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Study of Safety and Preliminary Efficacy for LDK378 in Japanese Patients With Genetic Alterations in Anaplastic Lymphoma Kinase (ALK)

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ClinicalTrials.gov Identifier: NCT01634763
Recruitment Status : Completed
First Posted : July 6, 2012
Last Update Posted : July 27, 2016
Sponsor:
Information provided by (Responsible Party):
Novartis ( Novartis Pharmaceuticals )

Brief Summary:
Estimation of the Maximum tolerated dose (MTD) and/or Recommended dose (RD) of LDK378 as a single agent when administered orally to Japanese patients with tumors characterized by genetic alterations in anaplastic lymphoma kinase (ALK)

Condition or disease Intervention/treatment Phase
Tumors Characterized by Genetic Alterations in Anaplastic Lymphoma Kinase (ALK) Drug: LDK378 Phase 1

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 22 participants
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Basic Science
Official Title: A Phase I, Multicenter, Open-label Dose Escalation Study of LDK378, Administered Orally in Japanese Patients With Tumors Characterized by Genetic Alterations in ALK
Study Start Date : June 2012
Actual Primary Completion Date : January 2016
Actual Study Completion Date : January 2016

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Lymphoma
Drug Information available for: Ceritinib

Arm Intervention/treatment
Experimental: Dose-escalation
Open-label dose escalation study of LDK378, administered orally in Japanese patients with tumors characterized by genetic alterations in anaplastic lymphoma kinase (ALK)
Drug: LDK378
Experimental: Dose-expansion
Open-label study of LDK378, administered orally in Japanese patients with tumors characterized by genetic alterations in ALK to see further safety, anti-tumor activity, and PK data in patients who has progressed since prior therapy with alectinib
Drug: LDK378



Primary Outcome Measures :
  1. Maximum tolerated dose (MTD) and/or Recommended dose (RD) of LDK378 [ Time Frame: During the first cycle (including the Pharmacokinetics [PK] run-in period) of LDK378 treatment. A treatment cycle consists of 21 days of daily dosing of LDK378. ]
    As a single agent when administered orally to Japanese patients with tumors characterized by genetic alterations in ALK. The number of patients and category of Dose Limiting Toxicities (DLTs)


Secondary Outcome Measures :
  1. The safety and tolerability of LDK378, including both acute and chronic toxicities [ Time Frame: Until disease progression or unacceptable toxicity occurs, or patient withdrawal ]
    Adverse drug reactions and serious adverse drug reactions, changes in hematology and blood chemistry values, assessments of physical examinations, vital signs and electrocardiograms

  2. Plasma concentration of LDK378 [ Time Frame: PK run-in (0,0.5, 1, 2, 3, 4, 6, 8, 24, 48, and 72 hrs), Cycle1Day1 (0, 0.5, 1, 2, 3, 6, 8 and 24 hrs), Cycle2Day1 (0, 1, 2, 4, 6, 8 and 24 hrs), Day1 of every subsequent cycles up to Cycle6 ]
    Single and multiple-dose PK of LDK378

  3. Preliminary anti-tumor activity of LDK378 [ Time Frame: Baseline and every 6 weeks until disease progression or unacceptable toxicity occurs, or patient withdrawal ]
    As a single agent when administered orally to Japanese patients with tumors characterized by genetic alterations in ALK at MTD and/or RD by Computed tomography (CT) / Magnetic resonance imaging (MRI). Overall response rate (complete response [CR] or partial response [PR]) and disease control rate (CR or PR or stable disease [SD]) defined according to RECIST, duration of response and progression-free survival

  4. PK parameter: AUClast [ Time Frame: PK run-in (0,0.5, 1, 2, 3, 4, 6, 8, 24, 48, and 72 hrs), Cycle1Day1 (0, 0.5, 1, 2, 3, 6, 8 and 24 hrs), Cycle2Day1 (0, 1, 2, 4, 6, 8 and 24 hrs), Day1 of every subsequent cycles up to Cycle6 ]
    Single and multiple-dose PK of LDK378

  5. PK parameter: AUCtau [ Time Frame: PK run-in (0,0.5, 1, 2, 3, 4, 6, 8, 24, 48, and 72 hrs), Cycle1Day1 (0, 0.5, 1, 2, 3, 6, 8 and 24 hrs), Cycle2Day1 (0, 1, 2, 4, 6, 8 and 24 hrs), Day1 of every subsequent cycles up to Cycle6 ]
    Single and multiple-dose PK of LDK378

  6. PK parameter: Cmax [ Time Frame: PK run-in (0,0.5, 1, 2, 3, 4, 6, 8, 24, 48, and 72 hrs), Cycle1Day1 (0, 0.5, 1, 2, 3, 6, 8 and 24 hrs), Cycle2Day1 (0, 1, 2, 4, 6, 8 and 24 hrs), Day1 of every subsequent cycles up to Cycle6 ]
    Single and multiple-dose PK of LDK378

