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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

This study is currently recruiting participants.
Verified September 2017 by NRG Oncology
Sponsor:
ClinicalTrials.gov Identifier:
NCT03180502
First Posted: June 8, 2017
Last Update Posted: September 7, 2017
The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
Collaborator:
National Cancer Institute (NCI)
Information provided by (Responsible Party):
NRG Oncology
  Purpose
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.

Condition Intervention Phase
1p/19q Co-deletion Anaplastic Astrocytoma Diffuse Astrocytoma Glioma IDH1 Gene Mutation IDH2 Gene Mutation Oligoastrocytoma Oligodendroglioma WHO Grade III Glioma Radiation: IMRT (Intensity-Modulated Radiation Therapy) Radiation: Proton Beam Radiation Therapy Drug: Temozolomide Phase 2

Study Type: Interventional
Study Design: Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase II Randomized Trial of Proton Vs. Photon Therapy (IMRT) for Cognitive Preservation in Patients With IDH Mutant, Low to Intermediate Grade Gliomas

Resource links provided by NLM:


Further study details as provided by NRG Oncology:

Primary Outcome Measures:
  • 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


Secondary Outcome Measures:
  • 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.


Other Outcome Measures:
  • 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.


Estimated Enrollment: 120
Actual Study Start Date: August 2, 2017
Estimated Study Completion Date: August 31, 2027
Estimated Primary Completion Date: May 15, 2022 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
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.
Radiation: IMRT (Intensity-Modulated Radiation Therapy)
Undergo IMRT
Other Names:
  • IMRT
  • Intensity Modulated RT
  • Intensity-Modulated Radiotherapy
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
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.
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

  Show Detailed Description

  Eligibility

Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


Ages Eligible for Study:   18 Years and older   (Adult, Senior)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • 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
  • Appropriate stage for study entry based on the following diagnostic workup:

    • History/physical examination within 60 days prior to registration
    • Imaging of the brain within 60 days prior to registration
  • 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 60 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
  • CD4 lymphocyte count is highly encouraged
  • Women of childbearing age must have a negative serum pregnancy test within 14 days prior to registration
  • Post-operative magnetic resonance (MR) imaging must be obtained for radiation therapy planning; enrolling sites are highly encouraged to obtain thin-slice volumetric fluid attenuated inversion recovery (FLAIR) and T1 post contrast sequences for planning purposes
  • STEP 2 REGISTRATION
  • The following baseline neurocognitive assessments must be completed and uploaded within 27 calendar days prior to step 2 registration: HVLT-R, TMT, and COWA

    • NOTE: Completed baseline neurocognitive assessments can be uploaded at the time of step 1 registration
  • The following baseline patient reported outcome assessments must be completed and uploaded within 27 calendar days prior to Step 2 registration: MDASI-BT, LASA QOL, WPAI
  • Financial clearance for proton therapy treatment within 30 days following step 1 registration
  • Centrally reviewed histologically proven diagnosis of supratentorial, Word Health Organization (WHO) grade II or III astrocytoma, oligodendroglioma or oligoastrocytoma; tissue must be submitted x calendar days after step 1 registration
  • Documentation must be uploaded within 15 business days and will be verified by the translational/pathology study co-chairs within 5 business days after receiving the upload; the documentation should demonstrate 1) evaluation of known IDH1 and IDH2 mutational hotspots (sequencing is encouraged) evaluation of chromosomes 1p and 19q copy number utilizing either fluorescence in situ hybridization (FISH) or other suitable assay

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
  Contacts and Locations
Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03180502


Locations
United States, Pennsylvania
NRG Oncology Recruiting
Philadelphia, Pennsylvania, United States, 19103
Contact: David R. Grosshans, MD, PhD    713-745-8795    dgrossha@mdanderson.org   
Principal Investigator: David R. Grosshans         
Sponsors and Collaborators
NRG Oncology
National Cancer Institute (NCI)
Investigators
Principal Investigator: David Grosshans NRG Oncology
  More Information

Responsible Party: NRG Oncology
ClinicalTrials.gov Identifier: NCT03180502     History of Changes
Other Study ID Numbers: NRG-BN005
NCI-2017-00203 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
NRG-BN005 ( Other Identifier: NRG Oncology )
NRG-BN005 ( Other Identifier: CTEP )
U10CA180868 ( U.S. NIH Grant/Contract )
First Submitted: June 5, 2017
First Posted: June 8, 2017
Last Update Posted: September 7, 2017
Last Verified: September 2017
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No

Additional relevant MeSH terms:
Glioma
Astrocytoma
Oligodendroglioma
Neoplasms, Neuroepithelial
Neuroectodermal Tumors
Neoplasms, Germ Cell and Embryonal
Neoplasms by Histologic Type
Neoplasms
Neoplasms, Glandular and Epithelial
Neoplasms, Nerve Tissue
Temozolomide
Dacarbazine
Antineoplastic Agents, Alkylating
Alkylating Agents
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents