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Everolimus, Temozolomide, and Radiation Therapy in Treating Patients With Newly Diagnosed Glioblastoma

Study Purpose

RATIONALE: Everolimus may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth and by blocking some of the blood flow to the tumor. Drugs used in chemotherapy, such as temozolomide, work in different ways to stop the growth of cancer cells, either by killing the cells or by stopping them from dividing. Radiation therapy uses high-energy x-rays to kill tumor cells. Giving everolimus together with temozolomide and radiation therapy may kill more tumor cells. PURPOSE: This phase I/II trial is studying the side effects and best dose of everolimus when given together with temozolomide and radiation therapy in treating patients with newly diagnosed glioblastoma.

Recruitment Criteria

Accepts Healthy Volunteers Healthy volunteers are participants who do not have a disease or condition, or related conditions or symptoms	No
Study Type An interventional clinical study is where participants are assigned to receive one or more interventions (or no intervention) so that researchers can evaluate the effects of the interventions on biomedical or health-related outcomes. An observational clinical study is where participants identified as belonging to study groups are assessed for biomedical or health outcomes. Searching Both is inclusive of interventional and observational studies.	Interventional
Eligible Ages	18 Years and Over
Gender	All

More Inclusion & Exclusion Criteria

DISEASE CHARACTERISTICS:

- Histologically confirmed diagnosis of 1 of the following: - Glioblastoma multiforme (grade 4 astrocytoma) - Other grade 4 astrocytoma variants (e.g., giant cell) - No grade 4 oligodendrogliomas or oligoastrocytomas.

- Gliosarcoma.

- Newly diagnosed disease.

- Measurable disease ≥ 1 cm³ (phase I patients only) - Some patients may be registered on protocol NCCTG-947252.

- No oligodendrogliomas or oligoastrocytomas.

PATIENT CHARACTERISTICS:

Inclusion criteria:

- ECOG performance status 0-2.

- ANC ≥ 1,500/μL.

- Hemoglobin ≥ 9.0 g/dL.

- Platelet count ≥ 100,000/μL.

- Total bilirubin ≤ 2.5 x institutional upper limit of normal (ULN) - Serum total cholesterol < 350 mg/dL.

- Serum total triglycerides < 400 mg/dL.

- AST ≤ 2.5 x ULN.

- Creatinine ≤ 1.5 x ULN.

- Not pregnant or nursing.

- Negative pregnancy test.

- Fertile patients must use effective contraception during and for 60 days after completion of study therapy.

- Must be willing to undergo 2 mandatory research PET or PET/CT scans (all MCR and MCJ patients in phase I and MCR only patients in phase II) - Must be willing to abstain from eating or drinking grapefruit or grapefruit juice during study treatment.

- Must be willing to follow a diet low in fat and cholesterol while taking everolimus.

- Must be willing to have imaging scans submitted for central review.

- Ability to understand and willingness to sign a written informed consent.

Exclusion criteria:

- Other active cancers requiring therapy to control disease or prior cancer diagnoses which pose a greater than 30% risk of death within the next 2 years.

- Gastrointestinal tract disease resulting in an inability to take oral medication or a requirement for IV alimentation, prior surgical procedures affecting absorption, or active uncontrolled peptic ulcer disease.

- Uncontrolled intercurrent illness including, but not limited to, any of the following: - Ongoing, uncontrolled, or active (acute or chronic) infection or disorder.

- Symptomatic congestive heart failure.

- Unstable angina pectoris.

- Cardiac arrhythmia.

- Psychiatric illness/social situations that would limit compliance with study requirements.

- Severely impaired lung function.

- Uncontrolled diabetes (fasting serum glucose > 2 x ULN) OR diabetes that would interfere with the performance of the FDG-PET/CT or FDG-PET scans.

- Liver disease (e.g., cirrhosis, chronic active hepatitis, chronic persistent hepatitis, or history of hepatitis B) - Known HIV positivity.

- Positive hepatitis B antigen (HBsAg) or hepatitis C serology (HCV) tests.

- Any history of allergy or intolerance to dacarbazine (DTIC) - Significant traumatic injury within the past 21 days.

- Severe allergy to sulfa medications.

