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

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

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.

Study Overview

• Status: Completed
• Conditions: Solid Tumours
• Intervention / Treatment: Drug: Olaparib tablet dosing

• Study Type: Interventional
• Enrollment (Actual): 56
• Phase: Phase 1

Contacts and Locations

Study Locations

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

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 75 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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 Plan

How is the study designed?

Design Details

• Allocation: Non-Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Other: Normal renal function; Patients with calculated serum creatinine clearance ≥81 mL/min (using Cockcroft-Gault equation).	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
Other: Mild renal impairment; Patients with calculated serum creatinine clearance 51-80 mL/min (using Cockcroft-Gault equation).	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
Other: Moderate renal impairment; Patients with calculated serum creatinine clearance 31-50 mL/min (using Cockcroft-Gault equation).	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

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Cmax of Olaparib	Maximum plasma drug concentration of olaparib	Part A: pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 48, 72 and 96 hours post-dose
AUC of Olaparib	Area under plasma concentration-time curve from zero to infinity of olaparib	Part A: pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 48, 72 and 96 hours post-dose
AUC0-t of Olaparib	Area under plasma concentration-time curve from zero to the last measurable time point of olaparib	Part A: pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 48, 72 and 96 hours post-dose
Tmax of Olaparib	Time to reach maximum plasma concentration of olaparib	Part A: pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 48, 72 and 96 hours post-dose
Vz/F of Olaparib	Apparent volume of distribution of olaparib	Part A: pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 48, 72 and 96 hours post-dose
CL/F of Olaparib	Apparent plasma clearance of olaparib	Part A: pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 48, 72 and 96 hours post-dose
CLR of Olaparib	Renal clearance of olaparib, calculated as the ratio of amount of drug excreted over 24 hours to AUC0-24	Part A: Day 1, 0-12 hours and 12-24 hours post-dose
t1/2 of Olaparib	Terminal half-life of olaparib	Part A: pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 48, 72 and 96 hours post-dose

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Protein Binding of Olaparib	Degree to which olaparib binds to the proteins within blood plasma	Part A: Day 1, 1 hour post-dose
Free Cmax of Olaparib	Cmax of unbound olaparib; calculated by multiplying total Cmax value by estimated protein binding	Part A: Day 1, 1 hour post-dose
Free AUC of Olaparib	AUC of unbound olaparib; calculated by multiplying total AUC by estimated protein binding	Part A: Day 1, 1 hour post-dose
CL/F of Unbound Olaparib	Calculated from dose divided by free AUC	Part A: Day 1, 1 hour post-dose

Collaborators and Investigators

• Sponsor: AstraZeneca
• Investigators: Study Director: Anitra Fielding, AstraZeneca Senior Research Physician; Principal Investigator: Christian Rolfo, UZ Antwerpen

Publications and helpful links

General Publications

• Rolfo C, de Vos-Geelen J, Isambert N, Molife LR, Schellens JHM, De Greve J, Dirix L, Grundtvig-Sorensen P, Jerusalem G, Leunen K, Mau-Sorensen M, Plummer R, Learoyd M, Bannister W, Fielding A, Ravaud A. Pharmacokinetics and Safety of Olaparib in Patients with Advanced Solid Tumours and Renal Impairment. Clin Pharmacokinet. 2019 Sep;58(9):1165-1174. doi: 10.1007/s40262-019-00754-4.

Study record dates

Study Major Dates

• Study Start: November 1, 2013
• Primary Completion (Actual): March 1, 2015
• Study Completion (Actual): February 1, 2016

Study Registration Dates

• First Submitted: July 4, 2013
• First Submitted That Met QC Criteria: July 4, 2013
• First Posted (Estimate): July 10, 2013

Study Record Updates

• Last Update Posted (Estimate): October 13, 2016
• Last Update Submitted That Met QC Criteria: August 19, 2016
• Last Verified: August 1, 2016

More Information

Terms related to this study

• Keywords: pharmacokinetics,; cancer,; oncology,; neoplasm,; anticancer drug,; area under curve,; olaparib,; solid tumour,; mild renal impairment,; moderate renal impairment
• Additional Relevant MeSH Terms: Neoplasms; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antineoplastic Agents; Poly(ADP-ribose) Polymerase Inhibitors; Olaparib
• Other Study ID Numbers: D0816C00006; 2013-002225-30 (EudraCT Number)