  7. PK parameter: Tmax [ Time Frame: PK run-in (0,0.5, 1, 2, 3, 4, 6, 8, 24, 48, and 72 hrs), Cycle1Day1 (0, 0.5, 1, 2, 3, 6, 8 and 24 hrs), Cycle2Day1 (0, 1, 2, 4, 6, 8 and 24 hrs), Day1 of every subsequent cycles up to Cycle6 ]
    Single and multiple-dose PK of LDK378

  8. PK parameter: the apparent elimination half-life (T1/2) [ Time Frame: PK run-in (0,0.5, 1, 2, 3, 4, 6, 8, 24, 48, and 72 hrs), Cycle1Day1 (0, 0.5, 1, 2, 3, 6, 8 and 24 hrs), Cycle2Day1 (0, 1, 2, 4, 6, 8 and 24 hrs), Day1 of every subsequent cycles up to Cycle6 ]
    Single and multiple-dose PK of LDK378

  9. PK parameter: accumulation ratio (Racc) [ Time Frame: PK run-in (0,0.5, 1, 2, 3, 4, 6, 8, 24, 48, and 72 hrs), Cycle1Day1 (0, 0.5, 1, 2, 3, 6, 8 and 24 hrs), Cycle2Day1 (0, 1, 2, 4, 6, 8 and 24 hrs), Day1 of every subsequent cycles up to Cycle6 ]
    Single and multiple-dose PK of LDK378



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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Patients 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 alterations in ALK. For non-small cell lung cancer (NSCLC), an ALK translocation must be detected by Fluorescent in situ hybridization (FISH) in ≥15% of tumor cells. Local site documented results on ALK alteration are acceptable for enrollment of the patients. Central confirmation of local results is not required.

    --Eastern Cooperative Oncology Group (ECOG) performance status grade ≤ 2

  • Adequate organ function
  • Dose-expansion part: Patients must have NSCLC that has progressed since prior therapy with alectinib. Alectinib must have been the only prior ALK inhibitor received by the patient prior to trial entry.

Exclusion Criteria:

  • Patients with symptomatic Central Nerve System (CNS) metastases who are neurologically unstable or require increasing doses of steroids to control their CNS disease
  • Patients with unresolved nausea, vomiting or diarrhea > Common Terminology Criteria for Adverse Events (CTCAE) grade 1
  • Other concurrent severe and/or uncontrolled medical conditions
  • Patients who have been treated with chemotherapy or biologic therapy or other investigational agent < 2 weeks prior to starting the daily dosing of the study drug for compounds with a half-life ≤ 3 days, and < 4 weeks prior to starting the daily dosing of the study drug for compounds with a prolonged half-life (< 6 weeks for patients that received nitrosoureas or mitomycin-C)
  • Unresolved toxicity greater than CTCAE grade 1 or unstable toxicity from previous anti-cancer therapy or radiotherapy (excluding neurotoxicity, alopecia, ototoxicity, lymphopenia), or incomplete recovery from previous surgery, unless agreed by Novartis and the Principal Investigator and documented
  • Patients who have received radiotherapy to lung within 4 weeks prior to starting the daily dosing of the study drug or patients who have not recovered from radiotherapy-related toxicities. For all other anatomic sites radiotherapy to a large volume (including whole brain radiotherapy) < 2 weeks prior to starting the daily dosing of the study drug, and patients who have received radiotherapy to a small volume (including stereotactic radiotherapy to the CNS) < 3 days prior to starting the study drug.

Other protocol-defined inclusion/exclusion criteria may apply.


Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01634763


Locations
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Japan
Novartis Investigative Site
Sunto-gun, Shizuoka, Japan, 411-8777
Novartis Investigative Site
Koto, Tokyo, Japan, 135-8550
Novartis Investigative Site
Fukuoka, Japan, 811-1395
Sponsors and Collaborators
Novartis Pharmaceuticals
Investigators
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Study Director: Novartis Pharmaceuticals Novartis Pharmaceuticals

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
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Responsible Party: Novartis Pharmaceuticals
ClinicalTrials.gov Identifier: NCT01634763     History of Changes
Other Study ID Numbers: CLDK378X1101
First Posted: July 6, 2012    Key Record Dates
Last Update Posted: July 27, 2016
Last Verified: July 2016
Keywords provided by Novartis ( Novartis Pharmaceuticals ):
Phase I, open-label, dose escalation, oral LDK378, Japanese patients with tumors characterized by ALK genetic alterations
Additional relevant MeSH terms:
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Lymphoma
Neoplasms by Histologic Type
Neoplasms
Lymphoproliferative Disorders
Lymphatic Diseases
Immunoproliferative Disorders
Immune System Diseases
Ceritinib
Antineoplastic Agents
Protein Kinase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action