Clinical trial NCT00085254: Cilengitide, Temozolomide, and Radiation Therapy in Treating Patients With Newly Diagnosed Glioblastoma Multiforme
Official title: A Safety Run-in/Randomized Phase II Trial of EMD 121974 in Conjunction With Concomitant and Adjuvant Temozolomide With Radiation Therapy in Patients With Newly Diagnosed Glioblastoma Multiforme
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
PHASE2
Conditions: Adult Giant Cell Glioblastoma
Adult Glioblastoma
Adult Gliosarcoma
Lead sponsor: National Cancer Institute (NCI)
Sponsor class: NIH
First posted: 2004-06-11
Enrollment: 112
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: Cilengitide may stop the growth of cancer by stopping blood flow to the tumor. Drugs used in chemotherapy, such as temozolomide, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Radiation therapy uses high-energy x-rays to damage tumor cells. Giving cilengitide together with temozolomide and radiation therapy may kill more tumor cells. This randomized phase I/II trial is studying the side effects and best dose of cilengitide when given together with temozolomide and radiation therapy and to compare how well they work in treating patients with newly diagnosed glioblastoma multiforme

Detailed description: 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

Eligibility criteria: 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

Primary outcomes:
measure: Dose Limiting Toxicities of EMD + RT and TMZ
timeFrame: 10 weeks
measure: Maximum Tolerated or Tolerable Dose (MTD) - 3 Pre-defined Doses
timeFrame: 10 weeks
measure: Overall Survival (Phase II)
timeFrame: up to 36 months
Secondary outcomes:
measure: Overall Survival Based on Dose Level - Phase 2
timeFrame: Up to 3 years
measure: Frequency of Hematologic and Nonhematologic Adverse Events
timeFrame: Up to 1 year
Other outcomes:
Locations:
city: Birmingham
country: United States
facility: University of Alabama at Birmingham
state: Alabama
city: Atlanta
country: United States
facility: Emory University
state: Georgia
city: Baltimore
country: United States
facility: Johns Hopkins University
state: Maryland
city: Boston
country: United States
facility: Massachusetts General Hospital
state: Massachusetts
city: Detroit
country: United States
facility: Henry Ford Hospital
state: Michigan
city: Winston-Salem
country: United States
facility: Wake Forest University Health Sciences
state: North Carolina
city: Cleveland
country: United States
facility: Cleveland Clinic Foundation
state: Ohio
city: Philadelphia
country: United States
facility: University of Pennsylvania
state: Pennsylvania
Study officials:
affiliation: National Cancer Institute (NCI)
name: Louis Nabors, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Nabors LB, Mikkelsen T, Hegi ME, Ye X, Batchelor T, Lesser G, Peereboom D, Rosenfeld MR, Olsen J, Brem S, Fisher JD, Grossman SA; New Approaches to Brain Tumor Therapy (NABTT) Central Nervous System Consortium. A safety run-in and randomized phase 2 study of cilengitide combined with chemoradiation for newly diagnosed glioblastoma (NABTT 0306). Cancer. 2012 Nov 15;118(22):5601-7. doi: 10.1002/cncr.27585. Epub 2012 Apr 19.