Study to Assess the Blood Levels and Safety of Olaparib in Patients With Advanced Solid Tumours and Normal or Impaired Kidney Function

Solid Tumours Clinical Trial

Official title:

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

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT01894256
• Other study ID #: D0816C00006
• Secondary ID: 2013-002225-30
• Status: Active, not recruiting
• Phase: Phase 1
• First received: July 4, 2013
• Last updated: November 16, 2015
• Start date: November 2013
• Est. completion date: April 2016

Study information

• Verified date: November 2015
• Source: AstraZeneca
• Contact: n/a
• Is FDA regulated: No
• Health authority: Belgium: Federal Agency for Medicinal Products and Health ProductsBelgium: Institutional Review BoardNetherlands: The Central Committee on Research Involving Human Subjects (CCMO)Netherlands: Medical Ethics Review Committee (METC)Denmark: Danish Dataprotection AgencyDenmark: Ethics CommitteeUnited Kingdom: Medicines and Healthcare Products Regulatory AgencyUnited Kingdom: Research Ethics CommitteeFrance: Institutional Ethical Committee
• Study type: Interventional

Clinical Trial 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.

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 57
• Est. completion date: April 2016
• Est. primary completion date: March 2015
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years to 75 Years

Eligibility

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.

Study Design

Allocation: Non-Randomized, Endpoint Classification: Pharmacokinetics Study, Intervention Model: Single Group Assignment, Masking: Open Label

Related Conditions & MeSH terms

• Solid Tumours

Intervention

Drug:
• Olaparib tablet dosing
Part A - single 300mg oral dose olaparib (administered as 2x150mg tablets) Part B - 300mg oral dose olaparib (administered as 2x150mg tablets) bd

Locations

Country	Name	City	State
Belgium	Research Site	Brussels (Jette)
Belgium	Research Site	Edegem
Belgium	Research Site	Leuven
Belgium	Research Site	Liege
Belgium	Research Site	Wilrijk
Denmark	Research Site	Herlev
Denmark	Research Site	København Ø
France	Research Site	Bordeaux
France	Research Site	Dijon
Netherlands	Research Site	Amsterdam
Netherlands	Research Site	Maastricht
United Kingdom	Research Site	Newcastle Upon Tyne
United Kingdom	Research Site	Surrey

Sponsors (1)

