PrimaryTo assess the safety and tolerability of olaparib when given in addition to abiraterone and torecommend, by assessment of dose-limiting toxicities and other safety and tolerability data, adose of olaparib for further study when given in…
ID
Source
Brief title
Condition
- Reproductive neoplasms male malignant and unspecified
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Primary outcome variables:
• Safety and tolerability
* Assessment of adverse events (AEs) graded by Common Terminology Criteria for
Adverse Events (CTCAE) v4.0, vital signs (including blood pressure, pulse), and
evaluation of laboratory parameters (clinical chemistry and haematology).
* Incidence of dose-limiting toxicities (DLTs)
Secondary outcome
Secondary outcome variables:
• Pharmacokinetics
* Olaparib and abiraterone PK parameters (where the data allow): maximum plasma
concentration at steady state (Cmax ss), time to reach maximum plasma
concentration at steady state (tmax ss), area under the plasma
concentration-time curve at steady state (AUCss), minimum plasma concentration
at steady state (Cmin ss)
Background summary
Prostate cancer is a heterogeneous disease and androgen deprivation therapy
with luteinizing hormone releasing hormone (LHRH) analogs or orchidectomy is
usually initially effective at controlling metastatic disease, but patients
inevitably progress from an androgen-sensitive to a castration-resistant
phenotype. Until recently, effective treatment at this stage has been largely
limited to docetaxel chemotherapy after studies showed it could improve overall
survival in this population. Cabazitaxel, enzalutamide, abiraterone acetate
(hereafter referred to as abiraterone) and radium-223 have now been shown to
give further improvements in time to progression and overall survival when used
after docetaxel therapy.
The optimum strategy for managing patients after docetaxel has not been
established, but in many countries all 4 of these agents are licensed for use
in the post-docetaxel phase of metastatic CRPC, with enzalutamide and
abiraterone, which both target the androgen receptor (AR) pathway, being
preferred because of their good tolerability profiles and absence of
chemotherapy-associated side effects. In Part A of this study, metastatic CRPC
patients will be recruited irrespective of whether they have already had
chemotherapy in order to facilitate recruitment to this part of the study.
Recent pre-clinical data demonstrate a role for PARP-1, distinct from its role
in DNA repair, in AR-dependent transcriptional signalling. Specifically
relevant to this study is the observation that PARP-1 inhibition co-operates
with androgen depletion to suppress cell proliferation. Furthermore,
chromosomal rearrangements placing coding region on erythroblast
transformation-specific (ETS) genes (eg, ETS-related gene [ERG]) occur with
high frequency in prostate cancer and result in AR-dependent expression of
pro-tumourigenic ETS genes. ERG has been shown to physically interact with
PARP-1, and PARP-1 inhibition preferentially sensitises ETS over-expressing
xenografts to PARP inhibition. In addition, over-expression of ERG leads to
accelerated
carcinogenesis in mouse prostates with phosphatase and tensin homolog (PTEN)
deletion, and PTEN loss itself has been suggested to sensitise cells to PARP
inhibitors
Hence, there is a rationale for combination of olaparib with abiraterone in
prostate cancer and a possibility that this combination may be preferentially
active based on measures of ETS fusions (eg, ERG expression), AR status and
PTEN. There may also be a small number of patients who may benefit due to the
presence of a BRCA
mutation in their tumour. Although only a small number of patients have
germline mutations,the number with somatic mutations may be significantly
higher.
This study will evaluate the investigational drug olaparib when given on a
background of the approved drug abiraterone in patients with metastatic CRPC.
Part A of this study will provide an initial assessment of safety/tolerability
and potential for pharmacokinetic (PK) interaction between the drugs. For the
randomised phase of this study, only post-chemotherapy CRPC patients will be
studied (chemotherapy-naive CRPC patients will be recruited in another study).
This therefore facilitates a robust assessment of the primary endpoint of
radiologic progression-free survival (radiologic PFS, rPFS) within a reasonable
timeframe for a Phase II study.
