Everolimus, Temozolomide, and Radiation Therapy in Treating Patients With Newly Diagnosed Glioblastoma Multiforme
NCT ID: NCT01062399
Last Updated: 2022-06-09
Study Results
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View full resultsBasic Information
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COMPLETED
PHASE1/PHASE2
279 participants
INTERVENTIONAL
2010-12-31
2022-05-20
Brief Summary
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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.
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Detailed Description
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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.
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.
Conditions
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Study Design
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RANDOMIZED
PARALLEL
TREATMENT
NONE
Study Groups
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Ph I: RT + TMZ + RAD001 2.5 mg/day
Radiation therapy (RT), concurrent temozolomide (TMZ), and concurrent RAD001 2.5 mg/day followed by post-radiation temozolomide and post-radiation RAD001 10 mg/day.
concurrent temozolomide
During radiation: temozolomide 75 mg/m2/day orally daily during radiation therapy; one hour prior to radiation and in the morning on weekends on days 1-42. Dose rounded to the nearest 5 mg.
Radiation therapy
Intensity Modulated RT (IMRT) allowed. For both IMRT and 3D conformal radiotherapy (3D-CRT) plans, one treatment of 2 Gy given daily 5 days per week for a total of 60 Gy over 6 weeks.
concurrent RAD001 2.5 mg/day
During radiation: RAD001 2.5 mg orally daily during radiation therapy; one hour prior to radiation and in the morning on weekends on days 1-42.
post-radiation RAD001 10 mg/day
Post-radiation: RAD001 10 mg orally daily on days 1-28 of each cycle, for up to 12 cycles, starting 28 days after the completion of radiation therapy (Cycle = 28 days).
post-radiation temozolomide
Post-radiation: temozolomide 150 mg/m2/day - 200 mg/m2/day orally daily on days 1-5 of each cycle, starting 28 days after the completion of radiation therapy for up to 12 cycles (Cycle = 28 days)
Ph I: RT + TMZ + RAD001 5 mg/day
Radiation therapy, concurrent temozolomide, and concurrent RAD001 5 mg/day followed by post-radiation temozolomide and post-radiation RAD001 10 mg/day.
concurrent temozolomide
During radiation: temozolomide 75 mg/m2/day orally daily during radiation therapy; one hour prior to radiation and in the morning on weekends on days 1-42. Dose rounded to the nearest 5 mg.
Radiation therapy
Intensity Modulated RT (IMRT) allowed. For both IMRT and 3D conformal radiotherapy (3D-CRT) plans, one treatment of 2 Gy given daily 5 days per week for a total of 60 Gy over 6 weeks.
concurrent RAD001 5 mg/day
During radiation: RAD001 5 mg orally daily during radiation therapy; one hour prior to radiation and in the morning on weekends on days 1-42.
post-radiation RAD001 10 mg/day
Post-radiation: RAD001 10 mg orally daily on days 1-28 of each cycle, for up to 12 cycles, starting 28 days after the completion of radiation therapy (Cycle = 28 days).
post-radiation temozolomide
Post-radiation: temozolomide 150 mg/m2/day - 200 mg/m2/day orally daily on days 1-5 of each cycle, starting 28 days after the completion of radiation therapy for up to 12 cycles (Cycle = 28 days)
Ph I: RT + TMZ + RAD001 10 mg/day
Radiation therapy, concurrent temozolomide, and concurrent RAD001 10 mg/day followed by post-radiation temozolomide and post-radiation RAD001 10 mg/day.
concurrent RAD001 10 mg/day
During radiation: RAD001 10 mg orally daily during radiation therapy; one hour prior to radiation and in the morning on weekends on days 1-42.
concurrent temozolomide
During radiation: temozolomide 75 mg/m2/day orally daily during radiation therapy; one hour prior to radiation and in the morning on weekends on days 1-42. Dose rounded to the nearest 5 mg.
Radiation therapy
Intensity Modulated RT (IMRT) allowed. For both IMRT and 3D conformal radiotherapy (3D-CRT) plans, one treatment of 2 Gy given daily 5 days per week for a total of 60 Gy over 6 weeks.
post-radiation RAD001 10 mg/day
Post-radiation: RAD001 10 mg orally daily on days 1-28 of each cycle, for up to 12 cycles, starting 28 days after the completion of radiation therapy (Cycle = 28 days).
post-radiation temozolomide
Post-radiation: temozolomide 150 mg/m2/day - 200 mg/m2/day orally daily on days 1-5 of each cycle, starting 28 days after the completion of radiation therapy for up to 12 cycles (Cycle = 28 days)
Ph II: RT + TMZ
Radiation therapy and concurrent temozolomide followed by post-radiation temozolomide
concurrent temozolomide
During radiation: temozolomide 75 mg/m2/day orally daily during radiation therapy; one hour prior to radiation and in the morning on weekends on days 1-42. Dose rounded to the nearest 5 mg.
