A Phase I/II Study of Bortezomib in Combination with Paclitaxel, Carboplatin, and Concurrent Thoracic Radiation Therapy for Non–Small-Cell Lung Cancer: North Central Cancer Treatment Group (NCCTG)-N0321
Authors: Yujie Zhao, Nathan R. Foster, Jeffrey P. Meyers, Sachdev P. Thomas, Donald W. Northfelt, Kendrith M. Rowland, Bassam I. Mattar, David B. Johnson, Julian R. Molina, Sumithra J. Mandrekar, Steven E. Schild, James D. Bearden, Marie-Christine Aubry, Alex A. Adjei
Journal: Journal of Thoracic Oncology (2014)

IntroductionDespite the advances in radiation techniques and chemotherapy, survival with current platinum-based chemotherapy and concomitant thoracic radiation remains dismal. Bortezomib, a proteasome inhibitor, modulates apoptosis and cell cycle through disruption of protein degradation. The combination of bortezomib and carboplatin/paclitaxel and concurrent radiation in unresectable stage III non–small-cell lung cancer was evaluated in this phase I/II study.MethodsPatients with histologic or cytologic confirmed stage III nonmetastatic non–small-cell lung cancer who were candidates for radiation therapy were eligible. In the phase I portion, patients received escalating doses of bortezomib, paclitaxel, and carboplatin concomitantly with thoracic radiation (60 Gy/30 daily fractions) using a modified 3 + 3 design. The primary endpoint for the phase II portion was the 12-month survival rate (12MS). A one-stage design with an interim analysis yielded 81% power to detect a true 12MS of 75%, with a 0.09 level of significance if the true 12MS was 60% using a sample size of 60 patients. Secondary endpoints consisted of adverse events (AEs), overall survival, progression-free survival, and the confirmed response rate.ResultsThirty-one patients enrolled during the phase I portion of the trial, of which four cancelled before receiving treatment, leaving 27 evaluable patients. Of these 27 patients, two dose-limiting toxicities were observed, one (grade 3 pneumonitis) at dose level 1 (bortezomib at 0.5 mg/m2, paclitaxel at 150 mg/m2, and carboplatin at area under the curve of 5) and one (grade 4 neutropenia lasting ≥8 days) at dose level 6 (bortezomib 1.2 mg/m2, paclitaxel 175 mg/m2, and carboplatin at area under the curve of 6). During the phase I portion, the most common grade 3 of 4 AEs were leukopenia (44%), neutropenia (37%), dyspnea (22%), and dysphagia (11%). Dose level 6 was declared to be the recommended phase II dose (RP2D) and the phase II portion of the study opened. After the first 26 evaluable patients were enrolled to the RP2D, a per protocol interim analysis occurred. Of these 26 patients, 23 (88%) survived at least 6 months (95% confidence interval [CI], 70–98%), which was enough to continue to full accrual per study design. However, due to slow accrual, the study was stopped after 27 evaluable patients were enrolled (6—phase I RP2D; 21—phase II). Of these 27 patients, the 12MS was 73% (95% CI, 58–92%), the median overall survival was 25.0 months (95% CI, 15.6–35.8), and the median progression-free survival was 8.4 months (95% CI, 4.1–10.5). The confirmed response rate was 26% (seven of 27; 95% CI, 11–46%), consisting of four partial responses and three complete responses. Grade 3+ and grade 4+ AEs occurred in 82% and 56% of patients, respectively. One patient experienced grade 5 pneumonitis that was possibly related to the treatment. Grade 3 and 4 hematological toxicities were observed in 82% and 56% patients, respectively.ConclusionsThe addition of bortezomib to concurrent carboplatin/paclitaxel and radiation seemed to be feasible, although associated with increased hematological toxicities. A favorable median overall survival of 25 months suggests a potential benefit for this regimen.