Study objective
Primary
To assess the safety and tolerability of olaparib when given in addition to
abiraterone and to
recommend, by assessment of dose-limiting toxicities and other safety and
tolerability data, a
dose of olaparib for further study when given in addition to abiraterone.
Secondary
To evaluate the presence of any drug interaction between olaparib and
abiraterone by
determination of steady state exposure to olaparib in the presence and absence
of abiraterone,
and determination of steady state exposure to abiraterone in the presence and
absence of
olaparib.
Study design
This is a study in patients with metastatic CRPC. Part A is an open-label
safety run-in study to assess the safety, tolerability and pharmacokinetics
(PK) of olaparib when given in addition to abiraterone 1000 mg once daily.
Abiraterone is indicated in combination with prednisone or prednisolone for the
treatment of patients with metastatic CRPC. Prednisone or prednisolone 5 mg
twice daily (bid) will be administered with the abiraterone in this study, but
throughout this protocol the treatment will
be referred to simply as abiraterone.
All patients will attend a screening visit within 28 days before starting study
treatment.
Patients will attend the clinic on the first day of study treatment, then at 1,
2, 4, 8 and 12 weeks, and every 12 weeks thereafter.
Cohort 1 (up to 6 patients)
At least 3 and up to 6 evaluable patients will be enrolled in Cohort 1.
Patients will receive olaparib 200 mg bid and abiraterone 1000 mg once daily.
Dose-limiting toxicities (DLTs) will be assessed by a Safety Review Committee
(SRC) after a minimum of 14 days* treatment.
Cohort 2 (12 patients)
If the combination of olaparib 200 mg bid and abiraterone 1000 mg once daily is
tolerated, a cohort of 12 patients (split into 2 groups of 6 patients) will be
treated with olaparib 300 mg bid given in addition to abiraterone 1000 mg once
daily.
Dose-limiting toxicities will be assessed by the SRC after a minimum of 14
days* treatment with both olaparib and abiraterone.
Group 1:
Patients will receive olaparib alone (300 mg bid) for between 3 and 7 days.
Blood samples will then be collected to determine the steady state PK profile
for olaparib. Patients will then receive abiraterone (1000 mg once daily)
starting from the day after the olaparib PK profile has been collected.
Olaparib and abiraterone will continue to be dosed in combination for at least
5 days, then blood samples will be collected again to determine both olaparib
and abiraterone PK profiles.
Group 2:
Patients will receive abiraterone alone (1000 mg once daily) for between 5 and
7 days. Blood samples will then be collected to determine the steady state PK
profile for abiraterone.
Patients will receive olaparib (300 mg bid) starting immediately after the
24-hour abiraterone PK sample has been collected. Olaparib and abiraterone will
continue to be dosed in combination for at least 3 days, then blood samples
will be collected again to determine both
olaparib and abiraterone PK profiles.
Cohort 3 (12 patients)
If 4 or more DLTs occur in Cohort 2, a further 12-patient cohort may be
recruited and treated with olaparib 200 mg bid given in addition to abiraterone
1000 mg once daily and evaluated for safety, tolerability and PK as above. If
>=4 DLTs occur in this cohort, the study will be
stopped.
Optional blood samples for pharmacogenetic research will be obtained from
consenting patients and stored for long-term exploratory purposes.
A follow-up visit will be conducted 30 days (±7 days) after the last dose of
study treatment (olaparib/placebo or abiraterone).
Intervention
The investigational product (olaparib) and additional study drugs (abiraterone
and prednisone/prednisolone) should be taken orally with water. Patients should
aim to take their doses at similar times each day, with the twice daily doses
approximately 12 hours apart.
Patients must fast (except water) from at least 2 hours before until 1 hour
after each dose (morning and evening).
Cohort 1:
200 mg olaparib (2 x 100 mg tablets) bid.
1000 mg abiraterone (4 x 250 mg tablets) once daily in the morning and
prednisone or prednisolone 5 mg (1 x 5 mg tablet) bid.
Cohort 2, Group 1:
300 mg olaparib (2 x 150 mg tablets) bid, starting on Day 1.
