Pharmacokinetic and Safety Study of Niraparib With Normal or Moderate Hepatic Impairment Patients

NCT03359850 | Completed Phase 1 Results DMC FDA Drug

• 2 other identifiers: 2133543000-01-003
• Study Type: interventional
• Target: 17
• Locations: 1 country
• Sites: 5

Brief Summary

Niraparib (Zejula®)is extensively metabolized and eliminated primarily by hepatic and renal pathways. The purpose of this study is to evaluate pharmacokinetics and safety of niraparib in patients with moderate hepatic impairment, for the purpose of providing recommendations to guide the initial dose and dose titration in this patient population.

Conditions

Ovarian Neoplasms; Neoplasms; Solid Tumor; Hepatic Impairment

Outcome Measures

Primary Outcomes (6)

• Area Under the Plasma Concentration-time Curve From Time 0 to the Time of the Last Quantifiable Concentration (AUClast) of Niraparib and Its Major Metabolite (M1) During PK Phase

  Blood samples were collected at indicated time points to evaluate AUC (last) of niraparib and M1. PK parameters were calculated by standard non-compartmental analysis.

  Pre-dose, 1, 2, 3, 4, 6, 8, 12, 24, 48, 72, 120, 168 hours post dose Day 1

• Area Under the Plasma Concentration-time Curve From Time 0 Extrapolated to Infinity (AUC 0-infinity) of Niraparib and M1 During PK Phase

  Blood samples were collected at indicated time points to evaluate AUC (0-infinity) of niraparib and M1. PK parameters were calculated by standard non-compartmental analysis.

  Pre-dose, 1, 2, 3, 4, 6, 8, 12, 24, 48, 72, 120, 168 hours post dose Day 1

• Observed Maximum Plasma Concentration (Cmax) of Niraparib and M1 During PK Phase

  Blood samples were collected at indicated time points to evaluate Cmax of niraparib and M1. PK parameters were calculated by standard non-compartmental analysis.

  Pre-dose, 1, 2, 3, 4, 6, 8, 12, 24, 48, 72, 120, 168 hours post dose Day 1

• Time to Maximum Concentration (Tmax) of Niraparib and M1 During PK Phase

  Blood samples were collected at indicated time points to evaluate tmax of niraparib and M1. PK parameters were calculated by standard non-compartmental analysis.

  Pre-dose, 1, 2, 3, 4, 6, 8, 12, 24, 48, 72, 120, 168 hours post dose Day 1

• Terminal Half-life (t½) of Niraparib and M1 During PK Phase

  Blood samples were collected at indicated time points to evaluate t1/2 of niraparib and M1. PK parameters were calculated by standard non-compartmental analysis.

  Pre-dose, 1, 2, 3, 4, 6, 8, 12, 24, 48, 72, 120, 168 hours post dose Day 1

• Apparent Total Body Clearance (CL/F) of Niraparib and M1 During PK Phase

  CL/F is calculated as Dose/(AUC 0-inf). Blood samples were collected at indicated time points to evaluate CL/F of niraparib and M1. PK parameters were calculated by standard non-compartmental analysis. Not applicable (NA) indicates that CL/F could not be measured for M1 since the dose of metabolite is unknown and only known dose is that of parent niraparib.

  Pre-dose, 1, 2, 3, 4, 6, 8, 12, 24, 48, 72, 120, 168 hours post dose Day 1

Secondary Outcomes (24)

• Number of Participants With Treatment-Emergent Adverse Events (TEAE) Including Non-serious Adverse Events (Non-SAEs), Serious Adverse Events (SAEs) and Discontinuations Due to AEs During PK Phase

  Up to Day 8

• Change From Baseline in Hemoglobin (Hb) During PK Phase

  Baseline and at Day 8

• Change From Baseline in Platelets, Neutrophils, Monocytes, Lymphocytes and Leukocyte During PK Phase

  Baseline and Day 8

• Change From Baseline in Clinical Chemistry Parameter of Protein and Albumin During PK Phase

  Baseline and Day 8

• Change From Baseline in Clinical Chemistry Parameter of Alkaline Phosphatase, Alanine Aminotransferase (ALT), Aspartate Aminotransferase (AST) and Lactate Dehydrogenase (LDH) During PK Phase

  Baseline and Day 8

Other Outcomes (2)

• Plasma Protein Unbound Fraction (Fu) of Niraparib and M1 During PK Phase

  Pre-dose, 3 hours and 168 hours post dose Day 1

• Clearance of Unbound Niraparib and M1 (CLfu/F) During PK Phase

  Pre-dose, 3 hours and 168 hours post dose Day 1

Study Arms (2)

Normal hepatic function (Group 1):

EXPERIMENTAL

To evaluate the pharmocokinetics and safety of niraparib

Drug: Niraparib

Moderate hepatic impairment (Group 2):

EXPERIMENTAL

To evaluate the pharmocokinetics and safety of niraparib

Drug: Niraparib

Interventions

Niraparib DRUG

Niraparib is a potent, orally active PARP1 and PARP2 inhibitor being developed as a treatment for patients with tumors that harbor defects in the homologous recombination DNA repair pathway or that are driven by PARP-mediated transcription factors.

