eligibility Criteria: Inclusion Criteria: * ECOG Performance Status of ≤ 2 and life expectancy of ≥ 12 weeks. * Diagnosed with a locally advanced or metastatic malignancy that has progressed despite standard therapy, or for which no effective standard therapy exists. Only patients with tumors characterized by genetic abnormalities in ALK were enrolled. * For NSCLC, an ALK translocation must be detected by FISH in ≥ 15% of tumor cells. * In patients with diseases other than NSCLC, ALK translocation is not required and overexpression of ALK protein may be considered indicative of a genetic abnormality in ALK. * Patients with measurable or non-measurable disease as determined by modified RECIST version 1.0 in dose-escalation phase, and patients with at least one measurable lesion as determined by RECIST 1.0 in expansion phase. Exclusion Criteria: * Patients with symptomatic central nervous system (CNS) metastases who were neurologically unstable or required increasing doses of steroids to control their CNS disease were excluded. * Patients with a prior or current history of a second malignancy, impaired GI function, history of pancreatitis or increased amylase or lipase, known diagnosis of HIV, and clinically significant cardiac disease were excluded. * Patients treated with chemotherapy or biologic therapy or other investigational agent \< 2 weeks prior to starting study drug for compounds with a half-life ≤ 3 days, and \< 4 weeks prior to starting study drug for compounds with a prolonged half-life were excluded. * Further, patients treated with medications that were known to be strong inhibitors or inducers of CYP3A4/5 that could not be discontinued at least a week prior to start of treatment with LDK378 and for the duration of the study were also excluded. Other protocol-defined inclusion/exclusion criteria may apply
healthy Volunteers: false
minimum Age: 18 Years
sex: ALL
std Ages: ADULT
OLDER_ADULT

Treatment arms and interventions

arm Groups

description
NSCLC patients previously treated with an ALK inhibitor
intervention Names
Drug: LDK378
label
LDK378 750 mg: Arm 1A and Arm 1B
type
EXPERIMENTAL
description
NSCLC patients not previously treated with an ALK inhibitor
intervention Names
Drug: LDK378
label
LDK378 750 mg: Arm 2
type
EXPERIMENTAL
description
Patients with other tumors that are ALK positive other than NSCLC
intervention Names
Drug: LDK378
label
LDK378 750 mg: Arm 3
type
EXPERIMENTAL

interventions

arm Group Labels
LDK378 750 mg: Arm 1A and Arm 1B
LDK378 750 mg: Arm 2
LDK378 750 mg: Arm 3
description
LDK378 is a selective and a potent inhibitor of anaplastic lymphoma kinase (ALK) activity, is a capsule and is administered orally.
name
LDK378
type
DRUG

Study design

allocation

NON_RANDOMIZED

intervention Model

PARALLEL

masking Info

masking: NONE

primary Purpose

TREATMENT

Enrollment

count: 304
type: ACTUAL

Registered outcome plans (not posted results)

primary Outcomes

description
The maximum tolerated dose (MTD) was defined as the highest dose for a given schedule that was expected to cause DLTs in no more than 33% of patients during the first cycle of treatment. A patient with multiple occurrences of a DLT under one treatment is counted only once in the AE category for that treatment. MTD was determined at 750mg.
measure
Number of Participants With Dose Limiting Toxicities (DLTs)
time Frame
33 months

