The primary objective of this study is to investigate the effect of itraconazole on thepharmacokinetics (PK) of olaparib following oral dosing of the tablet formulation inpatients with advanced solid tumours.The secondary objectives are: to…
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Source
Brief title
Condition
- Other condition
Synonym
Health condition
Cancer: Solid tumour (Malignant solid tumour)
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Primary objective:
To investigate the effect of itraconazole on the PK
of olaparib following oral dosing of the tablet
formulation in patients with advanced solid
tumours
Primary outcome variable(s):
Maximum plasma olaparib concentration (Cmax)
Olaparib area under the plasma concentration
time curve from zero to infinity (AUC) (or area
under the plasma concentration time curve from
zero to the last measurable time point, AUC0-t, if
AUC is not adequately estimable)
PK pharmacokinetics
Secondary outcome
Secondary objectives:
To characterise the PK of olaparib following oral
dosing of the tablet formulation in the presence
and absence of itraconazole
To demonstrate exposure to itraconazole and
hydroxy-itraconazole
To investigate the effect of olaparib on the QT
interval corrected for heart rate (QTc) following
single (Part A) and multiple (Part B) oral doses of
the tablet formulation
To investigate further the safety and tolerability of
olaparib tablets in patients with advanced solid
tumours
Secondary outcome variables:
Time to reach maximum plasma concentration for
olaparib (tmax),
Olaparib area under the plasma concentration
time curve from zero to the last measurable time
point (AUC0-"),
Olaparib apparent clearance (CL/F),
Olaparib apparent volume of distribution (Vz/F),
Olaparib terminal half-life (t1/2)
Itraconazole Cmax, AUC0-", tmax, and CL/F;
hydroxy-itraconazole Cmax, AUC0-", and tmax
ECG intervals (including QT and QTc interval)
Assessment of AEs, graded by CTCAE v4.03,
physical examination (including BP and pulse),
and evaluation of laboratory parameters (clinical
chemistry, haematology, and urinalysis)
Background summary
This study has been designed as a 2-part sequential study to allow the
investigation of the
effect of itraconazole, a CYP3A4 inhibitor, on the PK of olaparib within each
patient. Due to
existing pre-clinical data, it is not possible to use healthy volunteers for
this study. It is
therefore relevant to use patients with advanced solid tumours.
The tablet dose chosen will deliver exposure that has been previously
demonstrated to be
tolerated in cancer patients and is the dose intended to be used in Phase III
studies conducted
in the monotherapy maintenance setting.
Study objective
The primary objective of this study is to investigate the effect of
itraconazole on the
pharmacokinetics (PK) of olaparib following oral dosing of the tablet
formulation in
patients with advanced solid tumours.
The secondary objectives are: to characterise the PK of olaparib following oral
dosing of the tablet formulation in the presence and absence of itraconazole, to
demonstrate exposure to itraconazole and hydroxy-itraconazole, to investigate
the
effect of olaparib on the QT interval corrected for heart rate (QTc) following
single
(Part A) and multiple (Part B) oral doses of the tablet formulation, and to
investigate further the safety and tolerability of olaparib tablets in patients
with
advanced solid tumours (Part C).
Study design
This is a 3-part study in patients with advanced solid tumours: Part A will
assess the effect of
itraconazole on the PK parameters of olaparib and will determine the effect of
olaparib on the
QT interval following single oral dosing; Part B will determine the effect of
olaparib on the
QT Interval following multiple oral dosing; Part C will allow patients
continued access to
olaparib after the PK and QT phases and will provide for additional safety data
collection. A
total of 48 patients are planned to be enrolled; at least 42 evaluable patients
will be required to
complete the study. Patients will participate as a single cohort in all parts
of the study.
Part A is a non-randomised, open-label, 2-treatment design. Patients will
receive the
following 2 study treatments: a single oral dose of olaparib alone (tablet
formulation), and a
single oral dose of olaparib administered concomitantly with itraconazole.
Patients will check
into the clinic the evening of Day -2. Baseline digital electrocardiogram
(dECG) assessments
will be obtained on Day -1 at clock times matched to the planned/scheduled dECG
assessment
times on Day 1 of dosing. On Day 1, patients will receive a single oral dose of
olaparib
100 mg in the morning after an overnight fast and will remain fasting for 4
hours post-dose.
Patients will remain resident until 24 hours after the dose of olaparib, during
which time PK
blood samples, dECGs, and other safety information will be collected. The dECGs
performed
on Day 1 and Day 9 will be clock-matched to the actual times that the Day -1
dECGs are
performed. Patients will then return to the clinic on an outpatient basis for
PK assessments on
Days 3 and 4. On Day 5, patients will commence daily doses of itraconazole (200
mg once
daily [od]) for 7 days. Itraconazole doses should be taken with a full meal,
except for the dose
on the morning of Day 9, which will be taken after an overnight fast. Patients
will selfadminister
their itraconazole doses on an outpatient basis from Day 5 until the morning of
Day 8. On the evening of Day 8, patients will check into the clinic. On the
morning of Day 9,
patients will receive a single oral dose of olaparib 100 mg (administered
concomitantly with
the itraconazole dose) after an overnight fast and will remain fasting for 4
hours post-dose.
