Condition category
Cancer
Date applied
13/07/2016
Date assigned
03/08/2016
Last edited
24/11/2016
Prospective/Retrospective
Prospectively registered
Overall trial status
Ongoing
Recruitment status
Recruiting

Plain English Summary

Lay summary under review with external organisation

Trial website

Contact information

Type

Public

Primary contact

Dr Sue Bell

ORCID ID

Contact details

Clinical Trials Research Unit
Leeds Institute of Clinical Trials Research
University of Leeds
Leeds
LS2 9JT
United Kingdom
+44 13 343 1492
plato@leeds.ac.uk

Additional identifiers

EudraCT number

N/A

ClinicalTrials.gov number

N/A

Protocol/serial number

31184

Study information

Scientific title

PLATO - PersonaLising Anal cancer radioTherapy dOse - Incorporating Anal Cancer Trials (ACT) ACT3, ACT4 and ACT5

Acronym

PLATO

Study hypothesis

PLATO is an integrated protocol, comprising 3 separate trials (ACT3, ACT4 and ACT5) which aims to optimise radiotherapy dose (in combination with chemotherapy) for low-, intermediate- and high-risk anal cancer.

ACT3:
ACT3 is a non-randomised phase II trial for patients with early, small tumours who have undergone surgery (local excision). The aim of this study is to determine whether a treatment strategy of surgery alone, i.e. no further treatment, for patients with margins >1mm, and highly selective low-dose radiotherapy with chemotherapy for patients with close margins ≤1mm, results in acceptably low rates of cancer recurrence.

ACT4:
ACT4 is a randomised phase II trial for patients with intermediate-risk disease. The aim of this study is to compare standard-dose chemoradiotherapy (50.4Gy in 28 fractions) with reduced-dose chemoradiotherapy (41.4Gy in 23 fractions), to see if less radiotherapy is able to maintain the excellent success rates in treating the cancer, while reducing the side effects of treatment.

ACT5:
ACT5 is a randomised seamless pilot/phase II/phase III trial for patients with locally advanced anal cancer. The aim of this study is to compare standard-dose chemoradiotherapy (53.2Gy in 28 fractions) with two higher doses of chemoradiotherapy (58.8Gy and 61.6Gy, both in 28 fractions), to see if giving a higher dose of radiotherapy reduces the chance of the cancer coming back, whilst not causing too many extra side effects.

Ethics approval

Yorkshire & The Humber - Bradford Leeds Research Ethics Committee, 06/07/2016, ref: 16/YH/0157

Study design

Both; Interventional; Design type: Treatment, Drug, Radiotherapy, Active Monitoring

Primary study design

Interventional

Secondary study design

Randomised controlled trial

Trial setting

Hospitals

Trial type

Treatment

Patient information sheet

Not available in web format, please use the contact details below to request a patient information sheet

Condition

Specialty: Cancer, Primary sub-specialty: Colorectal; UKCRC code/ Disease: Cancer/ Malignant neoplasms of digestive organs

Intervention

ACT3:
Observation arm
No further treatment after local excision.

Intervention arm
Either a 3D conformal plan or a single phase inverse-planned IMRT treatment plan delivered with multiple fields, or arc techniques. Choice of delivery technique is at the discretion of the treating clinician.
PTV_A = 41.4Gy in 23F (1.8Gy per F) in 4.5 weeks
Chemotherapy: Mitomycin C 12mg/m2 iv Day 1 & Capecitabine 852mg/m2 oral bd 5 days/week (on days of radiotherapy) for 23 days

ACT4:
All patients will receive IMRT where different dose fractionations are delivered to the elective nodal region (PTV_E) and to the areas of gross tumour (PTV_A). A single phase inverse-planned IMRT treatment plan should be produced and delivered with multiple fields or arc techniques.

