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

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

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

Study Overview

• Status: Completed
• Conditions: Stage IIIB Non-small Cell Lung Cancer; Recurrent Non-small Cell Lung Cancer; Stage IV Non-small Cell Lung Cancer; Malignant Pleural Effusion
• Intervention / Treatment: Other: laboratory biomarker analysis; Drug: gemcitabine hydrochloride; Drug: carboplatin; Drug: bortezomib

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Actual): 34
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • California
    • Duarte, California, United States, 91010
      • City of Hope

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: Treatment (gemcitabine hydrochloride, carboplatin, 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.

Other: laboratory biomarker analysis; Correlative studies; Drug: gemcitabine hydrochloride; Given IV; Other Names: Gemzar; gemcitabine; dFdC; difluorodeoxycytidine hydrochloride; Drug: carboplatin; Given IV; Other Names: Carboplat; CBDCA; JM-8; Paraplatin; Paraplat; Drug: bortezomib; Given IV; Other Names: MLN341; LDP 341; VELCADE

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: National Cancer Institute (NCI)
• Investigators: Principal Investigator: Angela Davies, City of Hope Medical Center

Study record dates

Study Major Dates

• Study Start: September 1, 2002
• Primary Completion (Actual): May 1, 2004

Study Registration Dates

• First Submitted: January 24, 2003
• First Submitted That Met QC Criteria: January 26, 2003
• First Posted (Estimate): January 27, 2003

Study Record Updates

• Last Update Posted (Estimate): January 23, 2013
• Last Update Submitted That Met QC Criteria: January 22, 2013
• Last Verified: January 1, 2013

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Respiratory Tract Diseases; Neoplasms; Lung Diseases; Neoplasms by Site; Pleural Diseases; Respiratory Tract Neoplasms; Thoracic Neoplasms; Carcinoma, Bronchogenic; Bronchial Neoplasms; Pleural Neoplasms; Lung Neoplasms; Carcinoma, Non-Small-Cell Lung; Pleural Effusion, Malignant; Pleural Effusion; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Antiviral Agents; Enzyme Inhibitors; Antimetabolites, Antineoplastic; Antimetabolites; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Gemcitabine; Carboplatin; Bortezomib
• Other Study ID Numbers: NCI-2012-02503; N01CM17101 (U.S. NIH Grant/Contract); PHI-40; CDR0000258189 (Registry Identifier: PDQ (Physician Data Query))