Bortezomib and Topotecan in Treating Patients With Advanced Solid Tumors

Study Overview
=================
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.

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)

Conditions
-----------------
Lung Cancer, Unspecified Adult Solid Tumor, Protocol Specific

Intervention / Treatment
-----------------
* Drug: bortezomib
* Drug: topotecan hydrochloride
* Other: flow cytometry
* Other: immunoenzyme technique
* Other: immunohistochemistry staining method
* Other: laboratory biomarker analysis


Participation Criteria
=================
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

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Intervention/Treatment |
| --- |
|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|
|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: flow cytometry|No description|
|Other: immunoenzyme technique|No description|
|Other: immunohistochemistry staining method|No description|
|Other: laboratory biomarker analysis|No description|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 | 
| Response rate | As assessed by RECIST criteria | At baseline and every 2 courses during treatment | 
| Best response | Best response is determined from the sequence of objective status. | From start of treatment until disease progression/recurrence | 
| 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 | 
| 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 | 
| 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 | 
| 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 | 
| 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 | 
| 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 | 
| 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 | 
| 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 | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
unspecified adult solid tumor, protocol specific, extensive stage small cell lung cancer, recurrent small cell lung cancer