Clinical Trials Register

Summary
EudraCT Number:	2016-000862-49
Sponsor's Protocol Code Number:	RG_15-011
National Competent Authority:	Denmark - DHMA
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2016-09-07
Trial results

Index
A. PROTOCOL INFORMATION
B. SPONSOR INFORMATION
C. APPLICANT IDENTIFICATION
D. IMP IDENTIFICATION
D.8 INFORMATION ON PLACEBO
E. GENERAL INFORMATION ON THE TRIAL
F. POPULATION OF TRIAL SUBJECTS
G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
P. END OF TRIAL

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A. Protocol Information

A.1

Member State Concerned

Denmark - DHMA

A.2

EudraCT number

2016-000862-49

A.3

Full title of the trial

Can we Save the rectum by watchful waiting or TransAnal surgery following (chemo)Radiotherapy versus Total mesorectal excision for early REctal Cancer? Fase 3

not applicable

A.3.1

Title of the trial for lay people, in easily understood, i.e. non-technical, language

Can we save the rectum by watchful waiting or local surgery following (chemo)Radiotherapy versus radical surgery for early rectal Cancer? Fase 3

not applicable

A.3.2

Name or abbreviated title of the trial where available

STAR-TReC

not applicable

A.4.1

Sponsor's protocol code number

RG_15-011

A.7

Trial is part of a Paediatric Investigation Plan

A.8

EMA Decision number of Paediatric Investigation Plan

B. Sponsor Information
B.Sponsor: 1
B.1.1	Name of Sponsor	The University of Birmingham
B.1.3.4	Country	United Kingdom
B.3.1 and B.3.2	Status of the sponsor	Non-Commercial
B.4 Source(s) of Monetary or Material Support for the clinical trial:
B.4.1	Name of organisation providing support	Cancer Research UK
B.4.2	Country	United Kingdom
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	The University of Birmingham
B.5.2	Functional name of contact point	Mr Simon Bach
B.5.3	Address:
B.5.3.1	Street Address	School of Cancer Sciences, Academic Dept of Surgery
B.5.3.2	Town/ city	Edgbaston, Birmingham
B.5.3.3	Post code	B15 2TH
B.5.3.4	Country	United Kingdom
B.5.4	Telephone number	01216978449
B.5.5	Fax number	01214721230
B.5.6	E-mail	s.p.bach@bham.ac.uk

D. IMP Identification
D.IMP: 1
D.1.2 and D.1.3	IMP Role	Test
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	Yes
D.2.1.1.1	Trade name	Capecitabine
D.2.1.1.2	Name of the Marketing Authorisation holder	Roche Registration Limited
D.2.1.2	Country which granted the Marketing Authorisation	United Kingdom
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.1	Product name	Capecitabine
D.3.4	Pharmaceutical form	Film-coated tablet
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Oral use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	Capecitabine
D.3.9.1	CAS number	N/A
D.3.9.2	Current sponsor code	N/A
D.3.9.4	EV Substance Code	AS1
D.3.10	Strength
D.3.10.1	Concentration unit	mg/m2 milligram(s)/square meter
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	825
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	Yes
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	No
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	No
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No

D.8 Information on Placebo
D.8 Placebo: 1
D.8.1	Is a Placebo used in this Trial?	Yes

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Early rectal cancer

E.1.1.1

Medical condition in easily understood language

Early rectal cancer

E.1.1.2

Therapeutic area

Diseases [C] - Cancer [C04]

MedDRA Classification

E.1.3

Condition being studied is a rare disease

E.2 Objective of the trial

E.2.1

Main objective of the trial

STAR-TREC is a phase III study that will evaluate the safety of standard surgical resection of early rectal cancer compared to preoperative chemo-radiotherapy and selective transanal microsurgery to those who fail to demonstarte a complete response to chemoradiation. The phase III study is based on patients preference and the patients can thereby choose whether they want to be included in a randomization between standard surgery ant the experimental arms of chemo-radiation and then selective transanal microsurgery. The other option is not to have standard surgery within the randomization algorithm and randomize between long or short course radiation therapy before transanal microsurgery. The phase 2 of the study demonstrated 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.

The aim of the STAR-TREC study is to investigate the oncological outcome of organ saving treatment of early rectal cancer compared to standard surgery. Phase III of STAR TRECis a multi-centre randomised trial comparing radical surgery versus organ saving treatment using (chemo)radiotherapy followed by selective transanal microsurgery.
The proportion of patients with successful organ preservation at 30
months from the start date of (chemo)radiotherapy.
Organ preservation is considered to have failed (a) if the rectum is
removed; (b) if the patient develops unequivocal locoregional cancer
recurrence or (c) if the patient has a stoma.