Patients will remain resident until 24 hours after the dose of olaparib, during
which time PK
blood samples, dECGs, and other safety information will be collected. Patients
will then
return to the clinic on an outpatient basis for PK assessments on Days 11 and
12. On
Days 1 and 9 of Part A patients should be fasted over the same time period as
Day -1.
Part B is an open-label study in the same patients who participated in Part A.
Upon
completion of Part A, providing the patient continues to meet the study
inclusion and
exclusion criteria, and following a washout period of at least 7 days and no
more than 14 days
between the last dose in Part A and Day -1 of Part B, each patient will receive
olaparib
300 mg twice daily (bd) for 5 days. Patients will check into the clinic on the
evening of
Day -2. On Day -1, baseline dECG assessments will be performed at clock times
matched to
the planned/scheduled dECG assessment times on Day 5. Patients will be
discharged from the
clinic on the evening of Day -1. Patients will self-administer their olaparib
doses under fasted
conditions (from 1 hour prior to 2 hours after dosing) from Day 1 up to the
morning of Day 4
on an outpatient basis. On the evening of Day 4, patients will check back into
the clinic, and
will receive their Day 4 evening dose. On the morning of Day 5, patients will
receive their
Day 5 morning dose after an overnight fast and will remain fasting for 4 hours
post-dose.
Patients will undergo dECG and PK assessments pre-dose and for 12 hours
post-dose. The dECGs performed on Day 5 will be clock-matched to the actual
times that the Day -1 dECGs
are performed. Patients will be discharged from the clinic after completing
12-hour
assessments on Day 5, and will self-administer their evening Day 5 dose of
olaparib. On
Day 5 of Part B patients should be fasted over the same time period as Day -1.
In both Parts A and B, patients are allowed to undergo the baseline dECG
evaluations
(scheduled for Day -1) within 3 days prior to the start of dosing, if
necessary, as long as the
washout period by the start of Day -1 procedures has been at least 7 days since
the previous
treatment. If baseline assessments are done earlier than Day -1, then the
periods of in-house
confinement will be adjusted accordingly, eg, if baseline assessments are on
Day -3, then
patients will check into the clinic the evening of Day -4 and will leave the
clinic either the
morning of Day -2 after the 24-hour dECG measurement for Part A, or the evening
of Day -3
after the 12-hour dECG measurement for Part B. Patients will check back into
the clinic in
the evening of Day -1.
On completion of Part B, patients may be entered into Part C and continue to
take olaparib
tablets (300 mg bd) if they and the investigator agree that this is
appropriate. Patients should
start Part C immediately after the last dose received in Part B. Patients will
have weekly
clinic visits for the first 4 weeks; thereafter visits will be every 4 weeks.
Part C will be of
12 months* duration from the date the last patient enters this part of the
study.
During and after Part C, patients may continue to take olaparib, if they and
the investigator
deem it appropriate, until such time as their disease progresses, the
investigator believes they
are no longer deriving clinical benefit, or they stop taking the olaparib for
any other reason.
After the end of Part C (12 months after the last patient entered Part C),
patients will be seen
as per their normal routine clinical schedule and no clinical data will be
collected, other than
serious adverse events (SAEs) and drug dispensing/accountability.
Patients will return to the clinic for follow-up assessments 30 days (±7 days)
after their last
dose (regardless of whether the last dose was in Part A, Part B, Part C, or the
continued-access
phase after Part C). If a patient discontinues olaparib during Part C, they
will also attend a
study treatment discontinuation visit.
Intervention
Taking Investigational product, itraconazol and QT Interval measurements.
Study burden and risks
The patient will be asked to get admitteed to the hospital to take
itraconazole, beside of that to take investigational medication, while for the
patient no curative treatment is possible.
Louis pasteurlaan Louis pasteurlaan 5
Zoetemeer 2719 EE
NL
Louis pasteurlaan Louis pasteurlaan 5
Zoetemeer 2719 EE
NL
Listed location countries
Age
Inclusion criteria
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.
Exclusion criteria
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 patients, eg, patients who are known to be serologically
positive for human immunodeficiency virus (HIV)
18. Patients with known active hepatic disease (ie, hepatitis B or C)
19. Patients with a known hypersensitivity to itraconazole or any of the excipients of
the product
20. Patients with a known hypersensitivity to olaparib or any of the excipients of the
product
21. Mean QTc with Fridericia*s correction (QTcF) >470 ms in screening ECG or
history of familial long QT syndrome:
- a marked baseline prolongation of QT/QTc interval (eg, repeated demonstration
of a QTc interval >470 ms)
- a history of additional risk factors for Torsade de pointes (eg, heart failure,
hypokalaemia, family history of long QT syndrome)
22. The use of concomitant medications that prolong the QT/QTc interval
23. Concomitant medication contraindicated for use with itraconazole (including, but
not limited to): cisapride, oral midazolam, nisoldipine, pimozide, quinidine,
dofetilide, triazolam, levacetylmethadol (levomethadyl), 3-hydroxy-3-methylglutaryl
coenzyme A (HMG-CoA)-reductase inhibitors metabolized by CYP3A4,
such as lovastatin and simvastatin, ergot alkaloids metabolized by CYP3A4, such as
dihydroergotamine, ergometrine (ergonovine), ergotamine and methylergometrine
(methylergonovine).
24. Clinical judgment by the investigator that the patient should not participate in the
study
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2013-001892-18-NL |
| Other | http://www.clinicaltrials.gov. |
| CCMO | NL45022.068.13 |