Study to Assess the Blood Levels and Safety of Olaparib in Patients With Advanced Solid Tumours and Normal or Impaired Kidney Function
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
Allocation: Non-Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Enrollment: 56.0
Sex: All
Minimum age: 18 Years
Maximum age: 75 Years
Healthy volunteers: No
Keywords: oncology,; cancer,; neoplasm,; anticancer drug,; pharmacokinetics,; area under curve,; olaparib,; solid tumour,; mild renal impairment,; moderate renal 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 renal impairment compared to patients with
      normal renal function; Part B will allow eligible study patients 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 renal impairment, the following criterion must
        be met:

          1. Patients must have stable renal impairment (moderate or mild), depending on creatinine
             clearance estimated using the Cockcroft-Gault equation (moderate 31 to 50 mL/min; mild
             51 to 80 mL/min), for at least 2 months prior to the start of the study. For inclusion
             in the study as a patient with normal renal function, the following criterion must be
             met:

          2. Calculated serum creatinine clearance greater than or equal to 81 mL/min (using
             Cockcroft-Gault equation). All patients must fulfil the following criteria:

          3. Provision of written informed consent prior to any study specific procedures .

          4. Patients must be greater than or equal to 18 and less than or equal to 75 years of
             age.

          5. Histologically or, where appropriate, cytologically confirmed malignant solid tumour
             refractory or resistant to standard therapy or for which no suitable effective
             standard therapy exists.

          6. BMI between 18-30 kg/m2.

          7. Normal liver and bone marrow function measured within 28 days prior to administration
             of IP as defined below: Haemoglobin (Hb) greater than or equal to 10.0 g/dL, with no
             blood transfusions in the previous 28 days.

             Absolute neutrophil count (ANC) greater than or equal to 1.5 x 109/L. White blood
             cells (WBC) greater than 3 x 109/L. Platelet count greater than or equal to 100 x
             109/L. Total bilirubin less than or equal to 1.5 x institutional upper limit of normal
             (ULN) (except in the case of Gilbert's disease).

             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 5x ULN.

          8. Eastern Cooperative Oncology Group (ECOG) performance status less than or equal to 2.

          9. Patients must have a life expectancy greater than or equal to 12 weeks.

         10. 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).

         11. Patients are willing and able to comply with the protocol for the duration of the
             study including undergoing treatment and scheduled visits and examinations.

         12. 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:-

        Patients must 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. Participation in another clinical study with an investigational medicinal product (IP)
             during the last 14 days (or a longer period depending on the defined characteristics
             of the agent used).

          4. Renal transplant and end stage renal disease (ESRD) patients.

          5. Patients receiving any systemic chemotherapy or radiotherapy (except for palliative
             reasons) within 2 weeks prior to study treatment (or a longer period depending on the
             defined characteristics of the agents used). 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. For Part A only, drugs which affect creatinine clearance such as cephalosporin
             antibiotics, ascorbic acid, trimethoprim, cimetidine and quinine should not be used
             within the 7 days prior to dosing with olaparib.

          8. Treatment in the previous 3 months with any drug known to have a well-defined
             potential for hepatotoxicity (eg, halothane).

          9. Persistent toxicities (greater than or equal to CTCAE Grade 2) caused by previous
             cancer therapy, excluding alopecia.

         10. Patients with myelodysplastic syndrome/acute myeloid leukaemia.

         11. 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.

         12. Major surgery within 2 weeks of starting study treatment and patients must have
             recovered from any effects of major surgery.

         13. 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.

         14. Patients with a history of heart failure or left ventricular dysfunction.

         15. Patients who have gastric, gastro-oesophageal or oesophageal cancer.

         16. Patients unable to swallow orally administered medication and patients with
             gastrointestinal disorders or significant gastrointestinal resection likely to
             interfere with the absorption of olaparib.

         17. Breastfeeding women.

         18. Immunocompromised patients eg, patients who are known to be serologically positive for
             human immunodeficiency virus (HIV).

         19. Patients with known active hepatic disease (eg, hepatitis B or C).

         20. Patients with a known hypersensitivity to olaparib or any of the excipients of the
             product.

         21. Resting ECG at screening with measurable QTc greater than 470 msec at 2 or more time
             points within a 24 hour period or family history of long QT syndrome.

         22. Clinical judgment by the investigator that the patient should not participate in the
             study.