An Open-label, Multicenter, Phase II Study of LDK378 in Patients With Non-small Cell Lung Cancer Harboring ROS1 Rearrangement

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. 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. We 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 and to identify biomarker to predict the tumor response to LDK378.

Study Overview

• Status: Unknown
• Conditions: Non-small Cell Lung Cancer (NSCLC)
• Intervention / Treatment: Drug: LDK378

• Study Type: Interventional
• Enrollment (Anticipated): 32
• Phase: Phase 2

Contacts and Locations

Study Locations

• Korea, Republic of
  • Seoul, Korea, Republic of, 03722
    • Recruiting
    • Yonsei Cancer Center at Yonsei University Medical Center
    • Contact: Byung Chul Cho, M.D., Ph.D.; Phone Number: 82-2-2228-0880; Email: CBC1971@yuhs.ac

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 20 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Subjects with histologically or cytologically confirmed, unresectable NSCLC that carries a ROS1 rearrangement, as per FISH assay (Abbott Molecular Inc.)
• ECOG performance status of 0 to 2
• Male or female; ≥ 20 years of age
• Subjects must have received at least 1 platinum doublet to treat their locally advanced or metastatic NSCLC
• Subjects whose disease has progressed within 6 months Subjects with measurable lesion (using RECIST 1.1 criteria)
• Subjects must have recovered from all toxicities related to prior anticancer therapies to grade ≤ 2
• Subjects must have archival tissue sample available, collected either at the time of diagnosis of NSCLC or any time since
• Provision of written informed consent prior to any study specific procedures

Exclusion Criteria:

• Any unresolved chronic toxicity greater than CTC grade 2 from previous anticancer therapy.
• Any major operation or irradiation within 4 weeks of baseline disease assessment
• Any clinically significant gastrointestinal abnormalities which may impair intake or absorption of the study drug
• Subjects with symptomatic central nervous system (CNS) metastases who are neurologically unstable or have required increasing doses of steroids within the 2 weeks prior to study entry to manage CNS symptoms
• Other co-existing malignancies or malignancies diagnosed within the last 5 years with the exception of basal cell carcinoma or cervical cancer in situ or treated thyroid cancer.
• Subjects with an uncontrolled major cardiovascular disease (including AMI within 12 months, unstable angina within 6 months, over NYHA class III congestive heart failure, congenital long QT syndrome, 2° or more AV Block and uncontrolled hypertension)
• Pregnant or lactating female
• Evidence of any other significant clinical disorder or laboratory finding that makes it undesirable for the patient to participate in the study

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: LDK378 arm	Drug: LDK378; LDK378 750mg oral administration and continuously (28-day treatment schedule as one treatment cycle)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Overall response rate (ORR)	Lesions measurements are performed by CT or MRI scan, evaluation by RECIST criteria v1.1	1 month after treatment

Collaborators and Investigators

• Sponsor: Yonsei University

Study record dates

Study Major Dates

• Study Start (Actual): September 1, 2013
• Primary Completion (Anticipated): December 1, 2019
• Study Completion (Anticipated): December 1, 2019

Study Registration Dates

• First Submitted: October 9, 2013
• First Submitted That Met QC Criteria: October 14, 2013
• First Posted (Estimate): October 17, 2013

Study Record Updates

• Last Update Posted (Actual): January 11, 2019
• Last Update Submitted That Met QC Criteria: January 9, 2019
• Last Verified: January 1, 2019

More Information

Terms related to this study

• Keywords: non-small cell lung cancer (NSCLC)
• Additional Relevant MeSH Terms: Respiratory Tract Diseases; Neoplasms; Lung Diseases; Neoplasms by Site; Respiratory Tract Neoplasms; Thoracic Neoplasms; Carcinoma, Bronchogenic; Bronchial Neoplasms; Lung Neoplasms; Carcinoma, Non-Small-Cell Lung; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antineoplastic Agents; Protein Kinase Inhibitors; Ceritinib
• Other Study ID Numbers: 4-2013-0237