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Proton Beam or Intensity-Modulated Radiation Therapy in Preserving Brain Function in Patients With IDH Mutant Grade II or III Glioma

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ClinicalTrials.gov Identifier: NCT03180502
Recruitment Status : Recruiting
First Posted : June 8, 2017
Last Update Posted : July 24, 2019
Sponsor:
Collaborator:
National Cancer Institute (NCI)
Information provided by (Responsible Party):
NRG Oncology

Tracking Information
First Submitted Date  ICMJE June 5, 2017
First Posted Date  ICMJE June 8, 2017
Last Update Posted Date July 24, 2019
Actual Study Start Date  ICMJE August 2, 2017
Estimated Primary Completion Date January 2025   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: June 6, 2017)
Change in cognition as measured by the CTB COMP score [ Time Frame: Baseline to up to 10 years ]
Assessed with a general linear model with maximum likelihood estimation. Three models will be conducted. Baseline CTB COMP score, treatment arm, time, treatment by time interaction (if significant) and stratification factors will be included in the model for the primary endpoint. A second model will be built with these same variables and relevant covariates, such as total volume of intracranial disease, gross tumor volume (GTV) and clinical tumor volume (CTV) size, histology, anti-epileptic use, and disease response to therapy (as measured by Response Assessment in Neuro-Oncology [RANO] criteria
Original Primary Outcome Measures  ICMJE Same as current
Change History Complete list of historical versions of study NCT03180502 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE
 (submitted: June 6, 2017)
  • Change in quality of life as measured by the LASA scale [ Time Frame: Up to 10 years ]
    The change from baseline to each follow-up time point (calculated as baseline score subtracted from follow-up score) will be compared between treatment arms using a t-test, or Wilcoxon test if the data is not normally distributed. A one-sided alpha=0.05 will be used for the LASA. A general linear model with maximum likelihood estimation will be used to assess symptom and QOL trends across time.
  • Change in symptoms as measured by MDASI-BT [ Time Frame: Baseline to up to 10 years ]
    The change from baseline to each follow-up time point (calculated as baseline score subtracted from follow-up score) will be compared between treatment arms using a t-test, or Wilcoxon test if the data is not normally distributed. A reduced one-sided significance level will be used for the multiple comparisons in the MDASI-BT using the Bonferroni adjustment (alpha=0.017 for disease related factors and alpha=0.025 for treatment related symptoms and overall impact). A general linear model with maximum likelihood estimation will be used to assess symptom trends across time.
  • Cognition as measured by COWA [ Time Frame: Up to 10 years ]
    The COWA will be analyzed using a general linear model with maximum likelihood estimation. Standardized scores will be used.
  • Cognition as measured by TMT parts A and B [ Time Frame: Up to 10 years ]
    The TMT parts A & B will be analyzed using a general linear model with maximum likelihood estimation. Standardized scores will be used.
  • Cognition as measured by HVLT-R [ Time Frame: Up to 10 years ]
    The HVLT-R will be analyzed using a general linear model with maximum likelihood estimation. Standardized scores will be used.
  • Incidence of adverse events (AEs) graded according to the National Cancer Institute's Common Terminology for Adverse Events version 4.0 [ Time Frame: Up to 10 years ]
    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. Grade 3+ treatment related AEs will be compared between arms using a chi-square test, or Fisher's exact test if cell frequencies are < 5, at the one-sided 0.05 significance level.
  • Local control as assessed by RANO criteria [ Time Frame: Up to 10 years ]
    Local control will be estimated using cumulative incidence, treating death prior to an event as a competing risk. Gray's test will be used to compare local control rates between arms. Cause-specific Cox proportional hazards models will be used for local control, adjusting for treatment arm and stratification factors. A two-sided significance level of 0.05 will be used for comparisons between arms.
  • Overall survival (OS) [ Time Frame: From randomization to the date of death, assessed up to 10 years ]
    OS will be estimated using the Kaplan-Meier method and compared between arms using the log rank test. Cox proportional hazards models will be used for OS adjusting for treatment arm and stratification factors.
  • Progression-free survival (PFS) [ Time Frame: From date of randomization to date of progression or death, whichever occurs first, assessed up to 10 years ]
    A confidence interval will be used to determine if the PFS rate in the proton arm is greater than that in the photon at 1 year. PFS will be estimated using the Kaplan-Meier method and compared between arms using the log rank test. Cox proportional hazards models will be used for PFS adjusting for treatment arm and stratification factors.
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures
 (submitted: June 6, 2017)
  • Assessment of dose-response relationships [ Time Frame: Up to 10 years ]
    The dose-response relationship between cognition, using the CTB COMP and each individual test score, and neuro-anatomic dosimetry, including the hippocampus and whole brain, will be assessed. The decline, as calculated using the Reliable Change Index, will be used to determine neurocognitive impairment. The dose-response curve will be modeled using a non-linear model.
  • Assessment of tumor molecular status [ Time Frame: Up to 10 years ]
    Cognition, using the CTB COMP and each individual test score, will be compared by 1p19q status. A general linear model using maximum likelihood estimation will be built for CTB COMP and each individual test score over time including baseline test score, 1p19q status, treatment arm, and stratification factors.
Original Other Pre-specified Outcome Measures Same as current
 
