The primary objective of this study is to investigate the effect of food on the pharmacokinetics(PK) of olaparib following oral dosing of the tablet formulation in patients with advancedsolid tumours.The secondary objectives are to investigate the…
ID
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
To investigate the effect of food on the
pharmacokinetics (PK) of olaparib following oral
dosing of the tablet formulation in patients with
advanced solid tumours
Primary outcome variable(s):
Maximum plasma concentration (Cmax), time to
reach maximum plasma concentration (tmax), area
under the plasma concentration time curve from
zero to the last measurable time point (AUC0-t),
area under the plasma concentration time curve
from zero to infinity (AUC), apparent clearance
following oral administration (CL/F), apparent
volume of distribution (Vz/F), terminal rate
constant (!z), and terminal half-life (t1/2). Other
parameters may be determined if deemed
appropriate.
Secondary outcome
To investigate the effect of olaparib on the QT
interval following oral dosing of the tablet
formulation in patients with advanced solid
tumours
Secondary outcome variables:
ECG intervals (including QT and QTc interval)
To assess the safety and tolerability of olaparib
following oral dosing of the tablet formulation in
patients with advanced solid tumours
Secondary outcome variables:
Assessment of AEs, graded by CTCAE (v4.03),
physical examination (including BP and pulse),
and evaluation of laboratory parameters (clinical
chemistry, haematology, and urinalysis)
AE adverse event; BP blood pressure; CTCAE Common Terminology Criteria for
Adverse Event; ECG
electrocardiogram
Background summary
The food-effect part of this study has been designed as a 2-treatment period
crossover study to
allow the investigation of the effect of food within each patient and in a
randomised manner.
A crossover design is the recommended design for food effect studies to reduce
inter-patient
variability.
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 to be used in the monotherapy
maintenance setting
in Phase III.
This study is robustly designed to assess the primary objective while
minimising the number
of patients exposed to olaparib. AstraZeneca considers that olaparib continues
to demonstrate
an overall acceptable benefit-risk balance to support its further clinical
development.
Pre-clinical and emerging clinical tolerability data from patients indicate
that olaparib is
generally well tolerated by patients with advanced cancer (please refer to the
IB for details).
All AE, vital sign, and laboratory data will be collected and reviewed by the
Principal
Investigator (PI) and clinical research staff on an ongoing basis.
Although patients may not initially gain any benefit from participation in Part
A or Part B of
the study due to the short dosing periods, some benefit may be gained in Part
C. If the
investigator believes it is in the patient*s interest, the patient may continue
treatment with
olaparib tablets until such time as their disease progresses, the investigator
believes they are
no longer deriving clinical benefit, or they stop taking the olaparib tablets
for any other
reason.
The data generated from this study will support further development of olaparib
for the
treatment of cancer. The benefit/risk assessment for the conduct of this study
of olaparib
tablets in patients is acceptable.
Study objective
The primary objective of this study is to investigate the effect of food on the
pharmacokinetics
(PK) of olaparib following oral dosing of the tablet formulation in patients
with advanced
solid tumours.
The secondary objectives are 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
following oral
dosing of the tablet formulation in patients with advanced solid tumours.
Study design
This is a 3-part study in patients with advanced solid tumours: Part A will
determine the effect
of food on the pharmacokinetics of olaparib and the effect of olaparib on QT
interval
following a single oral dose of olaparib tablets; Part B will determine the
effect of olaparib on
the QT interval following multiple oral dosing of olaparib tablets; Part C will
allow patients continued access to olaparib tablets after PK and QT phases and
will provide for additional
safety data collection. A total of 48 patients are planned to be enrolled, with
at least
42 evaluable patients required to complete the study.
