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

PRIMARY OBJECTIVES:

I. To assess the safety profile of EMD 121974 (cilengitide) when administered as a one-hour
infusion twice a week concurrently with concomitant and adjuvant temozolomide with radiation
therapy for newly diagnosed glioblastoma multiforme. (Safety Run-In)

II. To estimate overall survival in newly diagnosed patients with glioblastoma multiforme
treated with EMD 121974 concurrently with concomitant and adjuvant temozolomide with
radiation therapy. (Phase II)

SECONDARY OBJECTIVES:

I. To estimate and compare overall survival between a low dose treatment group and a high
dose treatment group in newly diagnosed patients with glioblastoma multiforme treated with
EMD 121974 concurrently with concomitant and adjuvant temozolomide with radiation therapy.
(Phase II)

II. To determine the toxicity of EMD 121974 (cilengitide) when it is administered in
conjunction with concomitant and adjuvant temozolomide with radiation therapy in patients
with newly diagnosed glioblastoma multiforme. (Phase II)

III. To evaluate the molecular profile of individual patients and correlate molecular
expression profiles with clinical outcomes. (Phase II)

IV. To characterize tumor blood volume, tumor blood flow, and permeability ratios using
perfusion MR in newly diagnosed glioblastoma multiforme and follow these parameters during
treatment with EMD 121974 (cilengitide). (Phase II)

OUTLINE: This is an open-label, multicenter, safety run-in study of cilengitide followed by
a randomized phase II study.

Safety Run-In:

INITIATION COURSE: Patients receive cilengitide IV over 1 hour on days 1 and 4. Treatment
repeats weekly for 10 weeks. Patients also receive oral temozolomide and undergo
radiotherapy one hour later on days 1-5 of weeks 1-6.

MAINTENANCE COURSES: Patients receive oral temozolomide once daily on days 1-5 in courses
1-6. Patients also receive cilengitide IV on days 1, 4, 8, 11, 15, 18, 22, and 25. Courses
repeat every 28 days in the absence of disease progression or unacceptable toxicity.

Cohorts of 3-6 patients receive escalating doses of cilengitide (3 Pre-defined study dose
levels are defined as: 500, 1000 and 2000mg). The MTD is defined as the dose preceding that
at which 2 of 3 or 3 of 6 patients experience dose-limiting toxicity. If no MTD (maximum
tolerable dose) is defined through three steps of the dose escalation process, we will
pursue the phase II safety/efficacy study with randomized treatment allocation. Patients
will be randomized into one of two pre-specified treatment dosage arms, 500mg group or
2000mg group.

PHASE II:

Patients are stratified according to age (50 and under vs over 50), Karnofsky performance
score (60%-80% vs 90%-100%), and tumor status (measurable vs nonmeasurable). Patients are
randomized to 1 of 2 treatment arms.

ARM I: Patients receive radiotherapy and temozolomide as in safety run-in initiation course
and cilengitide at the lower dose as in safety run-in initiation and maintenance courses.

ARM II: Patients receive radiotherapy and temozolomide as in safety run-in initiation course
and cilengitide at the higher dose as in safety run-in initiation and maintenance courses.

Patients are followed every 2 months.

PROJECTED ACCRUAL: A total of 9-112 patients (9-18 for safety run-in and 94 [47 per
treatment arm] for phase II) will be accrued for this study within 1.5-37 months

Inclusion Criteria:

- Patients must have histologically confirmed supratentorial grade IV astrocytoma
(glioblastoma multiforme)

- Patients must not have received prior radiation therapy, chemotherapy, immunotherapy
or therapy with biologic agent (including immunotoxins, immunoconjugates, antisense,
peptide receptor antagonists, interferons, interleukins, TIL, LAK or gene therapy),
or hormonal therapy for their brain tumor; glucocorticoid therapy is allowed

- Patients must have a Karnofsky performance status >= 60% (i.e. the patient must be
able to care for himself/herself with occasional help from others)

- Absolute neutrophil count >= 1500/mm^3

- Platelets >= 100,000/mm^3

- Creatinine =< 1.5 mg/dl or creatinine clearance >= 60 mL/min

- Total bilirubin =< 1.5 mg/dl

- Transaminases =< 4 times above the upper limits of the institutional normal

- Patients must be able to provide written informed consent

- Patients must have recovered from the immediate post-operative period and be
maintained on a stable corticosteroid regimen (no increase for 5 days) prior to the
start of treatment

- Patients with the potential for pregnancy or impregnating their partner must agree to
follow acceptable birth control methods to avoid conception; women of childbearing
potential must have a negative pregnancy test

- Patients must have a Mini Mental State Exam score of >= 15

- Patients must have tumor tissue form completed and signed by a pathologist

Exclusion Criteria:

- Patients with serious concurrent infection or medical illness, which would jeopardize
the ability of the patient to receive the treatment outlined in this protocol with
reasonable safety

- Patients who are pregnant or breast-feeding

- Patients receiving concurrent therapy for their tumor (i.e. chemotherapeutics or
investigational agents)

- Patients with a concurrent or prior malignancy are ineligible unless they are
patients with curatively treated carcinoma-in-situ or basal cell carcinoma of the
skin; patients who have been free of disease (any prior malignancy) for >= five years
are eligible for this study

- Patients who are unable to undergo an MRI evaluation

- Patients with a history of wound-healing disorders, advanced coronary disease, or
with a recent history (# 1 year) of peptic ulcer disease are ineligible