Study design and objective

This is an open-label, multi-center, two cohort, single-arm, phase 2 trial of oral crizotinib in patients with advanced NSCLC harboring MET exon 14 skipping mutation (cohort 1) or high MET gene copy numbers of seven or more (cohort 2) (Fig. 1). The population in cohort 1 includes patients with advanced NSCLC harboring MET exon 14 skipping mutation who have not received prior MET inhibitor treatments. We will confirm MET gene alterations using a validated RT-PCR and/or NGS assay. Our primary objective is to assess the antitumor activity of oral single-agent crizotinib for advanced MET exon 14 skipping mutation-positive or MET high gene copy number-positive NSCLCs as measured by the objective response rate (ORR). Our secondary objectives included assessing secondary measures of antitumor activity by duration of response (DR); disease control rate at 8, 16, and 24 weeks; and PFS and overall survival and the safety and tolerability of oral crizotinib. This study will be conducted according to the standards of Good Clinical Practice and in compliance with the principles of the Declaration of Helsinki, and our Institutional Review Board has approved the protocol registered in the University Hospital Medical Information Network Clinical Trials Registry as UMIN000031623 (https://upload.umin.ac.jp/cgi-open-bin/ctr_e/ctr_view.cgi?recptno=R000035817). In this study, academic hospitals where at least one investigator-initiated clinical trial has been conducted in accordance with GCP standards will be recruited. Therefore, this study will be conducted at National Hospital Organization Kyushu Cancer Center, Okayama University Hospital, Hyogo Cancer Center, Nagoya University Hospital, Shizuoka Cancer Center, Kanazawa University Hospital, National Cancer Center Hospital, National Cancer Center Hospital East, and Hokkaido University Hospital, Japan.

Eligibility criteria

Table 1 shows key inclusion and exclusion criteria.

Table 1 Inclusion and exclusion criteria Full size table

Patient registration

After eligibility criteria have been confirmed and informed consent has been obtained, eligible patients are registered, and the investigators initiate the planned treatment. On the consent form, participants will be asked if they agree to the use of their data should they choose to withdraw from the trial. Participants will also be asked for permission for the research team to share relevant data with people from the Universities taking part in the research or from regulatory authorities, where relevant. This trial involves collecting biological specimens for storage.

Treatment plan

Crizotinib 250 mg BID will be administered orally at the same time on each day on a continuous daily dosing schedule unless sufficient toxicity develops to warrant dosing interruption/dose reduction. The cycles are defined as 28-day periods.

Efficacy and safety evaluation

Table 2 lists the time points for assessments of efficacy, adverse events, laboratory safety assessments (hematology, coagulation, and chemistry), physical examination, ECG, and tumor measurements. We will perform CTs and/or MRI scans every 8 weeks, and after 12 cycles, every 12 weeks for tumor assessments.

Table 2 Schedule of activities Full size table

Adverse events

Adverse events will be classified based on the type, incidence, severity (graded by the National Cancer Institute Common Terminology Criteria for Adverse Events [CTCAE] Version 4.03), timing, seriousness, and relatedness. Adverse events are defined as the appearance of (or worsening of any pre-existing) undesirable sign, symptom, or medical condition that occurs after the first dose of the study treatment. Adverse event monitoring should be continued for at least 28 days following the last dose of the study treatment or until the start of subsequent antineoplastic chemotherapy.

Data collection and management

All data will be recorded in a case report form (CRF) by investigators or clinical research coordinators. The completed CRFs will be submitted to the data center at the Five Rings Company. All study documents will be regarded as confidential. In the data center, the data will be stored and handled in a secure server maintaining the anonymity of participants.

Statistical method

In cohort 1, an ORR of 20% is a clinically meaningful threshold for this study. We based the sample size on the exact binomial distribution. Assuming a null hypothesis of a 20% ORR and an alternative hypothesis of a 50% ORR, and a one-sided alpha error of 0.05 (one-side) and 80% power, the required evaluable patients with MET exon 14 skipping mutation-positive NSCLC is 19.

We expect cohort 2 to include mostly second- or later-line patients. The ORR of second-line single-agent chemotherapy in that clinical setting is approximately 10%. The ORRs of second- or later-line treatment with PD-1/PD-L1 inhibitor for patients previously treated with platinum-based chemotherapy are 18–20% [12,13,14,15].

We determined the sample size for cohort 2 based on the precision of ORR as a primary endpoint.

Monitoring

An independent Data and Safety Monitoring Committee has been established to assess the safety data when serious adverse events may occur. A qualified and independent auditor is appointed to audit the trial systems, and the trial was conducted before and during the study in accordance with a written procedure.

Post-trial care

This clinical trial will adopt clinical trial insurance; if serious harm occurs following the clinical trial, the affected participants will receive appropriate coverage.