Non-small Cell Lung Cancer Harboring ROS1 RearrangementPhase 2NCT03399487
A Study of LDK378 in Patients With Non-small Cell Lung Cancer Harboring ROS1 Rearrangement
A Phase 2 study testing LDK378(Ceritinib) in people with Non-small Cell Lung Cancer Harboring ROS1 Rearrangement, run by Yonsei University at 1 site in South Korea.
Trial 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… Read more about this study
- Who is it for?
- Ages 20 years and older
- Conditions the study is for
- Non-small Cell Lung Cancer Harboring ROS1 Rearrangement
- What is being tested?
- LDK378(Ceritinib)
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 46 participants
- Where
- 1 siteSouth Korea
- Study dates
- 24 Jul 2018to Oct 2020
- Phase
- Phase 2
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 20 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- histologically or cytologically confirmed, stage IV or recurrent NSCLC that carries a ROS1 rearrangement, as per anchored multiplex PCR
- ECOG performance status of 0 to 2
- Male or female≥ 20 years of age
- treatment naive or may be allowed up to 2 prior systemic anti-cancer therapy for their stage IV or recurrent NSCLC, which includes cytotoxic chemotherapy and I-O, but excludes crizotinib.
- measurable lesion (using RECIST 1.1 criteria)
- measurable lesion (using RECIST 1.1 criteria)
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- archival tissue sample available, collected either at the time of diagnosis of NSCLC or any time since
- Subjects who meet the following criteria:
- ANC 1.5 x 109/L -Platelet 100 x 109/L
- creatinine 1.5 x ULN
- AST (SGOT) and ALT (SGPT) 3 x ULN (If there is Liver Metastasis 5 x ULN
- Total bilirubin 1.5 x ULN
- written informed consent prior to any study specific procedures
- Leptomeningeal carcinomatosis may be included
Who cannot join
- More than two actionable mutations
- Patients who received prior crizotinib 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 who have CNS complications that require urgent neurosurgical intervention(e.g. resection or shunt placement)
- Other co-existing malignancies or malignancies diagnosed within the last 3 years with the exception of basal cell carcinoma or cervical cancer in situ or treated thyroid cancer.
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- 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
- Patients with known history of extensive disseminated bilateral interstitial fibrosis or interstitial lung disease, including a history of pneumonitis, hypersensitivity pneumonitis, interstitial pneumonia, obliterative bronchiolitis, and clinically significant radiation pneumonitis (i.e. affecting activities of daily living or requiring therapeutic intervention).
- Receiving medications that meet one of the following criteria and that cannot be discontinued at least 1 week prior to the start of treatment with LDK378 and for the duration of participation (see Appendix 1 Tables):
- Medication with a known risk of prolonging the QT interval or inducing Torsades de Pointes (please refer to http://www.azcert.org/medical-pros/drug-lists/drug-lists.cfm)
- Strong inhibitors or strong inducers of CYP3A4/5 (please refer to http://medicine.iupui.edu/flockhart/table.htm or http://www.druginteractioninfo.org)
- Medications with a low therapeutic index that are primarily metabolized by CYP3A4/5, CYP2C8 and/or CYP2C9 (please refer to http://medicine.iupui.edu/flockhart/table.htm or http://www.druginteractioninfo.org)
- Therapeutic doses of warfarin sodium (Coumadin) or any other coumadin-derived anti-coagulant. Anticoagulants not derived from warfarin are allowed (eg, dabigatran, rivaroxaban, apixaban).
- Unstable or increasing doses of corticosteroids
- enzyme-inducing anticonvulsive agents
- herbal supplements
- Patients who have received thoracic radiotherapy to lung fields ≤ 4 weeks prior to starting the study treatment or patients who have not recovered from radiotherapy-related toxicities. For all other anatomic sites (including radiotherapy to thoracic vertebrae and ribs), radiotherapy ≤ 2 weeks prior to starting the study treatment or patients who have not recovered from radiotherapy-related toxicities. Palliative radiotherapy for bone lesions ≤ 2 weeks prior to starting study treatment is allowed.
Trial locations and contacts
1 site in 1 country.
South Korea1 site, 1 recruiting
- Recruiting
Division of Medical Oncology, Yonsei Cancer Center, Yonsei University College of Medicine
Seoul, 120-752
Byoung Chul Cho, MD, 82-2-2228-8126, cbc1971@yuhs.ac
About this study
Official title: An Open-label, Multicenter, Phase II Study of LDK378 in Patients With Non-small Cell Lung Cancer Harboring ROS1 Rearrangement
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.
Read more
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.
