A Phase I, Multi-center, Open Label, Drug-drug Interaction Study to Assess the Effect of Ceritinib on the Pharmacokinetics of Warfarin and Midazolam in Patients With ALK-positive Advanced Tumors

A Phase I, Multi-center, Open Label, Drug-drug Interaction Study to Assess the Effect of Ceritinib on the Pharmacokinetics of Warfarin and Midazolam Administered as a Two-drug Cocktail in Patients With ALK-positive Advanced Tumors Including Non-small Cell Lung Cancer (NSCLC)

The purpose of this study was to evaluate the potential inhibitory effects of ceritinib on the CYP3A4- and CYP2C9-mediated metabolism of the probe drugs midazolam and warfarin, respectively, when administered simultaneously as a cocktail. The results obtained from this drug interaction study would provide guidance that would enable an update to the ceritinib labeling and ouldl help guide recommendations for administration of co-medications in future clinical trials.

Study Overview

• Status: Completed
• Conditions: ALK-positive Advanced Tumors
• Intervention / Treatment: Drug: warfarin; Drug: midazolam; Drug: ceritinib

• Study Type: Interventional
• Enrollment (Actual): 33
• Phase: Phase 1

Contacts and Locations

Study Locations

• Denmark
  • Copenhagen, Denmark, DK-2100
    • Novartis Investigative Site
• Italy
  • MI
    • Milano, MI, Italy, 20133
      • Novartis Investigative Site
    • Rozzano, MI, Italy, 20089
      • Novartis Investigative Site
  • MO
    • Modena, MO, Italy, 41124
      • Novartis Investigative Site
  • PD
    • Padova, PD, Italy, 35100
      • Novartis Investigative Site
• Spain
  • Madrid, Spain, 28046
    • Novartis Investigative Site
  • Madrid, Spain, 28050
    • Novartis Investigative Site
  • Galicia
    • La Coruna, Galicia, Spain, 15006
      • Novartis Investigative Site
• United States
  • Michigan
    • Detroit, Michigan, United States, 48202-2689
      • Henry Ford Hospital SC
    • Detroit, Michigan, United States, 48201
      • Karmanos Cancer Institute Oncology Department
  • Texas
    • San Antonio, Texas, United States, 78229
      • Cancer Therapy & Research Center UT Health Science Center SC-4

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:

Histologically or cytologically confirmed diagnosis of stage IIIB (and is not a candidate for definitive multimodality therapy) or stage IV NSCLC demonstrated ALK-positive or an advanced tumor, other than NSCLC, that carries an ALK genetic alteration (mutation, translocation or amplification) and/or ALK overexpression that has progressed despite standard therapy, or for which no effective standard therapy exists.

• The test to confirm ALK-positivity may be performed in archival tumor (obtained at or since the time of diagnosis), or in a newly obtained tumor sample taken prior to the first day of study drug. Results confirming ALK-positive status must be available before initiating treatment with ceritinib.
• Patients who have received prior chemotherapy, other ALK inhibitors, biologic therapy, or other investigational agents, must have recovered from all toxicities related to prior anticancer therapies to grade ≤ 1 (CTCAE v 4.03) prior to starting study drug. Patients with grade ≤ 2 peripheral neuropathy or any grade of alopecia, nail changes or skin changes are allowed to enter the study.
• Patients who have been treated with chemotherapy, with biological therapy or other investigational agent must have discontinued the treatment at least 2 weeks (14 days) prior to starting the study drug on Study Day 1.In case last chemotherapy contained nitrosourea or mitomycin C, the treatment was discontinued at least 6 weeks prior to starting study drug.
• Patient has the ability to understand and provide signed informed consent.

Exclusion Criteria:

