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

A Phase I, Multicenter, Open-label Dose Escalation Study of LDK378, Administered Orally in Japanese Patients With Tumors Characterized by Genetic Alterations in ALK

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)

Study Overview

• Status: Completed
• Conditions: Tumors Characterized by Genetic Alterations in Anaplastic Lymphoma Kinase (ALK)
• Intervention / Treatment: Drug: LDK378

• Study Type: Interventional
• Enrollment (Actual): 22
• Phase: Phase 1

Contacts and Locations

Study Locations

• Japan
  • Fukuoka, Japan, 811-1395
    • Novartis Investigative Site
  • Shizuoka
    • Sunto-gun, Shizuoka, Japan, 411-8777
      • Novartis Investigative Site
  • Tokyo
    • Koto, Tokyo, Japan, 135-8550
      • Novartis Investigative Site

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:

• 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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Allocation: Non-Randomized
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / 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

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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 ALK. The number of patients and category of Dose Limiting Toxicities (DLTs)	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.

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
The safety and tolerability of LDK378, including both acute and chronic toxicities	Adverse drug reactions and serious adverse drug reactions, changes in hematology and blood chemistry values, assessments of physical examinations, vital signs and electrocardiograms	Until disease progression or unacceptable toxicity occurs, or patient withdrawal
Plasma concentration of LDK378	Single and multiple-dose PK of LDK378	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
Preliminary anti-tumor activity of LDK378	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	Baseline and every 6 weeks until disease progression or unacceptable toxicity occurs, or patient withdrawal
PK parameter: AUClast	Single and multiple-dose PK of LDK378	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
PK parameter: AUCtau	Single and multiple-dose PK of LDK378	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
PK parameter: Cmax	Single and multiple-dose PK of LDK378	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
PK parameter: Tmax	Single and multiple-dose PK of LDK378	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
PK parameter: the apparent elimination half-life (T1/2)	Single and multiple-dose PK of LDK378	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
PK parameter: accumulation ratio (Racc)	Single and multiple-dose PK of LDK378	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

Collaborators and Investigators

• Sponsor: Novartis Pharmaceuticals

Publications and helpful links

General Publications

• Ono A, Murakami H, Serizawa M, Wakuda K, Kenmotsu H, Naito T, Taira T, Koh Y, Ohde Y, Nakajima T, Endo M, Takahashi T. Drastic initial response and subsequent response to two ALK inhibitors in a patient with a highly aggressive ALK-rearranged inflammatory myofibroblastic tumor arising in the pleural cavity. Lung Cancer. 2016 Sep;99:151-4. doi: 10.1016/j.lungcan.2016.07.002. Epub 2016 Jul 5.
• Nishio M, Murakami H, Horiike A, Takahashi T, Hirai F, Suenaga N, Tajima T, Tokushige K, Ishii M, Boral A, Robson M, Seto T. Phase I Study of Ceritinib (LDK378) in Japanese Patients with Advanced, Anaplastic Lymphoma Kinase-Rearranged Non-Small-Cell Lung Cancer or Other Tumors. J Thorac Oncol. 2015 Jul;10(7):1058-66. doi: 10.1097/JTO.0000000000000566.

Helpful Links

• Results for CLDK378X1101 can be found on the Novartis Clinical Trial Results Website

Study record dates

Study Major Dates

• Study Start: June 1, 2012
• Primary Completion (Actual): January 1, 2016
• Study Completion (Actual): January 1, 2016

Study Registration Dates

• First Submitted: July 3, 2012
• First Submitted That Met QC Criteria: July 3, 2012
• First Posted (Estimate): July 6, 2012

Study Record Updates

• Last Update Posted (Actual): December 19, 2020
• Last Update Submitted That Met QC Criteria: December 16, 2020
• Last Verified: July 1, 2016

More Information

Terms related to this study

• Keywords: Phase I, open-label, dose escalation, oral LDK378, Japanese patients with tumors characterized by ALK genetic alterations
• Additional Relevant MeSH Terms: Immune System Diseases; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Lymphoma; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antineoplastic Agents; Protein Kinase Inhibitors; Ceritinib
• Other Study ID Numbers: CLDK378X1101