Ignite Creation Date:
2024-05-06 @ 10:57 AM
Last Modification Date:
2024-10-26 @ 12:38 PM
Study NCT ID:
NCT03399487
Status:
UNKNOWN
Last Update Posted:
2019-01-11
First Post:
2017-09-21
Brief Title:
A Study of LDK378 in Patients With Non-small Cell Lung Cancer Harboring ROS1 Rearrangement
Sponsor:
Yonsei University
Organization:
Yonsei University
Study Overview
Official Title:
An Open-label Multicenter Phase II Study of LDK378 in Patients With Non-small Cell Lung Cancer Harboring ROS1 Rearrangement
Status:
UNKNOWN
Status Verified Date:
2019-01
Last Known Status:
RECRUITING
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
None
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 ALKMET 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
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 ALKMET 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 32 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 015 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
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 015 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 Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
False
Is a FDA Regulated Device?:
False
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None