Descriptive Information
Brief Title  ICMJE Proton Beam or Intensity-Modulated Radiation Therapy in Preserving Brain Function in Patients With IDH Mutant Grade II or III Glioma
Official Title  ICMJE A Phase II Randomized Trial of Proton Vs. Photon Therapy (IMRT) for Cognitive Preservation in Patients With IDH Mutant, Low to Intermediate Grade Gliomas
Brief Summary This randomized phase II clinical trial studies the side effects and how well proton beam or intensity-modulated radiation therapy works in preserving brain function in patients with IDH mutant grade II or III glioma. Proton beam radiation therapy uses tiny charged particles to deliver radiation directly to the tumor and may cause less damage to normal tissue. Intensity-modulated or photon beam radiation therapy uses high-energy x-ray beams shaped to treat the tumor and may also cause less damage to normal tissue. Patients will be more likely to be randomized to proton beam radiation therapy. It is not yet known if proton beam radiation therapy is more effective than photon-based beam intensity-modulated radiation therapy in treating patients with glioma.
Detailed Description

PRIMARY OBJECTIVES:

I. To determine whether proton therapy, compared to intensity-modulated radiation therapy (IMRT), preserves cognitive outcomes over time as measured by the Clinical Trial Battery Composite (CTB COMP) score (calculated from the Hopkins Verbal Learning Test Revised [HVLT-R]) Total Recall, HVLT-R Delayed Recall, HVLT-R Delayed Recognition, Controlled Oral Word Association (COWA) test, Trail Making Test (TMT) part A and part B.

SECONDARY OBJECTIVES:

I. To assess whether treatment with proton therapy preserves neurocognitive function as measured separately by each test, HVLT-R, TMT parts A & B, and COWA.

II. To document and compare treatment related symptoms, overall symptom impact, and disease related factor groupings, utilizing the M.D. Anderson Symptom Inventory Brain Tumor (MDASI-BT), for both treatment arms.

III. To assess whether treatment with proton therapy, compared to IMRT, results in superior quality of life as measured by the Linear Analog Scale Assessment (LASA) scale.

IV. To compare local control patterns of failure and overall and progression-free survival between the two treatment arms.

V. To assess adverse events.

TERTIARY OBJECTIVES:

I. To assess the impact of chemotherapy use on cognitive outcomes, symptom outcomes and quality of life.

II. To assess dose-response relationships between neuro-anatomic dosimetry and cognitive outcomes within and between treatment arms.

III. To evaluate the association between tumor molecular status and cognition at baseline and within and between treatment arms over time.

IV. To assess patterns of failure and pseudo progression as a function of radiation delivery type and dose received.

V. To assess local control, overall survival and, progression free survival in IDH mutant grade II and III tumors.

VI. To collect blood samples for future studies seeking to correlate changes in peripheral blood biomarkers (genes, micro ribonucleic acid [RNA], proteins, lymphocyte count, melatonin, etc) and the study endpoints.

VII. To document and compare the impact of low to intermediate gliomas and therapy on patients' work and activity participation (The Work Productivity and Activity Impairment [WPAI:GH] Questionnaire: General Health version 2.0) as well as the relationship between changes in patients' work and activity participation and neurocognitive function and patient reported symptoms and interference.

OUTLINE: Patients are randomized to 1 of 2 treatment arms.

