Vaccine Therapy in Treating Patients With Newly Diagnosed Glioblastoma Multiforme

OBJECTIVES:

Primary

- To assess humoral and cellular immune responses to adjuvant PEP-3-KLH conjugate vaccine
in patients with newly diagnosed glioblastoma multiforme (GBM).

- To assess the clinical efficacy of the PEP-3-KLH conjugate vaccine, in terms of
progression-free survival, in patients with newly diagnosed GBM.

Secondary

- To determine whether patients with GBM, who are known to be at least mildly
immunosuppressed, can respond to standard and proven vaccine strategies.

- To assess for any potential toxicity to the PEP-3-KLH conjugate vaccine in patients
with newly diagnosed GBM.

OUTLINE: This is a multicenter study. Patients are stratified according to participating
center.

At the time the study was initiated, standard of care temozolomide was not established,
therefore, Arm I (ACTIVATE)was given without monthly cycles of temozolomide. At the point of
interim analysis, monthly cycles of temozolomide had become standard of care. Arm II was
then given the standard of care 5-day cycles of monthly temozolomide and during this time,
dose-intensified temozolomide was in trials to compare with the 5-day temozolomide.
Therefore, Arm III was initiated to determine the immunologic effects of 21-day monthly
cycles of temozolomide with vaccine.

- Arm I (ACTIVATE): Patients receive PEP-3-KLH conjugate vaccine and sargramostim
(GM-CSF) intradermally on days 1, 15, and 29 and then monthly in the absence of disease
progression or unacceptable toxicity.

- Arm II (ACT II Standard (STD)): Patients first receive 3 initial vaccinations of an
epidermal growth factor receptor variant III (EGRRvIII)- specific peptide (PEP-3)
keyhole limpet hemocyanin (KLH) conjugate vaccine and sargramostim (GM-CSF) biweekly
starting within 6 weeks of completing radiation. Additional vaccinations are given
until clinical or radiographic evidence of progression or death. Patients subsequently
receive temozolomide at a targeted dose of 200 mg/m2 for the first 5 days of a 28 day
cycle.

- Arm III (ACT II Dose-intensified (DI)): Patients first receive 3 initial vaccinations
of an epidermal growth factor receptor variant III (EGRRvIII)- specific peptide (PEP-3)
keyhole limpet hemocyanin (KLH) conjugate vaccine and sargramostim (GM-CSF) biweekly
starting within 6 weeks of completing radiation. Additional vaccinations are given
until clinical or radiographic evidence of progression or death. Patients subsequently
receive temozolomide at a targeted dose of 100 mg/m2 for the first 21 days of a 28 day
cycle.

- Patients undergo delayed-type hypersensitivity (DTH) skin testing* at baseline,
after the third vaccination, and then monthly thereafter. Patients also undergo
leukapheresis to obtain sufficient peripheral blood lymphocytes for immunologic
monitoring at baseline, after the third vaccination, and then, if applicable, at
the time of positive DTH response, disease progression, or after the sixth course
of post-radiotherapy temozolomide. Methods used for immunologic monitoring include
Enzyme-linked Immunospot(ELISPOT) assays, cytotoxicity assays, fluorescence
activated cell sorting (FACS), and ELISA.

NOTE: *Patients with positive DTH skin testing, also undergo skin punch biopsies.

After completion of study therapy, patients are followed periodically.

Inclusion Criteria:

- Histologically confirmed newly diagnosed glioblastoma multiforme

- Has undergone prior gross total resection (GTR) followed by conformal radiotherapy*
with or without concurrent chemotherapy

- GTR is defined as ≥ 95% volumetric resection of the contrast-enhancing component
on the preoperative MRI

- Residual radiographic contrast enhancement on post-resection CT scan or MRI must
be ≤ 1 cm in maximal diameter in any two perpendicular axial planes

- No evidence of disease progression after completion of radiotherapy* NOTE:
*Patients may enroll in part 2 of the study within 2 weeks after surgery; these
patients will receive radiotherapy with concurrent chemotherapy during the study

- EGFRvIII-positive tumor by immunohistochemistry, polymerase chain reaction, or
related molecular techniques

- Karnofsky performance status 80-100%

- Curran group status I-IV

- Signed informed consent form

Exclusion Criteria:

- Absolute Neutrophil Count (ANC) < 1,000/mm³

- Platelet count < 50,000/mm³

- Prothrombin Time/Partial Thromboplastin Time (PT/PTT) > 1.5 times normal

- Positive hepatitis B (HB) surface antigen (HbsAg), antibody to hepatitis B surface
antigen (anti-HBs), and antibody to hepatitis B core antigen (anti-HBc)

- Pregnant or nursing

- Positive pregnancy test

- Active infection requiring treatment

- Unexplained febrile illness (T max > 101.5 F)

- Inflammatory bowel disease, lupus erythematosus, rheumatoid arthritis, or other
autoimmune disease

- Known immunosuppressive disease

- Known HIV infection

- Diffuse leptomeningeal disease

- Unstable or severe concurrent medical condition, such as severe heart and lung
disease or active hepatitis

- Demonstrated allergy to temozolomide or inability to tolerate temozolomide for
reasons other than lymphopenia

- Concurrent corticosteroids (except for nasal or inhaled steroids) at a dose above
physiologic levels (> 2 mg of dexamethasone/day).