E.2.2

Secondary objectives of the trial

 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)

not applicable

E.2.3

Trial contains a sub-study

E.2.3.1

Full title, date and version of each sub-study and their related objectives

no sub -study

not applicable

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).
• 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

not applicable

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)
• Pregnant, lactating or pre-menopausal women not using adequate contraception.
• Unable or unwilling to provide written informed consent

not applicable

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 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%.
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.
Accuracy of MRI in predicting STAR-TREC eligibility
30-day mortality
6 month mortality
Surgical morbidity
Rate of tumour recurrence or regrowth within the bowel wall (experimental arm)
Rate of tumour recurrence within the mesorectum (experimental arm)
Rate of distant metastases
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.
Bowel, bladder and sexual dysfunction (measured by EORTC QLQ CR29 & C30,
LARS score and ICIQ-MLUTS/ICIQ-FLUTS)
EFFICACY
Proportion of patients with/ without a stoma at 30 days and one year
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
Proportion of patients identified by clinical and MRI assessment as suitable for
active monitoring
Conversion rates from organ saving to radical surgery
Disease free survival
Quality of life (measured by EORTC QLQ CR29 & C30, EuroQol EQ-5D, LARS score
and ICIQ-MLUTS/ICIQ-FLUTS)
Overall survival
Phase III:
Secondary outcomes for the 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 surgeryNon-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)
Secondary endpoints for analyses incorporating the non-randomised standard surgery
comparator:
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 trialtreatment or date of initial surgery until death (any cause))
Decision regret at 12 and 24 months

not applicable

E.5.1.1

Timepoint(s) of evaluation of this end point

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

not applicable

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

not applicable

E.5.2.1

Timepoint(s) of evaluation of this end point

not applicable

E.6 and E.7 Scope of the trial

E.6

Scope of the trial

E.6.1

Diagnosis

E.6.2

Prophylaxis

E.6.3

Therapy

Yes

E.6.4

Safety

Yes

E.6.5

Efficacy

Yes

E.6.6

Pharmacokinetic

E.6.7

Pharmacodynamic

E.6.8

Bioequivalence

E.6.9

Dose response

E.6.10

Pharmacogenetic

E.6.11

Pharmacogenomic

E.6.12

Pharmacoeconomic

E.6.13

Others

Yes

E.6.13.1

Other scope of the trial description

Feasibility of recruitment

not applicable

E.7

Trial type and phase

E.7.1

Human pharmacology (Phase I)

E.7.1.1

First administration to humans

E.7.1.2

Bioequivalence study

E.7.1.3

Other

E.7.1.3.1

Other trial type description

E.7.2

Therapeutic exploratory (Phase II)

E.7.3

Therapeutic confirmatory (Phase III)

Yes

E.7.4

Therapeutic use (Phase IV)

E.8 Design of the trial

E.8.1

Controlled

Yes

E.8.1.1

Randomised

Yes

E.8.1.2

Open

Yes

E.8.1.3

Single blind

E.8.1.4

Double blind

E.8.1.5

Parallel group

E.8.1.6

Cross over

E.8.1.7

Other

Yes

E.8.1.7.1

Other trial design description

not applicable

patientpreference for randomization

E.8.2

Comparator of controlled trial

E.8.2.1

Other medicinal product(s)

E.8.2.2

Placebo

E.8.2.3

Other

Yes

E.8.2.3.1

Comparator description

not applicable

Standard surgery

E.8.2.4

Number of treatment arms in the trial

E.8.3

The trial involves single site in the Member State concerned

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

E.8.5

The trial involves multiple Member States

Yes

E.8.5.1

Number of sites anticipated in the EEA

E.8.6 Trial involving sites outside the EEA

E.8.6.1

Trial being conducted both within and outside the EEA

E.8.6.2

Trial being conducted completely outside of the EEA

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.

not applicable

E.8.9 Initial estimate of the duration of the trial

E.8.9.1

In the Member State concerned years

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

E.8.9.2

In all countries concerned by the trial months

E.8.9.2

In all countries concerned by the trial days

F. Population of Trial Subjects

F.1 Age Range

F.1.1

Trial has subjects under 18

F.1.1.1

In Utero

F.1.1.2

Preterm newborn infants (up to gestational age < 37 weeks)

F.1.1.3

Newborns (0-27 days)

F.1.1.4

Infants and toddlers (28 days-23 months)

F.1.1.5

Children (2-11years)

F.1.1.6

Adolescents (12-17 years)

F.1.2

Adults (18-64 years)

Yes

F.1.2.1

Number of subjects for this age range:

F.1.3

Elderly (>=65 years)

Yes

F.1.3.1

Number of subjects for this age range:

F.2 Gender

F.2.1

Female

Yes

F.2.2

Male

Yes

F.3 Group of trial subjects

F.3.1

Healthy volunteers

F.3.2

Patients

Yes

F.3.3

Specific vulnerable populations

F.3.3.1

Women of childbearing potential not using contraception

F.3.3.2

Women of child-bearing potential using contraception

F.3.3.3

Pregnant women

F.3.3.4

Nursing women

F.3.3.5

Emergency situation

F.3.3.6

Subjects incapable of giving consent personally

F.3.3.6.1

Details of subjects incapable of giving consent

not applicable

F.3.3.7

Others

F.3.3.7.1

Details of other specific vulnerable populations

not applicable

F.4 Planned number of subjects to be included

F.4.1

In the member state

F.4.2

For a multinational trial

F.4.2.1

In the EEA

280

F.4.2.2

In the whole clinical trial

400

F.5

Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)

All participants in STAR-TREC will receive either Surgery, with two thirds of the patients also receiving either radiotherapy or chemo-radiotherapy.

The end of treatment for each patient is surgery. Therefore there will not be anything withheld after the research has finished. All patients will be followed up as per clinical practice.

not applicable

G. Investigator Networks to be involved in the Trial
G.4 Investigator Network to be involved in the Trial: 1
G.4.1	Name of Organisation	West Midlands Clinical Research Network

N. Review by the Competent Authority or Ethics Committee in the country concerned

Competent Authority Decision

Authorised

Date of Competent Authority Decision

2016-11-01

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2020-06-04

P. End of Trial
P.	End of Trial Status	Completed

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Orphan Designation Number:
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