Clinical study design
This study was a multicenter, open-label, single-arm, prospective, phase I study that combined dose escalation and expansion to evaluate treatment tolerability, safety, and efficacy. This study was performed in accordance with the ethical principles outlined in the Declaration of Helsinki and was approved by the institutional ethics committees of the participating institutes. As the Clinical Trials Act was revised during this clinical trial, this study was reviewed and approved by the certified review board of Shizuoka Cancer Center. All patients provided written informed consent prior to enrollment. The study was registered with the University Hospital Medical Information Network in Japan (UMIN 000014764) and the Japan Registry of Clinical Trials (jRCTs042180077).
Elderly patients with unresectable stage III NSCLC were eligible for this study. The eligibility criteria were as follows: (1) cytologically or histologically confirmed NSCLC; (2) clinical stage III (based on the 7th edition of the International Union for Cancer Control TNM classification ) and unresectable locally advanced tumor; (3) curative radiotherapy was feasible (including percent lung volume receiving at least 20 Gy [V20] ≤ 35%, no contralateral hilar lymph node metastasis, no associated separate tumor nodule in the same lobe as the primary, no atelectasis of unilateral whole lung); (4) no prior chemotherapy or thoracic radiotherapy; (5) at least one measurable lesion according to Response Evaluation Criteria in Solid Tumors (RECIST ver1.1) ; (6) age ≥ 75 years; (7) Eastern Cooperative Oncology Group performance status (ECOG-PS) score 0–1; (8) sufficient function of major internal organs (lung: a blood gas oxygen level in room air of ≥ 70 torr; bone marrow: a neutrophil count of ≥ 1,500/mm3, a hemoglobin content of ≥ 9.0 g/dL, a platelet count of ≥ 100,000/mm3; liver: aspartate aminotransferase [AST] and alanine aminotransferase [ALT] levels of ≤ 100 IU/mL, a total bilirubin concentration of ≤ 1.5 mg/dL; kidneys: a creatinine concentration of ≤ 1.2 mg/dL); (9) life expectancy of at least 90 days. All eligible patients underwent computed tomography (CT) scans of the thorax and abdomen within 28 days before enrollment. Brain CT, magnetic resonance imaging, and positron emission tomography were performed within 42 days before enrollment. Patients who had active concomitant malignancy or radiographically confirmed interstitial pneumonia, active severe infection, or other serious comorbidities were excluded.
All patients received nab-paclitaxel and carboplatin weekly for 6 weeks (Fig. 1). Carboplatin was administered at a fixed area under the plasma concentration time curve (AUC) dose of 2 mg/mL/min via intravenous infusion for 60 min on days 1, 8, 15, 22, 29, and 36, and nab-paclitaxel was administered at a dose of 30 mg/m2 (dose level 1) or 40 mg/m2 (dose level 2) via intravenous infusion for 60 min on days 1, 8, 15, 22, 29, and 36. For chemotherapy administration, patients had to meet the following criteria: ECOG-PS 0–1, no fever suggestive of infection, no interruption of radiation therapy, a neutrophil count of ≥ 1,000/mm3, a platelet count of ≥ 75,000/mm3; a creatinine concentration of ≤ 1.2 mg/dL, and other non-hematologic toxicities of grade ≤ 2 except for electrolyte abnormalities without clinical symptoms.
All patients received linear accelerator photon beam radiation at 6–10 MV from day 1 onwards. The primary tumor and involved lymph nodes received 64 Gy in 2-Gy fractions over 6.5 weeks. Three-dimensional treatment planning systems were used in this study. The gross tumor volume (GTV) was delineated according to the primary tumor and any regional nodal involvement determined from CT and PET/CT information. The clinical target volume (CTV) was defined and contoured to 5–10 mm around the GTV. The planning target volume (PTV) included CTV plus a margin of ≥ 5 mm. Elective nodal irradiation was not performed in this study. Beam shaping was accomplished using a multileaf collimator. The dose was prescribed to the isocenter. Per-protocol PTV coverage was achieved when more than 95% of the PTV received 93% or more of the prescribed dose and when minimum margin values for both CTV and PTV were achieved. Normal tissue dosimetric constraints were as follows: maximum spinal cord dose was 52 Gy and 1 cc dose was 48 Gy; normal lung volume irradiated with ≥ 20 Gy was 35% of total lung volume minus GTV. The dose was calculated using heterogeneity correction. Intensity-modulated radiation therapy was not acceptable in this study. If any of the following interruption criteria were met, thoracic radiotherapy was interrupted: a neutrophil count of < 500/mm3, a platelet count of < 25,000/mm3, fever of ≥ 38°C suggesting infection, grade 3 or 4 esophagitis or dermatitis, or any grade of pneumonitis.
