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.
- Conditions
- Cancer: Solid tumour (Malignant solid tumour)CancerSolid tumour10019654
- Registration Number
- NL-OMON45128
- Lead Sponsor
- Astra Zeneca
- Brief Summary
Not available
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- Completed
- Sex
- Not specified
- Target Recruitment
- 12
For inclusion in the study as a patient with hepatic impairment:
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, see Section 6.2.1.1. 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 *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
4. 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
All patients must fulfill the following criteria:
5. Provision of written informed consent prior to any study specific procedures.
6. Patients must be *18 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 *-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 *9.0 g/dL, with no blood transfusions in the previous 28 days
* Absolute neutrophil count (ANC) *1.5 x 109/L
* White blood cells (WBC) >3 x 109/L
* Platelet count *75 x 109/L
* Serum creatinine *1.5 x institutional ULN
9. Calculated serum creatinine clearance >50 mL/min (using Cockcroft-Gault formula or by 24-hour urine collection)
10. Eastern Cooperative Oncology Group (ECOG) performance status * 2.
11. Patients must have a life e
Patients should not enter the study if any of the following exclusion criteria are fulfilled:
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 (see Section 5.6 for guidelines and washout periods).
7. Toxicities (*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.
12. 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 olaprib.
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 >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 exclusion criteria 1 to 18, patients with normal hepatic function should not enter the study if the following exclusion criterion is fulfilled:
19. History or presence of hepatic disease known to interfere with the absorption, distribution, metabolism or excretion of olaparib.
In addition to exclusion criteria 1 to 18, patients with mild or moderat
Study & Design
- Study Type
- Interventional
- Study Design
- Not specified
- Primary Outcome Measures
Name Time Method <p>Pharmacokinetics (primary variables)<br /><br>In Part A, the following variables will be calculated for olaparib where the<br /><br>data allow: maximum plasma concentration (Cmax), time to reach maximum plasma<br /><br>concentration (tmax), area under the plasma concentration time curve from zero<br /><br>to the last measureable time point (AUC 0-t), area under the plasma<br /><br>concentration time curve from zero to infinity (AUC), apparent clearance<br /><br>following oral administration (CL/F), terminal half-life (t*), apparent volume<br /><br>of distribution (Vz/F) and terminal rate constant (*z).<br /><br>Pharmacokinetics will not be measured in Part B.</p><br>
- Secondary Outcome Measures
Name Time Method <p>Safety<br /><br>Assessment of adverse events (AEs) graded by Common Terminology Criteria for<br /><br>Adverse Events (CTCAE) v4.0, standard 12 lead electrocardiograms (ECGs),<br /><br>physical examination, vital signs (including blood pressure, pulse), and<br /><br>evaluation of laboratory parameters (clinical chemistry, haematology, and<br /><br>urinalysis).<br /><br>Exploratory<br /><br>In Part A, plasma protein binding at 1 hour after dosing, used to calculate<br /><br>free Cmax (Cmax of unbound olaparib), free AUC (AUC of unbound olaparib) and<br /><br>unbound CL/F (CL/F of unbound olaparib).</p><br>