LDK378 in Crizotinib naïve Adult Patients With ALK-activated Non-small Cell Lung Cancer

Study Overview
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Brief Summary
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A single-arm, open-label, two-stage multicenter, phase II study. Patients were pre-screened for ALK positive status. Treatment with LDK378 at 750 mg qd was continued until the patient experienced unacceptable toxicity that precluded further treatment, discontinued treatment at the discretion of the investigator or patient, started a new anticancer therapy and/or died. LDK378 was continued beyond RECIST defined progressive disease (PD) as assessed by the investigator, if in the judgment of the investigator, there was evidence of clinical benefit. Patients who discontinued the study medication in the absence of progression continued to be followed for tumor assessment until the time of PD as assessed by the investigator. Male and female patients aged 18 or over with ALK-rearranged non-small cell cancer (NSCLC) were screened for eligibility. Patients had to have received no prior crizotinib, and had to be chemotherapy-naïve or been pretreated with cytotoxic chemotherapy (up to three prior lines).

Official Title
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A Phase II, Multicenter, Single-arm Study of Oral LDK378 in Crizotinib naïve Adult Patients With ALK-activated Non-small Cell Lung Cancer

Conditions
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Non-Small Cell Lung Cancer

Intervention / Treatment
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* Drug: LDK378


Participation Criteria
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Eligibility Criteria
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Key Inclusion criteria: Histologically or cytologically confirmed diagnosis of stage IIIB or IV NSCLC that carried an ALK rearrangement, as per the FDA-approved Vysis ALK break-apart FISH assay (Abbott Molecular Inc.) Age 18 years or older at the time of informed consent. Patients must have NSCLC that had progressed during or after the last chemotherapy regimen received prior to the first dose of LDK378, if chemotherapy was received Patients must have been chemotherapy-naive or had received 1-3 lines of cytotoxic chemotherapy to treat their locally advanced or metastatic NSCLC Patients must have had a tumor tissue sample available, collected either at the time of diagnosis of NSCLC or any time since. Patients must have recovered from all toxicities related to prior anticancer therapies to grade ≤ 2, except for patients with grade 2 nausea/vomiting and/or grade 2 diarrhea despite optimal supportive therapy who were not allowed to participate in the study. Key Exclusion criteria: Prior treatment with crizotinib, or any other ALK inhibitor investigational agent, for NSCLC Patients with known hypersensitivity to any of the excipients of LDK378. Patients with symptomatic central nervous system (CNS) metastases who were neurologically unstable or had required increasing doses of steroids within the 2 weeks prior to study entry to manage CNS symptoms. History of carcinomatous meningitis. Presence or history of a malignant disease other than NSCLC that has been diagnosed and/or required therapy within the past 3 years. Clinically significant, uncontrolled heart disease.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: LDK378 (Ceritinib)<br>Participants on this arm took oral LDK378 750 mg once daily. | Drug: LDK378<br>* LDK378/Ceritinib was supplied as 150 mg hard gelatin capsules and administered orally<br>* Other names: Ceritinib;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Response Rate (ORR) by Investigator Assessment | ORR per RECIST 1.1 calculated as the percentage of participants with a best overall response (OR) defined as complete response (CR) or partial response (PR) as assessed by the investigator. CR:Disappearance of all non-nodal target lesions. In addition, any pathological lymph nodes assigned as target lesions must have a reduction in short axis to < 10 mm. PR: At least a 30% decrease in the sum of diameter of all target lesions, taking as reference the baseline sum of diameters. | every 8 weeks (i.e. every 2 cycles; cycle = 28 days), starting from the first day of treatment with LDK378 until permanent discontinuation of study drug up to 5 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| ORR by Blinded Independent Review Committee (BIRC) | ORR per RECIST 1.1 calculated as the percentage of participants with a best overall response (OR) defined as complete response (CR) or partial response (PR) as assessed by BIRC. CR: Disappearance of all non-nodal target lesions. In addition, any pathological lymph nodes assigned as target lesions must have a reduction in short axis to < 10 mm. PR: At least a 30% decrease in the sum of diameter of all target lesions, taking as reference the baseline sum of diameters. | every 8 weeks (i.e. every 2 cycles; cycle = 28 days), starting from the first day of treatment with LDK378 until permanent discontinuation of study drug up to 5 years | 
