Bortezomib and Topotecan in Treating Patients With Advanced Solid Tumors

Lung Cancer Clinical Trial

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)

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00388089
• Other study ID #: CDR0000505990
• Secondary ID: P30CA093373UCDCC
• Status: Completed
• Phase: Phase 1
• First received: October 12, 2006
• Last updated: June 25, 2010
• Start date: December 2004
• Est. completion date: June 2008

Study information

• Verified date: December 2007
• Source: University of California, Davis
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Federal Government
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 24
• Est. completion date: June 2008
• Est. primary completion date: November 2007
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years and older

Eligibility

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

Study Design

Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Related Conditions & MeSH terms

• Lung Cancer
• Lung Neoplasms
• Small Cell Lung Carcinoma
• 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
• 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:
• flow cytometry
No description
• immunoenzyme technique
No description
• immunohistochemistry staining method
No description
• laboratory biomarker analysis
No description

Locations

Country	Name	City	State
United States	University of California Davis Cancer Center	Sacramento	California

Sponsors (2)

Lead Sponsor	Collaborator
University of California, Davis	National Cancer Institute (NCI)

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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.	Monitored on an ongoing basis during the study	Yes
Secondary	Toxicity	Toxicity will be evaluated based on the standard NCI CTC grading criteria version 3.0.	On Day 8 and at beginning of subsequent cycles	Yes
Secondary	Response rate	As assessed by RECIST criteria	At baseline and every 2 courses during treatment	No
Secondary	Best response	Best response is determined from the sequence of objective status.	From start of treatment until disease progression/recurrence	No
Secondary	Survival	Patients will be followed for 30 days after removal from study treatment or until all treatment-related toxicities resolve to < grade 1.	From registration to time of death due to any cause	No
Secondary	Progression-free survival	If a patient has not progressed or died, progression-free survival is censored at the time of last follow-up.	From registration to the first observation of disease progression or death due to any cause	No
Secondary	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.	From pre-treatment to post-treatment	No
Secondary	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.	From pre-treatment to post-treatment	No
Secondary	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.	From pre-treatment to post-treatment	No
Secondary	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.	From pre-treatment to post-treatment	No
Secondary	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.	From pre-treatment to post-treatment	No
Secondary	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.	From pre-treatment to post-treatment	No