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, 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. Prophylactic use followed by surgical resection in stage III non–small-cell lung of colony-stimulating factors during the study was not allowed. cancer, five patients achieved complete pathologic response Therapeutic use of colony-stimulating factors in patients with and two other patients were found to have necrosis occurred 24 serious neutropenic complications, such as tissue infection, in 99% of tumor tissue. Here, we report a phase I/II study sepsis syndrome, fungal infection, and so on, was allowed at the evaluating carboplatin/paclitaxel/bortezomib in combination investigator’s discretion. Recombinant erythropoietin to main- with concurrent radiation as primary definitive treatment for tain adequate hemoglobin levels and avoid packed red blood patients with unresectable local regionally advanced NSCLC. cell transfusions was allowed. PATIENTS AND METHODS Chemotherapy Eligibility Criteria Bortezomib was administered by intravenous push Patients with histologic or cytologic confirmed inoper- on days 1, 4, 8, and 11 of each 21-day cycle. Paclitaxel was able nonmetastatic (stage IIIA or IIIB according to American administered intravenously over 3 hours on day 2 of each Joint Committee on Cancer staging system 6th edition) cycle. Carboplatin was administered as a 30-minute intrave- non–small-cell lung carcinoma (NSCLC) requiring RT were nous infusion immediately after paclitaxel infusion on day 2 of eligible for the study. Other eligibility criteria included the fol- each cycle. Thirty minutes before the paclitaxel dose, patients lowing: aged 18 years or older; Eastern Cooperative Oncology were premedicated with 10 to 20 mg dexamethasone intrave- Group performance status (ECOG PS) ≤1; life expectancy of nously or orally, 25 to 50 mg diphenhydramine HCl intrave- 12 weeks or longer; absolute neutrophil count ≥1.5 × 109/liter; nously, and 50 mg ranitidine or 300 mg cimetidine or 20 mg platelet count ≥100 × 109/liter; total serum bilirubin ≤1.5 mg/dl famotidine intravenously. Bactrim 1 tablet twice daily was or direct bilirubin ≤1.5 × upper limits of normal (ULN); and administered twice per week continuously during treatment.

