Bortezomib and Topotecan in Treating Patients With Advanced Solid Tumors

• ClinicalTrials.gov Identifier: NCT00388089
• Recruitment Status: Completed
• First Posted: October 13, 2006
• Last Update Posted: June 29, 2010
• Sponsor: University of California, Davis
• Collaborator: National Cancer Institute (NCI)
• Information provided by: University of California, Davis

Tracking Information

• First Submitted Date: October 12, 2006
• First Posted Date: October 13, 2006
• Last Update Posted Date: June 29, 2010
• Study Start Date: December 2004
• Actual Primary Completion Date: November 2007 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: June 25, 2010)

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.

• Original Primary Outcome Measures: Not Provided

Current Secondary Outcome Measures (submitted: June 25, 2010)

• 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 ]
  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 [ 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.
• Biological activity of bortezomib as measured by flow cytometry [ 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.

• Original Secondary Outcome Measures: Not Provided
• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Bortezomib and Topotecan in Treating Patients With Advanced Solid Tumors
• 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)

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 Type: Interventional
• Study Phase: Phase 1
• Study Design: Allocation: N/A; Intervention Model: Single Group Assignment; Masking: None (Open Label); Primary Purpose: Treatment

Condition

• Lung Cancer
• Unspecified Adult Solid Tumor, Protocol Specific

Intervention

• 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/m2
  Other 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/m2
  Other Name: Hycamtin
• Other: flow cytometry
  No description
• Other: immunoenzyme technique
  No description
• Other: immunohistochemistry staining method
  No description
• Other: laboratory biomarker analysis
  No description

• Study Arms: Not Provided
• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: June 25, 2010): 24
• Original Enrollment: Not Provided
• Actual Study Completion Date: June 2008
• Actual Primary Completion Date: November 2007 (Final data collection date for primary outcome measure)

Eligibility 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

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: United States

Administrative Information

• NCT Number: NCT00388089
• Other Study ID Numbers: CDR0000505990; P30CA093373 ( U.S. NIH Grant/Contract ); UCDCC-157 ( Other Identifier: University of California, Davis - Cancer Center ); 200412738 ( Other Identifier: University of California, Davis - IRB ); GSK-8531 ( Other Grant/Funding Number: GlaxoSmithKline ); MILLENNIUM-X05131 ( Other Grant/Funding Number: Millennium Pharmaceuticals )
• Has Data Monitoring Committee: Yes
• U.S. FDA-regulated Product: Not Provided
• IPD Sharing Statement: Not Provided
• Responsible Party: Angela Davies, MD, University of California, Davis
• Study Sponsor: University of California, Davis
• Collaborators: National Cancer Institute (NCI)

Investigators

• Study Chair: Angela Davies, MD; University of California, Davis

• PRS Account: University of California, Davis
• Verification Date: December 2007