title: 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.
abstract: BACKGROUND
  Despite 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.
  
  
  METHODS
  Patients 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.
  
  
  RESULTS
  Thirty-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/m, paclitaxel at 150 mg/m, 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/m, paclitaxel 175 mg/m, 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.
  
  
  CONCLUSIONS
  The 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.
authors.affiliation: *Department of Medicine, Roswell Park Cancer Institute, Buffalo, NY; †Alliance Statistics and Data Center, Mayo Clinic, Rochester, MN; ‡Illinois CancerCare, Peoria, IL; §Hematology/Oncology and **Radiation Oncology, Mayo Clinic, Scottsdale, AZ; ‖Carle Cancer Center Community Clinical Oncology Program, Urbana, IL; ¶Wichita Community Clinical Oncology Program, Wichita, KS; #Oncology and ‡‡Laboratory Medicine and Pathology, and Anatomic Pathology, Mayo Clinic, Rochester, MN; and ††Upstate Carolina CCOP, Spartanburg, SC.
authors.forename: Yujie
authors.initials: Y
authors.lastname: Zhao
authors.forename: Nathan R
authors.initials: NR
authors.lastname: Foster
authors.forename: Jeffrey P
authors.initials: JP
authors.lastname: Meyers
authors.forename: Sachdev P
authors.initials: SP
authors.lastname: Thomas
authors.forename: Donald W
authors.initials: DW
authors.lastname: Northfelt
authors.forename: Kendrith M
authors.initials: KM
authors.lastname: Rowland
authors.forename: Bassam I
authors.initials: BI
authors.lastname: Mattar
authors.forename: David B
authors.initials: DB
authors.lastname: Johnson
authors.forename: Julian R
authors.initials: JR
authors.lastname: Molina
authors.forename: Sumithra J
authors.initials: SJ
authors.lastname: Mandrekar
authors.forename: Steven E
authors.initials: SE
authors.lastname: Schild
authors.forename: James D
authors.initials: JD
authors.lastname: Bearden
authors.forename: Marie-Christine
authors.initials: MC
authors.lastname: Aubry
authors.forename: Alex A
authors.initials: AA
authors.lastname: Adjei
mesh_terms: D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D001897:Boronic Acids / Q000008:administration & dosage; D000069286:Bortezomib; D016190:Carboplatin / Q000008:administration & dosage; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000473:pathology / Q000532:radiotherapy*; D059248:Chemoradiotherapy; D005260:Female; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000473:pathology / Q000532:radiotherapy*; D008297:Male; D008875:Middle Aged; D017239:Paclitaxel / Q000008:administration & dosage; D011719:Pyrazines / Q000008:administration & dosage; D016019:Survival Analysis
chemical_list: D001897:Boronic Acids; D011719:Pyrazines; D000069286:Bortezomib; D016190:Carboplatin; D017239:Paclitaxel