PMID- 25247339 OWN - NLM STAT- MEDLINE DCOM- 20151030 LR - 20211021 IS - 1556-1380 (Electronic) IS - 1556-0864 (Print) IS - 1556-0864 (Linking) VI - 10 IP - 1 DP - 2015 Jan TI - 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. PG - 172-80 LID - 10.1097/JTO.0000000000000383 [doi] AB - INTRODUCTION: 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. FAU - Zhao, Yujie AU - Zhao Y AD - *Department of Medicine, Roswell Park Cancer Institute, Buffalo, NY; daggerAlliance Statistics and Data Center, Mayo Clinic, Rochester, MN; double daggerIllinois CancerCare, Peoria, IL; section signHematology/Oncology and **Radiation Oncology, Mayo Clinic, Scottsdale, AZ; ||Carle Cancer Center Community Clinical Oncology Program, Urbana, IL; paragraph signWichita Community Clinical Oncology Program, Wichita, KS; #Oncology and double daggerdouble daggerLaboratory Medicine and Pathology, and Anatomic Pathology, Mayo Clinic, Rochester, MN; and daggerdaggerUpstate Carolina CCOP, Spartanburg, SC. FAU - Foster, Nathan R AU - Foster NR FAU - Meyers, Jeffrey P AU - Meyers JP FAU - Thomas, Sachdev P AU - Thomas SP FAU - Northfelt, Donald W AU - Northfelt DW FAU - Rowland, Kendrith M Jr AU - Rowland KM Jr FAU - Mattar, Bassam I AU - Mattar BI FAU - Johnson, David B AU - Johnson DB FAU - Molina, Julian R AU - Molina JR FAU - Mandrekar, Sumithra J AU - Mandrekar SJ FAU - Schild, Steven E AU - Schild SE FAU - Bearden, James D 3rd AU - Bearden JD 3rd FAU - Aubry, Marie-Christine AU - Aubry MC FAU - Adjei, Alex A AU - Adjei AA LA - eng GR - CA33601/CA/NCI NIH HHS/United States GR - N01 CA035431/CA/NCI NIH HHS/United States GR - U10 CA031946/CA/NCI NIH HHS/United States GR - U10 CA180821/CA/NCI NIH HHS/United States GR - N01 CA035119/CA/NCI NIH HHS/United States GR - CA-25224/CA/NCI NIH HHS/United States GR - CA-35113/CA/NCI NIH HHS/United States GR - U10 CA035431/CA/NCI NIH HHS/United States GR - U10 CA025224/CA/NCI NIH HHS/United States GR - CA31946/CA/NCI NIH HHS/United States GR - U10 CA033601/CA/NCI NIH HHS/United States GR - CA-35195/CA/NCI NIH HHS/United States GR - U10 CA035195/CA/NCI NIH HHS/United States GR - UG1 CA189861/CA/NCI NIH HHS/United States GR - U10 CA035113/CA/NCI NIH HHS/United States GR - P30 CA015083/CA/NCI NIH HHS/United States GR - U10 CA035119/CA/NCI NIH HHS/United States GR - UG1 CA189808/CA/NCI NIH HHS/United States PT - Clinical Trial, Phase I PT - Clinical Trial, Phase II PT - Journal Article PT - Multicenter Study PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't PL - United States TA - J Thorac Oncol JT - Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer JID - 101274235 RN - 0 (Boronic Acids) RN - 0 (Pyrazines) RN - 69G8BD63PP (Bortezomib) RN - BG3F62OND5 (Carboplatin) RN - P88XT4IS4D (Paclitaxel) SB - IM MH - Aged MH - Antineoplastic Combined Chemotherapy Protocols/*therapeutic use MH - Boronic Acids/administration & dosage MH - Bortezomib MH - Carboplatin/administration & dosage MH - Carcinoma, Non-Small-Cell Lung/*drug therapy/pathology/*radiotherapy MH - Chemoradiotherapy MH - Female MH - Humans MH - Lung Neoplasms/*drug therapy/pathology/*radiotherapy MH - Male MH - Middle Aged MH - Paclitaxel/administration & dosage MH - Pyrazines/administration & dosage MH - Survival Analysis PMC - PMC4320011 MID - NIHMS629274 EDAT- 2014/09/24 06:00 MHDA- 2015/10/31 06:00 PMCR- 2016/01/01 CRDT- 2014/09/24 06:00 PHST- 2014/09/24 06:00 [entrez] PHST- 2014/09/24 06:00 [pubmed] PHST- 2015/10/31 06:00 [medline] PHST- 2016/01/01 00:00 [pmc-release] AID - S1556-0864(15)30787-5 [pii] AID - 10.1097/JTO.0000000000000383 [doi] PST - ppublish SO - J Thorac Oncol. 2015 Jan;10(1):172-80. doi: 10.1097/JTO.0000000000000383.