Bortezomib Plus Gemcitabine and Carboplatin in Treating Patients With Advanced or Recurrent Non-Small Cell Lung Cancer

Study Overview
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Brief Summary
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Bortezomib may stop the growth of cancer cells by blocking the enzymes necessary for cancer cell growth. Drugs used in chemotherapy use different ways to stop tumor cells from dividing so they stop growing or die. Combining more than one chemotherapy drug and bortezomib may kill more tumor cells

Detailed Description
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PRIMARY OBJECTIVES: I. Determine the safety and feasibility of combining bortezomib with gemcitabine and carboplatin in patients with advanced or recurrent non-small cell lung cancer. II. Determine the maximum tolerated dose of bortezomib administered in combination with gemcitabine and carboplatin in these patients. III. Correlate results from laboratory studies on patient tissue and serum specimens with potential predictors of response in patients treated with this regimen. IV. Determine, preliminarily, the response of patients treated with this regimen. OUTLINE: This is a multicenter, dose-escalation study of bortezomib. Patients receive gemcitabine IV over 30 minutes on days 1 and 8, carboplatin IV over 15-30 minutes on day 1, followed 1 hour later by bortezomib IV over 3-5 seconds on days 1, 4, 8, and 11. Treatment repeats every 21 days for up to 6 courses in the absence of disease progression or unacceptable toxicity. Patients with a clinical or radiographic response may continue receiving bortezomib beyond 6 courses. Cohorts of 3-6 patients receive escalating doses of bortezomib until the maximum tolerated dose (MTD) is determined. The MTD is defined as the dose preceding that at which 2 of 3 or 2 of 6 patients experience dose-limiting toxicity. Once the MTD is determined, at least 10 additional patients with chemotherapy-naive disease receive treatment as above with the MTD of bortezomib. Patients are followed for survival.

Official Title
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A Phase I Study Of PS-341 In Combination With Gemcitabine And Carbloplatin In Selected Stage IIIB Or IV Non-Small Cell Lung Cancer

Conditions
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Malignant Pleural Effusion, Recurrent Non-small Cell Lung Cancer, Stage IIIB Non-small Cell Lung Cancer, Stage IV Non-small Cell Lung Cancer

Intervention / Treatment
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* Drug: gemcitabine hydrochloride
* Drug: carboplatin
* Drug: bortezomib
* Other: laboratory biomarker analysis


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histologically or cytologically confirmed non-small cell lung cancer Selected stage IIIB (malignant pleural effusion) or stage IV disease Recurrent disease after first-line therapy allowed Patients who received prior platinum-based chemotherapy must have no disease progression during or within 3 months after completion of therapy Patients who are enrolled at the maximum tolerated dose must have chemotherapy-naïve disease Evaluable disease Asymptomatic brain metastases allowed if treated with surgical resection or radiotherapy, neurologically stable, and off steroids for at least 4 weeks Performance status - Karnofsky 60-100% More than 3 months Absolute neutrophil count at least 1,500/mm^3 Platelet count at least 100,000/mm^3 Bilirubin no greater than 1.5 mg/dL AST no greater than 2.5 times upper limit of normal Creatinine normal Creatinine clearance at least 50 mL/min No symptomatic congestive heart failure No unstable angina pectoris No cardiac arrhythmia Not pregnant or nursing Negative pregnancy test Fertile patients must use effective contraception No peripheral neuropathy grade 2 or greater No prior allergic reactions to compounds of similar chemical or biological composition to bortezomib or other agents used in this study No concurrent ongoing or active infection No other concurrent uncontrolled illness No psychiatric illness or social situation that would preclude study compliance No concurrent routine filgrastim (G-CSF) See Disease Characteristics No more than 1 prior chemotherapy regimen At least 4 weeks since prior chemotherapy (6 weeks for mitomycin or nitrosoureas) and recovered No prior gemcitabine See Disease Characteristics See Disease Characteristics At least 4 weeks since prior radiotherapy and recovered See Disease Characteristics More than 30 days since prior investigational drugs No prior bortezomib No concurrent anticonvulsant therapy No concurrent combination antiretroviral therapy for HIV-positive patients No other concurrent investigational or commercial agents or therapies with intent to treat malignancy

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment (gemcitabine hydrochloride, carboplatin, bortezomib)<br>Patients receive gemcitabine IV over 30 minutes on days 1 and 8, carboplatin IV over 15-30 minutes on day 1, followed 1 hour later by bortezomib IV over 3-5 seconds on days 1, 4, 8, and 11. Treatment repeats every 21 days for up to 6 courses in the absence of disease progression or unacceptable toxicity. Patients with a clinical or radiographic response may continue receiving bortezomib beyond 6 courses. | Drug: gemcitabine hydrochloride<br>* Given IV<br>* Other names: Gemzar;Drug: carboplatin<br>* Given IV<br>* Other names: Paraplatin;Drug: bortezomib<br>* Given IV<br>* Other names: VELCADE;Other: laboratory biomarker analysis<br>* Correlative studies<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Toxicities at each dose level, graded using the CTC version 2.0 | Summarized in terms of type (organ affected or laboratory determination such as absolute neutrophil count), severity, (by NCI Common Toxicity Criteria and nadir or maximum values for the laboratory measures, time of onset (i.e. course number), duration, and reversibility or outcome. Tables will be created to summarize these toxicities and side effects by dose and course. | 18 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Response rate, assessed by standard RECIST criteria | Summarized by exact binomial confidence intervals. | Up to 2 years | 
| Survival | Summarized with Kaplan-Meier plots. | From registration to time of death due to any cause, assessed up to 2 years | 
| Time to failure | Summarized with Kaplan-Meier plots. | Up to 2 years |