Clinical trial NCT02040870: LDK378 in Adult Chinese Patients With ALK-rearranged (ALK-positive) Advanced Non-small Cell Lung Cancer (NSCLC) Previously Treated With Crizotinib
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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
PHASE2
Conditions: Non-Small Cell Lung Cancer
Keywords: Non-Small Cell lung Cancer
NSCLC
ALK
LDK378
ALK-rearranged
ALK-positive
advanced non-small cell lung cancer
Lead sponsor: Novartis
Sponsor class: INDUSTRY
First posted: 2014-01-20
Enrollment: 103
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief 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.

Detailed 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.

Eligibility criteria: 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.

Primary outcomes:
measure: Primary Pharmacokinetics (PK) Parameters of of LDK378 After Daily Oral Dose: AUClast, AUC0-24h, AUCinf
timeFrame: 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))
measure: Primary Pharmacokinetics (PK) Parameter of of LDK378 After Daily Oral Dose: AUC0-24h
timeFrame: Cycle 2 Day 1 (after one cycle (28 days) of continous dosing)(0h, 1h, 2h, 3h, 4h , 6h , 8h and 24h)
measure: Primary Pharmacokinetics (PK) Parameter of LDK378 After Daily Oral Dose: Cmax
timeFrame: 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)
measure: Primary Pharmacokinetics (PK) Parameter of LDK378 After Daily Oral Dose: Tmax
timeFrame: 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)
measure: Overall Summary of Adverse Events (AEs) - Per Occurence
timeFrame: up to 41 months
Secondary outcomes:
measure: Overall Response Rate (ORR) Per RECIST 1.1 Per Investigator Assessment
timeFrame: 40 months
measure: ORR Per RECIST 1.1 Per Blind Independent Review Committee (BIRC) Assessment
timeFrame: 40 months
measure: Duration of Response (DOR) Per Investigator Assessment
timeFrame: 40 months
measure: Disease Control Rate (DCR) Per Investigator Assessment
timeFrame: 40 months
measure: Time to Response (TTR) Per Investigator Assessment
timeFrame: 40 months
measure: Overall Intracranial Response Rate (OIRR) Per Investigator Assessment
timeFrame: 40 months
measure: Overall Intracranial Response Rate (OIRR) Per BIRC Assessment
timeFrame: 40 months
measure: Progression Free Survival (PFS) Per Investigator Assessment
timeFrame: 40 months
measure: Overall Survival (OS)
timeFrame: 40 months
measure: Duration of Response (DOR) Per BIRC Assessment
timeFrame: 40 months
measure: Disease Control Rate (DCR) Per BIRC Assessment
timeFrame: 40 months
measure: Time to Response (TTR) Per BIRC Assessment
timeFrame: 40 months
measure: Progression Free Survival (PFS) Per BIRC Assessment
timeFrame: 40 months
Other outcomes:
Locations:
city: Beijing
country: China
facility: Novartis Investigative Site
state: Beijing
city: Chongqing
country: China
facility: Novartis Investigative Site
state: Chongqing
city: Guangzhou
country: China
facility: Novartis Investigative Site
state: Guangdong
city: Changchun
country: China
facility: Novartis Investigative Site
state: Jilin
city: Shanghai
country: China
facility: Novartis Investigative Site
state: Shanghai
city: Shanghai
country: China
facility: Novartis Investigative Site
state: Shanghai
city: Xi'an
country: China
facility: Novartis Investigative Site
state: Shanxi
city: Chengdu
country: China
facility: Novartis Investigative Site
state: Sichuan
city: Hangzhou
country: China
facility: Novartis Investigative Site
state: Zhejiang
city: Beijing
country: China
facility: Novartis Investigative Site
city: Beijing
country: China
facility: Novartis Investigative Site
city: Beijing
country: China
facility: Novartis Investigative Site
city: Chongqing
country: China
facility: Novartis Investigative Site
city: Guang Dong Province
country: China
facility: Novartis Investigative Site
city: Guangzhou
country: China
facility: Novartis Investigative Site
Study officials:
affiliation: Novartis Pharmaceuticals
name: Novartis Pharmaceuticals
role: STUDY_DIRECTOR
References: