Primary:To compare the efficacy of olaparib when given in addition to abiraterone, with placebo givenin addition to abiraterone, by assessment of radiologic progression-free survival (rPFS) usingResponse Evaluation Criteria in Solid Tumours version…
ID
Source
Brief title
Condition
- Reproductive neoplasms male malignant and unspecified
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
• Efficacy
* rPFS, defined as the time from randomisation to disease progression according
to RECIST 1.1 (for soft tissue disease) and/or PCWG-2 criteria (for bone
disease), or death.
Secondary outcome
• Efficacy
* Overall survival (OS)
* Time to second progression (PFS2)
* Tumour response in terms of ORR (malignant soft tissue response and overall
radiological response [malignant soft tissue response by RECIST 1.1 and overall
radiological response by RECIST 1.1 and PCWG-2])
* TFST for prostate cancer and TSST for prostate cancer
• Safety and tolerability
* Assessment of AEs graded by CTCAE v4.0, vital signs (including blood
pressure, pulse), and evaluation of laboratory parameters (clinical chemistry
and haematology).
• Biomarkers
* Percentage change from baseline in PSA levels and PSA response
* Change in CTC numbers
* ERG expression/fusion and BRCA status; if the number of events in these
groups is sufficient then the primary analysis of rPFS will be repeated in all
ERG expression/fusion-positive and BRCA mutation patients.
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 compare the efficacy of olaparib when given in addition to abiraterone, with
placebo given
in addition to abiraterone, by assessment of radiologic progression-free
survival (rPFS) using
Response Evaluation Criteria in Solid Tumours version 1.1 (RECIST 1.1) and
Prostate Cancer
Working Group 2 (PCWG-2) criteria.
Secondary:
To compare the safety and tolerability of olaparib when given in addition to
abiraterone, with placebo given in addition to abiraterone.
To assess the anti-tumour activity of olaparib when given in addition to
abiraterone, compared with placebo given in addition to abiraterone, by
measurement of changes in circulating prostate specific antigen (PSA) and
circulating tumour cells (CTCs), calculation of overall radiological objective
response rate (ORR) (by RECIST 1.1 and PCWG-2 bone scan criteria) and malignant
soft tissue ORR (by RECIST 1.1), time to first subsequent therapy (TFST) for
prostate cancer, and time to second subsequent therapy (TSST) for prostate
cancer.
To assess the efficacy of olaparib when given in addition to abiraterone,
compared with placebo given in addition to abiraterone, by assessment of
overall survival (OS).
To assess the efficacy of olaparib when given in addition to abiraterone,
compared with placebo given in addition to abiraterone, by assessment of time
from randomisation to second progression (PFS2).
To investigate BRCA and ATM mutations as candidate predictors of response to
olaparib.
Study design
This is a study in patients with metastatic CRPC. Part B is a randomised,
double-blind, placebocontrolled comparison of the efficacy, safety and
tolerability of the dose of olaparib selected from Part A when given in
addition to abiraterone, versus placebo given in addition to abiraterone.
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.
Part B: Randomised part
Patients who have been dosed in Part A of the study may not participate in Part
B.
Patients will receive olaparib or placebo (randomisation ratio 1:1), at the
dose of 300 mg bid (determined by Part A), and abiraterone 1000 mg once daily.
They will attend the clinic on the first day of study treatment, then every 4
weeks up to Week 52, and every 12 weeks thereafter.
Tumour evaluation using RECIST 1.1 and PCWG-2 criteria will be conducted at
screening and then every 12 weeks from the date of randomisation until
objective disease progression (every 24 weeks after Week 72). Patients will be
evaluated until disease progression regardless of whether study treatment is
discontinued, and will then be followed for PFS2 and survival.
An archival tumour sample will be collected, where available, to measure ERG
expression/fusion status and BRCA mutation; other biomarkers such as androgen
receptor (AR) and phosphatase and tensin homolog (PTEN) may also be measured.
Blood samples will be collected for measurement of the following:
• PSA
• Biomarkers: where assays are available for measuring markers as a surrogate
for tumour tissue (urine also may be tested)
• CTCs: enumeration and characterisation where assays are available for
measuring markers as a surrogate for tumour tissue.
Patient reported outcomes (PROs) will be measured using the Brief Pain
Inventory - Short Form (BPI-SF), an individual item on bone pain and the FACT-P
(Functional Assessment of Cancer Therapy - Prostate Cancer) questionnaires.
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).
300 mg olaparib or placebo (2 x 150 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.
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
postdocetaxel 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
benefit-risk assessment, therefore, strongly favours the current and proposed
olaparib study in patients with advanced prostate cancer.
Building 411A Floor 4
Södertälje 15185
SE
Building 411A Floor 4
Södertälje 15185
SE
Listed location countries
Age
Inclusion 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. Castration
resistant 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.
9. For the randomised phase only, patients must have received chemotherapy in
the form of docetaxel treatment for metastatic castration-resistant prostate
cancer. Note: patients who discontinued docetaxel for toxicity reasons and
without completing the full course will still be eligible to enter this study
provided they received at least 2 cycles of chemotherapy. Provide informed
consent for the pharmacogenetic sampling and analyses.
Exclusion criteria
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:* Absolute neutrophil count (ANC) <1.5 x
109/L* 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 to comply with study procedures, restrictions
and requirements.
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 | NL49745.068.14 |