LDK378 in Adult Patients With ALK-activated NSCLC Previously Treated With Chemotherapy and Crizotinib

A Phase II, Multicenter, Single-arm Study of Oral LDK378 in Adult Patients With ALK-activated Non-small Cell Lung Cancer Previously Treated With Chemotherapy and Crizotinib

Status

Completed

Phases

Phase 2

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT01685060

Enrollment

140

Registered

2012-09-13

Start date

2012-11-26

Completion date

2016-03-29

Last updated

2017-06-19

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

Non-Small Cell Lung Cancer

Keywords

Non-Small Cell Lung Cancer, NSCLC, ALK, LDK378, Ceritinib

Brief summary

A single-arm, open-label, multicenter, phase II study. Treatment with LDK378 750 mg qd continued until the patient experienced unacceptable toxicity that precluded further treatment, discontinued treatment at the discretion of the investigator or patient, started a new anti-cancer therapy and/or died. LDK378 could be 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. In these patients tumor assessment would continue as per the schedule of assessments until treatment with LDK378 was permanently discontinued. 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

Interventions

DRUGLDK378

Ceritinib/LDK378 was supplied as 150 mg hard gelatin capsules and were administered orally, once-daily at a dose of 750 mg on a continuous dosing schedule (5 x 150 mg capsules).

Study design

Allocation

Intervention model

SINGLE_GROUP

Primary purpose

TREATMENT

Masking

NONE

Eligibility

Sex/Gender

ALL

Age

18 Years to No maximum

Healthy volunteers

Inclusion criteria

Inclusion critieria: * Histologically or cytologically confirmed diagnosis of stage IIIB or IV NSCLC that carries an ALK rearrangement, as per the FDA-approved FISH assay (Abbott Molecular Inc.). * Age 18 years or older at the time of informed consent. * Patients must have NSCLC that has progressed during therapy with crizotinib or within 30 days of the last dose * Patients must have received 1-3 lines of cytotoxic chemotherapy (of which 1 must have been a platinum doublet) to treat their locally advanced or metastatic NSCLC * Patients must have 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 will not be allowed to participate in the study.

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 * Systemic anti-cancer therapy given after the last dose of crizotinib and prior to starting study drug.

Design outcomes

Primary

Measure	Time frame	Description
Overall Response Rate (ORR) to LDK378 Per Investigator Assessment	6 cycles of 28 days up to 24 weeks	ORR per RECIST 1.1 calculated as the percentage of patients with a best overall confirmed response defined as complete response or partial response (CR+PR) as assessed by 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 1. PR: At least a 30% decrease in the sum of diameter of all target lesions, taking as reference the baseline sum of diameters.

Secondary

Measure	Time frame	Description
Duration of Response (DOR) by Investigator	6 cycles of 28 days up to 24 weeks	DOR, calculated as the time from the date of the first confirmed CR or PR to the first documented progression or death due to any cause, by 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 1. PR: At least a 30% decrease in the sum of diameter of all target lesions, taking as reference the baseline sum of diameters.
Duration of Response (DOR) by BIRC	6 cycles of 28 days up to 24 weeks	DOR, calculated as the time from the date of the first documented CR or PR to the first documented progression or death due to underlying cancer, by BIRC (Blinded Imaging Review Committee). 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 1. PR: At least a 30% decrease in the sum of diameter of all target lesions, taking as reference the baseline sum of diameters.
Disease Control Rate (DCR)	6 cycles of 28 days up to 24 weeks	DCR was calculated as the percentage of patients with best overall response of CR, PR, SD, or non-CR non-PD (NCRNPD), per RECIST 1.1 by 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 1. PR: At least a 30% decrease in the sum of diameter of all target lesions, taking as reference the baseline sum of diameters. Stable Disease (SD): Neither sufficient shrinkage to qualify for PR or CR nor an increase in lesions which would qualify for PD. Non-CR/Non-PD (NCRNPD): 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.
Time to Response (TTR) Per Investigator	6 cycles of 28 days up to 24 weeks	TTR is the time from date of start of treatment to the first CR or PR observed which were confirmed afterwards.
Time to Response (TTR) Per BIRC	6 cycles of 28 days up to 24 weeks	TTR is the time from date of start of treatment to the first CR or PR observed which are confirmed afterwards.
ORR Per Blinded Independent Review Committee (BIRC) Assessment	6 cycles of 28 days up to 24 weeks	ORR (CR+PR) by BIRC is calculated as the percentage of patients with a best overall confirmed response defined as complete response or partial response (CR+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 1. PR: At least a 30% decrease in the sum of diameter of all target lesions, taking as reference the baseline sum of diameters.
Progression-free Survival (PFS) Per BIRC	6 cycles of 28 days up to 24 weeks	PFS, defined as the time from date of start of treatment to the date of event defined as the first documented progression or death due to any cause. If a patient had no event or when the patient received any further anticancer therapy in the absence of disease progression, progression-free survival was censored at the date of last adequate tumor assessment.
Overall Intracranial Response Rate (OIRR) Per Investigator	6 cycles of 28 days up to 24 weeks	OIRR calculated as the ORR (CR+PR) of lesions in the brain for patients who had measureable disease in the brain at baseline.
Overall Intracranial Response Rate (OIRR) Per BIRC	6 cycles of 28 days up to 24 weeks	OIRR calculated as the ORR (CR+PR) of lesions in the brain for patients who had measureable disease in the brain at baseline.
Overall Survival (OS)	6 cycles of 28 days up to 24 weeks	OS, defined as the time from date of randomization/start of treatment to date of death due to any cause. If a patient was not known to have died, survival was censored at the date of last known date patient alive.
Progression-free Survival (PFS) Per Investigator	6 cycles of 28 days up to 24 weeks	PFS, defined as the time from date of start of treatment to the date of event defined as the first documented progression or death due to any cause. If a patient had no event or when the patient received any further anticancer therapy in the absence of disease progression, progression-free survival was censored at the date of last adequate tumor assessment.

Countries

Canada, France, Germany, Hong Kong, Italy, Japan, Netherlands, Singapore, South Korea, Spain, United Kingdom, United States

Participant flow

Pre-assignment details

Approximately 137 patients were planned to be enrolled. A total of 140 patients were enrolled and treated with ceritinib.

Participants by arm

Arm	Count
LDK378 750mg Patients treated with ceritinib/LDK378 750 mg once-daily, fasted.	140
Total	140

Withdrawals & dropouts

Period	Reason	FG000
Overall Study	Adverse Event	12
Overall Study	Death	8
Overall Study	Lost to Follow-up	1
Overall Study	Physician Decision	14
Overall Study	Progressive disease	69
Overall Study	Rollover patients	16
Overall Study	Subject/guardian decision	20

Baseline characteristics

Characteristic	LDK378 750mg
Age, Continuous	51.2 Years STANDARD_DEVIATION 11.62
Sex: Female, Male Female	70 Participants
Sex: Female, Male Male	70 Participants

Adverse events

Event type	EG000 affected / at risk
deaths Total, all-cause mortality	— / —
other Total, other adverse events	139 / 140
serious Total, serious adverse events	67 / 140

Outcome results

Primary

Overall Response Rate (ORR) to LDK378 Per Investigator Assessment

ORR per RECIST 1.1 calculated as the percentage of patients with a best overall confirmed response defined as complete response or partial response (CR+PR) as assessed by 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 1. PR: At least a 30% decrease in the sum of diameter of all target lesions, taking as reference the baseline sum of diameters.