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A Phase I/II Study of Bortezomib in Combination with Paclitaxel

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A Phase I/II Study of Bortezomib in Combination with Paclitaxel View metadata, citation and similar papers at core.ac.uk brought to you by CORE provided by Elsevier - Publisher Connector Original Article 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 Yujie Zhao, MD, PhD,* Nathan R. Foster, MS,† Jeffrey P. Meyers, BA,† Sachdev P. Thomas, MD,‡ Donald W. Northfelt, MD,§ Kendrith M. Rowland Jr., MD,║ Bassam I. Mattar, MD,¶ David B. Johnson, MD,¶ Julian R. Molina, MD, PhD,# Sumithra J. Mandrekar, PhD,† Steven E. Schild, MD,** James D. Bearden III, MD,†† Marie-Christine Aubry, MD,‡‡ and Alex A. Adjei, MD, PhD* were observed, one (grade 3 pneumonitis) at dose level 1 (bortezo- Introduction: Despite the advances in radiation techniques and che- mib at 0.5 mg/m2, paclitaxel at 150 mg/m2, and carboplatin at area motherapy, survival with current platinum-based chemotherapy and under the curve of 5) and one (grade 4 neutropenia lasting ≥8 days) concomitant thoracic radiation remains dismal. Bortezomib, a pro- at dose level 6 (bortezomib 1.2 mg/m2, paclitaxel 175 mg/m2, and car- teasome inhibitor, modulates apoptosis and cell cycle through dis- boplatin at area under the curve of 6). During the phase I portion, the ruption of protein degradation. The combination of bortezomib and most common grade 3 of 4 AEs were leukopenia (44%), neutrope- carboplatin/paclitaxel and concurrent radiation in unresectable stage nia (37%), dyspnea (22%), and dysphagia (11%). Dose level 6 was III non–small-cell lung cancer was evaluated in this phase I/II study. declared to be the recommended phase II dose (RP2D) and the phase Methods: Patients with histologic or cytologic confirmed stage III non- II portion of the study opened. After the first 26 evaluable patients metastatic non–small-cell lung cancer who were candidates for radiation were enrolled to the RP2D, a per protocol interim analysis occurred. therapy were eligible. In the phase I portion, patients received escalating Of these 26 patients, 23 (88%) survived at least 6 months (95% con- doses of bortezomib, paclitaxel, and carboplatin concomitantly with tho- fidence interval [CI], 70–98%), which was enough to continue to full racic 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 accrual per study design. However, due to slow accrual, the study rate (12MS). A one-stage design with an interim analysis yielded 81% was stopped after 27 evaluable patients were enrolled (6—phase I power to detect a true 12MS of 75%, with a 0.09 level of significance if RP2D; 21—phase II). Of these 27 patients, the 12MS was 73% (95% the true 12MS was 60% using a sample size of 60 patients. Secondary CI, 58–92%), the median overall survival was 25.0 months (95% CI, endpoints consisted of adverse events (AEs), overall survival, progres- 15.6–35.8), and the median progression-free survival was 8.4 months sion-free survival, and the confirmed response rate. (95% CI, 4.1–10.5). The confirmed response rate was 26% (seven of Results: Thirty-one patients enrolled during the phase I portion of the 27; 95% CI, 11–46%), consisting of four partial responses and three trial, of which four cancelled before receiving treatment, leaving 27 complete responses. Grade 3+ and grade 4+ AEs occurred in 82% evaluable patients. Of these 27 patients, two dose-limiting toxicities 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, *Department of Medicine, Roswell Park Cancer Institute, Buffalo, NY; respectively. †Alliance Statistics and Data Center, Mayo Clinic, Rochester, MN; Conclusions: The addition of bortezomib to concurrent carboplatin/ ‡Illinois CancerCare, Peoria, IL; §Hematology/Oncology and **Radiation paclitaxel and radiation seemed to be feasible, although associated Oncology, Mayo Clinic, Scottsdale, AZ; ║Carle Cancer Center Community Clinical Oncology Program, Urbana, IL; ¶Wichita Community Clinical with increased hematological toxicities. A favorable median overall Oncology Program, Wichita, KS; #Oncology and ‡‡Laboratory Medicine survival of 25 months suggests a potential benefit for this regimen. and Pathology, and Anatomic Pathology, Mayo Clinic, Rochester, MN; and ††Upstate Carolina CCOP, Spartanburg, SC. (J Thorac Oncol. 