LDK378 in Adult Chinese Patients With ALK-rearranged (ALK-positive) Advanced Non-small Cell Lung Cancer (NSCLC) Previously Treated With Crizotinib

Study Overview
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Brief Summary
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A single-Arm, open-label, multi-center, phase I/II study in which the pharmacokinetics, safety, tolerability and efficacy of LDK378 will be assessed in adult Chinese patients with locally advanced or metastatic NSCLC harboring a confirmed ALK rearrangement. Patients must have demonstrated progression during or after crizotinib treatment whether or not previously treated with cytotoxic chemotherapy. Approximately 100 patients will be enrolled. For the first 15 patients enrolled in this study, patients will have an additional 5-day PK run-in period before treatment period. The pharmacokinetics profile of LDK378 in Chinese adult patients with ALK-rearranged NSCLC will be evaluated.

Detailed Description
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This is a phase I/II, open-label, multi-center study in which the PK, safety, tolerability and efficacy of LDK378 will be assessed in adult Chinese patients with locally advanced or metastatic NSCLC harboring a confirmed ALK rearrangement (positive) as assessed using the Vysis ALK Break Apart FISH Probe Kit (Abbott Molecular Inc.) or positive as assessed by immunohistochemistry (IHC) test (Ventana Medical Systems, Inc) using rabbit monoclonal primary antibody assay (D5F3). Patients must have demonstrated progression during or after crizotinib treatment whether or not previously treated with cytotoxic chemotherapy. Approximately 100 patients with locally advanced or metastatic NSCLC which carry ALK -rearrangement will be enrolled in the study. The first 15 patients to be enrolled in the study will have PK sampling over 120-hour during the 5-day PK run-in period following a single oral dose at 750 mg. After the PK run-in period, the treatment period will start in which LDK378 will be given starting on Cycle 1 Day 1 in a continuous daily oral dosing in 28-day cycles. Separated from these 15 patients, the rest of the enrolled patients will receive LDK378 treatment at 750 mg QD on Cycle 1 Day 1. Tumor response will be evaluated every 8 weeks (i.e. every 2 cycles) starting from the first day of treatment with LDK378 until the time of RECIST-defined PD by investigator assessment, withdrawal of consent for further follow-up, loss to follow-up or death.

Official Title
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A Phase I/II, Multicenter, Open-label, Single-arm Study of LDK378, Administered Orally in Adult Chinese Patients With ALK-rearranged (ALK-positive) Advanced Non-small Cell Lung Cancer (NSCLC) Previously Treated With Crizotinib Study Type: Interventional

