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

Status

Completed

Phases

Phase 1

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT01894243

Enrollment

Registered

2013-07-10

Start date

2014-03-13

Completion date

2017-03-30

Last updated

2019-09-13

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

Solid Tumours

Keywords

oncology,, cancer,, neoplasm,, anticancer drug,, pharmacokinetics,, area under curve,, olaparib,, solid tumour,, mild hepatic impairment,, moderate hepatic impairment

Brief summary

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.

Interventions

DRUGOlaparib tablet dosing

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

Study design

Allocation

NON_RANDOMIZED

Intervention model

PARALLEL

Primary purpose

OTHER

Masking

NONE

Eligibility

Sex/Gender

ALL

Age

18 Years to 130 Years

Healthy volunteers

Inclusion criteria

- For inclusion in the study as a patient with hepatic impairment, the following criterion must be met: 1. Patients must have stable mild hepatic impairment (as defined by Child-Pugh classification), for at least 1 month prior to the start of the study or stable moderate hepatic impairment ( as defined by Child Pugh classification) for at least 2 weeks prior to the start of the study. Patients with hepatic metastases and/or HCC are eligible for the study, providing the hepatic metastases or HCC are not the sole reason for any changes in liver function satisfying the criteria for mild or moderate hepatic impairment as defined by the Child Pugh criteria. Patients must have globally impaired hepatic function to participate in the study. For inclusion in the study as a patient with normal hepatic function, the following criteria must be met: 2. Negative result for serum hepatitis B surface antigen and hepatitis C antibody. 3. Total bilirubin less than or equal to1.5 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. 4. Aspartate aminotransferase or serum glutamic oxaloacetic transaminase (AST), alanine aminotransferase or serum glutamic pyruvic transaminase (ALT) less than or equal to 2.5 x institutional ULN unless liver metastases are present in which case it must be less than or equal to 5 x ULN. All patients must fulfil the following criteria: 5. Provision of written informed consent prior to any study specific procedures. 6. Patients must be greater than or equal to18 years of age. 7. Histologically or, where appropriate, cytologically confirmed malignant solid tumour refractory or resistant to standard therapy or for which no suitable effective standard therapy exists. In case of HCC, histological or cytological confirmation is not required in the following situations, as per international guidelines of the scientific societies European Society for Medical Oncology (ESMO) and American Association for the Study of Liver Diseases (AASLD): * Nodules \>2 cm with a typical feature of HCC on a dynamic imaging technique, or any nodule associated with α-fetoprotein (AFP) concentration \>400 ng/ml or rising AFP on sequential determinations, do not require biopsy but should be considered as proven HCC (Jelic et al 2010). * Nodules \>1 cm found on ultrasound screening of a cirrhotic liver should be investigated further with either 4-phase multi-detector CT scan or dynamic contrast enhanced MRI. If the appearances are typical of HCC (ie, hyper-vascular in the arterial phase with washout in the portal venous or delayed phase), the lesion should be treated as HCC. If the findings are not characteristic or the vascular profile is not typical, a second contrastenhanced study with the other imaging modality should be performed, or the lesion should be biopsied (level II) (Bruix et al 2011). 8. Normal organ and bone marrow function measured within 28 days prior to administration of IP as defined below: Haemoglobin greater than or equal to 9.0 g/dL, with no blood transfusions in the previous 28 days. Absolute neutrophil count (ANC) greater than or equal to1.5 x 109/L. White blood cells (WBC) greater than 3 x 109/L. Platelet count greater than or equal to 75 x 109/L. Serum creatinine less than or equal to1.5 x institutional ULN. 9. Calculated serum creatinine clearance greater than 50 mL/min (using Cockcroft-Gault formula or by 24-hour urine collection). 10. Eastern Cooperative Oncology Group (ECOG) performance status less than or equal to 2. 11. Patients must have a life expectancy greater than or equal to 8 weeks. 12. Evidence of non childbearing status for women of childbearing potential, or postmenopausal status: negative urine or serum pregnancy test within 28 days of study treatment, confirmed prior to treatment on Day 1 of the first treatment period in Part A. Postmenopausal is defined as: Amenorrheic for 1 year or more following cessation of exogenous hormonal treatments. Luteinising hormone and follicle-stimulating hormone levels in the postmenopausal range for women under 50 years of age. Radiation-induced oophorectomy with last menses greater than 1 year ago. Chemotherapy-induced menopause with greater than 1 year interval since last menses. Surgical sterilisation (bilateral oophorectomy or hysterectomy). 13. Patients are willing and able to comply with the protocol for the duration of the study including undergoing treatment and scheduled visits and examinations. 14. Patients must be on a stable concomitant medication regimen (with the exception of electrolyte supplements), defined as no changes in medication or in dose within 2 weeks prior to start of olaparib dosing, except for bisphosphonates, denosumab and corticosteroids, which should be stable for at least 4 weeks prior to start of olaparib dosing.