1000 mg abiraterone (4 x 250 mg tablets) once daily, in the morning, and
prednisone or prednisolone 5 mg bid, starting the day after completion of the
olaparib PK profiling.
Cohort 2, Group 2:
1000 mg abiraterone (4 x 250 mg tablets) once daily, in the morning, and
prednisone or prednisolone 5 mg bid, starting on Day 1.
300 mg olaparib (2 x 150 mg tablets) bid, starting after completion of the
abiraterone PK profiling (after the 24-hour sample).
Cohort 3, Groups 1 and 2 (if required):
200 mg olaparib (2 x 100 mg tablets) bid, as described for Cohort 2, Groups 1
and 2.
1000 mg abiraterone (4 x 250 mg tablets) once daily, in the morning, and
prednisone or prednisolone 5 mg bid, as described for Cohort 2, Groups 1 and 2.
Duration of treatment
Patients will continue to receive study treatment until disease progression, or
until a time when the Investigator considers that they are no longer deriving
clinical benefit, or they stop taking treatment for any other reason including
having met any of the criteria for treatment discontinuation.
Study burden and risks
Once patients with prostate cancer have progressed from an androgen-sensitive
to a castrationresistant phenotype, docetaxel is an accepted first-line
treatment, with cabazitaxel, enzalutamide and abiraterone indicated in the
post-docetaxel phase. There is a clear clinical need to enhance the care of
patients who have suffered disease progression during orfollowing docetaxel
therapy. Because of abiraterone*s effectiveness in this setting and thepromise
of PARP inhibition enhancing its effects, a randomised trial comparing olaparib
plusabiraterone to placebo plus abiraterone is appropriate.
In view of the potential for olaparib, given in addition to abiraterone, to
have anti-tumour
activity in metastatic CRPC population, the current study is designed to allow
for patients to continue on olaparib/abiraterone therapy until progression of
disease. However, patients may stop treatment at any time if they choose to do
so or if the Investigator believes it is in the best interest of the patient.
Additionally, in the event of unmanageable toxicity, directions for reducing or
stopping olaparib are provided. The assessment of HRQL will provide information
on patients* experience of the treatment and will be part of the benefit-risk
assessment.
The molecular targeting of olaparib to specific subsets of tumours may provide
an opportunity for more effective and potentially less toxic cancer treatments
in the advanced disease setting compared with currently available regimens.
Based on the available data on efficacy and safety (see the olaparib IB),
AstraZeneca believes that olaparib continues to demonstrate an overall positive
benefit-risk balance to support its further clinical development. The
benefitrisk assessment, therefore, strongly favours the current and proposed
olaparib study in patients with advanced prostate cancer.
Building 411A Floor 4
Sodertalje 15185
SE
Building 411A Floor 4
Sodertalje 15185
SE
Listed location countries
Age
Inclusion criteria
For inclusion in the study, patients should fulfil the following criteria:
1. Provision of signed and dated written informed consent prior to any study specific
procedures.
2. Male aged 18 years and older.
3. Histologically or cytologically proven diagnosis of prostate cancer.
4. Candidate for abiraterone therapy with documented evidence of metastatic
castration-resistant prostate cancer. Metastatic status is defined as at least one
documented metastatic lesion on either bone scan or CT/MRI scan. Castrationresistant
prostate cancer is defined as rising PSA or other signs of disease
progression despite treatment with androgen deprivation therapy and the presence
of a castrate level of testosterone (<=50 ng/dL).
5. Eastern Cooperative Oncology Group (ECOG) performance status 0 to 2 with no
deterioration over the previous 2 weeks.
6. Patients must have a life expectancy >=12 weeks.
7. Patients are willing and able to comply with the protocol for the duration of the
study including undergoing treatment and scheduled visits and examinations, and
completing PRO instruments.
8. Patients must be on a stable concomitant medication regimen, 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.;For the Pharmacogenetic optional study 1 extra criterion:
- provide informed consent for the pharmacogenetic sampling and analysis
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 both
AstraZeneca staff, its agents and/or staff at the study site).