ARM I: Patients undergo photon-based IMRT once daily (QD), 5 days a week for 6 weeks for a total of 30 fractions. Beginning 4 weeks after completion of radiation therapy, patients receive standard of care temozolomide for 5 days. Treatment repeats every 28 days for up to 12 courses in the absence of disease progression of unacceptable toxicity.

ARM II: Patients undergo proton beam radiation therapy QD, 5 days a week for 6 weeks for a total of 30 fractions. Beginning 4 weeks after completion of radiation therapy, patients receive standard of care temozolomide for 5 days. Treatment repeats every 28 days for up to 12 courses in the absence of disease progression of unacceptable toxicity.

After completion of study treatment, patients are followed up at 6 and 12 months and then yearly for 10 years.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE
  • 1p/19q Co-deletion
  • Anaplastic Astrocytoma
  • Diffuse Astrocytoma
  • Glioma
  • IDH1 Gene Mutation
  • IDH2 Gene Mutation
  • Oligoastrocytoma
  • Oligodendroglioma
  • WHO Grade III Glioma
Intervention  ICMJE
  • Radiation: IMRT (Intensity-Modulated Radiation Therapy)
    Undergo IMRT
    Other Names:
    • IMRT
    • Intensity Modulated RT
    • Intensity-Modulated Radiotherapy
  • Radiation: Proton Beam Radiation Therapy
    Undergo proton beam radiation therapy
  • Drug: Temozolomide
    Chemotherapy drug
    Other Names:
    • CCRG-81045
    • Imidazo[5,1-d]-1,2,3,5-tetrazine-8-carboxamide, 3, 4-dihydro-3-methyl-4-oxo-
    • M & B 39831
    • M and B 39831
    • Methazolastone
    • RP-46161
    • SCH 52365
    • Temcad
    • Temodal
    • Temodar
    • Temomedac
Study Arms  ICMJE
  • Active Comparator: Arm I (photon-based IMRT, temozolomide)
    Patients undergo photon-based IMRT QD, 5 days a week for 6 weeks for a total of 30 fractions. Beginning 4 weeks after completion of radiation therapy, patients receive standard of care temozolomide for 5 days. Treatment repeats every 28 days for up to 12 courses in the absence of disease progression of unacceptable toxicity.
    Interventions:
    • Radiation: IMRT (Intensity-Modulated Radiation Therapy)
    • Drug: Temozolomide
  • Experimental: Arm II (proton beam radiation therapy, temozolomide)
    Patients undergo proton beam radiation therapy QD, 5 days a week for 6 weeks for a total of 30 fractions. Beginning 4 weeks after completion of radiation therapy, patients receive standard of care temozolomide for 5 days. Treatment repeats every 28 days for up to 12 courses in the absence of disease progression of unacceptable toxicity.
    Interventions:
    • Radiation: Proton Beam Radiation Therapy
    • Drug: Temozolomide
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: June 6, 2017)
120
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE January 2030
Estimated Primary Completion Date January 2025   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  • Prior to STEP 1 REGISTRATION
  • Tumor tissue must be available for submission for central pathology review
  • Documentation from the enrolling site confirming the presence of IDH mutation and 1p/19q status; the provided information must document assays performed in clinical laboratory improvement amendments (CLIA)-approved laboratories
  • Only English speaking patients are eligible to participate as the cognitive and quality of life assessments are available only in English
  • The patient or a legally authorized representative must provide study-specific informed consent prior to study entry
  • Karnofsky performance status of >= 70 within 30 days prior to registration
  • Absolute neutrophil count (ANC) >= 1,500 cells/mm^3
  • Platelets >= 100,000 cells/mm^3
  • Hemoglobin >= 10.0 g/dl (Note: The use of transfusion or other intervention to achieve hemoglobin [Hgb] >= 10.0 g/dl is acceptable)
  • Bilirubin =< 1.5 upper limit of normal (ULN)
  • Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) =< 3 x ULN
  • BUN < 30 mg/dl
  • Serum creatinine < 1.5 mg/dl
  • Post-operative magnetic resonance (MR) imaging with contrast is mandatory obtained for radiation therapy planning; enrolling sites are highly encouraged to obtain thin-slice (<1.5 mm) 3D T1 pre and post contrast and Axial T2/FLAIR sequences for planning purposes
  • Prior to STEP 2 REGISTRATION
  • The following baseline neurocognitive assessments must be completed and uploaded prior to step 2 registration: HVLT-R, TMT Parts A and B, and COWA
  • Completion of all items on the following baseline quality of life forms: MDASI-BT, LASA QOL, WPAI-GH and Employment Questionnaire. These quality of life forms will be required and data entered at step 2 registration.
  • Financial clearance for proton therapy treatment prior to step 2 registration
  • Centrally reviewed histologically proven diagnosis of supratentorial, Word Health Organization (WHO) grade II or III astrocytoma, oligodendroglioma or oligoastrocytoma, with IDH mutation