Part A of this study is a randomised, open-label, 2-treatment period crossover
design. Each
patient will receive a single oral dose of olaparib tablets 300 mg in each of 2
treatment periods
(once in the overnight fasted state and once immediately following a high-fat
meal), with at
least 5 and no more than 14 days (washout) between doses. Digital
electrocardiogram
(dECG), PK assessments, and safety assessments will be obtained for up to 72
hours post-dose
in each treatment period. Additionally, during the first treatment period,
patients will undergo
baseline dECG assessments on Day -1 (ie, the day prior to dosing) at clock
times matched to
planned/scheduled dECG assessment times on the dosing day (Day 1). Patients
will check
into the clinic on the evening of Day -2 (first treatment period) or on the
evening of Day -1
(second treatment period) and remain resident until 24 hours after each dose of
olaparib
tablets. The dECGs performed on Day 1 of each treatment period will be
clock-time matched
to the actual times that the Day -1 dECGs are performed in the first treatment
period. Patients
will return to the clinic for assessments on Days 3 and 4 of each treatment
period. On Day 1 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 5 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 tablets
300 mg twice daily (bd) for 5 days. Patients will check into the clinic in the
evening of
Day -2. On Day -1, baseline dECG assessments will be performed at clock times
matched to
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-time 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 tablets.
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 Day -1 (baseline)
dECG
evaluations on Day -2 or Day -3, if necessary, as long as the washout period by
the start of
baseline procedures for Part B has been at least 5 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. For example, if baseline assessments are on Day
-3, then
patients will check into the clinic in the evening of Day -4 and will leave the
clinic 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 tablets, 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 tablets 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 tablets during Part C,
they will also
attend a study treatment discontinuation visit.
Intervention
Taking Investigational product, eat high fat, normal or no breakfast and QT
Interval measurements.
Study burden and risks
The patient will be asked to get admitteed to the hospital (for 3 times) to eat
3 different kind of breakfasts, beside of that to take investigational
medication, while for the patient no curative treatment is possible.
Louis pasteurlaan Louis pasteurlaan 5
Zoetermeer 2719 EE
NL
Louis pasteurlaan Louis pasteurlaan 5
Zoetermeer 2719 EE
NL
Listed location countries
Age
Inclusion criteria
1. Provision of written informed consent prior to any study specific procedures
2. Patients aged >=18 years
3. Able to eat a high-fat meal within a 30-minute period, as provided by the study site
4. Histologically or, where appropriate, cytologically confirmed malignant solid tumour refractory or resistant to standard therapy or for which no suitable effective standard therapy exists
5. Normal organ and bone marrow function measured within 28 days prior to administration of investigational product (IP) as defined below:
* Haemoglobin >=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 <=5 x ULN
* Serum creatinine <=1.5 x institutional ULN
* Serum potassium, sodium, magnesium and calcium within the institutional normal range
6. Calculated serum creatinine clearance >50 mL/min (using Cockroft-Gault formula or by 24-hour urine collection)
7. Eastern Cooperative Oncology Group (ECOG) performance status <=2
8. Patients must have a life expectancy of >=16 weeks.
9. 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 >1 year ago
* Chemotherapy-induced menopause with >1 year interval since last menses
* Surgical sterilisation (bilateral oophorectomy or hysterectomy)
10. Patients are willing and able to comply with the protocol for the duration of the study including undergoing treatment and scheduled visits and examinations
11. 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
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. 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.
8. Major surgery within 2 weeks of starting study treatment and patients must have recovered from any effects of any major surgery.
9. Patients unable to fast for up to 14 hours
10. 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
computed tomography (HRCT) scan, or any psychiatric disorder that prohibits obtaining
informed consent.
11. 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.
12. Patients with a history of heart failure or left ventricular dysfunction, and patients who require calcium channel blockers
13. Patients with type I or type II diabetes
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 absorption of 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 olaparib or any of the excipients of the product
20. 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)
21. The use of concomitant medications that prolong the QT/QTc interval
22. 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 | EUCTR2013-001891-39-NL |
| Other | http://www.clinicaltrials.gov |
| CCMO | NL45021.068.13 |