The EMBRACE study: This Phase II trial is evaluating an oral drug (Olaparib) in the treatment of HR-deficient metastatic breast cancer and relapsed ovarian cancer without BRCA1 and BRCA2 mutationsPhase 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

Exclusion

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 platinum chemotherapy for metastatic/relapsed disease, except:
a. TNBC patients where a suitable tumour tissue sample collected following receipt of platinum containing therapy is available. Neoadjuvant platinum containing therapy is also permitted providing screening is undertaken on a post-platinum tumour tissue specimen (e.g. mastectomy or local resection).
b. HGSOC patients with somatic or germline mutations in HRD genes other than BRCA1/2 may receive prior lines of non-study treatment and will be eligible after receiving previous treatment for metastatic/relapsed disease.
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 (see Section 5 for guidelines and wash out periods).
- Azole antifungals
- Macrolide antibiotics
- Protease inhibitors
16. Current toxicities (CTCAE = 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 earlystage 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 = 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 (see Appendix 3 for details).
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