Anti-Infective Agents

All Drugs and Chemicals

Antineoplastic Agents

Itraconazole

Olaparib

Hydroxyitraconazole

Poly(ADP-ribose) Polymerase Inhibitors

Enzyme Inhibitors

Clotrimazole

Miconazole

Antifungal Agents

Cytochrome P-450 Enzyme Inhibitors

Hormones

Hormone Antagonists

Cytochrome P-450 CYP3A Inhibitors

Sequential treatments of olaparib alone followed by olaparib+itraconazole, with a washout period in between.

Blood samples taken pre and post dosing with olaparib+/- itraconazole

Pharmacokinetic sampling

Olaparib tablets: Part A 100mg od, days 1 and 9 only. Part B 10x300mg doses over 5 days (300mg bd).

Olaparib tablet dosing

Itraconazole 200mg od Part A days 5 to 11 only

Anitra Fielding

Ruth Plummer, Prof

This is a 3-part study in patients with advanced solid tumours: Part A will assess the effect of itraconazole on the PK parameters of olaparib and will determine the effect of olaparib on the QT interval following single oral dosing; Part B will determine the effect of olaparib on the QT Interval following multiple oral dosing; Part C will allow patients continued access to olaparib after the PK and QT phases and will provide for additional safety data collection. A total of 48 patients are planned to be enrolled; at least 42 evaluable patients will be required to complete the study. Patients will participate as a single cohort in all parts of the study.

To Assess the Effect of Itraconazole (a CYP3A4 Inhibitor) on the Pharmacokinetics of Olaparib, and the Effect of Olaparib on QT Interval Following Oral Dosing of a Tablet Formulation to Patients With Advanced Solid Tumours

A Non-randomised, Open-label, Sequential, Three-part, Phase I Study to Assess the Effect of Itraconazole (a CYP3A4 Inhibitor) on the Pharmacokinetics of Olaparib Following Oral Dosing of a Tablet Formulation, and to Provide Data on the Effect of Olaparib on QT Interval Following Oral Dosing of a Tablet Formulation to Patients With Advanced Solid Tumours

Rate and extent of absorption of olaparib following single (Part A) and multiple (Part B) oral doses of olaparib tablet formulation by assessment of maximum plasma olaparib concentration (Cmax)

Rate and extent of absorption of olaparib following single (Part A) and multiple (Part B) oral doses of olaparib tablet formulation by assessment of area under the plasma concentration time curve from zero to infinity (AUC)

Rate and extent of absorption of olaparib following single (Part A) and multiple (Part B) oral doses of olaparib tablet formulation by assessment of area under the plasma concentration time curve from zero to the last measurable time point, (AUC0-t)

Rate and extent of absorption of olaparib following following single (Part A) and multiple (Part B) oral doses of olaparib tablet formulation by assessment of time to reach maximum plasma concentration for olaparib (tmax)

Rate and extent of absorption of olaparib following following single (Part A) and multiple (Part B) oral doses of olaparib tablet formulation by assessment of area under the plasma concentration time curve from zero to the last measurable time point (AUC0-τ)

Rate and extent of absorption of olaparib following following single (Part A) and multiple (Part B) oral doses of olaparib tablet formulation by assessment of time olaparib apparent clearance (CL/F)

Rate and extent of absorption of olaparib following following single (Part A) and multiple (Part B) oral doses of olaparib tablet formulation by assessment of olaparib apparent volume of distribution (Vz/F)

Rate and extent of absorption of olaparib following following single (Part A) and multiple (Part B) oral doses of olaparib tablet formulation by assessment of olaparib terminal half-life (t1/2).

Rate and extent of absorption of itraconazole by assessment of maximum plasma itraconazole concentration (Cmax).

Rate and extent of absorption of itraconazole by assessment of area under the plasma concentration time curve from zero to the last measurable time point (AUC0-τ)

Rate and extent of absorption of itraconazole by assessment of time to reach maximum plasma concentration for itraconazole (tmax)

Rate and extent of absorption of itraconazole by assessment of itraconazole apparent clearance (CL/F)

Rate and extent of absorption of hydroxyl -itraconazole by assessment of maximum plasma hydroxyl -itraconazole concentration (Cmax).

