Everolimus, Temozolomide, and Radiation Therapy in Treating Patients With Newly Diagnosed Glioblastoma Multiforme (RTOG 0913)

This study is ongoing, but not recruiting participants.
Sponsor:
Collaborator:
Information provided by (Responsible Party):
Radiation Therapy Oncology Group
ClinicalTrials.gov Identifier:
NCT01062399
First received: February 3, 2010
Last updated: October 8, 2013
Last verified: October 2013

February 3, 2010
October 8, 2013
December 2010
December 2014   (final data collection date for primary outcome measure)
  • Dose-limiting toxicity (phase I) [ Time Frame: From start of treatment to eight weeks. ] [ Designated as safety issue: Yes ]
  • Progression-free survival (phase II) [ Time Frame: From randomization to date of progression, death or last follow-up. Analysis occurs after 134 events (death or progression) have been reported. ] [ Designated as safety issue: No ]
  • Dose-limiting toxicity (phase I) [ Designated as safety issue: Yes ]
  • Progression-free survival (phase II) [ Designated as safety issue: No ]
Complete list of historical versions of study NCT01062399 on ClinicalTrials.gov Archive Site
  • Safety profile of RAD001 in combination with radiation and temozolomide (Phase I) [ Time Frame: From start of treatment to eight weeks. ] [ Designated as safety issue: Yes ]
  • Overall survival (phase II) [ Time Frame: From randomization to date of death or last follow-up. Analysis occurs at the same time as the primary outcome analysis. ] [ Designated as safety issue: No ]
  • The safety profile of RAD001 in combination with radiation and temozolomide (Phase II) [ Time Frame: Analysis occurs at the same time as the primary outcome analysis. ] [ Designated as safety issue: Yes ]
  • Akt/mTOR axis predicts response to RAD001 (Phase II) [ Time Frame: From randomization to date of death or last follow-up. Analysis occurs at the same time as the primary outcome analysis if the biomarker is available. ] [ Designated as safety issue: No ]
  • Association between MGMT status and response to RAD001 (Phase II) [ Time Frame: From randomization to date of death or last follow-up. Analysis occurs at the same time as the primary outcome analysis if the biomarker is available. ] [ Designated as safety issue: No ]
  • Treatment-related toxicity, as measured by the CTEP Active Version of the CTCAE (phase I and II) [ Designated as safety issue: Yes ]
  • Overall survival (phase II) [ Designated as safety issue: No ]
Not Provided
Not Provided
 
Everolimus, Temozolomide, and Radiation Therapy in Treating Patients With Newly Diagnosed Glioblastoma Multiforme
Phase I/II Trial of Concurrent RAD001 (Everolimus) With Temozolomide/Radiation Followed by Adjuvant RAD001/Temozolomide in Newly Diagnosed Glioblastoma

RATIONALE: Everolimus may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth and by blocking blood flow to the tumor. 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. 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 and to see how well it works in treating patients with newly diagnosed glioblastoma multiforme.

OBJECTIVES:

Primary

  • To define the maximum tolerated dose of everolimus (up to an established dose of 10 mg/day) when combined with concurrent radiotherapy and temozolomide in patients with newly diagnosed glioblastoma multiforme. (Phase I)
  • To determine the efficacy of everolimus in combination with radiotherapy and temozolomide followed by adjuvant everolimus in combination with temozolomide, as measured by progression-free survival, in these patients. (Phase II)

Secondary

  • To characterize the safety profile of everolimus in combination with radiotherapy and temozolomide in these patients. (Phase I)
  • To determine the overall survival of these patients. (Phase II)
  • To further evaluate the safety profile of everolimus in combination with radiotherapy and temozolomide in these patients. (Phase II)
  • To determine if activation of the Akt/mTOR axis predicts response to everolimus. (Phase II)
  • To determine if there is an association between tumor MGMT gene methylation status and response to everolimus. (Phase II)

OUTLINE: This is a multicenter, phase I, dose-escalation study of everolimus followed by a phase II, randomized study.

