Brain and Central Nervous System TumorsPhase 1/2RTOG 0913NCT01062399
Everolimus, Temozolomide, and Radiation Therapy in Treating Patients With Newly Diagnosed Glioblastoma Multiforme
A Phase 1/2 study testing concurrent RAD001 10 mg/day, concurrent temozolomide and Radiation therapy in people with Brain and Central Nervous System Tumors, run by Radiation Therapy Oncology Group at 36 sites in 3 countries.
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… Read more about this study
- Who is it for?
- Ages 18 to 120 years
- Conditions the study is for
- Brain and Central Nervous System Tumors
- What is being tested?
- concurrent RAD001 10 mg/day, concurrent temozolomide and Radiation therapy
- Type of treatment
- Pill or oral medicine, Surgery or procedure
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 279 participants
- Where
- 36 sitesin 3 countries
- Study dates
- Dec 2010to 20 May 2022
- Phase
- Phase 1/2
- Are there results?
- Yes, posted in the registrySummary in the doctors' view
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 to 120 years
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- 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.
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- 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
Who cannot join
- 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.
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- 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
Trial locations and contacts
36 sites in 3 countries.
36 sites in 3 countries
United States34 sites
Summa Center for Cancer Care at Akron City Hospital
Akron, Ohio, 44309-2090
New York Oncology Hematology, PC at Albany Regional Cancer Care
Albany, New York, 12206
Winship Cancer Institute of Emory University
Atlanta, Georgia, 30322
St. Agnes Hospital Cancer Center
Baltimore, Maryland, 21229
Barberton Citizens Hospital
Barberton, Ohio, 44203
Dana-Farber/Brigham and Women's Cancer Center
Boston, Massachusetts, 02115
Blumenthal Cancer Center at Carolinas Medical Center
Charlotte, North Carolina, 28232-2861
Cleveland Clinic Taussig Cancer Center
Cleveland, Ohio, 44195
Willamette Valley Cancer Center - Eugene
Eugene, Oregon, 97401
University of Florida Shands Cancer Center
Gainesville, Florida, 32610-0232
Adams Cancer Center
Gettysburg, Pennsylvania, 17325
Cherry Tree Cancer Center
Hanover, Pennsylvania, 17331
St. Vincent Oncology Center
Indianapolis, Indiana, 46260
Baptist Cancer Institute - Jacksonville
Jacksonville, Florida, 32207
Integrated Community Oncology Network at Southside Cancer Center
Jacksonville, Florida, 32207
Baptist Medical Center South
Jacksonville, Florida, 32258
Integrated Community Oncology Network
Jacksonville Beach, Florida, 32250
St. Barnabas Medical Center Cancer Center
Livingston, New Jersey, 07039
Medical College of Wisconsin Cancer Center
Milwaukee, Wisconsin, 53226
CCOP - Christiana Care Health Services
Newark, Delaware, 19713
Integrated Community Oncology Network - Orange Park
Orange Park, Florida, 32073
Florida Cancer Center - Palatka
Palatka, Florida, 32177
Regional Cancer Center at Singing River Hospital
Pascagoula, Mississippi, 39581
Rhode Island Hospital Comprehensive Cancer Center
Providence, Rhode Island, 02903
McGlinn Family Regional Cancer Center at Reading Hospital and Medical Center
Reading, Pennsylvania, 19612-6052
University Radiation Oncology at Parkridge Hospital
Rochester, New York, 14626
James P. Wilmot Cancer Center at University of Rochester Medical Center
Rochester, New York, 14642
Flagler Cancer Center
Saint Augustine, Florida, 32086
Huntsman Cancer Institute at University of Utah
Salt Lake City, Utah, 84112
University of Texas Health Science Center at San Antonio
San Antonio, Texas, 78229-3900
H. Lee Moffitt Cancer Center and Research Institute at University of South Florida
Tampa, Florida, 33612-9497
Tyler Cancer Center
Tyler, Texas, 75702
Waukesha Memorial Hospital Regional Cancer Center
Waukesha, Wisconsin, 53188
York Cancer Center at Apple Hill Medical Center
York, Pennsylvania, 17405
Canada1 site
Ottawa Hospital Regional Cancer Centre - General Campus
Ottawa, Ontario, K1Y 4E9
About this study
Official title: 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.
Read the 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.
