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

This study is ongoing, but not recruiting participants.
Sponsor:
Collaborators:
NRG Oncology
Information provided by (Responsible Party):
Radiation Therapy Oncology Group
ClinicalTrials.gov Identifier:
NCT01062399
First received: February 3, 2010
Last updated: July 16, 2014
Last verified: July 2014
  Purpose

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.


Condition Intervention Phase
Brain and Central Nervous System Tumors
Drug: everolimus
Drug: temozolomide
Radiation: 3-dimensional conformal radiation therapy
Radiation: intensity-modulated radiation therapy
Phase 1
Phase 2

Study Type: Interventional
Study Design: Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: Phase I/II Trial of Concurrent RAD001 (Everolimus) With Temozolomide/Radiation Followed by Adjuvant RAD001/Temozolomide in Newly Diagnosed Glioblastoma

Resource links provided by NLM:


Further study details as provided by Radiation Therapy Oncology Group:

Primary Outcome Measures:
  • 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 ]

Secondary Outcome Measures:
  • 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 ]

Estimated Enrollment: 246
Study Start Date: December 2010
Estimated Primary Completion Date: December 2014 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
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.
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
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.
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

Detailed Description:

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 (closed to accrual 7/3/12): 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 (opened to accrual 12/19/12): 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.

  Eligibility

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

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
  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: NCT01062399

  Show 36 Study Locations
Sponsors and Collaborators
Radiation Therapy Oncology Group
NRG Oncology
Investigators
Principal Investigator: Prakash Chinnaiyan, MD H. Lee Moffitt Cancer Center and Research Institute
  More Information

Additional Information:
No publications provided

Responsible Party: Radiation Therapy Oncology Group
ClinicalTrials.gov Identifier: NCT01062399     History of Changes
Other Study ID Numbers: RTOG 0913, RTOG-0913, CDR0000664302, NCI-2011-00885
Study First Received: February 3, 2010
Last Updated: July 16, 2014
Health Authority: United States: Federal Government

Keywords provided by Radiation Therapy Oncology Group:
adult glioblastoma
adult giant cell glioblastoma
adult gliosarcoma

Additional relevant MeSH terms:
Central Nervous System Neoplasms
Glioblastoma
Nervous System Neoplasms
Astrocytoma
Glioma
Neoplasms
Neoplasms by Histologic Type
Neoplasms by Site
Neoplasms, Germ Cell and Embryonal
Neoplasms, Glandular and Epithelial
Neoplasms, Nerve Tissue
Neoplasms, Neuroepithelial
Nervous System Diseases
Neuroectodermal Tumors
Dacarbazine
Everolimus
Sirolimus
Temozolomide
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

ClinicalTrials.gov processed this record on October 21, 2014