An Open-label, Non-randomised, Multicentre, Comparative, Phase I Study of the Pharmacokinetics, Safety and Tolerability of Olaparib Following a Single Oral 300 mg Dose to Patients with Advanced Solid Tumours and Normal Renal Function or Renal Impairment.
- Conditions
- Cancer: Solid tumour (Malignant solid tumour)CancerSolid tumour10038430
- Registration Number
- NL-OMON40271
- 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 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 *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 *18 and *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) *10.0 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 *100 x 109/L
* Total bilirubin *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) *2.5 x institutional ULN unless liver metastases are present in which case it must be *5x ULN
8. Eastern Cooperative Oncology Group (ECOG) performance status * 2.
9. Patients must have a life expectancy *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 >1 year ago
* Chemotherapy-induced menopause with >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.
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 (*CTCAE Grade 2) caused by previous cancer therapy, excluding alopecia.
10. Patients with myelodysplatic 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 >470 msec at 2 or more time points within a 24 hour period or family histor
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 measurable time point (AUC0-t), area under the plasma<br /><br>concentration-time curve from zero to infinity (AUC), apparent plasma clearance<br /><br>following oral administration (CL/F), terminal half-life (t*), apparent volume<br /><br>of distribution (Vz/F), terminal rate constant (*z) and renal clearance (CLR).<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>