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

Study Overview
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Brief Summary
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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.

Detailed Description
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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. 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.

Official Title
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Phase I/II Trial of Concurrent RAD001 (Everolimus) With Temozolomide/Radiation Followed by Adjuvant RAD001/Temozolomide in Newly Diagnosed Glioblastoma

Conditions
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Brain and Central Nervous System Tumors

Intervention / Treatment
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* Drug: concurrent RAD001 10 mg/day
* Drug: concurrent temozolomide
* Radiation: Radiation therapy
* Drug: concurrent RAD001 2.5 mg/day
* Drug: concurrent RAD001 5 mg/day
* Drug: post-radiation RAD001 10 mg/day
* Drug: post-radiation temozolomide


Participation Criteria
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Eligibility Criteria
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Inclusion criteria: Histologically proven diagnosis of glioblastoma (WHO grade IV) confirmed by central pathology review prior to Step 2 registration. Since gliosarcoma is a variant of glioblastoma, gliosarcoma is also an eligible diagnosis. 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. The tumor must have a supratentorial component Patients must have recovered from the effects of surgery, postoperative infection, and other complications. 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. History/physical examination within 14 days prior to step 2 registration Neurologic examination within 14 days prior to step 2 registration Documentation of steroid doses within 14 days prior to step 2 registration Karnofsky performance status ≥ 70 Age ≥ 18 years 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.) 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 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 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 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. For females of child-bearing potential, negative serum pregnancy test within 14 days prior to step 2 registration Women of childbearing potential and male participants must practice adequate contraception Patient must provide study-specific informed consent prior to registration Exclusion criteria: Prior invasive malignancy (except non-melanomatous skin cancer) unless disease free for a minimum of 3 years (For example, carcinoma in situ of the breast, oral cavity, or cervix are all permissible) Recurrent or multifocal malignant glioma Metastases detected below the tentorium or beyond the cranial vault Prior use of Gliadel wafers or any other intratumoral or intracavitary treatment Prior radiotherapy to the head or neck (except for T1 glottic cancer), resulting in overlap of radiation therapy fields 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. Prior radiation therapy or chemotherapy for glioblastoma 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