• Patients with known hypersensitivity to any of the excipients of ceritinib (microcrystalline cellulose, mannitol, crospovidone, colloidal silicon dioxide and magnesium stearate), midazolam and warfarin as described in the local product information.
• History of carcinomatous meningitis.
• Presence or history of a malignant disease other than an ALK-positive advanced tumor that has been diagnosed and/or required therapy within the past 3 years. Exceptions to this exclusion include the following: completely resected basal cell and squamous cell skin cancers, and completely resected carcinoma in situ of any type.
• Clinically significant, uncontrolled heart disease and/or recent cardiac event (within 6 months), such as:
• Unstable angina within 6 months prior to screening.
• Myocardial infarction within 6 months prior to screening.
• History of documented congestive heart failure (New York Heart Association functional classification III-IV).
• Uncontrolled hypertension defined by a Systolic Blood Pressure ≥ 160 mmHg and/or Diastolic Blood Pressure ≥ 100 mmHg, with or without antihypertensive medication. Initiation or adjustment of antihypertensive medication (s) was allowed prior to screening.
• Ventricular arrhythmias.
• Supraventricular and nodal arrhythmias not controlled with medication.
• Other cardiac arrhythmia not controlled with medication.
• Corrected QT (QTcF) > 470 ms using Fridericia's correction on the screening electrocardiogram (ECG) (as mean of triplicate ECGs).
• Uncontrolled hypertension defined by a Systolic Blood Pressure (SBP) ≥ 160 mmHg and/or Diastolic Blood Pressure (DBP) ≥ 100 mmHg, with or without anti-hypertensive medication.
• Patient has history of interstitial lung disease or interstitial pneumonitis, including clinically significant radiation pneumonitis (i.e., affecting activities of daily living or requiring therapeutic intervention).

Other Protocol defined Inclusion/Exclusion may applied.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Other
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Ceritinib	Drug: warfarin; Drug: midazolam; Drug: ceritinib

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Phamacokinetics (PK) parameters of probe drugs and their metabolites in the absence or presence of ceritinib dosing, including but not limited to: AUCinf	Days 1,2,3,4,5,6,7,28,29,30,31,32,33,34 and once every 21 days until death or up to 24 months.
PK parameters of probe drugs and their metabolites in the absence or presence of ceritinib dosing, including but not lastlimited to: AUC	Days 1,2,3,4,5,6,7,28,29,30,31,32,33,34 and once every 121 days until death or up to 24 months.
PK parameters of probe drugs and their metabolites in the absence or presence of ceritinib dosing, including but not lastlimited to:Cmax	Days 1,2,3,4,5,6,7,28,29,30,31,32,33,34 and once every 21 days until death or up to 24 months.
PK parameters of probe drugs and their metabolites in the absence or presence of ceritinib dosing, including but not lastlimited to:Tmax	Days 1,2,3,4,5,6,7,28,29,30,31,32,33,34 and once every 21 days until death or up to 24 months.

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Ctrough concentrations of ceritinib		Days 1,2,3,4,5,6,7,28,29,30,31,32,33,34 and once every 21 days until death or up to 24 months.
Number of participants with Adverse Events as a measure of safety and tolerability	This will be done by looking at the vital signs, lab values and ECG	Days 1,2,3,4,5,6,7,28,29,30,31,32,33,34 and once every 21 days until death or up to 24 months.
Objective Response Rate (ORR)	Tumor evaluation will be determined locally by investigator per RECIST 1.1	Baseline, every 6 weeks until week 27
Duration of Response (DOR)	Tumor evaluation will be determined locally by investigatorper RECIST 1.1	Baseline, every 6 weeks until week27

Collaborators and Investigators

• Sponsor: Novartis Pharmaceuticals

Publications and helpful links

Helpful Links

• Results for CLDK378A2103 can be found on the Novartis Clinical Trial Results Website

Study record dates

Study Major Dates

• Study Start (Actual): October 23, 2015
• Primary Completion (Actual): December 12, 2017
• Study Completion (Actual): December 12, 2017

Study Registration Dates

• First Submitted: March 16, 2015
• First Submitted That Met QC Criteria: April 16, 2015
• First Posted (Estimate): April 21, 2015

Study Record Updates

• Last Update Posted (Actual): December 19, 2020
• Last Update Submitted That Met QC Criteria: December 16, 2020
• Last Verified: July 1, 2019

More Information

Terms related to this study

• Keywords: midazolam; warfarin; ALK; ceritinib; ALK-positive advanced tumors; CYP3A-4; Drug drug intereaction
• Additional Relevant MeSH Terms: Neoplasms; Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Central Nervous System Depressants; Enzyme Inhibitors; Anesthetics, Intravenous; Anesthetics, General; Anesthetics; Antineoplastic Agents; Tranquilizing Agents; Psychotropic Drugs; Protein Kinase Inhibitors; Hypnotics and Sedatives; Adjuvants, Anesthesia; Anti-Anxiety Agents; GABA Modulators; GABA Agents; Anticoagulants; Midazolam; Warfarin; Ceritinib
• Other Study ID Numbers: CLDK378A2103; 2014-003741-95 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No