2. Previous treatment in the present study.
3. Treatment with any of the following:
* Previous exposure to any 2nd generation anti-hormonal including abiraterone
and enzalutamide
* More than 2 prior courses of chemotherapy for metastatic prostate cancer
* Previous use of immunotherapy or radium-223 for the treatment of metastatic
prostate cancer
* Any investigational agents or study drugs from a previous clinical study within
30 days of the first dose of study treatment
* Any previous exposure to a CYP17 (17α-hydroxylase/C17,20-lyase) inhibitor
* Substrates of CYP2D6 with a narrow therapeutic index (eg, thioridazine)
* Potent inhibitors or inducers of CYP3A4 within 2 weeks before the first dose of
study treatment (3 weeks for St John*s Wort)
* Any previous treatment with a PARP inhibitor, including olaparib.
4. With the exception of alopecia or toxicities related to the use of gonadotropinreleasing
hormone agonists, any unresolved toxicities from prior therapy greater
than CTCAE Grade 2 at the time of starting study treatment.
5. Spinal cord compression or brain metastases unless asymptomatic, treated and
stable and not requiring steroids for at least 4 weeks prior to start of study treatment.
6. As judged by the Investigator, any evidence of severe or uncontrolled systemic
diseases, including uncontrolled hypertension, active bleeding diatheses, or active
infection including hepatitis B, hepatitis C and human immunodeficiency virus
(HIV). Screening for chronic conditions is not required.
7. Any of the following cardiac criteria:
* Mean resting QTc >470 msec obtained from 3 ECGs
* Any clinically important abnormalities in rhythm, conduction or morphology of
resting ECG eg, complete left bundle branch block, third degree heart block
* Any factors that increase the risk of QTc prolongation or risk of arrhythmic
events such as heart failure, hypokalaemia, congenital long QT syndrome,
family history of long QT syndrome or unexplained sudden death under
40 years of age or any concomitant medication known to prolong the QT
interval.
8. Other malignancy within the last 5 years except: adequately treated non-melanoma
skin cancer or other solid tumours including lymphomas (without bone marrow
involvement) curatively treated with no evidence of disease for >=5 years.
9. Inadequate bone marrow reserve or organ function as demonstrated by any of the
following laboratory values:
* Platelet count <100 x 109/L
* Haemoglobin (Hb) <100 g/L
* Aspartate aminotransferase (AST) or alanine aminotransferase (ALT)
>2.5 x upper limit of normal (ULN) if no demonstrable liver metastases or
>5 x ULN in the presence of liver metastases
* Total bilirubin >1.5 x ULN if no liver metastases or >3 x ULN in the presence
of liver metastases (except in the case of Gilbert*s disease)
* Creatinine >1.5 x ULN concurrent with creatinine clearance <50 mL/min
(measured or calculated by Cockcroft and Gault equation); confirmation of
creatinine clearance is only required when creatinine is >1.5 x ULN
* If bone metastases are present and liver function is otherwise considered
adequate by the Investigator then elevated alkaline phosphatase (ALP) will not
exclude the patient.
10. Refractory nausea and vomiting, chronic gastrointestinal diseases, inability to
swallow the formulated product or previous significant bowel resection that would
preclude adequate absorption of olaparib or abiraterone.
11. History of hypersensitivity to active or inactive excipients of olaparib or abiraterone
or drugs with a similar chemical structure or class to olaparib or abiraterone.
12. Patients with myelodysplastic syndrome/acute myeloid leukaemia.
13. Current disease or condition known to interfere with absorption, distribution,
metabolism, or excretion of drugs, at the Investigator*s discretion.
14. Major surgery within 2 weeks of starting study treatment and patients must have
recovered from any effects of any major surgery.
15. Judgment by the Investigator that the patient should not participate in the study if
the patient is unlikely;For the Pharmacogenetic optional study 2 extra criteria are set:
• Previous allogeneic bone marrow transplant.
• Non-leukocyte depleted whole blood transfusion within 120 days of the date of the
pharmacogenetic sample collection.
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 | EUCTR2013-003520-37-NL |
| ClinicalTrials.gov | NCT01972217 |
| CCMO | NL46930.068.14 |