Progressive, platinum-resistant or refractory, high-grade ovarian, fallopian tube or primary peritoneal cancer with high risk of bowel obstruction. Cancer Progressive, platinum-resistant or refractory, high-grade ovarian, fallopian tube or primary peritoneal cancer with high risk of bowel obstruction.
Conditions
Interventions
This is a single-arm trial where participants with recurrent platinum-resistant ovarian cancer and clinical and/or radiological features indicating an increased risk of developing subacute bowel obstr
Sponsors
University of Manchester
Eligibility
Sex/Gender
Female
Inclusion criteria
Inclusion criteria: 1. Histologically confirmed, progressive, platinum-resistant or refractory, high-grade ovarian, fallopian tube or primary peritoneal cancer for which weekly paclitaxel would be a potential treatment option 2. Aged 16 years or over 3. Patients who are at risk of bowel obstruction are eligible for the trial. Features that are compatible with this diagnosis include increasing abdominal pain and swelling, borborygmi, change in bowel habit, extensive serosal disease or dilated or tethered bowel on radiological investigation. It is anticipated that one or more of these should be present in eligible patients. Previous bowel obstruction is permitted providing patients can take oral medication and there is no concern about absorption of oral medication. Recto sigmoid involvement is permitted. 4. Adequate haematological function: Hb = 100 g/l, Neutrophils = 1.5 x 109/l, Platelets = 100 x 109/l; coagulation: INR <1.4 (unless therapeutically anti-coagulated) and/or APPT ratio <1.4 5. Adequate renal function defined as GFR =50ml/min and Creatinine clearance =50 mL/min using modified Wright or Cockcroft-Gault formula 6. Adequate liver function: bilirubin = 1.5 xULN, transaminases = 3 xULN 7. Any number of previous anti-cancer treatments permitted including weekly paclitaxel in the first-line setting 8. Controlled hypertension permitted. Patients must have a blood pressure (BP) of = Systolic BP (SBP) :150/ Diastolic BP (DBP) 90 mmHg, with or without anti-hypertensive medication. BP measurements must be taken in the clinic setting by a medical professional within 2 weeks prior to starting study. A maximum of 3 anti-hypertensive medications are permitted and it is strongly recommended that patients who are on 3 anti-hypertensive medications be followed by a cardiologist or a primary care physician for management of BP while on study. 9. ECOG performance status 0-2 and life expectancy of over 12 weeks 10. Adequately controlled thyroid function, with no symptoms of thyroid dysfunction 11. Measurable disease by RECIST 1.1 12. Previous bevacizumab is permitted but patients cannot have been treated with VEGF RTKi previously 13. Written informed consent 14. Able to swallow and retain oral medications and without gastrointestinal (GI) illnesses that would preclude absorption of cediranib or olaparib
Exclusion criteria
Exclusion criteria: 1. Patients with a known hypersensitivity to olaparib, cediranib or paclitaxel or any of the excipients of the products 2. Concurrent medical illness that would impact on compliance with the protocol including myelodysplastic syndrome (MDS)/ acute myeloid leukaemia (AML) or with features which suggestive of MDS/AML 3. Uncontrolled brain metastases or seizures. A scan to confirm the absence of brain metastases is not required. Central nervous system metastases: 3.1. Symptomatic uncontrolled brain metastases requiring corticosteroid treatment 3.2. History of spinal cord compression unless after definitive treatment the patient has clinically stable disease (SD) for at least 28 days prior to starting IMPs. In the absence of these features and in an asymptomatic patient a scan to confirm the absence of brain metastases is not required. 4. Known positivity for Hep B, Hep C or HIV 5. Resting ECG with QTc > 470msec on 2 or more time points within a 24- hour period or family history of long QT syndrome 6. Concomitant use of known strong CYP3A4/5 inhibitors such as such as ketoconazole, itraconazole, ritonavir, indinavir, saquinavir, telithromycin, clarithromycin and nelfinavir. Concomitant use of inducers or inhibitors (e.g., phenobarbital, phenytoin, rifampicin, rifabutin, rifapentine, carbamazepine, nevirapine and St John's Wort) is also excluded. The required washout period prior to starting olaparib is 2 weeks. 7. 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 for other agents. 8. Another cancer, which has been active within the previous 5 years, except for adequately treated cone-biopsied in situ carcinoma of the cervix uteri and basal or squamous cell carcinoma of the skin and no evidence of recurrence of other malignancy 9. Female patients who are able to become pregnant (or are already pregnant or lactating) unless the following apply: Those who have a negative serum or urine pregnancy test before enrolment and agree to use two highly effective forms of contraception (oral, injected or implanted hormonal contraception and condom, have an intra-uterine device and condom, diaphragm with spermicidal gel and condom) for four weeks before entering the trial, during the trial and for six months afterwards are considered eligible. Alternatively if the patient can abstain from sexual intercourse for the same interval, then they are eligible to participate. 10. Patients who are planning to receive maintenance bevacizumab 11. Radiotherapy, surgery or tumour embolization within 28 days before the first dose of cediranib 12. No additional concurrent anti-cancer therapy is permitted 13. No cause of malabsorption e.g. uncontrolled diarrhoea or poorly controlled stoma, is permitted 14. Patients who have or have had prior leukoencephalopathy, recent (within the past 6 months) arterial thromboembolic event (MI/CVA within previous 6 months), previous or concurrent fistula, previous or concurrent GI perforation, concurrent intra-abdominal abscess, previous VEGF RTKi or clinically relevant proteinuria, are excluded 15. Inability to comply with the protocol 16. Major surgery within two weeks of starting study treatment and patients must have recovered from any effects o
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Safety of combining cediranib with weekly paclitaxel is measured by the analysis of the number participants who are free of grade III-V gastrointestinal of perforation and fistula, which is causally related to cediranib or the cediranib olaparib combination, during cediranib treatment for up to 4 weeks after stopping cediranib. | — |
Secondary
| Measure | Time frame |
|---|---|
| 1. The proportion of participants hospitalised for bowel obstruction 2. The number of grade III or more toxicities excluding gastrointestinal perforation/ fistula as assessed by CTCAE 4.03. 3. Treatment compliance, as assessed by the dose intensity of paclitaxel, cediranib and, expressed as the {[total delivered dose/actual time taken to complete therapy]/ [standard dose/planned time to complete therapy]} x (actual number of cycle /planned number of cycles), and the dose intensity of cediranib and olaparib treatment, expressed as [number of days’ drug was taken correctly x 100/ number of days for which drug was prescribed] 4. Investigator-determined Objective Response Rate assessed by RECIST 1.1 within 18 weeks of starting paclitaxe 5. Progression Free Survival measured as the time from date of registration to date of investigator-assessed objective progression via RECIST v1.1 or death from any cause in the absence of progression 6. Overall survival defined as the time from date of registration to date of death | — |
Countries
England, United Kingdom
Contacts
Public ContactAnn White
Outcome results
None listed