Pharmacokinetic Drug-Drug Interaction Study of Rucaparib

Study Overview
=================
Brief Summary
-----------------
The purpose of this study is to assess pharmacokinetic concentrations of multiple probes alone followed by assessment of the same drug pharmacokinetic concentrations when the patient has steady-state exposure to rucaparib followed by cycle-by-cycle treatment with rucaparib continuing until disease progression or other reason for discontinuation.

Detailed Description
-----------------
This is a Phase 1, open-label, sequential, drug-drug-interaction (DDI) study in patients with advanced solid tumors. The study will consist of 2 parts: a DDI part (Part I) and a rucaparib treatment part (Part II). In Part I, the PK of cytochrome P450 (CYP) cocktail probes: caffeine, S-warfarin, omeprazole, and midazolam and a P-glycoprotein probe (digoxin) will be assessed with and without rucaparib treatment. Patients will receive single doses of CYP drug cocktail (caffeine, warfarin, omeprazole, and midazolam) on Day 1 and Day 12, and single doses of digoxin on Day 2 and Day 13. Continuous treatment with 600 mg rucaparib twice daily (BID) will start on Day 5 and will last until at least Day 16 of Part I. In Part II, the treatment with rucaparib in 28-day cycles will continue until progression of disease, unacceptable toxicity, or other reason for discontinuation.

Official Title
-----------------
A Phase 1, Open-label, Multiple-probe Drug-drug Interaction Study to Determine the Effect of Rucaparib on Pharmacokinetics of Caffeine, S-Warfarin, Omeprazole, Midazolam, and Digoxin in Patients With Advanced Solid Tumors

Conditions
-----------------
Neoplasms

Intervention / Treatment
-----------------
* Drug: Caffeine
* Drug: Warfarin
* Drug: Omeprazole
* Drug: Midazolam
* Drug: digoxin
* Drug: Vitamin K
* Drug: Rucaparib


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Histologically or cytologically confirmed advanced solid tumor Have evidence of measurable disease as defined by RECIST Version 1.1 Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 Adequate bone marrow, renal, and liver function Exclusion Criteria: Prior treatment with chemotherapy, radiation, antibody therapy or other immunotherapy, gene therapy, vaccine therapy, angiogenesis inhibitors, or experimental drugs within 14 days prior to Day 1 Prior treatment with any poly adenosine diphosphate ribose polymerase inhibitor (PARPi) Arterial or venous thrombi (including cerebrovascular accident), myocardial infarction, admission for unstable angina, cardiac angioplasty, stenting or poorly controlled hypertension within the last 3 months prior to Screening; Pre-existing duodenal stent, recent or existing bowel obstruction, and/or any gastrointestinal disorder or defect that would, in the opinion of the Investigator, interfere with absorption of study drugs Current use of therapeutic anticoagulation (low molecular weight heparin, oral anticoagulant agents including acetylsalicylic acid), Current use of one of the probe drugs; Untreated or symptomatic central nervous system (CNS) metastases. Evidence or history of bleeding disorder Participation in another investigational drug trial within 30 days prior to Day 1 (or 5 times the half-life of the drug, whichever is longer) or exposure to more than three new investigational agents within 12 months prior to Day 1; Acute illness within 14 days prior to Day 1 unless mild in severity and approved by the Investigator and Sponsor's medical representative Active second malignancy, i.e., patient known to have potentially fatal cancer present for which they may be (but not necessarily) currently receiving treatment.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Other
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Other: single arm probe drugs and rucaparib<br>Caffeine Warfarin Vitamin K Omeprazole Midazolam Digoxin rucaparib | Drug: Caffeine<br>* 200 mg (4 x 50mg) Tablet<br>Drug: Warfarin<br>* 10 mg (2 x 5mg) Tablet<br>* Other names: Marevan®;Drug: Omeprazole<br>* 40 mg Tablet<br>* Other names: Losec®; MUPS®;Drug: Midazolam<br>* 5 mg/mL<br>* Other names: Midazolam Accord®; versed;Drug: digoxin<br>* .25 mg Tablet<br>* Other names: lanoxin®;Drug: Vitamin K<br>* 10 mg Tablet<br>* Other names: warfarin antagonist;Drug: Rucaparib<br>* 200 & 300 mg tablet<br>* Other names: CO-338;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| PK parameters for caffeine, S-warfarin, omeprazole, midazolam, and digoxin with and without rucaparib treatment to be calculated from the plasma concentration-time data | Maximum plasma concentration [Cmax] | Days 1-5 and Days 12-16 | 
| PK parameters for caffeine, S-warfarin, omeprazole, midazolam, and digoxin with and without rucaparib treatment to be calculated from the plasma concentration-time data | Area under the concentration-time curve (AUC) up to time t, where t is the last time point with concentrations above the lower limit of quantitation [AUC0-last ] | Days 1-5 and Days 12-16 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| PK parameters for caffeine, S-warfarin, omeprazole, midazolam, and digoxin with and without rucaparib treatment to be calculated from the plasma concentration-time data | Area Under the Curve, from time zero up to infinity with extrapolation of the terminal phase [AUC0-inf] | Days 1-5 and Days 12-16 | 
| Tolerability and safety of rucaparib with and without co-administration of the probe drugs assessed by incidence of Adverse Events (AEs), clinical laboratory abnormalities, and dose modifications | Incidence of Adverse Events (AEs), clinical laboratory abnormalities, and dose modifications | Days 1-16 | 
| PK parameters will be calculated for rucaparib at steady-state | Trough plasma concentration [Ctrough] | Day 7-12 | 
| PK parameters will be calculated for rucaparib at steady-state | Maximum plasma concentration during a dosing interval at steady-state [Cmax,ss] | Day 7-12 | 
| PK parameters will be calculated for rucaparib at steady-state | Time to attain maximum plasma concentration at steady-state [tmax,ss] | Day 7-12 | 
| PK parameters will be calculated for rucaparib at steady-state | Area Under the Curve over a dosing interval τ at steady-state [AUCτ,ss] | Day 7-12 | 
| PK parameters for caffeine, S-warfarin, omeprazole, midazolam, and digoxin with and without rucaparib treatment to be calculated from the plasma concentration-time data | Terminal half-life [t1/2] | Days 1-5 and Days 12-16 | 
| PK parameters for caffeine, S-warfarin, omeprazole, midazolam, and digoxin with and without rucaparib treatment to be calculated from the plasma concentration-time data | Time to attain maximum plasma concentration [tmax] | Days 1-5 and Days 12-16 | 
| PK parameters for caffeine, S-warfarin, omeprazole, midazolam, and digoxin with and without rucaparib treatment to be calculated from the plasma concentration-time data | Apparent clearance [CL/F] | Days 1-5 and Days 12-16 | 
| PK parameters for caffeine, S-warfarin, omeprazole, midazolam, and digoxin with and without rucaparib treatment to be calculated from the plasma concentration-time data | Apparent volume of distribution during terminal phase [Vz/F] | Days 1-5 and Days 12-16 | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
rucaparib, CO-338, Clovis, Clovis Oncology, PARP Inhibitor, Drug-Drug Interaction