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Olaparib

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Poly(ADP-ribose) Polymerase Inhibitors

Enzyme Inhibitors

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Aspartic Acid

Patients with:

(i) negative result for serum hepatitis B surface antigen and hepatitis C antibody (ii) total bilirubin ≤1.5 x institutional upper limit of normal (ULN), albumin and prothrombin time within normal limits and must not have ascites (unless related to disease under study) or encephalopathy (iii) aspartate aminotransferase or serum glutamic oxaloacetic transaminase (AST), alanine aminotransferase or serum glutamic pyruvic transaminase (ALT) ≤2.5 x institutional ULN unless liver metastases are present in which case it must be ≤5 x ULN

As defined by the Child-Pugh Classification System.

Part A - single 300mg oral dose olaparib (administered as 2x150mg tablets) Part B - 300mg oral dose olaparib (administered as 2x150mg tablets) bd

Olaparib tablet dosing

Anitra Fielding

Christian Rolfo

This is a 2-part study in patients with advanced solid tumours. Part A will investigate the PK of olaparib in patients with mild or moderate hepatic impairment compared to patients with normal hepatic function; Part B will allow patients with mild or moderate hepatic impairment or normal hepatic function continued access to olaparib after the PK phase and will provide additional safety data.

Study to Assess the Blood Levels and Safety of Olaparib in Patients With Advanced Solid Tumours and Normal Liver Function or Mild or Moderate Liver Impairment

An Open-label, Non-randomised, Multicentre, Comparative, Phase I Study to Determine the Pharmacokinetics, Safety and Tolerability of Olaparib Following a Single Oral 300 mg Dose to Patients With Advanced Solid Tumours and Normal Hepatic Function or Mild or Moderate Hepatic Impairment

Summary of Geometric Least Squares (GLS) Mean for normal, mild and moderate hepatic impairment

Summary of ratio of Geometric Least Squares (GLS) Means

Summary of Geometric Least Squares (GLS) Mean

Summary of Ratio of Geometric Least Squares (GLS) Means

Summary of Geometric Least Squares (GLS) Mean for ratio of mild hepatic impairment compared to normal

Summary of Geometric Least Squares (GLS) Means

AstraZeneca

Normal (Part A)

Mild (Part A)

Moderate (Part A)

Normal (Part B)

Mild (Part B)

Moderate (Part B)

Olaparib 300 mg (2x150 mg tablets) single dose administered to patients with normal hepatic function

Normal Hepatic Function

Olaparib 300 mg (2x150 mg tablets) single dose administered to patients with mild hepatic function

Mild Hepatic Impairment

Olaparib 300 mg (2x150 mg tablets) single dose administered to patients with moderate hepatic function

Moderate Hepatic Impairment

Total

Age, Continuous

Sex: Female, Male

Anitra Fielding - Senior Research Physician

Moderate Hepatic Function

PK Analysis Set (Part A) One patient excluded from mild impairment arm due to surgery that may affect olaparib absorption.

Maximum Plasma Concentration (Cmax)

Olaparib 300 mg (2x150 mg tablets) single dose administered to patients with mild/normal hepatic function

GLSMean Ratio of Mild to Normal

Olaparib 300 mg (2x150 mg tablets) single dose administered to patients with moderate/normal hepatic function

GLSMean Ratio of Moderate to Normal

PK Analysis Set (Part A) One patient excluded from mild impairment group due to surgery that may affect olaparib absorption.

Ratio of Maximum Plasma Concentration (Cmax) - Mild vs Normal and Moderate vs Normal

Area Under the Plasma Concentration Time Curve From Zero to Infinity (AUC)

Ratio of Area Under the Plasma Concentration Time Curve From Zero to Infinity (AUC) - Mild vs Normal and Moderate vs Normal

Area Under the Plasma Concentration Time Curve From Zero to the Last Measureable Time Point(AUC 0-t)

Ratio of Area Under the Plasma Concentration Time Curve From Zero to the Last Measureable Time Point(AUC 0-t)

Apparent Clearance Following Oral Administration (CL/F)