Rate and extent of absorption of hydroxy-itraconazole by assessment of hydroxy-itraconazole apparent clearance (CL/F)

Rate and extent of absorption of hydroxyl -itraconazole by assessment time to reach maximum plasma concentration for hydroxyl-itraconazole (tmax)

Rate and extent of absorption of hydroxyl -itraconazole by assessment of area under the plasma concentration time curve from zero to the last measurable time point (AUC0-τ)

Assessment of the time between the start of the Q wave and the end of the T wave in the heart's electrical cycle (the QT interval), uncorrected and corrected for heart rate (QTc) following single (Part A) and multiple (Part B) oral doses of olaparib tablet formulation.

Assessment of adverse events (AEs), graded by CTCAE (v4.0): Adverse events (AEs) will be collected from the time of signed informed consent throughout the treatment period in Part A and Part B up to and including the 30-day follow-up period. In Part C, AEs will be collected until 12 months after the last patient entered Part C, and including the 30 day follow-up period for any patients who discontinue

These will occur at screening, on the day before dosing in each treatment period and 30 days after last dose in Parts A and B. In Part C, will be assessed weekly for a 28-day period followed by every 4 weeks up to 12 months after the last patient enters Part C and at treatment discontinuation. All will be assessed 30 days after last dose.

Assessment of vital signs (including BP and pulse). These will occur at screening, on the day before dosing in each treatment period and 30 days after last dose in Parts A and B. In Part C, all except ECG will be assessed weekly for a 28-day period followed by every 4 weeks up to 12 months after the last patient enters Part C and at treatment discontinuation. All will be assessed 30 days after last dose.

Assessment of laboratory parameters (clinical chemistry, hematology, and urinalysis) : These will occur at screening, on the day before dosing in each treatment period and 30 days after last dose in Parts A and B. In Part C, all except ECG will be assessed weekly for a 28-day period followed by every 4 weeks up to 12 months after the last patient enters Part C and at treatment discontinuation. All will be assessed 30 days after last dose.

AstraZeneca

Hematinics

Coagulants

Amino Acids

Antibodies

Hepatitis C Antibodies

Immunoglobulins

Liver Extracts

Thrombin

Bilirubin

N-Methylaspartate

Alanine

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

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

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

Urinary Tract, Sexual Organs, and Pregnancy Conditions

All Conditions

Renal Insufficiency

Patients with calculated serum creatinine clearance ≥81 mL/min (using Cockcroft-Gault equation).

Patients with calculated serum creatinine clearance 51-80 mL/min (using Cockcroft-Gault equation).

Patients with calculated serum creatinine clearance 31-50 mL/min (using Cockcroft-Gault equation).

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 renal impairment compared to patients with normal renal function; Part B will allow eligible study patients 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 or Impaired Kidney Function

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

Degree to which olaparib binds to the proteins within blood plasma

Cmax of unbound olaparib; calculated by multiplying total Cmax value by estimated protein binding

AUC of unbound olaparib; calculated by multiplying total AUC by estimated protein binding

Maximum plasma drug concentration of olaparib

Area under plasma concentration-time curve from zero to infinity of olaparib

Area under plasma concentration-time curve from zero to the last measurable time point of olaparib

Time to reach maximum plasma concentration of olaparib

Apparent volume of distribution of olaparib

Renal clearance of olaparib, calculated as the ratio of amount of drug excreted over 24 hours to AUC0-24

AE data were collected on Days 1-5, and at 30 days following the date of last dose of study medication if the subject discontinued in Part A.

Patients from Part A of the study with calculated serum creatinine clearance ≥81 mL/min (using Cockcroft-Gault equation). Received single dose of 300 mg olaparib (2 x 150 mg tablets) in fasted condition (1 hour before their olaparib dose until 2 hours after dosing).

Part A Normal Renal Function

Patients in Part A of the study with stable renal impairment with calculated serum creatinine clearance 51 to 80 mL/min (using Cockcroft-Gault equation), for at least 2 months prior to the start of the study.

Received single dose of 300 mg olaparib (2 x 150 mg tablets) in fasted condition (1 hour before their olaparib dose until 2 hours after dosing).

