Nivolumab Maintenance as Monotherapy after Carboplatin Plus Nab-Paclitaxel for First-Line Treatment of Advanced Non-Small-Cell Lung Cancer: Study Protocol for Feasibility

The aim of this study is to determine the feasibility of nivolumab as maintenance therapy after first-line chemotherapy with carboplatin plus nab-paclitaxel in non-small-cell lung cancer. Since we cannot change the dose of nivolumab, we will investigate the recommended doses and cycles of pretreatment chemotherapy with carboplatin plus nab-paclitaxel that affect maintenance therapy. The primary endpoint is incidence of any grade ≥ 3 adverse events during the first 12 weeks of nivolumab treatment. Twelve patients are required in this study.


Introduction
Nivolumab, a fully Immunoglobulin G4 (IgG4) programmed death-1 antibody, has demonstrated activity and tolerability in previously treated advanced non-small-cell lung cancer (NSCLC) [1]. A significant improvement in overall survival (OS) with nivolumab was observed in squamous NSCLC patients in the CheckMate 017 trial (nivolumab versus docetaxel) and in non-squamous NSCLC patients in the CheckMate 057 trial (nivolumab versus docetaxel) [2,3]. Nivolumab was also associated with longer progression-free survival (PFS) compared with docetaxel in the CheckMate 017 trial. In the study of nivolumab in combination with platinum-based doublet chemotherapy in NSCLC, it has been reported that the safe profile of nivolumab and platinum-based chemotherapy was consistent with what would be expected for individual drugs [4]. However, treatmentrelated adverse events led to discontinuation in 21% of patients, and discontinuation of treatment associated with adverse events was higher with combination therapy [4].
The safety and efficacy of pemetrexed and bevacizumab have been proven as maintenance therapy for non-squamous NSCLC. Continued maintenance therapy with pemetrexed after induction therapy with cisplatin plus pemetrexed significantly improved PFS and OS compared with placebo therapy for non-squamous NSCLC, and switching to maintenance therapy with pemetrexed after platinumbased doublet chemotherapy also improved PFS and OS [5,6]. Continued maintenance therapy with bevacizumab after carboplatin plus paclitaxel had a significant survival benefit compared with carboplatin plus paclitaxel alone therapy [7]. Nab-paclitaxel as maintenance therapy after carboplatin plus nab-paclitaxel in squamous NSCLC is under clinical trial [8]. Maintenance therapy after first-line chemotherapy is being established as a common treatment for both non-squamous and squamous NSCLC.
Based on these considerations, we conducted a feasibility study of nivolumab as maintenance therapy after first-line chemotherapy with carboplatin plus nab-paclitaxel for NSCLC.

Protocol of the Study Objective
The study is a feasibility study that is designed to demonstrate the safety and efficacy of maintenance nivolumab monotherapy administered to patients with advanced NSCLC who showed clinical benefit from first-line chemotherapy with carboplatin plus nabpaclitaxel.

Endpoints
The primary endpoint is determination of the optimal doses and cycles of first-line chemotherapy with carboplatin plus nab-paclitaxel in accordance with the incidence of any grade ≥ 3 events during the first 12 weeks of nivolumab treatment. The secondary endpoints are response rate, disease control rate, PFS, and OS.

Inclusion criteria
The inclusion criteria are: Histologically or cytologically confirmed NSCLC

Registration
An eligible report form will be sent to the registration center at the Clinical Research Institute of Kyushu Medical Center. Information on necessary follow-up tests will then be sent from the registration center.

Study Design
This study is being conducted in accordance with the Declaration of Helsinki and is registered with the University Hospital Medical Information Network in Japan, number UMIN000027985. The research protocol was approved by the ethics committee of Kyushu Medical Center (registration number 17A105).

Treatment plan and evaluation
According to the study of nivolumab in combination with platinumbased chemotherapy, it has been reported that 45% of patients had grade 3 or 4 treatment-related adverse events [4]. Therefore, we stipulated that induction chemotherapy is unacceptable if nivolumab maintenance monotherapy has an incidence of more than 45% for grade 3 or 4 adverse events. If three or more of the first six patients who had been originally allocated to level 1 experience nivolumabinduced grade 3-4 toxicity, an additional six patients will be enrolled to level 0. (Level 1, carboplatin at an area under the concentration time curve (AUC) 6 mg/ml/min on day 1+nab-paclitaxel 100 mg/m 2 on days 1, 8, and 15 with treatment cycles repeated every 3 weeks for a planned maximum of four cycles; Level 0, carboplatin AUC 5 mg/ml/min on day 1+nab-paclitaxel 100 mg/m 2 on days 1, 8, and 15 with treatment cycles repeated every 3 weeks for a planned maximum of three cycles). If two or less of the first six patients in level 1 experience nivolumab-induced grade 3-4 toxicity, an additional six patients will be enrolled to level 1. We will evaluate optimal doses and cycles of first-line chemotherapy with carboplatin plus nab-paclitaxel for a phase II study. The investigator will evaluate the grade of any adverse events before, during (until first 12 weeks), and after nivolumab monotherapy. In addition, the decision to administer nivolumab monotherapy will be made within 3-5 weeks after the end of first-line chemotherapy with carboplatin plus nab-paclitaxel. Evaluations of toxicity are based on the National Cancer Institute Common Terminology Criteria for Adverse Events, version 4.0 (NCI-CTCAE v4.0). Tumor response is also evaluated every month by Response Evaluation Criteria in Solid Tumors (RECIST) version. 1.1 criteria against the target lesion.

Confidentiality
Clinical data is used for research purposes only. Results are kept anonymous and safe.