GLSMean Ration of Mild to Normal

Ratio of Apparent Clearance Following Oral Administration (CL/F)

Time to Reach Maximum Plasma Concentration (Tmax)

Terminal Half-life (t½)

Apparent Volume of Distribution (Vz/F)

Overall Study

Neoplasms

All Conditions

Musculoskeletal Diseases

Digestive System Diseases

Rare Diseases

Giant Cell Tumors

Giant Cell Tumor of Tendon Sheath

Liver Diseases

Gastrointestinal Diseases

Pigmented Villonodular Synovitis

Participants with moderate hepatic impairment who will receive a single oral dose of pexidartinib.

Sex-, age-, and weight-matched healthy participants who will receive a single oral dose of pexidartinib.

Single, 200-mg capsule will be administered orally on Day 1 with 240 mL of water, following an overnight fast of at least 10 hours.

Pexidartinib

Clinical Study Leader

The pharmacokinetics of a single dose of pexidartinib was investigated in participants with impaired hepatic function and compared with healthy control participants with normal hepatic function.

Pexidartinib is an orally administered tyrosine kinase inhibitor, currently approved in the US for the treatment of adult patients with symptomatic tenosynovial giant cell tumor (TGCT) associated with severe morbidity or functional limitations and not amenable to improvement with surgery.

The primary objective of this study is to determine the plasma pharmacokinetics (PK) of pexidartinib after a single oral dose of 200 mg in participants with moderate hepatic impairment (HI) as defined by National Cancer Institute Organ Dysfunction Working Group (NCI-ODWG) criteria compared to the healthy controls participants with normal hepatic function.

Study of Pexidartinib in Participants With Moderate Hepatic Impairment Compared With Healthy Participants

An Open-label, Single-dose Study to Assess the Pharmacokinetics of Pexidartinib in Subjects With Moderate Hepatic Impairment Compared to Healthy Subjects

De-identified individual participant data (IPD) and applicable supporting clinical trial documents may be available upon request at https://vivli.org/. In cases where clinical trial data and supporting documents are provided pursuant to our company policies and procedures, Daiichi Sankyo will continue to protect the privacy of our clinical trial participants. Details on data sharing criteria and the procedure for requesting access can be found at this web address: https://vivli.org/ourmember/daiichi-sankyo/

Maximum Plasma Concentration (Cmax) is defined as the maximum observed plasma concentration and was calculated using non-compartmental analysis.

Time of Maximum Plasma Concentration (Tmax) is defined as the time of maximum observed plasma concentration and was calculated using non-compartmental analysis.

Area Under the Plasma Concentration-Time Curve up to the Last Quantifiable Concentration Post-Dose (AUClast) is defined as AUC from time 0 to the last measurable concentration, as calculated by the linear up-log down trapezoidal method and was calculated using non-compartmental analysis.

Area Under the Plasma Concentration-Time Curve up to Infinity (AUCinf ) is defined as area under the plasma concentration-time curve from the time of dosing extrapolated to infinity and was calculated using non-compartmental analysis.

Elimination Rate Constant (Kel) is defined as elimination rate constant and was calculated using non-compartmental analysis.

Terminal Elimination Half-Life (t1/2) is defined as terminal elimination half-life and was calculated using non-compartmental analysis.

Total Apparent Clearance (CL/F) is defined as total apparent clearance and was calculated using non-compartmental analysis.

Volume of Distribution in the Terminal Phase (Vz/F) is defined as volume of distribution in the terminal phase and was calculated using non-compartmental analysis.

Maximum Plasma Concentration (Tmax) is defined as time of maximum observed plasma concentration and was calculated using non-compartmental analysis.

Area Under the Concentration-Time Curve (AUCinf) is defined as area under the plasma concentration-time curve from the time of dosing extrapolated to infinity and AUClast is defined as AUC from time 0 to the last measurable concentration, as calculated by the linear up-log down trapezoidal method. AUCinf and AUClast are reported and were calculated using non-compartmental analysis.