Also known as: Zejula®

Moderate hepatic impairment (Group 2):; Normal hepatic function (Group 1):

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• All patients:
• To be considered eligible to participate in this study, all of the following requirements must be met:
• Patient, male or female, is at least 18 years of age.
• Patient has a diagnosis of advanced solid malignancy that has failed standard therapy or for which standard therapy is not likely to provide meaningful benefit, or patient has refused standard therapy.
• Patient has an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1.
• Patient is able to take oral medications.
• Female patient, if of childbearing potential, has a negative serum pregnancy test within 72 hours prior to taking study drug and agrees to abstain from activities that could result in pregnancy from enrollment through 120 days after the last dose of study treatment, or be of non-childbearing potential. Non-childbearing potential is defined as (by other than medical reasons):
• ≥45 years of age and has not had menses for \> 1 year.
• Amenorrheic for \< 2 years without a hysterectomy Post hysterectomy, bilateral oophorectomy, or tubal ligation..
• Note: Abstinence is acceptable if this is the established and preferred contraception for the patient.
• Male patient agrees to use an adequate method of contraception starting with the first dose of study treatment through 120 days after the last dose of study treatment..
• Patient is able to understand the study procedures and agrees to participate in the study by providing written informed consent.
• Patients with normal hepatic function (Group 1):
• Patients screened for the normal hepatic function group must meet the following additional criteria to be eligible for enrollment:
• Patient has no history of hepatic impairment.

You may not qualify if:

• Patients will not be eligible for study entry if any of the following criteria are met:
• All patients:
• Patient has undergone palliative radiotherapy within 1 week of study drug administration, encompassing \>20% of the bone marrow.
• Patient is starting chemotherapy within 3 weeks of study drug administration.
• Patient has a known hypersensitivity to the components of niraparib or excipients
• Patients who received colony-stimulating factors within 2 weeks prior to the first dose of study treatment are not eligible.
• Patient has persistent chemotherapy associated Grade 2 or greater toxicity except for neuropathy, alopecia or fatigue.
• Patient has symptomatic uncontrolled brain or leptomeningeal metastases.
• Patient has undergone major surgery within 3 weeks of starting the study or patient has not recovered from any effects of any major surgery.
• Patient is considered a poor medical risk due to a serious, uncontrolled medical disorder (other than hepatic impairment) or active, uncontrolled infection.
• Patient has received a transfusion (platelets or red blood cells) within 3 weeks of receiving niraparib.
• Patient is pregnant, breastfeeding, or expecting to conceive children while receiving study treatment or for 3 months after the last dose of study treatment.
• Patient has a known history of myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML).
• Patient is currently receiving, or unable to refrain from taking from 4 days prior to dosing until the time of the last PK blood draw, any of the following cytochrome (CYP) 1A2 substrates: alosetron, duloxetine, melatonin, ramelteon, tacrine, tizanidine, and theophylline.
• Patient is unable to refrain from any intake of grapefruit or grapefruit juice within 4 days of the first administration of niraparib until the final PK sample collection.

Sponsors & Collaborators

• Tesaro, Inc.: lead

Study Sites (5)

GSK Investigational Site

Los Angeles, California, 90033, United States

Location

GSK Investigational Site

Newport Beach, California, 92663, United States

Location

GSK Investigational Site

Aurora, Colorado, 80045, United States

Location

GSK Investigational Site

Atlanta, Georgia, 30322, United States

Location

GSK Investigational Site

Houston, Texas, 77030, United States

Location

Related Publications (1)

• Akce M, El-Khoueiry A, Piha-Paul SA, Bacque E, Pan P, Zhang ZY, Ewesuedo R, Gupta D, Tang Y, Milton A, Zajic S, Judson PL, O'Bryant CL. Pharmacokinetics and safety of niraparib in patients with moderate hepatic impairment. Cancer Chemother Pharmacol. 2021 Nov;88(5):825-836. doi: 10.1007/s00280-021-04329-8. Epub 2021 Jul 29.

  PMID: 34324028 DERIVED

MeSH Terms

Conditions

Ovarian Neoplasms; Neoplasms

Interventions

niraparib

Condition Hierarchy (Ancestors)

Endocrine Gland Neoplasms; Neoplasms by Site; Ovarian Diseases; Adnexal Diseases; Genital Diseases, Female; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Genital Neoplasms, Female; Urogenital Neoplasms; Genital Diseases; Endocrine System Diseases; Gonadal Disorders

Results Point of Contact

• Title: GSK Response Center
• Organization: GlaxoSmithKline

GSKClinicalSupportHD@gsk.com

866-435-7343

Study Officials

• GSK Clinical Trials

  GlaxoSmithKline

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: SINGLE
• Who Masked: PARTICIPANT
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: October 3, 2017
• First Posted: December 2, 2017
• Study Start: February 20, 2018
• Primary Completion: September 16, 2019
• Study Completion: June 24, 2020
• Last Updated: May 28, 2021
• Results First Posted: November 16, 2020

Record last verified: 2021-05

Data Sharing

• IPD Sharing: Will not share

Locations

US (5)