Standard-dose arm
PTV_A: 50.4Gy in 28F in 5.5 weeks
PTV_E: 40.0Gy in 28F in 5.5 weeks
Chemotherapy: Mitomycin C 12mg/m2 iv Day 1 & Capecitabine 852mg/m2 oral bd 5 days/week (on days of radiotherapy) for 28 days

Reduced-dose (experimental) arm
PTV_A: 41.4Gy in 23F in 4.5 weeks
PTV_E: 34.5Gy in 23F in 4.5 weeks
Chemotherapy: Mitomycin C 12mg/m2 iv Day 1 & Capecitabine 852mg/m2 oral bd 5 days/week (on days of radiotherapy) for 23 days

ACT5:
All patients will receive IMRT where different dose fractionations are delivered to the elective nodal region (PTV_E) and to the areas of gross tumour (PTV_A and PTV_N). A single phase inverse-planned IMRT treatment plan should be produced and delivered with multiple fields or arc techniques.

Standard-dose arm
PTV_A: 53.2.Gy in 28F in 5.5 weeks
PTV_N: 50.4Gy in 28F in 5.5 weeks (involved nodes ≤3cm)
53.2Gy in 28F in 5.5 weeks (involved nodes >3cm)
PTV_E: 40.0Gy in 28F in 5.5 weeks

Dose escalation arm 1
PTV_A: 53.2Gy in 28F in 5.5 weeks
PTV_Boost: 58.8Gy in 28F in 5.5 weeks
PTV_N: 53.2Gy in 28F in 5.5 weeks (involved nodes ≤3cm)
53.2Gy in 28F in 5.5 weeks (involved nodes >3cm)
PTV_E: 40.0Gy in 28F in 5.5 weeks

Dose escalation arm 2
PTV_A: 53.2Gy in 28F in 5.5 weeks
PTV_Boost: 61.6Gy in 28F in 5.5 weeks
PTV_N: 53.2Gy in 28F in 5.5 weeks (involved nodes ≤3cm)
53.2Gy in 28F in 5.5 weeks (involved nodes >3cm)
PTV_E: 40.0Gy in 28F in 5.5 weeks

Chemotherapy in all ACT5 arms (centre choice):
Mitomycin C 12mg/m2 iv Day 1 & Capecitabine 852mg/m2 oral bd 5 days/week (on days of radiotherapy) for 28 days,
or
Mitomycin C 12mg/m2 iv Day 1 & 5-FU 1000mg/m2 per 24 hours by continuous iv infusion Days 1-4 and Days 29-32

Follow-up (ACT3, ACT4 and ACT5)
All patients will be followed up at the following time points:
1. 6 weeks
2. 3-monthly (Years 1-2)
3. 6 monthly (Year 3), then
4. Annually (Years 4+ until 3 years post close of recruitment or death)
All timings are from the end of treatment, except the ACT3 observation arm, which is from the date of registration.

Registration / Randomisation process
Following confirmation of written informed consent and eligibility, participants will be registered (ACT3) or randomised (ACT4/5) into the trial by an authorised member of staff at the trial site. Registration/randomisation will be performed centrally using the CTRU automated 24-hour system which can be accessed via the web or telephone.

ACT4:
Patients will be randomised on a 1:2 basis (standard-dose:reduced-dose) to receive either standard-dose IMRT in combination with chemotherapy or reduced-dose IMRT in combination with chemotherapy. A computer-generated minimisation program that incorporates a random element will be used to ensure the treatment groups are well-balanced for the following participant characteristics:
1. T-stage (T1, T2)
2. N-stage (N0, NX)
3. Gender (M, F)
4. HIV status (positive, negative)
5. Randomising centre

ACT5:
For the pilot study and Phase II trial, patients will be randomised on a 1:1:1 basis to receive either standard-dose IMRT in combination with chemotherapy, or one of two increased-dose experimental arms of IMRT with SIB in combination with chemotherapy. In the Phase III trial, participants will be randomised on a 1:1 basis to receive either standard-dose IMRT in combination with chemotherapy, or the most ‘acceptable’ increased dose arm of IMRT with SIB in combination with chemotherapy. A computer-generated minimisation program that incorporates a random element will be used to ensure the treatment groups are well-balanced for the following participant characteristics:
1. T-stage (T2/3, T4)
2. N-stage (NX/0/1, N2/3)
3. Gender (M, F)
4. HIV status (positive, negative)
5. Chemotherapy regimen (5FU, Capecitabine)
6. Randomising centre

Intervention type

Other

Phase

Drug names

Primary outcome measures

Locoregional failure (failure at the primary site (local) and/or surrounding nodal sites (regional) i.e. any failure within the pelvis up to the level of the sacral promontory) at 3 years post close of recruitment.