AUCinf is defined as area under the plasma concentration-time curve from the time of dosing extrapolated to infinity and AUClast is defined as AUC from time 0 to the last measurable concentration, as calculated by the linear up-log down trapezoidal method. MPR is defined as a metabolite to parent ratio with metabolite as the numerator and the parent as the denominator. MPR corrected for molecular weight of ZAAD-1006a of AUCinf and AUClast are reported and were calculated using non-compartmental analysis.

Protein binding (percentage bound) was determined in all participants at 2.5h and 24h post-dose. Plasma was harvested and analyzed for the quantification of pexidartinib using a validated liquid chromatography-tandem mass spectrometry method and the ZAAD-1006a metabolite was analyzed using a qualified liquid chromatography-tandem mass spectrometry assay.

A Treatment-Emergent Adverse Event (TEAE) is defined as any event not present prior to the initiation of the drug treatment or any event already present that worsens in either intensity or frequency following exposure to the drug treatment.

Daiichi Sankyo

Adverse events were defined as any untoward, unfavorable, unintended medical occurrence in a participant administered a pharmaceutical product and which does not necessarily have to have a causal relationship with this treatment. All-cause mortality includes all deaths that occurred during the study and within the 30 days after the last dose of the study drug.

Healthy matched participants with normal HF who received 200mg pexidartinib on Day 1 with 240 mL water. Participants fasted for at least 10h before pexidartinib dosing and continued to fast for at least 4h after pexidartinib administration.

Normal HF

Participants with moderate HI who received 200mg pexidartinib on Day 1 with 240 mL water. Participants fasted for at least 10h before pexidartinib dosing and continued to fast for at least 4h after pexidartinib administration. Moderate hepatic impairment (HI) was assessed by National Cancer Institute - Organ Dysfunction Working Group (NCI-ODWG).

Moderate HI

Age, Categorical

Race (NIH/OMB)

Weight

Baseline characteristics were assessed using the Safety Analysis Set.

Contact for Clinical Trial Information

Pharmacokinetic parameter was assessed using the Pharmacokinetic Analysis Set.

Maximum Plasma Concentration (Cmax) of Pexidartinib Following a Single Dose in Participants With Moderate Hepatic Impairment Compared to Healthy Participants

Time of Maximum Plasma Concentration (Tmax) of Pexidartinib Following a Single Dose in Participants With Moderate Hepatic Impairment Compared to Healthy Participants

Area Under the Plasma Concentration-Time Curve up to the Last Quantifiable Concentration Post-Dose (AUClast) of Pexidartinib Following a Single Dose in Participants With Moderate Hepatic Impairment Compared to Healthy Participants

The pharmacokinetic parameter of Area Under the Plasma Concentration-Time Curve up to Infinity was assessed using the Pharmacokinetic Analysis Set except for 1 participant that did not meet the protocol inclusion criteria for this analysis.

Area Under the Plasma Concentration-Time Curve up to Infinity (AUCinf ) of Pexidartinib Following a Single Dose in Participants With Moderate Hepatic Impairment Compared to Healthy Participants

The pharmacokinetic parameter of Elimination Rate Constant was assessed using the Pharmacokinetic Analysis Set except for 1 participant that did not meet the protocol inclusion criteria for this analysis..

Elimination Rate Constant (Kel) of Pexidartinib Following a Single Dose in Participants With Moderate Hepatic Impairment Compared to Healthy Participants

The pharmacokinetic parameter of Terminal Elimination Half-Life was assessed using the Pharmacokinetic Analysis Set except for 1 participant that did not meet the protocol inclusion criteria for this analysis.

Terminal Elimination Half-Life (t1/2) of Pexidartinib Following a Single Dose in Participants With Moderate Hepatic Impairment Compared to Healthy Participants

The pharmacokinetic parameter of Total Apparent Clearance was assessed using the Pharmacokinetic Analysis Set except for 1 participant that did not meet the protocol inclusion criteria for this analysis.

