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
Condition: Solid Tumours
MeSH terms: Neoplasms
Intervention: Olaparib tablet dosing
Intervention description: Part A - single 300mg oral dose olaparib (administered as 2x150mg tablets) Part B - 300mg oral dose olaparib (administered as 2x150mg tablets) bd
Intervention MeSH terms: Olaparib
Phase: Phase 1
Study type: Interventional
Primary purpose: Other
Allocation: Non-Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Enrollment: 31.0
Sex: All
Minimum age: 18 Years
Maximum age: 130 Years
Healthy volunteers: No
Keywords: oncology,; cancer,; neoplasm,; anticancer drug,; pharmacokinetics,; area under curve,; olaparib,; solid tumour,; mild hepatic impairment,; moderate hepatic impairment

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.
    

Eligibility criteria:

        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 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 moderate hepatic impairment should not enter the study if the following
        exclusion criteria are fulfilled: 20. Patients with hepatic encephalopathy (as described in
        the Child Pugh Classification system).

        21. 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).

        22. Change in dose regimen of medically required medication within the last 2 weeks before
        screening and/or the use of disallowed co-medication in the 3 weeks prior to admission to
        the clinic.

        23. Presence of acute liver disease caused by drug toxicity or by an infection. 24. Severe
        portal hypertension or surgical porto-systemic shunts. 25. Biliary obstruction or other
        causes of hepatic impairment not related to parenchymal disorder and/or disease of the
        liver.

        26. Oesophageal variceal bleeding within the past 2 months. 27. Anticoagulant therapy with
        warfarin or related coumarins.