Study to Assess the Effect of Rifampicin (CYP Inducer) on Blood Levels and Safety of Olaparib in Patients With Advanced Solid Tumours

NCT01929603 | Completed Phase 1

• 1 other identifier: D0816C00008
• Study Type: interventional
• Target: 32
• Locations: 2 countries
• Sites: 5

Brief Summary

This is a 2-part study in patients with advanced solid tumours. Part A will investigate the effect of rifampicin on the PK parameters of olaparib in patients; Part B will allow patients continued access to olaparib after the PK phase and will provide additional safety data.

Conditions

Solid Tumours

Keywords

oncology, cancer, tumour, anticancer drug, pharmacokinetics, olaparib, rifampicin, neoplasm, CYP P450 inducer

Outcome Measures

Primary Outcomes (3)

• Pharmacokinetics of olaparib by assessment of maximum plasma olaparib concentration (Cmax)

  Rate and extent of absorption of olaparib following single oral doses of olaparib tablet formulation by assessment of maximum plasma olaparib concentration (Cmax). Olaparib doses are first without, then with rifampicin.

  Blood samples are collected on olaparib dosing days (Day 1 and 14) at pre-dose, 0.25 , 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 48, and 72 hours post olaparib dose Part A.

• Pharmacokinetics of olaparib by assessment of area under the plasma concentration time curve from zero to infinity (AUC)

  Rate and extent of absorption of olaparib following single oral doses of olaparib tablet formulation by assessment of area under the plasma concentration time curve from zero to infinity (AUC). Olaparib doses are first without, then with rifampicin.

  Blood samples are collected on olaparib dosing days (Day 1 and 14) at pre-dose, 0.25 , 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 48, and 72 hours post olaparib dose Part A.

• Pharmacokinetics of olaparib by assessment of area under the plasma concentration time curve from zero to the last measurable time point, AUC0-t, if AUC is not adequately estimable.

  Rate and extent of absorption of olaparib following single oral doses of olaparib tablet formulation by assessment of area under the plasma concentration time curve from zero to the last measurable time point, AUC0-t, if AUC is not adequately estimable. Olaparib doses are first without, then with rifampicin.

  Blood samples are collected on olaparib dosing days (Day 1 and 14) at pre-dose, 0.25 , 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 48, and 72 hours post olaparib dose Part A.

Secondary Outcomes (14)

• Pharmacokinetics of olaparib by assessment of time to reach maximum plasma concentration for olaparib (tmax).

  Blood samples are collected on olaparib dosing days (Day 1 and 14) at pre-dose, 0.25 , 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 48, and 72 hours post olaparib dose Part A.

• Pharmacokinetics of olaparib by assessment of olaparib area under the plasma concentration time curve from zero to the last measurable time point (AUC0-τ).

  Blood samples are collected on olaparib dosing days (Day 1 and 14) at pre-dose, 0.25 , 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 48, and 72 hours post olaparib dose Part A.

• Pharmacokinetics of olaparib by assessment of olaparib apparent clearance (CL/F).

  Blood samples are collected on olaparib dosing days (Day 1 and 14) at pre-dose, 0.25 , 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 48, and 72 hours post olaparib dose Part A.

• Pharmacokinetics of olaparib by assessment of olaparib apparent volume of distribution (Vz/F).

  Blood samples are collected on olaparib dosing days (Day 1 and 14) at pre-dose, 0.25 , 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 48, and 72 hours post olaparib dose Part A.

• Pharmacokinetics of olaparib by assessment of olaparib terminal half-life (t1/2).

  Blood samples are collected on olaparib dosing days (Day 1 and 14) at pre-dose, 0.25 , 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 48, and 72 hours post olaparib dose Part A.

Study Arms (1)

Olaparib alone, olaparib+rifampicin

EXPERIMENTAL

Sequential treatments of olaparib alone followed by olaparib+rifampicin, with a washout period inbetween.

Procedure: Pharmacokinetic sampling; Drug: Rifampicin; Drug: Olaparib tablet dosing

Interventions

Pharmacokinetic sampling PROCEDURE

Blood sampling to measure olaparib, rifampicin and 4β-hydroxycholesterol

Olaparib alone, olaparib+rifampicin

Rifampicin DRUG

Rifampicin (CYP inducer) 600mg taken once daily from Day 5 to Day 14 (Part A)

Olaparib alone, olaparib+rifampicin

Olaparib tablet dosing DRUG

Olaparib 300mg tablet taken on Days 1 and 14 (Part A). Part B dosing is 300mg olaparib bi-daily

