Clinical Trials /

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

NCT03180502

Description:

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.

Related Conditions:
  • Astrocytoma
  • Glioma
  • Oligoastrocytoma
  • Oligodendroglioma
Recruiting Status:

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

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

Clinical Trial IDs

  • ORG STUDY ID: NRG-BN005
  • SECONDARY ID: NCI-2017-00203
  • SECONDARY ID: NRG-BN005
  • SECONDARY ID: NRG-BN005
  • SECONDARY ID: NRG-BN005
  • SECONDARY ID: U10CA180868
  • NCT ID: NCT03180502

Conditions

  • 1p/19q Co-deletion
  • Anaplastic Astrocytoma
  • Diffuse Astrocytoma
  • Glioma
  • IDH1 Gene Mutation
  • IDH2 Gene Mutation
  • Oligoastrocytoma
  • Oligodendroglioma
  • WHO Grade III Glioma

Interventions

DrugSynonymsArms
TemozolomideCCRG-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, TemomedacArm I (photon-based IMRT, temozolomide)

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.

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.
    

Trial Arms

NameTypeDescriptionInterventions
Arm I (photon-based IMRT, temozolomide)Active ComparatorPatients 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.
  • Temozolomide
Arm II (proton beam radiation therapy, temozolomide)ExperimentalPatients 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.
  • Temozolomide

Eligibility 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
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Change in cognition as measured by the CTB COMP score
Time Frame:Baseline to up to 10 years
Safety Issue:
Description: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

Measure:Change in quality of life as measured by the LASA scale
Time Frame:Up to 10 years
Safety Issue:
Description: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.
Measure:Change in symptoms as measured by MDASI-BT
Time Frame:Baseline to up to 10 years
Safety Issue:
Description: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.
Measure:Cognition as measured by COWA
Time Frame:Up to 10 years
Safety Issue:
Description:The COWA will be analyzed using a general linear model with maximum likelihood estimation. Standardized scores will be used.
Measure:Cognition as measured by TMT parts A and B
Time Frame:Up to 10 years
Safety Issue:
Description:The TMT parts A & B will be analyzed using a general linear model with maximum likelihood estimation. Standardized scores will be used.
Measure:Cognition as measured by HVLT-R
Time Frame:Up to 10 years
Safety Issue:
Description:The HVLT-R will be analyzed using a general linear model with maximum likelihood estimation. Standardized scores will be used.
Measure: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
Safety Issue:
Description: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.
Measure:Local control as assessed by RANO criteria
Time Frame:Up to 10 years
Safety Issue:
Description: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.
Measure:Overall survival (OS)
Time Frame:From randomization to the date of death, assessed up to 10 years
Safety Issue:
Description: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.
Measure:Progression-free survival (PFS)
Time Frame:From date of randomization to date of progression or death, whichever occurs first, assessed up to 10 years
Safety Issue:
Description: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.

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:NRG Oncology

Last Updated

June 6, 2017