E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
|
E.1.1.1 | Medical condition in easily understood language |
|
E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
MedDRA Classification |
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 aim of the STAR-TREC study is to assess the feasibility of successfully recruiting to a large, multi-centre randomised trial comparing radical surgery versus organ saving treatment using (chemo)radiotherapy followed by selective transanal microsurgery.
STAR-TREC is a phase II feasibility study that will evaluate whether it is possible to accelerate patient recruitment from 2 per month, as attained in the previous TREC study, to 6 per month over a two-year period. This would demonstrate deliverability of a phase III study incorporating 400 patients to evaluate differences in pelvic relapse rates between organ saving and standard surgery. Randomising 70-80 patients per year in phase III would achieve this target in 4 years (including patients treated in phase II).
PHASE II PRIMARY ENDPOINTS 1. Year 1: randomise at least 4 cases per month internationally (n=48) 2. Year 2: randomise at least 6 cases per month internationally (n=72) |
|
E.2.2 | Secondary objectives of the trial |
Secondary Objectives:
1. Year 1: Can one international partner procure independent STAR-TREC funding? Successful international collaboration will be necessary to deliver a future phase III study of 400 patients.
2. Year 1: Can one international partner open the STAR-TREC study to recruitment?
3. Efficacy of organ preserving treatment arms on completion of phase II study: Is the organ saving rate > 50% at 12 months (following randomisation) in the experimental arms ? This figure is intended as a guide to both the STAR-TREC DMEC and any phase III peer review.
4. We expect that the actual organ saving rate would lie between 60-70%. Using a target of 50% in phase II will allow for the relatively small sample size. We consider that this metric of efficacy would be suitable for early publication (with toxicity data) as it does not constitute a primary outcome for phase III.
5. Proportion of patients undergoing primary TME surgery (control-group) accurately staged by MRI and satisfying |
|
E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
• Biopsy proven adenocarcinoma of the rectum • mriT1-3bN0 (with ≤5mm of mesorectal invasion) rectal tumour or endorectal ultrasound defined rectal cancer uT1-uT3b (optional: in centres where high quality ERUS is available and patient unable to tolerate MRI) • MDT determines that all of the following treatment options are feasible: (a) TME surgery, (b) CRT (c) SCPRT d) TEM • Patients with equivocal radiological lesions e.g. mesorectal, retroperitoneal, liver, lung are eligible if agreed by MDT • Aged 16 or over in UK (18 or over in the Netherlands and Denmark). Pre-treatment, the following criteria must be met: • Estimated creatinine clearance >50 mls/min • Absolute neutrophil count >1.5x109/l; platelets >100 x 109/L • Serum transaminase <3 x Upper Limit Normal/l (ULN) • Bilirubin <1.5 x ULN • ECOG performance status 0-1 • If female and of childbearing potential, must: o Have a negative pregnancy test ≤72hours prior to initiating study treatment o Agree to avoid pregnancy during and for 6 months after study treatment • If male with a partner of childbearing potential, must: o Agree to use adequate, medically approved, contraceptive precautions during and for 90 days after the last dose of study treatment • Patient able and willing to provide written informed consent for the study
|
|
E.4 | Principal exclusion criteria |
• Unequivocal evidence of metastatic disease (includes resectable metastases) • MRI node positive (defined by protocol guidelines) • MRI extramural vascular invasion (mriEMVI) positive (defined by protocol guidelines) • MRI defined mucinous tumour • Mesorectal fascia threatened (< 1 mm on MRI) • Maximum tumour diameter > 40mm as measured from everted edges on sagittal MRI • Tumour position anterior, above the peritoneal reflection on MRI or EUS • No residual luminal tumour following endoscopic resection • Contraindications to radiotherapy including previous pelvic radiotherapy • Uncontrolled cardiorespiratory comorbidity (includes patients with inadequately controlled angina or myocardial infarction within 6 months prior to randomisation) • Known dihydropyrimidine dehydrogenase (DPYD) deficiency • Known Gilberts disease (hyperbilirubinaemia) • Taking warfarin that cannot be discontinued at least 7 days prior to starting treatment or substituted by low molecular weight heparin • Taking phenytoin or sorivudine or its chemically related anologues, such as brivudine (see Section 8.4.5 for further details) • As metronidazole interacts with capecitabine, patients who are taking Metronidazole, should be stopped at point of study entry (randomisation) • Pregnant, lactating or pre-menopausal women not using adequate contraception. • History of severe and unexpected reactions to fluoropyrimidine therapy • Unable or unwilling to provide written informed consent
|
|
E.5 End points |
E.5.1 | Primary end point(s) |
Primary outcome measure
The primary endpoint of the STAR-TREC feasibility study is:
• RECRUITMENT RATE - measured at 12 and 24 months. Target recruitment rates are ≥4 and ≥6 patients randomised per month at 12 and 24 months respectively for total accrual of 120 international cases. Each individual country will attempt to exceed the minimum recruitment required to sustain phase III (UK 75, the Netherlands 75, Denmark 30).
If recruitment is on target in year two then consideration will be given to an early application for transition to phase III with a funding application and a formal protocol amendment.
|
|
E.5.1.1 | Timepoint(s) of evaluation of this end point |
The primary outcome is recruitment. Recruitment will be measured at 12 amd 24 months post the start of recruitment. |
|
E.5.2 | Secondary end point(s) |
The core secondary endpoints of this phase II trial are: • Procurement of STAR-TREC funding by one international partner • Opening of STAR-TREC by one international partner • Efficacy of organ preserving treatment arm on completion of phase II study: Is an organ saving rate > 50% at 12 months (following randomisation) achieved in the experimental arms?
Additional outcome measures pertinent to a future phase III study examining the safety and efficacy of organ saving versus standard surgery will also be collected. • SAFETY o Accuracy of MRI in predicting STAR-TREC eligibility o 30-day mortality o 6 month mortality o Surgical morbidity o Rate of tumour recurrence or regrowth within the bowel wall (experimental arm) o Rate of tumour recurrence within the mesorectum (experimental arm) o Rate of distant metastases o Pelvic failure rate: expressed as a sum of the following (i) unresectable pelvic tumour, (ii) cases requiring beyond TME surgery or (iii) tumour recurrence or regrowth ≤1mm from the circumferential surgical margin after TME surgery. o Bowel, bladder and sexual dysfunction (measured by EORTC QLQ CR29 & C30, LARS score and ICIQ-MLUTS)
• EFFICACY o Proportion of patients with/ without a stoma at one year o Histopathological assessment of tumour down-staging following radiotherapy according to depth of tumour invasion and the incidence of other high-risk features in comparison to non-irradiated (control) group. o Proportion of patients identified by clinical and MRI assessment as suitable for active monitoring o Conversion rates from organ saving to radical surgery o Disease free survival o Quality of life (measured by EORTC QLQ CR29 & C30, EuroQol EQ-5D, LARS score and ICIQ-MLUTS) o Overall survival
|
|
E.5.2.1 | Timepoint(s) of evaluation of this end point |
The core secondary endpoints of this phase II trial are: • Procurement of STAR-TREC funding by one international partner • Opening of STAR-TREC by one international partner • Efficacy of organ preserving treatment arm on completion of phase II study: Is an organ saving rate > 50% at 12 months (following randomisation) achieved in the experimental arms?
These main secondary ouctomes will all be measured at 12 months. |
|
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 | No |
E.6.4 | Safety | No |
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 | Yes |
E.6.13.1 | Other scope of the trial description |
Feasibility of recruitment |
|
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 | 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 |
|
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 | 20 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 3 |
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 12 months after the last data capture, i.e. 12 months after date of the last visit of the last patient undergoing the protocol based therapy. Long-term follow-up, to at least 5 years after randomisation of the last patient, constitutes the non-interventional phase of the trial.
This will allow sufficient time for the completion of protocol procedures, data collection and data input.
|
|
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 | 1 |
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 | 1 |