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

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

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.

Study Overview

• Status: Completed
• Conditions: Advanced Solid Tumors, Excluding Breast Cancer
• Intervention / Treatment: Drug: caffeine; Drug: diclofenac; Drug: omeprazole; Drug: midazolam; Drug: TKI258

• Study Type: Interventional
• Enrollment (Actual): 39
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • Kansas
    • Kansas City, Kansas, United States, 66160
      • University of Kansas Cancer Center Medical Center
  • Michigan
    • Detroit, Michigan, United States, 48202-2689
      • Henry Ford Hospital Henry Ford
  • Minnesota
    • Minneapolis, Minnesota, United States, 55455
      • University of Minnesota
  • Nevada
    • Las Vegas, Nevada, United States, 89169
      • Comprehensive Cancer Centers
  • New Jersey
    • New Brunswick, New Jersey, United States, 08901
      • Cancer Institute of New Jersey Dept of Cancer Institute of NJ

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:

• 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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: NA
• Interventional Model: SINGLE_GROUP
• Masking: NONE

Number of Arms

1

Arms and Interventions

Participant Group / 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

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
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),
Probe substrate PK parameters: AUCtlast (Area Under the Curve)	multiple time-points over 24h post dose on day 1 and Day 13 (DDI phase),
Probe substrate PK parameters: AUCinf	multiple time-points over 24h post dose on day 1 and Day 13 (DDI phase),
Probe substrate PK parameters:Tmax (Time to maximum concentration)	multiple time-points over 24h post dose on day 1 and Day 13 (DDI phase),
Probe substrate PK parameters: HL (Half-life time)	multiple time-points over 24h post dose on day 1 and Day 13 (DDI phase),
Probe substrate PK parameters:CL/F (Apparent Oral Clearance)	multiple time-points over 24h post dose on day 1 and Day 13 (DDI phase),
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

Outcome Measure	Measure Description	Time Frame
Frequency and severity of AEs (Adverse Events)		up to at least 30 days after the last dose of dovitinib (TKI258)
Preliminary evidence of antitumor activity of dovitinib (TKI258)	overall response based on investigator's assessment and best overall response using RECIST 1.1	every 8 weeks until progression of disease
Frequency and severity of SAEs (Serious Adverse Events)		up to at least 30 days after the last dose of dovitinib (TKI258)

Collaborators and Investigators

• Sponsor: Novartis Pharmaceuticals

Publications and helpful links

Helpful Links

• Results for CTKI258A2119 can be found on the Novartis Clinical Trial Results Website

Study record dates

Study Major Dates

• Study Start: May 1, 2012
• Primary Completion (ACTUAL): July 1, 2014
• Study Completion (ACTUAL): July 1, 2014

Study Registration Dates

• First Submitted: March 23, 2012
• First Submitted That Met QC Criteria: May 10, 2012
• First Posted (ESTIMATE): May 11, 2012

Study Record Updates

• Last Update Posted (ACTUAL): December 21, 2020
• Last Update Submitted That Met QC Criteria: December 17, 2020
• Last Verified: May 1, 2015

More Information

Terms related to this study

• Keywords: cancer, tumors, phase I, drug-drug interaction, pharmacokinetic, probe drug, caffeine, diclofenac, omeprazole, midazolam, CYP1A2, CYP2C9, CYP2C19, CYP3A4
• Additional Relevant MeSH Terms: Skin Diseases; Neoplasms; Neoplasms by Site; Breast Diseases; Breast Neoplasms; Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Central Nervous System Depressants; Peripheral Nervous System Agents; Enzyme Inhibitors; Analgesics; Sensory System Agents; Anesthetics, Intravenous; Anesthetics, General; Anesthetics; Anti-Inflammatory Agents, Non-Steroidal; Analgesics, Non-Narcotic; Anti-Inflammatory Agents; Antirheumatic Agents; Cyclooxygenase Inhibitors; Purinergic Antagonists; Purinergic Agents; Gastrointestinal Agents; Tranquilizing Agents; Psychotropic Drugs; Hypnotics and Sedatives; Adjuvants, Anesthesia; Anti-Anxiety Agents; GABA Modulators; GABA Agents; Anti-Ulcer Agents; Proton Pump Inhibitors; Phosphodiesterase Inhibitors; Purinergic P1 Receptor Antagonists; Central Nervous System Stimulants; Midazolam; Diclofenac; Caffeine; Omeprazole
• Other Study ID Numbers: CTKI258A2119; 2011-001489-16 (EUDRACT_NUMBER)