Bortezomib and Topotecan in Treating Patients With Advanced Solid Tumors
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|ClinicalTrials.gov Identifier: NCT00388089|
Recruitment Status : Completed
First Posted : October 13, 2006
Last Update Posted : June 29, 2010
RATIONALE: Bortezomib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Drugs used in chemotherapy, such as topotecan, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Giving bortezomib together with topotecan may kill more tumor cells.
PURPOSE: This phase I trial is studying the side effects and best dose of bortezomib and topotecan in treating patients with advanced solid tumors.
|Condition or disease||Intervention/treatment||Phase|
|Lung Cancer Unspecified Adult Solid Tumor, Protocol Specific||Drug: bortezomib Drug: topotecan hydrochloride Other: flow cytometry Other: immunoenzyme technique Other: immunohistochemistry staining method Other: laboratory biomarker analysis||Phase 1|
- 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 these patients.
- 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 toxicity.
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.
|Study Type :||Interventional (Clinical Trial)|
|Actual Enrollment :||24 participants|
|Intervention Model:||Single Group Assignment|
|Masking:||None (Open Label)|
|Official Title:||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)|
|Study Start Date :||December 2004|
|Actual Primary Completion Date :||November 2007|
|Actual Study Completion Date :||June 2008|
- Drug: bortezomib
Dose level A: 1 mg/m2; Dose level B: 1.3 mg/m2; Dose level C: 1.6 mg/m2; Dose level D: 1.6 mg/m2Other Name: PS-341, Velcade
- Drug: topotecan hydrochloride
Dose level A: 3 mg/m2; Dose level B: 3 mg/m2; Dose level C: 3 mg/m2; Dose level D: 4 mg/m2Other Name: Hycamtin
- Other: flow cytometry
- Other: immunoenzyme technique
- Other: immunohistochemistry staining method
- Other: laboratory biomarker analysis
- Safety [ Time Frame: Monitored on an ongoing basis during the study ]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.
- Toxicity [ Time Frame: On Day 8 and at beginning of subsequent cycles ]Toxicity will be evaluated based on the standard NCI CTC grading criteria version 3.0.
- Response rate [ Time Frame: At baseline and every 2 courses during treatment ]As assessed by RECIST criteria
- Best response [ Time Frame: From start of treatment until disease progression/recurrence ]Best response is determined from the sequence of objective status.
- Survival [ Time Frame: From registration to time of death due to any cause ]Patients will be followed for 30 days after removal from study treatment or until all treatment-related toxicities resolve to < grade 1.
- Progression-free survival [ Time Frame: From registration to the first observation of disease progression or death due to any cause ]If a patient has not progressed or died, progression-free survival is censored at the time of last follow-up.
- Topoisomerase levels as assessed by western blot and tumor tissue biopsy [ Time Frame: From pre-treatment to post-treatment ]The aim of these molecular correlates is to examine the relationship between these studies and the clinical response to treatment.
- NF-kB and BCL-2 family activity as assessed by immunohistochemistry [ Time Frame: From pre-treatment to post-treatment ]The aim of these molecular correlates is to examine the relationship between these studies and the clinical response to treatment.
- Loss of p27 as assessed by immunohistochemistry [ Time Frame: From pre-treatment to post-treatment ]The aim of these molecular correlates is to examine the relationship between these studies and the clinical response to treatment.
- Hypoxia-induced plasma proteins as measured by enzyme-linked immunosorbent assay (ELISA) [ Time Frame: From pre-treatment to post-treatment ]
- Shed tumor DNA in plasma [ Time Frame: From pre-treatment to post-treatment ]
- Biological activity of bortezomib as measured by flow cytometry [ Time Frame: From pre-treatment to post-treatment ]
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT00388089
|United States, California|
|University of California Davis Cancer Center|
|Sacramento, California, United States, 95817|
|Study Chair:||Angela Davies, MD||University of California, Davis|