Secondary outcome measures

1. Acute toxicities, assessed according to the current NCI-CTCAE or RTOG (for skin toxicity) criteria, during each week of treatment (with the exception of the ACT3 observation arm)
2. Late toxicities, measured by patient reported outcomes via EORTC QLQ-C30 and CR29 questionnaires at 6 weeks, 6, 12, 24 and 36 months post the end of treatment
3. Treatment compliance, measured on a weekly basis by assessment of total dose of radiotherapy received, duration of treatment, delays to treatment due to toxicity, and any chemotherapy dose modifications
4. Clinical response rate (cRR) (ACT4 and 5), assessed by MRI imaging in accordance with the Tumour Regression Grading System at 3 and 6 months post end of treatment
5. Disease-free survival (DFS), defined as time from randomisation to first documented evidence of pelvic failure.
6. Colostomy-free survival (CFS), measured at baseline, prior to the start of treatment and throughout follow-up and will look at patients who have a pre-treatment colostomy that is still present at 12 months post end of treatment, patients who have a colostomy fitted due to a treatment related toxicity or local disease failure
7. Progression-free survival (PFS), defined as time from randomisation to first documented evidence of disease progression or death from any cause
8. Overall survival (OS), defined as time from randomisation to date of death from any cause
9. Patient Reported Outcome Measures (PROMs), assessed by EORTC QLQ-C30 and CR29 questionnaires at baseline, end of treatment and 6 weeks, 6, 12, 24 and 36 months post the end of treatment

Descriptive outcomes:
1. Pattern of pelvic failures i.e. site and position of failure
2. Proportion of participants undergoing salvage surgery (ACT4 and 5)

Overall trial start date

01/06/2015

Overall trial end date

28/02/2027

Reason abandoned

Eligibility

Participant inclusion criteria

Key inclusion criteria for all three trials include:
1. Provision of written informed consent
2. Histologically-proven, invasive primary squamous, basaloid, or cloacogenic carcinoma of the anus
3. Adequate bone marrow, hepatic and renal function
4. HIV negative or HIV positive and receiving effective antiretroviral therapy and CD4 count >200
5. Aged 16 years or over
6. Fit for all protocol defined treatments
7. Prepared to practice methods of contraception during treatment and until 6 months post end of treatment
8. Able to undergo all mandated staging and follow-up investigations, including MRI

Trial-specific inclusion criteria:
ACT3
T1 N0 or Nx anal margin tumour treated by local excision; ECOG performance status 0-2

ACT4
T1-2 up to 4cm N0 or Nx anal canal or anal margin tumour; ECOG performance status 0-1

ACT5
T2 N1-3 or T3-4 Nany anal canal or anal margin tumour; ECOG performance status 0-1

Participant type

Patient

Age group

Adult

Gender

Both

Target number of participants

Planned Sample Size: 929; UK Sample Size: 814

Participant exclusion criteria

Key exclusion criteria for all three trials include:
1. Definite evidence of metastatic disease
2. Prior invasive malignancy unless disease-free for a minimum of 3 years (exluding basal cell carcinoma of the skin or other in situ carcinomas)
3. Prior systemic chemotherapy for anal cancer
4. Prior radiotherapy to the pelvis
5. Uncontrolled cardiorespiratory comorbidity
6. Pregnant or lactating
7. Immunocompromised (organ transplant)

Trial-specific exclusion criteria:
ACT3
Where a piecemeal local excision precludes assessment of tumour size and margin status