Radiation therapy
Intensity Modulated RT (IMRT) allowed. For both IMRT and 3D conformal radiotherapy (3D-CRT) plans, one treatment of 2 Gy given daily 5 days per week for a total of 60 Gy over 6 weeks.
post-radiation RAD001 10 mg/day
Post-radiation: RAD001 10 mg orally daily on days 1-28 of each cycle, for up to 12 cycles, starting 28 days after the completion of radiation therapy (Cycle = 28 days).
post-radiation temozolomide
Post-radiation: temozolomide 150 mg/m2/day - 200 mg/m2/day orally daily on days 1-5 of each cycle, starting 28 days after the completion of radiation therapy for up to 12 cycles (Cycle = 28 days)
Ph II: RT + TMZ + RAD001
Radiation therapy, concurrent temozolomide, and concurrent RAD001 10 mg/day followed by post-radiation temozolomide and post-radiation RAD001 10 mg/day.
concurrent RAD001 10 mg/day
During radiation: RAD001 10 mg orally daily during radiation therapy; one hour prior to radiation and in the morning on weekends on days 1-42.
concurrent temozolomide
During radiation: temozolomide 75 mg/m2/day orally daily during radiation therapy; one hour prior to radiation and in the morning on weekends on days 1-42. Dose rounded to the nearest 5 mg.
Radiation therapy
Intensity Modulated RT (IMRT) allowed. For both IMRT and 3D conformal radiotherapy (3D-CRT) plans, one treatment of 2 Gy given daily 5 days per week for a total of 60 Gy over 6 weeks.
post-radiation RAD001 10 mg/day
Post-radiation: RAD001 10 mg orally daily on days 1-28 of each cycle, for up to 12 cycles, starting 28 days after the completion of radiation therapy (Cycle = 28 days).
post-radiation temozolomide
Post-radiation: temozolomide 150 mg/m2/day - 200 mg/m2/day orally daily on days 1-5 of each cycle, starting 28 days after the completion of radiation therapy for up to 12 cycles (Cycle = 28 days)
Interventions
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concurrent RAD001 10 mg/day
During radiation: RAD001 10 mg orally daily during radiation therapy; one hour prior to radiation and in the morning on weekends on days 1-42.
concurrent temozolomide
During radiation: temozolomide 75 mg/m2/day orally daily during radiation therapy; one hour prior to radiation and in the morning on weekends on days 1-42. Dose rounded to the nearest 5 mg.
Radiation therapy
Intensity Modulated RT (IMRT) allowed. For both IMRT and 3D conformal radiotherapy (3D-CRT) plans, one treatment of 2 Gy given daily 5 days per week for a total of 60 Gy over 6 weeks.
concurrent RAD001 2.5 mg/day
During radiation: RAD001 2.5 mg orally daily during radiation therapy; one hour prior to radiation and in the morning on weekends on days 1-42.
concurrent RAD001 5 mg/day
During radiation: RAD001 5 mg orally daily during radiation therapy; one hour prior to radiation and in the morning on weekends on days 1-42.
post-radiation RAD001 10 mg/day
Post-radiation: RAD001 10 mg orally daily on days 1-28 of each cycle, for up to 12 cycles, starting 28 days after the completion of radiation therapy (Cycle = 28 days).
post-radiation temozolomide
Post-radiation: temozolomide 150 mg/m2/day - 200 mg/m2/day orally daily on days 1-5 of each cycle, starting 28 days after the completion of radiation therapy for up to 12 cycles (Cycle = 28 days)
Other Intervention Names
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Eligibility Criteria
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Inclusion Criteria
2. Tumor tissue available for correlative studies (Required only in phase II portion, as described below).
* Patients must have at least 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.
* Diagnosis must be made by surgical excision, either partial or complete. Stereotactic biopsy or Cavitron ultrasonic aspirator (CUSA)-derived tissue is not allowed for patients on Phase II, as it will not provide sufficient tissue for the required MGMT and pAKT/pMTOR analyses.
3. The tumor must have a supratentorial component
4. Patients must have recovered from the effects of surgery, postoperative infection, and other complications.
5. A diagnostic contrast-enhanced MRI or CT scan (if MRI is not available due to non-compatible devices) of the brain must be performed preoperatively and postoperatively. The postoperative scan must be done within 28 days prior to step 2 registration, ,preferably within 96 hours of surgery. Preoperative and postoperative scans must be the same type.
