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