- Inability to tolerate levofloxacin with dapsone or pentamidine (inhaled or IV) PRIOR CONCURRENT THERAPY:
Inclusion criteria:
- At least 1 week, but no more than 6 weeks since prior surgical resection or biopsy.

- Must comply with antibiotic prophylaxis with either trimethoprim/sulfamethoxazole (daily or 3 times per week), oral dapsone (daily) combined with daily levofloxacin, or monthly pentamidine (inhaled or IV) combined with daily levofloxacin.

Exclusion criteria:

- Prior chemotherapy for any brain tumor.

- Prior temozolomide or mTOR inhibitor therapies.

- Any prior cranial radiotherapy.

- Planned immunization with attenuated live vaccines ≤ 7 days prior to and during study period.

- At least 21 days since prior major surgery (excluding neurosurgical biopsy, resection of brain tumor, or treatment of immediate post-neurosurgical complication [e.g., intracranial hematoma]) - Concurrent or prior treatment for this cancer with any other investigational agents.

- Concurrent enzyme-inducing anticonvulsants (EIACs) or other strong inducers of CYP3A4 (i.e., carbamazepine, phenytoin, phenobarbital/primidone, rifabutin, rifampin, or St. John's wort) - Concurrent therapeutic doses of warfarin.

- Low molecular weight heparin is allowed.

- Concurrent systematic leukocyte growth factors (e.g., G-CSF or GM-CSF), except for the treatment of severe neutropenia.

- Concurrent drugs or substances known to inhibit or induce CYP3A.

- Other concurrent chronic treatment with immunosuppressive agents except dexamethasone.

- Other concurrent anticancer agents.

- Concurrent live vaccines

Trial Details

Trial ID: This trial id was obtained from ClinicalTrials.gov, a service of the U.S. National Institutes of Health, providing information on publicly and privately supported clinical studies of human participants with locations in all 50 States and in 196 countries.	NCT00553150
Phase Phase 1: Studies that emphasize safety and how the drug is metabolized and excreted in humans. Phase 2: Studies that gather preliminary data on effectiveness (whether the drug works in people who have a certain disease or condition) and additional safety data. Phase 3: Studies that gather more information about safety and effectiveness by studying different populations and different dosages and by using the drug in combination with other drugs. Phase 4: Studies occurring after FDA has approved a drug for marketing, efficacy, or optimal use.	Phase 1/Phase 2
Lead Sponsor The sponsor is the organization or person who oversees the clinical study and is responsible for analyzing the study data.	Alliance for Clinical Trials in Oncology
Principal Investigator The person who is responsible for the scientific and technical direction of the entire clinical study.	Jann N. Sarkaria, MD
Principal Investigator Affiliation	Mayo Clinic
Agency Class Category of organization(s) involved as sponsor (and collaborator) supporting the trial.	Other, NIH
Overall Status	Completed
Countries	United States
Conditions The disease, disorder, syndrome, illness, or injury that is being studied.	Brain and Central Nervous System Tumors

Additional Details

OBJECTIVES:

- To determine the maximum tolerated dose (MTD) of everolimus in combination with temozolomide and 3D-conformal radiotherapy or intensity-modulated radiotherapy (IMRT) followed by adjuvant temozolomide with or without everolimus in patients with newly diagnosed glioblastoma.

(Mayo Clinic Rochester [MCR] AND Mayo Clinic Jacksonville [MCJ] patients only) (Phase I)

- To assess and describe the adverse events of everolimus in combination with temozolomide and 3D-conformal radiotherapy or IMRT followed by adjuvant temozolomide with or without everolimus in patients with newly diagnosed glioblastoma.

(MCR and MCJ patients only) (Phase I)

- To assess treatment effectiveness of everolimus in combination with temozolomide and 3D-conformal radiotherapy or IMRT followed by adjuvant temozolomide with or without everolimus, until progression, in patients with newly diagnosed glioblastoma.

(all North Central Cancer Treatment Group [NCCTG] patients) (Phase II)

- To characterize the toxicities of everolimus in combination with temozolomide and 3D-conformal radiotherapy or IMRT followed by adjuvant temozolomide with or without everolimus in patients with newly diagnosed glioblastoma.