Brief Summary
This phase III trial compares temporally-modulated pulsed radiation therapy versus standard radiation therapy in treating patients with newly diagnosed, IDH wildtype, MGMT-unmethylated glioblastoma. After completion of surgery, the standard of care for glioblastoma is radiation therapy. Radiation therapy uses high energy x-rays, particles, or radioactive seeds to kill cancer cells and shrink tumors. For older and frail patients, standard treatment also includes the chemotherapy drug temozolomide. Temozolomide is in a class of medications called alkylating agents. It works by damaging the cell's DNA and may kill tumor cells and slow down or stop tumor growth. Approximately 70% of glioblastoma patients have MGMT-unmethylated status. MGMT unmethylated tumors are less likely to respond to temozolomide chemotherapy, so there is more reliance on radiation therapy to kill the tumor cells. Recent clinical trials studying new therapies for MGMT-unmethylated glioblastoma have failed to improve outcomes over temozolomide. These recent studies also indicate that 80% of patients experience a decline in memory and thinking function after treatment. TMPRT differs from standard radiation therapy by delivering the same amount of radiation dose in 10-13 "pulses" with 3-minute breaks between pulses. TMPRT with temozolomide may work better than standard radiation therapy with temozolomide in increasing survival, as well as improving memory and thinking function in patients with newly diagnosed, IDH wildtype, MGMT-unmethylated glioblastoma.
Brief Title
Temporally-Modulated Pulsed Radiation Therapy Versus Standard Radiation Therapy for the Treatment of Newly Diagnosed, IDH Wildtype, MGMT-Unmethylated Glioblastoma
Detailed Description
PRIMARY OBJECTIVE:
I. To determine whether TMPRT concurrently with TMZ can significantly improve time to neurocognitive function (NCF) failure compared to standard radiation therapy (RT) with temozolomide for patients with MGMT-unmethylated GBM.
SECONDARY OBJECTIVES:
I. To determine whether TMPRT can significantly improve time to NCF failure for the subset of older patients (age ≥ 65) with MGMT-unmethylated GBM.
II. To evaluate between arm differences in NCF across time. III. To evaluate whether TMPRT prolongs overall survival (OS) compared to the control arm.
IV. To determine if progression free survival (PFS) is prolonged after TMPRT compared to the control arm.
V. To determine if TMPRT improves quality of life (QoL), compared to the control arm, as measured by the Functional Assessment of Cancer Therapy - Brain (FACT-Br) Total Score.
VI. To determine if TMPRT improves patient-reported cognitive outcome (PRCO) compared to the control arm, as measured by the Functional Assessment of Cancer Therapy - Brain Cognitive Index (FACT-Br- CI).
VII. To determine the impact of TMPRT on longitudinal changes in frailty after treatment compared to the control arm, as measured by the Deficit Accumulation Frailty Index (DAFI) derived from the Practical Geriatric Assessment (PGA).
VIII. To evaluate if TMPRT reduces toxicity compared to the control arm.
EXPLORATORY OBJECTIVES:
I. To evaluate the impact of TMPRT on functional, social, and emotional QoL compared to the control arm, as measured by the FACT-Br.
II. To evaluate the impact of TMPRT on longitudinal changes of specific geriatric assessment subscales compared to the control arm, as measured by the PGA.
III. To evaluate the impact of TMPRT on treatment burden during RT compared to the control arm, as measured by the FACT-Br Physical Wellbeing subscale (FACT-Br PWB).
IV. To investigate if TMPRT results in less white matter injury on post-treatment magnetic resonance imaging (MRI).
V. To collect blood samples for future translational studies. VI. To correlate NCF with QoL and frailty. VII. To determine if baseline NCF, QoL, and frailty are associated with OS. VIII. To correlate adverse events with baseline frailty and specific geriatric assessment subscales.
IX. To determine the concordance between institutional and central MGMT promoter status.
OUTLINE: Patients are randomized to 1 of 2 arms.
ARM 1:
CONCURRENT TREATMENT (CYCLE 1): Patients receive standard RT over 12-15 minutes daily, 5 days a week, for 3 or 6 weeks. Patients also receive temozolomide orally (PO) once daily (QD) on days 1-21 or 1-42. Cycle 1 treatment continues for 21 or 42 days in in the absence of disease progression or unacceptable toxicity.
ADJUVANT TREATMENT (CYCLES 2+): Approximately 1 month after completion of standard RT, patients receive temozolomide PO QD on days 1-5 of each cycle. Cycles repeat every 28 days for 6 cycles in the absence of disease progression or unacceptable toxicity.
ARM 2:
CONCURRENT TREATMENT (CYCLE 1): Patients receive TMPRT, delivered as 10-13 "pulses" over 30-40 minutes each with a 3 minute break in between, 5 days a week for 3 or 6 weeks. Patients also receive temozolomide PO QD on days 1-21 or 1-42. Cycle 1 treatment continues for 21 or 42 days in in the absence of disease progression or unacceptable toxicity.