Exclusion criteria

- 1. Involvement in the planning and/or conduct of the study (applies to both AstraZeneca staff, its agents and/or staff at the study site). 2. Previous enrolment in the present study. 3. Treatment with any investigational product (IP) during the last 14 days (or a longer period depending on the defined characteristics of the agent used). 4. Treatment in the previous 3 months before dosing in this study with any drug known to have a well defined potential for hepatoxicity (eg, halothane). 5. Patients receiving any systemic chemotherapy or radiotherapy (except for palliative reasons) within 2 weeks prior to study treatment. The patient can receive a stable dose of bisphosphonates or denosumab for bone metastases before and during the study as long as these were started at least 4 weeks prior to treatment. 6. Patients who have received or are receiving inhibitors or inducers of CYP3A4 within the washout period. 7. Toxicities (greater than or equal to CTCAE Grade 2) caused by previous cancer therapy, excluding alopecia. 8. Patients with symptomatic uncontrolled brain metastases. A scan to confirm the absence of brain metastases is not required. Patients with asymptomatic brain metastases or with symptomatic but stable brain metastases can receive a stable dose of corticosteroids before and during the study as long as these were started at least 4 weeks prior to treatment. 9. Major surgery within 2 weeks of starting study treatment and patients must have recovered from any effects of major surgery. 10. Patients considered a poor medical risk due to a serious uncontrolled medical disorder, non malignant systemic disease, uncontrolled seizures, or active uncontrolled infection. Examples include, but are not limited to, uncontrolled ventricular arrhythmia, recent (within 3 months) myocardial infarction, uncontrolled major seizure disorder, unstable spinal cord compression, superior vena cava syndrome, extensive bilateral interstitial lung disease on high resolution computer tomography (HRCT) scan, or any psychiatric disorder that prohibits obtaining informed consent. 11. Patients with a history of heart failure or left ventricular dysfunction. 2\. Patients who have gastric, gastro-oesophageal or oesophageal cancer. 13. Patients unable to swallow orally administered medication and patients with gastrointestinal disorders or significant gastrointestinal resection likely to interfere with the absorption of olaparib. 14\. Breastfeeding women. 15. Immunocompromised patients eg, patients who are known to be serologically positive for human immunodeficiency virus (HIV). 16\. Patients with a known hypersensitivity to olaparib or any of the excipients of the product. 17. Resting ECG with measurable QTc greater than 470 msec on 2 or more time points within a 24 hour period or family history of long QT syndrome. 18\. Clinical judgment by the investigator that the patient should not participate in the study. In addition to

