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

Phase 1

Completed

• Conditions: Advanced Solid Tumors, Excluding Breast Cancer
• Interventions: Drug: caffeine; Drug: diclofenac; Drug: omeprazole; Drug: midazolam; Drug: TKI258

• Registration Number: NCT01596647
• Lead Sponsor: Novartis Pharmaceuticals

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.

Detailed Description

Not available

Study Timeline

• Study First Submitted: 2012-03-23
• Study Start: 2012-05
• Study First Submitted QC: 2012-05-10
• Study First Posted: 2012-05-11
• Primary Completion: 2014-07
• Study Completion: 2014-07
• Status Verified: 2015-05
• Last Update Submitted: 2020-12-17
• Last Update Posted: 2020-12-21

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 39

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 & Design

• Study Type: INTERVENTIONAL
• Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
TKI258 (dovitinib)	diclofenac	dovitinib, 5 days on / 2 days off dose schedule
TKI258 (dovitinib)	TKI258	dovitinib, 5 days on / 2 days off dose schedule
TKI258 (dovitinib)	caffeine	dovitinib, 5 days on / 2 days off dose schedule
TKI258 (dovitinib)	midazolam	dovitinib, 5 days on / 2 days off dose schedule
TKI258 (dovitinib)	omeprazole	dovitinib, 5 days on / 2 days off dose schedule

Primary Outcome Measures

Name	Time	Method
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: 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: AUCtlast (Area Under the Curve)	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

Name	Time	Method
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	overall response based on investigator's assessment and best overall response using RECIST 1.1
Frequency and severity of SAEs (Serious Adverse Events)	up to at least 30 days after the last dose of dovitinib (TKI258)

Trial Locations

Locations (5)

Comprehensive Cancer Centers; 🇺🇸 Las Vegas, Nevada, United States

University of Kansas Cancer Center Medical Center; 🇺🇸 Kansas City, Kansas, United States

Henry Ford Hospital Henry Ford; 🇺🇸 Detroit, Michigan, United States

Cancer Institute of New Jersey Dept of Cancer Institute of NJ; 🇺🇸 New Brunswick, New Jersey, United States

University of Minnesota; 🇺🇸 Minneapolis, Minnesota, United States