ADJUVANT TREATMENT (CYCLES 2+): Approximately 1 month after completion of standard RT, patients receive temozolomide PO QD on days 1-5 of each cycle. Cycles repeat every 28 days for 6 cycles in the absence of disease progression or unacceptable toxicity.
All patients also undergo computed tomography (CT) or MRI scans, as well as optional blood sample collection throughout the trial.
After completion of study treatment, patients are followed at months 1, 3, 5, 7, 9, and 12, then annually for 4 years.
I. To determine whether TMPRT concurrently with TMZ can significantly improve time to neurocognitive function (NCF) failure compared to standard radiation therapy (RT) with temozolomide for patients with MGMT-unmethylated GBM.
SECONDARY OBJECTIVES:
I. To determine whether TMPRT can significantly improve time to NCF failure for the subset of older patients (age ≥ 65) with MGMT-unmethylated GBM.
II. To evaluate between arm differences in NCF across time. III. To evaluate whether TMPRT prolongs overall survival (OS) compared to the control arm.
IV. To determine if progression free survival (PFS) is prolonged after TMPRT compared to the control arm.
V. To determine if TMPRT improves quality of life (QoL), compared to the control arm, as measured by the Functional Assessment of Cancer Therapy - Brain (FACT-Br) Total Score.
VI. To determine if TMPRT improves patient-reported cognitive outcome (PRCO) compared to the control arm, as measured by the Functional Assessment of Cancer Therapy - Brain Cognitive Index (FACT-Br- CI).
VII. To determine the impact of TMPRT on longitudinal changes in frailty after treatment compared to the control arm, as measured by the Deficit Accumulation Frailty Index (DAFI) derived from the Practical Geriatric Assessment (PGA).
VIII. To evaluate if TMPRT reduces toxicity compared to the control arm.
EXPLORATORY OBJECTIVES:
I. To evaluate the impact of TMPRT on functional, social, and emotional QoL compared to the control arm, as measured by the FACT-Br.
II. To evaluate the impact of TMPRT on longitudinal changes of specific geriatric assessment subscales compared to the control arm, as measured by the PGA.
III. To evaluate the impact of TMPRT on treatment burden during RT compared to the control arm, as measured by the FACT-Br Physical Wellbeing subscale (FACT-Br PWB).
IV. To investigate if TMPRT results in less white matter injury on post-treatment magnetic resonance imaging (MRI).
V. To collect blood samples for future translational studies. VI. To correlate NCF with QoL and frailty. VII. To determine if baseline NCF, QoL, and frailty are associated with OS. VIII. To correlate adverse events with baseline frailty and specific geriatric assessment subscales.
IX. To determine the concordance between institutional and central MGMT promoter status.
OUTLINE: Patients are randomized to 1 of 2 arms.
ARM 1:
CONCURRENT TREATMENT (CYCLE 1): Patients receive standard RT over 12-15 minutes daily, 5 days a week, for 3 or 6 weeks. Patients also receive temozolomide orally (PO) once daily (QD) on days 1-21 or 1-42. Cycle 1 treatment continues for 21 or 42 days in in the absence of disease progression or unacceptable toxicity.
ADJUVANT TREATMENT (CYCLES 2+): Approximately 1 month after completion of standard RT, patients receive temozolomide PO QD on days 1-5 of each cycle. Cycles repeat every 28 days for 6 cycles in the absence of disease progression or unacceptable toxicity.
ARM 2:
CONCURRENT TREATMENT (CYCLE 1): Patients receive TMPRT, delivered as 10-13 "pulses" over 30-40 minutes each with a 3 minute break in between, 5 days a week for 3 or 6 weeks. Patients also receive temozolomide PO QD on days 1-21 or 1-42. Cycle 1 treatment continues for 21 or 42 days in in the absence of disease progression or unacceptable toxicity.
ADJUVANT TREATMENT (CYCLES 2+): Approximately 1 month after completion of standard RT, patients receive temozolomide PO QD on days 1-5 of each cycle. Cycles repeat every 28 days for 6 cycles in the absence of disease progression or unacceptable toxicity.
All patients also undergo computed tomography (CT) or MRI scans, as well as optional blood sample collection throughout the trial.
After completion of study treatment, patients are followed at months 1, 3, 5, 7, 9, and 12, then annually for 4 years.
Categories
Completion Date
Completion Date Type
Estimated
Conditions
GLIOBLASTOMA, IDH-WILDTYPE
MGMT-UNMETHYLATED GLIOBLASTOMA
Eligibility Criteria
Inclusion Criteria:
* PRIOR TO STEP 1 REGISTRATION:
* No known IDH mutation. (If tested before step 1 registration, patients known to have IDH mutation in the tumor on local or other testing are ineligible and should not be registered).