Exclusion Criteria:

  • Definitive clinical or radiologic evidence of metastatic disease; if applicable
  • 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 permissible)
  • Prior cranial radiotherapy or radiotherapy to the head and neck where potential field overlaps would exist
  • Prior chemotherapy or radiotherapy for any brain tumor
  • Histologic diagnosis of glioblastoma (WHO grade IV) or pilocytic astrocytoma (WHO grade I)
  • Definitive evidence of multifocal disease
  • Planned use of cytotoxic chemotherapy during radiation (only adjuvant temozolomide therapy will be used on this protocol)
  • Patients with infra-tentorial tumors are not eligible
  • Prior history of neurologic or psychiatric disease believed to impact cognitive function
  • The use of memantine during or following radiation is NOT allowed
  • Severe, active co-morbidity defined as follows:

    • Unstable angina or congestive heart failure requiring hospitalization within 6 months prior to enrollment
    • Transmural myocardial infarction within the last 6 months prior to step 2 registration; evidence of recent myocardial infarction or ischemia by the findings of S-T elevations of >= 2 mm using the analysis of an electrocardiogram (EKG) performed within 28 days prior to step 2 registration (Note: EKG to be performed only if clinical suspicion of cardiac issue)
    • New York Heart Association grade II or greater congestive heart failure requiring hospitalization within 12 months prior to step 2 registration
    • Serious and inadequately controlled arrhythmia at step 2 registration
    • Serious or non-healing wound, ulcer or bone fracture or history of abdominal fistula, intra-abdominal abscess requiring major surgical procedure, open biopsy or significant traumatic injury within 28 days prior to step 2 registration, with the exception of the craniotomy for surgical resection
    • Acute bacterial or fungal infection requiring intravenous antibiotics at the time of step 2 registration
    • Hepatic insufficiency resulting in clinical jaundice and/or coagulation defects; note, however, that laboratory tests for coagulation parameters are not required for entry into this protocol
    • Chronic obstructive pulmonary disease exacerbation or other respiratory illness requiring hospitalization or precluding study therapy at the time of step 2 registration
    • Human immunodeficiency virus (HIV) positive with CD4 count < 200 cells/microliter; acquired immune deficiency syndrome (AIDS) based upon current Centers for Disease Control and Prevention (CDC) definition; note, however, that HIV testing is not required for entry into this protocol
    • Any other severe immunocompromised condition
    • 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
    • End-stage renal disease (i.e., on dialysis or dialysis has been recommended)
    • Any other major medical illnesses or psychiatric treatments that in the investigator's opinion will prevent administration or completion of protocol therapy
  • Inability to undergo MRI with and without contrast (e.g. claustrophobia, non-MRI compatible implant or foreign body, gadolinium allergy or renal dysfunction preventing the patient from receiving gadolinium- institutional guidelines should be used to determine if patients are at risk for renal dysfunction); note that patients with severe claustrophobia are permitted on this study if they are willing and able to undergo MRI with adequate sedation or anesthesia
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03180502
Other Study ID Numbers  ICMJE NRG-BN005
NCI-2017-00203 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
NRG-BN005
NRG-BN005 ( Other Identifier: NRG Oncology )
NRG-BN005 ( Other Identifier: CTEP )
U10CA180868 ( U.S. NIH Grant/Contract )
Has Data Monitoring Committee No
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE
Plan to Share IPD: No
Responsible Party NRG Oncology
Study Sponsor  ICMJE NRG Oncology
Collaborators  ICMJE National Cancer Institute (NCI)
Investigators  ICMJE
Principal Investigator: David Grosshans NRG Oncology
PRS Account NRG Oncology
Verification Date July 2019

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP