Dimethyl Fumarate, Temozolomide, and Radiation Therapy in Treating Patients With Newly Diagnosed Glioblastoma Multiforme

PRIMARY OBJECTIVES:

I. To determine the recommended phase 2 dose (RP2D) of dimethyl fumarate (DMF) when combined
with standard concurrent temozolomide and RT in subjects with newly diagnosed glioblastoma
multiforme (GBM).

SECONDARY OBJECTIVES:

I. To evaluate the safety, tolerance, and toxicity of DMF when combined with standard
concurrent temozolomide and RT in subjects with newly diagnosed GBM.

II. To obtain a preliminary estimate of the efficacy of DMF when combined with standard
concurrent temozolomide and RT in subjects with newly diagnosed GBM.

OUTLINE: This is a dose-escalation study of dimethyl fumarate.

CONCOMITANT THERAPY: Between 21 days (3 weeks) and 42 days (6 weeks) following the last
surgical procedure, patients receive temozolomide orally (PO) once daily (QD) for 42-49 days
and dimethyl fumarate PO twice daily (BID) or thrice daily (TID) continuously. Patients also
undergo radiation therapy 5 days a week over 6 weeks for a total of 30 fractions.

MAINTENANCE THERAPY: Patients continue to receive dimethyl fumarate PO BID or TID
continuously. Four weeks after completing concomitant temozolomide and radiation therapy,
patients also receive temozolomide PO QD on days 1-5. Treatment repeats every 28 days for 6
courses in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up for 30 days and then every 2
months thereafter.

Inclusion Criteria:

- Histopathologically proven diagnosis of glioblastoma or gliosarcoma (World Health
Organization [WHO] grade IV) following either a surgical resection or biopsy

- Eastern Cooperative Oncology Group (ECOG) performance status 0-2

- Subjects must have recovered from surgery or biopsy before study registration

- Therapy must begin between 21 days (3 weeks) and 42 days (6 weeks) after the most
recent brain tumor surgery(resection or biopsy)

- Documentation of steroid doses 10-14 days prior to study registration and stable or
decreasing steroid dose over the week prior to registration

- Absolute neutrophil count (ANC) >= 1500/mm^3

- Platelets >= 100,000/mm^3 (untransfused)

- Hemoglobin >= 10 g/dL (the use of transfusion or other intervention to achieve
hemoglobin >= 10 g/dL is acceptable)

- Creatinine =< 1.5 x upper limit of normal (ULN) for the laboratory or calculated or
actual creatinine clearance > 45 mL/min

- Total bilirubin =< 1.5 x ULN for the laboratory (total bilirubin criteria may be
waived if a subject has documented Gilbert's syndrome)

- Aspartate aminotransferase (AST) =< 3 x ULN for the laboratory

- Alanine aminotransferase (ALT) =< 3 x ULN for the laboratory

- Women of childbearing potential and male subjects must practice adequate contraception

- Ability to understand and the willingness to sign a written informed consent document

Exclusion Criteria:

- Prior invasive malignancy (except for non-melanoma skin cancer) unless disease free
for >= 3 years

- Recurrent malignant gliomas

- Metastases detected below the tentorium or beyond the cranial vault

- Prior chemotherapy or radiation therapy (RT) for the diagnosis of GBM or for cancers
of the head and neck

- Clinically significant cardiac disease, including major cardiac dysfunction, such as
uncontrolled angina, clinical congestive heart failure with New York Heart Association
(NYHA) class III or IV, ventricular arrhythmias requiring anti-arrhythmic therapy

- Pregnant or lactating women

- History of allergic reactions or intolerance to any of the required agents on the
study

- History of hypersensitivity to dacarbazine

- Any treatment for GBM, other than surgery or anti-epileptic therapy, within 30 days
prior to study treatment initiation

- Other condition(s) that in the opinion of the investigator might compromise the
objectives of the study or increase patient risk