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

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.