| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Advanced or recurrent endometrial carcinoma or carcinosarcoma |
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| E.1.1.1 | Medical condition in easily understood language |
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| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10014733 |
| E.1.2 | Term | Endometrial cancer |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
The trial is evaluating two new tablet medications; cediranib and olaparib in endometrial cancer.
The principal aim of the trial is to find out whether the two new treatments, cediranib tablets with paclitaxel chemotherapy (Arm 2), and cediranib tablets with olaparib tablets (Arm 3), are more effective at treating endometrial cancer than standard paclitaxel chemotherapy (Arm 1).
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| E.2.2 | Secondary objectives of the trial |
The other main aims of the trial are to find out:
* Whether the two new treatments cause more or fewer side-effects than standard chemotherapy.
* How each of these treatments impact on the daily life of women receiving the treatment by asking trial participants to regularly complete quality-of-life questionnaires.
* Whether we can learn how these treatments work in women with endometrial cancer by taking some additional blood tests for research. We also want to genetically test some cancer biopsy samples to see if we can predict which women will benefit from olaparib treatment (Arm 3). Only some hospitals are helping us with this part of the study as we need to process the samples quickly. We will ask the permission of women allocated to Arm 3 (cediranib tablets with olaparib tablets) at participating hospitals to take a small biopsy from their cancer before they start treatment. It is optional to donate blood or tissue samples. |
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal 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 0-1.
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. |
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| E.4 | Principal 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 and potential for reactivation during treatment.
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 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:
i. true sexual abstinence (when this is in line with the preferred and usual lifestyle of the participant)
ii. a combination of male condom plus one of:
• vasectomised sexual partner, with participant assurance that partner received post-vasectomy confirmation of azoospermia
• Tubal occlusion
• Intrauterine device provided coils are copper-banded
• Etonogestrel implants (eg, Implanon®, Norplant®)
• Normal and low dose combined oral pills
• Hormonal shot or injection (eg, Depo-Provera)
• Intrauterine system device (eg, levonorgestrel-releasing intrauterine system -Mirena®)
• Norelgestromin/ethinyl estradiol transdermal system
• Intravaginal device (eg, ethinyl estradiol and etonogestrel)
• 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, impending fistulation seen on radiological imaging, 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 any of the excipients of the products.
16. Known hypersensitivity to paclitaxel that in the opinion of the investigator would prevent administration of a weekly paclitaxel regimen.
17. Exposure to an investigational agent within 30 days or 5 half-lives (whichever is the longer) prior to enrolment.
18. 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, uncontrolled major seizure disorder, unstable spinal cord compression, superior vena cava syndrome, extensive interstitial bilateral lung disease on High Resolution Computed Tomography (HRCT) scan or any psychiatric disorder that prohibits obtaining informed consent.
19. Myelodysplastic syndrome (MDS), acute myeloid leukaemia (AML) or features suggestive of MDS/AML.
20. Other malignancy within the last 5 years except: adequately treated non-melanoma skin cancer, curatively treated in situ cancer of the cervix, ductal carcinoma in situ (DCIS), or other solid tumours including lymphomas (without bone marrow involvement) curatively treated with no evidence of disease for ≥5 years.
21. Prior allogeneic bone marrow transplant or double umbilical cord blood transplantation.
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| E.5 End points |
| E.5.1 | Primary end point(s) |
| The primary outcome measure is progression-free survival (PFS) rate at three months. This is defined as the proportion of participants free from investigator assessed objective disease progression by RECIST v1.1, or death from any cause, three months from the date of randomisation. Measurable disease and non-measurable disease visible on the baseline CT scan will be identified and described by radiologists according to strict RECIST v1.1 criteria. The CT scan will be repeated at six- and twelve-weeks’ post-randomisation and the changes assessed against the baseline scan. In each trial arm, the proportion of participants who are alive and do not meet the RECIST v1.1 criteria for disease progression will be calculated out of all participants allocated to that arm. |
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Baseline at screening, and 6- and 12-weeks after randomisation. |
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| E.5.2 | Secondary end point(s) |
1. Radiological response rate assessed by RECIST v1.1.
2. Median progression-free survival (PFS) where PFS is measured as the time from date of randomisation to date of investigator-assessed objective progression via RECIST v1.1 or death from any cause in the absence of progression.
3. Six-month PFS rate, defined as the proportion of participants free from investigator assessed objective disease progression by RECIST v1.1, or death from any cause, six months from the date of randomisation.
4. Toxicities of any grade associated with each regimen as assessed by CTCAE version 4.03.
5. Median overall survival defined as the time from date of randomisation to date of death.
6. Quality of life measured using the EORTC QLQ-C30 tool and EN24 endometrial cancer-specific module.
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
1, 2. CT scans at screening, 6- and 12-weeks after randomisation, and 12-weekly after that.
3. CT scans at screening, 6-, 12-, 24-weeks after randomisation.
4. Day 1 of each 28 day cycle during treatment, and assessment 30 days after end of treatment.
5. Survival assessed at 3-monthly follow-up until end of trial or death.
6. Quality of life measured at screening, day 1 of each 28 day cycle, monthly until disease progression, and assessment 30 days after end of treatment. |
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| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | No |
| E.6.6 | Pharmacokinetic | No |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | Yes |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 3 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 15 |
| E.8.5 | The trial involves multiple Member States | No |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | No |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.7 | Trial has a data monitoring committee | No |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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| The end of the trial is defined as the date of final data capture to meet trial endpoints. The trial will end once all participants have met at least one of the criteria: completed 12 months’ follow-up (including treatment), withdrawn from follow-up, been lost to follow-up, experienced disease progression, or died. |
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| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 3 |
| E.8.9.1 | In the Member State concerned months | 0 |
| E.8.9.1 | In the Member State concerned days | 4 |
| E.8.9.2 | In all countries concerned by the trial years | 3 |
| E.8.9.2 | In all countries concerned by the trial months | 0 |
| E.8.9.2 | In all countries concerned by the trial days | 4 |
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