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

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ClinicalTrials.gov Identifier: NCT01283516
Recruitment Status : Completed
First Posted : January 26, 2011
Results First Posted : August 11, 2014
Last Update Posted : March 15, 2019
Sponsor:
Information provided by (Responsible Party):
Novartis ( Novartis Pharmaceuticals )

Tracking Information
First Submitted Date  ICMJE January 24, 2011
First Posted Date  ICMJE January 26, 2011
Results First Submitted Date  ICMJE May 29, 2014
Results First Posted Date  ICMJE August 11, 2014
Last Update Posted Date March 15, 2019
Actual Study Start Date  ICMJE January 24, 2011
Actual Primary Completion Date May 3, 2016   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: November 28, 2018)
Number of Participants With Dose Limiting Toxicities (DLTs) [ Time Frame: 33 months ]
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.
Original Primary Outcome Measures  ICMJE
 (submitted: January 24, 2011)
Determination of the proper dose of LDK378 to be used in clinical trials [ Time Frame: 48 weeks ]
Change History Complete list of historical versions of study NCT01283516 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE
 (submitted: November 28, 2018)
  • Overall Response Rate (ORR) Based on Investigator Assessment [ Time Frame: 275 weeks ]
    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).
  • Overall Response Rate Based on Blinded Independent Review Committee (BIRC) Assessment [ Time Frame: 275 weeks ]
    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).
  • Duration of Response (DOR) Based on Investigator Assessment [ Time Frame: 275 weeks ]
    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.
  • Duration of Response (DOR) Based on BIRC [ Time Frame: 275 weeks ]
    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.
  • Progression-free Survival Based on Investigator Assessment [ Time Frame: 275 weeks ]
    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.
  • Progression-free Survival Based on BIRC Assessment [ Time Frame: 275 weeks ]
    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.
  • Primary Pharmacokinetics (PK) Parameter: AUC0-last [ Time Frame: PK run-in of Dose Escalation phase ]
    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.
  • 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 ]
    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.
  • 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 ]
    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.
  • 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 ]
    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.
  • Secondary Pharmacokinetics (PK) Parameter: T1/2 [ Time Frame: PK Run-in dose escalation phase ]
    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.
  • Secondary Pharmacokinetics (PK) Parameter: CL/F [ Time Frame: PK Run-in dose escalation phase ]
    CL/F is the apparent total body clearance of drug from the plasma
  • Secondary Pharmacokinetics (PK) Parameter: Vz/F [ Time Frame: PK Run-in dose escalation phase ]
    Vz/F is the apparent volume of distribution during terminal phase (associated with Lambda_z)
  • Secondary Pharmacokinetics (PK) Parameter: CLss/F [ Time Frame: Cycle 1 Day 8 of dose escalation phase, Cycle 2 Day 1 of dose escalation & dose expansion phases ]
    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.
  • Secondary Pharmacokinetics (PK) Parameter: Racc [ Time Frame: Cycle 1 Day 8 of dose escalation phase, Cycle 2 Day 1 of dose escalation & dose expansion phases ]
    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.
Original Secondary Outcome Measures  ICMJE
 (submitted: January 24, 2011)
  • Type and Category of Study Drug Related Adverse Events [ Time Frame: 120 weeks ]
  • Absorption and Plasma Concentrations of LDK378 [ Time Frame: 120 weeks ]
  • Overall response rate of tumor [ Time Frame: 120 weeks ]
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE A Dose Escalation/Expansion Study of LDK378 in Patients With Tumors Characterized by Genetic Abnormalities in Anaplastic Lymphoma Kinase
Official Title  ICMJE 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)
Brief Summary This study assessed the safety and efficacy of LDK378 in adult patients with genetic abnormalities in anaplastic lymphoma kinase (ALK).
Detailed Description Not Provided
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 1
Study Design  ICMJE Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE Tumors Characterized by Genetic Abnormalities of ALK
Intervention  ICMJE Drug: LDK378
LDK378 is a selective and a potent inhibitor of anaplastic lymphoma kinase (ALK) activity, is a capsule and is administered orally.
Study Arms  ICMJE
  • Experimental: LDK378 750 mg: Arm 1A and Arm 1B
    NSCLC patients previously treated with an ALK inhibitor
    Intervention: Drug: LDK378
  • Experimental: LDK378 750 mg: Arm 2
    NSCLC patients not previously treated with an ALK inhibitor
    Intervention: Drug: LDK378
  • Experimental: LDK378 750 mg: Arm 3
    Patients with other tumors that are ALK positive other than NSCLC
    Intervention: Drug: LDK378
Publications *

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: July 18, 2014)
304
Original Estimated Enrollment  ICMJE
 (submitted: January 24, 2011)
70
Actual Study Completion Date  ICMJE May 3, 2016
Actual Primary Completion Date May 3, 2016   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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

Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Australia,   Belgium,   Canada,   Germany,   Italy,   Korea, Republic of,   Netherlands,   Singapore,   Spain,   United Kingdom,   United States
Removed Location Countries Ireland,   New Zealand
 
Administrative Information
NCT Number  ICMJE NCT01283516
Other Study ID Numbers  ICMJE CLDK378X2101
2010-019827-70 ( EudraCT Number )
Has Data Monitoring Committee No
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE
Plan to Share IPD: Undecided
Responsible Party Novartis ( Novartis Pharmaceuticals )
Study Sponsor  ICMJE Novartis Pharmaceuticals
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Study Director: Novartis Pharmaceuticals Novartis Pharmaceuticals
PRS Account Novartis
Verification Date November 2018

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP