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 | Completed Phase 1 Results

• 2 other identifiers: D0816C000052013-002246-37
• Study Type: interventional
• Target: 31
• Locations: 5 countries
• Sites: 12

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.

Conditions

Solid Tumours

Keywords

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

Outcome Measures

Primary Outcomes (11)

• Maximum Plasma Concentration (Cmax)

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

  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.

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

  Summary of ratio of Geometric Least Squares (GLS) Means

  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.

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

  Summary of Geometric Least Squares (GLS) Mean

  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.

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

  Summary of Ratio of Geometric Least Squares (GLS) Means

  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.

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

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

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

  Summary of Ratio of Geometric Least Squares (GLS) Means

  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 Clearance Following Oral Administration (CL/F)

  Summary of Geometric Least Squares (GLS) Means

  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.

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

  Summary of Ratio of Geometric Least Squares (GLS) Means

  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.

• 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.

Study Arms (3)

Normal hepatic function

OTHER

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

Drug: Olaparib tablet dosing

Mild hepatic impairment

OTHER

As defined by the Child-Pugh Classification System.

Drug: Olaparib tablet dosing

Moderate hepatic impairment

OTHER

As defined by the Child-Pugh Classification System.

Drug: Olaparib tablet dosing

Interventions

Olaparib tablet dosing DRUG

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

Mild hepatic impairment; Moderate hepatic impairment; Normal hepatic function

Eligibility Criteria

• Age: 18 Years - 130 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Negative result for serum hepatitis B surface antigen and hepatitis C antibody.
• 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.
• 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:
• Provision of written informed consent prior to any study specific procedures.
• Patients must be greater than or equal to18 years of age.
• 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).
• 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.
• Calculated serum creatinine clearance greater than 50 mL/min (using Cockcroft-Gault formula or by 24-hour urine collection).
• Eastern Cooperative Oncology Group (ECOG) performance status less than or equal to 2.
• Patients must have a life expectancy greater than or equal to 8 weeks.
• 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:

You may not qualify if:

• Involvement in the planning and/or conduct of the study (applies to both AstraZeneca staff, its agents and/or staff at the study site).
• Previous enrolment in the present study.
• Treatment with any investigational product (IP) during the last 14 days (or a longer period depending on the defined characteristics of the agent used).
• 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).
• 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.
• Patients who have received or are receiving inhibitors or inducers of CYP3A4 within the washout period.
• Toxicities (greater than or equal to CTCAE Grade 2) caused by previous cancer therapy, excluding alopecia.
• 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.
• Major surgery within 2 weeks of starting study treatment and patients must have recovered from any effects of major surgery.
• 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.
• Patients with a history of heart failure or left ventricular dysfunction.
• \. 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.
• \. Breastfeeding women. 15. Immunocompromised patients eg, patients who are known to be serologically positive for human immunodeficiency virus (HIV).
• \. 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.
• \. Fluctuating or rapidly deteriorating hepatic function as indicated by widely varying or worsening of clinical and/or laboratory signs of hepatic impairment within the screening period (eg, advanced ascites, fever, active gastrointestinal bleeding).

Sponsors & Collaborators

• AstraZeneca: lead

Study Sites (12)

Research Site

Brno, 656 53, Czechia

Location

Research Site

Bordeaux, 33075, France

Location

Research Site

Bordeaux, 33076, France

Location

Research Site

Dijon, 21079, France

Location

Research Site

Grenoble, 38043, France

Location

Research Site

Lyon, 69373, France

Location

Research Site

Paris, 75651, France

Location

Research Site

Amsterdam, 1066 CX, Netherlands

Location

Research Site

Maastricht, 6202 AZ, Netherlands

Location

Research Site

Seoul, 06591, South Korea

Location

Research Site

London, United Kingdom

Location

Research Site

Sutton, SM2 5PT, United Kingdom

Location

MeSH Terms

Conditions

Neoplasms

Results Point of Contact

• Title: Anitra Fielding - Senior Research Physician
• Organization: AstraZeneca

ClinicalTrialTransparency@astrazeneca.com

Study Officials

• Anitra Fielding

  AstraZeneca Senior Research Physician

  STUDY DIRECTOR

• Christian Rolfo

  UZ Antwerpen

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: GT60
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: OTHER
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: July 4, 2013
• First Posted: July 10, 2013
• Study Start: March 13, 2014
• Primary Completion: November 29, 2016
• Study Completion: March 30, 2017
• Last Updated: September 13, 2019
• Results First Posted: September 13, 2019

Record last verified: 2019-07

Locations

KR (1); GB (2); NL (2); FR (6); CZ (1)