A Study of LDK378 in Patients With Non-small Cell Lung Cancer Harboring ROS1 Rearrangement

Phase 2

• Conditions: Non-small Cell Lung Cancer Harboring ROS1 Rearrangement
• Interventions: Drug: LDK378(Ceritinib)

• Registration Number: NCT03399487
• Lead Sponsor: Yonsei University

Brief Summary

Lung cancer is the most leading cause of cancer-related mortality worldwide. Most of the patients with lung cancer are advanced stage at the time of diagnosis.

The two oncogenes that are important in lung cancer are epidermal growth factor receptor (EGFR) and K-ras, mutated in 10% and 15% of non-small cell lung cancer (NSCLC) patients. Large-scale DNA sequencing efforts have identified mutations in BRAF, PI3KCA and ERBB2 that together represent another 5% of NSCLC patients. The success of EGFR tyrosine kinase inhibitors (TKIs), such as gefitinib or erlotinib, and more recently ALK/MET TKI, crizotinib, highlights the need to develop more genetically matched therapies. Therefore, genetic classification of lung cancer has become increasingly important along with the advances with targeted therapies.

ROS1 is a receptor tyrosine kinase with constitutive kinase activity. ROS1 was previously discovered in cell lines where ROS1 fused with other proteins to act as a driver oncogene. In 2007, Rikova et al reported ROS1 fusion as driver mutations in NSCLC cell line (HCC78; SLC34A2-ROS1) and NSCLC patient (CD74-ROS1). Li et al also found about 1% of samples harboring CD74-ROS1 fusion in 202 resected lung adenocarcinomas from never smokers. The incidence was as high as 10% in East Asian population. Currently there are now at least 13 ROS1 fusion variants involving 8 fusion partners (CD74-, SLC34A2-, FIG-, TPM3-, SDC4-, LRIG3-, ERZ-, KDERL2-) identified in ROS1 positive NSCLC.

Interestingly, preclinical and clinical data have shown ROS1-positive tumors are sensitive to crizotinib, because of potentially high common amino acid residues in the kinase domain between ALK and ROS1, which explain why crizotinib can inhibit both ROS1 and ALK to similar extent. Preliminary report from a phase I clinical trial of crizotinib in the ROS1-positive NSCLC expansion cohort showed an overall response rate (ORR) of 57%. Given that crizotinib has made remarkable clinical outcomes in phase I trial of ALK-positive NSCLC patients, clinical development of ROS1 inhibitors, including crizotinib, should be accelerated to provide targeted therapies to ROS1-positive NSCLC patients.

Detailed Description

Recently, our group found the prevalence of ROS1 rearrangement reached up to 3.2% in clinically selected population (never smokers) and 5% in genetically selected population (EGFR-/ALK-wild-type). These data strongly suggests that ROS1 rearrangement is a potential therapeutic target with relatively high incidence. In this study, investigator confirmed the presence of ROS1 fusion by RT-PCR and correlation between FISH and IHC (Cell Signaling Technology®).

LDK378 is an orally highly selective and potent ALK kinase inhibitor. In preclinical studies, LDK378 has much lower IC50 values than crizotinib in cell lines engineered to express ROS1 rearrangement (0.15 nM versus 3 nM) and is approximately 20-fold more potent. LDK378 is a potent inhibitor of tumor growth in rodent models of both ALCL and NSCLC.

Investigators suggest a phase II trial of LDK378 in advanced non-small cell lung cancer patients with ROS1 rearrangement. The aim of current trial is to evaluate the antitumor efficacy and safety profile of LDK378.

Study Timeline

• Study First Submitted: 2017-09-21
• Study First Submitted QC: 2018-01-12
• Study First Posted: 2018-01-16
• Study Start: 2018-07-24
• Status Verified: 2019-01
• Last Update Submitted: 2019-01-09
• Last Update Posted: 2019-01-11
• Primary Completion: 2020-05
• Study Completion: 2020-10

Recruitment & Eligibility

• Status: UNKNOWN
• Sex: All
• Target Recruitment: 46

Inclusion Criteria

Not provided

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Exclusion Criteria

Not provided

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Study & Design

• Study Type: INTERVENTIONAL
• Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Arm 1	LDK378(Ceritinib)	This study is a phase II, single-arm, open label study. All participating patients must sign on the written informed consent form, and a separate form of consent will be used for the use of tissue for the biomarker research. This clinical study is targeted for the patients who harbor ROS1 rearrangement and all patients will be treated with LDK378 750mg daily. The treatment period begins on Day 1 of Cycle 1 and 1 cycle consists of 28 days. Patients will be continued to receive study drug until the end of study unless the patients in disease progression, unacceptable toxicity, withdrawn consent, or by the investigator's judgment.

Primary Outcome Measures

Name	Time	Method
(ORR) overall response rate	2 years	The primary purpose is to investigate the overall response rate (ORR) of LDK378 by independent review committee (IRC) (Tumor assessment will measure the change of tumor size).

Secondary Outcome Measures

Name	Time	Method
Incidence of Treatment-related adverse events in AE event name and grade	After study completion (an average of 2 year)	Incidence of treatment-related adverse events
PFS (progression-free survival ) in months	up to 2 years	Progression-free survival in months
OS (overall survival) in months	up to 5 years	Overall survival in months
DCR (disease control rate) in percentage	After study completion (an average of 2 year)	Disease control rate in percentage

Trial Locations

Locations (1)

Division of Medical Oncology, Yonsei Cancer Center, Yonsei University College of Medicine; 🇰🇷 Seoul, Korea, Republic of