A Non-randomised, Open-label, Sequential, Three-part, Phase I Study to Assess the Effect of Itraconazole (a CYP3A4 Inhibitor) on the Pharmacokinetics of Olaparib Following Oral Dosing of a Tablet Formulation, and to Provide Data on the Effect of Olaparib on QT Interval Following Oral Dosing of a Tablet Formulation to Patients with Advanced Solid Tumours
- Conditions
- Cancer: Solid tumour (Malignant solid tumour)CancerSolid tumour
- Registration Number
- NL-OMON40540
- Lead Sponsor
- Astra Zeneca
- Brief Summary
Not available
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- Completed
- Sex
- Not specified
- Target Recruitment
- 12
For inclusion in the study, patients should fulfil the following criteria:
1. Provision of written informed consent prior to any study-specific procedures
2. Patients aged *18 years
3. Histologically or, where appropriate, cytologically confirmed malignant solid tumour refractory or resistant to standard therapy and for which no suitable effective standard therapy exists
4. 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) * 10.0 g/dL, with no blood transfusions in the previous 28 days
- Absolute neutrophil count (ANC) * 1.5 x 109/L
- White blood cells (WBC) >3 x 109/L
- Platelet count * 100 x 109/L
- Total bilirubin * 1.5 x institutional upper limit of normal (ULN) (except in the case of Gilbert*s disease)
- Aspartate aminotransferase (AST), alanine aminotransferase (ALT) * 2.5 x institutional ULN unless liver metastases are present in which case it must be * 5x ULN
- Serum creatinine * 1.5 x institutional ULN
- Serum potassium, sodium, magnesium, and calcium within the institutional normal range
5. Calculated serum creatinine clearance >50 mL/min (using Cockroft-Gault formula or by 24 hour urine collection)
6. Eastern Cooperative Oncology Group (ECOG) performance status *2
7. Patients must have a life expectancy of *16 weeks.
8. 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 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 postmenopausal
range for women under 50 years of age
- Radiation-induced oophorectomy with last menses >1 year ago
- Chemotherapy-induced menopause with >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.
10. 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.
Patients should 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 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 IP during the last 14 days (or a longer
period depending on the defined characteristics of the agents used)
4. 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.
5. Patients who have received or are receiving inhibitors or inducers of CYP3A4 (see
Section 5.6.1 for guidelines and washout periods)
6. Toxicities ( CTCAE Grade 2) caused by previous cancer therapy, excluding
alopecia
7. 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.
8. 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.
9. Major surgery within 2 weeks of starting study treatment and patients must have
recovered from any effects of any major surgery
10. Patients unable to fast for up to 14 hours
11. 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.
12. Patients with a history of poorly controlled hypertension with resting blood pressure
(BP) >150/100 mm Hg in the presence or absence of a stable regimen of
hypertensive therapy. Measurements will be made after the patient has been resting
supine for a minimum of 5 minutes. Two or more readings should be taken at
2-minute intervals and averaged. If the first 2 diastolic readings differ by more than
5 mm Hg, an additional reading should be obtained and averaged.
13. Patients with a history of heart failure, or left ventricular dysfunction, and patients
who require calcium channel blockers
14. Patients who have gastric, gastro-oesophageal or oesophageal cancer
15. Patients unable to swallow orally administered medication and patients with
gastrointestinal disorders or significant gastrointestinal resection likely to interfere with the absorption olaparib.
16. Breastfeeding women
17. Immunocompromised pat
Study & Design
- Study Type
- Interventional
- Study Design
- Not specified
- Primary Outcome Measures
Name Time Method <p>Primary objective:<br /><br><br /><br>To investigate the effect of itraconazole on the PK<br /><br>of olaparib following oral dosing of the tablet<br /><br>formulation in patients with advanced solid<br /><br>tumours<br /><br><br /><br><br /><br>Primary outcome variable(s):<br /><br><br /><br>Maximum plasma olaparib concentration (Cmax)<br /><br>Olaparib area under the plasma concentration<br /><br>time curve from zero to infinity (AUC) (or area<br /><br>under the plasma concentration time curve from<br /><br>zero to the last measurable time point, AUC0-t, if<br /><br>AUC is not adequately estimable)<br /><br>PK pharmacokinetics</p><br>
- Secondary Outcome Measures
Name Time Method