Working… Menu

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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details. Identifier: NCT00553150
Recruitment Status : Completed
First Posted : November 4, 2007
Results First Posted : January 11, 2017
Last Update Posted : February 13, 2020
National Cancer Institute (NCI)
Information provided by (Responsible Party):
Alliance for Clinical Trials in Oncology

Brief Summary:

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.

Condition or disease Intervention/treatment Phase
Brain and Central Nervous System Tumors Drug: everolimus Drug: temozolomide Radiation: radiation Phase 1 Phase 2

Show Show detailed description

Layout table for study information
Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 122 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Phase I/II Evaluation of Everolimus (RAD001), Radiation and Temozolomide (TMZ) Followed by Adjuvant Temozolomide and Everolimus in Newly Diagnosed Glioblastoma
Actual Study Start Date : March 2009
Actual Primary Completion Date : January 2012
Actual Study Completion Date : November 15, 2019

Arm Intervention/treatment
Experimental: Everolimus (RAD001), Radiation (RT), Temozolomide (TMZ)

Patients receive oral everolimus and oral temozolomide and 3D-conformal radiotherapy or IMRT as in phase I. Patients will undergo a 4-6 week rest period in course 2 and then proceed to adjuvant therapy.

Adjuvant therapy with everolimus and temozolomide (courses 3-8): Patients receive oral everolimus and oral temozolomide as in phase I.

Adjuvant therapy with everolimus alone (courses 9 and all subsequent courses): Patients receive oral everolimus as in phase I.

All patients undergo fludeoxyglucose (FDG)- or fluorothymidine-labeled PET/CT scans at baseline and periodically during treatment.

Drug: everolimus
Drug: temozolomide
Radiation: radiation

Primary Outcome Measures :
  1. Maximum Tolerated Dose (MTD) of Everolimus (RAD001) in Combination With Temozolomide (TMZ) and 3D-conformal Radiotherapy (RT) or Intensity-modulated Radiotherapy (IMRT) Followed by Adjuvant TMZ With or Without RAD001 (Phase I) [ Time Frame: Up to 49 days ]
    Patients were assessed during RT for dose-limiting toxicities (DLT), which were defined as failure to deliver greater than 75% of the planned doses of TMZ or RAD001 during RT, interruption of RT for more than 5 days because of toxicity, or the following: >= Grade 3 diarrhea or skin rash; >= Grade 4 neutropenia, leukopenia, or thrombocytopenia; >= Grade 4 hypertriglyceridemia, hypercholesterolemia, or hyperglycemia despite optimal medial management, other >= 3 non-hematologic events; or >= Grade 4 radiation dermatitis. Maximum tolerated dose (MTD) was defined a priori as the highest dose level at which 0 or 1 of 6 patients developed DLTs. The number of patients who developed DLTs are reported here by dose level, with the MTD reported in the statistical analysis section.

  2. Overall Survival at 12 Months (Phase II) [ Time Frame: at 12 months ]
    The primary endpoint is overall survival at 12 months (OS12) after entry into this study. The proportion of successes will be estimated using the binomial point estimator (number of successes divided by the total number of evaluable patients) and the binomial 95% confidence interval estimated. A patient who is evaluable and survive more than 12 months (i.e. 365 days or more) after start of therapy will be classified as a "success". Patients who die within 12 months after start of therapy will be considered to have "failed".

Secondary Outcome Measures :
  1. Response Rate, as Measured in Patients Receiving FLT-PET Imaging (Phase II) [ Time Frame: Up to 5 years ]
    The response rate is defined as the percentage of patients receiving F-fluorothymidine positron emission tomography (FLT-PET) imaging whose cancer shrinks or disappears after treatment. A reduction in standardized uptake value (SUV) of 30% or greater in the T1-post-gadolinium scan volume of interest (T1-gad VOI) or the total tumor VOI will be considered a responsive tumor.

