Clinical trial NCT01283516: A Dose Escalation/Expansion Study of LDK378 in Patients With Tumors Characterized by Genetic Abnormalities in Anaplastic Lymphoma Kinase
Official title: A Phase I, Multi-center, Open Label Dose Escalation Study of LDK378, Administered Orally in Adult Patients With Tumors Characterized by Genetic Abnormalities in Anaplastic Lymphoma Kinase (ALK)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Tumors Characterized by Genetic Abnormalities of ALK
Keywords: ALK inhibitor,
NSCLC,
LDK378,
ceritinib,
genetic abnormalities
Lead sponsor: Novartis
Sponsor class: INDUSTRY
First posted: 2011-01-26
Enrollment: 304
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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


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

Primary outcomes:
measure: Number of Participants With Dose Limiting Toxicities (DLTs)
timeFrame: 33 months
Secondary outcomes:
measure: Overall Response Rate (ORR) Based on Investigator Assessment
timeFrame: 275 weeks
measure: Overall Response Rate Based on Blinded Independent Review Committee (BIRC) Assessment
timeFrame: 275 weeks
measure: Duration of Response (DOR) Based on Investigator Assessment
timeFrame: 275 weeks
measure: Duration of Response (DOR) Based on BIRC
timeFrame: 275 weeks
measure: Progression-free Survival Based on Investigator Assessment
timeFrame: 275 weeks
measure: Progression-free Survival Based on BIRC Assessment
timeFrame: 275 weeks
measure: Primary Pharmacokinetics (PK) Parameter: AUC0-last
timeFrame: PK run-in of Dose Escalation phase
measure: Primary Pharmacokinetics (PK) Parameter: AUC0-24h
timeFrame: 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
measure: Primary Pharmacokinetics (PK) Parameter: Tmax
timeFrame: 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
measure: Primary Pharmacokinetics (PK) Parameter: Cmax
timeFrame: 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
measure: Secondary Pharmacokinetics (PK) Parameter: T1/2
timeFrame: PK Run-in dose escalation phase
measure: Secondary Pharmacokinetics (PK) Parameter: CL/F
timeFrame: PK Run-in dose escalation phase
measure: Secondary Pharmacokinetics (PK) Parameter: Vz/F
timeFrame: PK Run-in dose escalation phase
measure: Secondary Pharmacokinetics (PK) Parameter: CLss/F
timeFrame: Cycle 1 Day 8 of dose escalation phase, Cycle 2 Day 1 of dose escalation & dose expansion phases
measure: Secondary Pharmacokinetics (PK) Parameter: Racc
timeFrame: Cycle 1 Day 8 of dose escalation phase, Cycle 2 Day 1 of dose escalation & dose expansion phases
Other outcomes:
Locations:
city: Aurora
country: United States
facility: University of Colorado School of Medicine Colorado Univ
state: Colorado
city: Boston
country: United States
facility: Massachusetts General Hospital Mass General
state: Massachusetts
city: New York
country: United States
facility: Memorial Sloan Kettering MSK
state: New York
city: Philadelphia
country: United States
facility: Fox Chase Cancer Center Fox Chase Cancer (2)
state: Pennsylvania
city: Salt Lake City
country: United States
facility: University of Utah / Huntsman Cancer Institute Huntsman
state: Utah
city: Seattle
country: United States
facility: Seattle Cancer Care Alliance
state: Washington
city: Melbourne
country: Australia
facility: Novartis Investigative Site
state: Victoria
city: Leuven
country: Belgium
facility: Novartis Investigative Site
city: Toronto
country: Canada
facility: Novartis Investigative Site
state: Ontario
city: Koeln
country: Germany
facility: Novartis Investigative Site
state: Nordrhein-Westfalen
city: Essen
country: Germany
facility: Novartis Investigative Site
city: Heidelberg
country: Germany
facility: Novartis Investigative Site
city: Ulm
country: Germany
facility: Novartis Investigative Site
city: Milano
country: Italy
facility: Novartis Investigative Site
state: MI
city: Rozzano
country: Italy
facility: Novartis Investigative Site
state: MI
city: Seoul
country: Korea, Republic of
facility: Novartis Investigative Site
state: Korea
city: Amsterdam
country: Netherlands
facility: Novartis Investigative Site
city: Singapore
country: Singapore
facility: Novartis Investigative Site
city: Barcelona
country: Spain
facility: Novartis Investigative Site
state: Catalunya
city: Glasgow
country: United Kingdom
facility: Novartis Investigative Site
state: Scotland
city: Leicester
country: United Kingdom
facility: Novartis Investigative Site
Study officials:
affiliation: Novartis Pharmaceuticals
name: Novartis Pharmaceuticals
role: STUDY_DIRECTOR
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.
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.
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.
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.