Recruitment start date

01/09/2016

Recruitment end date

31/08/2021

Locations

Countries of recruitment

United Kingdom

Trial participating centre

St James’s University Hospital (ACT3, ACT4 or ACT5 from pilot phase onwards)
Beckett Street
Leeds
LS9 7TF
United Kingdom

Trial participating centre

Oxford Cancer and Haematology Centre (ACT3, ACT4 or ACT5 from pilot phase onwards)
Churchill Hospital Old Road Headington
Oxford
OX3 7LE
United Kingdom

Trial participating centre

Mount Vernon Hospital (ACT3, ACT4 or ACT5 from pilot phase onwards)
Rickmansworth Road
Northwood
HA6 2RN
United Kingdom

Trial participating centre

Velindre Cancer Centre (ACT3, ACT4 or ACT5 from pilot phase onwards)
Velindre Road Whitchurch
Cardiff
CF14 2TL
United Kingdom

Trial participating centre

Bristol Haematology and Oncology Centre (ACT3, ACT4 or ACT5 from pilot phase onwards)
Horfield Road
Bristol
BS2 8ED
United Kingdom

Trial participating centre

Sussex Cancer Centre (ACT3, ACT4 or ACT5 from pilot phase onwards)
Royal Sussex County Hospital
Brighton
BN2 5BE
United Kingdom

Trial participating centre

Guy’s Hospital (ACT3, ACT4 or ACT5 from pilot phase onwards)
Great Maze Pond
London
SE1 9RT
United Kingdom

Trial participating centre

Royal Surrey County Hospital (ACT3, ACT4 or ACT5 from pilot phase onwards)
Egerton Road
Guildford
GU2 7XX
United Kingdom

Trial participating centre

The Royal Marsden Hospital (ACT3, ACT4 or ACT5 from pilot phase onwards)
Fulham Road
London
SW3 6JJ
United Kingdom

Trial participating centre

The Royal Marsden Hospital (ACT3, ACT4 or ACT5 from pilot phase onwards)
Downs Road
Sutton
SM2 5PT
United Kingdom

Trial participating centre

Cambridge University Hospitals NHS Foundation Trust (ACT3, ACT4 or ACT5 from pilot phase onwards)
Addenbrooke's Hospital Hills Road
Cambridge
CB2 0QQ
United Kingdom

Trial participating centre

Beatson West of Scotland Cancer Centre (ACT3, ACT4 or ACT5 from pilot phase onwards)
1053 Great Western Road
Glasgow
G12 0YN
United Kingdom

Trial participating centre

Edinburgh Cancer Centre (ACT3, ACT4 or ACT5 from pilot phase onwards)
Western General Hospital Crewe Road
Edinburgh
EH4 2XU
United Kingdom

Trial participating centre

North Wales Cancer Treatment Centre (ACT3, ACT4 or ACT5 from pilot phase onwards)
Glan Clwyd Hospital
Rhyl
LL18 5UJ
United Kingdom

Trial participating centre

Saint Luke’s Centre for Radiation Oncology at Beaumont Hospital (ACT5 from pilot phase onwards)
Beaumont Road
Dublin
9
Ireland

Trial participating centre

Aberdeen Royal Infirmary
Foresterhill
Aberdeen
AB25 2ZN
United Kingdom

Trial participating centre

Belfast City Hospital
51 Lisburn Road
Belfast
BT9 7AB
United Kingdom

Trial participating centre

Castle Hill Hospital
Castle Road
Cottingham
HU16 5JQ
United Kingdom

Trial participating centre

Charing Cross Hospital
Fulham Palace Road
London
W6 8RF
United Kingdom

Trial participating centre

Cheltenham General Hospital
Sandford Road
Cheltenham
GL53 7AN
United Kingdom

Trial participating centre

City Hospital
Hucknall Road
Nottingham
NG5 1PB
United Kingdom

Trial participating centre

Clatterbridge Cancer Centre
Clatterbridge Road Bebington
Wirral
CH63 4JY
United Kingdom

