Pharmacokinetic Drug-Drug Interaction Study of Rucaparib (DDI)

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

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.

Study Overview

• Status: Completed
• Conditions: Neoplasms
• Intervention / Treatment: Drug: Rucaparib; Drug: Caffeine; Drug: Warfarin; Drug: Omeprazole; Drug: Midazolam; Drug: digoxin; Drug: Vitamin K

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.

• Study Type: Interventional
• Enrollment (Actual): 17
• Phase: Phase 1

Contacts and Locations

Study Locations

• Poland
  • Poznan, Poland, 60-693
    • Med Polonia
  • Szczecin, Poland, 71-730
    • Zachodniopomorskie Centrum Onkologii Centrum Innowacji
  • Mokra 7
    • Kajetany, Mokra 7, Poland, 05-830
      • Biovirtus Research Site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Other
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Other: single arm probe drugs and rucaparib; Caffeine Warfarin Vitamin K Omeprazole Midazolam Digoxin rucaparib

Drug: Rucaparib; 200 & 300 mg tablet; Other Names: Rubraca; CO-338; rucaparib camsylate; Drug: Caffeine; 200 mg (4 x 50mg) Tablet; Drug: Warfarin; 10 mg (2 x 5mg) Tablet; Other Names: Marevan®; Drug: Omeprazole; 40 mg Tablet; Other Names: Losec®; MUPS®; Drug: Midazolam; 5 mg/mL; Other Names: Midazolam Accord®; versed; Drug: digoxin; .25 mg Tablet; Other Names: lanoxin®; Drug: Vitamin K; 10 mg Tablet; Other Names: warfarin antagonist

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

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Response will be determined using Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 and tumor markers per applicable criteria for a given tumor type	28 day cycles with response evaluation every 8 weeks(±7 days) until week 24 thereafter every 12 weeks (±14 days)	From cycle 1 Day 1until radiologically confirmed disease progression, death, or initiation of subsequent treatment whichever comes first up to 52 weeks

Collaborators and Investigators

• Sponsor: zr Pharma & GmbH

Publications and helpful links

General Publications

• Xiao JJ, Nowak D, Ramlau R, Tomaszewska-Kiecana M, Wysocki PJ, Isaacson J, Beltman J, Nash E, Kaczanowski R, Arold G, Watkins S. Evaluation of Drug-Drug Interactions of Rucaparib and CYP1A2, CYP2C9, CYP2C19, CYP3A, and P-gp Substrates in Patients With an Advanced Solid Tumor. Clin Transl Sci. 2019 Jan;12(1):58-65. doi: 10.1111/cts.12600. Epub 2018 Dec 20.

Study record dates

Study Major Dates

• Study Start (Actual): April 1, 2016
• Primary Completion (Actual): March 1, 2017
• Study Completion (Actual): September 1, 2019

Study Registration Dates

• First Submitted: March 30, 2016
• First Submitted That Met QC Criteria: April 12, 2016
• First Posted (Estimated): April 15, 2016

Study Record Updates

• Last Update Posted (Actual): June 9, 2023
• Last Update Submitted That Met QC Criteria: June 7, 2023
• Last Verified: June 1, 2023

More Information

Terms related to this study

• Keywords: PARP Inhibitor; Drug-Drug Interaction; CO-338; Clovis; Clovis Oncology; rucaparib
• Additional Relevant MeSH Terms: Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Anti-Arrhythmia Agents; Central Nervous System Depressants; Enzyme Inhibitors; Anesthetics, Intravenous; Anesthetics, General; Anesthetics; Fibrin Modulating Agents; Purinergic Antagonists; Purinergic Agents; Antineoplastic Agents; Gastrointestinal Agents; Protective Agents; Cardiotonic Agents; Micronutrients; Tranquilizing Agents; Psychotropic Drugs; Hypnotics and Sedatives; Adjuvants, Anesthesia; Anti-Anxiety Agents; GABA Modulators; GABA Agents; Poly(ADP-ribose) Polymerase Inhibitors; Vitamins; Anticoagulants; Antifibrinolytic Agents; Hemostatics; Coagulants; Anti-Ulcer Agents; Proton Pump Inhibitors; Phosphodiesterase Inhibitors; Purinergic P1 Receptor Antagonists; Central Nervous System Stimulants; Digoxin; Midazolam; Vitamin K; Rucaparib; Warfarin; Caffeine; Omeprazole
• Other Study ID Numbers: CO-338-044

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO