Sponsor: University of Oxford
EudraCT number: 2016‐000559‐28
Paclitaxel, olaparib and cediranib in BRCA mutated platinum-resistant ovarian cancer.
This multi-centre, randomised, open-label phase II trial compares the activity and toxicity of chemotherapy (weekly Paclitaxel) to a novel agent Olaparib, and also Olaparib to the combination of Olaparib and Cediranib in women with advanced ovarian cancer and a gene mutation (BRCA gene). Olaparib is expected to be as active but less toxic than chemotherapy. This is the first time that the combination of Olaparib and Cediranib has been tested in women with multiply relapsed platinum resistant ovarian cancer and a BRCA mutation.
OCTOVA is being funded by an educational grant from AstraZeneca (AZ) as part of the AZ-ECMC alliance.
Open to recruitment
Target recruitment: 132 patients
Churchill Hospital Oxford
Beatson West of Scotland Cancer Centre
Royal Marsden Hospital Chelsea
Royal Marsden Hospital Sutton
A patient will be eligible for inclusion in this study if all of the following criteria apply:
1.Female patients, age 16 years 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.
2.Patients can have received prior PARP inhibitor and antiangiogenic therapy with bevacizumab, but there must be 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 ≥ 10 mm in the longest diameter (except lymph nodes which must have short axis ≥ 15 mm) with computed tomography (CT) or magnetic resonance imaging (MRI) and which is suitable for accurate repeated measurements.
4.Sufficient archival tissue confirming histological diagnosis available.
5.ECOG performance status 0-2.
6.Able to swallow and retain oral medications.
7.Life expectancy > 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 ≥ 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 as defined in the protocol.
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. Negative urine or serum pregnancy test within 28 days of study treatment, confirmed prior to treatment on day 1. Pregnancy test will be performed monthly in women of child bearing potential. Postmenopausal is defined in the protocol.
- 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.
- Concomitant use of potent inducers of UGT/PgP.
- Persistent toxicities (>=CTCAE grade 2), with the exception of alopecia, caused by previous cancer therapy.
- Resting ECG with QTc > 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 (see protocol for details).
- 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. See examples in protocol.
- Patients with increased risk of thrombotic events or who have a history of thrombotic events.
- Any psychiatric disorder that prohibits obtaining informed consent.
- If prior anthracycline or chest radiotherapy, Left Ventricular Ejection Fraction (LVEF) < institutional lower limit of normal.
- Poorly controlled hypertension (persistently elevated > 150/100mmHg, either systolic or diastolic or both, despite anti-hypertensive medication).
- 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, as defined in the protocol.
- Known hypersensitivity to cediranib, olaparib, paclitaxel or any of its excipients
- Other psychological, social or medical condition, physical examination finding or a laboratory abnormality that the Investigator considers would make the patient a poor trial candidate or could interfere with protocol compliance or the interpretation of trial results.
- Any other active malignancy, with the exception of adequately treated cone-biopsied in situ carcinoma of the cervix uteri and non-melanoma skin lesions.
- Patients who are known to be serologically positive for Hepatitis B, Hepatitis C or HIV.
- Immunocompromised patients e.g., patients who are taking immunosuppressive drugs.
- Efficacy of olaparib compared to weekly paclitaxel or the combination of olaparib and cediranib in patients with platinum resistant BRCA mutated ovarian cancer
- Safety and tolerability of the combination of olaparib and cediranib
- Overall Survival
- Objective response rate
- Pharmacokinetics (PK) of olaparib when administered alone and co-administered with cediranib
- Translational research (identification of potential biomarkers of response)