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

• 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: Novartis Pharmaceuticals
• Information provided by (Responsible Party): Novartis ( Novartis Pharmaceuticals )

Tracking Information

• First Submitted Date: January 24, 2011
• First Posted Date: January 26, 2011
• Results First Submitted Date: May 29, 2014
• Results First Posted Date: August 11, 2014
• Last Update Posted Date: March 15, 2019
• Actual Study Start Date: January 24, 2011
• Actual Primary Completion Date: May 3, 2016 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (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 (submitted: January 24, 2011): Determination of the proper dose of LDK378 to be used in clinical trials [ Time Frame: 48 weeks ]

Current Secondary Outcome Measures (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 (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: 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)
• 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: Interventional
• Study Phase: Phase 1
• Study Design: Allocation: Non-Randomized; Intervention Model: Parallel Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Condition: Tumors Characterized by Genetic Abnormalities of ALK

Intervention

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

• 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 *

• 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.

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: July 18, 2014): 304
• Original Estimated Enrollment (submitted: January 24, 2011): 70
• Actual Study Completion Date: May 3, 2016
• Actual Primary Completion Date: May 3, 2016 (Final data collection date for primary outcome measure)

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

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: 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: NCT01283516
• Other Study ID Numbers: 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

• Plan to Share IPD: Undecided

• Current Responsible Party: Novartis ( Novartis Pharmaceuticals )
• Original Responsible Party: External Affairs, Novartis Pharmaceuticals
• Current Study Sponsor: Novartis Pharmaceuticals
• Original Study Sponsor: Same as current
• Collaborators: Not Provided

Investigators

• Study Director: Novartis Pharmaceuticals; Novartis Pharmaceuticals

• PRS Account: Novartis
• Verification Date: November 2018