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

Brain and Central Nervous System Tumors Clinical Trial

— RTOG 0913  

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01062399
• Other study ID #: RTOG 0913
• Secondary ID: RTOG-0913CDR0000
• Status: Completed
• Phase: Phase 1/Phase 2
• Start date: December 2010
• Est. completion date: May 20, 2022

Study information

• Verified date: May 2022
• Source: Radiation Therapy Oncology Group
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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.

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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 279
• Est. completion date: May 20, 2022
• Est. primary completion date: June 2016
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 120 Years

Eligibility

Inclusion criteria:

1. 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.

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:

1. 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)

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

Related Conditions & MeSH terms

• Brain and Central Nervous System Tumors
• Central Nervous System Neoplasms
• Glioblastoma
• Nervous System Neoplasms

Intervention

Drug:
• 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:
• 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.

Drug:
• 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)

Locations

Country	Name	City	State
Canada	Ottawa Hospital Regional Cancer Centre - General Campus	Ottawa	Ontario
Israel	Tel-Aviv Sourasky Medical Center	Tel Aviv
United States	Summa Center for Cancer Care at Akron City Hospital	Akron	Ohio
United States	New York Oncology Hematology, PC at Albany Regional Cancer Care	Albany	New York
United States	Winship Cancer Institute of Emory University	Atlanta	Georgia
United States	St. Agnes Hospital Cancer Center	Baltimore	Maryland
United States	Barberton Citizens Hospital	Barberton	Ohio
United States	Dana-Farber/Brigham and Women's Cancer Center	Boston	Massachusetts
United States	Blumenthal Cancer Center at Carolinas Medical Center	Charlotte	North Carolina
United States	Cleveland Clinic Taussig Cancer Center	Cleveland	Ohio
United States	Willamette Valley Cancer Center - Eugene	Eugene	Oregon
United States	University of Florida Shands Cancer Center	Gainesville	Florida
United States	Adams Cancer Center	Gettysburg	Pennsylvania
United States	Cherry Tree Cancer Center	Hanover	Pennsylvania
United States	St. Vincent Oncology Center	Indianapolis	Indiana
United States	Baptist Cancer Institute - Jacksonville	Jacksonville	Florida
United States	Baptist Medical Center South	Jacksonville	Florida
United States	Integrated Community Oncology Network at Southside Cancer Center	Jacksonville	Florida
United States	Integrated Community Oncology Network	Jacksonville Beach	Florida
United States	St. Barnabas Medical Center Cancer Center	Livingston	New Jersey
United States	Medical College of Wisconsin Cancer Center	Milwaukee	Wisconsin
United States	CCOP - Christiana Care Health Services	Newark	Delaware
United States	Integrated Community Oncology Network - Orange Park	Orange Park	Florida
United States	Florida Cancer Center - Palatka	Palatka	Florida
United States	Regional Cancer Center at Singing River Hospital	Pascagoula	Mississippi
United States	Rhode Island Hospital Comprehensive Cancer Center	Providence	Rhode Island
United States	McGlinn Family Regional Cancer Center at Reading Hospital and Medical Center	Reading	Pennsylvania
United States	James P. Wilmot Cancer Center at University of Rochester Medical Center	Rochester	New York
United States	University Radiation Oncology at Parkridge Hospital	Rochester	New York
United States	Flagler Cancer Center	Saint Augustine	Florida
United States	Huntsman Cancer Institute at University of Utah	Salt Lake City	Utah
United States	University of Texas Health Science Center at San Antonio	San Antonio	Texas
United States	H. Lee Moffitt Cancer Center and Research Institute at University of South Florida	Tampa	Florida
United States	Tyler Cancer Center	Tyler	Texas
United States	Waukesha Memorial Hospital Regional Cancer Center	Waukesha	Wisconsin
United States	York Cancer Center at Apple Hill Medical Center	York	Pennsylvania

Sponsors (3)

Lead Sponsor	Collaborator
Radiation Therapy Oncology Group	National Cancer Institute (NCI), NRG Oncology

Countries where clinical trial is conducted

United States,  Canada,  Israel, 

References & Publications (2)

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 Radi — View Citation

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 — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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.
Primary	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	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.
Secondary	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.
Secondary	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.