Clinical trial NCT00388089: 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
Overall status: COMPLETED
Phase: PHASE1
Conditions: 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
Lead sponsor: University of California, Davis
Sponsor class: OTHER
Collaborators: name: National Cancer Institute (NCI)
First posted: 2006-10-13
Enrollment: 24
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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.

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

Primary outcomes:
measure: Safety
timeFrame: Monitored on an ongoing basis during the study
Secondary outcomes:
measure: Toxicity
timeFrame: On Day 8 and at beginning of subsequent cycles
measure: Response rate
timeFrame: At baseline and every 2 courses during treatment
measure: Best response
timeFrame: From start of treatment until disease progression/recurrence
measure: Survival
timeFrame: From registration to time of death due to any cause
measure: Progression-free survival
timeFrame: From registration to the first observation of disease progression or death due to any cause
measure: Topoisomerase levels as assessed by western blot and tumor tissue biopsy
timeFrame: From pre-treatment to post-treatment
measure: NF-kB and BCL-2 family activity as assessed by immunohistochemistry
timeFrame: From pre-treatment to post-treatment
measure: Loss of p27 as assessed by immunohistochemistry
timeFrame: From pre-treatment to post-treatment
measure: Hypoxia-induced plasma proteins as measured by enzyme-linked immunosorbent assay (ELISA)
timeFrame: From pre-treatment to post-treatment
measure: Shed tumor DNA in plasma
timeFrame: From pre-treatment to post-treatment
measure: Biological activity of bortezomib as measured by flow cytometry
timeFrame: From pre-treatment to post-treatment
Other outcomes:
Locations:
city: Sacramento
country: United States
facility: University of California Davis Cancer Center
state: California
Study officials:
affiliation: University of California, Davis
name: Angela Davies, MD
role: STUDY_CHAIR
References: