Phase I/II Study of Two Different Schedules of Bortezomib (VELCADE, PS-341) and Pemetrexed (ALIMTA) in Advanced Solid Tumors, With Emphasis on Non-Small Cell Lung Cancer (NSCLC)
Phase I/II Study of Two Different Schedules of Bortezomib (VELCADE, PS-341) and Pemetrexed (ALIMTA) in Advanced Solid Tumors, With Emphasis on Non-Small Cell Lung Cancer (NSCLC)
RATIONALE: Bortezomib and pemetrexed disodium may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Giving bortezomib together with pemetrexed disodium may kill more tumor cells.
PURPOSE: This phase I/II trial is studying the side effects and best dose of two different schedules of bortezomib when given together with pemetrexed disodium and to see how well they work in treating patients with advanced non-small cell lung cancer or other solid tumors.
OBJECTIVES:
Primary
Secondary
Tertiary
OUTLINE: This is a phase I, dose-escalation study of bortezomib followed by a phase II, open-label study.
Phase I: Patients will be accrued, in an alternating fashion, to 1 of 2 treatment groups.
In both groups, treatment repeats every 21 days in the absence of unacceptable toxicity or disease progression.
Cohorts of 3-6 patients per group receive escalating doses of bortezomib until the maximum tolerated dose (MTD) is determined. The MTD is defined as the dose preceding that at which 2 of 3 or 2 of 6 patients experience dose-limiting toxicity.
Blood is drawn at baseline and prior to courses 2 and 3 for correlative and molecular studies.
Tumor tissue and blood samples from patients enrolled in the phase II portion of the study are examined for various biological markers. Immunohistochemistry is used to measure BCL-2 gene, BCL-xL gene, BAX gene, and p27. Reverse transcriptase-polymerase chain reaction is used to assay the expression of thymidylate synthase, folsyl-polyglutamate synthase, and reduced folate carrier. Levels of plasminogen-activator inhibitor 1 gene, vascular endothelial growth factor, and osteopontin are measured by immunoenzyme techniques. The nuclear expression of NF-kB and p27 in blood is compared before and after study treatment by flow cytometry.
After completion of study treatment, patients in phase I are followed for 30 days and patients in phase II are followed periodically.
DISEASE CHARACTERISTICS:
Cytologically or histologically confirmed diagnosis of 1 of the following:
Advanced solid tumor that progressed after standard therapy or for which no effective curative therapy exists (phase I)
Stage IIIB (pleural effusion) or IV non-small cell lung cancer (NSCLC) (phase II)
Measurable disease
No symptomatic brain metastasis or disease requiring steroids and anticonvulsants
PATIENT CHARACTERISTICS:
Zubrod performance status 0-2 (phase I) or 0-1 (phase II)
Life expectancy ≥ 3 months
Creatinine ≤ 1.5 mg/dL OR creatinine clearance ≥ 50 mL/min
Bilirubin normal
AST ≤ 2.5 times upper limit of normal
Granulocyte count ≥ 1,500/mm³
Platelet count of ≥ 100,000/mm³
Not pregnant or nursing
Negative pregnancy test
Fertile patients must use effective contraception during and for 3 months after completion of study treatment
No pre-existing neuropathy ≥ grade 2
No other prior malignancy except for the following (phase II):
No hypersensitivity to bortezomib, boron, or mannitol
No cardiovascular complications, including any of the following:
Myocardial infarction within the past 6 months
New York Heart Association class III-IV heart failure
Uncontrolled angina
Severe uncontrolled ventricular arrhythmias
Electrocardiographic (ECG) evidence of acute ischemia or active conduction system abnormalities
PRIOR CONCURRENT THERAPY: