| Eligibility |
Inclusion Criteria:
1. Female patients, age = 16 years with relapsed epithelial ovarian, primary peritoneal
or fallopian tube cancer who have relapsed within 12 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, but there must be a > 6 month
interval since treatment.
3. Patients can have received prior antiangiogenic therapy, but there must be a > 6 month
interval since treatment; except for bevacizumab where a 6 week interval is required.
4. 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.
5. Sufficient archival tissue confirming histological diagnosis available.
6. ECOG PS 0-2
7. Able to swallow and retain oral medications.
8. Life expectancy > 12 weeks in terms of disease related mortality
9. 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.
10. Written (signed and dated) informed consent prior to any study specific procedures and
be capable of co-operating with protocol.
11. Patients must have
• Haemoglobin = 9.0 g/dL and no blood transfusions in the 28 days prior to
randomisation
12. Patients must have normal organ and bone marrow function measured within 14 days prior
to administration of study treatment as defined below:
- Absolute neutrophil count (ANC) = 1.5 x 109/L
- Platelet count > 100 x 109/L
- Total bilirubin = 1.5 x institutional upper limit of normal (ULN)
- AST (SGOT)/ALT (SGPT) = 2.5 x institutional upper limit of normal unless liver
metastases are present in which case it must be = 5x ULN
- Serum creatinine = 1.5 x institutional upper limit of normal (ULN) or calculated
creatinine clearance >50 ml/min calculated using Cockroft-Gault, Jelliffe or
Wright (see Appendix 4)
- Urine dipstick for proteinuria <2+. If urine dipstick is = 2+ on two occasions
more than one week apart then a 24-hour urine must demonstrate = 1 g of protein
in 24 hours or protein/creatinine ratio < 1.5.
Exclusion Criteria:
1. Received previous single agent weekly paclitaxel for relapsed disease.
2. 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 as:
- Amenorrheic for 1 year or more following cessation of exogenous hormonal
treatments
- LH and FSH levels in the post-menopausal range for women under 50,
- radiation-induced oophorectomy with last menses >1 year ago,
- chemotherapy-induced menopause with >1 year interval since last menses, or
surgical sterilisation (bilateral oophorectomy or hysterectomy).
3. Treatment with any other investigational agent, systemic chemotherapy, or
participation in another interventional clinical trial within 28 days prior to
enrolment.
4. Radiotherapy within 2 weeks from the last dose prior to study treatment
5. 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.
6. Concomitant use of known CYP3A4 inhibitors such as ketoconazole, itraconazole,
ritonavir, indinavir, saquinavir, telithromycin, clarithromycin and nelfinavir.
7. Concomitant use of potent inducers of CYP3A4 such as rifampicin, carbamazepine,
phenobarbital, phenytoin and St. John Wort.
8. Persistent toxicities (>=CTCAE grade 2) caused by previous cancer therapy with the
exception of alopecia.
9. Resting ECG with QTc > 470msec on 2 or more time points within a 24 hour period or
family history of long QT syndrome.
10. Blood transfusions within 1 month prior to study start
11. Patients with myelodysplastic syndrome/acute myeloid leukaemia.
12. Patients with symptomatic, untreated, uncontrolled brain or meningeal metastases or
tumour.
a. A scan to confirm the absence of brain metastases is not required. b. Patients with
radiological evidence of stable brain metastases are eligible, providing that they are
asymptomatic and: i. Do not require corticosteroids, or ii. Have previously been
treated with corticosteroids, with clinical and radiological evidence of stabilisation
at least 10 days after discontinuation of steroids iii. The patient can receive a
stable dose of corticosteroids before and during the study as long as these were
started at least 28 days prior to treatment.
13. Major surgery within 14 days of starting study treatment
14. Patients who have not recovered from any effects of any major surgery.
15. 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, uncontrolled ventricular arrhythmia, recent (within 3
months) myocardial infarction, unstable spinal cord compression (untreated and
unstable for at least 28 days prior to study entry), superior vena cava syndrome,
extensive bilateral lung disease on HRCT scan
16. Any psychiatric disorder that prohibits obtaining informed consent.
17. Left Ventricular Ejection Fraction (LVEF) < institutional lower limit of normal, when:
i. Prior treatment with anthracyclines (excluding liposomal doxorubicin) ii. Prior
treatment with trastuzumab iii. A NYHA classification of II controlled with treatment
(see Appendix 2) iv. Prior central thoracic RT, including RT to the heart v. History
of myocardial infarction within the prior 12 months
18. Poorly controlled hypertension (persistently elevated > 150/100mmHg, either systolic
or diastolic or both, despite anti-hypertensive medication)
19. History of inflammatory bowel disease
20. History of cerebrovascular accident (including transient ischaemic attacks) within
last 12 months.
21. Gastro intestinal impairment that could affect ability to take, or absorption of, oral
medicines including sub- acute or complete bowel obstruction
22. Evidence of severe or uncontrolled cardiac disease
23. Evidence of active bleeding or bleeding diathesis. Defined as significant haemorrhage
(>30mL bleeding/episode in previous 3 months) or haemoptysis (>5mL fresh blood in
previous 4 weeks)
24. Known treatment-limiting hypersensitivity to cediranib, olaparib, paclitaxel or any of
its excipients
25. 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.
26. 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.
27. Patients who are known to be serologically positive for Hepatitis B, Hepatitis C or
HIV.
28 Immunocompromised patients e.g., patients who are taking immunosuppressive drugs.
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