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Trial registered on ANZCTR


Registration number
ACTRN12617000855325
Ethics application status
Approved
Date submitted
2/06/2017
Date registered
9/06/2017
Date last updated
21/03/2018
Type of registration
Prospectively registered

Titles & IDs
Public title
A clinical research study testing olaparib, in Homologous recombination (HR) deficient metastatic breast and relapsed ovarian cancer in patients who do not have hereditary mutations in BReast CAncer susceptibility gene 1 and gene 2 (BRCA1 and BRCA2)
Scientific title
Phase II clinical trial of the PARP inhibitor, olaparib, in HR-deficient metastatic breast and relapsed ovarian cancer in patients without germline mutations in BRCA1 and BRCA2: The EMBRACE study
Secondary ID [1] 291530 0
CTC0160
Universal Trial Number (UTN)
Trial acronym
EMBRACE study
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Triple negative breast cancer 302650 0
High grade serous ovarian cancer 302651 0
Condition category
Condition code
Cancer 302165 302165 0 0
Breast
Cancer 302166 302166 0 0
Ovarian and primary peritoneal

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Olaparib is the study intervention in this trial. Olaparib (LynparzaTM) is a poly(ADP-ribose) polymerase (PARP) inhibitor. The inactive ingredients are copovidone, colloidal silicon dioxide, mannitol, sodium stearyl fumarate, hydroxypropyl methylcellulose (hypromellose), macrogol 400 (polyethylene glycol 400), titanium dioxide, iron oxide yellow and iron oxide black.
It is provided as tablets each containing 100mg or 150mg olaparib for oral administration. administered as 300 mg orally twice daily until disease progression or unacceptable toxicity. Each bottle contains 32 tablets. Patients will be asked to return unused drug and empty drug containers at each return visit for adherence.
Olaparib should be commenced within 7 days after registration and will be continued until disease progression or unacceptable toxicity.

Intervention code [1] 297664 0
Treatment: Drugs
Comparator / control treatment
No control group
Control group
Uncontrolled

Outcomes
Primary outcome [1] 301639 0
To determine the activity of olaparib in each tumour cohort (TNBC and HGSOC), as measured by the objective tumour response rate according to RECIST v1.1 (confirmed partial or complete response).
Timepoint [1] 301639 0
Within 6 months of registration.
Objective Tumour Response Rate is defined as the proportion of evaluable patients with confirmed Complete or Partial Response according to RECIST v1.1 in each tumour cohort (TNBC and HGSOC).
Secondary outcome [1] 333384 0
To determine progression free survival (PFS) in each tumour cohort (TNBC and HGSOC).
Disease progression is defined according to RECIST v1.1
Timepoint [1] 333384 0
PFS is defined as the interval from date of registration to the date of first evidence of disease progression or death, whichever occurs first. Participants will be followed up for a minimum of 6 months and a maximum of 5 years.
Secondary outcome [2] 333385 0
To determine response rate according to cause of HR pathway deficiency (methylation vs other) in each tumour cohort (TNBC and HGSOC).
Response Rate according to HR deficiency defined as the proportion of evaluable patients with confirmed Complete or Partial Response by RECIST v1.1 according to cause of HR pathway deficiency (methylation vs other).
Timepoint [2] 333385 0
In individuals this would be best response at any time point, though it would usually be expected that any responses occur with 6 months of registration.
Secondary outcome [3] 333386 0
To determine the side effect profile according to reported adverse events.
Participants will have blood tests collected at every study visit for review of potential side effects such as kidney function and an increase in size of red blood cells. Your doctor will monitor these results during the study and refer you for further tests if they are required. If possible side effects such as nausea, diarrhoea and vomiting occur, you will be offered
medication to control these symptoms.
Timepoint [3] 333386 0
A safety assessment should be performed 30 - 42 days after the last dose of study treatment and must include any adverse events occurring within 30 days after the last dose of study treatment.
Secondary outcome [4] 333387 0
To determine the activity of olaparib in the HGSOC cohort as determined by the CA125 response according to GCIG criteria.
Timepoint [4] 333387 0
CA125 response is defined as the proportion of evaluable patients with confirmed CA125 response according to GCIG criteria in the HGSOC tumour cohort. This assessment will occur approximately 6 - 12 months after the objective tumour response rate is assessed.