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
- Brain and Central Nervous System Tumors
- Being tested
- concurrent RAD001 10 mg/day, concurrent temozolomide, Radiation therapy, concurrent RAD001 2.5 mg/day, concurrent RAD001 5 mg/day
- Keywords
- adult glioblastoma, adult giant cell glioblastoma, adult gliosarcoma
- Medical subject headings
- Central Nervous System Neoplasms, Glioblastoma, Gliosarcoma
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
concurrent RAD001 10 mg/dayDrug
Also called everolimus
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 temozolomideDrug
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 therapyRadiation
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/dayDrug
Also called everolimus
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/dayDrug
Also called everolimus
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/dayDrug
Also called everolimus
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 temozolomideDrug
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)
| Study group | Role | What they receive |
|---|---|---|
| Ph I: RT + TMZ + RAD001 2.5 mg/day | Experimental | 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. Receives: Drug: concurrent temozolomide; Radiation: Radiation therapy; Drug: concurrent RAD001 2.5 mg/day; Drug: post-radiation RAD001 10 mg/day; Drug: post-radiation temozolomide |
| Ph I: RT + TMZ + RAD001 5 mg/day | Experimental | Radiation therapy, concurrent temozolomide, and concurrent RAD001 5 mg/day followed by post-radiation temozolomide and post-radiation RAD001 10 mg/day. Receives: Drug: concurrent temozolomide; Radiation: Radiation therapy; Drug: concurrent RAD001 5 mg/day; Drug: post-radiation RAD001 10 mg/day; Drug: post-radiation temozolomide |
| Ph I: RT + TMZ + RAD001 10 mg/day | Experimental | Radiation therapy, concurrent temozolomide, and concurrent RAD001 10 mg/day followed by post-radiation temozolomide and post-radiation RAD001 10 mg/day. Receives: Drug: concurrent RAD001 10 mg/day; Drug: concurrent temozolomide; Radiation: Radiation therapy; Drug: post-radiation RAD001 10 mg/day; Drug: post-radiation temozolomide |
| Ph II: RT + TMZ | Active comparator | Radiation therapy and concurrent temozolomide followed by post-radiation temozolomide Receives: Drug: concurrent temozolomide; Radiation: Radiation therapy; Drug: post-radiation RAD001 10 mg/day; Drug: post-radiation temozolomide |
| Ph II: RT + TMZ + RAD001 | Experimental | Radiation therapy, concurrent temozolomide, and concurrent RAD001 10 mg/day followed by post-radiation temozolomide and post-radiation RAD001 10 mg/day. Receives: Drug: concurrent RAD001 10 mg/day; Drug: concurrent temozolomide; Radiation: Radiation therapy; Drug: post-radiation RAD001 10 mg/day; Drug: post-radiation temozolomide |
What is being measured
The primary outcome is the main question the study is designed to answer.
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
Measured: 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.
Measured: 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 outcomes (3)
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.
Measured: 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.
Measured: 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.
Measured: 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.
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted4 Feb 2010 (estimated)
- Study startDec 2010
- Primary completionJun 2016
- Study completion20 May 2022
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Publications (2)Papers the sponsor has linked to this study.
- Other trials for Brain and Central Nervous System TumorsStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 1/2
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Enrolment
- 279 participants (actual)
Sponsor and investigators
- Lead sponsor
- Radiation Therapy Oncology Group
- Sponsor type
- Research network
- Collaborators
- National Cancer Institute (NCI), NRG Oncology
- Responsible party
- Sponsor
- Investigators
- Prakash Chinnaiyan, MD, Principal investigator, William Beaumont Hospital and Oakland University School of Medicine
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT01062399
- Sponsor's protocol ID
- RTOG 0913
- Other IDs
- RTOG-0913, CDR0000664302, NCI-2011-00885
- Acronym
- RTOG 0913
- Status last verified
- May 2022
- First submitted
- 3 Feb 2010
- Last updated
- 9 Jun 2022
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- Yes
Publications
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.
PubMed 23725999Chinnaiyan 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.
PubMed 29126203
Study at a glance
From the registry record, last updated by the sponsor on 9 Jun 2022. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Phase I/II Trial of Concurrent RAD001 (Everolimus) With Temozolomide/Radiation Followed by Adjuvant RAD001/Temozolomide in Newly Diagnosed Glioblastoma
- ClinicalTrials.gov ID
- NCT01062399
- Acronym / sponsor ID
- RTOG 0913 / RTOG 0913
- Conditions
- Brain and Central Nervous System Tumors
- Keywords
- adult glioblastoma, adult giant cell glioblastoma, adult gliosarcoma
- Phase
- Phase 1/2
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 279 participants (actual)
- Lead sponsor
- Radiation Therapy Oncology GroupResearch network
- Collaborators
- National Cancer Institute (NCI), NRG Oncology
- Study start
- Dec 2010
- Primary completion
- Jun 2016 (actual)
- Study completion
- 20 May 2022 (actual)
- First posted
- 4 Feb 2010 (estimated)
- Results
- Posted 23 Jan 2018
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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
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.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Number of arms
- 5
| Arm | Type | Receives |
|---|---|---|
