Bortezomib and Topotecan in Treating Patients With Advanced Solid Tumors

Phase 1

Completed

• Conditions: Lung Cancer; Unspecified Adult Solid Tumor, Protocol Specific

• Registration Number: NCT00388089
• Lead Sponsor: University of California, Davis

Brief Summary

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.

Detailed Description

OBJECTIVES:

Primary

* Evaluate the safety and feasibility of bortezomib and topotecan hydrochloride in patients with advanced solid tumors.

Secondary

* 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 Timeline

• Study Start: 2004-12
• Study First Submitted: 2006-10-12
• Study First Submitted QC: 2006-10-12
• Study First Posted: 2006-10-13
• Primary Completion: 2007-11
• Status Verified: 2007-12
• Study Completion: 2008-06
• Last Update Submitted: 2010-06-25
• Last Update Posted: 2010-06-29

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 24

Inclusion Criteria

Not provided

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Exclusion Criteria

Not provided

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Study & Design

• Study Type: INTERVENTIONAL
• Study Design: SINGLE_GROUP

Primary Outcome Measures

Name	Time	Method
Safety	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.

Secondary Outcome Measures

Name	Time	Method
Toxicity	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	At baseline and every 2 courses during treatment	As assessed by RECIST criteria
Best response	From start of treatment until disease progression/recurrence	Best response is determined from the sequence of objective status.
Survival	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	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	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	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	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)	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.
Shed tumor DNA in plasma	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.
Biological activity of bortezomib as measured by flow cytometry	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.

Trial Locations

Locations (1)

University of California Davis Cancer Center; 🇺🇸 Sacramento, California, United States