Back to resultsBortezomib and Topotecan in Treating Patients With Advanced Solid Tumors
Primary Purpose
Lung Cancer, Unspecified Adult Solid Tumor, Protocol Specific
Status
Completed
Phase
Phase 1
Locations
United States
Study Type
Interventional
Intervention
bortezomib
topotecan hydrochloride
flow cytometry
immunoenzyme technique
immunohistochemistry staining method
laboratory biomarker analysis
Sponsored by
About this trial
This is an interventional treatment trial for Lung Cancer focused on measuring unspecified adult solid tumor, protocol specific, extensive stage small cell lung cancer, recurrent small cell lung cancer
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
Sites / Locations
- University of California Davis Cancer Center
Outcomes
Primary Outcome Measures
Safety
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
Toxicity will be evaluated based on the standard NCI CTC grading criteria version 3.0.
Response rate
As assessed by RECIST criteria
Best response
Best response is determined from the sequence of objective status.
Survival
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
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
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
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
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)
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
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
The aim of these molecular correlates is to examine the relationship between these studies and the clinical response to treatment.
Full Information
NCT ID
NCT00388089
First Posted
October 12, 2006
Last Updated
June 25, 2010
Sponsor
University of California, Davis
Collaborators
National Cancer Institute (NCI)
1. Study Identification
Unique Protocol Identification Number
NCT00388089
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)
Study Type
Interventional
2. Study Status
Record Verification Date
December 2007
Overall Recruitment Status
Completed
Study Start Date
December 2004 (undefined)
Primary Completion Date
November 2007 (Actual)
Study Completion Date
June 2008 (Actual)
3. Sponsor/Collaborators
Name of the Sponsor
University of California, Davis
Collaborators
National Cancer Institute (NCI)
4. Oversight
Data Monitoring Committee
Yes
5. 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.
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.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Lung Cancer, Unspecified Adult Solid Tumor, Protocol Specific
Keywords
unspecified adult solid tumor, protocol specific, extensive stage small cell lung cancer, recurrent small cell lung cancer
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 1
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
24 (Actual)
8. Arms, Groups, and Interventions
Intervention Type
Drug
Intervention Name(s)
bortezomib
Other Intervention Name(s)
PS-341, Velcade
Intervention Description
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
Intervention Name(s)
topotecan hydrochloride
Other Intervention Name(s)
Hycamtin
Intervention Description
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
Other
Intervention Name(s)
flow cytometry
Intervention Description
No description
Intervention Type
Other
Intervention Name(s)
immunoenzyme technique
Intervention Description
No description
Intervention Type
Other
Intervention Name(s)
immunohistochemistry staining method
Intervention Description
No description
Intervention Type
Other
Intervention Name(s)
laboratory biomarker analysis
Intervention Description
No description
Primary Outcome Measure Information:
Title
Safety
Description
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.
Time Frame
Monitored on an ongoing basis during the study
Secondary Outcome Measure Information:
Title
Toxicity
Description
Toxicity will be evaluated based on the standard NCI CTC grading criteria version 3.0.
Time Frame
On Day 8 and at beginning of subsequent cycles
Title
Response rate
Description
As assessed by RECIST criteria
Time Frame
At baseline and every 2 courses during treatment
Title
Best response
Description
Best response is determined from the sequence of objective status.
Time Frame
From start of treatment until disease progression/recurrence
Title
Survival
Description
Patients will be followed for 30 days after removal from study treatment or until all treatment-related toxicities resolve to < grade 1.
Time Frame
From registration to time of death due to any cause
Title
Progression-free survival
Description
If a patient has not progressed or died, progression-free survival is censored at the time of last follow-up.
Time Frame
From registration to the first observation of disease progression or death due to any cause
Title
Topoisomerase levels as assessed by western blot and tumor tissue biopsy
Description
The aim of these molecular correlates is to examine the relationship between these studies and the clinical response to treatment.
Time Frame
From pre-treatment to post-treatment
Title
NF-kB and BCL-2 family activity as assessed by immunohistochemistry
Description
The aim of these molecular correlates is to examine the relationship between these studies and the clinical response to treatment.
Time Frame
From pre-treatment to post-treatment
Title
Loss of p27 as assessed by immunohistochemistry
Description
The aim of these molecular correlates is to examine the relationship between these studies and the clinical response to treatment.
Time Frame
From pre-treatment to post-treatment
Title
Hypoxia-induced plasma proteins as measured by enzyme-linked immunosorbent assay (ELISA)
Description
The aim of these molecular correlates is to examine the relationship between these studies and the clinical response to treatment.
Time Frame
From pre-treatment to post-treatment
Title
Shed tumor DNA in plasma
Description
The aim of these molecular correlates is to examine the relationship between these studies and the clinical response to treatment.
Time Frame
From pre-treatment to post-treatment
Title
Biological activity of bortezomib as measured by flow cytometry
Description
The aim of these molecular correlates is to examine the relationship between these studies and the clinical response to treatment.
Time Frame
From pre-treatment to post-treatment
10. Eligibility
Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
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
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Angela Davies, MD
Organizational Affiliation
University of California, Davis
Official's Role
Study Chair
Facility Information:
Facility Name
University of California Davis Cancer Center
City
Sacramento
State/Province
California
ZIP/Postal Code
95817
Country
United States
12. IPD Sharing Statement
Learn more about this trial
Bortezomib and Topotecan in Treating Patients With Advanced Solid Tumors
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