Bortezomib and Topotecan in Treating Patients With Advanced Solid Tumors

Sponsor

University of California, Davis (Other)

Overall Status

Completed

CT.gov ID

NCT00388089

Collaborator

National Cancer Institute (NCI) (NIH)

Enrollment

Location

Duration (Months)

0.6

Patients Per Site Per Month

Study Details

Study Description

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.

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

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 Design

Study Type:

Interventional

Actual Enrollment :

24 participants

Allocation:

N/A

Intervention Model:

Single Group Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

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 :

Dec 1, 2004

Actual Primary Completion Date :

Nov 1, 2007

Actual Study Completion Date :

Jun 1, 2008

Outcome Measures

Primary Outcome Measures

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

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.

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

DISEASE CHARACTERISTICS:

Histologically or cytologically confirmed advanced solid tumor, meeting 1 of the following criteria:
Disease progressed after ≥ 1 prior standard therapy regimen
Treatment-naive with no standard therapy of curative intent available
Not a candidate for standard therapy due to poor performance status
Patients with small cell lung cancer are enrolled after the maximum tolerated dose has been determined
Must have tumor accessible for biopsy
Measurable disease by RECIST criteria or evaluable disease (e.g., pleural effusion, ascites, or bone metastasis)
Disease in previously irradiated sites is considered measurable provided there is clear disease progression after radiotherapy
Asymptomatic brain metastasis treated by prior surgical resection or radiotherapy allowed if both of the following criteria are met:
Neurologically stable
Off steroids and anticonvulsants for ≥ 4 weeks

PATIENT CHARACTERISTICS:

Karnofsky performance status 60-100%
Life expectancy ≥ 3 months
Absolute neutrophil count ≥ 1,500/mm³
Platelet count ≥ 100,000/mm³
Creatinine clearance ≥ 40 mL/min
Bilirubin ≤ 1.5 times upper limit of normal (ULN)
AST and ALT ≤ 3.0 times ULN
Not pregnant or nursing
Negative pregnancy test
Fertile patients must use effective contraception
No preexisting neuropathy ≥ grade 2 within the past 14 days
No hypersensitivity to bortezomib, boron, or mannitol
No myocardial infarction within the past 6 months
No New York Heart Association class III or IV heart failure
No uncontrolled angina, severe uncontrolled ventricular arrhythmias, or ECG evidence of acute ischemia or active conduction system abnormalities