secondary Outcomes

description
Overall response rate (ORR) was defined as the percentage of participants with a best overall complete response (CR) or partial response (PR) per RECIST 1.0. Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0) for target lesions and assessed by MRI. Both CR and PR had to be confirmed by repeat assessments performed no less than 4 weeks after the criteria for response were first met. CR was the disappearance of all target lesions. PR was at least a 30% decrease in the sum of the longest diameter of all target lesions, taking as reference the baseline sum of the longest diameters. Both CR and PR had to be confirmed by repeat assessments performed no less than 4 weeks after the criteria for response were first met. CR = at least two determinations of CR, at least 4 weeks apart before progression. PR = at least two determinations of PR or better at least 4 weeks apart before progression (and not qualifying for a CR).
measure
Overall Response Rate (ORR) Based on Investigator Assessment
time Frame
275 weeks
description
Overall response rate (ORR) was defined as the percentage of participants with a best overall complete response (CR) or partial response (PR) per RECIST 1.0. Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0) for target lesions and assessed by MRI, CR was the disappearance of all target lesions. PR was at least a 30% decrease in the sum of the longest diameter of all target lesions, taking as reference the baseline sum of the longest diameters. Both CR and PR had to be confirmed by repeat assessments performed no less than 4 weeks after the criteria for response were first met. CR = at least two determinations of CR, at least 4 weeks apart before progression. PR = at least two determinations of PR or better at least 4 weeks apart before progression (and not qualifying for a CR).
measure
Overall Response Rate Based on Blinded Independent Review Committee (BIRC) Assessment
time Frame
275 weeks
description
Duration of response (DOR) was defined as the time from first documented response (partial response (PR) or complete response (CR)) to the date of first documented disease progression (PD) or death due to any cause, among patients with a confirmed PR or CR per RECIST 1.0.
measure
Duration of Response (DOR) Based on Investigator Assessment
time Frame
275 weeks
description
Duration of response (DOR) was defined as the time from first documented response (partial response (PR) or complete response (CR)) to the date of first documented disease progression (PD) or death due to any cause, among patients with a confirmed PR or CR per RECIST 1.0.
measure
Duration of Response (DOR) Based on BIRC
time Frame
275 weeks
description
Progression-free survival (PFS) was defined as the time from the start date of study drug to the date of the first radiologically documented progressive disease (PD) per RECIST 1.0. or death due to any cause.
measure
Progression-free Survival Based on Investigator Assessment
time Frame
275 weeks
description
Progression-free survival (PFS) was defined as the time from the start date of study drug to the date of the first radiologically documented progressive disease (PD) per RECIST 1.0. or death due to any cause.
measure
Progression-free Survival Based on BIRC Assessment
time Frame
275 weeks
description
The AUC from time zero to the last quantifiable concentration point (Tlast). Blood samples for PK analysis of LDK378 were collected during the study from patients receiving LDK378.
measure
Primary Pharmacokinetics (PK) Parameter: AUC0-last
time Frame
PK run-in of Dose Escalation phase
description
Blood samples for PK analysis of LDK378 were collected during the study from patients receiving LDK378. AUC0 - 24 is the AUC calculated to 24 hour. Cycle 1 Day 1 = C1D1; Cycle 1 Day 8 = C1D8; Cycle 2 Day 1 = C2D1. However, there was no PK sampling during C1D1 and C2D1 except for 750 mg dose to compute PK parameter AUC0-24.
measure
Primary Pharmacokinetics (PK) Parameter: AUC0-24h
time Frame
PK run-in of dose escalation phase, Cycle 1 Day 8 of dose escalation phase, Cycle 1, Day 1 of dose escalation phase, Cycle 2 Day 1 of dose escalation & dose expansion phases
description
Tmax is the time to reach Cmax. Blood samples for PK analysis of LDK378 were collected during the study from patients receiving LDK378. Blood samples for PK analysis of LDK378 were collected during the study from patients receiving LDK378. Cycle 1 Day 1 = C1D1; Cycle 1 Day 8 = C1D8; Cycle 2 Day 1 = C2D1. However, there was no PK sampling during C1D1 and C2D1 except for 750 mg dose to compute PK parameter Tmax.
measure
Primary Pharmacokinetics (PK) Parameter: Tmax
time Frame
PK run-in of dose escalation phase, Cycle 1 Day 8 of dose escalation phase, Cycle 1, Day 1 of dose escalation phase, Cycle 2 Day 1 of dose escalation & dose expansion phases
description
Cmax is the maximum observed concentration. Blood samples for PK analysis of LDK378 were collected during the study from patients receiving LDK378. However, there was no PK sampling during C1D1 and C2D1 except for 750 mg dose to compute PK parameter Cmax.
measure
Primary Pharmacokinetics (PK) Parameter: Cmax
time Frame
PK run-in of dose escalation phase, Cycle 1 Day 8 of dose escalation phase, Cycle 1, Day 1 of dose escalation ion phase, Cycle 2 Day 1 of dose escalation & expansion phases
description
T1/2 is the elimination half-life associated with the terminal slope (λz) of a semi logarithmic concentration-time curve (time). Blood samples for PK analysis of LDK378 were collected during the study from patients receiving LDK378. Blood samples for PK analysis of LDK378 were collected during the study from patients receiving LDK378.
measure
Secondary Pharmacokinetics (PK) Parameter: T1/2
time Frame
PK Run-in dose escalation phase
description
CL/F is the apparent total body clearance of drug from the plasma
measure
Secondary Pharmacokinetics (PK) Parameter: CL/F
time Frame
PK Run-in dose escalation phase

Full study description

brief Summary: This study assessed the safety and efficacy of LDK378 in adult patients with genetic abnormalities in anaplastic lymphoma kinase (ALK).

Source references

references

citation
Tan DS, Thomas M, Kim DW, Szpakowski S, Urban P, Mehra R, Chow LQM, Sharma S, Solomon BJ, Felip E, Camidge DR, Vansteenkiste J, Petruzzelli L, Pantano S, Shaw AT. Genetic landscape of patients with ALK-rearranged non-small-cell lung cancer (NSCLC) and response to ceritinib in ASCEND-1 study. Lung Cancer. 2022 Jan;163:7-13. doi: 10.1016/j.lungcan.2021.11.007. Epub 2021 Nov 20.
pmid
34890832
type
DERIVED
citation
Kim DW, Mehra R, Tan DSW, Felip E, Chow LQM, Camidge DR, Vansteenkiste J, Sharma S, De Pas T, Riely GJ, Solomon BJ, Wolf J, Thomas M, Schuler M, Liu G, Santoro A, Sutradhar S, Li S, Szczudlo T, Yovine A, Shaw AT. Activity and safety of ceritinib in patients with ALK-rearranged non-small-cell lung cancer (ASCEND-1): updated results from the multicentre, open-label, phase 1 trial. Lancet Oncol. 2016 Apr;17(4):452-463. doi: 10.1016/S1470-2045(15)00614-2. Epub 2016 Mar 11.
pmid
26973324
type
DERIVED
citation
Richly H, Kim TM, Schuler M, Kim DW, Harrison SJ, Shaw AT, Boral AL, Yovine A, Solomon B. Ceritinib in patients with advanced anaplastic lymphoma kinase-rearranged anaplastic large-cell lymphoma. Blood. 2015 Sep 3;126(10):1257-8. doi: 10.1182/blood-2014-12-617779. No abstract available.
pmid
26337354
type
DERIVED
citation
Shaw AT, Kim DW, Mehra R, Tan DS, Felip E, Chow LQ, Camidge DR, Vansteenkiste J, Sharma S, De Pas T, Riely GJ, Solomon BJ, Wolf J, Thomas M, Schuler M, Liu G, Santoro A, Lau YY, Goldwasser M, Boral AL, Engelman JA. Ceritinib in ALK-rearranged non-small-cell lung cancer. N Engl J Med. 2014 Mar 27;370(13):1189-97. doi: 10.1056/NEJMoa1311107.
pmid
24670165
type
DERIVED