  • Phase I: Patients undergo radiotherapy (intensity-modulated or 3-dimensional conformal radiotherapy) 5 days a week for 6 weeks and receive oral everolimus and oral temozolomide once daily for 6 weeks. Beginning 28 days after the completion of therapy, patients receive adjuvant oral everolimus once daily on days 1-28 and oral temozolomide once daily on days 1-5. Treatment with adjuvant everolimus and temozolomide repeats every 28 days for up to 12 courses in the absence of disease progression or unacceptable toxicity.
  • Phase II: Patients are stratified according to recursive partitioning analysis class (III vs IV vs V). Patients are randomized to 1 of 2 treatment arms.

    • Arm I: Patients undergo radiotherapy (intensity-modulated or 3-dimensional conformal radiotherapy) 5 days a week for 6 weeks and receive oral temozolomide once daily for 6 weeks. Beginning 28 days after the completion of therapy, patients receive adjuvant oral temozolomide once daily on days 1-5. Treatment with adjuvant temozolomide repeats every 28 days for up to 12 courses in the absence of disease progression or unacceptable toxicity.
    • Arm II: Patients receive treatment as in phase I. Tumor tissue, plasma, and urine samples may be collected for correlative laboratory studies (mandatory for phase II).

After completion of study treatment, patients are followed up every 3 months for 1 year, every 4 months for 1 year, and then every 6 months thereafter.

Interventional
Phase 1
Phase 2
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
Brain and Central Nervous System Tumors
  • Drug: everolimus
    Given orally
  • Drug: temozolomide
    Given orally
  • Radiation: 3-dimensional conformal radiation therapy
    Given 5 days a week for 6 weeks
  • Radiation: intensity-modulated radiation therapy
    Given 5 days a week for 6 weeks
  • Active Comparator: Arm I (phase II)
    Patients undergo radiotherapy (intensity-modulated or 3-dimensional conformal radiotherapy) 5 days a week for 6 weeks and receive oral temozolomide once daily for 6 weeks. Beginning 28 days after the completion of therapy, patients receive adjuvant oral temozolomide once daily on days 1-5. Treatment with adjuvant temozolomide repeats every 28 days for up to 12 courses in the absence of disease progression or unacceptable toxicity.
    Interventions:
    • Drug: temozolomide
    • Radiation: 3-dimensional conformal radiation therapy
    • Radiation: intensity-modulated radiation therapy
  • Experimental: Arm II (phase II)
    Patients undergo radiotherapy (intensity-modulated or 3-dimensional conformal radiotherapy) 5 days a week for 6 weeks and receive oral everolimus and oral temozolomide once daily for 6 weeks. Beginning 28 days after the completion of therapy, patients receive adjuvant oral everolimus once daily on days 1-28 and oral temozolomide once daily on days 1-5. Treatment with adjuvant everolimus and temozolomide repeats every 28 days for up to 12 courses in the absence of disease progression or unacceptable toxicity.
    Interventions:
    • Drug: everolimus
    • Drug: temozolomide
    • Radiation: 3-dimensional conformal radiation therapy
    • Radiation: intensity-modulated radiation therapy
Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Active, not recruiting
246
Not Provided
December 2014   (final data collection date for primary outcome measure)

DISEASE CHARACTERISTICS:

  • Histologically confirmed glioblastoma multiforme (GBM) (WHO grade IV) by central pathology review

    • Gliosarcoma allowed
    • Tumor must have a supratentorial component
  • Diagnosis must have been made by surgical excision, either partial or complete excision, within the past 5 weeks

    • Stereotactic biopsy or Cavitron ultrasonic aspirator-derived tissue are not allowed
  • Tumor tissue available for correlative studies (phase II only)

    • Patients must have ≥ 1 block of tissue; if a block cannot be submitted, two tissue specimens punched with a skin punch (2 mm diameter) from the tissue block containing the tumor may be submitted
  • No recurrent or multifocal malignant glioma
  • No metastases detected below the tentorium or beyond the cranial vault

PATIENT CHARACTERISTICS:

