Neoplasms
Conditions
Keywords
rucaparib, CO-338, Clovis, Clovis Oncology, PARP inhibitor, hepatic impairment
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.
Interventions
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.
Sponsors
pharmaand GmbH
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
OTHER
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Maximum plasma rucaparib concentration (Cmax) | day 1 to day 7 | PK parameter of rucaparib to be calculated from the plasma concentration-time data |
| Area under the plasma rucaparib concentration-time curve from time zero up to the last time point with quantifiable concentration (AUC0-last) | day 1 to day 7 | PK parameter of rucaparib to be calculated from the plasma concentration-time data |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Apparent clearance (CL/F) of rucaparib | day 1 to day 7 | PK parameter of rucaparib to be calculated from the plasma concentration-time data |
| Apparent volume of distribution during terminal phase (Vz/F) of rucaparib | day 1 to day 7 | PK parameter of rucaparib to be calculated from the plasma concentration-time data |
| Trough plasma concentration of rucaparib at steady state (Cmin,ss) | approximately 4 months | PK parameter of rucaparib to be calculated from the plasma concentration-time data |
| Renal clearance (CLR) of rucaparib | day 1 to day 2 | PK parameter of rucaparib to be calculated from the plasma and urine concentration-time data |
| Cumulative amount of rucaparib excreted in urine during urine collection period post rucaparib dose | day 1 to day 2 | PK parameter of rucaparib to be calculated based on urine concentration-time data |
| Fraction of administered rucaparib excreted into urine (Fe/F) during urine collection period post rucaparib dose | day 1 to day 2 | PK parameter of rucaparib to be calculated based on the amount of rucaparib recovered in urine |
| Incidence of Adverse Events [Safety and Tolerability] | From Day 1 to last patient visit in Part II (approximately 2 years) | — |
| Incidence of clinical laboratory abnormalities [Safety and Tolerability] | From Day 1 to last patient visit in Part II (approximately 2 years) | — |
| Incidence of dose modifications [Safety and Tolerability] | From Day 1 to last patient visit in Part II (approximately 2 years) | — |
| Area under the plasma rucaparib concentration-time curve from time zero up to time infinity (AUC0-inf) | day 1 to day 7 | PK parameter of rucaparib to be calculated from the plasma concentration-time data |
| Terminal half-life (t1/2) of rucaparib | day 1 to day 7 | PK parameter of rucaparib to be calculated from the plasma concentration-time data |
| Time to attain maximum plasma rucaparib concentration (Tmax) | day 1 to day 7 | PK parameter of rucaparib to be calculated from the plasma concentration-time data |
Other
| Measure | Time frame | Description |
|---|---|---|
| Terminal half-life (t1/2) of metabolite | day 1 to day 7 | PK parameter for rucaparib metabolite(s) to be calculated from plasma concentration-time data |
| Time to attain maximum plasma metabolite concentration (Tmax) | day 1 to day 7 | PK parameter for rucaparib metabolite(s) to be calculated from plasma concentration-time data |
| Plasma trough concentration of metabolite(s) at steady state (Cmin,ss) | day 1 to day 7 | PK parameter for rucaparib metabolite(s) to be calculated from plasma concentration-time data |
| Renal clearance (CLR) of metabolite(s) | day 1 to day 2 | PK parameters for rucaparib metabolite(s) to be calculated from plasma and urine concentration-time data |
| Cumulative amount of rucaparib metabolite(s) excreted in urine during urine collection period post rucaparib dose | day 1 to day 2 | PK parameter for rucaparib metabolite(s) to be calculated from urine concentration-time data |
| Maximum plasma metabolite concentration (Cmax) | day 1 to day 7 | PK parameter for rucaparib metabolite(s) to be calculated from plasma concentration-time data |
| Area under the plasma metabolite concentration-time curve from time zero up to time infinity (AUC0-inf) | day 1 to day 7 | PK parameter for rucaparib metabolite(s) to be calculated from plasma concentration-time data |
| Area under the plasma metabolite concentration-time curve from time zero up to the last time point with quantifiable concentrations (AUC0-last) | day 1 to day 7 | PK parameter for rucaparib metabolite(s) to be calculated from plasma concentration-time data |
Countries
Poland, Slovakia, United Kingdom
Outcome results
None listed