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 |
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, healthrelated 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%. |
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E.2.2 | Secondary objectives of the trial |
- Demonstrate efficacy and low toxicity of mesorectal radiation fields for treatment of early rectal cancer. - Establish safety of mesorectal radiation and selective transanal microsurgical excision for organ preservation in early rectal cancer. - Establish the safety and efficacy of non-operative management of CR in the context of early rectal cancer treatment. - Compare the toxicity and quality of life outcomes for patients undergoing standard TME surgery with those who receive organpreserving treatments. - Investigate the potential of genomic markers in blood (ctDNA), associated with persistence of tumour tissue, to facilitate the selection of patients for an organ saving approach based upon the likelihood of treatment success. - Evaluate the utility of ctDNA for determination of partial versus complete response |
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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 E4. |
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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) |
The primary endpoint of the STAR-TREC phase III study is the proportion of patients with successful organ preservation at 30 months from the XML File Identifier: iuzNMkBNxdZKk9y9yV0YSCHFBZY= Page 11/22 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 |
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E.5.2 | Secondary end point(s) |
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: nonrandomised 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 |
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 | 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) | No |
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 | Yes |
E.8.1.7.1 | Other trial design description |
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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 | No |
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 | 5 |
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 | 4 |
E.8.9.1 | In the Member State concerned months | 0 |
E.8.9.1 | In the Member State concerned days | 0 |
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 | 0 |