Eligibility
Key inclusion criteria
1. Patients, aged 18 years and older, that are either:
a) men or women with confirmed evidence of metastatic triple negative breast cancer (TNBC) (ER- PR- HER2- by usual site assessment)
OR
b) women with confirmed evidence of relapsed high grade serous ovarian cancer (including fallopian tube cancer or primary peritoneal cancer) or high grade endometrioid ovarian cancer (HGSOC).

2. Patients meeting eligibility criteria 1a (TNBC cohort) must have received anthracycline and taxane containing chemotherapy.

3. Patients meeting eligibility criteria 1b (HGSOC cohort) must have received adjuvant platinum containing chemotherapy.

4. Tumour demonstrates genetic or epigenetic evidence of HR deficiency as reported by either by the usual site assessment or on central laboratory testing by the HR deficiency screening.

5. Target lesions according to RECIST v1.1. Patients with only non-target lesions are ineligible. Patients with rising CA125 only are ineligible.

6. Performance status of ECOG 0 - 1.

7. Adequate bone marrow function (e.g. Hb greater than or equal to 100 g/L, platelets greater than or equal to 100 x 109/L, ANC greater than or equal to 1.5 x 109/L), with no blood product transfusions or growth factors received within 28 days.

8. Adequate liver function (e.g. serum bilirubin less than or equal to 1.5 x ULN, ALT/AST less than or equal to 2.5 x ULN unless liver metastases are present in which case AST/ALT less than or equal to 5x ULN).

9. Adequate renal function (e.g. creatinine clearance greater than or equal to 50 mL/min

10. Willing and able to comply with all study requirements, including treatment, timing and/or nature of required assessments.

11. Signed, written informed consent.

Minimum age
18 Years
Maximum age
No limit
Gender
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
1. Known carriers of pathogenic or likely pathogenic germline BRCA1/2 mutations .This must be tested prior to study entry, either by the usual site assessment or on central laboratory testing by the HR deficiency screening.

2. Tumour demonstrates pathogenic or likely pathogenic germline BRCA1 or BRCA2 mutations on central laboratory testing.

3. Symptomatic uncontrolled brain metastases. A scan to confirm the absence of brain metastases is not required unless clinically indicated. The patient can receive a stable dose of corticosteroids for brain metastasis, before and during the study, as long as these were started at least 28 days prior to commencing study treatment, and provided this is not the only site of measurable disease.

4. First relapse with measurable disease on imaging within 6 months following completion of debulking and chemotherapy (HGSOC cohort only). Interval debulking and pre-operative chemotherapy will be allowed.

5. Any previous treatment for metastatic/relapsed disease, except for:
a. TNBC patients with rapidly progressive disease who cannot wait for the MPSI results may receive non-study first-line treatment, and will be eligible after receiving not more than one line of treatment for metastatic disease
b. Patients may receive a stable dose bisphosphonates or denosumab for bone metastases, before and during the study, as long as these were started at least 28 days prior to commencing study treatment.
c. Patients without somatic BRCA1/2 mutations may receive prior lines of non-study treatment, and will be eligible after receiving previous treatment for metastatic/relapsed

6. Participation in another clinical study with an investigational product within 28 days prior to commencing study treatment

7. Treatment with another anti-cancer treatment within 28 days prior to commencing study treatment.

8. Any previous treatment with a PARP inhibitor, including olaparib.

9. Known hypersensitivity to any excipients of olaparib.

10. Patients who are unable to swallow orally administered medication or have gastrointestinal disorders likely to interfere with absorption of the study medication (e.g. including but not limited to partial bowel obstruction or chronic malabsorption syndrome, Crohn’s disease and ulcerative colitis).