In the phase I part, groups of three to six patients were End Points and Statistical Analysis entered at different dose levels after the dose escalation The primary endpoint of the phase I portion was the scheme given in Table 1. In the phase II part, bortezomib at MTD of the treatment combination using a modified cohort 1.2 mg/m2, paclitaxel at 175 mg/m2, and carboplatin at AUC of of three design,26 where the MTD was defined as the highest 6 were administered. safely tolerated dose where at most two of six patients experienced a dose-limiting toxicity (DLT), with the next higher Radiation Therapy dose level having at least three of six patients with a DLT. Any RT administering 2 Gy once daily began on day 1 of the following were considered DLTs over the 6 weeks of of chemotherapy for all patients. Three-dimensional radio- combined chemotherapy/RT, including a 4-week observation, therapy with no inhomogeneity corrections was used. where the DLT needed to be possibly, probably, or definitely Intensity modulated radiotherapy was not allowed. Elective related to study treatment: grade 4 radiation dermatitis, grade nodal irradiation was administered for the first 42 to 44 4 neutropenia or thrombocytopenia lasting at least 8 days or Gy. The primary tumor, mediastinum, and ipsilateral hilum grade 4 febrile neutropenia (first 3 weeks of chemotherapy were covered with a 2-cm margin to block edge. The mini- only for hematologic DLTs), grade ≥3 esophagitis requir- mal mediastinal volume superiorly to inferiorly extended ing hospitalization, grade ≥3 pneumonitis requiring oxygen, from the top of T1 superiorly to 5 cm below the carina infe- grade 4 dyspnea at rest, and other nonhematologic grade 4 riorly. Elective inclusion of the supraclavicular fossa was toxicities not manageable with medical interventions (intra- allowed at the discretion of the treating physician. If supra- venous, narcotic). If the study did not reach the MTD by dose clavicular disease was present, both fossae were treated. level 6 (Table 1), dose level 6 would be considered the RP2D. After 42 to 44 Gy was given, off-cord oblique fields treated The primary endpoint of the phase II portion of the study gross disease (primary tumor and enlarged lymph nodes was 12-month survival, where all patients enrolled at the MTD (>1 cm in short diameter)) with 2 cm margins between the (or RP2D) would be included in the analysis. The 12-month tumor and block edge. A total dose of 60 Gy was delivered survival rate was calculated using Kaplan–Meier methodol- to the isocenter in 30 fractions given 5 days per week at 2 ogy. 27 A one-stage design with an interim analysis was used Gy daily. The spinal cord was limited to a maximum dose to test whether there was sufficient evidence to determine that of 48 Gy. The total lung volume receiving 20 Gy or greater the 12-month survival rate was at least 75% (i.e., clinically was limited to 40% or less. One-third of the heart could promising) versus at most 60% (i.e., clinically inactive). After not receive greater than 60 Gy, two-third of the heart could the first 26 evaluable patients had been on-study for 6 months, not receive more than 50 Gy, and the entire heart could not an interim analysis was performed. At least 21 of these 26 receive more than 40 Gy. patients surviving greater than or equal to 6 months postregistration would be considered sufficient activity to continue to Response and Toxicity Criteria full accrual. Otherwise, the study would be stopped early for All toxicities were graded using National Cancer lack of efficacy. At least 41 of all 60 (68%) evaluable patients Institute Common Terminology Criteria for Adverse Events surviving greater than or equal to 12 months postregistration version 3.0 (before December 31, 2010) or Common would be considered adequate evidence of promising activity Terminology Criteria for Adverse Events version 4.0 (after and would warrant further testing of this regimen in subse- January 1, 2011). Assessment of disease response occurred quent studies. This design yielded 81% power to detect a true 4 weeks postradiotherapy, 3 months postradiotherapy, every 12-month survival rate of 75%, with a 0.09 level of signifi- 3 months for 1 year postradiotherapy, and every 6 months cance if the true 12-month survival rate was 60%. thereafter for a maximum of 5 years from time of registration. Secondary end points were adverse event rates, overall Treatment response was evaluated using Response Evaluation survival (defined as the time from registration to death due to Criteria in Solid Tumors criteria.25 any cause), progression-free survival (defined to be the length of time from study registration to the first of either disease progression or death due to any cause), confirmed tumor response TABLE 1. Dose Escalation Scheme (defined to be a complete response or partial response noted as Dose Bortezomib Paclitaxel Carboplatin the objective status on two consecutive evaluations at least 4 Level (mg/m2) (mg/m2) AUC weeks apart), and treatment tolerability. The maximum grade −1 0.5 120 5 for each type of adverse event was recorded for each patient, 0 0.5 135 5 and frequency tables were used to determine adverse event 1a 0.5 150 5 patterns for both phases of the study (regardless of attribution 2 0.8 150 5 to the study treatment). The commonly occurring grade 3 and 3 1.0 150 5 greater adverse events (>5%) were also reported, including all 4 1.0 175 5 grade 4 or higher adverse events. Kaplan–Meier methodol- ogy was used to estimate the distributions of overall survival 5 1.0 175 6 and progression-free survival27 for the RP2D patients only. 6 1.2 175 6 The confirmed response rate was estimated by the number of aStarting dose level. patients who had documented confirmed responses (PR or CR AUC, area under the curve. maintained for a minimum of 4 weeks) divided by the total

174 Copyright © 2014 by the International Association for the Study of Lung Cancer Journal of Thoracic Oncology ® • Volume 10, Number 1, January 2015 Bortezomib, Paclitaxel, Carboplatin, and Concurrent Radiation in NSCLC

number of evaluable patients for the RP2D patients only. All TABLE 2. Consort Diagram patients who were eligible and started treatment were evaluable for all primary and secondary endpoints in this study. All analyses were conducted using SAS version 9.3 on data available as of March 18, 2014. Data collection and statistical analyses were conducted by the Alliance Statistics and Data Center. Data quality was ensured by review of data by the Alliance Statistics and Data Center and by the study chairper- son following Alliance policies.