2015;10: 172–180) The study was also supported, in part, by grants from the National Cancer Institute (CA31946) to the Alliance for Clinical Trials in Oncology (Monica M. Bertagnolli, MD) and to the Alliance Statistics and Data Center (Daniel J. Sargent, PhD, CA33601). ung cancer is the most common cause of cancer deaths in The remaining authors have no funding or conflicts of interest to disclose. Lthe United States with an estimated mortality of 159,480 Address for correspondence: Alex A. Adjei, MD, PhD, Roswell Park Cancer in 2013.1 Non–small-cell lung cancer (NSCLC) accounts for Institute, Elm & Carlton Streets, Buffalo, NY 14263. E-mail: Alex. approximately 85% to 90% of lung cancer diagnoses. Only [email protected] DOI: 10.1097/JTO.0000000000000383 25% to 30% of patients with NSCLC have early stage and Copyright © 2014 by the International Association for the Study of Lung Cancer localized disease that is resectable (stage I or II) at the time of ISSN: 1556-0864/15/1001-0172 diagnosis.2 For the 30% of patients with regionally advanced, 172 Journal of Thoracic Oncology ® • Volume 10, Number 1, January 2015 Journal of Thoracic Oncology ® • Volume 10, Number 1, January 2015 Bortezomib, Paclitaxel, Carboplatin, and Concurrent Radiation in NSCLC inoperable disease, the recommended therapeutic approach is aspartate transaminase ≤3 ×ULN and creatinine ≤1.5 ×ULN. combined modality therapy with thoracic radiation therapy Patients with weight loss of 10% or greater in past 3 months, (RT) and chemotherapy.3–6 Despite the advances in irradiation forced expiratory volume in 1 second less than 1 liter or 35% techniques and improved chemotherapy, local and distant con- of predicted forced expiratory volume in 1 second, history trol remain suboptimal, and the majority of patients continue of before RT to the chest and systemic chemotherapy for to die from distant metastases.5,7–10 To improve efficacy of this NSCLC, major surgery or unhealed wound ≤2 weeks before treatment approach, chemoradiotherapy incorporating novel registration, New York Heart Association classification III or molecular targeting agents is being actively investigated. IV, uncontrolled infection, and peripheral neuropathy ≥ grade Bortezomib (VELCADE, PS-341) is a dipeptide boronic 2 were excluded. Written informed consent approved by insti- acid analogue that reversibly inhibits the 26S proteasome, a tutional review boards and the National Cancer Institute were large protease complex that degrades ubiquitinated proteins. obtained from eligible patients before prestudy assessments. By blocking proteolysis, bortezomib leads to accumulation of proteins involved in multiple signal transduction pathways, Study Design resulting in cell cycle arrest, apoptosis and down-regulation of This was a multicenter co-operative group, open-label, angiogenesis. For example, it stabilizes the cyclin-dependent single-arm, combined phase I dose-escalation, and phase II kinase inhibitors p21 and p27 and blocks cell division in the study to assess the safety, tolerability, and efficacy of carbo- G -M phase of the cell cycle. It inhibits the degradation of 2 platin/paclitaxel/bortezomib and concurrent daily thoracic RT the wild-type tumor suppressor protein p53 and suppresses in advanced nonmetastatic NSCLC. Patients received esca- the activation of oncogene nuclear factor (NF)-κB. It inhibits lating doses of carboplatin/paclitaxel/bortezomib, up to the overexpression of antiapoptotic protein B-cell lymphoma 2 RP2D recommended in a previous phase I study evaluating 11–14 and favorably modulates apoptosis. this combination.22 After determination of RP2D, additional Bortezomib has been approved for the treatment of patients were enrolled for the phase II part of the study. multiple myeloma and mantle cell non-Hodgkin’s lymphoma. Eligible patients received treatment in an outpatient set- In NSCLC, bortezomib has been combined with docetaxel, ting with chemotherapy and radiotherapy concurrently deliv- pemetrexed, gemcitabine/carboplatin, carboplatin/bevaci- ered over a 6-week period. Complete blood cell counts were zumab, vorinostat, and erlotinib in clinical studies with various 15–21 obtained weekly during periods of active study treatment, at 4 levels of activity observed. In a phase I study combining weeks postradiation, and at each post-treatment follow-up visit. bortezomib and carboplatin/paclitaxel, the maximum tolerated Serum chemistries were collected before each cycle of che- dose (MTD) and the recommended phase II dose (RP2D) was 2 2 motherapy and at each post-treatment follow-up visit. A chest found to be bortezomib 1.2 mg/m , paclitaxel 175 mg/m and computed tomography was performed at baseline, 4 weeks post- carboplatin at area under the curve (AUC) of 6, and a schedule radiation, 3 months postradiation, and then every 3 months for of bortezomib given on days 1, 4, and 8 followed by paclitaxel 1 year, followed by computed tomography every 6 months for a and carboplatin on day 2 every 21 days was found to be more maximum of 5 years from the time of registration. Full support- efficacious than when paclitaxel and carboplatin were given on ive care, including blood-product support, antibiotic treatment, day 1 of each cycle.22 Furthermore, bortezomib was found to be 23 antidiarrheals, analgesics, antiemetics, and medications used synergistic with radiotherapy in vitro and in animal models. for the prevention and treatment of radiation esophagitis, nutri- In a 12-patient phase I study evaluating carboplatin/paclitaxel/ tional evaluation, and treatment of other newly diagnosed or bortezomib and concurrent radiotherapy as induction therapy concurrent medical conditions was provided.
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