Design outcomes

Primary

Measure	Time frame	Description
Maximum Plasma Concentration (Cmax)	Blood samples are collected at pre-dose, 0.25 , 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 48, 72 and 96 hours post olaparib dose in Part A.	Summary of Geometric Least Squares (GLS) Mean for normal, mild and moderate hepatic impairment
Ratio of Maximum Plasma Concentration (Cmax) - Mild vs Normal and Moderate vs Normal	Blood samples are collected at pre-dose, 0.25 , 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 48, 72 and 96 hours post olaparib dose in Part A.	Summary of ratio of Geometric Least Squares (GLS) Means
Area Under the Plasma Concentration Time Curve From Zero to Infinity (AUC)	Blood samples are collected at pre-dose, 0.25 , 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 48, 72 and 96 hours post olaparib dose in Part A.	Summary of Geometric Least Squares (GLS) Mean
Ratio of Area Under the Plasma Concentration Time Curve From Zero to Infinity (AUC) - Mild vs Normal and Moderate vs Normal	Blood samples are collected at pre-dose, 0.25 , 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 48, 72 and 96 hours post olaparib dose in Part A.	Summary of Ratio of Geometric Least Squares (GLS) Means
Area Under the Plasma Concentration Time Curve From Zero to the Last Measureable Time Point(AUC 0-t)	Blood samples are collected at pre-dose, 0.25 , 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 48, 72 and 96 hours post olaparib dose in Part A.	Summary of Geometric Least Squares (GLS) Mean for ratio of mild hepatic impairment compared to normal
Ratio of Area Under the Plasma Concentration Time Curve From Zero to the Last Measureable Time Point(AUC 0-t)	Blood samples are collected at pre-dose, 0.25 , 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 48, 72 and 96 hours post olaparib dose in Part A.	Summary of Ratio of Geometric Least Squares (GLS) Means
Apparent Clearance Following Oral Administration (CL/F)	Blood samples are collected at pre-dose, 0.25 , 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 48, 72 and 96 hours post olaparib dose in Part A.	Summary of Geometric Least Squares (GLS) Means
Ratio of Apparent Clearance Following Oral Administration (CL/F)	Blood samples are collected at pre-dose, 0.25 , 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 48, 72 and 96 hours post olaparib dose in Part A.	Summary of Ratio of Geometric Least Squares (GLS) Means
Time to Reach Maximum Plasma Concentration (Tmax)	Blood samples are collected at pre-dose, 0.25 , 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 48, 72 and 96 hours post olaparib dose in Part A.	—
Terminal Half-life (t½)	Blood samples are collected at pre-dose, 0.25 , 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 48, 72 and 96 hours post olaparib dose in Part A.	—
Apparent Volume of Distribution (Vz/F)	Blood samples are collected at pre-dose, 0.25 , 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 48, 72 and 96 hours post olaparib dose in Part A.	—

Countries

Czechia, France, Netherlands, South Korea, United Kingdom

Participant flow

Recruitment details

The first patient was enrolled on 13 March 2014 and the last patient was enrolled on 23 January 2015. Patients were enrolled at 8 centers in 3 countries. Of the 31 patients enrolled, 24 were assigned to treatment.

Pre-assignment details

Approximately 30 patients were planned to be enrolled with at least 24 evaluable patients required to complete Part A (8 patients with normal hepatic function, 8 with mild hepatic impairment and 8 with moderate hepatic impairment). An evaluable patient is defined as a patient having full PK sampling to 96 hours post-dose of olaparib

Participants by arm

Arm	Count
Normal Hepatic Function Olaparib 300 mg (2x150 mg tablets) single dose administered to patients with normal hepatic function	13
Mild Hepatic Impairment Olaparib 300 mg (2x150 mg tablets) single dose administered to patients with mild hepatic function	10
Moderate Hepatic Impairment Olaparib 300 mg (2x150 mg tablets) single dose administered to patients with moderate hepatic function	8
Total	31

Withdrawals & dropouts

Period	Reason	FG000	FG001	FG002
Overall Study	Adverse Event	0	1	2
Overall Study	Condition under investigation worsened	8	6	2
Overall Study	Death	0	0	3
Overall Study	Lack of Efficacy	3	3	1
Overall Study	Other	1	0	0
Overall Study	Subject decision	1	0	0

Baseline characteristics

Characteristic	Normal Hepatic Function	Mild Hepatic Impairment	Moderate Hepatic Impairment	Total
Age, Continuous	56.4 years STANDARD_DEVIATION 8.35	57.4 years STANDARD_DEVIATION 10.7	67.9 years STANDARD_DEVIATION 9.22	56.8 years STANDARD_DEVIATION 9.23
Sex: Female, Male Female	8 Participants	4 Participants	2 Participants	14 Participants
Sex: Female, Male Male	5 Participants	6 Participants	6 Participants	17 Participants

Adverse events

Event type	EG000 affected / at risk	EG001 affected / at risk	EG002 affected / at risk	EG003 affected / at risk	EG004 affected / at risk	EG005 affected / at risk
deaths Total, all-cause mortality	0 / 13	0 / 10	0 / 8	1 / 13	1 / 10	4 / 8
other Total, other adverse events	10 / 13	3 / 10	5 / 8	13 / 13	10 / 10	7 / 8
serious Total, serious adverse events	1 / 13	0 / 10	1 / 8	3 / 13	3 / 10	4 / 8