* The primary objective of this study is to investigate the effect of rifampicin on the pharmacokinetics (PK) of olaparib following oral dosing of the tablet formulation in patients with advanced solid tumours.* The secondary objectives are to…
ID
Source
Brief title
Condition
- Miscellaneous and site unspecified neoplasms malignant and unspecified
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Pharmacokinetics
In Part A, the following variables will be calculated for olaparib where the
data allow:
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 plasma clearance following oral
administration (CL/F), apparent volume of distribution (Vz/F), terminal rate
constant (*z), and terminal half-life (t1/2).
Pharmacokinetics will not be measured in Part B.
Secondary outcome
Safety
Assessment of adverse events (AEs) graded by Common Terminology Criteria for
Adverse Events (CTCAE) v4.0, physical examination, vital signs (including blood
pressure, pulse), standard 12-lead electrocardiogram (ECG), and evaluation of
laboratory parameters (clinical chemistry, haematology, and urinalysis).
Background summary
Olaparib (AZD2281, KU-0059436) is a potent polyadenosine 5*diphosphoribose
[poly ADP ribose] polymerisation (PARP) inhibitor (PARP-1, -2 and -3) that is
being developed as an oral therapy, both as a monotherapy (including
maintenance) and for combination with chemotherapy and other anti-cancer
agents.
PARP inhibition is a novel approach to targeting tumours with deficiencies in
deoxyribonucleic acid (DNA) repair mechanisms. PARP enzymes are essential for
repairing DNA single strand breaks (SSBs). Inhibiting PARPs leads to the
persistence of SSBs, which are then converted to the more serious DNA double
strand breaks (DSBs) during the process of DNA replication. During the process
of cell division, DSBs can be efficiently repaired in normal cells by
homologous recombination repair. Tumours with homologous recombination repair
deficiencies (HRD), such as ovarian cancers in patients with breast cancer gene
(BRCA)1/2 mutations, cannot accurately repair the DNA damage, which may become
lethal to cells as it accumulates. In such tumour types, olaparib may offer a
potentially efficacious and less toxic cancer treatment compared with currently
available chemotherapy regimens.
Olaparib has been shown to inhibit selected tumour cell lines in vitro and in
xenograft and primary explant models as well as in genetic BRCA knock-out
models, either as a stand-alone treatment or in combination with established
chemotherapies. Cells deficient in homologous recombination DNA repair factors,
notably BRCA1/2, are particularly sensitive to olaparib treatment.
Study objective
* The primary objective of this study is to investigate the effect of
rifampicin 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
rifampicin, to demonstrate exposure to rifampicin, to demonstrate induction of
cytochrome P450 (CYP) by rifampicin, and to assess the safety and tolerability
of single and multiple oral doses of olaparib tablets in patients with advanced
solid tumours
Study design
This is a 2-part study in patients with advanced solid tumours: Part A will
assess the effect of rifampicin on the PK parameters of olaparib, and Part B
will allow patients continued access to olaparib after the PK phase and will
provide additional safety data. Approximately 18 patients are planned to be
enrolled; at least 16 evaluable patients will be required to complete the
study. Patients will participate as a single cohort in all parts of the study.
Intervention
In Part A, each patient will receive a single 300 mg oral dose of olaparib,
given as the tablet formulation, on Days 1 and 14 after an overnight fast. Each
dose will comprise 2 x 150 mg tablets for oral administration. Each patient
will receive rifampicin 600 mg once daily on Days 5 to 17. Each dose will
comprise 2 x 300 mg rifampicin capsules for oral administration. The rifampicin
doses will be taken in the morning at least 30 minutes prior to breakfast
except on Day 14 when rifampicin will be co-administered with olaparib after an
overnight fast.
In Part B, patients will receive 300 mg oral olaparib (administered as 2 x 150
mg tablets) twice daily for the duration of their participation.
Study burden and risks
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). Although patients may not initially gain
any benefit from participation in Part A of the study due to the short dosing
period, some benefit may be gained in Part B. 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 in
patients is acceptable.
Building 411A, Floor 4
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Building 411A, Floor 4
Sodertalje SE-15185
SE
Listed location countries
Age
Inclusion 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 or 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
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 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 >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 exceptionof 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
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
6. Toxicities (*Common Toxicity Criteria for Adverse Events [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 brain metastases. A scan to confirm the absence of brain metastases is not required.
9. Major surgery within 2 weeks of starting study treatment and patients must have recovered from any effects of major surgery
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 computer tomography (HRCT) scan, or any psychiatric disorder that prohibits obtaining informed consent.
11. Patients who have diabetes mellitus
12. Patients who have gastric, gastro-oesophageal, or oesophageal cancer
13. Patients unable to swallow orally administered medication and patients with gastrointestinal disorders or significant gastrointestinal resection likely to interfere with the absorption of olaparib
14. Breastfeeding women
15. Immunocompromised patients, eg, patients who are known to be serologically positive for human immunodeficiency virus (HIV)
16. Patients with known active hepatic disease (eg, hepatitis B or C)
17. Patients with a known hypersensitivity to rifampicin or any of the excipients of the product
18. Patients with a known hypersensitivity to olaparib or any of the excipients of the product
19. Resting electrocardiogram (ECG) at screening with measurable QT interval (QT) corrected for heart rate (QTc) >470 msec at 2 or more time points within a 24 hour period or family history of long QT syndrome
20. Concomitant medication contraindicated for use with rifampicin (including, but not limited to): atazanavir, darunavir, fosamprenavir, ritonavir-boosted saquinavir, saquinavir, or tipranavir
21. Patients who receive a seasonal flu vaccine (including H1N1, H1N5) must defer enrolment for 28 days post-vaccination.
22. Patients who have jaundice
23. Patients who weigh <50 kg
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 | EUCTR2013-002969-19-NL |
| CCMO | NL46174.068.13 |