Clinical trial NCT03521037: Rucaparib Hepatic Impairment Study in Patients With a Solid Tumor
Official title: A Phase 1, Open-Label, Parallel Group Study to Determine the Pharmacokinetics, Safety and Tolerability of Rucaparib in Patients With an Advanced Solid Tumor and Either Moderate Hepatic Impairment or Normal Hepatic Function
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Neoplasms
Keywords: rucaparib
CO-338
Clovis
Clovis Oncology
PARP inhibitor
hepatic impairment
Lead sponsor: pharmaand GmbH
Sponsor class: INDUSTRY
First posted: 2018-05-11
Enrollment: 16
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: OTHER

Brief summary: Phase 1, open-label, parallel group, PK, safety and tolerability study in patients with an advanced solid tumor and either normal hepatic function (Group 1, n = 8) or moderate hepatic impairment (Group 2, n = 8) according to the NCI-ODWG criteria. Patients in Group 1 and Group 2 may be enrolled in parallel, with preferential enrollment of Group 2 patients before Group 1 patients. The study will consist of 2 parts: a single-dose PK part (Part I) and a continuous rucaparib treatment part (Part II).

Detailed description: In Part I, eligible patients will receive a single oral dose of 600 mg rucaparib followed by intensive plasma PK sampling up to Day 7 (hour 144). In Part II, patients may continue to receive continuous oral rucaparib in 28 day cycles. The starting dose for all Group 1 patients will be 600 mg BID. The first 2 patients with moderate hepatic impairment (Group 2) that enter Part II will receive a starting dose of 400 mg BID rucaparib; a lower dose of rucaparib may also be set based on PK results observed in Part I. If this initial starting dose is determined to be safe and tolerable as determined by real-time PK data and dose limiting toxicities (DLT) observed during the first 28 days of rucaparib, the starting dose of rucaparib may be increased in subsequent Group 2 patients. The starting dose for Group 2 patients may also be lowered, based on the patients' real time PK and emerging safety data. The Sponsor and key clinical research organization (CRO) staff will review available adverse event, laboratory, and PK data to determine the starting dose for subsequent Group 2 patients, as well as allowing intra-patient dose escalation of rucaparib after Cycle 1.Treatment with rucaparib will continue until progression of disease, unacceptable toxicity, death, loss to follow-up, withdrawal of consent, or other appropriate clinical reason for discontinuation.

Eligibility criteria: Inclusion Criteria:

All Patients:

* Patients ≥18 years of age at the time the ICF is signed;
* Patients with a histologically or cytologically confirmed advanced solid tumor who, in the opinion of the Investigator, could potentially benefit from treatment with rucaparib
* ECOG PS less than or equal to 2
* Adequate bone marrow and renal function

Hepatically Impaired Patients (in addition):

* Stable hepatic impairment as judged by the Investigator
* Moderate Hepatic Impairment (NCI-ODWG criteria) during Screening

Patients with Normal Hepatic Function (in addition):

• Normal Hepatic Function (NCI-ODWG criteria)

Exclusion Criteria:

All Patients:

* Prior treatment with chemotherapy, radiation, antibody therapy or other immunotherapy, gene therapy, vaccine therapy, angiogenesis inhibitors, or investigational drugs within 14 days prior to day 1
* Ongoing toxicity ≥ Grade 2 per Common Terminology Criteria for Adverse Events criteria (CTCAE version 4.03)
* Prior treatment with any poly adenosine diphosphate ribose polymerase inhibitor
* 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, and/or any gastrointestinal disorder or defect that would, in the opinion of the Investigator, interfere with absorption of rucaparib
* Hospitalization for bowel obstruction within 3 months prior to Day 1
* Untreated or symptomatic central nervous system (CNS) metastases
* Evidence or history of bleeding disorder
* Acute illness within 14 days prior to Day 1
* Active second malignancy

Hepatically Impaired Patients (in addition):

* Severe hepatic encephalopathy (Grade \>2);
* History of liver transplantation;
* Advanced ascites or ascites that require drainage and albumin supplementation, as judged by the Investigator;
* Acute damage of the liver with Grade 4 AST/ALT values

Primary outcomes:
measure: Maximum plasma rucaparib concentration (Cmax)
timeFrame: day 1 to day 7
measure: Area under the plasma rucaparib concentration-time curve from time zero up to the last time point with quantifiable concentration (AUC0-last)
timeFrame: day 1 to day 7
Secondary outcomes:
measure: Area under the plasma rucaparib concentration-time curve from time zero up to time infinity (AUC0-inf)
timeFrame: day 1 to day 7
measure: Terminal half-life (t1/2) of rucaparib
timeFrame: day 1 to day 7
measure: Time to attain maximum plasma rucaparib concentration (Tmax)
timeFrame: day 1 to day 7
measure: Apparent clearance (CL/F) of rucaparib
timeFrame: day 1 to day 7
measure: Apparent volume of distribution during terminal phase (Vz/F) of rucaparib
timeFrame: day 1 to day 7
measure: Trough plasma concentration of rucaparib at steady state (Cmin,ss)
timeFrame: approximately 4 months
measure: Renal clearance (CLR) of rucaparib
timeFrame: day 1 to day 2
measure: Cumulative amount of rucaparib excreted in urine during urine collection period post rucaparib dose
timeFrame: day 1 to day 2
measure: Fraction of administered rucaparib excreted into urine (Fe/F) during urine collection period post rucaparib dose
timeFrame: day 1 to day 2
measure: Incidence of Adverse Events [Safety and Tolerability]
timeFrame: From Day 1 to last patient visit in Part II (approximately 2 years)
measure: Incidence of clinical laboratory abnormalities [Safety and Tolerability]
timeFrame: From Day 1 to last patient visit in Part II (approximately 2 years)
measure: Incidence of dose modifications [Safety and Tolerability]
timeFrame: From Day 1 to last patient visit in Part II (approximately 2 years)
Other outcomes:
measure: Maximum plasma metabolite concentration (Cmax)
timeFrame: day 1 to day 7
measure: Area under the plasma metabolite concentration-time curve from time zero up to the last time point with quantifiable concentrations (AUC0-last)
timeFrame: day 1 to day 7
measure: Area under the plasma metabolite concentration-time curve from time zero up to time infinity (AUC0-inf)
timeFrame: day 1 to day 7
measure: Terminal half-life (t1/2) of metabolite
timeFrame: day 1 to day 7
measure: Time to attain maximum plasma metabolite concentration (Tmax)
timeFrame: day 1 to day 7
measure: Plasma trough concentration of metabolite(s) at steady state (Cmin,ss)
timeFrame: day 1 to day 7
measure: Renal clearance (CLR) of metabolite(s)
timeFrame: day 1 to day 2
measure: Cumulative amount of rucaparib metabolite(s) excreted in urine during urine collection period post rucaparib dose
timeFrame: day 1 to day 2
Locations:
city: Biała Podlaska
country: Poland
facility: Wojewódzki Szpital Specjalistyczny w Białej Podlaskiej
city: Poznań
country: Poland
facility: Med Polonia Sp. z o.o.
city: Szczecin
country: Poland
facility: Zachodniopomorskie Centrum Onkologii w Szczecinie
city: Warszawa
country: Poland
facility: BioVirtus Centrum Medyczne
city: Bratislava
country: Slovakia
facility: Summit Clinical Research s.r.o.
city: Newcastle Upon Tyne
country: United Kingdom
facility: Northern Centre for Cancer Care
Study officials:
References: