or its analogues

- No prior radiotherapy to > 30% of bone marrow

- No concurrent drugs that may induce CYP3A4 activity

- No concurrent warfarin

- No concurrent grapefruit or grapefruit juice

- No concurrent use or planned use of vaccines containing live virus