Phase I Study of Weekly Bortezomib (VELCADE, PS-341) and Weekly Topotecan (HYCAMTIN) in Solid Tumor Patients With an Emphasis on Small Cell Lung Cancer (SCLC)
- Evaluate the safety and feasibility of bortezomib and topotecan hydrochloride in
patients with advanced solid tumors.
- Determine the maximum tolerated dose (MTD) of bortezomib and topotecan hydrochloride in
- Determine, preliminarily, the efficacy of this regimen in these patients.
- Perform laboratory correlative studies on tumor tissue and blood samples from these
patients to investigate potential predictors of response.
- Obtain fresh tumor tissue for correlative studies from a subset of patients with small
cell lung cancer treated at the MTD.
OUTLINE: This is a dose-escalation study.
Patients receive topotecan hydrochloride IV over 30 minutes followed by bortezomib IV on
days 1, 8, and 15. Treatment repeats every 28 days for up to 6 courses in the absence of
disease progression or unacceptable toxicity. Patients with stable or responding disease may
continue to receive bortezomib alone in the absence of disease progression or unacceptable
Cohorts of 3-6 patients receive escalating doses of topotecan hydrochloride and bortezomib
until the maximum tolerated dose (MTD) is determined. The MTD is defined as the dose
preceding that at which 2 of 6 patients experience dose-limiting toxicity.
Ten additional patients with small cell lung cancer are treated at the MTD. These patients
undergo tumor biopsy at baseline and before the second course of therapy.
Tumor tissue is collected at baseline in all patients. Blood samples are collected at
baseline, at the beginning of courses 2 and 3, and after completion of study treatment.
Samples are examined for topoisomerase-1 levels by western blotting; BCL-2, BCL-xL, BAX, and
p27 by immunohistochemistry; hypoxia-inducible factor-1, plasminogen-activator inhibitor 1,
vascular endothelial growth factor, and osteopontin by immunoenzyme techniques; and NF-kB
and p27 nuclear expression by flow cytometry.
After completion of study treatment, patients are followed for 30 days.
PROJECTED ACCRUAL: A total of 34 patients will be accrued for this study.
Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment
If cumulative toxicities are seen in subsequent treatment cycles, a decision regarding modification or discontinuation of the study drug and/or patient enrollment will be made by the sponsor in conjunction with the investigator.
Monitored on an ongoing basis during the study
Angela Davies, MD
University of California, Davis
United States: Federal Government
|University of California Davis Cancer Center||Sacramento, California 95817|