The proteasome inhibitor, bortezomib, in combination with gemcitabine (Gem) and carboplatin (Carbo) in advanced non-small cell lung cancer (NSCLC): Final results of a phase I California Cancer Consortium study

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Abstract
7106 Background: Bortezomib (Velcade, PS-341), a dipeptidyl boronic acid, is a selective and reversible inhibitor of the 26S proteasome of the ubiquitin protein degradation pathway. Gem/Carbo is an accepted first-line treatment for advanced NSCLC. This NCI-sponsored phase I trial examined the safety and tolerability of bortezomib days 1, 4, 8, & 11; Gem days 1 & 8 and Carbo day 1 on a 21-day cycle. Methods: Three dose levels were tested with the following ranges: bortezomib 1.0 –1.3 mg/m2, Gem 800 –1000 mg/m2, Carbo AUC 5.0. Dose limiting toxicity (DLT) was defined as: grade (GR) 4 platelets (plts) (< 10K), GR3 plts (≤ 50K) with bleeding, febrile neutropenia, GR4 ANC ≥ 7 days, or any ≥ GR3 non-heme toxicity except alopecia or inadequately treated nausea, emesis, or diarrhea. Results: 16 (10 chemonaive) NSCLC patients (pts) were treated. Pt characteristics: Median age: 54; Sex M/F = 8/8; KPS ≤80/>80 = 6/10; stage IIIB/IV = 1/15. One DLT was seen at dose level 2: GR3 plts (26K) with minor hemoptysis. Two DLTs were seen at dose level 3: GR3 plts (27K) with genitourinary bleed and GR4 plts (9K) with no bleeding. Most common GR3/4 toxicities were: GR3 plts in 23/49 cycles, GR4 plts in 3/49 cycles and GR3/4 granulocytopenia in 12/49 cycles. Treatment was generally well tolerated with myelosuppression primarly being asymptomatic. In 10 evaluable pts there were 4 partial responses and 5 pts with stable disease. Conclusions: The recommended phase II doses for this regimen are: bortezomib 1.0 mg/m2, Gem 1000 mg/m2 and Carbo AUC 5. Translational Research Funding (TRF) for ongoing molecular correlates will examine ERCC1 mRNA levels in tumor and ERCC1 polymorphisms in genomic DNA. This study forms the basis for SWOG 0339 a phase II trial of this combination for the first-line treatment of advanced NSCLC. (NCI NO1-CM17101, Millennium)

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