  • Karnofsky performance status 70-100%
  • ANC ≥ 1,800/mm^3
  • Platelet count ≥ 100,000/mm^3
  • Hemoglobin ≥ 10.0 g/dL (transfusion or other intervention allowed)
  • PT/INR ≤ 1.5
  • BUN ≤ 30 mg/dL
  • Serum creatinine ≤ 1.5 times upper limit of normal (ULN)
  • Bilirubin ≤ 1.5 times normal
  • ALT and AST ≤ 2.5 times normal
  • Fasting serum cholesterol ≤ 300 mg/dL OR ≤ 7.75 mmol/L AND fasting triglycerides ≤ 2.5 times ULN (if one or both of these thresholds are exceeded, patients are eligible only after initiation of appropriate lipid-lowering medication)
  • Not pregnant or nursing
  • Negative pregnancy test
  • Fertile patients must use effective contraception
  • No other invasive malignancy within the past 3 years except for nonmelanoma skin cancer or carcinoma in situ of the breast, oral cavity, or cervix
  • No severe, active co-morbidity, defined as follows:

    • NYHA class III-IV symptomatic congestive heart failure
    • Unstable angina pectoris, symptomatic congestive heart failure, myocardial infarction within the past 6 months, serious uncontrolled cardiac arrhythmia, or any other clinically significant cardiac disease
    • Severely impaired lung function, defined as spirometry and DLCO that is 50% of the normal predicted value and/or oxygen saturation that is ≤ 88% at rest on room air
    • Uncontrolled diabetes, defined as fasting serum glucose > 1.5 times ULN
    • Active (acute or chronic) or uncontrolled severe infections requiring IV antibiotics
    • Liver disease such as cirrhosis, chronic active hepatitis, or chronic persistent hepatitis
    • AIDS based upon current Centers for Disease Control and Prevention definition or known HIV seropositivity (HIV testing is not required for study entry)
    • Active connective tissue disorders such as lupus erythematosus or scleroderma that, in the opinion of the treating physician, may put the patient at high risk for radiation toxicity
    • Other major medical illness or psychiatric impairment that, in the investigator's opinion, will prevent administration or completion of study treatment
  • No impaired gastrointestinal (GI) function or GI disease that may significantly alter the absorption of everolimus (e.g., ulcerative disease, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome, or small bowel resection)
  • No history of deep vein thrombosis or pulmonary embolism
  • No prior allergic reaction to temozolomide
  • No known hypersensitivity to mTOR inhibitors (e.g., sirolimus, temsirolimus, everolimus) or to their excipients

PRIOR CONCURRENT THERAPY:

  • See Disease Characteristics
  • Recovered from the effects of surgery, postoperative infection, and other complications
  • No prior temozolomide
  • No prior mTOR inhibitor (e.g., sirolimus, temsirolimus, everolimus)
  • No prior Gliadel wafers or any other intratumoral or intracavitary treatment
  • No prior radiotherapy to the head or neck (except for T1 glottic cancer) resulting in overlap of radiotherapy fields
  • No prior chemotherapy or radiosensitizers for cancer of the head and neck region

    • Prior chemotherapy for a different cancer is allowed
  • No prior radiotherapy or chemotherapy for GBM
  • No prior or concurrent treatment on any other therapeutic clinical study
  • At least 14 days since prior and no concurrent enzyme-inducing anti-epileptic drugs
  • Concurrent anticoagulation allowed provided target INR ≤ 1.5 AND patient is on a stable dose of warfarin or low molecular weight heparin for > 2 weeks
Both
18 Years and older
No
Contact information is only displayed when the study is recruiting subjects
United States,   Canada,   Israel
 
NCT01062399
RTOG 0913, RTOG-0913, CDR0000664302
Yes
Radiation Therapy Oncology Group
Radiation Therapy Oncology Group
National Cancer Institute (NCI)
Principal Investigator: Prakash Chinnaiyan, MD H. Lee Moffitt Cancer Center and Research Institute
Radiation Therapy Oncology Group
October 2013

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP