| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Locally advanced biliary tract cancer |
|
| 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 | 21.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10004586 |
| E.1.2 | Term | Bile duct adenocarcinoma non-resectable |
| 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 | 10008594 |
| E.1.2 | Term | Cholangiocarcinoma 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 |
Feasibility:
The main objective of the feasibility part of the trial is to determine if it is feasible to deliver SBRT in a multicentre trial setting in a rare disease. In particular, will clinicians recruit to the trial and will sufficient patients accept randomisation.
Phase II:
The main objective of this trial to find out if giving SBRT after chemotherapy is better than giving chemotherapy on its own to treat patients with locally advanced biliary tract cancer (BTC). |
|
| E.2.2 | Secondary objectives of the trial |
Feasibility:
Compare the side effects in each arm
To find out if giving SBRT after chemotherapy is better than giving chemotherapy on its own
To find out if giving chemotherapy followed by SBRT can make disease which is inoperable operable following treatment
To compare the quality of life in each arm
Phase II
Compare the side effects in each arm
To find out if giving chemotherapy followed by SBRT can make disease which is inoperable operable following treatment
To compare the quality of life in each arm
|
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. A histopathological/cytological diagnosis of locally advanced, non-resectable biliary tract carcinoma (intra- or extra-hepatic), (excluding cancer of the gall bladder and ampullary carcinoma)
2. Not suitable for radical surgery, or medically unfit for surgery as decided by a hepatobiliary MDT
3. Tumour visible on cross-sectional imaging
4. Measurable disease (according to RECIST criteria v1.1). (If disease is not measurable using RECIST v1.1, the tumour must be visible for targeting with radiation).
5. Tumour (and nodes if involved) must be ≤12 cm in the longest dimension. For patients with non-measurable disease, sites should use the CT reconstructions (coronal or sagittal views) to measure tumour size.
6. Adequate biliary drainage
7. WHO PS 0 or 1
8. Adequate haematological function:
• Haemoglobin ≥ 100 g/L (the use of transfusion to achieve desired Hb is acceptable)
• White blood cell count (WBC) ≥ 3.0 x 109/L
• Absolute neutrophil count (ANC) ≥1.5 x 109/L
• Platelet count ≥ 100 x 109/L
9. Adequate liver function:
• Total bilirubin ≤3.0 x ULN. Total bilirubin levels must be considered stable by the treating clinician e.g. more than one reading is required to show they are stable. Exceptions are possible for patients with known documented cases of Gilbert’s syndrome, as long as the Bilirubin is stable and the treating clinician feels that the increased bilirubin is not due to obstruction or cholangitis.
• ALT and/or AST ≤ 2.5 x ULN
• ALP ≤ 5 x ULN
• Albumin > 25 g/L
10. Adequate renal function:
• Serum urea < 1.5 x ULN
• Serum creatinine < 1.5 x ULN
• GFR ≥ 45 mL/min using a validated creatinine clearance calculation (e.g. Cockroft-Gault or Wright formula). If the calculated creatinine clearance is less than 45 mL/min, GFR should be assessed using an isotopic clearance method to confirm GFR ≥ 45 mL/min. Alternatively, if calculated GFR is <45mL/min, a protein/creatinine ratio can be used in 24 hours collected urine to confirm GFR ≥ 45 mL/min .
11. Life expectancy >12 weeks
12. 16 years of age or over
13. Patients may have had prior chemotherapy as long as patient meets all other inclusion/exclusion criteria.
14. Patient must have given written informed consent
|
|
| E.4 | Principal exclusion criteria |
1. Metastatic disease
2. Direct tumour extension in the duodenum, stomach, small bowel or large bowel.
3. Previous abdominal radiotherapy or previous selective internal radiotherapy such as hepatic arterial Yttrium therapy
4. Previous hypersensitivity to platinum salts
5. 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 (including diabetes with established sensory peripheral neuropathy, unstable or uncompensated respiratory, cardiac, hepatic or renal disease)
5. 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 (including diabetes with established sensory peripheral neuropathy, unstable or uncompensated respiratory, cardiac, hepatic or renal disease)
6. Patients who have a concurrent malignancy that is clinically unstable and requires tumour-directed treatment are not eligible. Exceptions include low grade malignancies that do not require active treatment, such as early prostate cancer under surveillance or chronic lymphocytic leukaemia.
7. History of prior malignancy that could interfere with the response evaluation or survival. 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 malignancy diagnosed over two years ago and radically treated.
7
8. Other concomitant anti-cancer therapy (except steroids)
9. Any psychiatric or other disorder likely to impact on informed consent.
10. Women who are pregnant or breast feeding
NB. Whilst not excluded, patients with significant hearing impairment must be made aware of potential ototoxicity and may choose not to be included. If included, it is recommended that audiograms be carried out at baseline and prior cycle 2 of CisGem
|
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Feasibility:
An average recruitment rate of at least 1 patient per month once 6 sites have been activated.
Phase II:
Progression free survival |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
Feasibility:
The primary endpoint is the monthly rate of recruitment into the trial once all required sites have been activated (approximately 6 months after activation of the first site).
The decision to move from feasibility into the full randomised phase II will be based upon achieving the target recruitment rate of 1 patient/month. In February 2017 the TMG agreed to expand the patient population to include patients with tumours up to 12 cm. The change in this inclusion criteria has no effect on the sample size assumptions and therefore there is no change to the sample size required. If the target recruitment remains unachievable after approximately 18 months recruitment in total, then we would conclude that the trial is not feasible.
Phase II: 9 months after last patient randomised. |
|
| E.5.2 | Secondary end point(s) |
Feasibility:
Worse grade of AE (CTCAE 4.03)
Pattern of treatment failure
Best overall response (RECIST v1.1)
Progression Free Survival at 9 months after randomisation
Progression Free Survival
Overall Survival
Quality of Life
Achieving downstaging permitting surgery
Time to treatment failure
Phase II:
Worse grade of AE (CTCAE 4.03)
Pattern of treatment failure
Best overall response (RECIST v1.1)
Duration of response
Progression Free Survival at 9 months after randomisation
Overall Survival
Quality of Life
Downstaging permitting surgery
Time to treatment failure
|
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
Worse grade of AE (CTCAE 4.03)- Days 1 & 8 of chemotherapy, pre and during SBRT, end of treatment and at 3 month and 6 month follow up
Pattern of treatment failure- end of treatment
Best overall response- Every 3 months until progression
Progression Free Survival - 9 months after randomisation
Overall Survival- death
Quality of Life- Every 3 months until progression
Downstaging permitting surgery- 1 month post SBRT
Time to treatment failure - very 3 months until progression/death/patient starts new treatment
|
|
| 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 | No |
| 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) | No |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | Yes |
| E.8.2.3.1 | Comparator description |
| Chemotherapy (6 cycles) & Stereotactic body radiotherapy Vs, chemotherapy (8 cycles) |
|
| E.8.2.4 | Number of treatment arms in the trial | 2 |
| 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 | 17 |
| 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 trial will be two years after enrolment of the final patient, or once all patients have died, whichever happens first |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 8 |
| E.8.9.1 | In the Member State concerned months | 0 |
| E.8.9.1 | In the Member State concerned days | 1 |
| E.8.9.2 | In all countries concerned by the trial years | 8 |
| E.8.9.2 | In all countries concerned by the trial months | 0 |
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