None listed
Conditions
Brief summary
Study purpose The purpose of this study is to test new combinations of drugs for ovarian cancer that has come back after first-line treatment. The new combinations of treatment include olaparib given by itself, olaparib given with an antibody (durvalumab), or olaparib given with chemotherapy (cyclophosphamide) and then with an antibody (durvalumab). These new combinations may slow the progression of the cancer and delay the time until chemotherapy treatment is needed. Who is it for? You may be eligible for this study if you are a female aged over 18 years and have a histologically proven diagnosis of high-grade serous or carcinoma of the ovary, fallopian tube or peritoneum, at first asymptomatic CA125 progression which responded to platinum-based chemotherapy. Study details Participants will be randomly assigned (by chance) to one of three treatment groups. One group will receive two medications, olaparib taken by mouth twice a day, followed by durvalumab given into a vein and at the same time olaparib, then olaparib only. The second group will receive three medications, olaparib taken by mouth twice a day and at the same time cyclophosphamide taken by mouth once daily for 5 days of every week, followed by durvalumab given into a vein and at the same time olaparib, then olaparib only. The third group will receive one medication, olaparib taken by mouth twice a day. Participants will attend a number of hospital visits to give blood and answer questionnaires about their quality of life. It is hoped that this research may help people in the future who have the same kind of cancer as you have.
Interventions
Interventional
Treatment: Drugs - Olaparib is a PARP inhibitor, targeting DNA repair processes.
Treatment: Drugs - Cyclophosphamide is a chemotherapy that has been used for the treatment of ovarian cancers for many years.
Treatment: Drugs - Durvalumab is a PD-L1 inhibitor, an antibody (a type of human protein) that works by blocking a body substance called PD-L1. Blocking (inhibiting) PD-L1 helps the body’s immune system to attack cancer cells.
Patients will be randomised to:
A) Olaparib ta
Interventional Treatment: Drugs - Olaparib is a PARP inhibitor, targeting DNA repair processes. Treatment: Drugs - Cyclophosphamide is a chemotherapy that has been used for the treatment of ovarian cancers for many years. Treatment: Drugs - Durvalumab is a PD-L1 inhibitor, an antibody (a type of human protein) that works by blocking a body substance called PD-L1. Blocking (inhibiting) PD-L1 helps the body’s immune system to attack cancer cells. Patients will be randomised to: A) Olaparib tablets 300mg orally twice daily for 12 weeks, followed in the absence of progression according to RECIST 1.1 by olaparib 300 mg twice daily plus durvalumab 1500mg IV every 4 weeks for 12 cycles, followed by olaparib alone until progression; B) Olaparib 300mg twice daily plus oral cyclophosphamide 50mg daily for 5 out of 7 days a week (1000mg per 4 weeks), for 3 x four-weekly cycles over 12 weeks, followed in the absence of progression according to RECIST 1.1 by olaparib plus durvalumab (dosing schedule as above) for 12 cycles, followed by olaparib alone until progression; C) Olaparib 300mg twice daily until progression. Participant compliance with olaparib and cyclophosphamide will be determined at each clinic visit by reviewing patient diaries.
Sponsors
The University of Sydney
Study design
Allocation
Randomised controlled trial
Intervention model
Parallel
Primary purpose
Treatment
Masking
Open (masking not used) (Investigator)
Eligibility
Sex/Gender
All
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Women, aged 18 years and older, with histologically confirmed high-grade serous carcinoma of the ovary, fallopian tube or primary peritoneum. 2. Undergone prior adequate debulking surgery, as appropriate, and 1 line of platinum-based chemotherapy. Patients who received bevacizumab or hormonal therapy as part of first-line treatment are eligible. 3. Known germline BRCA1 and BRCA2 status. Both BRCA mutant and BRCA wild-type patients are eligible, but they must have normalisation of CA125 to less than upper limit of normal (ULN), defined as 35 units/mL, by the end of first-line chemotherapy. 4. CA125 progression after first-line treatment, occurring 6 months or more following the last dose of chemotherapy. Participants must have raised CA125 readings twice the ULN (greater than or equal to 70 kU/L) on 2 occasions at least 1 week apart. The following circumstances are also considered eligible: • If CA125 is less than 70 kU/L, patient must have evaluable disease on imaging (RECIST measurable or non-measurable); • In the absence of RECIST measurable disease, CA125 progression (greater than or equal to 70 kU/L) after first-line treatment occurring 4 months or more following last dose of chemotherapy is allowed. 5. No indication for immediate chemotherapy or secondary debulking surgery. 6. ECOG performance status of 0-1. 7. Confirmation of the availability of tumour tissue (FFPE) for translational studies (a cell pellet from ascites or pleural fluid is not acceptable). If no tissue is available, patients will not be eligible for this study. 8. Adequate bone marrow function (measured within 28 days prior to registration and with values within the ranges specified below): • Absolute neutrophil count equal to or greater than 1.5 x 109 /L • Platelet count equal to or greater than 100 x 109 /L • Haemoglobin equal to or greater than 100 g/L with no blood transfusion in the past 28 days • Peripheral blood smear must not show any features suggestive of myelodysplastic syndrome/acute myeloblastic leukaemia. 9. Adequate liver function, as follows: • Total bilirubin equal to or less than 1.5 x institutional upper limit of normal (ULN) • Alkaline phosphatase (ALP), equal to or less than 2.5 x ULN (or equal to or less than 5 x ULN if liver metastases AST (SGOT), ALT (SGPT are present) 10. Adequate renal function, as follows: • Serum creatinine equal to or less than 1.5 x ULN, or • Creatinine clearance greater than 50mL/min (Cockcroft-Gault Formula) 11. Willing and able to comply with all study requirements, including treatment, timing and/or nature of required assessments. 12. Signed, written informed consent prior to any study specific procedures.
Exclusion criteria
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.
Outcome results
None listed