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Pharmacokinetic Drug-drug Interaction Study of Dovitinib (TKI258) in Patients With Advanced Solid Tumors

Sponsor
Novartis Pharmaceuticals (Industry)
Overall Status
Completed
CT.gov ID
NCT01596647
Collaborator
(none)
39
Enrollment
5
Locations
1
Arm
26
Duration (Months)
7.8
Patients Per Site
0.3
Patients Per Site Per Month

Study Details

Study Description

Brief Summary

This is a multi-center, open-label, phase I study to assess the effects of dovitinib (TKI258) on the pharmacokinetics of a cocktail of caffeine, diclofenac, omeprazole and midazolam in patients with advanced solid tumors, excluding breast cancer. The aim of this study is to evaluate the potential effect of dovitinib (TKI258) on the metabolism of the probe drugs caffeine, diclofenac, omeprazole and midazolam, which are metabolized by CYP1A2, CYP2C9, CYP2C19 and CYP3A4 respectively (Cytochrome P450 isoenzyme), comparing the single-dose pharmacokinetics (AUCtlast, AUCinf and Cmax parameters) of each of the individual probe drug co-administered with and without multiple dose of dovitinib (TKI258) 500 mg under a 5 days on / 2 days off dose schedule. The study foresees two treatment phases: DDI (drug-drug interaction) followed by post-DDI. During the DDI phase patients receive treatment with the probe drug cocktail and dovitinib (TKI258). During the post-DDI phase patients may continue to receive treatment with dovitinib (TKI258) until disease progression (assessed by RECIST 1.1), unacceptable toxicity, death or discontinuation from the study treatment for any other reason.

Condition or Disease Intervention/Treatment Phase
Phase 1

Study Design

Study Type:
Interventional
Actual Enrollment :
39 participants
Allocation:
N/A
Intervention Model:
Single Group Assignment
Masking:
None (Open Label)
Primary Purpose:
Treatment
Official Title:
A Phase I, Multi-center, Open-label, Drug-drug Interaction Study to Assess the Effect of TKI258 on the Pharmacokinetics of Caffeine, Diclofenac, Omeprazole and Midazolam Administered as a Four-drug Cocktail in Patients With Advanced Solid Tumors, Excluding Breast Cancer
Study Start Date :
May 1, 2012
Actual Primary Completion Date :
Jul 1, 2014
Actual Study Completion Date :
Jul 1, 2014

Arms and Interventions

Arm Intervention/Treatment
Experimental: TKI258 (dovitinib)

dovitinib, 5 days on / 2 days off dose schedule

Drug: caffeine
single dose of the probe drug cocktail contains: caffeine, diclofenac, omeprazole and midazolam
Other Names:
  • probe drug

    • Drug: diclofenac
    single dose of the probe drug cocktail contains: caffeine, diclofenac, omeprazole and midazolam
    Other Names:
  • probe drug

    • Drug: omeprazole
    single dose of the probe drug cocktail contains: caffeine, diclofenac, omeprazole and midazolam
    Other Names:
  • probe drug

    • Drug: midazolam
    single dose of the probe drug cocktail contains: caffeine, diclofenac, omeprazole and midazolam
    Other Names:
  • probe drug

    • Drug: TKI258
    dovitinib, 5 days on / 2 days off dose schedule
    Other Names:
  • dovitinib

    		•

    Outcome Measures

    Primary Outcome Measures

    1. Probe substrate pharmacokinetics (PK) parameters: Cmax (Maximum (peak) concentration of drug) [multiple time-points over 24h post dose on day 1 and Day 13 (DDI phase),]

    2. Probe substrate PK parameters: AUCtlast (Area Under the Curve) [multiple time-points over 24h post dose on day 1 and Day 13 (DDI phase),]

    3. Probe substrate PK parameters: AUCinf [multiple time-points over 24h post dose on day 1 and Day 13 (DDI phase),]

    4. Probe substrate PK parameters:Tmax (Time to maximum concentration) [multiple time-points over 24h post dose on day 1 and Day 13 (DDI phase),]