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 120 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Ph I: RT + TMZ + RAD001 2.5 mg/day<br>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. | Drug: concurrent temozolomide<br>* 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.<br>Radiation: Radiation therapy<br>* 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.<br>Drug: concurrent RAD001 2.5 mg/day<br>* 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.<br>* Other names: everolimus;Drug: post-radiation RAD001 10 mg/day<br>* 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).<br>* Other names: everolimus;Drug: post-radiation temozolomide<br>* 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)<br>|
| Experimental: Ph I: RT + TMZ + RAD001 5 mg/day<br>Radiation therapy, concurrent temozolomide, and concurrent RAD001 5 mg/day followed by post-radiation temozolomide and post-radiation RAD001 10 mg/day. | Drug: concurrent temozolomide<br>* 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.<br>Radiation: Radiation therapy<br>* 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.<br>Drug: concurrent RAD001 5 mg/day<br>* 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.<br>* Other names: everolimus;Drug: post-radiation RAD001 10 mg/day<br>* 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).<br>* Other names: everolimus;Drug: post-radiation temozolomide<br>* 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)<br>|
| Experimental: Ph I: RT + TMZ + RAD001 10 mg/day<br>Radiation therapy, concurrent temozolomide, and concurrent RAD001 10 mg/day followed by post-radiation temozolomide and post-radiation RAD001 10 mg/day. | Drug: concurrent RAD001 10 mg/day<br>* 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.<br>* Other names: everolimus;Drug: concurrent temozolomide<br>* 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.<br>Radiation: Radiation therapy<br>* 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.<br>Drug: post-radiation RAD001 10 mg/day<br>* 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).<br>* Other names: everolimus;Drug: post-radiation temozolomide<br>* 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)<br>|
| Active Comparator: Ph II: RT + TMZ<br>Radiation therapy and concurrent temozolomide followed by post-radiation temozolomide | Drug: concurrent temozolomide<br>* 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.<br>Radiation: Radiation therapy<br>* 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.<br>Drug: post-radiation RAD001 10 mg/day<br>* 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).<br>* Other names: everolimus;Drug: post-radiation temozolomide<br>* 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)<br>|
| Experimental: Ph II: RT + TMZ + RAD001<br>Radiation therapy, concurrent temozolomide, and concurrent RAD001 10 mg/day followed by post-radiation temozolomide and post-radiation RAD001 10 mg/day. | Drug: concurrent RAD001 10 mg/day<br>* 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.<br>* Other names: everolimus;Drug: concurrent temozolomide<br>* 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.<br>Radiation: Radiation therapy<br>* 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.<br>Drug: post-radiation RAD001 10 mg/day<br>* 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).<br>* Other names: everolimus;Drug: post-radiation temozolomide<br>* 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)<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Phase I: Number of Patients With Dose-limiting Toxicity (DLT) | DLT is defined as any of the following events occurring during the first 8 weeks of treatment with RAD001 and temozolomide and attributable to the study drugs: any grade 3 or 4 thrombocytopenia, grade 4 anemia, or grade 4 neutropenia lasting more than 7 days; any non-hematologic grade 3 or greater adverse event (AE), excluding alopecia, despite maximal medical therapy; any grade 4 radiation-induced skin changes; failure to recover from adverse events to be eligible for re-treatment with RAD001 and temozolomide within 14 days of the last dose of either drug; or any episode of non-infectious pneumonitis grade 2, 3, or 4 of any duration. Adverse events are graded using CTCAE v4.0. Grade refers to the severity of the AE. The CTCAE v4.0 assigns Grades 1 through 5 with unique clinical descriptions of severity for each AE based on this general guideline: Grade 1 Mild AE, Grade 2 Moderate AE, Grade 3 Severe AE, Grade 4 Life-threatening or disabling AE, Grade 5 Death related to AE | From start of treatment to eight weeks. | 
| Phase II: Progression-free Survival (PFS) | Using the Response Assessment in Neuro- Oncology (RANO) criteria, the progression is defined by any of the following: > 25% increase in sum of the products of perpendicular diameters of enhancing lesions compared to the smallest tumor measurement obtained either at baseline (if no decrease) or best response, on stable or increasing doses of corticosteroids; Significant increase in T2/FLAIR non-enhancing lesion on stable or increasing doses of corticosteroids compared to baseline scan or best response following initiation of therapy, not due to co-morbid events; Any new lesion; Clear clinical deterioration not attributable to other causes apart from the tumor or changes in corticosteroid dose; Failure to return for evaluation due to death or deteriorating condition; Clear progression of non-measurable disease. PFS time is defined as time from registration to date of progression, death, or last known follow-up (censored). PFS rates are estimated using the Kaplan-Meier method. | Analysis occured after 134 events (progression or death) were reported. Patients were followed from randomization to death or study termination whichever occurs first, up to 36.7 months. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Phase II: Overall Survival (OS) | Overall survival time is defined as time from/randomization to the date of death from any cause and is estimated by the Kaplan-Meier method. Patients last known to be alive are censored at the date of last contact. | Analysis occured after 134 events (progression or death) were reported. Patients were followed from randomization to death or study termination whichever occurs first, up to 36.7 months. | 
| Phase I: Distribution of Worst Adverse Event Grade | AE reporting in Phase I was split up by treatment timing: concurrent treatment (RT, TMZ, RAD001); post-RT treatment (TMZ, RAD001) along with all AE's reported in follow-up. The worst/highest grade of any adverse event reported in each time period was determined for each patient. The percentage of patients in each grade level is reported. Adverse events are graded using CTCAE v4.0. Grade refers to the severity of the AE. The CTCAE v4.0 assigns Grades 1 through 5 with unique clinical descriptions of severity for each AE based on this general guideline: Grade 1 Mild AE, Grade 2 Moderate AE, Grade 3 Severe AE, Grade 4 Life-threatening or disabling AE, Grade 5 Death related to AE. | Analysis occured after 134 events (progression or death) were reported. Patients were followed from randomization to death or study termination whichever occurs first, up to 36.7 months. | 
| Phase II: Distribution of Worst Adverse Event Grade | The worst/highest grade of any adverse event reported was determined for each patient. The percentage of patients in each grade level is reported. Adverse events are graded using CTCAE v4.0. Grade refers to the severity of the AE. The CTCAE v4.0 assigns Grades 1 through 5 with unique clinical descriptions of severity for each AE based on this general guideline: Grade 1 Mild AE, Grade 2 Moderate AE, Grade 3 Severe AE, Grade 4 Life-threatening or disabling AE, Grade 5 Death related to AE. | Analysis occured after 134 events (progression or death) were reported. Patients were followed from randomization to death or study termination whichever occurs first, up to 36.7 months. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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adult glioblastoma, adult giant cell glioblastoma, adult gliosarcoma