Part A Mild Renal Impairment

Patients in Part A of the study with stable renal impairment with calculated serum creatinine clearance 31 to 50 mL/min (using Cockcroft-Gault equation), for at least 2 months prior to the start of the study.

Received single dose of 300 mg olaparib (2 x 150 mg tablets) in fasted condition (1 hour before their olaparib dose until 2 hours after dosing).

Part A Moderate Renal Impairment

Patients in Part B of the study with calculated serum creatinine clearance ≥81 mL/min (using Cockcroft-Gault equation). Received single dose of 300 mg olaparib (2 x 150 mg tablets) in fasted condition (1 hour before their olaparib dose until 2 hours after dosing).

Part B Normal Renal Function

Patient in Part B of the study with stable renal impairment with calculated serum creatinine clearance 51 to 80 mL/min (using Cockcroft-Gault equation), for at least 2 months prior to the start of the study.

Received single dose of 300 mg olaparib (2 x 150 mg tablets) in fasted condition (1 hour before their olaparib dose until 2 hours after dosing).

Part B Mild Renal Impairment

Patient in Part B of the study with stable renal impairment with calculated serum creatinine clearance 31 to 50 mL/min (using Cockcroft-Gault equation), for at least 2 months prior to the start of the study.

Received single dose of 300 mg olaparib (2 x 150 mg tablets) in fasted condition (1 hour before their olaparib dose until 2 hours after dosing).

Part B Moderate Renal Impairment

Patients with calculated serum creatinine clearance ≥81 mL/min (using Cockcroft-Gault equation). Received single dose of 300 mg olaparib (2 x 150 mg tablets) in fasted condition (1 hour before their olaparib dose until 2 hours after dosing).

Normal Renal Function

Patients with stable renal impairment with calculated serum creatinine clearance 51 to 80 mL/min (using Cockcroft-Gault equation), for at least 2 months prior to the start of the study.

Received single dose of 300 mg olaparib (2 x 150 mg tablets) in fasted condition (1 hour before their olaparib dose until 2 hours after dosing).

Mild Renal Impairment

Patients with stable renal impairment with calculated serum creatinine clearance 31 to 50 mL/min (using Cockcroft-Gault equation), for at least 2 months prior to the start of the study.

Received single dose of 300 mg olaparib (2 x 150 mg tablets) in fasted condition (1 hour before their olaparib dose until 2 hours after dosing).

Moderate Renal Impairment

Ethnicity (NIH/OMB)

Race (NIH/OMB)

Data are presented for Part A and Part B.

Dr Anitra Fielding

Null hypothesis: There are no clinically significant differences in the PK of olaparib when administered to patients with moderate or mild renal impairment compared to patients with normal renal function.

PK analysis set: All patients who receive an olaparib dose and have full PK sampling up to 96 hours post-dose.

Any patients with major protocol deviations that affected the evaluability of the PK profile were excluded.

Cmax of Olaparib

AUC of Olaparib

AUC0-t of Olaparib

Tmax of Olaparib

Vz/F of Olaparib

CL/F of Olaparib

Subset of PK analysis set with urine samples available. PK analysis set: All patients who receive an olaparib dose and have full PK sampling up to 96 hours post-dose.

Any patients with major protocol deviations that affected the evaluability of the PK profile were excluded.

CLR of Olaparib

t1/2 of Olaparib

Subset of PK analysis set with protein binding blood sample available. PK analysis set: All patients who receive an olaparib dose and have full PK sampling up to 96 hours post-dose.

Any patients with major protocol deviations that affected the evaluability of the PK profile were excluded.

Protein Binding of Olaparib

Free Cmax of Olaparib

Free AUC of Olaparib

CL/F of Unbound Olaparib

Part A

Part B

Rifampin

Anti-Bacterial Agents

Antibiotics, Antitubercular

Antitubercular Agents

Sequential treatments of olaparib alone followed by olaparib+rifampicin, with a washout period inbetween.

