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

Study Overview
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Brief Summary
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RATIONALE: Drugs used in chemotherapy, such as temozolomide, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Everolimus may stop the growth of tumor cells by blocking blood flow to the tumor and by blocking some of the enzymes needed for cell growth. Giving everolimus together with temozolomide may kill more tumor cells. PURPOSE: This phase II trial is studying how well giving everolimus together with temozolomide works in treating patients with stage IV melanoma that cannot be removed by surgery

Detailed Description
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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. Evaluate confirmed response rate. 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.

Official Title
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A Phase II Study of Temozolomide and Everolimus (RAD001) Therapy for Metastatic Melanoma

Conditions
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Melanoma (Skin)

Intervention / Treatment
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* Drug: everolimus
* Drug: temozolomide


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: everolimus + temozolomide<br>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. | Drug: everolimus<br> <br> Drug: temozolomide<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 9-week Progression-free Survival Rate | The primary endpoint of this trial is the 9 week PFS rate. A patient is a success if they are progression free at their cycle 2 evaluation (approximately 9 weeks post registration). All patients, who meet the eligibility criteria, sign a consent form, and start treatment will be included in the evaluation of the 9-week PFS rate (evaluable patients). The proportion of successes will be estimated by the number of successes divided by the total number of evaluable patients. Confidence intervals for the true success proportion will be calculated using the properties of the binomial distribution. If some patients are lost to follow up prior to their cycle 2 evaluation, the Kaplan-Meier method will be used to estimate the 9 week PFS rate. Progression is defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0), as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions. | at 9 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Survival Time | Survival time is defined as the time from registration to death due to any cause. The distribution of survival time will be estimated using the method of Kaplan-Meier. | Time from registration to death due to any cause; Up to 5 years | 
| Time to Disease Progression | Time to disease progression is defined as the time from registration to the earliest date documentation of disease progression. If a patient dies without a documentation of disease progression the patient will be considered to have had tumor progression at the time of their death unless there is sufficient documented evidence to conclude no progression occurred prior to death. The distribution of time to progression will be estimated using the method of Kaplan-Meier. Progression is defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0), as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions. | Time from registration to the earliest date documentation of disease progression; Up to 5 years | 
| Confirmed Response Rate (Complete Response and Partial Response) | Confirmed response rates will be evaluated by dividing the number of confirmed responders (i.e. patients that achieve a CR or PR on consecutive evaluations) by the total number of evaluable patients. Confidence intervals for the true response rate will be calculated using the properties of the binomial distribution. | Up to 5 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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stage IV melanoma