Bortezomib and Topotecan in Treating Patients With Advanced Solid Tumors

This study has been completed.
Sponsor:
Collaborator:
Information provided by:
University of California, Davis
ClinicalTrials.gov Identifier:
NCT00388089
First received: October 12, 2006
Last updated: June 25, 2010
Last verified: December 2007
  Purpose

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 Intervention 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

Study Type: Interventional
Study Design: Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: 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)

Resource links provided by NLM:


Further study details as provided by University of California, Davis:

Primary Outcome Measures:
  • Safety [ Time Frame: Monitored on an ongoing basis during the study ] [ Designated as safety issue: Yes ]
    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 [ Time Frame: On Day 8 and at beginning of subsequent cycles ] [ Designated as safety issue: Yes ]
    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 ] [ Designated as safety issue: No ]
    As assessed by RECIST criteria

  • Best response [ Time Frame: From start of treatment until disease progression/recurrence ] [ Designated as safety issue: No ]
    Best response is determined from the sequence of objective status.

  • Survival [ Time Frame: From registration to time of death due to any cause ] [ Designated as safety issue: No ]
    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 ] [ Designated as safety issue: No ]
    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 ] [ Designated as safety issue: No ]
    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 ] [ Designated as safety issue: No ]
    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 ] [ Designated as safety issue: No ]
    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 ] [ Designated as safety issue: No ]
    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 ] [ Designated as safety issue: No ]
    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 ] [ Designated as safety issue: No ]
    The aim of these molecular correlates is to examine the relationship between these studies and the clinical response to treatment.


Enrollment: 24
Study Start Date: December 2004
Study Completion Date: June 2008
Primary Completion Date: November 2007 (Final data collection date for primary outcome measure)
Intervention Details:
    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
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.

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
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
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00388089

Locations
United States, California
University of California Davis Cancer Center
Sacramento, California, United States, 95817
Sponsors and Collaborators
University of California, Davis
Investigators
Study Chair: Angela Davies, MD University of California, Davis
  More Information

Additional Information:
No publications provided

Responsible Party: Angela Davies, MD, University of California, Davis
ClinicalTrials.gov Identifier: NCT00388089     History of Changes
Other Study ID Numbers: CDR0000505990, P30CA093373, UCDCC-157, 200412738, GSK-8531, MILLENNIUM-X05131
Study First Received: October 12, 2006
Last Updated: June 25, 2010
Health Authority: United States: Federal Government

Keywords provided by University of California, Davis:
unspecified adult solid tumor, protocol specific
extensive stage small cell lung cancer
recurrent small cell lung cancer

Additional relevant MeSH terms:
Lung Neoplasms
Small Cell Lung Carcinoma
Neoplasms
Respiratory Tract Neoplasms
Thoracic Neoplasms
Neoplasms by Site
Lung Diseases
Respiratory Tract Diseases
Carcinoma, Bronchogenic
Bronchial Neoplasms
Topotecan
Bortezomib
Topoisomerase I Inhibitors
Topoisomerase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Pharmacologic Actions
Antineoplastic Agents
Therapeutic Uses

ClinicalTrials.gov processed this record on July 31, 2014