SOLACE 2: This Phase II trial is comparing the effectiveness of a chemotherapy drug (Olaparib) alone and as part of a combination therapy in patients with recurrent ovarian, fallopian tube or primary peritoneal cancers that have homologous recombination repair defectsA Phase II randomised trial comparing immune priming by low dose oral cyclophosphamide plus olaparib versus priming by olaparib alone, prior to combination therapy with olaparib plus durvalumab, versus single agent olaparib alone, in asymptomatic platinum-sensitive recurrent ovarian, fallopian tube or primary peritoneal cancers with homologous recombination repair defects

Exclusion

1. Previous randomisation in the present study.
2. Any previous treatment with a PARP inhibitor, including olaparib.
3. Any previous treatment with durvalumab, or any other anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CTLA-4 antibodies or any other antibody or drug specifically targeting T cell co-stimulation or immune checkpoint pathways.
4. Concomitant use of known strong CYP3A inhibitors (e.g. itraconazole, telithromycin, clarithromycin, protease inhibitors boosted with ritonavir or cobicistat, indinavir, saquinavir, nelfinavir, boceprevir, telaprevir) or moderate CYP3A inhibitors (e.g. ciprofloxacin, erythromycin, diltiazem, fluconazole, verapamil). The required washout period prior to starting olaparib is 2 weeks.
5. Concomitant use of known strong (e.g. phenobarbital, enzalutamide, phenytoin, rifampicin, rifabutin, rifapentine, carbamazepine, nevirapine and St John’s Wort) or moderate CYP3A inducers (e.g. bosentan, efavirenz, modafinil). The required washout period prior to starting olaparib is 5 weeks for enzalutamide or phenobarbital and 3 weeks from the last study dose for other agents.).
6. Treatment with any investigational product during the last 14 days (or a longer period depending on the defined characteristics of the agents used).
7. Patients receiving any systemic anti-cancer treatment (including endocrine therapy, chemotherapy or VEGF-targeted agents) or radiotherapy (except for palliative reasons), within 14 days from the last dose prior to study treatment (or a longer period depending on the defined characteristics of the agents used).
8. 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).
9. Suspected brain or leptomeningeal metastases, untreated brain metastases or current clinical or radiological progression of known brain metastases, or requirement for steroid therapy for brain metastases. Patients with treated brain metastases are eligible if they have been stable and off steroids for equal to or greater than 3 weeks.
10. Patients with known haemorrhagic cystitis.
11. No history of other active malignancy.
12. History of known or suspected auto-immune disease other than vitiligo, type 1 diabetes, residual hypothyroidism due to an autoimmune condition requiring only hormone replacement, or psoriasis not requiring systematic treatment within the last 2 years.
13. Prior allogeneic organ transplant, double umbilical cord blood transplantation, inflammatory bowel disease (e.g. Crohn’s disease, ulcerative colitis), pneumonitis, tuberculosis, or primary immunodeficiency.
14. Patients with prior diagnosis of myelodysplastic syndrome or acute myeloid leukaemia. Any abnormal blood films at baseline need to be reviewed to exclude these conditions.
15. Current or prior use of immunosuppressive medication within 28 days before the first dose of durvalumab, with the exception of intranasal and inhaled corticosteroids or systemic corticosteroids at physiological doses, which are not to exceed 10 mg/day of prednisone or an equivalent corticosteroid. In the case of short term use of systemic corticosteroids (less than 24 hours within 28 days) of greater than 10 mg/day of prednisone or an equivalent corticosteroid, the required washout period prior to starting the first dose of durvalumab is 7 days.
16. Receipt of live attenuated vaccination within 30 days before the first dose of durvalumab.
17. Whole blood transfusions in the last 120 days prior to entry to the study (packed red blood cells and platelet transfusions are acceptable outside of 28 days prior to registration).
18. Patients with documented serologically positive hepatitis B or C (defined as positive result for hepatitis B core antibody or hepatitis C antibody).
19. Patients who are known to be serologically positive for human immunodeficiency virus (HIV).
20. Within 28 days of registration, patients must have two ECG assessments within a 24 hour period. Patients must not have a resting ECG with a QTc interval of >470 msec or a family history of long QT syndrome.
21. Patients considered a poor medical risk due to a serious, uncontrolled medical disorder, non-malignant systemic disease or active, uncontrolled infection. Examples include, but are not limited to, symptomatic congestive heart failure, uncontrolled hypertension, uncontrolled ventricular arrhythmia, recent (within 3 months) myocardial infarction, unstable angina pectoris, uncontrolled major seizure disorder, unstable spinal cord compression, superior vena cava syndrome, extensive interstitial bilateral lung disease on High Resolution Computed Tomography (HRCT) scan, active peptic ulcer disease or gastritis, active bleeding diathesis, or any psychiatric disorder/social situation that would limit compliance with study requirements or compromise the ability of the subject to give written informed consent.
22. Major surgical procedure within 14 days prior to study treatment, or still recovering from any effects of major surgery.
23. Any unresolved toxicity NCI CTCAE Grade >1 from previous anticancer therapy. Subjects with Grade equal to or less than 2 neuropathy or Grade equal to or less than 2 alopecia are exceptions to this criterion.
24. Patients with known hypersensitivity to cyclophosphamide or any excipients of olaparib, cyclophosphamide or durvalumab.
25. Life expectancy of less than 12 months.
26. Pregnancy, lactation, or inadequate contraception. Most patients would have undergone prior oophorectomy and hysterectomy as part of surgical treatment for ovarian cancer. For women who have ovaries and uterus in situ, they must be post-menopausal, infertile, or use a reliable means of contraception. Women of childbearing potential must have a negative pregnancy test done within 7 days prior to registration.