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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)

Phase 1
18 Years
Not Enrolling
Lung Cancer, Unspecified Adult Solid Tumor, Protocol Specific

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Trial Information

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)



- Evaluate the safety and feasibility of bortezomib and topotecan hydrochloride in
patients with advanced solid tumors.


- 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

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.

Inclusion Criteria


- 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


- 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


- 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

Type of Study:


Study Design:

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

Outcome Measure:


Outcome 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.

Outcome Time Frame:

Monitored on an ongoing basis during the study

Safety Issue:


Principal Investigator

Angela Davies, MD

Investigator Role:

Study Chair

Investigator Affiliation:

University of California, Davis


United States: Federal Government

Study ID:




Start Date:

December 2004

Completion Date:

June 2008

Related Keywords:

  • Lung Cancer
  • Unspecified Adult Solid Tumor, Protocol Specific
  • unspecified adult solid tumor, protocol specific
  • extensive stage small cell lung cancer
  • recurrent small cell lung cancer
  • Lung Neoplasms
  • Small Cell Lung Carcinoma
  • Neoplasms



University of California Davis Cancer Center Sacramento, California  95817