11. Blood transfusions within 28 days prior to commencing study treatment. Whole blood transfusions in the last 120 days prior to entry to the study (packed red blood cells and platelet transfusions are acceptable, for timing refer to inclusion criteria no.7)

12. Patients with myelodysplastic syndrome/acute myeloid leukaemia. Patients with a peripheral blood smear with features suggestive of MDS/AML are not eligible.

13. Uncontrolled seizures.

14. Known interstitial lung disease/pneumonitis.

15. Receiving the following classes of inhibitors of CYP3A4
- Azole antifungals
- Macrolide antibiotics
- Protease inhibitors

16. Current toxicities (CTCAE greater than or equal to grade 2) caused by previous cancer therapy (except alopecia or peripheral neuropathy).

17. Not recovered from the effects of major surgery, if the surgery was within 14 days prior to starting study treatment.

18. Life expectancy of less than 3 months.

19. History of another malignancy within 3 years prior to registration. Patients with or who:
a) curatively treated early stage cervical carcinoma or carcinoma in situ,
b) non-melanomatous carcinoma of the skin,
c) superficial bladder tumours (T1a [Non-invasive tumour], and Tis[Carcinoma in situ]),
d) treated thyroid papillary cancer,
e) are disease-free from other malignancies for greater than or equal to 3 years prior to registration
are eligible for this study.

20. Concurrent illness, including severe infection that may jeopardise the ability of the patient to undergo the procedures outlined in this protocol with reasonable safety.

21. Serious medical or psychiatric conditions that might limit the ability of the patient to comply with the protocol.

22. Pregnancy, lactation, or inadequate contraception. Women must be post-menopausal, infertile, or use two highly effective means of contraception. Women of childbearing potential must have a negative pregnancy test done within 7 days prior to registration. Men must have been surgically sterilised or use a double barrier method of contraception.

23. Patients with a known hypersensitivity to olaparib or any of the excipients of the product.

24. Previous allogenic bone marrow transplant or double umbilical cord blood transplantation (dUCBT)

25. Resting ECG with QTc > 470 msec on 2 or more time points within a 24 hour period or family history of long QT syndrome

Study design
Purpose of the study
Treatment
Allocation to intervention
Non-randomised trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Single group
Other design features
Phase
Phase 2
Type of endpoint(s)
Safety/efficacy
Statistical methods / analysis
A two-stage Simon design will be used for enrolment of patients in each cohort (15 in stage 1 and 15 in stage 2). This sample size of 30 patients per cohort (60 total) will give 80% power and 95% confidence to exclude response rates of 10% and 15% in favour of an informative rate of 30% and 35% for the breast and ovarian cohorts respectively.
The primary analysis will be a calculation of the Objective Tumour Response Rate (OTRR) in each tumour cohort according to RECIST v1.1 (proportion of evaluable patients with confirmed Complete or Partial Response).

Recruitment
Recruitment status
Recruiting
Date of first participant enrolment
Anticipated
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
NSW,QLD,WA,VIC
Recruitment hospital [1] 7980 0
St George Hospital - Kogarah
Recruitment hospital [2] 7981 0
Westmead Hospital - Westmead
Recruitment hospital [3] 7982 0
Peter MacCallum Cancer Centre - Melbourne
Recruitment hospital [4] 8061 0
Icon Cancer Care Wesley - Auchenflower
Recruitment hospital [5] 8062 0
Royal Brisbane & Womens Hospital - Herston
Recruitment hospital [6] 9402 0
Mercy Hospital for Women - Heidelberg
Recruitment hospital [7] 9403 0
Fiona Stanley Hospital - Murdoch
Recruitment postcode(s) [1] 15955 0
2217 - Kogarah
Recruitment postcode(s) [2] 15956 0
2145 - Westmead
Recruitment postcode(s) [3] 15957 0
3000 - Melbourne
Recruitment postcode(s) [4] 16102 0
4066 - Auchenflower
Recruitment postcode(s) [5] 16103 0
4029 - Herston
Recruitment postcode(s) [6] 18102 0
3084 - Heidelberg
Recruitment postcode(s) [7] 18103 0
6150 - Murdoch

