| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Advanced recurrent and metastatic cervical cancer. |
|
| E.1.1.1 | Medical condition in easily understood language |
| Cervical cancer which has come back or spread around the body. |
|
| 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 | LLT |
| E.1.2 | Classification code | 10008231 |
| E.1.2 | Term | Cervical cancer recurrent |
| E.1.2 | System Organ Class | 100000004864 |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10008235 |
| E.1.2 | Term | Cervical cancer stage III |
| E.1.2 | System Organ Class | 100000004864 |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10008236 |
| E.1.2 | Term | Cervical cancer stage IV |
| E.1.2 | System Organ Class | 100000004864 |
|
| 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 primary objective is to demonstrate improved Progression Free Survival (PFS) compared to placebo for patients with advanced/recurrent cervical cancer after systemic chemotherapy for advanced /recurrent disease.
|
|
| E.2.2 | Secondary objectives of the trial |
| The secondary objectives are to establish toxicity, tolerability and quality of life for patients receiving the combination of Cediranib/Olaparib compared to the placebo. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Patients over 18 years of age
2. Histologically proven carcinoma of the cervix (squamous, adenocarcinoma or mixed adeno/squamous).
3. Completion of first line platinum-based chemotherapy for advanced /recurrent disease, leading to either a complete response, partial response or stable disease.
4. ECOG performance status 0 or 1
5. Randomisation within 6 weeks of completion of chemotherapy
6. Patients may have received previous chemoradiotherapy and neoadjuvant chemotherapy given with a curative intent.
7. Creatinine Clearance ≥ 51mls/min
8. Adequate haematological and biochemical function, as follows:
Haemoglobin > 10g/dl (with no blood transfusion in the 28 days prior to randomisation) Neutrophils > 1.5 x 109/l
Platelets > 100 x 109/l
Bilirubin < 1.5 x ULN
ALT or AST/ SGOT < 3 x ULN (or ≤5 x ULN if hepatic metastases present)
Alkaline Phosphatase < 3 x ULN (or ≤5 x ULN if hepatic metastases present)
Adequate coagulation, as follows:
Prothrombin ratio (PTR) / INR ≤ 1.5 or
PTR / INR between 2.0 and 3.0 for patients on stable doses of anticoagulants
Partial thromboplastin time <1.2 x control
9. Life expectancy >12 weeks.
10. Informed written consent
11. Contrast enhanced computerised tomography (CT) scan or magnetic resonance imaging (MRI) of the abdomen and pelvis and a CT scan of the chest within 28 days prior to commencing randomisation (with RECIST 1.1)
12. Adequately controlled thyroid function, with no symptoms of thyroid dysfunction
13. Able to swallow and retain oral medications and without gastrointestinal (GI) illnesses that would preclude absorption of cediranib or olaparib.
|
|
| E.4 | Principal exclusion criteria |
1. Disease that is potentially treatable with exenterative surgery.
2. Relapse confined to the pelvis after radical surgery in circumstance where radiotherapy or chemoradiotherapy would be appropriate.
3. More than one line of prior chemotherapy for advanced/recurrent disease. Neoadjuvant chemotherapy is not counted.
4. Prior treatment with anti-angiogenic agents (with the exception of bevacizumab given as part of first line chemotherapy)
5. Persisting ≥Grade 2 CTCAE from previous anti-cancer previous systemic anti-cancer therapy except haematological toxicity (see inclusion criteria “Adequate haematological function”) and alopecia.
6. History of other malignancy within the previous 5 years except for:
Curatively treated basal cell or squamous cell carcinoma of skin; in situ cancer of the cervix, ductal carcinoma in situ of the breast or stage 1, grade 1 endometrial carcinoma.
Curatively treated other solid tumors including lymphomas (without bone marrow involvement) with no evidence of disease for ≥5 years prior to start of IPs.
7. Pregnant or lactating women.
8. Fertile woman of childbearing potential not willing to use adequate contraception (oral contraceptives, intrauterine device or barrier method of contraception in conjunction with spermicidal jelly or surgically sterile) for the study duration and at least six months afterwards
9. Evidence of uncontrolled infection. (Defined as infection that cannot be resolved readily with antibiotics prior to patient entry into the trial for example a pelvic collection)
10. History of pelvic fistulae.
11. History of abdominal fistula that has been surgically corrected within 6 months of starting treatment. Patient should be deemed low risk of recurrent fistula
12. Sub-acute or acute intestinal obstruction.
13. Major surgery within 28 days or anticipated while on study.
14. Non-healing wound, ulcer or bone fracture.
15. Active bleeding.
16. History or evidence of thrombotic or haemorrhagic disorders.
17. History of stroke or transient ischemic attack within 6 months
18. Proteinuria > 1+ on dipstick on two consecutive dipsticks taken no less than 1 week apart, unless urinary protein is <1.5g in a 24 hour period.
