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

Non-Small Cell Lung Cancer Clinical Trial

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02040870
• Other study ID #: CLDK378A2109
• Status: Completed
• Phase: Phase 1/Phase 2
• Start date: March 7, 2014
• Est. completion date: July 27, 2017

Study information

• Verified date: January 2019
• Source: Novartis
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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.

Description:

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 103
• Est. completion date: July 27, 2017
• Est. primary completion date: July 27, 2017
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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.

Related Conditions & MeSH terms

• Carcinoma, Non-Small-Cell Lung
• Lung Neoplasms
• Non-Small Cell Lung Cancer

Intervention

Drug:
• LDK378
750 mg once daily

Locations

Country	Name	City	State
China	Novartis Investigative Site	Beijing	Beijing
China	Novartis Investigative Site	Beijing
China	Novartis Investigative Site	Beijing
China	Novartis Investigative Site	Beijing
China	Novartis Investigative Site	Changchun	Jilin
China	Novartis Investigative Site	Chengdu	Sichuan
China	Novartis Investigative Site	Chongqing	Chongqing
China	Novartis Investigative Site	Chongqing
China	Novartis Investigative Site	Guang Dong Province
China	Novartis Investigative Site	Guangzhou
China	Novartis Investigative Site	Guangzhou	Guangdong
China	Novartis Investigative Site	Hangzhou	Zhejiang
China	Novartis Investigative Site	Shanghai	Shanghai
China	Novartis Investigative Site	Shanghai	Shanghai
China	Novartis Investigative Site	Xi'an	Shanxi

Sponsors (1)

Lead Sponsor	Collaborator
Novartis Pharmaceuticals

Country where clinical trial is conducted

China, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	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	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	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)
Primary	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	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	Overall Survival (OS)	OS, defined as time from first dose of LDK378 to death due to any cause.	40 months
Secondary	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
Secondary	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
Secondary	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
Secondary	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