Clinical trial NCT01894256: Study to Assess the Blood Levels and Safety of Olaparib in Patients With Advanced Solid Tumours and Normal or Impaired Kidney Function
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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Solid Tumours
Keywords: oncology,
cancer,
neoplasm,
anticancer drug,
pharmacokinetics,
area under curve,
olaparib,
solid tumour,
mild renal impairment,
moderate renal impairment
Lead sponsor: AstraZeneca
Sponsor class: INDUSTRY
First posted: 2013-07-10
Enrollment: 56
Sex: ALL
Minimum age (years): 18
Maximum age (years): 75
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL

Brief 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.

Primary outcomes:
measure: Cmax of Olaparib
timeFrame: 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
measure: AUC of Olaparib
timeFrame: 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
measure: AUC0-t of Olaparib
timeFrame: 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
measure: Tmax of Olaparib
timeFrame: 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
measure: Vz/F of Olaparib
timeFrame: 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
measure: CL/F of Olaparib
timeFrame: 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
measure: CLR of Olaparib
timeFrame: Part A: Day 1, 0-12 hours and 12-24 hours post-dose
measure: t1/2 of Olaparib
timeFrame: 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
Secondary outcomes:
Other outcomes:
measure: Protein Binding of Olaparib
timeFrame: Part A: Day 1, 1 hour post-dose
measure: Free Cmax of Olaparib
timeFrame: Part A: Day 1, 1 hour post-dose
measure: Free AUC of Olaparib
timeFrame: Part A: Day 1, 1 hour post-dose
measure: CL/F of Unbound Olaparib
timeFrame: Part A: Day 1, 1 hour post-dose
Locations:
city: Brussels (Jette)
country: Belgium
facility: Research Site
city: Edegem
country: Belgium
facility: Research Site
city: Leuven
country: Belgium
facility: Research Site
city: Liege
country: Belgium
facility: Research Site
city: Wilrijk
country: Belgium
facility: Research Site
city: Herlev
country: Denmark
facility: Research Site
city: København Ø
country: Denmark
facility: Research Site
city: Bordeaux
country: France
facility: Research Site
city: Dijon
country: France
facility: Research Site
city: Amsterdam
country: Netherlands
facility: Research Site
city: Maastricht
country: Netherlands
facility: Research Site
city: Newcastle Upon Tyne
country: United Kingdom
facility: Research Site
city: Surrey
country: United Kingdom
facility: Research Site
Study officials:
affiliation: AstraZeneca Senior Research Physician
name: Anitra Fielding
role: STUDY_DIRECTOR
affiliation: UZ Antwerpen
name: Christian Rolfo
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.