Familial ovarian cancer / Posted 3 years ago
Randomised phase II Trial of olaparib, chemotherapy or olaparib and cediranib in patients with BRCA mutated platinum–resistant ovarian cancer
Women with platinum resistant ovarian cancer (OC) have limited responses to standard therapy, and clinical trials with novel agents are therefore highly justified. Olaparib is a potent PARP inhibitor that has shown enhanced activity in women with relapsed BRCA-mutated OC in both platinum sensitive and resistant settings. Angiogenesis inhibitors, such as the oral tyrosine kinase inhibitor cediranib, are active in OC, and have shown additive effects when combined with PARP inhibitors preclinically, as hypoxia-induced downregulation of homologous recombination repair genes, BRCA1, 2 and RAD51 enhances PARP inhibitor sensitivity. Recent phase 2 trials in relapsed platinum-sensitive OC have also shown benefit from the combination of olaparib and cediranib compared to olaparib alone. The OCTOVA trial investigates the benefit of single agent olaparib compared to olaparib and cediranib or weekly paclitaxel in women with BRCA-mutated platinum-resistant OC.
Inclusion Criteria :
- Female patients, age 16 years or over with relapsed BRCA (germline or somatic) mutated epithelial ovarian, primary peritoneal or fallopian tube cancer who have relapsed in a platinum resistant time frame, i.e. have progressed within 6 months of previous platinum-based therapy. Their most recent chemotherapy does not have to have been platinum-based.
- Patients can have received prior PARP inhibitor and antiangiogenic therapy with bevacizumab, but there must be more than a 6 month interval since treatment.
3. Measurable disease by RECIST Version 1.1 performed in past 4 weeks. At least one lesion, not previously irradiated, that can be accurately measured at baseline as greater than or equal to 10 mm with CT or MRI.
4. Sufficient archival tissue confirming histological diagnosis available.
5. ECOGPS 0-2 6. Able to swallow and retain oral medications.
7. Life expectancy more than 12 weeks in terms of disease related mortality
8. Patient is willing and able to comply with the protocol for the duration of the study including undergoing treatment and scheduled visits and examinations including follow up.
9. Written (signed and dated) informed consent prior to any study specific procedures and be capable of co-operating with protocol.
10. Patients must have Haemoglobin greater than or equal to 10.0 g/dL and no blood transfusions in the 28 days prior to randomisation
11. Patients must have normal organ and bone marrow function measured within 14 days prior to administration of study treatment.
Exclusion Criteria :
A patient will not be eligible for the trial if any of the following apply:
- Received previous single agent weekly paclitaxel for relapsed disease.
- Pregnant or breast-feeding women or women of childbearing potential unless effective methods of contraception are used during the trial and for 6 months after stopping treatment.
- Treatment with any other investigational agent, systemic chemotherapy, or participation in another interventional clinical trial within 28 days prior to enrolment.
- Radiotherapy within 2 weeks from the last dose prior to study treatment
- Started a stable dose of bisphosphonates for bone metastases less than 4 weeks prior to treatment with study drug e.g. patient is eligible and can continue to take bisphosphonates if these were started at least 4 weeks prior to treatment with study drug.
- Concomitant use of known CYP3A4 inhibitors such as ketokonazole, itraconazole, ritonavir, indinavir, saquinavir, telithromycin, clarithromycin and nelfinavir.
- Concomitant use of potent inducers of CYP3A4 such as rifampicin, carbamazepine, phenobarbital, phenytoin and St. John Wort.
- Persistent toxicities with the exception of alopecia, caused by previous cancer therapy.
- Resting ECG with QTc greater than 470msec on 2 or more time points within a 24 hour period or family history of long QT syndrome.
- Blood transfusions within 1 month prior to study start
- Patients with myelodysplastic syndrome/acute myeloid leukaemia.
- Patients with symptomatic, untreated, uncontrolled brain or meningeal metastases or tumour.
- Major surgery within 14 days of starting study treatment
- Patients who have not recovered from any effects of any major surgery.
- Patients considered a poor medical risk due to a serious, uncontrolled medical disorder, non-malignant systemic disease or active, uncontrolled infection.
- History of inflammatory bowel disease
- History of cerebrovascular accident (including transient ischaemic attacks) within last 12 months.
- Gastro intestinal impairment that could affect ability to take, or absorption of, oral medicines including sub- acute or complete bowel obstruction
- Evidence of severe or uncontrolled cardiac disease
- Evidence of active bleeding or bleeding diathesis.
- Known treatment limiting hypersensitivity to cediranib, olaparib, paclitaxel or any of its excipients
- Other psychological, social or medical condition, physical examination finding or a laboratory abnormality
- Any other active malignancy, with the exception of adequately treated cone-biopsied in situ carcinoma of the cervix uteri and non-melanoma skin lesions, requiring treatment/or whose prognosis will prevent readout from trial endpoints.
- Patients who are known to be serologically positive for Hepatitis B, Hepatitis C or HIV.
- Immunocompromised patients.
Study start date :
Study end date :
Wales-Based Study Contact :
please speak to your clinician