RESULTS Radiation Therapy Quality Assessment RT plans and port films were reviewed for all 48 patients. These were reviewed in detail by two NCCTG inves- tigators and one Radiologic Physics Center reviewer based on protocol specified criteria. There were 44 (92%) patients with no deviations, three (6%) had minor deviations and one (2%) had a major deviation.

Patient Characteristics and Reasons Off Treatment Phase I Thirty-one patients with locally advanced stage IIIA or IIIB NSCLC were enrolled into the phase I portion of the trial from April 25, 2005, to July 13, 2009, of which 27 were deemed evaluable because four patients withdrew before receiving treatment. Patients were enrolled to a total of six dose levels (Table 1), where dose level 6 was the dose selected for the phase II portion of the study (Table 2 Consolidated Standards of Reporting Trials [CONSORT] diagram for further details). The characteristics of the phase I patients are summarized in Table 3. The median age of the 27 patients was 63 years (range, 45–78). Seventeen (63%) patients were men and 10 (37%) patients were women. Approximately 33% of patients presented with stage IIIA disease, whereas 67% of patients presented with stage IIIB disease. Fifteen patients have ended active treatment. Approximately 67% (18 of 27) of (56%) had an ECOG PS of 0, and 12 patients (44%) had an patients completed the entire protocol treatment. Among the ECOG PS of 1 (Table 3). All patients ended active treatment, nine patients who ended treatment early, 4 (44%) discontinued with most completing the study per protocol (17/27; 63%). treatment due to adverse events, 2 (22%) discontinued treat- Of the other 10 patients, five went off treatment early due to ment due to disease progression, 1 (11%) patient refused fur- adverse events, three went off treatment due to disease pro- ther treatment, and the other 2 (22%) went off for other reasons. gression, and two went off treatment for other reasons. Phase II (RP2D) Tolerability and Toxicity Only 21 patients were enrolled to the phase II portion Phase I because the study was closed early due to slow accrual. In addi- Twenty-seven patients were evaluable for adverse tion, seven patients were enrolled at the recommended phase II events across the six phase I dose levels (Table 4). Dose level dose (RP2D) during the phase I portion (dose level 6). These 28 1 resulted in one of six patients experiencing a DLT (grade patients were enrolled from July 31, 2008 to January 14, 2011. 3 pneumonitis requiring oxygen). Although no patients expe- Of the 28 patients enrolled, 27 were deemed evaluable because rienced a DLT per protocol for dose levels 2 to 5, we did one patient withdrew before receiving treatment (Table 2 the enroll six patients at dose level 3 because one of the first three CONSORT diagram for further details). There were 17 (63%) patients went off treatment early due to adverse events. Dose men and 10 (34%) women, with a median age of 58 years level 6 enrolled six evaluable patients with only one patient (range, 43–79). Approximately 48% of patients presented with experiencing a DLT (grade 4 neutropenia lasting ≥8 days). stage IIIA disease, whereas 52% of patients had stage IIIB dis- Dose level 6 (bortezomib: 1.2 mg/m2; paclitaxel: 175 mg/m2; ease. Nine patients (33%) had a baseline ECOG PS of 0, and carboplatin: AUC of 6 for 2 cycles with concurrent radiation) 18 patients (67%) had an ECOG PS of 1 (Table 3). All patients was chosen as the RP2D because we went through all 6 dose