* Availability of formalin-fixed paraffin-embedded (FFPE) tumor tissue block and hematoxylin and eosin (H\&E) stained slide to be sent for central pathology review for confirmation of histology and MGMT promoter methylation status. Surgical resection is required; stereotactic biopsy alone is not allowed because it will not provide sufficient tissue for MGMT analysis. Note that tissue for central pathology review and central MGMT assessment must be shipped to the New York University (NYU) Center for Biospecimen Research and Development (CBRD) on or before postoperative calendar day 30. If tissue cannot be shipped by postoperative calendar day 30, then patients may NOT enroll on this trial as central pathology review will not be complete in time for the patient to start treatment no later than 8 weeks following surgery. Results of central pathology review and central MGMT analysis will generally be completed within 10 business days of receipt of tissue. Results will be entered by the central lab directly into Rave. Note: In the event of an additional tumor resection(s), tissue must be shipped within 30 days of the most recent resection and the latest resection must have been performed within 30 days after the initial resection.
* Negative urine or serum pregnancy test (in persons of childbearing potential) within 14 days prior to Step 1 registration. Childbearing potential is defined as any person who has experienced menarche and who has not undergone surgical sterilization (hysterectomy or bilateral oophorectomy) or who is not postmenopausal.
* No known leptomeningeal disease or metastatic disease outside the brain.
* Age ≥ 18
* Because neurocognitive testing is the primary goal of this study, patients must be proficient in English or French Canadian.
* Karnofsky Performance Status ≥ 70
* Hemoglobin ≥ 10 g/dl (Note: the use of transfusion or other intervention to achieve hemoglobin (Hgb) ≥ 10.0 g/dl is acceptable)
* Leukocytes ≥ 2,000/mm\^3 OR absolute neutrophil count ≥ 1,500/mm\^3
* Platelets ≥ 100,000/mm\^3
* Creatinine clearance (CrCl) ≥ 50 mL/min
* Total bilirubin ≤ 1.5 x institutional upper limit of normal (ULN)
* Aspartate aminotransferase (AST)(serum glutamic oxaloacetic transaminase \[SGOT\]) and alanine aminotransferase (ALT)(serum glutamic pyruvate transaminase \[SGPT\]) ≤ 3 x ULN
* No prior cranial radiation therapy that would result in overlap of radiation therapy fields.
* No previous therapy for GBM except surgery, laser interstitial thermal therapy (LITT) or Gliadel wafer.
* Note: 5-aminolevulinic acid (ALA)-mediated fluorescence-guided resection (FGR) photodynamic therapy (PDT) or fluorescein administered prior to/during surgery to aid resection is not exclusionary and is not considered a chemotherapy or intracerebral agent.
* No history of unstable angina requiring hospitalization in the last 3 months
* No history of myocardial infarction within the last 3 months
* New York Heart Association Functional Classification II or better (NYHA Functional Classification III/IV are not eligible) (Note: Patients with known history or current symptoms of cardiac disease, or history of treatment with cardiotoxic agents, should have a clinical risk assessment of cardiac function using the New York Heart Association Functional Classification)
* No active infection currently requiring IV antibiotic management
* No chronic obstructive pulmonary disease exacerbation or other acute respiratory illness precluding study therapy
* No movement disorder that could impede ability to lie still with an immobilization mask for approximately 40 minutes
* No significant sensory deficits (i.e., blindness, mutism) that would prohibit participation of NCF testing
* No history of allergic reaction attributed to compounds of similar chemical or biological composition to temozolomide
* PRIOR TO STEP 2 REGISTRATION:
* The following baseline neurocognitive tests must be completed within 28 days prior to Step 2 registration: (Hopkins Verbal Learning Test - Revised \[HVLT-R\], Trail Making Test \[TMT\], Controlled Oral Word Association \[COWA\]). The neurocognitive tests will be uploaded into RAVE for evaluation by Dr. Wefel. The following scores must be obtained for patient eligibility: HVLT-R Total Recall \> 5, HVLT-R Delayed Recall \> 3, HVLT-R Delayed Recognition \> -10, TMT Part A . 2738, TMT Part B . 3724, COWA . 12. Central review of the Neurocognitive tests will be completed in Rave within 3 business days after the upload is completed. Users with the Rave clinical research associate (CRA) role will be able to view the results in Rave. The CRA must confirm that the results are available and meet eligibility requirements prior to proceeding with Step 2 Registration.
* NOTE: Completed baseline neurocognitive tests can be uploaded at the time of Step 1 registration.
* Note: Patients whose neurocognitive test scores do not meet the criteria above will not be eligible for the study and will be reported as ineligible due to "Failure to meet Neurocognitive testing criteria" on Step 2 registration.
* Pathology proven diagnosis of IDH-wildtype glioblastoma with unmethylated MGMT promoter confirmed by central pathology review. IDH mutation testing by at least one method (such as immunohistochemistry for IDH1 R132H) must be performed as part of standard of care and no mutation must be found (i.e. IDH-wildtype). (If a mutation is identified then the patient will be ineligible and must be registered as ineligible at Step 2.)
* Central pathology review will generally be completed within 10 business days of receipt of the tissue. Users with the Rave CRA role will be able to view the results in Rave. It must be confirmed that the results are available and meet eligibility requirements prior to proceeding with Step 2 Registration.