Lead Sponsor	Collaborator
AstraZeneca

Countries where clinical trial is conducted

Belgium,  Denmark,  France,  Netherlands,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Changes in plasma protein binding of olaparib and subsequent effects on pharmacokinetics: free maximum plasma concentration of unbound olaparib (Cmax)	In Part A, plasma protein binding at 1 hour after dosing, used to calculate free Cmax (Cmax of unbound olaparib)	Blood sample taken at 1 hour post first olaparib dose	No
Other	Changes in plasma protein binding of olaparib and subsequent effects on pharmacokinetics: free area under the plasma concentration-time curve from zero to infinity of unbound olaparib (AUC)	In Part A, plasma protein binding at 1 hour after dosing, used to calculate free AUC (AUC of unbound olaparib)	Blood sample taken at 1 hour post first olaparib dose	No
Other	Changes in plasma protein binding of olaparib and subsequent effects on pharmacokinetics: free apparent plasma clearance of unbound olaparib (CL/F)	In Part A, plasma protein binding at 1 hour after dosing, used to calculate unbound CL/F (CL/F of unbound olaparib)	Blood sample taken at 1 hour post first olaparib dose	No
Primary	Pharmacokinetics of olaparib: maximum olaparib concentration (Cmax)	In Part A, the following variable will be calculated for olaparib where the data allow: maximum plasma concentration (Cmax). Pharmacokinetics will not be measured in Part B	Blood samples will be collected on Day 1 of Part A at these time points: pre-dose, 0.25,0.5,1,1.5,2,3,4,6,8,12,24,48,72 and 96 hours post-dose.	No
Primary	Pharmacokinetics of olaparib : time to maximum concentration (tmax)	In Part A, the following variable will be calculated for olaparib where the data allow: time to reach maximum plasma concentration (tmax). Pharmacokinetics will not be measured in Part B	Blood samples will be collected on Day 1 of Part A at these time points: pre-dose, 0.25,0.5,1,1.5,2,3,4,6,8,12,24,48,72 and 96 hours post-dose.	No
Primary	Pharmacokinetics of olaparib: area under the plasma concentration-time curve from zero to the last measurable time point (AUC0-t)	In Part A, the following variable will be calculated for olaparib where the data allow: area under the plasma concentration-time curve from zero to the last measurable time point (AUC0-t). Pharmacokinetics will not be measured in Part B	Blood samples will be collected on Day 1 of Part A at these time points: pre-dose, 0.25,0.5,1,1.5,2,3,4,6,8,12,24,48,72 and 96 hours post-dose.	No
Primary	Pharmacokinetics of olaparib : area under the plasma concentration-time curve from zero to infinity (AUC)	In Part A, the following variable will be calculated for olaparib where the data allow: area under the plasma concentration-time curve from zero to infinity (AUC). Pharmacokinetics will not be measured in Part B	Blood samples will be collected on Day 1 of Part A at these time points: pre-dose, 0.25,0.5,1,1.5,2,3,4,6,8,12,24,48,72 and 96 hours post-dose.	No
Primary	Pharmacokinetics of olaparib : apparent plasma clearance following oral administration (CL/F)	In Part A, the following variable will be calculated for olaparib where the data allow: apparent plasma clearance following oral administration (CL/F). Pharmacokinetics will not be measured in Part B	Blood samples will be collected on Day 1 of Part A at these time points: pre-dose, 0.25,0.5,1,1.5,2,3,4,6,8,12,24,48,72 and 96 hours post-dose.	No
Primary	Pharmacokinetics of olaparib : terminal half-life (t½)	In Part A, the following variable will be calculated for olaparib where the data allow: terminal half-life (t½). Pharmacokinetics will not be measured in Part B	Blood samples will be collected on Day 1 of Part A at these time points: pre-dose, 0.25,0.5,1,1.5,2,3,4,6,8,12,24,48,72 and 96 hours post-dose.	No
Primary	Pharmacokinetics of olaparib : apparent volume of distribution (Vz/F)	In Part A, the following variable will be calculated for olaparib where the data allow: apparent volume of distribution (Vz/F). Pharmacokinetics will not be measured in Part B	Blood samples will be collected on Day 1 of Part A at these time points: pre-dose, 0.25,0.5,1,1.5,2,3,4,6,8,12,24,48,72 and 96 hours post-dose.	No
Primary	Pharmacokinetics of olaparib : terminal rate constant (?z)	In Part A, the following variable will be calculated for olaparib where the data allow: terminal rate constant (?z). Pharmacokinetics will not be measured in Part B	Blood samples will be collected on Day 1 of Part A at these time points: pre-dose, 0.25,0.5,1,1.5,2,3,4,6,8,12,24,48,72 and 96 hours post-dose.	No
Primary	Pharmacokinetics of olaparib : renal clearance (CLR)	In Part A, the following variable will be calculated for olaparib where the data allow: renal clearance (CLR). Pharmacokinetics will not be measured in Part B	Blood samples will be collected on Day 1 of Part A at these time points: pre-dose, 0.25,0.5,1,1.5,2,3,4,6,8,12,24,48,72 and 96 hours post-dose.	No
Secondary	Assessment of the safety and tolerability of olaparib by collection of adverse event reports	Assessment of adverse events (AEs) graded by Common Terminology Criteria for Adverse Events (CTCAE) v4.0	From baseline, every visit until 30 days after last dose, assessed up to 20 months.	Yes
Secondary	Determine safety and tolerability of olaparib by assessment of 12 lead Electrocardiograms	Assessment of standard 12 lead electrocardiograms (ECGs)	Part A: baseline, days 1 and 3. Part B: Day 1 then every 4 weeks. Final assessment within 30 days after last dose.	Yes
Secondary	Determine safety and tolerability of olaparib by physical examination	Assessment of physical examination	Part A: baseline, day -1 and within 30 days after last dose. Part B: Day 1.	Yes
Secondary	Determine safety and tolerability of olaparib by assessment of vital signs	Assessment of standard vital signs (including blood pressure, pulse)	Part A: baseline, days 1,2 and 3. Part B: Days 1,8,15,22,29 then every 4 weeks. Final assessment within 30 days after last dose.	Yes
Secondary	Determine safety and tolerability of olaparib by assessment of body temperature	Assessment of standard vital signs (body temperature)	Part A: baseline, day 1. Part B: Days 1,8,15,22,29 then every 4 weeks. Final assessment within 30 days after last dose.	Yes
Secondary	Determine safety and tolerability of olaparib by assessment of clinical chemistry results	Assessment of laboratory parameters (clinical chemistry)	Part A: baseline, days -1 and 3. Part B: Days 1,8,15,22,29 then every 4 weeks. Final assessment within 30 days after last dose.	Yes
Secondary	Determine safety and tolerability of olaparib by assessment of haematology results	Assessment of laboratory parameters (haematology)	Part A: baseline, days -1 and 3. Part B: Days 1,8,15,22,29 then every 4 weeks. Final assessment within 30 days after last dose.	Yes
Secondary	Determine safety and tolerability of olaparib by assessment of urinalysis results	Assessment of laboratory parameters (urinalysis)	Part A: baseline, days -1 and 3. Part B: Days 1,8,15,22,29 then every 4 weeks. Final assessment within 30 days after last dose.	Yes