TABLE 3. Baseline Demographics Phase 1 Dose Levels Combined Phase 1 2 3 4 5 6a Phase 1 Phase II RP2Db (n = 6) (n = 3) (n = 6) (n = 3) (n = 3) (n = 6) (n = 27) (n = 27) Age Median 58.5 70.0 61.0 75.0 68.0 55.5 63.0 58.0 Range (55.0–78.0) (68.0–76.0) (55.0–68.0) (45.0–78.0) (63.0–70.0) (47.0–65.0) (45.0–78.0) (43.0–79.0) Gender Female 2 (33.3%) 1 (33.3%) 1 (16.7%) 3 (100.0%) 1 (33.3%) 2 (33.3%) 10 (37.0%) 10 (37.0%) Male 4 (66.7%) 2 (66.7%) 5 (83.3%) 0 (0.0%) 2 (66.7%) 4 (66.7%) 17 (63.0%) 17 (63.0%) Tumor stage IIIA 1 (16.7%) 1 (33.3%) 0 (0.0%) 1 (33.3%) 2 (66.7%) 4 (66.7%) 9 (33.3%) 13 (48.1%) IIIB 4 (66.7%) 1 (33.3%) 6 (100.0%) 2 (66.7%) 1 (33.3%) 0 (0.0%) 14 (51.9%) 11 (40.7%) IIIB with 1 (16.7%) 1 (33.3%) 0 (0.0%) 0 (0.0%) 0 (0.0%) 2 (33.3%) 4 (14.8%) 3 (11.1%) pleural effusion N-stage N1 1 (20.0%) 0 (0.0%) 0 (0.0%) 0 (0.0%) 0 (0.0%) 1 (16.7%) 2 (7.7%) 4 (14.8%) N2 1 (20.0%) 2 (66.7%) 2 (33.3%) 2 (66.7%) 2 (66.7%) 5 (83.3%) 14 (53.8%) 16 (59.3%) N3 3 (60.0%) 1 (33.3%) 4 (66.7%) 1 (33.3%) 1 (33.3%) 0 (0.0%) 10 (38.5%) 7 (25.9%) ECOG PS 0 5 (83.3%) 1 (33.3%) 3 (50.0%) 2 (66.7%) 2 (66.7%) 2 (33.3%) 15 (55.6%) 9 (33.3%) 1 1 (16.7%) 2 (66.7%) 3 (50.0%) 1 (33.3%) 1 (33.3%) 4 (66.7%) 12 (44.4%) 18 (66.7%) Pretreatment supraclavicular involvement Ye s 3 (50.0%) 0 (0.0%) 1 (16.7%) 0 (0.0%) 1 (33.3%) 1 (16.7%) 6 (22.2%) 4 (14.8%) No 3 (50.0%) 3 (100.0%) 5 (83.3%) 3 (100.0%) 2 (66.7%) 5 (83.3%) 21 (77.8%) 23 (85.2%) Maximum pretreatment tumor size (cm) <3 0 (0.0%) 1 (33.3%) 1 (16.7%) 0 (0.0%) 0 (0.0%) 1 (16.7%) 3 (11.1%) 4 (14.8%) 3–6 4 (66.7%) 2 (66.7%) 1 (16.7%) 3 (100.0%) 2 (66.7%) 3 (50.0%) 15 (55.6%) 15 (55.6%) >6 2 (33.3%) 0 (0.0%) 4 (66.7%) 0 (0.0%) 1 (33.3%) 2 (33.3%) 9 (33.3%) 8 (29.6%) Weight loss past 3 months <5% 3 (50.0%) 3 (100.0%) 5 (83.3%) 3 (100.0%) 3 (100.0%) 5 (83.3%) 22 (81.5%) 22 (81.5%) 5–10% 3 (50.0%) 0 (0.0%) 1 (16.7%) 0 (0.0%) 0 (0.0%) 1 (16.7%) 5 (18.5%) 5 (18.5%) Diabetes No diabetes 4 (66.7%) 3 (100.0%) 6 (100.0%) 3 (100.0%) 3 (100.0%) 6 (100.0%) 25 (92.6%) 26 (96.3%) T ype II 2 (33.3%) 0 (0.0%) 0 (0.0%) 0 (0.0%) 0 (0.0%) 0 (0.0%) 2 (7.4%) 1 (3.7%)

