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

NCT02422589 | Completed Phase 1 FDA Drug

• 2 other identifiers: CLDK378A21032014-003741-95
• Study Type: interventional
• Target: 33
• Locations: 4 countries
• Sites: 11

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.

Conditions

ALK-positive Advanced Tumors

Keywords

ALK-positive advanced tumors; midazolam; warfarin; ceritinib; ALK; CYP3A-4; Drug drug intereaction

Outcome Measures

Primary Outcomes (4)

• 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 Outcomes (4)

• 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

  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)

  Baseline, every 6 weeks until week 27

• Duration of Response (DOR)

  Baseline, every 6 weeks until week27

Study Arms (1)

Ceritinib

EXPERIMENTAL

Drug: ceritinib; Drug: warfarin; Drug: midazolam

Interventions

ceritinib DRUG

Ceritinib

warfarin DRUG

Ceritinib

midazolam DRUG

Ceritinib

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

• 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.
• 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).

Sponsors & Collaborators

• Novartis Pharmaceuticals: lead

Study Sites (11)

Karmanos Cancer Institute Oncology Department

Detroit, Michigan, 48201, United States

Location

Henry Ford Hospital SC

Detroit, Michigan, 48202-2689, United States

Location

Cancer Therapy & Research Center UT Health Science Center SC-4

San Antonio, Texas, 78229, United States

Location

Novartis Investigative Site

Copenhagen, DK-2100, Denmark

Location

Novartis Investigative Site

Milan, MI, 20133, Italy

Location

Novartis Investigative Site

Rozzano, MI, 20089, Italy

Location

Novartis Investigative Site

Modena, MO, 41124, Italy

Location

Novartis Investigative Site

Padua, PD, 35100, Italy

Location

Novartis Investigative Site

A Coruña, Galicia, 15006, Spain

Location

Novartis Investigative Site

Madrid, 28046, Spain

Location

Novartis Investigative Site

Madrid, 28050, Spain

Location

Related Links

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

MeSH Terms

Interventions

ceritinib; Warfarin; Midazolam

Intervention Hierarchy (Ancestors)

4-Hydroxycoumarins; Coumarins; Benzopyrans; Pyrans; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Benzodiazepines; Benzazepines

Study Officials

• Novartis Pharmaceuticals

  Novartis Pharmaceuticals

  STUDY DIRECTOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: OTHER
• Intervention Model: SINGLE GROUP
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: March 16, 2015
• First Posted: April 21, 2015
• Study Start: October 23, 2015
• Primary Completion: December 12, 2017
• Study Completion: December 12, 2017
• Last Updated: December 19, 2020

Record last verified: 2019-07

Data Sharing

• IPD Sharing: Will not share

Locations

ES (3); IT (4); DK (1); US (3)