* Note: Patients with tissue that is insufficient or inadequate for analysis, has failed MGMT testing, or has indeterminate or methylated MGMT promoter are excluded and will be reported as a "central pathology review failure" on step 2 registration.
* PRIOR TO STEP 1 REGISTRATION:
* No known IDH mutation. (If tested before step 1 registration, patients known to have IDH mutation in the tumor on local or other testing are ineligible and should not be registered).
* Availability of formalin-fixed paraffin-embedded (FFPE) tumor tissue block and hematoxylin and eosin (H\&E) stained slide to be sent for central pathology review for confirmation of histology and MGMT promoter methylation status. Surgical resection is required; stereotactic biopsy alone is not allowed because it will not provide sufficient tissue for MGMT analysis. Note that tissue for central pathology review and central MGMT assessment must be shipped to the New York University (NYU) Center for Biospecimen Research and Development (CBRD) on or before postoperative calendar day 30. If tissue cannot be shipped by postoperative calendar day 30, then patients may NOT enroll on this trial as central pathology review will not be complete in time for the patient to start treatment no later than 8 weeks following surgery. Results of central pathology review and central MGMT analysis will generally be completed within 10 business days of receipt of tissue. Results will be entered by the central lab directly into Rave. Note: In the event of an additional tumor resection(s), tissue must be shipped within 30 days of the most recent resection and the latest resection must have been performed within 30 days after the initial resection.
* Negative urine or serum pregnancy test (in persons of childbearing potential) within 14 days prior to Step 1 registration. Childbearing potential is defined as any person who has experienced menarche and who has not undergone surgical sterilization (hysterectomy or bilateral oophorectomy) or who is not postmenopausal.
* No known leptomeningeal disease or metastatic disease outside the brain.
* Age ≥ 18
* Because neurocognitive testing is the primary goal of this study, patients must be proficient in English or French Canadian.
* Karnofsky Performance Status ≥ 70
* Hemoglobin ≥ 10 g/dl (Note: the use of transfusion or other intervention to achieve hemoglobin (Hgb) ≥ 10.0 g/dl is acceptable)
* Leukocytes ≥ 2,000/mm\^3 OR absolute neutrophil count ≥ 1,500/mm\^3
* Platelets ≥ 100,000/mm\^3
* Creatinine clearance (CrCl) ≥ 50 mL/min
* Total bilirubin ≤ 1.5 x institutional upper limit of normal (ULN)
* Aspartate aminotransferase (AST)(serum glutamic oxaloacetic transaminase \[SGOT\]) and alanine aminotransferase (ALT)(serum glutamic pyruvate transaminase \[SGPT\]) ≤ 3 x ULN
* No prior cranial radiation therapy that would result in overlap of radiation therapy fields.
* No previous therapy for GBM except surgery, laser interstitial thermal therapy (LITT) or Gliadel wafer.
* Note: 5-aminolevulinic acid (ALA)-mediated fluorescence-guided resection (FGR) photodynamic therapy (PDT) or fluorescein administered prior to/during surgery to aid resection is not exclusionary and is not considered a chemotherapy or intracerebral agent.
* No history of unstable angina requiring hospitalization in the last 3 months
* No history of myocardial infarction within the last 3 months
* New York Heart Association Functional Classification II or better (NYHA Functional Classification III/IV are not eligible) (Note: Patients with known history or current symptoms of cardiac disease, or history of treatment with cardiotoxic agents, should have a clinical risk assessment of cardiac function using the New York Heart Association Functional Classification)
* No active infection currently requiring IV antibiotic management
* No chronic obstructive pulmonary disease exacerbation or other acute respiratory illness precluding study therapy
* No movement disorder that could impede ability to lie still with an immobilization mask for approximately 40 minutes
* No significant sensory deficits (i.e., blindness, mutism) that would prohibit participation of NCF testing
* No history of allergic reaction attributed to compounds of similar chemical or biological composition to temozolomide
* PRIOR TO STEP 2 REGISTRATION:
* The following baseline neurocognitive tests must be completed within 28 days prior to Step 2 registration: (Hopkins Verbal Learning Test - Revised \[HVLT-R\], Trail Making Test \[TMT\], Controlled Oral Word Association \[COWA\]). The neurocognitive tests will be uploaded into RAVE for evaluation by Dr. Wefel. The following scores must be obtained for patient eligibility: HVLT-R Total Recall \> 5, HVLT-R Delayed Recall \> 3, HVLT-R Delayed Recognition \> -10, TMT Part A . 2738, TMT Part B . 3724, COWA . 12. Central review of the Neurocognitive tests will be completed in Rave within 3 business days after the upload is completed. Users with the Rave clinical research associate (CRA) role will be able to view the results in Rave. The CRA must confirm that the results are available and meet eligibility requirements prior to proceeding with Step 2 Registration.
* NOTE: Completed baseline neurocognitive tests can be uploaded at the time of Step 1 registration.