• Patients unable to undergo MRI imaging because of non-compatible devices can be enrolled, provided pre- and post-operative contrast enhanced CT scans are obtained and are of sufficient quality.
6. History/physical examination within 14 days prior to step 2 registration
7. Neurologic examination within 14 days prior to step 2 registration
8. Documentation of steroid doses within 14 days prior to step 2 registration
9. Karnofsky performance status ≥ 70
10. Age ≥ 18 years
11. Complete blood count (CBC)/differential obtained within 14 days prior to step 2 registration, with adequate bone marrow function defined as follows:
* Absolute neutrophil count (ANC) ≥ 1,800 cells/mm3;
* Platelets ≥ 100,000 cells/mm3;
* Hemoglobin ≥ 10.0 g/dl (Note: The use of transfusion or other intervention to achieve Hgb ≥ 10.0 g/dl is acceptable.)
12. Prothrombin time/international normalized ratio (PT INR) ≤ 1.5 for patients not on warfarin confirmed by testing within 14 days prior to step 2 registration.
Patients on full-dose anticoagulants (eg, warfarin or low molecular weight heparin) must meet both of the following criteria:
* No active bleeding or pathological condition that carries a high risk of bleeding (eg, tumor involving major vessels or known varices)
* In-range INR (between 2 and 3) on a stable dose of oral anticoagulant or on a stable dose of low molecular weight heparin
13. Adequate renal function, as defined below:
* Blood urea nitrogen (BUN) ≤ 30 mg/dl within 14 days prior to step 2 registration
* Serum creatinine ≤ 1.5 x upper limit of normal (ULN) within 14 days prior to step 2 registration
14. Adequate hepatic function, as defined below:
* Bilirubin ≤ 1.5 x normal range within 14 days prior to step 2 registration
* Alanine aminotransferase (ALT) ≤ 2.5 x normal range within 14 days prior to step 2 registration
* Aspartate aminotransferase (AST) ≤ 2.5 x normal range within 14 days prior to step 2 registration
15. Fasting serum cholesterol ≤300 mg/dL OR ≤7.75 mmol/L AND fasting triglycerides ≤ 2.5 x ULN (upper limit of normal). Note: If one or both of these thresholds are exceeded, the patient can only be included after initiation of appropriate lipid lowering medication.
16. For females of child-bearing potential, negative serum pregnancy test within 14 days prior to step 2 registration
17. Women of childbearing potential and male participants must practice adequate contraception
18. Patient must provide study-specific informed consent prior to registration
Exclusion Criteria
2. Recurrent or multifocal malignant glioma
3. Metastases detected below the tentorium or beyond the cranial vault
4. Prior use of Gliadel wafers or any other intratumoral or intracavitary treatment
5. Prior radiotherapy to the head or neck (except for T1 glottic cancer), resulting in overlap of radiation therapy fields
6. Prior chemotherapy or radiosensitizers for cancer of the head and neck region; note that prior chemotherapy for a different cancer is allowable, except prior temozolomide or RAD001.
7. Prior radiation therapy or chemotherapy for glioblastoma
8. Severe, active co-morbidity, defined as follows:
* Symptomatic congestive heart failure of New York heart Association Class III or IV
* Unstable angina pectoris, symptomatic congestive heart failure, myocardial infarction within the last 6 months, serious uncontrolled cardiac arrhythmia or any other clinically significant cardiac disease
* Severely impaired lung function as defined as spirometry and diffusing capacity of the lungs for carbon monoxide (DLCO) that is 50% of the normal predicted value and/or 02 saturation that is 88% or less at rest on room air
* Uncontrolled diabetes as defined by fasting serum glucose \>1.5 x ULN
* Active (acute or chronic) or uncontrolled severe infections requiring intravenous antibiotics
* Liver disease such as cirrhosis, chronic active hepatitis or chronic persistent hepatitis
* Acquired immune deficiency syndrome (AIDS) based upon current Centers for Disease Control and Prevention (CDC) definition or known HIV seropositivity; note, however, that HIV testing is not required for entry into this protocol. The need to exclude patients with HIV/AIDS from this protocol is necessary because the treatments involved in this protocol may be significantly immunosuppressive.