Dose-limiting toxicity (DLT) was defined according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) version 4.0. DLT was evaluated from day 1 to day 90 and included non-hematologic toxicities of grade 4, non-hematologic toxicities of grade 3 lasting for 3 days or longer that did not improve with proper supportive care (excluding laboratory abnormalities without clinical symptoms), neutropenia of grade 4 lasting 8 days or more, febrile neutropenia, thrombocytopenia of grade 4 (or thrombocytopenia of grade 3 requiring platelet transfusion), skipping chemotherapy more than once, incompletion of radiotherapy by day 58, pneumonitis of grade 2 during study treatment, or pneumonitis of grade 3 after study treatment. At least three patients were enrolled at each dose level. First, three patients received dose level 1 (nab-paclitaxel 30 mg/m2), and no intrapatient dose escalation was allowed. If a DLT was observed in these first three patients, three more patients were enrolled at this dose level and dose escalation to the next dose level continued if less than three out of six patients experienced a DLT. The maximum tolerated dose (MTD) was defined as the level before the one at which a DLT was observed in two out of three or three out of six patients. The RD was defined as the level below the MTD. If the MTD was not reached by dose level 2, this level was considered the RD.
Evaluation of efficacy and safety
All eligible patients underwent complete blood cell count, blood chemistry test, and chest X-ray once a week during the study period. CT was performed every 6–12 weeks during the first year and every 12–24 weeks thereafter. All responses were defined according to RECIST version 1.1. Progression-free survival (PFS) was defined as the time from enrollment to the date of confirmation of progressive disease or the date of death from any cause (whichever occurred earlier). Overall survival (OS) was defined as the time from enrollment until death from any cause. Toxicity was assessed according to NCI-CTCAE version 4.0.
The primary endpoint of the dose expansion study was the treatment completion rate. Treatment completion was defined as the receipt of at least five doses of nab-paclitaxel plus carboplatin and 64 Gy of thoracic radiotherapy within 58 days from the start of treatment. We considered tolerability and safety to be the most important aspects for elderly Japanese patients because severe lung toxicities have been reported in these patients [11, 12]. In addition, we considered that the regimen to be effective if the tolerability was the same as that of carboplatin/paclitaxel in non-elderly patients with locally advanced NSCLC .
Based on the results of a previous comparative phase III study using carboplatin/paclitaxel in non-elderly patients , the expected treatment completion rate for the present study was assumed to be 85%, with 60% set as the lower limit of interest. Based on this assumption, the study was designed to have a power of 90% and a one-sided alpha error of 0.10, resulting in a requirement of 20 patients. However, because patient enrollment was slower than planned, we changed the power from 90–80% after the start of the study. Consequently, the required number of patients was 14, and the planned number of registrations was 15. The expansion study included patients from the dose-escalation study treated at the RD. Secondary endpoints of the expansion study were the response rate, PFS, OS, 2-year survival rate, location of progression, and safety. PFS and OS were estimated using the Kaplan–Meier method. All statistical analyses were performed using JMP 10 for Windows (SAS Institute Inc., Cary, NC, USA) and R4.0.3 (R Foundation for Statistical Computing, Vienna, Austria).
Initially, the enrolled patients were followed up without anticancer treatment after the end of the study. However, as durvalumab was approved as a maintenance therapy for locally advanced NSCLC patients who were treated with platinum-based definitive chemoradiotherapy and had no disease progression after chemoradiotherapy, durvalumab maintenance therapy after study treatment was allowed since February 2019.