Abstract 1803: Phase I/II study of bortezomib in combination with carboplatin and bevacizumab as first line therapy in patients with advanced non-small cell lung cancer (NSCLC)

Abstract Background: Bortezomib (Velcade®) is a selective and reversible inhibitor of the 26S proteasome. It has shown pre-clinical and clinical activity in NSCLC. This phase I/II trial examines the safety and efficacy of bortezomib in combination with carboplatin and bevacizumab as first line treatment for advanced NSCLC. Methods: Three dose levels of weekly bortezomib were tested with the fixed standard doses of carboplatin (AUC 6) and bevacizumab (15 mg/kg) q 3 wks using a standard 3+3 dose escalation phase I design. Bortezomib doses were 1.3, 1.6 and 1.8 mg/m2 weekly on D1 and D8 of q 3wk cycle. A maximum of 6 cycles were administered. Patients with complete response (CR), partial response (PR) or stable disease (SD) were continued on single agent bevacizumab (15 mg/kg q 3wks) as maintenance therapy. Dose limiting toxicity (DLT) was defined as any of the following toxicity during the first cycle of treatment : grade (GR) 4 neutropenia or thrombocytopenia, any ≥GR 3 non-heme toxicity except alopecia or inadequately treated nausea or vomiting, neurosensory toxicity of GR 2 with pain or any neurotoxicity &amp;gt;GR2. Results: Twelve chemonaive NSCLC patients (pts) were treated (3, 4 and 5 pts in dose level I, II and III respectively). Pt characteristics: median age 63 (49-73); sex M/F 7/5; ECOG performance status ≤1/2/unknown: 10/1/1; stage IIIB/IV: 2/10. No DLT was observed during the first cycle in all 12 patients. Total of 45 cycles of combination therapy with carboplatin, bortezomib and bevacizumab were administered so far and two patients are actively on treatment. The most common treatment related GR 3/4 toxicities during the subsequent cycles were thrombocytopenia (5/12), neutropenia (2/12), diarrhea (2/12), hypertension (1/12), arterial thrombosis (1/12), confusion (1/12), nausea, vomiting (1/12), fatigue (1/12), anorexia (1/12), dyspnea (1/12) and pain (1/12). The GR 2 sensory neuropathy was seen in 1 pt at 1.8 mg/m2 dose level after 5 cycles. Of 10 evaluable pts, there were 3 PRs and 3 SDs (disease control rate of 60%). 4 patients completed six planned cycles of treatment. Three patients had progressive disease after the first two cycles. Conclusion: The recommended phase II dose for this regimen is: carboplatin AUC 6, bevacizumab 15 mg/kg on D1 and bortezomib 1.8 mg/m2 on D1 and D8 on q 21 day cycle. The regimen was well tolerated with interesting clinical activity in first line treatment of NSCLC. The accrual to the study is ongoing. The phase II portion of the study will plan to include the biomarker studies to evaluate the combined anti-angiogenic effect of bortezomib and bevacizumab in NSCLC pts. Acknowledgement: Supported by Millennium Pharmaceuticals, Inc. and Roche Pharmaceuticals Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 1803.

Topic: Ubiquitin and proteasome pathways
Subfield: Molecular Biology
Field: Biochemistry, Genetics and Molecular Biology
Domain: Life Sciences