* Active connective tissue disorders, such as lupus or scleroderma, that in the opinion of the treating physician may put the patient at high risk for radiation toxicity
* Other major medical illnesses or psychiatric impairments that in the investigator's opinion will prevent administration or completion of protocol therapy
18 Years
120 Years
ALL
No
Sponsors
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National Cancer Institute (NCI)
NIH
NRG Oncology
OTHER
Radiation Therapy Oncology Group
NETWORK
Responsible Party
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Principal Investigators
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Prakash Chinnaiyan, MD
Role: PRINCIPAL_INVESTIGATOR
William Beaumont Hospital and Oakland University School of Medicine
Locations
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CCOP - Christiana Care Health Services
Newark, Delaware, United States
University of Florida Shands Cancer Center
Gainesville, Florida, United States
Baptist Cancer Institute - Jacksonville
Jacksonville, Florida, United States
Integrated Community Oncology Network at Southside Cancer Center
Jacksonville, Florida, United States
Baptist Medical Center South
Jacksonville, Florida, United States
Integrated Community Oncology Network
Jacksonville Beach, Florida, United States
Integrated Community Oncology Network - Orange Park
Orange Park, Florida, United States
Florida Cancer Center - Palatka
Palatka, Florida, United States
Flagler Cancer Center
Saint Augustine, Florida, United States
H. Lee Moffitt Cancer Center and Research Institute at University of South Florida
Tampa, Florida, United States
Winship Cancer Institute of Emory University
Atlanta, Georgia, United States
St. Vincent Oncology Center
Indianapolis, Indiana, United States
St. Agnes Hospital Cancer Center
Baltimore, Maryland, United States
Dana-Farber/Brigham and Women's Cancer Center
Boston, Massachusetts, United States
Regional Cancer Center at Singing River Hospital
Pascagoula, Mississippi, United States
St. Barnabas Medical Center Cancer Center
Livingston, New Jersey, United States
New York Oncology Hematology, PC at Albany Regional Cancer Care
Albany, New York, United States
University Radiation Oncology at Parkridge Hospital
Rochester, New York, United States
James P. Wilmot Cancer Center at University of Rochester Medical Center
Rochester, New York, United States
Blumenthal Cancer Center at Carolinas Medical Center
Charlotte, North Carolina, United States
Summa Center for Cancer Care at Akron City Hospital
Akron, Ohio, United States
Barberton Citizens Hospital
Barberton, Ohio, United States
Cleveland Clinic Taussig Cancer Center
Cleveland, Ohio, United States
Willamette Valley Cancer Center - Eugene
Eugene, Oregon, United States
Adams Cancer Center
Gettysburg, Pennsylvania, United States
Cherry Tree Cancer Center
Hanover, Pennsylvania, United States
McGlinn Family Regional Cancer Center at Reading Hospital and Medical Center
Reading, Pennsylvania, United States
York Cancer Center at Apple Hill Medical Center
York, Pennsylvania, United States
Rhode Island Hospital Comprehensive Cancer Center
Providence, Rhode Island, United States
University of Texas Health Science Center at San Antonio
San Antonio, Texas, United States
Tyler Cancer Center
Tyler, Texas, United States
Huntsman Cancer Institute at University of Utah
Salt Lake City, Utah, United States
Medical College of Wisconsin Cancer Center
Milwaukee, Wisconsin, United States
Waukesha Memorial Hospital Regional Cancer Center
Waukesha, Wisconsin, United States
Ottawa Hospital Regional Cancer Centre - General Campus
Ottawa, Ontario, Canada
Tel-Aviv Sourasky Medical Center
Tel Aviv, , Israel
Countries
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References
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Chinnaiyan P, Won M, Wen PY, Rojiani AM, Wendland M, Dipetrillo TA, Corn BW, Mehta MP. RTOG 0913: a phase 1 study of daily everolimus (RAD001) in combination with radiation therapy and temozolomide in patients with newly diagnosed glioblastoma. Int J Radiat Oncol Biol Phys. 2013 Aug 1;86(5):880-4. doi: 10.1016/j.ijrobp.2013.04.036. Epub 2013 May 29.
Chinnaiyan P, Won M, Wen PY, Rojiani AM, Werner-Wasik M, Shih HA, Ashby LS, Michael Yu HH, Stieber VW, Malone SC, Fiveash JB, Mohile NA, Ahluwalia MS, Wendland MM, Stella PJ, Kee AY, Mehta MP. A randomized phase II study of everolimus in combination with chemoradiation in newly diagnosed glioblastoma: results of NRG Oncology RTOG 0913. Neuro Oncol. 2018 Apr 9;20(5):666-673. doi: 10.1093/neuonc/nox209.
Other Identifiers
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RTOG-0913
Identifier Type: -
Identifier Source: secondary_id
CDR0000664302
Identifier Type: -
Identifier Source: secondary_id
NCI-2011-00885
Identifier Type: REGISTRY
Identifier Source: secondary_id
RTOG 0913
Identifier Type: -
Identifier Source: org_study_id
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