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Trial details imported from ClinicalTrials.gov

For full trial details, please see the original record at https://clinicaltrials.gov/show/NCT01283516




Registration number
NCT01283516
Ethics application status
Date submitted
24/01/2011
Date registered
26/01/2011
Date last updated
15/03/2019

Titles & IDs
Public title
A Dose Escalation/Expansion Study of LDK378 in Patients With Tumors Characterized by Genetic Abnormalities in Anaplastic Lymphoma Kinase
Scientific 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)
Secondary ID [1] 0 0
2010-019827-70
Secondary ID [2] 0 0
CLDK378X2101
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Tumors Characterized by Genetic Abnormalities of ALK 0 0
Condition category
Condition code
Human Genetics and Inherited Disorders 0 0 0 0
Other human genetics and inherited disorders
Reproductive Health and Childbirth 0 0 0 0
Fetal medicine and complications of pregnancy

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Treatment: Drugs - LDK378

Experimental: LDK378 750 mg: Arm 1A and Arm 1B - NSCLC patients previously treated with an ALK inhibitor

Experimental: LDK378 750 mg: Arm 2 - NSCLC patients not previously treated with an ALK inhibitor

Experimental: LDK378 750 mg: Arm 3 - Patients with other tumors that are ALK positive other than NSCLC


Treatment: Drugs: LDK378
LDK378 is a selective and a potent inhibitor of anaplastic lymphoma kinase (ALK) activity, is a capsule and is administered orally.

Intervention code [1] 0 0
Treatment: Drugs
Comparator / control treatment
Control group

Outcomes
Primary outcome [1] 0 0
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.
Timepoint [1] 0 0
33 months
Secondary outcome [1] 0 0
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).
Timepoint [1] 0 0
275 weeks
Secondary outcome [2] 0 0
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).
Timepoint [2] 0 0
275 weeks
Secondary outcome [3] 0 0
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.
Timepoint [3] 0 0
275 weeks
Secondary outcome [4] 0 0
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.
Timepoint [4] 0 0
275 weeks
Secondary outcome [5] 0 0
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.
Timepoint [5] 0 0
275 weeks
Secondary outcome [6] 0 0
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.
Timepoint [6] 0 0
275 weeks
Secondary outcome [7] 0 0
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.
Timepoint [7] 0 0
PK run-in of Dose Escalation phase
Secondary outcome [8] 0 0
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.
Timepoint [8] 0 0
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
Secondary outcome [9] 0 0
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.
Timepoint [9] 0 0
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
Secondary outcome [10] 0 0
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.
Timepoint [10] 0 0
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 outcome [11] 0 0
Secondary Pharmacokinetics (PK) Parameter: T1/2 - T1/2 is the elimination half-life associated with the terminal slope (?z) 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.
Timepoint [11] 0 0
PK Run-in dose escalation phase
Secondary outcome [12] 0 0
Secondary Pharmacokinetics (PK) Parameter: CL/F - CL/F is the apparent total body clearance of drug from the plasma
Timepoint [12] 0 0
PK Run-in dose escalation phase
Secondary outcome [13] 0 0
Secondary Pharmacokinetics (PK) Parameter: Vz/F - Vz/F is the apparent volume of distribution during terminal phase (associated with Lambda_z)
Timepoint [13] 0 0
PK Run-in dose escalation phase
Secondary outcome [14] 0 0
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.
Timepoint [14] 0 0
Cycle 1 Day 8 of dose escalation phase, Cycle 2 Day 1 of dose escalation & dose expansion phases
Secondary outcome [15] 0 0
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.
Timepoint [15] 0 0
Cycle 1 Day 8 of dose escalation phase, Cycle 2 Day 1 of dose escalation & dose expansion phases

Eligibility
Key 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.
Minimum age
18 Years
Maximum age
No limit
Gender
Both males and females
Can healthy volunteers participate?
No
Key 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 design
Purpose of the study
Treatment
Allocation to intervention
Non-randomised trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Parallel
Other design features
Phase
Phase 1
Type of endpoint(s)
Statistical methods / analysis

Recruitment
Recruitment status
Completed
Data analysis
Reason for early stopping/withdrawal
Other reasons
Date of first participant enrolment
Anticipated
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
VIC
Recruitment hospital [1] 0 0
Novartis Investigative Site - Melbourne
Recruitment postcode(s) [1] 0 0
3000 - Melbourne
Recruitment outside Australia
Country [1] 0 0
United States of America
State/province [1] 0 0
Colorado
Country [2] 0 0
United States of America
State/province [2] 0 0
Massachusetts
Country [3] 0 0
United States of America
State/province [3] 0 0
New York
Country [4] 0 0
United States of America
State/province [4] 0 0
Pennsylvania
Country [5] 0 0
United States of America
State/province [5] 0 0
Utah
Country [6] 0 0
United States of America
State/province [6] 0 0
Washington
Country [7] 0 0
Belgium
State/province [7] 0 0
Leuven
Country [8] 0 0
Canada
State/province [8] 0 0
Ontario
Country [9] 0 0
Germany
State/province [9] 0 0
Nordrhein-Westfalen
Country [10] 0 0
Germany
State/province [10] 0 0
Essen
Country [11] 0 0
Germany
State/province [11] 0 0
Heidelberg
Country [12] 0 0
Germany
State/province [12] 0 0
Ulm
Country [13] 0 0
Italy
State/province [13] 0 0
MI
Country [14] 0 0
Korea, Republic of
State/province [14] 0 0
Korea
Country [15] 0 0
Netherlands
State/province [15] 0 0
Amsterdam
Country [16] 0 0
Singapore
State/province [16] 0 0
Singapore
Country [17] 0 0
Spain
State/province [17] 0 0
Catalunya
Country [18] 0 0
United Kingdom
State/province [18] 0 0
Scotland
Country [19] 0 0
United Kingdom
State/province [19] 0 0
Leicester

Funding & Sponsors
Primary sponsor type
Commercial sector/Industry
Name
Novartis Pharmaceuticals
Address
Country

Ethics approval
Ethics application status

Summary
Brief summary
This study assessed the safety and efficacy of LDK378 in adult patients with genetic
abnormalities in anaplastic lymphoma kinase (ALK).
Trial website
https://clinicaltrials.gov/show/NCT01283516
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 0 0
Novartis Pharmaceuticals
Address 0 0
Novartis Pharmaceuticals
Country 0 0
Phone 0 0
Fax 0 0
Email 0 0
Contact person for public queries
Name 0 0
Address 0 0
Country 0 0
Phone 0 0
Fax 0 0
Email 0 0
Contact person for scientific queries

Summary results
Other publications