* Note: Patients whose neurocognitive test scores do not meet the criteria above will not be eligible for the study and will be reported as ineligible due to "Failure to meet Neurocognitive testing criteria" on Step 2 registration.
* Pathology proven diagnosis of IDH-wildtype glioblastoma with unmethylated MGMT promoter confirmed by central pathology review. IDH mutation testing by at least one method (such as immunohistochemistry for IDH1 R132H) must be performed as part of standard of care and no mutation must be found (i.e. IDH-wildtype). (If a mutation is identified then the patient will be ineligible and must be registered as ineligible at Step 2.)
* Central pathology review will generally be completed within 10 business days of receipt of the tissue. Users with the Rave CRA role will be able to view the results in Rave. It must be confirmed that the results are available and meet eligibility requirements prior to proceeding with Step 2 Registration.
* Note: Patients with tissue that is insufficient or inadequate for analysis, has failed MGMT testing, or has indeterminate or methylated MGMT promoter are excluded and will be reported as a "central pathology review failure" on step 2 registration.
Inclusion Criteria
Inclusion Criteria:
* PRIOR TO STEP 1 REGISTRATION:
* No known IDH mutation. (If tested before step 1 registration, patients known to have IDH mutation in the tumor on local or other testing are ineligible and should not be registered).
* Availability of formalin-fixed paraffin-embedded (FFPE) tumor tissue block and hematoxylin and eosin (H\&E) stained slide to be sent for central pathology review for confirmation of histology and MGMT promoter methylation status. Surgical resection is required; stereotactic biopsy alone is not allowed because it will not provide sufficient tissue for MGMT analysis. Note that tissue for central pathology review and central MGMT assessment must be shipped to the New York University (NYU) Center for Biospecimen Research and Development (CBRD) on or before postoperative calendar day 30. If tissue cannot be shipped by postoperative calendar day 30, then patients may NOT enroll on this trial as central pathology review will not be complete in time for the patient to start treatment no later than 8 weeks following surgery. Results of central pathology review and central MGMT analysis will generally be completed within 10 business days of receipt of tissue. Results will be entered by the central lab directly into Rave. Note: In the event of an additional tumor resection(s), tissue must be shipped within 30 days of the most recent resection and the latest resection must have been performed within 30 days after the initial resection.
* Negative urine or serum pregnancy test (in persons of childbearing potential) within 14 days prior to Step 1 registration. Childbearing potential is defined as any person who has experienced menarche and who has not undergone surgical sterilization (hysterectomy or bilateral oophorectomy) or who is not postmenopausal.
* No known leptomeningeal disease or metastatic disease outside the brain.
* Age ≥ 18
* Because neurocognitive testing is the primary goal of this study, patients must be proficient in English or French Canadian.
* Karnofsky Performance Status ≥ 70
* Hemoglobin ≥ 10 g/dl (Note: the use of transfusion or other intervention to achieve hemoglobin (Hgb) ≥ 10.0 g/dl is acceptable)
* Leukocytes ≥ 2,000/mm\^3 OR absolute neutrophil count ≥ 1,500/mm\^3
* Platelets ≥ 100,000/mm\^3
* Creatinine clearance (CrCl) ≥ 50 mL/min
* Total bilirubin ≤ 1.5 x institutional upper limit of normal (ULN)
* Aspartate aminotransferase (AST)(serum glutamic oxaloacetic transaminase \[SGOT\]) and alanine aminotransferase (ALT)(serum glutamic pyruvate transaminase \[SGPT\]) ≤ 3 x ULN
* No prior cranial radiation therapy that would result in overlap of radiation therapy fields.
* No previous therapy for GBM except surgery, laser interstitial thermal therapy (LITT) or Gliadel wafer.
* Note: 5-aminolevulinic acid (ALA)-mediated fluorescence-guided resection (FGR) photodynamic therapy (PDT) or fluorescein administered prior to/during surgery to aid resection is not exclusionary and is not considered a chemotherapy or intracerebral agent.
* No history of unstable angina requiring hospitalization in the last 3 months
* No history of myocardial infarction within the last 3 months
* New York Heart Association Functional Classification II or better (NYHA Functional Classification III/IV are not eligible) (Note: Patients with known history or current symptoms of cardiac disease, or history of treatment with cardiotoxic agents, should have a clinical risk assessment of cardiac function using the New York Heart Association Functional Classification)
* No active infection currently requiring IV antibiotic management
* No chronic obstructive pulmonary disease exacerbation or other acute respiratory illness precluding study therapy
* No movement disorder that could impede ability to lie still with an immobilization mask for approximately 40 minutes
* No significant sensory deficits (i.e., blindness, mutism) that would prohibit participation of NCF testing
* No history of allergic reaction attributed to compounds of similar chemical or biological composition to temozolomide
* PRIOR TO STEP 2 REGISTRATION:
* The following baseline neurocognitive tests must be completed within 28 days prior to Step 2 registration: (Hopkins Verbal Learning Test - Revised \[HVLT-R\], Trail Making Test \[TMT\], Controlled Oral Word Association \[COWA\]). The neurocognitive tests will be uploaded into RAVE for evaluation by Dr. Wefel. The following scores must be obtained for patient eligibility: HVLT-R Total Recall \> 5, HVLT-R Delayed Recall \> 3, HVLT-R Delayed Recognition \> -10, TMT Part A . 2738, TMT Part B . 3724, COWA . 12. Central review of the Neurocognitive tests will be completed in Rave within 3 business days after the upload is completed. Users with the Rave clinical research associate (CRA) role will be able to view the results in Rave. The CRA must confirm that the results are available and meet eligibility requirements prior to proceeding with Step 2 Registration.