aIncluded in phase II analysis. bThe recommended phase II dose (RP2D) included six phase I patients enrolled at dose level 6 and 21 patients enrolled during the phase II portion only. ECOG PS, Eastern Cooperative Oncology Group performance status. levels without reaching the MTD. Overall, 20 of 27 patients the patients enrolled at the recommended phase II dose. (74%) experienced grade 3 of 4 adverse events (regardless of Twenty-two of these 27 patients (82%) experienced at least attribution), and 11 of 27 (41%) experienced grade 4 adverse one grade 3 or worse adverse event (regardless of attribu- events (Table 4). No grade 5 adverse events occurred. The tion). In addition, 15 (56%) patients experienced at least one most commonly occurring grade 3 of 4 adverse events (fre- grade 4 or worse adverse event, including one patient with a quency, %) consisted of leukopenia (12, 44%), neutropenia grade 5 adverse event (pneumonitis that was possibly related (10, 37%), dyspnea (6, 22%), and dysphagia (3, 11%). All to treatment) (Table 4). The most commonly occurring grade commonly occurring grade 3 of 4 adverse events (>5%) are 3 adverse events (frequency, %) consisted of leukopenia (13, shown in Table 5, including all grade 4 adverse events. 48%), neutropenia (12, 44%), fatigue (6, 22%), and nausea (3, 11%) (Table 5). The most commonly occurring grade 4 Phase II (RP2D) adverse events (frequency, %) were all hematologic and con- Twenty-seven patients were evaluable for adverse sisted of thrombocytopenia (10, 37%), neutropenia (6, 22%), events in the phase II portion of the study (Tables 4 and 5). and leukopenia (4, 15%) (Table 5). Nonhematologic grade 4 Although dose reductions were needed at times, most patients adverse events (frequency, %) consisted of dyspnea (1, 4%), received the majority of the doses, as shown in Table 6 for depressed level of consciousness (1, 4%), myalgia (1, 4%),

176 Copyright © 2014 by the International Association for the Study of Lung Cancer Journal of Thoracic Oncology ® • Volume 10, Number 1, January 2015 Bortezomib, Paclitaxel, Carboplatin, and Concurrent Radiation in NSCLC

TABLE 4. Adverse Eventa Summary Phase 1 Dose Levels Combined Phase 1 2 3 4 5 6b Phase 1 Phase II RP2Dc,d (n = 6) (n = 3) (n = 6) (n = 3) (n = 3) (n = 6) (n = 27) (n = 27) DLT (%) 1 (16.7%) 0 (0.0%) 0 (0.0%) 0 (0.0%) 0 (0.0%) 1 (16.7%) 2 (7.4%) 1 (3.7%) Grade 3+ overall 5 (83.3%) 3 (100.0%) 4 (66.7%) 2 (66.7%) 2 (66.7%) 4 (66.7%) 20 (74.1%) 22 (81.5%) Grade 4+ overall 4 (66.7%) 2 (66.7%) 1 (16.7%) 1 (33.3%) 0 (0.0%) 3 (50.0%) 11 (40.7%) 15 (55.6%) Grade 3+ heme 3 (50.0%) 1 (33.3%) 2 (33.3%) 2 (66.7%) 2 (66.7%) 4 (66.7%) 14 (51.9%) 22 (81.5%) Grade 4 heme 2 (33.3%) 0 (0.0%) 1 (16.7%) 0 (0.0%) 0 (0.0%) 3 (50.0%) 6 (22.2%) 15 (55.6%) Grade 3+ nonhematologic 4 (66.7%) 3 (100.0%) 4 (66.7%) 1 (33.3%) 1 (33.3%) 3 (50.0%) 16 (59.3%) 12 (44.4%) Grade 4+ nonhematologic 2 (33.3%) 2 (66.7%) 0 (0.0%) 1 (33.3%) 0 (0.0%) 0 (0.0%) 5 (18.5%) 2 (7.4%)

