RATIONALE: Lonafarnib may stop the growth of tumor cells by blocking the enzymes necessary for their growth. Drugs used in chemotherapy, such as temozolomide, work in different ways to stop tumor cells from dividing so they stop growing or die. Giving lonafarnib together with temozolomide may kill more tumor cells.

PURPOSE: This phase I trial is studying the side effects and best dose of lonafarnib when given together with temozolomide in treating patients with recurrent primary supratentorial glioma.

Condition	Treatment or Intervention	Phase
adult brain tumor	Drug: lonafarnib  Drug: temozolomide  Procedure: chemotherapy  Procedure: enzyme inhibitor therapy	Phase I

Further Study Details: 

OBJECTIVES: Primary

• Determine the maximum tolerated dose and dose-limiting toxicity of lonafarnib when administered with temozolomide in patients with recurrent primary supratentorial gliomas.
• Determine the safety and tolerability of this regimen in these patients.

Secondary

• Determine the mechanism of action of lonafarnib in these patients.
• Determine the pharmacodynamics and pharmacokinetics of this regimen in these patients.
• Determine the activity of this regimen in these patients.
• Determine the response to this regimen in patients who have measurable disease.

OUTLINE: This is a nonrandomized, multicenter, open-label, dose-escalation study of lonafarnib.

Patients receive oral temozolomide once daily on days 2-6 of course 1 and on days 1-5 of all subsequent courses. Patients also receive oral lonafarnib twice daily on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

Cohorts of 3-6 patients receive escalating doses of lonafarnib until the maximum tolerated dose (MTD) is determined. The MTD is defined as the dose at which 1 of 6 patients experience dose-limiting toxicity. An additional 3 patients may be treated at the highest dose level achieved.

Patients are followed every 8 weeks for 6 months and then every 3 months thereafter.

PROJECTED ACCRUAL: A total of 3-30 patients will be accrued for this study.

Ages Eligible for Study:  18 Years and above,  Genders Eligible for Study:  Both

Criteria

DISEASE CHARACTERISTICS:

• Histologically confirmed primary supratentorial glioma
• Multifocal disease allowed
• Recurrent disease after prior surgery and/or radiotherapy
• Radiological evidence of increased and/or enhanced target lesion
• Amenable to temozolomide therapy

PATIENT CHARACTERISTICS: Age

• Over 18

Performance status

• ECOG 0-2 OR
• WHO 0-2

Life expectancy

• Not specified

Hematopoietic

• Neutrophil count ≥ 1,500/mm^3
• Platelet count ≥ 100,000/mm^3
• Hemoglobin ≥ 10.0 g/dL

Hepatic

• Alkaline phosphatase < 2.5 times upper limit of normal (ULN)
• Transaminases < 2.5 times ULN
• Bilirubin < 1.5 times ULN

Renal

• Creatinine < 1.7 mg/dL

Cardiovascular

• Cardiac function clinically normal
• Normal 12-lead ECG
• QTc ≤ 440 msec on ECG
• No ischemic heart disease within the past 6 months

Other

• Not pregnant or nursing
• Negative pregnancy test
• Fertile patients must use effective contraception during and for 3 months after study participation
• No unstable systemic disease
• No active uncontrolled infection
• No psychological, familial, sociological, or geographical condition that would preclude study compliance and follow-up
• No other active or recurrent malignancy within the past 5 years except cone biopsied carcinoma of the cervix or adequately treated basal cell or squamous cell skin cancer

PRIOR CONCURRENT THERAPY: Biologic therapy

• No concurrent anticancer biologic agents

Chemotherapy

• At least 4 weeks since prior chemotherapy (6 weeks for temozolomide)
• Prior adjuvant chemotherapy allowed
• No more than 1 prior chemotherapy regimen for recurrent disease
• No other concurrent chemotherapy

Endocrine therapy

• Concurrent corticosteroids allowed provided treatment remains at a stable or decreasing dose for at least 2 weeks

Radiotherapy

• See Disease Characteristics
• No concurrent radiotherapy

Surgery

• See Disease Characteristics
• At least 3 months since prior surgery for primary brain tumor

Other

• Concurrent anticonvulsants allowed
• No other concurrent anticancer agents
• No other concurrent investigational therapy

France
      Centre de Lutte Contre le Cancer Georges-Francois Leclerc, Dijon,  21079,  France; Recruiting
      Centre Regional Rene Gauducheau, Nantes-Saint Herblain,  44805,  France; Recruiting
Switzerland
      Centre Hospitalier Universitaire Vaudois, Lausanne,  CH-1011,  Switzerland; Recruiting

Study chairs or principal investigators

Mario Campone,  Study Chair,  Centre Regional Rene Gauducheau   
Roger Stupp, MD,  Study Chair,  Centre Hospitalier Universitaire Vaudois   

Study ID Numbers:  CDR0000362066; EORTC-16027; EORTC-26023; SPRI-P03174; NCT00083096
Record last reviewed:  January 2005
Last Updated:  April 5, 2005
Record first received:  May 14, 2004
ClinicalTrials.gov Identifier:  NCT00083096
Health Authority: United States: Federal Government
ClinicalTrials.gov processed this record on 2005-04-08