    5. Probe substrate PK parameters: HL (Half-life time) [multiple time-points over 24h post dose on day 1 and Day 13 (DDI phase),]

    6. Probe substrate PK parameters:CL/F (Apparent Oral Clearance) [multiple time-points over 24h post dose on day 1 and Day 13 (DDI phase),]

    7. Probe substrate PK parameters:Vz/F (apparent volume of distribution) [multiple time-points over 24h post dose on day 1 and Day 13 (DDI phase),]

    Secondary Outcome Measures

    1. Frequency and severity of AEs (Adverse Events) [up to at least 30 days after the last dose of dovitinib (TKI258)]

    2. Preliminary evidence of antitumor activity of dovitinib (TKI258) [every 8 weeks until progression of disease]

      overall response based on investigator's assessment and best overall response using RECIST 1.1

    3. Frequency and severity of SAEs (Serious Adverse Events) [up to at least 30 days after the last dose of dovitinib (TKI258)]

    Eligibility Criteria

    Criteria

    Ages Eligible for Study:
    18 Years and Older
    Sexes Eligible for Study:
    All
    Accepts Healthy Volunteers:
    No
    Inclusion Criteria:

    • Patients with a cytopathologically or histopathologically confirmed diagnosis of an advanced solid tumor, excluding breast cancer which has progressed despite standard therapy or for which no standard therapy exists

    • ECOG performance status 0 or 1 and anticipated life expectancy ≥ 3 months

    • Patient must meet protocol-specific laboratory values

    Exclusion Criteria:

    • Patients with brain metastases

    • Patients who have received or who are expected to receive any prohibited medications and therapies

    • Patients who have received CYP1A2 inducer, CYP2C9/2C19 inducer or CYP3A4 inducer medications within 30 days prior to start study treatment or are expected to receive during the first 14 days after starting the study treatment

    • Patients with a known hypersensitivity to benzodiazepines

    • Patients who have not recovered from previous anti-cancer therapies

    • Patient with impairment of gastrointestinal (GI) function or GI disease that may significantly alter the absorption of TKI258

    • Patients who have concurrent severe and/or uncontrolled concomitant medical conditions that could compromise participation in the study

    • Female patients who are pregnant or breast-feeding

    • Fertile males or women not willing to use highly effective methods of contraception

    • Other protocol-defined inclusion/exclusion criteria will apply

    Contacts and Locations

    Locations

    Site City State Country Postal Code
    1 University of Kansas Cancer Center Medical Center Kansas City Kansas United States 66160
    2 Henry Ford Hospital Henry Ford Detroit Michigan United States 48202-2689
    3 University of Minnesota Minneapolis Minnesota United States 55455
    4 Comprehensive Cancer Centers Las Vegas Nevada United States 89169
    5 Cancer Institute of New Jersey Dept of Cancer Institute of NJ New Brunswick New Jersey United States 08901

    Sponsors and Collaborators

    • Novartis Pharmaceuticals

    Investigators

    • Study Director: Novartis Pharmaceuticals, Novartis Pharmaceuticals

    Study Documents (Full-Text)

    None provided.

    More Information

    Additional Information:

    Publications

    None provided.
    Responsible Party:
    Novartis Pharmaceuticals
    ClinicalTrials.gov Identifier:
    NCT01596647
    Other Study ID Numbers:
    • CTKI258A2119
    • 2011-001489-16
    First Posted:
    May 11, 2012
    Last Update Posted:
    Dec 21, 2020
    Last Verified:
    May 1, 2015
    Keywords provided by Novartis Pharmaceuticals
    cancer, tumors, phase I, drug-drug interaction, pharmacokinetic, probe drug, caffeine, diclofenac, omeprazole, midazolam, CYP1A2, CYP2C9, CYP2C19, CYP3A4
    Additional relevant MeSH terms:
    Breast Neoplasms
    Diclofenac
    Midazolam
    Caffeine
    Omeprazole

    Study Results

    No Results Posted as of Dec 21, 2020