  2. Time to Progression (Phase II) [ Time Frame: Up to 5 years ]
    Time-to-disease progression is defined as the time from start of study therapy to documentation of disease progression. Patients who die without documentation of progression will be considered to have had tumor progression at the time of death unless there is documented evidence that no progression occurred before death. Patients who fail to return for evaluation after beginning therapy will be censored for progression on the last day of therapy. Patients who experience major treatment violations will be censored for progression on the date of treatment violation occurred. The time-to-progression distribution will be estimated using the Kaplan-Meier method. Progression is defined as at least a 25% increase in product of perpendicular diameters of contrast enhancement or mass or unequivocal increase in size of contrast enhancement or increase in mass effect as agreed upon independently by primary physician and quality control physicians or appearance of new lesions.

  3. Progression-free-survival at 6 Months (Phase II) [ Time Frame: at 6 months ]
    Progression-free-survival at 6 months: is the proportion of patients alive and progression-free at 6 months after start of regimen. This proportion will be estimated using the binomial point estimator and the binomial 95% confidence interval estimated. Progression is defined as at least a 25% increase in product of perpendicular diameters of contrast enhancement or mass or unequivocal increase in size of contrast enhancement or increase in mass effect as agreed upon independently by primary physician and quality control physicians or appearance of new lesions.

  4. Overall Survival Time [ Time Frame: Up to 15 years ]
    Overall survival: The overall survival or survival time is defined as the time from registration to death due to any cause. The distribution of overall survival will be estimated using the method of Kaplan-Meier method.

Information from the National Library of Medicine

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, Learn About Clinical Studies.

Layout table for eligibility information
Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No


  • 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


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)


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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its identifier (NCT number): NCT00553150

Show Show 178 study locations
Sponsors and Collaborators
Alliance for Clinical Trials in Oncology
National Cancer Institute (NCI)
Layout table for investigator information
Study Chair: Jann N. Sarkaria, MD Mayo Clinic
Publications of Results:
Ma D, Galanis E, Schiff D, et al.: NCCTG N057K phase II trial of everolimus, temozolomide, and radiotherapy in patients with newly diagnosed glioblastoma: A North Central Cancer Treatment Group trial. [Abstract] J Clin Oncol 30 (Suppl 15): A-2031, 2012.
Sarkaria JN, Peller PJ, Galanis E, et al.: FLT-PET analysis of early response to everolimus in newly diagnosed glioblastoma patients enrolled on NCCTG N057K. [Abstract] J Clin Oncol 29 (Suppl 15): A-e12501, 2011.

Layout table for additonal information
Responsible Party: Alliance for Clinical Trials in Oncology Identifier: NCT00553150    
Other Study ID Numbers: NCCTG-N057K
NCI-2009-00654 ( Registry Identifier: CTRP (Clinical Trials Reporting System) )
CDR0000573917 ( Registry Identifier: PDQ (Physician Data Query) )
First Posted: November 4, 2007    Key Record Dates
Results First Posted: January 11, 2017
Last Update Posted: February 13, 2020
Last Verified: February 2020
Keywords provided by Alliance for Clinical Trials in Oncology:
adult gliosarcoma
adult giant cell glioblastoma
adult glioblastoma
adult anaplastic astrocytoma
adult diffuse astrocytoma
adult pilocytic astrocytoma
adult subependymal giant cell astrocytoma
Additional relevant MeSH terms:
Layout table for MeSH terms
Nervous System Neoplasms
Central Nervous System Neoplasms
Neoplasms, Neuroepithelial
Neuroectodermal Tumors
Neoplasms, Germ Cell and Embryonal
Neoplasms by Histologic Type
Neoplasms, Glandular and Epithelial
Neoplasms, Nerve Tissue
Neoplasms by Site
Nervous System Diseases
Antineoplastic Agents
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Antineoplastic Agents, Alkylating
Alkylating Agents
Molecular Mechanisms of Pharmacological Action