| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
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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.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
AIMS
Phase II:
The aim of the STAR-TREC phase II 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.
Phase III:
The aims of the STAR-TREC phase III study are to evaluate whether (a) either a CRT or SCRT organ-saving strategy is superior in terms of achieving organ preservation, requirement for further surgery, treatment related toxicity, health-related quality of life, and other outcomes; (b) either or both organ-saving strategies lead to an acceptable rate of organ preservation of at least 50%.
PRIMARY OBJECTIVE
Phase II:
The STAR-TREC phase II feasibility study 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 pati |
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| E.2.2 | Secondary objectives of the trial |
Phase II:
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 DMC and any phase III peer review.
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 for organ preservation would be suitable for early publication (with toxicity data) as it does not constitute a primary outcome for phase III.
4. Proportion of patients undergoing primary TME surgery (control-group) accurately staged by MRI and satisfying |
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
• Biopsy proven adenocarcinoma of the rectum
• MRI-defined ≤T3b (with ≤5mm of mesorectal invasion) rectal tumour or endorectal ultrasound-defined ≤uT3b rectal cancer (optional: in centres where high quality endorectal ultrasound (ERUS) is available or patient unable to tolerate MRI)
• MDT determines that all of the following treatment options are reasonable and feasible: (a) TME surgery, (b) CRT (c) SCRT d) TEM.
• Eastern Cooperative Oncology Group (ECOG) performance status 0-1
• For patients choosing organ preservation only:
o If female and of childbearing potential, must:
- Have a negative pregnancy test within 7 days prior to study entry
- Agree to use adequate, medically approved, contraceptive precautions from trial entry until 6 months after the end of study treatment
o If non-sterilised male male with a partner of childbearing potential, must:
- Agree to use adequate, medically approved, contraceptive precautions from trial entry until 6 months after the end of study treatment
• Patient able and willing to provide written informed consent for the study |
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| E.4 | Principal exclusion criteria |
• Concomitant or previous malignancies within 3 years prior to trial entry, except those that in the opinion of the MDT are unlikely to relapse within 3 years or lead to death within 5 years
• Unequivocal evidence of metastatic disease (includes resectable metastases)
Patients with equivocal radiological lesions (e.g. retroperitoneal, liver, lung) that are not classified as M1 are eligible if agreed by MDT
• MRI node positive (≥N1, defined by protocol guidelines)
Patients with equivocal radiological findings that are either classified as NX or N0 are eligible
• MRI extramural vascular invasion (mriEMVI) positive (defined by protocol guidelines)
• MRI defined mucinous tumour
• Mesorectal fascia threatened (≤1 mm on MRI or ERUS)
• Maximum tumour diameter > 40mm (either measured from everted edges on sagittal MRI or on ERUS)
• 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 or arrhythmia within 6 months prior to trial entry)
• Known complete dihydropyrimidine dehydrogenase (DPYD) deficiency
• Known Gilbert’s disease (hyperbilirubinaemia)
• Taking coumarin-derivative anticoagulants (e.g. 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, within 4 weeks of trial entry (see Section 8.3.5 for further details)
• Taking metronidazole at study entry
• Pregnant or lactating women
• History of severe and unexpected reactions to fluoropyrimidine therapy
• Age <16 years (UK), <18 years (other countries)
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| E.5 End points |
| E.5.1 | Primary end point(s) |
Phase II:
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.
Phase III:
The primary endpoint of the STAR-TREC phase III study is the proportion of patients with successful organ preservation at 30 months from the start day of (chemo)radiotherapy treatment. This endpoint will be assessed for patients who prefer organ preservation and is defined as an in-situ rectum (includes patients subject to transanal local resection), no defunctioning stoma and an absence of active loco-regional cancer failure. The expected incidence of this outcome is approximately 60%. |
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
Phase II
The primary outcome is recruitment measured at 12 and 24 months after the recruitment start date.
Phase III
The primary outcome is the proportion of patients with successful organ preservation measured at 30 months from the start day of (chemo)radiotherapy treatment. |
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| E.5.2 | Secondary end point(s) |
Phase II:
• 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?
• 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)at 12 and 24 months compared to baseline.
• 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) at 12 and 24 months compared to baseline.
o Overall survival
Phase III:
A) Randomised comparison between organ-preserving strategies:
• Clinician-reported acute treatment related toxicity up to 30 days following completion of (chemo)radiotherapy
• Proportion of patients with CR to (chemo)radiation therapy
• Proportion of patients undergoing transanal local excision
• Time to event of organ loss assessed for patients who prefer organ preservation; defined as the length of time from the start date of trial treatment until TME surgery
• Non-regrowth pelvic tumour control to 36 months; defined as the length of time from the start date of trial treatment until death (any cause) or development of unequivocal pelvic recurrence but not including patients who developed local regrowth which was resected with clear margins using standard TME surgery
• Metastasis free survival to 36 months; defined as the length of time from the start date of trial treatment until death (any cause) or detection of distant metastasis
• Non-regrowth -disease free survival to 36 months; defined as the length of time from the start of trial treatment until death (any cause), detection of local pelvic recurrence or distant metastasis but not including patients who developed local regrowth which was resected with clear margins using standard TME surgery
• Overall survival to 60 months defined as the length of time from the start date of trial treatment until death (any cause)
B) Analyses incorporating the standard surgery comparator (phase II: randomised comparison; phase III: non-randomised comparison):
• Clinician-reported acute treatment related toxicity up to 30 days following completion of (chemo)radiotherapy or date of initial surgery
• Non-regrowth pelvic tumour control to 36 months; defined as the length of time from the start date of (chemo)radiotherapy or date of initial surgery until death (any cause) or development of unequivocal pelvic recurrence but not including patients who preferred organ preservation and developed local regrowth which was resected with clear margins using standard TME surgery
• Metastasis-free survival to 36 months; defined as the length of time from the start date of trial treatment or date of initial surgery until death (any cause) or detection of distant metastasis
• Disease-free survival to 36 months; defined as the length of time from the start date of trial treatment or date of initial surgery until death (any cause), detection of local pelvic recurrence or distant metastasis but not including patients who developed local regrowth which was resected with clear margins using standard TME surgery
• Overall survival to 60 months defined as the length of time from the start date of trial treatment or date of initial surgery until death (any cause))
• Decision regret at 24 months, measured using the validated Decision regret scale questionnaire/Treatment decision questionnaire.
C) Secondary endpoint for analyses of patient-reported outcomes including symptomatic toxicity and health-related quality of life (HRQoL) at baseline and 3, 12, 24 and 36 months after the start of trial-specific treatment:
o EORTC QLQ-C30
o EORTC QLQ-CR29
o EuroQoL EQ-5D-3L
o ICIQ-MLUTS
o ICIQ-FLUTS
o Low Anterior Resection Syndrome (LARS) Score |
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
Phase II
The main 3 secondary outcomes will all be measured at 12 months.
• 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?
Phase III
Toxicity up to 30 days following completion of (chemo)radiotherapy treatment or date of initial surgery
Non-regrowth pelvic tumour control at 36 months
Metastasis-free survival at 36 months
Disease-free survival at 36 months
Overall survival at 60 months
Decision regret at 24 months
HRQoL at 3, 12, 24 and 36 months compared to baseline |
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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 | 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 |
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| 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) | Yes |
| 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 |
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| 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 | 4 |
| 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
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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.
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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 | 1 |
| E.8.9.2 | In all countries concerned by the trial years | 12 |
| E.8.9.2 | In all countries concerned by the trial months | 6 |
| E.8.9.2 | In all countries concerned by the trial days | 31 |
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