Funding & Sponsors
Funding source category [1] 296019 0
Government body
Name [1] 296019 0
Cancer Australia
Address [1] 296019 0
Level 14,
300 Elizabeth Street
Surry Hills NSW 2000
Country [1] 296019 0
Australia
Primary sponsor type
University
Name
University of Sydney
Address
NHMRC Clinical Trials Centre
Lifehouse Level 6
119–143 Missenden Road
Camperdown NSW 2050
Country
Australia
Secondary sponsor category [1] 295360 0
None
Name [1] 295360 0
Address [1] 295360 0
Country [1] 295360 0
Other collaborator category [1] 279565 0
Other Collaborative groups
Name [1] 279565 0
Australia New Zealand Gynaecological Oncology Group (ANZGOG)
Address [1] 279565 0
Australia New Zealand Gynaecological Oncology Group
Level 6, Chris O'Brien Lifehouse
119-143 Missenden Road
CAMPERDOWN NSW 2050
Country [1] 279565 0
Australia
Other collaborator category [2] 279566 0
Other Collaborative groups
Name [2] 279566 0
Breast Cancer Trials
Address [2] 279566 0
Australia & New Zealand Breast Cancer Trials Group
PO Box 283
THE JUNCTION NSW 2291
Country [2] 279566 0
Australia

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 297281 0
SLHD Ethics Review Committee (RPAH Zone)
Ethics committee address [1] 297281 0
c/o Research Development Office
Royal Prince Alfred Hospital
Missenden Road
CAMPERDOWN NSW 2050
Ethics committee country [1] 297281 0
Australia
Date submitted for ethics approval [1] 297281 0
15/05/2017
Approval date [1] 297281 0
27/07/2017
Ethics approval number [1] 297281 0

Summary
Brief summary
This study is testing olaparib, in Homologous recombination (HR) deficient metastatic breast and relapsed ovarian cancer in patients who do not have hereditary mutations in BReast CAncer susceptibility gene 1 and gene 2 (BRCA1 and BRCA2).

Who is it for?
You may be eligible to join this study if you are aged 18 years or above and are either: a) men or women with confirmed evidence of metastatic triple negative breast cancer OR b) women with confirmed evidence of relapsed high grade serous ovarian cancer or high grade endometrioid ovarian cancer

Study details
All study participants will take olaparib 300 mg orally twice daily until disease progression or unacceptable toxicity. Assessments for safety and efficacy will be followed up for a minimum of 6 months

Olaparib, has been approved overseas and in Australia in women shown to have inherited changes in their BRCA1 or 2 genes. There is strong evidence to show that olaparib will also work in people who do not have any changes in their genes. The purpose of this study is to assess whether the olaparib is effective in treating these tumours.

Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 73562 0
Dr Katrin Sjoquist
Address 73562 0
NHMRC Clinical Trials Centre
92-94 Parramatta Road
Camperdown NSW 2050
Country 73562 0
Australia
Phone 73562 0
+61-2-9562-5000
Fax 73562 0
Email 73562 0
embrace@ctc.usyd.edu.au
Contact person for public queries
Name 73563 0
Ms Sarah Chinchen
Address 73563 0
NHMRC Clinical Trials Centre
Locked bag 77,
Camperdown NSW 1450
Country 73563 0
Australia
Phone 73563 0
+61-2-9562-5000
Fax 73563 0
Email 73563 0
embrace@ctc.usyd.edu.au
Contact person for scientific queries
Name 73564 0
Ms Sarah Chinchen
Address 73564 0
NHMRC Clinical Trials Centre
Locked bag 77,
Camperdown NSW 1450
Country 73564 0
Australia
Phone 73564 0
+61-2-9562-5000
Fax 73564 0
Email 73564 0
embrace@ctc.usyd.edu.au

No data has been provided for results reporting
Summary results
Not applicable