A Dose Escalation/Expansion Study of LDK378 in Patients With Tumors Characterized by Genetic Abnormalities in Anaplastic Lymphoma Kinase

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)

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

Study Overview

• Status: Completed
• Conditions: Tumors Characterized by Genetic Abnormalities of ALK
• Intervention / Treatment: Drug: LDK378

• Study Type: Interventional
• Enrollment (Actual): 304
• Phase: Phase 1

Contacts and Locations

Study Locations

• Australia
  • Victoria
    • Melbourne, Victoria, Australia, 3000
      • Novartis Investigative Site
• Belgium
  • Leuven, Belgium, 3000
    • Novartis Investigative Site
• Canada
  • Ontario
    • Toronto, Ontario, Canada, M5G 1Z6
      • Novartis Investigative Site
• Germany
  • Essen, Germany, 45147
    • Novartis Investigative Site
  • Heidelberg, Germany, 69120
    • Novartis Investigative Site
  • Ulm, Germany, 89081
    • Novartis Investigative Site
  • Nordrhein-Westfalen
    • Koeln, Nordrhein-Westfalen, Germany, 50937
      • Novartis Investigative Site
• Italy
  • MI
    • Milano, MI, Italy, 20141
      • Novartis Investigative Site
    • Rozzano, MI, Italy, 20089
      • Novartis Investigative Site
• Korea, Republic of
  • Korea
    • Seoul, Korea, Korea, Republic of, 03080
      • Novartis Investigative Site
• Netherlands
  • Amsterdam, Netherlands, 1066 CX
    • Novartis Investigative Site
• Singapore
  • Singapore, Singapore, 169610
    • Novartis Investigative Site
• Spain
  • Catalunya
    • Barcelona, Catalunya, Spain, 08035
      • Novartis Investigative Site
• United Kingdom
  • Leicester, United Kingdom, LE1 5WW
    • Novartis Investigative Site
  • Scotland
    • Glasgow, Scotland, United Kingdom, G12 0YN
      • Novartis Investigative Site
• United States
  • Colorado
    • Aurora, Colorado, United States, 80045
      • University of Colorado School of Medicine Colorado Univ
  • Massachusetts
    • Boston, Massachusetts, United States, 02114
      • Massachusetts General Hospital Mass General
  • New York
    • New York, New York, United States, 10017
      • Memorial Sloan Kettering MSK
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19111
      • Fox Chase Cancer Center Fox Chase Cancer (2)
  • Utah
    • Salt Lake City, Utah, United States, 84103
      • University of Utah / Huntsman Cancer Institute Huntsman
  • Washington
    • Seattle, Washington, United States, 98105
      • Seattle Cancer Care Alliance

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: LDK378 750 mg: Arm 1A and Arm 1B; NSCLC patients previously treated with an ALK inhibitor	Drug: LDK378; LDK378 is a selective and a potent inhibitor of anaplastic lymphoma kinase (ALK) activity, is a capsule and is administered orally.
Experimental: LDK378 750 mg: Arm 2; NSCLC patients not previously treated with an ALK inhibitor	Drug: LDK378; LDK378 is a selective and a potent inhibitor of anaplastic lymphoma kinase (ALK) activity, is a capsule and is administered orally.
Experimental: LDK378 750 mg: Arm 3; Patients with other tumors that are ALK positive other than NSCLC	Drug: LDK378; LDK378 is a selective and a potent inhibitor of anaplastic lymphoma kinase (ALK) activity, is a capsule and is administered orally.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants With Dose Limiting Toxicities (DLTs)	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.	33 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Overall Response Rate (ORR) Based on Investigator Assessment	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).	275 weeks
Overall Response Rate Based on Blinded Independent Review Committee (BIRC) Assessment	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).	275 weeks
Duration of Response (DOR) Based on Investigator Assessment	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.	275 weeks
Duration of Response (DOR) Based on BIRC	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.	275 weeks
Progression-free Survival Based on Investigator Assessment	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.	275 weeks
Progression-free Survival Based on BIRC Assessment	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.	275 weeks
Primary Pharmacokinetics (PK) Parameter: AUC0-last	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.	PK run-in of Dose Escalation phase
Primary Pharmacokinetics (PK) Parameter: AUC0-24h	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.	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
Primary Pharmacokinetics (PK) Parameter: Tmax	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.	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
Primary Pharmacokinetics (PK) Parameter: Cmax	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.	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
Secondary Pharmacokinetics (PK) Parameter: T1/2	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.	PK Run-in dose escalation phase
Secondary Pharmacokinetics (PK) Parameter: CL/F	CL/F is the apparent total body clearance of drug from the plasma	PK Run-in dose escalation phase
Secondary Pharmacokinetics (PK) Parameter: Vz/F	Vz/F is the apparent volume of distribution during terminal phase (associated with Lambda_z)	PK Run-in dose escalation phase
Secondary Pharmacokinetics (PK) Parameter: CLss/F	CLss/F is the apparent total body clearance of drug from the plasma. There was no PK sampling during C1D1 and C2D1 except for 750 mg dose to compute PK parameter CLss/F.	Cycle 1 Day 8 of dose escalation phase, Cycle 2 Day 1 of dose escalation & dose expansion phases
Secondary Pharmacokinetics (PK) Parameter: Racc	Racc is the accumulation ratio calculated using AUCtau values obtained from a dosing interval at steady-state divided by AUCtau at day 1 or PK run-in phase. AUCtau is the AUC calculated to the end of the dosing interval, tau. 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. However, there was no PK sampling during C1D1 and C2D1 except for 750 mg dose to compute PK parameter Racc.	Cycle 1 Day 8 of dose escalation phase, Cycle 2 Day 1 of dose escalation & dose expansion phases

Collaborators and Investigators

• Sponsor: Novartis Pharmaceuticals

Publications and helpful links

General Publications

• 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.
• 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.
• 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.
• 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.

Helpful Links

• Related Info

Study record dates

Study Major Dates

• Study Start (Actual): January 24, 2011
• Primary Completion (Actual): May 3, 2016
• Study Completion (Actual): May 3, 2016

Study Registration Dates

• First Submitted: January 24, 2011
• First Submitted That Met QC Criteria: January 24, 2011
• First Posted (Estimate): January 26, 2011

Study Record Updates

• Last Update Posted (Actual): March 15, 2019
• Last Update Submitted That Met QC Criteria: November 28, 2018
• Last Verified: November 1, 2018

More Information

Terms related to this study

• Keywords: genetic abnormalities; NSCLC,; ALK inhibitor,; LDK378,; ceritinib,
• Additional Relevant MeSH Terms: Congenital Abnormalities; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antineoplastic Agents; Protein Kinase Inhibitors; Ceritinib
• Other Study ID Numbers: CLDK378X2101; 2010-019827-70 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No