19. Significant cardiovascular disease (arterial thrombotic event within 12 months, uncontrolled hypertension, myocardial infarction or angina within 6 months, NYHA grade 2 or worse congestive cardiac failure, grade ≥ 3 peripheral vascular disease or cardiac arrhythmia requiring medication). Patients with rate-controlled atrial fibrillation are eligible.
20. Prolonged QTc (corrected) interval of >470ms on ECG or a family history of long QT syndrome.
21. Patients with symptomatic uncontrolled brain or meningeal metastases CNS disease
(A scan to confirm the absence of brain metastases is not required)
22. A history of poorly controlled hypertension or resting BP>140/90 mmHG in the presence or absence of a stable regimen of anti-hypertensive therapy (measurements will be made after the patient has been resting supine for a minimum of 5 minutes. Two or more readings should be taken at 2 minute intervals and averaged. If the first two diastolic readings differ by more than 5mmHG, then an additional reading should be obtained and averaged).
23. History of significant gastrointestinal impairment. Defined as active inflammatory bowel disease, bowel obstruction or any condition judged by the investigator to adversely impact on drug absorption or within 3 months prior to starting treatment.
24. Patients with myelodysplastic syndrome/acute myeloid leukaemia.
25. Evidence of any other disease, metabolic dysfunction, physical examination finding or laboratory finding giving reasonable suspicion of a disease or condition that contra-indicates the use of an investigational drug or puts the patient at high risk for treatment-related complications.
26. Patients who have been treated with potent inhibitors of CYP3A4 and 2C8 such as amiodaraone, clarithromycin, erythromycin, simvastatin, atorvastatin, lovastatin, montelukast sodium, verapamil, ketoconazole, miconazole, indinovir (and other antivirals) and diltiazem within 2 weeks of the first planned dose of cediranib will be excluded [NB These drugs are also prohibited during trial period]
27. Patients treated with CYP3A inhibitorsWithin 2 weeks of the first planned dose for strong inhibitors, and at least 1 week for moderate inhibitors.
28. Concomitant use of known strong CYP3A inducers
29. (LVEF) < lower limit of normal (LLN) per institutional guidelines, or <55%, if threshold for normal not otherwise specified by institutional guidelines
30. Patients who are known to be serologically positive for Hepatitis B, Hepatitis C or HIV, or who are receiving immunosuppressive treatment
(31. History of intra-abdominal abscess within 3 months prior to starting treatment.
32.Uncontrolled intercurrent illness
33.No prior allogeneic bone marrow transplant or double umbilical cord b |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| Primary Outcome Measure - Progression Free Survival. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Patients will be seen on a 4 weekly basis during the time they are on active treatment and will be treated until disease progression. RECIST measurements will be taken every 8 weeks either by CT or MRI scan. |
|
| E.5.2 | Secondary end point(s) |
Overall Survival
Tumour Response (RECIST v 1.1)
Quality of Life
Safety (Toxicity, SAEs)
|
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
Overall survival until trial end.
Event of interest = death from any cause
Event date = date of death
Tumour response
Patients will be seen on a 4 weekly basis during the time they are on active treatment and will be treated until disease progression. RECIST measurements will be taken every 8 weeks either by CT or MRI scan.
Quality of life
will be completed at the four weekly visits up to and only including the 28th week then stop. We will not collect QoL forms if DP is at >7 months
Safety
AE information will be collected until at least 28 days after the last dose of study therapy is administered or until all study therapy-related AEs have resolved, stabilised or been deemed irreversible.
|
|
| 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 | Yes |
| 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 | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| 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) | No |
| E.8.2.2 | Placebo | Yes |
| E.8.2.3 | Other | No |
| 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 | 26 |
| 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
|
| Unless early termination is required, the end of study will be once all patients have completed the minimum follow-up of seven months or have died/come off study for other reasons, together with sufficient time to collect outstanding data or resolve queries. The final statistical analysis will not be triggered until the end of study is reached (whether this is as planned or due to early termination) |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 1 |
| E.8.9.1 | In the Member State concerned months | 7 |
| E.8.9.1 | In the Member State concerned days | 28 |
| E.8.9.2 | In all countries concerned by the trial years | 2 |
| E.8.9.2 | In all countries concerned by the trial months | 3 |
| E.8.9.2 | In all countries concerned by the trial days | 28 |
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