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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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT02422589
Recruitment Status : Completed
First Posted : April 21, 2015
Last Update Posted : July 18, 2019
Sponsor:
Information provided by (Responsible Party):
Novartis ( Novartis Pharmaceuticals )

Brief Summary:
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.

Condition or disease Intervention/treatment Phase
ALK-positive Advanced Tumors Drug: ceritinib Drug: warfarin Drug: midazolam Phase 1

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 33 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Other
Official Title: 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)
Actual Study Start Date : October 23, 2015
Actual Primary Completion Date : December 12, 2017
Actual Study Completion Date : December 12, 2017


Arm Intervention/treatment
Experimental: Ceritinib Drug: ceritinib
Drug: warfarin
Drug: midazolam



Primary Outcome Measures :
  1. Phamacokinetics (PK) parameters of probe drugs and their metabolites in the absence or presence of ceritinib dosing, including but not limited to: AUCinf [ Time Frame: 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. ]
  2. PK parameters of probe drugs and their metabolites in the absence or presence of ceritinib dosing, including but not lastlimited to: AUC [ Time Frame: 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. ]
  3. PK parameters of probe drugs and their metabolites in the absence or presence of ceritinib dosing, including but not lastlimited to:Cmax [ Time Frame: 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. ]
  4. PK parameters of probe drugs and their metabolites in the absence or presence of ceritinib dosing, including but not lastlimited to:Tmax [ Time Frame: 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 :
  1. Ctrough concentrations of ceritinib [ Time Frame: 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. ]
  2. Number of participants with Adverse Events as a measure of safety and tolerability [ Time Frame: 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. ]
    This will be done by looking at the vital signs, lab values and ECG

  3. Objective Response Rate (ORR) [ Time Frame: Baseline, every 6 weeks until week 27 ]
    Tumor evaluation will be determined locally by investigator per RECIST 1.1

  4. Duration of Response (DOR) [ Time Frame: Baseline, every 6 weeks until week27 ]
    Tumor evaluation will be determined locally by investigatorper RECIST 1.1



Information from the National Library of Medicine

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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:

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.


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): NCT02422589


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

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Responsible Party: Novartis Pharmaceuticals
ClinicalTrials.gov Identifier: NCT02422589    
Other Study ID Numbers: CLDK378A2103
2014-003741-95 ( EudraCT Number )
First Posted: April 21, 2015    Key Record Dates
Last Update Posted: July 18, 2019
Last Verified: July 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Novartis ( Novartis Pharmaceuticals ):
ALK-positive advanced tumors
midazolam
warfarin
ceritinib
ALK
CYP3A-4
Drug drug intereaction
Additional relevant MeSH terms:
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Neoplasms
Ceritinib
Midazolam
Warfarin
Adjuvants, Anesthesia
Hypnotics and Sedatives
Central Nervous System Depressants
Physiological Effects of Drugs
Anti-Anxiety Agents
Tranquilizing Agents
Psychotropic Drugs
Anesthetics, Intravenous
Anesthetics, General
Anesthetics
GABA Modulators
GABA Agents
Neurotransmitter Agents
Molecular Mechanisms of Pharmacological Action
Anticoagulants
Antineoplastic Agents
Protein Kinase Inhibitors
Enzyme Inhibitors