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

This study has been completed.
Information provided by:
National Cancer Institute (NCI)
ClinicalTrials.gov Identifier:
First received: August 24, 2007
Last updated: February 2, 2013
Last verified: January 2009

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

Condition Intervention Phase
Melanoma (Skin)
Drug: everolimus
Drug: temozolomide
Genetic: reverse transcriptase-polymerase chain reaction
Other: flow cytometry
Other: immunohistochemistry staining method
Other: immunologic technique
Phase 2

Study Type: Interventional
Study Design: Masking: Open Label
Primary Purpose: Treatment
Official Title: A Phase II Study of Temozolomide and Everolimus (RAD001) Therapy for Metastatic Melanoma

Resource links provided by NLM:

Further study details as provided by National Cancer Institute (NCI):

Primary Outcome Measures:
  • 9-week progression-free survival rate [ Designated as safety issue: No ]

Secondary Outcome Measures:
  • Survival time [ Designated as safety issue: No ]
  • Time to disease progression [ Designated as safety issue: No ]
  • Confirmed response rate (complete response and partial response) [ Designated as safety issue: No ]
  • Microvascular density and VEGF expression as assessed by IHC [ Designated as safety issue: No ]
  • Plasma VEGF levels at baseline, 9 weeks, and at progression [ Designated as safety issue: No ]
  • Immunologic parameters [ Designated as safety issue: No ]
  • MGMT (O-6-methylguanine-DNA methyltransferase) [ Designated as safety issue: No ]

Estimated Enrollment: 43
Study Start Date: January 2008
Primary Completion Date: December 2009 (Final data collection date for primary outcome measure)
Detailed Description:



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


  • 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.


Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No


  • 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


  • 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


  • 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
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00521001

  Show 198 Study Locations
Sponsors and Collaborators
North Central Cancer Treatment Group
Study Chair: Ravi D. Rao, MD, MBBS Mayo Clinic
Investigator: Svetomir Markovic, MD, PhD Mayo Clinic
Investigator: William J. Maples, MD Mayo Clinic
Investigator: Michael K. Gornet, MD Mayo Clinic Hospital
Investigator: Edward T. Creagan, MD Mayo Clinic
Investigator: Barbara A. Pockaj, MD Mayo Clinic Hospital
Investigator: Judith S. Kaur, MD Mayo Clinic
  More Information

Additional Information:
Responsible Party: Jan C. Buckner, North Central Cancer Treatment Group
ClinicalTrials.gov Identifier: NCT00521001     History of Changes
Other Study ID Numbers: CDR0000562166, NCCTG-N0675
Study First Received: August 24, 2007
Last Updated: February 2, 2013
Health Authority: United States: Federal Government

Keywords provided by National Cancer Institute (NCI):
stage IV melanoma

Additional relevant MeSH terms:
Neoplasms by Histologic Type
Neoplasms, Germ Cell and Embryonal
Neoplasms, Nerve Tissue
Neuroectodermal Tumors
Neuroendocrine Tumors
Nevi and Melanomas
Alkylating Agents
Anti-Bacterial Agents
Anti-Infective Agents
Antibiotics, Antineoplastic
Antifungal Agents
Antineoplastic Agents
Antineoplastic Agents, Alkylating
Immunologic Factors
Immunosuppressive Agents
Molecular Mechanisms of Pharmacological Action
Pharmacologic Actions
Physiological Effects of Drugs
Therapeutic Uses

ClinicalTrials.gov processed this record on May 21, 2015