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

• ClinicalTrials.gov Identifier: NCT01634763
• Recruitment Status: Completed
• First Posted: July 6, 2012
• Last Update Posted: December 19, 2020
• Sponsor: Novartis Pharmaceuticals
• Information provided by (Responsible Party): Novartis ( Novartis Pharmaceuticals )

Tracking Information

• First Submitted Date: July 3, 2012
• First Posted Date: July 6, 2012
• Last Update Posted Date: December 19, 2020
• Study Start Date: June 2012
• Actual Primary Completion Date: January 2016 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: July 3, 2012)

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)

• Original Primary Outcome Measures: Same as current

Current Secondary Outcome Measures (submitted: July 3, 2012)

• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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

• Original Secondary Outcome Measures: Same as current
• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Study of Safety and Preliminary Efficacy for LDK378 in Japanese Patients With Genetic Alterations in Anaplastic Lymphoma Kinase (ALK)
• 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
• 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)
• Detailed Description: Not Provided
• Study Type: Interventional
• Study Phase: Phase 1
• Study Design: Allocation: Non-Randomized; Intervention Model: Single Group Assignment; Masking: None (Open Label); Primary Purpose: Basic Science
• Condition: Tumors Characterized by Genetic Alterations in Anaplastic Lymphoma Kinase (ALK)
• Intervention: Drug: LDK378

Study Arms

• 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)
  Intervention: 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
  Intervention: Drug: LDK378

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.

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: October 12, 2015): 22
• Original Estimated Enrollment (submitted: July 3, 2012): 24
• Actual Study Completion Date: January 2016
• Actual Primary Completion Date: January 2016 (Final data collection date for primary outcome measure)

Eligibility 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.

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: Japan

Administrative Information

• NCT Number: NCT01634763
• Other Study ID Numbers: CLDK378X1101
• Has Data Monitoring Committee: Not Provided
• U.S. FDA-regulated Product: Not Provided
• IPD Sharing Statement: Not Provided
• Current Responsible Party: Novartis ( Novartis Pharmaceuticals )
• Original Responsible Party: Same as current
• 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: July 2016