aAdverse events reported regardless of attribution. bIncluded in phase II analysis. cThe recommended phase II dose (RP2D) included six phase I patients enrolled at dose level 6 and 21 patients enrolled during the phase II portion only. dOne grade 5 pneumonitis possibly related to treatment occurred. DLT, dose-limiting toxicity. serum sodium decrease (1, 4%), serum potassium decrease (1, loss of p5334,35 and overexpression of B-cell lymphoma 2,36 and 4%), and hypoxia (1, 4%). All commonly occurring grade 3 promoting radiation sensitivity by accumulating cells in the of 4 adverse events (>5%) are shown in Table 5, including all radiosensitive G2 and M phases,37,38 therefore representing a grade 4 adverse events. promising strategy. Despite early termination of the study due to slow accrual, a promising 12-month survival of 73% and an Response and Survival of impressive median overall survival of about 25 months were Phase II Portion (RP2D) observed in this small study, which seems to be much higher than the overall survival reported with other chemotherapy A per protocol interim analysis occurred after the first 5,39,40 26 evaluable patients were enrolled. Of these 26 patients, 23 regimens. In two phase II studies evaluating weekly carbo- (88%) survived at least 6 months (95% confidence interval platin/paclitaxel and concurrent thoracic radiotherapy (regular [CI], 70–98%), which was enough to continue to full accrual fractions or hyperfractionated) followed by two cycles of con- per study design. However, due to slow accrual, the study was solidative carboplatin/paclitaxel chemotherapy, LUN-56 and stopped after 27 evaluable patients were enrolled (6—phase I LUN-63, the median length of overall survival was 17.4 and 14 months, respectively,41 and the 12-month survival rates were RP2D; 21—phase II). All 27 patients were evaluable for the 42 outcome measures of survival, progression-free survival, and 56% and 61%, respectively. When compared with historical confirmed response. Of all 27 patients, 17 (63%) have died, and data, our results suggested a potential survival benefit associ- the median follow-up time was 26.9 months (range, 5.7–56.7) ated with the addition of bortezomib and this approach war- for the 10 patients who were still alive. The 12-month sur- rants further investigation. vival rate was 73% (95% CI, 58–92%). The median survival When compared with other concurrent chemotherapy (Fig. 1) was 25.0 months (95% CI, 15.6–35.8 months), and regimens, a much higher rate of grade 3 (82%) and 4 (56%) hematological adverse events were observed in the phase II the median progression-free survival (Fig. 2) was 8.4 months 5,8,43 (95% CI, 4.1–10.5 months). The confirmed response rate was portion of this study. Because hematological toxicities, especially thrombocytopenia, are common toxicities of bort- 26% (seven of 27; 95% CI, 11–46%), which consisted of four 44 partial responses (15%) and three complete responses (11%). ezomib, the significant bone marrow suppression observed Clinical benefit rate (stable disease [10 patients] + confirmed with this regimen was not unexpected. However, the overlap- responses [seven patients]) was 63% (95% CI, 42–81%). ping toxicity profile of bortezomib and cytotoxic chemotherapy may render this regimen less tolerable and limit its usage. Despite the success in the treatment of hematological DISCUSSION malignancies, the activity of bortezomib in solid tumors, includ- When administered concurrently with thoracic radiation, ing NSCLC, overall has been less encouraging. Identification chemotherapy can sensitize tumor cells to radiation, and ulti- of patients who will likely gain benefit from the addition of mately improve the local control and survival in advanced non- bortezomib is essential. Moreover, because increased toxicities metastatic NSCLC. However, despite the successful application were observed with this regimen in comparison with histori- of chemoradiotherapy, the survival rate remains dismal. Novel cal data, proper selection of patients will be particularly impor- targeting therapeutic agents, including bevacizumab, erlotinib, tant to avoid unnecessary exposure to toxicities. In mantle cell gefitinib, and cetuximab, have been tested in combination lymphoma, patients with tumors that had low level proteasome with thoracic radiation in clinical studies.28–32 The incorpora- (prosome, macropain) subunit, alpha type 5 expression, or tion of the proteasome inhibitor bortezomib has the presumed higher NF-κB p65 expression seemed more likely to benefit advantages of disrupting signal transduction pathways that are from the addition of bortezomib as reported in the PINNACLE responsible for radio-resistance, such as activation of NF-κB,33 study, a phase II study comparing rituximab with and without

