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)
- Determine the safety, including dose-limiting toxicities, and feasibility of combining
bortezomib with pemetrexed disodium in patients with advanced non-small cell lung
cancer (NSCLC) or other solid tumors. (Phase I)
- Determine the response rate in patients with advanced NSCLC treated with this regimen.
- Compare the toxicity of 2 different schedules of bortezomib and pemetrexed disodium in
patients with advanced solid tumors. (Phase I)
- Determine the maximum tolerated dose (MTD) of bortezomib when administered with
pemetrexed disodium in 2 different treatment schedules in these patients. (Phase I)
- Determine, preliminarily, the efficacy of the combination of bortezomib and pemetrexed
disodium in patients with advanced solid tumors. (Phase I)
- Assess the overall survival and progression-free survival of these patients. (Phase II)
- Evaluate the frequency and severity of toxicities associated with this regimen. (Phase
- Perform laboratory correlative studies on tumor tissue and blood samples to investigate
potential predictors of response. (Phase II)
OUTLINE: This is a phase I, dose-escalation study of bortezomib followed by a phase II,
- Phase I: Patients will be accrued, in an alternating fashion, to 1 of 2 treatment
- Group I: Patients receive pemetrexed disodium IV on day 1 and bortezomib IV on
days 1, 4, 8, and 11.
- Group II: Patients receive pemetrexed disodium IV on day 1 and bortezomib IV on
days 1 and 8.
In both groups, treatment repeats every 21 days in the absence of unacceptable toxicity or
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.
- Phase II: Patients receive pemetrexed disodium bortezomib (at the MTD) as in either
group I or group II of the phase I portion of the study. Selection of the treatment
schedule is based upon observed toxicity, safety, tolerability, efficacy, and clinical
Blood is drawn at baseline and prior to courses 2 and 3 for correlative and molecular
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
After completion of study treatment, patients in phase I are followed for 30 days and
patients in phase II are followed periodically.
PROJECTED ACCRUAL: A total of 86 patients will be accrued for this study.
Masking: Open Label, Primary Purpose: Treatment
Response rate (Phase II)
Angela Davies, MD
University of California, Davis
United States: Federal Government
|University of California Davis Cancer Center||Sacramento, California 95817|