* NOTE: Completed baseline neurocognitive tests can be uploaded at the time of Step 1 registration.
* Note: Patients whose neurocognitive test scores do not meet the criteria above will not be eligible for the study and will be reported as ineligible due to "Failure to meet Neurocognitive testing criteria" on Step 2 registration.
* Pathology proven diagnosis of IDH-wildtype glioblastoma with unmethylated MGMT promoter confirmed by central pathology review. IDH mutation testing by at least one method (such as immunohistochemistry for IDH1 R132H) must be performed as part of standard of care and no mutation must be found (i.e. IDH-wildtype). (If a mutation is identified then the patient will be ineligible and must be registered as ineligible at Step 2.)
* Central pathology review will generally be completed within 10 business days of receipt of the tissue. Users with the Rave CRA role will be able to view the results in Rave. It must be confirmed that the results are available and meet eligibility requirements prior to proceeding with Step 2 Registration.
* Note: Patients with tissue that is insufficient or inadequate for analysis, has failed MGMT testing, or has indeterminate or methylated MGMT promoter are excluded and will be reported as a "central pathology review failure" on step 2 registration.
* PRIOR TO STEP 1 REGISTRATION:
* No known IDH mutation. (If tested before step 1 registration, patients known to have IDH mutation in the tumor on local or other testing are ineligible and should not be registered).
* Availability of formalin-fixed paraffin-embedded (FFPE) tumor tissue block and hematoxylin and eosin (H\&E) stained slide to be sent for central pathology review for confirmation of histology and MGMT promoter methylation status. Surgical resection is required; stereotactic biopsy alone is not allowed because it will not provide sufficient tissue for MGMT analysis. Note that tissue for central pathology review and central MGMT assessment must be shipped to the New York University (NYU) Center for Biospecimen Research and Development (CBRD) on or before postoperative calendar day 30. If tissue cannot be shipped by postoperative calendar day 30, then patients may NOT enroll on this trial as central pathology review will not be complete in time for the patient to start treatment no later than 8 weeks following surgery. Results of central pathology review and central MGMT analysis will generally be completed within 10 business days of receipt of tissue. Results will be entered by the central lab directly into Rave. Note: In the event of an additional tumor resection(s), tissue must be shipped within 30 days of the most recent resection and the latest resection must have been performed within 30 days after the initial resection.
* Negative urine or serum pregnancy test (in persons of childbearing potential) within 14 days prior to Step 1 registration. Childbearing potential is defined as any person who has experienced menarche and who has not undergone surgical sterilization (hysterectomy or bilateral oophorectomy) or who is not postmenopausal.
* No known leptomeningeal disease or metastatic disease outside the brain.
* Age ≥ 18
* Because neurocognitive testing is the primary goal of this study, patients must be proficient in English or French Canadian.
* Karnofsky Performance Status ≥ 70
* Hemoglobin ≥ 10 g/dl (Note: the use of transfusion or other intervention to achieve hemoglobin (Hgb) ≥ 10.0 g/dl is acceptable)
* Leukocytes ≥ 2,000/mm\^3 OR absolute neutrophil count ≥ 1,500/mm\^3
* Platelets ≥ 100,000/mm\^3
* Creatinine clearance (CrCl) ≥ 50 mL/min
* Total bilirubin ≤ 1.5 x institutional upper limit of normal (ULN)
* Aspartate aminotransferase (AST)(serum glutamic oxaloacetic transaminase \[SGOT\]) and alanine aminotransferase (ALT)(serum glutamic pyruvate transaminase \[SGPT\]) ≤ 3 x ULN
* No prior cranial radiation therapy that would result in overlap of radiation therapy fields.
* No previous therapy for GBM except surgery, laser interstitial thermal therapy (LITT) or Gliadel wafer.
* Note: 5-aminolevulinic acid (ALA)-mediated fluorescence-guided resection (FGR) photodynamic therapy (PDT) or fluorescein administered prior to/during surgery to aid resection is not exclusionary and is not considered a chemotherapy or intracerebral agent.