Trial participating centre

Colchester General Hospital
Turner Road
Colchester
CO4 5JL
United Kingdom

Trial participating centre

Hammersmith Hospital
Du Cane Road
London
W12 0HS
United Kingdom

Trial participating centre

Ipswich Hospital
Heath Road
Ipswich
IP4 5PD
United Kingdom

Trial participating centre

Kent and Canterbury Hospital
Ethelbert Road
Canterbury
CT1 3NG
United Kingdom

Trial participating centre

Leicester Royal Infirmary
Infirmary Square
Leicester
LE1 5WW
United Kingdom

Trial participating centre

Maidstone Hospital
Hermitage Lane
Maidstone
ME16 9QQ
United Kingdom

Trial participating centre

New Cross Hospital
Wolverhampton Road
Wolverhampton
WV10 0QP
United Kingdom

Trial participating centre

North Devon District Hospital
Raleigh Park
Barnstaple
EX31 4JB
United Kingdom

Trial participating centre

Northampton General Hospital
Cliftonville
Northampton
NN1 5BD
United Kingdom

Trial participating centre

Northern Centre for Cancer Care
Freeman Hospital Freeman Road High Heaton
Newcastle upon Tyne
NE7 7DN
United Kingdom

Trial participating centre

Queen Elizabeth Hospital
Mindelsohn Way Edgbaston
Birmingham
B15 2GW
United Kingdom

Trial participating centre

Royal Berkshire Hospital
London Road
Reading
RG1 5AN
United Kingdom

Trial participating centre

Royal Devon and Exeter Hospital
Barrack Road
Exeter
EX2 5DW
United Kingdom

Trial participating centre

Royal Free Hospital
Pond Street
London
NW3 2QG
United Kingdom

Trial participating centre

Royal Preston Hospital
Sharoe Green Lane Fulwood
Preston
PR2 9HT
United Kingdom

Trial participating centre

Royal Shrewsbury Hospital
Mytton Oak Road
Shrewsbury
SY3 8XQ
United Kingdom

Trial participating centre

Singleton Hospital
Sketty Lane Sketty
Swansea
SA2 8QA
United Kingdom

Trial participating centre

Southampton General Hospital
Tremona Road
Southampton
SO16 6YD
United Kingdom

Trial participating centre

St Bartholomew's Hospital
West Smithfield
London
EC1A 7BE
United Kingdom

Trial participating centre

The Christie Hospital
Wilmslow Road
Manchester
M20 4BX
United Kingdom

Trial participating centre

The Cumberland Infirmary
Newton Road
Carlisle
CA2 7HY
United Kingdom

Trial participating centre

The James Cook University Hospital
Marton Road
Middlesbrough
TS4 3BW
United Kingdom

Trial participating centre

University College Hospital
235 Euston Road
London
NW1 2BU
United Kingdom

Trial participating centre

Weston Park Hospital
Whitham Road
Sheffield
S10 2SJ
United Kingdom

Trial participating centre

Worcestershire Royal Hospital
Charles Hastings Way
Worcester
WR5 1DD
United Kingdom

Sponsor information

Organisation

University of Leeds

Sponsor details

Medicine and Health Faculty Office
Worsley Building
Leeds
LS2 9JT
United Kingdom

Sponsor type

Hospital/treatment centre

Website

Funders

Funder type

Charity

Funder name

Cancer Research UK

Alternative name(s)

CRUK

Funding Body Type

private sector organisation

Funding Body Subtype

other non-profit

Location

United Kingdom

Results and Publications

Publication and dissemination plan

To maintain the scientific integrity of the trial, data will not be released prior to the first publication of the analysis of the primary endpoint, either for trial publication or oral presentation purposes, without the permission of the DMEC and TSC. In addition, individual collaborators must not publish data concerning their participants which is directly relevant to the questions posed in the trial until the first publication of the analysis of the primary endpoint.
An electronic copy of peer-reviewed, published papers arising from this research will be deposited in the Europe PubMed Central database.

Intention to publish date

28/02/2028

Participant level data

Not provided at time of registration

Results - basic reporting

Publication summary

Publication citations

Additional files

Editorial Notes

24/11/2016: Internal review.