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

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.

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