* No history of unstable angina requiring hospitalization in the last 3 months
* No history of myocardial infarction within the last 3 months
* New York Heart Association Functional Classification II or better (NYHA Functional Classification III/IV are not eligible) (Note: Patients with known history or current symptoms of cardiac disease, or history of treatment with cardiotoxic agents, should have a clinical risk assessment of cardiac function using the New York Heart Association Functional Classification)
* No active infection currently requiring IV antibiotic management
* No chronic obstructive pulmonary disease exacerbation or other acute respiratory illness precluding study therapy
* No movement disorder that could impede ability to lie still with an immobilization mask for approximately 40 minutes
* No significant sensory deficits (i.e., blindness, mutism) that would prohibit participation of NCF testing
* No history of allergic reaction attributed to compounds of similar chemical or biological composition to temozolomide
* PRIOR TO STEP 2 REGISTRATION:
* The following baseline neurocognitive tests must be completed within 28 days prior to Step 2 registration: (Hopkins Verbal Learning Test - Revised \[HVLT-R\], Trail Making Test \[TMT\], Controlled Oral Word Association \[COWA\]). The neurocognitive tests will be uploaded into RAVE for evaluation by Dr. Wefel. The following scores must be obtained for patient eligibility: HVLT-R Total Recall \> 5, HVLT-R Delayed Recall \> 3, HVLT-R Delayed Recognition \> -10, TMT Part A . 2738, TMT Part B . 3724, COWA . 12. Central review of the Neurocognitive tests will be completed in Rave within 3 business days after the upload is completed. Users with the Rave clinical research associate (CRA) role will be able to view the results in Rave. The CRA must confirm that the results are available and meet eligibility requirements prior to proceeding with Step 2 Registration.
* NOTE: Completed baseline neurocognitive tests can be uploaded at the time of Step 1 registration.
* Note: Patients whose neurocognitive test scores do not meet the criteria above will not be eligible for the study and will be reported as ineligible due to "Failure to meet Neurocognitive testing criteria" on Step 2 registration.
* Pathology proven diagnosis of IDH-wildtype glioblastoma with unmethylated MGMT promoter confirmed by central pathology review. IDH mutation testing by at least one method (such as immunohistochemistry for IDH1 R132H) must be performed as part of standard of care and no mutation must be found (i.e. IDH-wildtype). (If a mutation is identified then the patient will be ineligible and must be registered as ineligible at Step 2.)
* Central pathology review will generally be completed within 10 business days of receipt of the tissue. Users with the Rave CRA role will be able to view the results in Rave. It must be confirmed that the results are available and meet eligibility requirements prior to proceeding with Step 2 Registration.
* Note: Patients with tissue that is insufficient or inadequate for analysis, has failed MGMT testing, or has indeterminate or methylated MGMT promoter are excluded and will be reported as a "central pathology review failure" on step 2 registration.
Gender
All
Gender Based
false
Healthy Volunteers
No
Last Update Post Date
Last Update Post Date Type
Actual
Last Update Submit Date
Minimum Age
18 Years
NCT Id
NCT07452458
Org Class
Other
Org Full Name
NRG Oncology
Org Study Id
NRG-CC017
Overall Status
Recruiting
Phases
Phase 3
Primary Completion Date
Primary Completion Date Type
Estimated
Official Title
A Randomized Phase III Study Comparing Temporally-Modulated Pulsed Radiation Therapy (TMPRT) Versus Standard Radiation Therapy With Temozolomide for Adults With Newly Diagnosed MGMT-Unmethylated Glioblastoma
Primary Outcomes
Outcome Description
This endpoint will be evaluated using each NCF testing interval. NCF failure is defined as a decline in NCF using the reliable change index (RCI) on at least one of the following tests: Hopkins Verbal Learning Test - Revised (HVLT-R) Total Recall, HVLT-R Delayed Recall, HVLT-R Delayed Recognition, Trail Making Test (TMT) Part A, TMT Part B, or Controlled Oral Word Association (COWA). The cumulative incidence approach will be used to estimate the time to neurocognitive failure to account for the competing risk of death. Gray's test will assess statistically significant differences in the distribution of NCF failure times (Gray 1988).
Outcome Measure
Neurocognitive function (NCF)
Outcome Time Frame
Up to 9 months after completion of radiation therapy (RT)
Secondary Ids
Secondary Id
NCI-2025-09197
Secondary Id
NRG-CC017
Secondary Id
NRG-CC017
Secondary Id
IVR-50415
Secondary Id
UG1CA189867
Secondary Outcomes
Outcome Description
Will be measured by the HVLT-R, COWA, and TMT. A mixed effects model will be used to assess changes of standardized neurocognitive scores across time using all available data while adjusting for stratification variables and other baseline characteristics. Fixed effects will consist of treatment arm, baseline score, Recursive Partitioning Analysis (RPA) class, fractionation, tumor treating fields therapy (TTFields), steroid use, anti-seizure medication use as well as the interaction between time and treatment arm.
Outcome Time Frame
Up to 9 months after completion of RT
Outcome Measure
Time to NCF failure in the subset of older patients (≤ 65 years)
Outcome Description
Will be measured by the HVLT-R, COWA, and TMT. A mixed effects model will be used to assess changes of standardized neurocognitive scores across time using all available data while adjusting for stratification variables and other baseline characteristics. Fixed effects will consist of treatment arm, baseline score, RPA class, fractionation, TTFields, steroid use, anti-seizure medication use as well as the interaction between time and treatment arm.
