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

NCT01894256 | Completed Phase 1 Results

• 2 other identifiers: D0816C000062013-002225-30
• Study Type: interventional
• Target: 56
• Locations: 5 countries
• Sites: 13

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.

Conditions

Solid Tumours

Keywords

oncology,; cancer,; neoplasm,; anticancer drug,; pharmacokinetics,; area under curve,; olaparib,; solid tumour,; mild renal impairment,; moderate renal impairment

Outcome Measures

Primary Outcomes (8)

• 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 Outcomes (4)

• Protein Binding of Olaparib

  Part A: Day 1, 1 hour post-dose

• Free Cmax of Olaparib

  Part A: Day 1, 1 hour post-dose

• Free AUC of Olaparib

  Part A: Day 1, 1 hour post-dose

Study Arms (3)

Normal renal function

OTHER

Patients with calculated serum creatinine clearance ≥81 mL/min (using Cockcroft-Gault equation).

Drug: Olaparib tablet dosing

Mild renal impairment

OTHER

Patients with calculated serum creatinine clearance 51-80 mL/min (using Cockcroft-Gault equation).

Drug: Olaparib tablet dosing

Moderate renal impairment

OTHER

Patients with calculated serum creatinine clearance 31-50 mL/min (using Cockcroft-Gault equation).

Drug: Olaparib tablet dosing

Interventions

Olaparib tablet dosing DRUG

Part A - single 300mg oral dose olaparib (administered as 2x150mg tablets) Part B - 300mg oral dose olaparib (administered as 2x150mg tablets) bd

Mild renal impairment; Moderate renal impairment; Normal renal function

Eligibility Criteria

• Age: 18 Years - 75 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Calculated serum creatinine clearance greater than or equal to 81 mL/min (using Cockcroft-Gault equation). All patients must fulfil the following criteria:
• Provision of written informed consent prior to any study specific procedures .
• Patients must be greater than or equal to 18 and less than or equal to 75 years of age.
• Histologically or, where appropriate, cytologically confirmed malignant solid tumour refractory or resistant to standard therapy or for which no suitable effective standard therapy exists.
• BMI between 18-30 kg/m2.
• 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.
• Eastern Cooperative Oncology Group (ECOG) performance status less than or equal to 2.
• Patients must have a life expectancy greater than or equal to 12 weeks.
• 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).
• Patients are willing and able to comply with the protocol for the duration of the study including undergoing treatment and scheduled visits and examinations.

You may not qualify if:

• Involvement in the planning and/or conduct of the study (applies to both AstraZeneca staff, its agents and/or staff at the study site).
• Previous enrolment in the present study.
• 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).
• Renal transplant and end stage renal disease (ESRD) patients.
• 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.
• Patients who have received or are receiving inhibitors or inducers of CYP3A4 within the washout period.
• 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.
• Treatment in the previous 3 months with any drug known to have a well-defined potential for hepatotoxicity (eg, halothane).
• Persistent toxicities (greater than or equal to CTCAE Grade 2) caused by previous cancer therapy, excluding alopecia.
• Patients with myelodysplastic syndrome/acute myeloid leukaemia.
• 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.
• Major surgery within 2 weeks of starting study treatment and patients must have recovered from any effects of major surgery.
• 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.
• Patients with a history of heart failure or left ventricular dysfunction.
• Patients who have gastric, gastro-oesophageal or oesophageal cancer.

Sponsors & Collaborators

• AstraZeneca: lead

Study Sites (13)

Research Site

Brussels (Jette), Belgium

Location

Research Site

Edegem, Belgium

Location

Research Site

Leuven, Belgium

Location

Research Site

Liège, Belgium

Location

Research Site

Wilrijk, Belgium

Location

Research Site

Herlev, Denmark

Location

Research Site

København Ø, Denmark

Location

Research Site

Bordeaux, France

Location

Research Site

Dijon, France

Location

Research Site

Amsterdam, Netherlands

Location

Research Site

Maastricht, Netherlands

Location

Research Site

Newcastle upon Tyne, United Kingdom

Location

Research Site

Surrey, United Kingdom

Location

Related Publications (1)

• 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.

  PMID: 30877569 DERIVED

MeSH Terms

Conditions

Neoplasms

Limitations and Caveats

Data are presented for Part A and Part B.

Results Point of Contact

• Title: Dr Anitra Fielding
• Organization: AstraZeneca

anitra.fielding@astrazeneca.com

+44 1625 582828

Study Officials

• Anitra Fielding

  AstraZeneca Senior Research Physician

  STUDY DIRECTOR

• Christian Rolfo

  UZ Antwerpen

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: July 4, 2013
• First Posted: July 10, 2013
• Study Start: November 1, 2013
• Primary Completion: March 1, 2015
• Study Completion: February 1, 2016
• Last Updated: October 13, 2016
• Results First Posted: April 19, 2016

Record last verified: 2016-08

Locations

DK (2); FR (2); NL (2); BE (5); GB (2)