TABLE 5. Commonly Occurring (>5%) Grade 3 of 4 Adverse Events,a Including All Grade 4 Adverse Events (by Phase of Study) Grade 3 Grade 4 Toxicity n (%) n (%) Phase 1 (n = 27) Hematologic Leukocyte count decreased 9 (33.3%) 3 (11.1%) Neutrophil count decreased 4 (14.8%) 6 (22.2%) Lymphocyte count decreased 2 (7.4%) 0 (0.0%) Platelet count decreased 2 (7.4%) 0 (0.0%) Nonhematologic Dyspnea 6 (22.2%) 0 (0.0%) Dysphagia 3 (11.1%) 0 (0.0%) Fatigue 2 (7.4%) 0 (0.0%) Febrile neutropenia 2 (7.4%) 0 (0.0%) Nausea 2 (7.4%) 0 (0.0%) Pneumonitis 2 (7.4%) 0 (0.0%) Dehydration 1 (3.7%) 1 (3.7%) Hypotension 1 (3.7%) 1 (3.7%) Myocardial ischemia 0 (0.0%) 2 (7.4%) Thrombosis 0 (0.0%) 2 (7.4%) Cardiac troponin I increased 0 (0.0%) 1 (3.7%) Phase II RP2D (n = 27) Hematologic Leukocyte count decreased 13 (48.1%) 4 (14.8%) Neutrophil count decreased 12 (44.4%) 6 (22.2%) Platelet count decreased 2 (7.4%) 10 (37.0%) Hemoglobin decreased 2 (7.4%) 0 (0.0%) Lymphocyte count decreased 0 (0.0%) 1 (3.7%) Nonhematologic Fatigue 6 (22.2%) 0 (0.0%) Nausea 3 (11.1%) 0 (0.0%) Dyspnea 2 (7.4%) 1 (3.7%) Anorexia 2 (7.4%) 0 (0.0%) Pneumonitis 2 (7.4%) 0 (0.0%) Syncope 2 (7.4%) 0 (0.0%) Depressed level of consciousness 1 (3.7%) 1 (3.7%) Serum sodium decreased 1 (3.7%) 1 (3.7%) Myalgia 1 (3.7%) 1 (3.7%) Serum potassium decreased 0 (0.0%) 1 (3.7%) Hypoxia 0 (0.0%) 1 (3.7%)

aAdverse events reported regardless of attribution. RP2D, recommended phase II dose.

TABLE 6. Dose-intensity of Chemotherapy and the Radiotherapy Received at the Recommended Phase II Dose % of Patients Who Median % of Per Protocol Chemotherapy/RT Cycle n Received Full Dosea Expected Dose (Range) Bortezomib 1 27 85% (23 of 27) 99 (50–107) 2 24 67% (16 of 24) 98 (13–103) Paclitaxel 1 27 100% (27 of 27) 100 (99–102) 2 24 79% (19 of 24) 100 (50–103) Carboplatin 1 27 100% (27 of 27) 100 (100–100) 2 24 83% (20 of 24) 100 (0–100) RTb 1–2b 27 85% (23 of 27) 100 (3–104)

aDefined as receiving at least 95% of the expected dose. bThe target dose was 6000 cGy given in 30 daily (except weekends) fractions of 200 cGy each, starting on day 1 for a total of 6 weeks (two cycles). Most patients received the full RT dose and most received the 30 total fractions, as expected. RT, radiation therapy.

178 Copyright © 2014 by the International Association for the Study of Lung Cancer Journal of Thoracic Oncology ® • Volume 10, Number 1, January 2015 Bortezomib, Paclitaxel, Carboplatin, and Concurrent Radiation in NSCLC

FIGURE 1. Overall survival of all patients treated on the recommended phase II dose.