Read the 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.
- Being tested
- LDK378(Ceritinib)
- Keywords
- NSCLC, ROS1 rearrangement, Ceritinib, LDK378
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
LDK378(Ceritinib)Drug
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.
| Study group | Role | What they receive |
|---|---|---|
| Arm 1 | Experimental | 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. Receives: Drug: LDK378(Ceritinib) |
What is being measured
The primary outcome is the main question the study is designed to answer.
(ORR) overall response rate
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).
Measured: 2 years
Secondary outcomes (4)
PFS (progression-free survival ) in months
Progression-free survival in months
Measured: up to 2 years
OS (overall survival) in months
Overall survival in months
Measured: up to 5 years
DCR (disease control rate) in percentage
Disease control rate in percentage
Measured: After study completion (an average of 2 year)
Incidence of Treatment-related adverse events in AE event name and grade
Incidence of treatment-related adverse events
Measured: After study completion (an average of 2 year)
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted16 Jan 2018
- Study start24 Jul 2018
- Primary completionMay 2020 (estimated)
- Study completionOct 2020 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for Non-small Cell Lung Cancer Harboring ROS1 RearrangementStudies of the same condition, open and under way.
- More trials run by Yonsei UniversityThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 2
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Enrolment
- 46 participants (estimated)
Sponsor and investigators
- Lead sponsor
- Yonsei University
- Sponsor type
- University, hospital or other
- Responsible party
- Sponsor
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT03399487
- Sponsor's protocol ID
- 4-2017-0240
- Status last verified
- Jan 2019
- First submitted
- 21 Sep 2017
- Last updated
- 11 Jan 2019
- Results posted
- No
- Data monitoring committee
- No
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- No
Study at a glance
From the registry record, last updated by the sponsor on 11 Jan 2019. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- An Open-label, Multicenter, Phase II Study of LDK378 in Patients With Non-small Cell Lung Cancer Harboring ROS1 Rearrangement
- ClinicalTrials.gov ID
- NCT03399487
- Acronym / sponsor ID
- 4-2017-0240
- Keywords
- NSCLC, ROS1 rearrangement, Ceritinib, LDK378
- Phase
- Phase 2
- Study type
- Interventional
- Recruitment status
- Unknown status
- Enrolment
- 46 participants (estimated)
- Lead sponsor
- Yonsei UniversityUniversity, hospital or other
- Study start
- 24 Jul 2018 (actual)
- Primary completion
- May 2020 (estimated)
- Study completion
- Oct 2020 (estimated)
- First posted
- 16 Jan 2018 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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 design
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Number of arms
- 1
| Arm | Type | Receives |
|---|---|---|
| Arm 1 | Experimental | Drug: 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. |
Who may qualify
- Ages
- 20 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (14 listed)
- histologically or cytologically confirmed, stage IV or recurrent NSCLC that carries a ROS1 rearrangement, as per anchored multiplex PCR
- ECOG performance status of 0 to 2
- Male or female≥ 20 years of age
- treatment naive or may be allowed up to 2 prior systemic anti-cancer therapy for their stage IV or recurrent NSCLC, which includes cytotoxic chemotherapy and I-O, but excludes crizotinib.
- measurable lesion (using RECIST 1.1 criteria)
Key exclusion criteria (18 listed)
- More than two actionable mutations
- Patients who received prior crizotinib 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 who have CNS complications that require urgent neurosurgical intervention(e.g. resection or shunt placement)
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| 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. | Drug | Arm 1 |
Primary outcome
(ORR) overall response rate
Time frame: 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).
4 secondary outcomes
PFS (progression-free survival ) in months
Time frame: up to 2 years
OS (overall survival) in months
Time frame: up to 5 years
DCR (disease control rate) in percentage
Time frame: After study completion (an average of 2 year)
Incidence of Treatment-related adverse events in AE event name and grade
Time frame: After study completion (an average of 2 year)
Results and safety
Results are not available in the source record.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 11 Jan 2019.
- Individual participant dataSharing planned: No
Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 2 study testing LDK378(Ceritinib) in people with Non-small Cell Lung Cancer Harboring ROS1 Rearrangement, run by Yonsei University at 1 site in South Korea.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 14 inclusion and 18 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: status not confirmed, as of the sponsor's last update on 11 Jan 2019. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in South Korea. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Results are not available in the source record.
How can a doctor refer a patient or contact the research team?
Contact Byoung Chul Cho, MD (82 2 2228 0880, cbc1971@yuhs.ac), or a site near the patient. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
(ORR) overall response rate (time frame: 2 years). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 11 Jan 2019.