Blood sampling to measure olaparib, rifampicin and 4β-hydroxycholesterol

Rifampicin (CYP inducer) 600mg taken once daily from Day 5 to Day 14 (Part A)

Rifampicin

Olaparib 300mg tablet taken on Days 1 and 14 (Part A). Part B dosing is 300mg olaparib bi-daily

Luc Dirix

This is a 2-part study in patients with advanced solid tumours. Part A will investigate the effect of rifampicin on the PK parameters of olaparib in patients; Part B will allow patients continued access to olaparib after the PK phase and will provide additional safety data.

Study to Assess the Effect of Rifampicin (CYP Inducer) on Blood Levels and Safety of Olaparib in Patients With Advanced Solid Tumours

A Non-randomised, Open-label, Sequential, Multicentre, Two-part, Phase I Study to Assess the Effect of Rifampicin, a CYP Inducer, on the Pharmacokinetics of Olaparib Following Oral Dosing of a Tablet Formulation in Patients With Advanced Solid Tumours

Rate and extent of absorption of olaparib following single oral doses of olaparib tablet formulation by assessment of maximum plasma olaparib concentration (Cmax). Olaparib doses are first without, then with rifampicin.

Rate and extent of absorption of olaparib following single oral doses of olaparib tablet formulation by assessment of area under the plasma concentration time curve from zero to infinity (AUC).

Olaparib doses are first without, then with rifampicin.

Rate and extent of absorption of olaparib following single oral doses of olaparib tablet formulation by assessment of area under the plasma concentration time curve from zero to the last measurable time point, AUC0-t, if AUC is not adequately estimable. Olaparib doses are first without, then with rifampicin.

Rate and extent of absorption of olaparib following single oral doses of olaparib tablet formulation by assessment of time to reach maximum plasma concentration for olaparib (tmax). Olaparib doses are first without, then with rifampicin.

Rate and extent of absorption of olaparib following single oral doses of olaparib tablet formulation by assessment of olaparib area under the plasma concentration time curve from zero to the last measurable time point (AUC0-τ). Olaparib doses are first without, then with rifampicin.

Rate and extent of absorption of olaparib following single oral doses of olaparib tablet formulation by assessment of olaparib apparent clearance (CL/F). Olaparib doses are first without, then with rifampicin.

Rate and extent of absorption of olaparib following single oral doses of olaparib tablet formulation by assessment of olaparib apparent volume of distribution (Vz/F). Olaparib doses are first without, then with rifampicin.

Rate and extent of absorption of olaparib following single oral doses of olaparib tablet formulation by assessment of olaparib terminal half-life (t1/2). Olaparib doses are first without, then with rifampicin.

Rate and extent of absorption of rifampicin following multiple doses of rifampicin by assessment of plasma concentrations of rifampicin during rifampicin dosing period.

Demonstration of CYP induction by assessment of plasma concentrations of 4β-hydroxycholesterol during rifampicin dosing period.

Assessment of adverse events (AEs) graded by Common Terminology Criteria for Adverse Events (CTCAE) v4.0

Assessment of standard 12 lead electrocardiograms (ECGs)

Assessment of standard vital signs (including blood pressure, pulse)

Assessment of laboratory parameters (clinical chemistry)

Assessment of laboratory parameters (haematology)

Assessment of laboratory parameters (urinalysis)

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
To Assess the Effect of Itraconazole (a CYP3A4 Inhibitor) on the Pharmacokinetics of Olaparib, and the Effect of Olaparib on QT Interval Following Oral Dosing of a Tablet Formulation to Patients With Advanced Solid Tumours	NCT01900028	Solid Tumours	Pharmacokinetic... Olaparib tablet... Itraconazole	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 to Assess the Blood Levels and Safety of Olaparib in Patients With Advanced Solid Tumours and Normal or Impaired Kidney Function	NCT01894256	Solid Tumours	Olaparib tablet...	18 Years - 75 Years	AstraZeneca
Study to Assess the Effect of Rifampicin (CYP Inducer) on Blood Levels and Safety of Olaparib in Patients With Advanced Solid Tumours	NCT01929603	Solid Tumours	Pharmacokinetic... Rifampicin Olaparib tablet...	18 Years - 99 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

Spots Global Cancer Trial Database for olaparib tablet dosing