A Phase I Study Of PS-341 In Combination With Gemcitabine And Carbloplatin In Selected Stage IIIB Or IV 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
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.
Inclusion Criteria:
Histologically or cytologically confirmed non-small cell lung cancer
Patients who received prior platinum-based chemotherapy must have no disease progression during or within 3 months after completion of therapy
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