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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Inclusion criteria: Histologically or cytologically confirmed diagnosis of NSCLC that carries an ALK rearrangement defined as positive using the FDA approved Vysis ALK Break Apart FISH Probe Kit (Abbott Molecular Inc.) test and scoring algorithm (including positivity criteria) or positive as assessed by the CFDA approved immunohistochemistry (IHC) test (Ventana Medical Systems, Inc) Age 18 years or older at the time of informed consent. Patients must have stage IIIB or IV NSCLC at the time of study entry and have had progressive disease during or after crizotinib treatment whether or not previously treated with cytotoxic chemotherapy. If treated with chemotherapy, maximum 2 lines are allowed. Exclusion Criteria: Patients with known hypersensitivity to any of the excipients of LDK378 Patients 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 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<br>daily dosing, 28-day cycle patients | Drug: LDK378<br>* 750 mg once daily<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Primary Pharmacokinetics (PK) Parameters of of LDK378 After Daily Oral Dose: AUClast, AUC0-24h, AUCinf | AUClast: The area under the concentration-time curve from time zero to the last measurable concentration time. AUC0-24h: The area under the plasma concentration-time curve calculated from time zero to 24 hours. AUCinf: Area under the plasma (serum, or blood) concentration versus time curve from time zero to infinity | PK run-in phase (0h, 1h, 2h, 3h, 4h, 6h, 8h, 24h, 48h, 72h, 96h after PK run-in dose and predose Cycle 1 day 1 (C1D1)(approximately 120h after PK run in dose)) | 
| Primary Pharmacokinetics (PK) Parameter of of LDK378 After Daily Oral Dose: AUC0-24h | AUC0-24h: The area under the plasma concentration-time curve calculated from time zero to 24 hours. | Cycle 2 Day 1 (after one cycle (28 days) of continous dosing)(0h, 1h, 2h, 3h, 4h , 6h , 8h and 24h) | 
| Primary Pharmacokinetics (PK) Parameter of LDK378 After Daily Oral Dose: Cmax | Cmax is the maximum (peak) concentration of drug in plasma | PK run-in phase (0h, 1h, 2h, 3h, 4h, 6h, 8h, 24h, 48h, 72h, 96h after PK run-in dose and predose Cycle 1 day 1 (C1D1)(approximately 120h after PK run in dose)) and C2D1(after one cycle (28 days) of continous dosing)(0h, 1h, 2h, 3h, 4h , 6h , 8h and 24h) | 
| Primary Pharmacokinetics (PK) Parameter of LDK378 After Daily Oral Dose: Tmax | Tmax is the time to reach maximum plasma concentration. | PK run-in phase (0h, 1h, 2h, 3h, 4h, 6h, 8h, 24h, 48h, 72h, 96h after PK run-in dose and predose Cycle 1 day 1 (C1D1)(approximately 120h after PK run in dose)) and C2D1(after one cycle (28 days) of continous dosing)(0h, 1h, 2h, 3h, 4h , 6h , 8h and 24h) | 
| Overall Summary of Adverse Events (AEs) - Per Occurence | Safety and tolerability of LDK378 at 750 mg once daily dose in Chinese adult patients with ALK-rearranged locally advanced or metastatic NSCLC | up to 41 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Response Rate (ORR) Per RECIST 1.1 Per Investigator Assessment | ORR calculated as the percentage of participants with a best overall response defined as complete response (CR) or partial response (PR). CR is the 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 is at least a 30% decrease in the sum of diameter of all target lesions, taking as reference the baseline sum of diameters. | 40 months | 
| ORR Per RECIST 1.1 Per Blind Independent Review Committee (BIRC) Assessment | ORR per RECIST 1.1 calculated as the percentage of participants with a best overall response defined as complete response (CR) or partial response (PR). CR is the 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 is at least a 30% decrease in the sum of diameter of all target lesions, taking as reference the baseline sum of diameters. | 40 months | 
| Duration of Response (DOR) Per Investigator Assessment | DOR, calculated as the time from the date of the first documented CR or PR to the first documented progression or all cause death. CR is the 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 is at least a 30% decrease in the sum of diameter of all target lesions, taking as reference the baseline sum of diameters. | 40 months | 
| Disease Control Rate (DCR) Per Investigator Assessment | DCR, calculated as the percentage of participants with best overall response of CR, PR, stable disease (SD) and Non-CR/Non-progressive disease (PD). CR is the 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 is at least a 30% decrease in the sum of diameter of all target lesions, taking as reference the baseline sum of diameters. PD is 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, the sum must also demonstrate an absolute increase of at least 5 mm. SD is neither sufficient shrinkage to qualify for PR or CR nor an increase in lesions which would qualify for PD. Non-CR/Non-PD refers to best overall responses that are neither CR nor PD per RECIST 1.1 criteria for patients with non-measurable disease only at baseline. | 40 months | 
| Time to Response (TTR) Per Investigator Assessment | TTR, calculated as the time from first dose of LDK378 to first documented response (CR+PR). CR is the 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 is at least a 30% decrease in the sum of diameter of all target lesions, taking as reference the baseline sum of diameters. | 40 months | 
| Overall Intracranial Response Rate (OIRR) Per Investigator Assessment | OIRR calculated as the ORR (CR+PR) of lesions in the brain for patients who have measureable disease in the brain at baseline. CR is the 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 is at least a 30% decrease in the sum of diameter of all target lesions, taking as reference the baseline sum of diameters. | 40 months | 
| Overall Intracranial Response Rate (OIRR) Per BIRC Assessment | OIRR calculated as the ORR (CR+PR) of lesions in the brain for patients who have measureable disease in the brain at baseline. CR is the 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 is at least a 30% decrease in the sum of diameter of all target lesions, taking as reference the baseline sum of diameters. | 40 months | 
| Progression Free Survival (PFS) Per Investigator Assessment | PFS, defined as time from first dose of LDK378 to progression or death due to any cause. | 40 months | 
| Overall Survival (OS) | OS, defined as time from first dose of LDK378 to death due to any cause. | 40 months | 
| Duration of Response (DOR) Per BIRC Assessment | DOR, calculated as the time from the date of the first documented CR or PR to the first documented progression or all cause death. CR is the 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 is at least a 30% decrease in the sum of diameter of all target lesions, taking as reference the baseline sum of diameters. | 40 months | 
| Disease Control Rate (DCR) Per BIRC Assessment | DCR, calculated as the percentage of participants with best overall response of CR, PR, stable disease (SD) and Non-CR/Non-progressive disease (PD). CR is the 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 is at least a 30% decrease in the sum of diameter of all target lesions, taking as reference the baseline sum of diameters. PD is 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, the sum must also demonstrate an absolute increase of at least 5 mm. SD is neither sufficient shrinkage to qualify for PR or CR nor an increase in lesions which would qualify for PD. Non-CR/Non-PD refers to best overall responses that are neither CR nor PD per RECIST 1.1 criteria for patients with non-measurable disease only at baseline. | 40 months | 
| Time to Response (TTR) Per BIRC Assessment | TTR, calculated as the time from first dose of LDK378 to first documented response (CR+PR). CR is the 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 is at least a 30% decrease in the sum of diameter of all target lesions, taking as reference the baseline sum of diameters. | 40 months | 
| Progression Free Survival (PFS) Per BIRC Assessment | PFS, defined as time from first dose of LDK378 to progression or death due to any cause. | 40 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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ALK, Non-Small Cell lung Cancer, NSCLC, LDK378, ALK-rearranged, ALK-positive, advanced non-small cell lung cancer