FIGURE 2. Progression-free survival of all patients treated on the recommended phase II dose. bortezomib.45 In relapsed/refractory follicular lymphoma, the 3. Pfister DG, Johnson DH, Azzoli CG, et al. American Society of Clinical presence of PSMB1 P11A (G allele) and low CD68 expression Oncology treatment of unresectable non–small-cell lung cancer guide- line: update 2003. J Clin Oncol 2004;22:330–353. (≤50 CD68-positive cells) were found to be associated with 4. Furuse K, Fukuoka M, Kawahara M, et al. Phase III study of concurrent improved outcome in patients treated with bortezomib–ritux- versus sequential thoracic radiotherapy in combination with mitomycin, imab versus rituximab.46 Future studies need to be conducted vindesine, and cisplatin in unresectable stage III non–small-cell lung can- to identify predictive biomarkers for bortezomib in NSCLC to cer. J Clin Oncol 1999;17:2692–2699. 5. Curran WJ Jr., Paulus R, Langer CJ, et al. Sequential vs. concurrent identify the suitable candidate for treatment with bortezomib. chemoradiation for stage III non–small cell lung cancer: randomized phase III trial RTOG 9410. J Natl Cancer Inst 2011;103:1452–1460. 6. Belani CP, Wang W, Johnson DH, et al. Phase III study of the Eastern ACKNOWLEDGMENTS Cooperative Oncology Group (ECOG 2597): induction chemotherapy This study was conducted as a collaborative trial of followed by either standard thoracic radiotherapy or hyperfractionated the North Central Cancer Treatment Group, Alliance, and accelerated radiotherapy for patients with unresectable stage IIIA and B Mayo Clinic and was supported, in part, by Public Health non–small-cell lung cancer. J Clin Oncol 2005;23:3760–3767. Service grants CA-25224, CA-35113, CA-35195, CA-35431, 7. Choy H, Akerly W, Safran H, et al. Paclitaxel plus carboplatin and concurrent radiation therapy for patients with locally advanced non–small cell and CA-35119. The content is solely the responsibility of the lung cancer. Semin Oncol 1996;23(Suppl 16):117–119. authors and does not necessarily represent the views of the 8. Vokes EE, Herndon JE 2nd, Kelley MJ, et al. Induction chemotherapy fol- National Cancer Institute or the National Institute of Health. lowed by chemoradiotherapy compared with chemoradiotherapy alone J.P. Meyers, BA received NCI grant for the submitted work, for regionally advanced unresectable stage III non–small-cell lung cancer: Cancer and Leukemia Group B. J Clin Oncol 2007;25:1698–1704. D.W. Northfelt, MD received Grant support for the submitted 9. Gandara DR, Chansky K, Albain KS, et al. Consolidation docetaxel work, J.D. Bearden III, MD received Upstate Carolina CCOP after concurrent chemoradiotherapy in stage IIIB non–small-cell lung grant for the submitted work, S.J. Mandrekar, PhD received cancer: phase II Southwest Oncology Group Study S9504. J Clin Oncol NCCTG NIH grant for the submitted work, S.E. Schild, MD 2003;21:2004–2010. received royalties for author of the lung cancer section of 10. Albain KS, Crowley JJ, Turrisi AT 3rd, et al. Concurrent cisplatin, etopo- side, and chest radiotherapy in pathologic stage IIIB non–small-cell lung UpToDate®, and D.B. Johnson, MD received support for cancer: a Southwest Oncology Group phase II study, SWOG 9019. J Clin travel from Wichita Community Clinical Oncology Program. Oncol 2002;20:3454–3460. 11. Edelman MJ. The potential role of bortezomib in combination with chemotherapy and radiation in non–small-cell lung cancer. Clin Lung Cancer REFERENCES 2005;7(Suppl 2):S64–S66. 1. Siegel R, Naishadham D, Jemal A. Cancer statistics, 2012. CA Cancer J 12. Chen D, Frezza M, Schmitt S, et al. Bortezomib as the first proteasome Clin 2012;62:10–29. inhibitor anticancer drug: current status and future perspectives. Curr 2. Strauss GM, Langer MP, Elias AD, et al. Multimodality treatment of stage Cancer Drug Targets 2011;11:239–253. IIIA non–small-cell lung carcinoma: a critical review of the literature and 13. Voorhees PM, Orlowski RZ. The proteasome and proteasome inhibitors strategies for future research. J Clin Oncol 1992;10:829–838. in cancer therapy. Annu Rev Pharmacol Toxicol 2006;46:189–213.

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