| Ph I: RT + TMZ + RAD001 2.5 mg/day | Experimental | Drug: concurrent temozolomide, Radiation: Radiation therapy, Drug: concurrent RAD001 2.5 mg/day, Drug: post-radiation RAD001 10 mg/day, Drug: post-radiation temozolomideRadiation therapy (RT), concurrent temozolomide (TMZ), and concurrent RAD001 2.5 mg/day followed by post-radiation temozolomide and post-radiation RAD001 10 mg/day. |
| Ph I: RT + TMZ + RAD001 5 mg/day | Experimental | Drug: concurrent temozolomide, Radiation: Radiation therapy, Drug: concurrent RAD001 5 mg/day, Drug: post-radiation RAD001 10 mg/day, Drug: post-radiation temozolomideRadiation therapy, concurrent temozolomide, and concurrent RAD001 5 mg/day followed by post-radiation temozolomide and post-radiation RAD001 10 mg/day. |
| Ph I: RT + TMZ + RAD001 10 mg/day | Experimental | Drug: concurrent RAD001 10 mg/day, Drug: concurrent temozolomide, Radiation: Radiation therapy, Drug: post-radiation RAD001 10 mg/day, Drug: post-radiation temozolomideRadiation therapy, concurrent temozolomide, and concurrent RAD001 10 mg/day followed by post-radiation temozolomide and post-radiation RAD001 10 mg/day. |
| Ph II: RT + TMZ | Active comparator | Drug: concurrent temozolomide, Radiation: Radiation therapy, Drug: post-radiation RAD001 10 mg/day, Drug: post-radiation temozolomideRadiation therapy and concurrent temozolomide followed by post-radiation temozolomide |
| Ph II: RT + TMZ + RAD001 | Experimental | Drug: concurrent RAD001 10 mg/day, Drug: concurrent temozolomide, Radiation: Radiation therapy, Drug: post-radiation RAD001 10 mg/day, Drug: post-radiation temozolomideRadiation therapy, concurrent temozolomide, and concurrent RAD001 10 mg/day followed by post-radiation temozolomide and post-radiation RAD001 10 mg/day. |
Who may qualify
- Ages
- 18 to 120 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (32 listed)
- 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).
- 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.
Key exclusion criteria (17 listed)
- 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
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| concurrent RAD001 10 mg/dayAlso: everolimusDuring radiation: RAD001 10 mg orally daily during radiation therapy; one hour prior to radiation and in the morning on weekends on days 1-42. | Drug | Ph I: RT + TMZ + RAD001 10 mg/day, Ph II: RT + TMZ + RAD001 |
| concurrent temozolomideDuring 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. | Drug | Ph I: RT + TMZ + RAD001 10 mg/day, Ph I: RT + TMZ + RAD001 2.5 mg/day, Ph I: RT + TMZ + RAD001 5 mg/day, Ph II: RT + TMZ, Ph II: RT + TMZ + RAD001 |
| Radiation therapyIntensity 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. | Radiation | Ph I: RT + TMZ + RAD001 10 mg/day, Ph I: RT + TMZ + RAD001 2.5 mg/day, Ph I: RT + TMZ + RAD001 5 mg/day, Ph II: RT + TMZ, Ph II: RT + TMZ + RAD001 |
| concurrent RAD001 2.5 mg/dayAlso: everolimusDuring 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. | Drug | Ph I: RT + TMZ + RAD001 2.5 mg/day |
| concurrent RAD001 5 mg/dayAlso: everolimusDuring radiation: RAD001 5 mg orally daily during radiation therapy; one hour prior to radiation and in the morning on weekends on days 1-42. | Drug | Ph I: RT + TMZ + RAD001 5 mg/day |
| post-radiation RAD001 10 mg/dayAlso: everolimusPost-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). | Drug | Ph I: RT + TMZ + RAD001 10 mg/day, Ph I: RT + TMZ + RAD001 2.5 mg/day, Ph I: RT + TMZ + RAD001 5 mg/day, Ph II: RT + TMZ, Ph II: RT + TMZ + RAD001 |
| post-radiation temozolomidePost-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) | Drug | Ph I: RT + TMZ + RAD001 10 mg/day, Ph I: RT + TMZ + RAD001 2.5 mg/day, Ph I: RT + TMZ + RAD001 5 mg/day, Ph II: RT + TMZ, Ph II: RT + TMZ + RAD001 |
Primary outcome
Phase I: Number of Patients With Dose-limiting Toxicity (DLT)
Time frame: From start of treatment to eight weeks.
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
Phase II: Progression-free Survival (PFS)
Time frame: 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.
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.
3 secondary outcomes
Phase II: Overall Survival (OS)
Time frame: 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
Time frame: 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
Time frame: 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.
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 9 Jun 2022.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
- Results publication: PubMed 23725999Chinnaiyan 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.
- Results publication: PubMed 29126203Chinnaiyan 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.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Prakash Chinnaiyan, MD principal investigator
William Beaumont Hospital and Oakland University School of Medicine
36 sites in 3 countries: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 1/2 study testing concurrent RAD001 10 mg/day, concurrent temozolomide and Radiation therapy in people with Brain and Central Nervous System Tumors, run by Radiation Therapy Oncology Group at 36 sites in 3 countries.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 32 inclusion and 17 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 9 Jun 2022. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 36 sites in United States, Canada, Israel. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this combined phase mean?
Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Yes. Results are posted in the registry (first posted 23 Jan 2018). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Phase I: Number of Patients With Dose-limiting Toxicity (DLT) (time frame: From start of treatment to eight weeks.). The study lists 2 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT01062399, which also lists 2 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 9 Jun 2022.