Advanced/metastatic endometrial cancer Cancer Advanced/metastatic endometrial cancer
Conditions
Interventions
Participants are randomised into one of the three study arms to receive treatment.
Arm 1 (control): Paclitaxel will be administered at 80 mg/m2 IV on days 1, 8 and 15 of a 28-day cycle for 6 cycles.
Sponsors
University of Manchester
Eligibility
Sex/Gender
Female
Age
16 Years to 100 Years
Inclusion criteria
Inclusion criteria: 1. Histologically confirmed advanced or recurrent endometrial carcinoma or carcinosarcoma 2. Aged >16 years 3. One prior line of platinum-containing chemotherapy for advanced/ recurrent disease or relapse within 12 months of adjuvant platinum-based chemotherapy 4. Ability to provide written informed consent that includes genetic research on tissue derived from biopsies and biomarker research. (If a participant declines to participate in optional exploratory genetic research or the optional biomarker research, there will be no penalty or loss of benefit to the participant. The participant will not be excluded from other aspects of the study). 5. Willing and able to comply with the trial visits and undergo treatment as scheduled 6. ECOG Performance Status 0-2 7. Life expectancy greater than 16 weeks 8. Measurable disease by RECIST v1.1 including at least one not previously irradiated lesion that is = 10 mm in the longest diameter (lymph nodes must have short axis = 15 mm) as determined by CT 9. Adequate haematological function: Hb = 100.0 g/l with no requirement for blood transfusion in the last 28 days, neutrophils = 1.5 x 109/l, platelets = 100 x 109/l; coagulation: INR <1.4 (unless therapeutically anti-coagulated) and APPT ratio <1.4 10. Adequate liver function: bilirubin =1.5 x ULN, transaminases (ALT and AST =2.5x ULN. AST or ALT <5x ULN allowed in the presence of parenchymal liver metastases 11. Adequate renal function defined as calculated creatinine clearance using modified Wright or Cockcroft-Gault formula = 51 ml/min or measured radioisotopic GFR = 51ml/min 12. Urine protein:creatinine ratio (UPC) =1 OR =2+ proteinuria on two consecutive dipsticks taken no less than 1 week apart. Patients with 2+ proteinuria on dipstick must also have UPC <0.5 on 2 consecutive samples 13. Adequately controlled thyroid function, with no symptoms of thyroid dysfunction 14. Ability to swallow oral medication (tablets) 15. Willing to stop taking herbal supplements, and (if allocated to Arm 3) willing to not consume grapefruit or grapefruit juice, during the treatment period and for 30 days after end of trial treatment
Exclusion criteria
Exclusion criteria: 1. Uncontrolled brain metastases or seizures. A scan to confirm the absence of brain metastases is not required 2. Known positivity for hepatitis B, hepatitis C or HIV due to the risk of transmitting the infection through blood or other body fluids. 3. Resting ECG with QTc > 470 ms on 2 or more time points within a 24 hour period or family history of long QT syndrome 4. Concomitant use of known strong CYP3A inhibitors (eg. itraconazole, telithromycin, clarithromycin, protease inhibitors boosted with ritonavir or cobicistat, indinavir, saquinavir, nelfinavir, boceprevir, telaprevir) or moderate CYP3A inhibitors (eg. ciprofloxacin, erythromycin, diltiazem, fluconazole, verapamil). The required washout period prior to starting olaparib is two weeks 5. Concomitant use of known strong (eg.phenobarbital,enzalutamide, phenytoin, rifampicin, rifabutin, rifapentine, carbamazepine, nevirapine and St John’s Wort) or moderate CYP3A inducers (eg. bosentan, efavirenz, modafinil). The required washout period prior to starting olaparib is 5 weeks for enzalutamide or phenobarbital and 3 weeks for other agents. 6. Pregnant or lactating. Pregnancy status in women of child bearing potential will be confirmed via a serum or urine pregnancy test no more than one week prior to randomisation, monthly during the treatment period, and at the end of treatment assessment. 7. Of child bearing potential AND not willing to ensure they use effective contraception throughout the treatment period and for six months following the end of treatment. Acceptable methods of contraception are: 7.1. True sexual abstinence (when this is in line with the preferred and usual lifestyle of the participant) 7.2. A combination of male condom plus one of the following: 7.2.1. Vasectomised sexual partner, with participant assurance that partner received post-vasectomy confirmation of azoospermia 7.2.2. Tubal occlusion 7.2.3. Intrauterine device provided coils are copper-banded 7.2.4. Etonogestrel implants (eg, Implanon®, Norplant®) 7.2.5. Normal and low dose combined oral pills 7.2.6. Hormonal shot or injection (eg, Depo-Provera) 7.2.7. Intrauterine system device (eg, levonorgestrel-releasing intrauterine system -Mirena®) 7.2.8. Norelgestromin/ethinyl estradiol transdermal system 7.2.9. Intravaginal device (eg, ethinyl estradiol and etonogestrel) 7.2.10. Cerazette (desogestrel). Cerazette is currently the only highly efficacious progesterone based pill. 8. Side effects of previous treatments have not resolved to grade 1 or less, with the exception of alopecia that is considered related to cytotoxic chemotherapy 9. Radiotherapy, chemotherapy, surgery or tumour embolisation within 28 days before the first dose of IMP 10. Additional concurrent anti-cancer therapy 11. Causes of malabsorption, e.g. uncontrolled diarrhoea or poorly controlled stoma 12. Bowel obstruction, fistulae, or extensive rectosigmoid involvement by cancer 13. Inadequately controlled hypertension, defined as =150/90 mmHg 14. Prior or concurrent therapy with a PARP or VEGF inhibitor 15. Known hypersensitivity to olaparib, cediranib or paclitaxel or any of the excipients of the products 16. Exposure to an investigational agent within 30 days or 5 half-lives (whichever is the longer) prior to enrolment 17. 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 arrhyth
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Proportion of participants who are disease progression free at three months as determined by CT scan (RECIST v1.1 reporting) at three months. | — |
Secondary
| Measure | Time frame |
|---|---|
| 1. Radiological response rate during the trial assessed by CT scan (RECIST v1.1 reporting) 2. Median time until disease progression 3. Proportion of participants who are disease progression free at six months as determined by CT scan (RECIST v1.1 reporting) at six months 4. The median overall survival time, calculated as median time from participant enrolment to death with those still alive censored at date last seen 5. All toxicities associated with each treatment regimen as assessed by CTCAE version 4.03 monthly until disease progression, and at the end of treatment 6. Quality of life as measured by the EORTC QLQ-C30 and EN28 questionnaires at the start of the trial, monthly until disease progression, and at the end of treatment | — |
Countries
England, Scotland, United Kingdom, Wales
Contacts
Public ContactClare Freestone
Outcome results
None listed