Total Apparent Clearance (CL/F) of Pexidartinib Following a Single Dose in Participants With Moderate Hepatic Impairment Compared to Healthy Participants

The pharmacokinetic parameter of Volume of Distribution in the Terminal Phase was assessed using the Pharmacokinetic Analysis Set except for 1 participant that did not meet the protocol inclusion criteria for this analysis.

Volume of Distribution in the Terminal Phase (Vz/F) Following a Single Dose in Participants With Moderate Hepatic Impairment Compared to Healthy Participants

Maximum Plasma Concentration (Cmax) of ZAAD-1006a Metabolite Following a Single Dose of Pexidartinib in Participants With Moderate Hepatic Impairment Compared to Healthy Participants

Maximum Plasma Concentration (Tmax) of ZAAD-1006a Metabolite Following a Single Dose of Pexidartinib in Participants With Moderate Hepatic Impairment Compared to Healthy Participants

AUCinf

AUClast

Pharmacokinetic parameters were assessed using the Pharmacokinetic Analysis Set.

Area Under the Concentration-Time Curve (AUCinf) of of ZAAD-1006a Metabolite Following a Single Dose of Pexidartinib in Participants With Moderate Hepatic Impairment Compared to Healthy Participants

Terminal Elimination Half-Life (t1/2) of ZAAD-1006a Metabolite Following a Single Dose of Pexidartinib in Subjects Participants With Moderate Hepatic Impairment Compared to Healthy Participants

MPR AUCinf

MPR AUClast

Metabolite-to-Parent Ratio (MPR) Corrected for Molecular Weight of ZAAD-1006a Metabolite Following a Single Dose of Pexidartinib in Participants With Moderate Hepatic Impairment Compared to Healthy Participants

Pexidartinib at 2.5hrs post-dose

Pexidartinib at 24hrs post-dose

ZAAD-1006a at 2.5hrs post-dose

ZAAD-1006a at 24hrs post-dose

The pharmacokinetic parameter of Percentage of Plasma Protein Binding was assessed using the Pharmacokinetic Analysis Set. Only those participants with data available at the specified timepoints were analyzed.

Percentage of Plasma Protein Binding of Pexidartinib and ZAAD-1006a Following a Single Dose in Participants With Moderate Hepatic Impairment Compared to Healthy Participants

Any TEAEs

Eye Disorders (Conjunctival haemorrhage)

Gastrointestinal Disorders (Dyspepsia)

Nervous System Disorders (Headache)

TEAEs were assessed using the Safety Analysis Set.

Number of Participants Reporting Treatment-Emergent Adverse Events (TEAE) by System Organ Class and Preferred Term Following a Single Dose of Pexidartinib in Participants With Moderate Hepatic Impairment Compared to Healthy Participants

Healthy matched participants with normal hepatic function (HF) who received 200mg pexidartinib on Day 1 with 240 mL water. Participants fasted for at least 10 hours(h) before pexidartinib dosing and continued to fast for at least 4h after pexidartinib administration.

Participants with moderate HI who received 200mg pexidartinib on Day 1 with 240 mL water. Participants fasted for at least 10 hours(h) before pexidartinib dosing and continued to fast for at least 4h after pexidartinib administration. Moderate hepatic impairment (HI) was assessed by National Cancer Institute - Organ Dysfunction Working Group (NCI-ODWG).

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Study to Assess the Blood Levels and Safety of Olaparib in Patients With Advanced Solid Tumours and Normal Liver Function or Mild or Moderate Liver Impairment	NCT01894243	Solid Tumours	Olaparib tablet...	18 Years - 130 Years	AstraZeneca
Study to Assess the Blood Levels and Safety of Olaparib in Patients With Advanced Solid Tumours and Normal Liver Function or Mild or Moderate Liver Impairment	NCT01894243	Solid Tumours	Olaparib tablet...	18 Years - 130 Years	AstraZeneca
Study of Pexidartinib in Participants With Moderate Hepatic Impairment Compared With Healthy Participants	NCT04223635	Moderate Hepati...	Pexidartinib	18 Years - 75 Years	Daiichi Sankyo

Spots Global Cancer Trial Database for moderate hepatic impairment