Bortezomib and Topotecan in Treating Patients With Advanced Solid Tumors

NCT ID: NCT00388089

Last Updated: 2010-06-29

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE1
• Total Enrollment: 24 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2004-12-31
• Study Completion Date: 2008-06-30

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.

Conditions

Lung Cancer; Unspecified Adult Solid Tumor, Protocol Specific

Study Design

• Allocation Method: NA
• Intervention Model: SINGLE_GROUP
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Interventions

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/m2

Intervention Type: 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/m2

Intervention Type: DRUG

flow cytometry

No description

Intervention Type: OTHER

immunoenzyme technique

No description

Intervention Type: OTHER

immunohistochemistry staining method

No description

Intervention Type: OTHER

laboratory biomarker analysis

No description

Intervention Type: OTHER

Other Intervention Names

PS-341, Velcade; Hycamtin

Eligibility Criteria

Inclusion Criteria

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

PRIOR CONCURRENT THERAPY:

• See Disease Characteristics
• Any number of prior chemotherapy regimens allowed
• At least 4 weeks since prior chemotherapy and recovered
• At least 2 weeks since prior radiotherapy and recovered
• No prior topotecan hydrochloride or bevacizumab
• At least 14 days since prior investigational drugs
• No concurrent anticonvulsants metabolized by the cytochrome P450 pathway

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

National Cancer Institute (NCI)

NIH

Sponsor Role: collaborator

University of California, Davis

OTHER

Sponsor Role: lead

Responsible Party

University of California, Davis

Principal Investigators

Angela Davies, MD

Role: STUDY_CHAIR

University of California, Davis

Locations

University of California Davis Cancer Center

Sacramento, California, United States

Countries

United States

Other Identifiers

P30CA093373

Identifier Type: NIH

Identifier Source: secondary_id

View Link

UCDCC-157

Identifier Type: OTHER

Identifier Source: secondary_id

200412738

Identifier Type: OTHER

Identifier Source: secondary_id

GSK-8531

Identifier Type: OTHER_GRANT

Identifier Source: secondary_id

MILLENNIUM-X05131

Identifier Type: OTHER_GRANT

Identifier Source: secondary_id

CDR0000505990

Identifier Type: -

Identifier Source: org_study_id