Clinical trial NCT01596647: Pharmacokinetic Drug-drug Interaction Study of Dovitinib (TKI258) in Patients With Advanced Solid Tumors
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 type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
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
Lead sponsor: Novartis
Sponsor class: INDUSTRY
First posted: 2012-05-11
Enrollment: 39
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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.


Eligibility criteria: 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

Primary outcomes:
measure: Probe substrate pharmacokinetics (PK) parameters: Cmax (Maximum (peak) concentration of drug)
timeFrame: multiple time-points over 24h post dose on day 1 and Day 13 (DDI phase),
measure: Probe substrate PK parameters: AUCtlast (Area Under the Curve)
timeFrame: multiple time-points over 24h post dose on day 1 and Day 13 (DDI phase),
measure: Probe substrate PK parameters: AUCinf
timeFrame: multiple time-points over 24h post dose on day 1 and Day 13 (DDI phase),
measure: Probe substrate PK parameters:Tmax (Time to maximum concentration)
timeFrame: multiple time-points over 24h post dose on day 1 and Day 13 (DDI phase),
measure: Probe substrate PK parameters: HL (Half-life time)
timeFrame: multiple time-points over 24h post dose on day 1 and Day 13 (DDI phase),
measure: Probe substrate PK parameters:CL/F (Apparent Oral Clearance)
timeFrame: multiple time-points over 24h post dose on day 1 and Day 13 (DDI phase),
measure: Probe substrate PK parameters:Vz/F (apparent volume of distribution)
timeFrame: multiple time-points over 24h post dose on day 1 and Day 13 (DDI phase),
Secondary outcomes:
measure: Frequency and severity of AEs (Adverse Events)
timeFrame: up to at least 30 days after the last dose of dovitinib (TKI258)
measure: Preliminary evidence of antitumor activity of dovitinib (TKI258)
timeFrame: every 8 weeks until progression of disease
measure: Frequency and severity of SAEs (Serious Adverse Events)
timeFrame: up to at least 30 days after the last dose of dovitinib (TKI258)
Other outcomes:
Locations:
city: Kansas City
country: United States
facility: University of Kansas Cancer Center Medical Center
state: Kansas
city: Detroit
country: United States
facility: Henry Ford Hospital Henry Ford
state: Michigan
city: Minneapolis
country: United States
facility: University of Minnesota
state: Minnesota
city: Las Vegas
country: United States
facility: Comprehensive Cancer Centers
state: Nevada
city: New Brunswick
country: United States
facility: Cancer Institute of New Jersey Dept of Cancer Institute of NJ
state: New Jersey
Study officials:
affiliation: Novartis Pharmaceuticals
name: Novartis Pharmaceuticals
role: STUDY_DIRECTOR
References: