| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| biliary tract carcinomas (including gallbladder cancer and cholangiocarcinomas) |
|
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 17.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10004595 |
| E.1.2 | Term | Bile duct cancer NOS |
| E.1.2 | System Organ Class | 100000004864 |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 17.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10008594 |
| E.1.2 | Term | Cholangiocarcinoma non-resectable |
| E.1.2 | System Organ Class | 100000004864 |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 17.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10017617 |
| E.1.2 | Term | Gallbladder cancer non-resectable |
| 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 |
Does the addition of cediranib to CisGem combination chemotherapy improve the progression-free survival of patients with advanced unresectable biliary tract cancer?
|
|
| E.2.2 | Secondary objectives of the trial |
Additional questions include the assessment of the effect of cediranib when added to CisGem chemotherapy on:
• Radiological response rate (by CT or MR scan, RECIST 1.1)
• Adverse Events (assessed by NCI CTCAE version 4.02)
• Biomarkers of disease activity and angiogenesis (including, but not limited to, circulating VEGF, sVEGFR2, bFGF, LDH, K-ras mutation and CA19-9)
|
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
• A histopathological/cytological diagnosis of non-resectable or recurrent/metastatic biliary tract carcinoma (intra- or extra-hepatic), gallbladder or ampullary carcinoma
• ECOG performance status 0, or 1
• Age ≥ 18
• Estimated life expectancy > 3 months
•Adequate haematological function:
o Haemoglobin ≥ 10g/dl*
o White blood cell count (WBC) ≥ 3.0 x 10*9/L
o absolute neutrophil count (ANC) ≥ 1.5 x 10*9/L
o Platelet count ≥ 10*9/L
*prior transfusions for patients with low haemoglobin are allowed
• Adequate liver function:
o Total bilirubin ≤1.5 x upper limit of normal (ULN) (except for patients with known documented cases of Gilbert’s syndrome)
o ALT and/or AST ≤ 5.0 x ULN (If liver metastases are present, ALT or AST < 5 x ULN)
o alkaline phosphatase ≤ 5 x ULN
• Adequate renal function:
o serum urea < 1.5 x ULN
o serum creatinine < 1.5 x ULN
o calculated GFR ≥ 45ml/min. If the calculated GFR is below 45, isotope EDTA confirmation of adequate renal function is required
• No evidence of active uncontrolled infection (patients on long-term antibiotics are eligible provided signs of active infection have resolved)
• Women of child-bearing potential must have a negative pregnancy test prior to study entry AND be using an adequate contraception method, which must be continued for 3 months after completion of chemotherapy
• Patient must have given written informed consent
|
|
| E.4 | Principal exclusion criteria |
• Significant haemorrhage (>30ml bleeding/episode in previous 3 months) or haemoptysis (>5 ml fresh blood) within 4 weeks of randomisation
• Patients with history of poorly controlled hypertension with resting blood pressure >150/100 mmHg in the presence or absence of a stable regimen of anti-hypertensive therapy, or patients who are requiring maximal doses of calcium channel blockers to stabilise blood pressure
• Incomplete recovery (CTCAE grade >1) from previous anti-cancer therapy (except haematological toxicity – see inclusion criteria for adequate haematological function), or alopecia
• unresolved biliary tree obstruction
• Any evidence of severe or uncontrolled systemic diseases which, in the view of the investigator, makes it undesirable for the patient to participate in the trial (e.g. unstable or uncompensated respiratory, cardiac, hepatic or renal disease)
• Untreated unstable brain or meningeal metastases. Patients with radiological evidence of stable brain metastases are eligible providing that they are asymptomatic and either do not require corticosteroids or have been treated with corticosteroids, with clinical and radiological evidence of stabilisation at least 10 days after discontinuation of steroids
• Greater than +1 proteinuria on two consecutive dipsticks taken no less than 1 week apart unless urinary protein <1.5g in a 24-hour period or protein/creatinine ratio < 1.5
• History of significant gastrointestinal impairment, as judged by the Principal Investigator that would significantly affect the absorption of cediranib
• Mean QTc with Bazetts correction >480 msec in screening ECG or history of familial long QT syndrome
• Recent (<14 days) major thoracic or abdominal surgery prior to randomisation, or a surgical incision that is not fully healed
• Pregnant or breast-feeding women
• Known hypersensitivity to cediranib or any of its excipients
• Known risk of the patient transmitting HIV, hepatitis B or C via infected blood
• Treatment with an investigational drug within 30 days prior to randomisation
• Other concomitant anti-cancer therapy (except steroids)
• Patients undergoing current treatment with curative intent
• History of prior malignancy that will interfere with the response evaluation (exceptions include in-situ carcinoma of the cervix treated by cone-biopsy/resection, non-metastatic basal and/or squamous cell carcinomas of the skin, any early stage (stage I) malignancy adequately resected for cure greater than 5 years previously)
• Any psychiatric or other disorder (eg symptomatic brain metastases) likely to impact on informed consent
• N.B. Whilst not excluded, patients with significant impaired hearing must be made aware of potential ototoxicity and may choose not to be included. If included, baseline audiograms are recommended and, in those randomised to cisplatin, should be followed by repeat audiograms prior to cycle 2
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|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Progression free survival will be defined according to RECIST criteria (version 1.1) with appropriate clinical assessment and radiological investigations and will be measured from the time of randomisation and up to at least 6 months.
The occurrence of pleural effusion or ascites confirmed by positive histology is considered as progressive disease. |
|
| 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 | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| 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 | Yes |
| 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 | 12 |
| 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 | Yes |
| 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
|
| The end of the trial will be two years after enrolment of the final patient or once all patients have progressed or died, whichever comes first. |
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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 | |
| E.8.9.1 | In the Member State concerned days | |
| 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 | 10 |
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