Outcome Time Frame
Up to 9 months after completion of RT
Outcome Measure
NCF across time
Outcome Description
The Functional Assessment of Cancer Therapy - Brain (FACT-Br) total score will be used to measure overall QoL. Scores will be analyzed similarly to the individual NCF tests as described above. Briefly, mixed effects models will be performed. If the time by treatment interaction is significant, then tests will be conducted at each timepoint, within the model framework. Missing data will also be assessed and sensitivity analyses performed as needed.
Outcome Time Frame
Up to 9 months after completion of RT
Outcome Measure
Quality of Life (QoL)
Outcome Description
Nine items make up the FACT-Br-Cognitive Index score that will be used to assess PRCO. Scores will be analyzed similarly to the individual NCF tests as described above. Briefly, mixed effects models will be performed. If the time by treatment interaction is significant, then tests will be conducted at each timepoint, within the model framework. Missing data will also be assessed and sensitivity analyses performed as needed.
Outcome Time Frame
Up to 9 months after completion of RT
Outcome Measure
Patient-reported cognitive outcomes (PRCO)
Outcome Description
The primary frailty endpoint is the Deficit Accumulation Frailty Index (DAFI) which requires at least 30 items in the score for it to be valid (Searle 2008). Thus, the NCF score will be removed from the DAFI score calculation since the primary endpoint of the trial is NCF. At least 90% of the DAFI must be completed to be included in the analysis. The continuous DAFI score will be analyzed similarly to the individual NCF tests as described above in the section. Briefly, mixed effects models will be performed. If the time by treatment interaction is significant, then tests will be conducted at each timepoint, within the model framework. Missing data will also be assessed and sensitivity analyses performed as needed.
Outcome Time Frame
Up to 9 months after completion of RT
Outcome Measure
Frailty
Outcome Description
OS rates will be estimated using the Kaplan-Meier method, and differences between treatment arms will be tested using the log rank test.
Outcome Time Frame
From the date of randomization to the date of death, or, otherwise, the last follow-up date on which the patient was reported alive, assessed up to 9 months after completion of RT
Outcome Measure
Overall survival (OS)
Outcome Description
PFS rates will be estimated using the Kaplan-Meier method, and differences between treatment arms will be tested using the log rank test.
Outcome Time Frame
From the date of randomization to the date of progression or death, whichever occurs first, or the last follow-up date on which the patient was reported alive, assessed up to 9 months after completion of RT
Outcome Measure
Progression-free survival (PFS)
Outcome Description
AEs will be evaluated using Common Terminology Criteria for Adverse Events version 5.0. Counts of all AEs by grade will be provided by treatment arm. Counts and frequencies will be provided for the worst grade AE experienced by the patient by treatment arm. The rate of grade 3+ AEs and the rate of grade 3+ central nervous system necrosis, stroke, and intra-cranial hemorrhage will be compared between treatment arms using a Chi-square test at a two-sided significance level of 0.05.
Outcome Time Frame
Up to 9 months after completion of RT
Outcome Measure
Incidence of adverse events (AEs)
Start Date
Start Date Type
Actual
Status Verified Date
First Post Date
First Post Date Type
Actual
First Submit Date
First Submit QC Date
Std Ages
Adult
Older Adult
Maximum Age Number (converted to Years and rounded down)
999
Minimum Age Number (converted to Years and rounded down)
18
Investigators
Investigator Type
Principal Investigator
Investigator Name
Justin Tang
Investigator Email
jtang@montefiore.org
Investigator Sponsor Organization
External
Study Department
Radiation Oncology
Study Division
Radiation Oncology
Categories Mesh Debug
Cancer --- NEOPLASMS
MeSH Terms
GLIOBLASTOMA
ASTROCYTOMA
GLIOMA
NEOPLASMS, NEUROEPITHELIAL
NEUROECTODERMAL TUMORS
NEOPLASMS, GERM CELL AND EMBRYONAL
NEOPLASMS BY HISTOLOGIC TYPE
NEOPLASMS
NEOPLASMS, GLANDULAR AND EPITHELIAL
NEOPLASMS, NERVE TISSUE
SPECIMEN HANDLING
MAGNETIC RESONANCE SPECTROSCOPY
RADIOTHERAPY
RADIATION
TEMOZOLOMIDE
CLINICAL LABORATORY TECHNIQUES
DIAGNOSTIC TECHNIQUES AND PROCEDURES
DIAGNOSIS
INVESTIGATIVE TECHNIQUES
SPECTRUM ANALYSIS
CHEMISTRY TECHNIQUES, ANALYTICAL
THERAPEUTICS
PHYSICAL PHENOMENA
DACARBAZINE
TRIAZENES
ORGANIC CHEMICALS
IMIDAZOLES
AZOLES
HETEROCYCLIC COMPOUNDS, 1-RING
HETEROCYCLIC COMPOUNDS