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
试验速览
- 阶段
- 3 期
- 状态
- 招募中
- 发起方
- NRG Oncology
- 入组人数
- 398
- 试验地点
- 54
- 主要终点
- Neurocognitive function (NCF)
研究概览
简要总结
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.
详细描述
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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Supportive Care
- 盲法
- Single (Outcomes Assessor)
盲法说明
As exploratory objectives of this study, T2/FLAIR sequences will be submitted for central analysis. Abnormal FLAIR volumes will be created in a semi-automated fashion by trained individuals using a consensus approach and blinded to the cognitive outcome data and treatment arm, as previously published (Bovi et al. 2019).
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •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
- •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.
- •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 .
- •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.
排除标准
- 未提供
研究组 & 干预措施
Arm 1 (standard RT, temozolomide)
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 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.
Patients also undergo CT or MRI scans, as well as optional blood sample collection throughout the trial.
干预措施: Radiation Therapy (Radiation)
Arm 2 (TMPRT, temozolomide)
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.
Patients also undergo CT or MRI scans, as well as optional blood sample collection throughout the trial.
干预措施: Temporally-modulated Pulsed Radiation Therapy (Radiation)
Arm 1 (standard RT, temozolomide)
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 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.
Patients also undergo CT or MRI scans, as well as optional blood sample collection throughout the trial.
干预措施: Temozolomide (Drug)
Arm 2 (TMPRT, temozolomide)
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.
Patients also undergo CT or MRI scans, as well as optional blood sample collection throughout the trial.
干预措施: Temozolomide (Drug)
Arm 1 (standard RT, temozolomide)
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 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.
Patients also undergo CT or MRI scans, as well as optional blood sample collection throughout the trial.
干预措施: Biospecimen Collection (Procedure)
Arm 1 (standard RT, temozolomide)
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 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.
Patients also undergo CT or MRI scans, as well as optional blood sample collection throughout the trial.
干预措施: Computed Tomography (Procedure)
Arm 1 (standard RT, temozolomide)
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 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.
Patients also undergo CT or MRI scans, as well as optional blood sample collection throughout the trial.
干预措施: Questionnaire Administration (Other)
Arm 1 (standard RT, temozolomide)
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 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.
Patients also undergo CT or MRI scans, as well as optional blood sample collection throughout the trial.
干预措施: Magnetic Resonance Imaging (Procedure)
Arm 2 (TMPRT, temozolomide)
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.
Patients also undergo CT or MRI scans, as well as optional blood sample collection throughout the trial.
干预措施: Biospecimen Collection (Procedure)
Arm 2 (TMPRT, temozolomide)
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.
Patients also undergo CT or MRI scans, as well as optional blood sample collection throughout the trial.
干预措施: Computed Tomography (Procedure)
Arm 2 (TMPRT, temozolomide)
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.
Patients also undergo CT or MRI scans, as well as optional blood sample collection throughout the trial.
干预措施: Magnetic Resonance Imaging (Procedure)
Arm 2 (TMPRT, temozolomide)
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.
Patients also undergo CT or MRI scans, as well as optional blood sample collection throughout the trial.
干预措施: Questionnaire Administration (Other)
结局指标
主要结局
Neurocognitive function (NCF)
时间窗: Up to 9 months after completion of radiation therapy (RT)
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).
次要结局
- Time to NCF failure in the subset of older patients (≤ 65 years)(Up to 9 months after completion of RT)
- Overall survival (OS)(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)
- NCF across time(Up to 9 months after completion of RT)
- Quality of Life (QoL)(Up to 9 months after completion of RT)
- Patient-reported cognitive outcomes (PRCO)(Up to 9 months after completion of RT)
- Frailty(Up to 9 months after completion of RT)
- Progression-free survival (PFS)(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)
- Incidence of adverse events (AEs)(Up to 9 months after completion of RT)