| Duration of Response (DOR) as Per Investigator | DOR, calculated as the time from the date of the first documented CR or PR to the first documented progression or death due to any cause, by investigator assessment per RECIST 1.1. CR: Disappearance of all non-nodal target lesions. In addition, any pathological lymph nodes assigned as target lesions must have a reduction in short axis to < 10 mm. PR: At least a 30% decrease in the sum of diameter of all target lesions, taking as reference the baseline sum of diameters. | every 8 weeks (i.e. every 2 cycles; cycle = 28 days), starting from the first day of treatment with LDK378 until permanent discontinuation of study drug up to 5 years | 
| Duration of Response (DOR) as Per BIRC | DOR, calculated as the time from the date of the first documented CR or PR to the first documented progression or death due to any cause, by BIRC assessment per RECIST 1.1. CR: Disappearance of all non-nodal target lesions. In addition, any pathological lymph nodes assigned as target lesions must have a reduction in short axis to < 10 mm. PR: At least a 30% decrease in the sum of diameter of all target lesions, taking as reference the baseline sum of diameters. | every 8 weeks (i.e. every 2 cycles; cycle = 28 days), starting from the first day of treatment with LDK378 until permanent discontinuation of study drug up to 5 years | 
| Disease Control Rate (DCR) as Per Investigator and BIRC | DCR per RECIST 1.1 is the percentage of participants with best overall response of CR, PR, stable disease (SD) or Non-CR/Non-PD. CR: Disappearance of all non-nodal target lesions. Also, any pathological lymph nodes assigned as target lesions must have a reduction in short axis to < 10 mm. PR: At least a 30% decrease in the sum of diameter of all target lesions, taking as reference the baseline sum of diameters. SD: Neither sufficient shrinkage to qualify for PR or CR nor an increase in lesions that would qualify for PD. PD: At least a 20% increase in the sum of diameter of all measured target lesions, taking as reference the smallest sum of diameter of all target lesions recorded at or after baseline. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5mm. | every 8 weeks (i.e. every 2 cycles; cycle = 28 days), starting from the first day of treatment with LDK378 until permanent discontinuation of study drug up to 5 years | 
| Time to Response (TTR) as Per Investigator | TTR, calculated as the time from first dose of LDK378 to first documented response (CR+PR), by investigator. This was only on participants with confirmed CR or PR. CR: Disappearance of all non-nodal target lesions. In addition, any pathological lymph nodes assigned as target lesions must have a reduction in short axis to < 10 mm. PR: At least a 30% decrease in the sum of diameter of all target lesions, taking as reference the baseline sum of diameters. | every 8 weeks (i.e. every 2 cycles; cycle = 28 days), starting from the first day of treatment with LDK378 until permanent discontinuation of study drug | 
| Time to Response (TTR) as Per BIRC | TTR, calculated as the time from first dose of LDK378 to first documented response (CR+PR), by BIRC assessment. This was only on participants with confirmed CR or PR. CR: Disappearance of all non-nodal target lesions. In addition, any pathological lymph nodes assigned as target lesions must have a reduction in short axis to < 10 mm. PR: At least a 30% decrease in the sum of diameter of all target lesions, taking as reference the baseline sum of diameters. | every 8 weeks (i.e. every 2 cycles; cycle = 28 days), starting from the first day of treatment with LDK378 until permanent discontinuation of study drug up to 5 years | 
| Overall Intracranial Response Rate (OIRR) as Per Investigator | OIRR calculated as the ORR (CR+PR) of lesions in the brain for patients who have measureable disease in the brain at baseline by investigator. | every 8 weeks (i.e. every 2 cycles; cycle = 28 days), starting from the first day of treatment with LDK378 until permanent discontinuation of study drug up to 5 years | 
| Overall Intracranial Response Rate (OIRR) as Per BIRC | OIRR calculated as the ORR (CR+PR) of lesions in the brain for patients who have measureable disease in the brain at baseline by BIRC. | every 8 weeks (i.e. every 2 cycles; cycle = 28 days), starting from the first day of treatment with LDK378 until permanent discontinuation of study drug up to 5 years | 
| Progression-free Survival (PFS) Per Investigator and BIRC | PFS, defined as time from first dose of LDK378 to progression or death due to any cause, as assessed by investigator and BIRC assessments. | every 8 weeks (i.e. every 2 cycles; cycle = 28 days), starting from the first day of treatment with LDK378 until permanent discontinuation of study drug up to 5 years | 
| Overall Survival (OS) | OS, defined as time from first dose of LDK378 to death due to any cause | Time from the date of first dose of LDK378 to the date of death due to any cause up to 5 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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lung cancer, Non-Small Cell Lung Cancer, Non small cell lung carcinoma, NSCLC, ALK, LDK378, Ceritinib, crizotinib naïve adult patients, ALK-activated non-small cell lung cancer, treatment of lung cancer after first metastasis, lung adenocarcinoma