Olaparib alone, olaparib+rifampicin

Eligibility Criteria

• Age: 18 Years - 99 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Provision of written informed consent prior to any study-specific procedures.
• Patients aged greater than or equal to 18 years.
• Histologically or, where appropriate, cytologically confirmed malignant solid tumour refractory or resistant to standard therapy or for which no suitable effective standard therapy exists.
• Patients must have normal organ and bone marrow function measured within 28 days prior to administration of investigational product (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 (AST), alanine aminotransferase (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, Serum creatinine less than or equal to 1.5 x institutional ULN.
• \. Calculated serum creatinine clearance greater than 50 mL/min (using Cockroft-Gault formula or by 24 hour urine collection).
• \. Eastern Cooperative Oncology Group (ECOG) performance status less than or equal to 2.
• \. Patients must have a life expectancy of greater than or equal to 16 weeks. 8. Evidence of non-childbearing status for women of childbearing potential, or post menopausal status: negative urine or serum pregnancy test within 28 days of study treatment, confirmed prior to treatment on Day 1 of Part A. Post-menopausal is defined as: Amenorrheic for 1 year or more following cessation of exogenous hormonal treatments.
• Luteinising hormone and follicle stimulating hormone levels in the post menopausal 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). 9. Patients are willing and able to comply with the protocol for the duration of the study including undergoing treatment and scheduled visits and examinations.
• \. 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 the 2 weeks prior to start of olaparib dosing, except for bisphosphonates, denosumab, and corticosteroids, which should be at a stable dose for at least 4 weeks prior to the start of olaparib dosing.

You may not qualify if:

• Involvement in the planning and/or conduct of the study (applies to AstraZeneca staff, its agents, and/or staff at the study site).
• Previous enrolment in the present study.
• Participation in another clinical study with an IP during the last 14 days (or a longer period depending on the defined characteristics of the agents used).
• 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.
• Toxicities (greater than or equal to Common Toxicity Criteria for Adverse Events \[CTCAE\] Grade 2) caused by previous cancer therapy, excluding alopecia.
• Any intake of grapefruit, grapefruit juice, Seville oranges, Seville orange marmalade, or other products containing grapefruit or Seville oranges within 7 days of the first administration of the IP until the end of Part A.
• Patients with brain metastases. A scan to confirm the absence of brain metastases is not required.
• 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 who have diabetes mellitus.
• Patients who have gastric, gastro-oesophageal, or oesophageal cancer .
• Patients unable to swallow orally administered medication and patients with gastrointestinal disorders or significant gastrointestinal resection likely to interfere with the absorption of olaparib.
• Breastfeeding women.
• Immunocompromised patients, eg, patients who are known to be serologically positive for human immunodeficiency virus (HIV).

Sponsors & Collaborators

• AstraZeneca: lead

Study Sites (5)

Research Site

Edegem, Belgium

Location

Research Site

Ghent, Belgium

Location

Research Site

Wilrijk, Belgium

Location

Research Site

Amsterdam, Netherlands

Location

Research Site

Maastricht, Netherlands

Location

Related Publications (1)

• Dirix L, Swaisland H, Verheul HM, Rottey S, Leunen K, Jerusalem G, Rolfo C, Nielsen D, Molife LR, Kristeleit R, Vos-Geelen J, Mau-Sorensen M, Soetekouw P, van Herpen C, Fielding A, So K, Bannister W, Plummer R. Effect of Itraconazole and Rifampin on the Pharmacokinetics of Olaparib in Patients With Advanced Solid Tumors: Results of Two Phase I Open-label Studies. Clin Ther. 2016 Oct;38(10):2286-2299. doi: 10.1016/j.clinthera.2016.08.010. Epub 2016 Oct 10.

  PMID: 27745744 DERIVED

Related Links

• D0816C00008\_Study\_Synopsis\_Redacted.pdf

MeSH Terms

Conditions

Neoplasms

Interventions

Rifampin

Intervention Hierarchy (Ancestors)

Rifamycins; Heterocyclic Compounds, 4 or More Rings; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds; Lactams, Macrocyclic; Macrocyclic Compounds; Polycyclic Compounds

Study Officials

• Anitra Fielding

  AstraZeneca Senior Research Physician

  STUDY DIRECTOR

• Luc Dirix

  GZA Ziekenhuizen Campus Sint-Augustinus

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Intervention Model: SINGLE GROUP
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: August 23, 2013
• First Posted: August 28, 2013
• Study Start: December 1, 2013
• Primary Completion: May 1, 2014
• Study Completion: November 1, 2016
• Last Updated: January 16, 2017

Record last verified: 2017-01

Locations

NL (2); BE (3)