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

NCT01596647 | Completed Phase 1

• 2 other identifiers: CTKI258A21192011-001489-16
• Study Type: interventional
• Target: 39
• Locations: 1 country
• Sites: 5

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.

Conditions

Advanced Solid Tumors, Excluding Breast Cancer

Keywords

cancer, tumors, phase I, drug-drug interaction, pharmacokinetic, probe drug, caffeine, diclofenac, omeprazole, midazolam, CYP1A2, CYP2C9, CYP2C19, CYP3A4

Outcome Measures

Primary Outcomes (7)

• 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 Outcomes (3)

• 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)

  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)

Study Arms (1)

TKI258 (dovitinib)

EXPERIMENTAL

dovitinib, 5 days on / 2 days off dose schedule

Drug: caffeine; Drug: diclofenac; Drug: omeprazole; Drug: midazolam; Drug: TKI258

Interventions

caffeine DRUG

single dose of the probe drug cocktail contains: caffeine, diclofenac, omeprazole and midazolam

Also known as: probe drug

TKI258 (dovitinib)

diclofenac DRUG

single dose of the probe drug cocktail contains: caffeine, diclofenac, omeprazole and midazolam

Also known as: probe drug

TKI258 (dovitinib)

omeprazole DRUG

single dose of the probe drug cocktail contains: caffeine, diclofenac, omeprazole and midazolam

Also known as: probe drug

TKI258 (dovitinib)

midazolam DRUG

single dose of the probe drug cocktail contains: caffeine, diclofenac, omeprazole and midazolam

Also known as: probe drug

TKI258 (dovitinib)

TKI258 DRUG

dovitinib, 5 days on / 2 days off dose schedule

Also known as: dovitinib

TKI258 (dovitinib)

Eligibility Criteria

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

You may qualify if:

• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• Novartis Pharmaceuticals: lead

Study Sites (5)

University of Kansas Cancer Center Medical Center

Kansas City, Kansas, 66160, United States

Location

Henry Ford Hospital Henry Ford

Detroit, Michigan, 48202-2689, United States

Location

University of Minnesota

Minneapolis, Minnesota, 55455, United States

Location

Comprehensive Cancer Centers

Las Vegas, Nevada, 89169, United States

Location

Cancer Institute of New Jersey Dept of Cancer Institute of NJ

New Brunswick, New Jersey, 08901, United States

Location

Related Links

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

MeSH Terms

Conditions

Neoplasms

Interventions

Caffeine; Diclofenac; Omeprazole; Midazolam; 4-amino-5-fluoro-3-(5-(4-methylpiperazin-1-yl)-1H-benzimidazol-2-yl)quinolin-2(1H)-one

Intervention Hierarchy (Ancestors)

Xanthines; Alkaloids; Heterocyclic Compounds; Purinones; Purines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Phenylacetates; Acids, Carbocyclic; Carboxylic Acids; Organic Chemicals; 2-Pyridinylmethylsulfinylbenzimidazoles; Sulfoxides; Sulfur Compounds; Pyridines; Heterocyclic Compounds, 1-Ring; Benzimidazoles; Benzodiazepines; Benzazepines

Study Officials

• Novartis Pharmaceuticals

  Novartis Pharmaceuticals

  STUDY DIRECTOR

Study Design

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

Study Record Dates

• First Submitted: March 23, 2012
• First Posted: May 11, 2012
• Study Start: May 1, 2012
• Primary Completion: July 1, 2014
• Study Completion: July 1, 2014
• Last Updated: December 21, 2020

Record last verified: 2015-05

Locations

US (5)