Add-Aspirin: A Trial Assessing the Effects of Aspirin on Disease Recurrence and Survival After Primary Therapy in Common Non Metastatic Solid Tumours

Breast Cancer Clinical Trial

Official title:

A Phase III, Double-blind, Placebo-controlled, Randomised Trial Assessing the Effects of Aspirin on Disease Recurrence and Survival After Primary Therapy in Common Non Metastatic Solid Tumours

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT02804815
• Other study ID #: 14/0814
• Secondary ID: 2013-004398-2812
• Status: Recruiting
• Phase: Phase 3
• Start date: October 2015
• Est. completion date: October 2026

Study information

• Verified date: November 2023
• Source: University College, London
• Contact: Alex Robbins
• Phone: 02076704906
• Email: mrcctu.add-aspirin[@]ucl.ac.uk
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

Add-Aspirin aims to assess whether regular aspirin use after standard curative therapy can prevent recurrence and improve survival in individuals with non-metastatic common tumours. The question will be assessed in four different tumour types (breast, colorectal, gastro-oesophageal and prostate) by means of parallel cohorts within an overarching trial protocol.

Eligible participants will be randomly assigned (double-blind) to either aspirin 100mg, aspirin 300mg or a matched placebo, to be taken daily for at least 5 years. Disease recurrence and survival will be assessed, along with adherence, toxicity, and other potential effects of aspirin (eg. cardiovascular).

There is a large body of evidence indicating that aspirin has anti-cancer effects. Meta-analyses of cardiovascular trials of aspirin have shown short-term effects on cancer mortality and a decrease in risk of metastases, suggesting a role for aspirin in the treatment as well as prevention of cancer. Additionally, large observational studies of individuals taking aspirin after cancer treatment have shown improved disease-specific and overall mortality for specific tumour types.

In the treatment setting, the risks of side effects associated with aspirin are expected to be outweighed by potential benefits. However, this has not yet been assessed in a randomised trial.

As a low cost, generic and widely available drug, which is generally safe, if aspirin is shown to be effective, it could have a huge impact on cancer outcomes globally.

Description:

A phase III, multi-centre, double-blind, placebo-controlled randomised trial which aims to assess whether regular aspirin use after standard therapy prevents recurrence and prolongs survival in participants with non-metastatic common solid tumours.

The trial has four parallel tumour site-specific cohorts (breast, colorectal, gastro-oesophageal and prostate cancer). An overarching protocol ensures each cohort is as comparable as possible to allow a combined analysis of overall survival as a co-primary outcome measure in addition to individual tumour site-specific analyses of disease recurrence and survival.

Participants who have undergone potentially curative treatment (surgery or other radical treatment), including any standard neo-adjuvant or adjuvant therapy for breast, colorectal, gastro-oesophageal or prostate cancer or have participated in any pre-approved trials and satisfy the eligibility criteria.

Participants will be randomly assigned to 100mg aspirin, 300mg aspirin or matched placebo. All tablets will be enteric-coated to be taken daily for at least five years. Prior to randomisation, all potential participants will take open-label 100mg aspirin daily for a run-in period of approximately 8 weeks to assess tolerability and adherence.

The trial incorporates a feasibility phase during which recruitment feasibility, treatment adherence, safety and use of the run-in period will be assessed.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 11000
• Est. completion date: October 2026
• Est. primary completion date: October 2026
• Accepts healthy volunteers: No
• Gender: All
• Age group: 16 Years and older

Eligibility

COMMON INCLUSION CRITERIA

• Written informed consent

• WHO performance status 0, 1 or 2

• Participants should not be and have no intention of pregnancy or breast feeding during trial treatment

• Previous or current participants of other primary treatment trials if agreed in advance between trials

• No clinical or radiological evidence of residual or distant disease

BREAST COHORT INCLUSION CRITERIA

• Men or women with histologically confirmed invasive breast cancer

• Undergone complete primary invasive tumour excision with clear margins

• Surgical staging of the axilla must have been undertaken by sentinel node biopsy, axillary sampling or dissection

• In those patients with a positive sentinel node biopsy:

o If 1, 2 or 3 nodes are positive, subsequent management of the axilla (with surgery, radiotherapy or no further intervention) should be completed prior to registration

o If 4 or more nodes are involved, patients must have undergone completion axillary node dissection

• Radiotherapy (RT)

• Patients who have undergone breastconserving surgery should have received adjuvant RT

• Patients who have undergone mastectomy should have received RT if they have more than 3 axillary lymph nodes involved

• Patients who have undergone mastectomy and have T3 tumours and/or 1, 2 or 3 involved lymph nodes may (or not) have received radiation per institutional practice

• Final histology must fall within at least one of these 3 groups:

• Node positive

• Node negative with highrisk features 2 or more of:

1. ER negative

2. HER2 positive

3. Grade 3

4. Lymphovascular invasion present

5. Age <35

6. Oncotype Dx score of >25

• In patients who have received neoadjuvant chemotherapy, patients are eligible if they have both a hormone receptor negative/HER2 negative tumour, a HER2 positive tumour or a hormone receptor positive grade 3 tumour and did not achieve a pathological complete response with neoadjuvant systemic therapy

• Known HER2 and ER status

• Timing of entry

o If no adjuvant chemotherapy or RT: registration within 12 wks of definitive surgery achieving clear margins

o Following adjuvant chemotherapy/RT: registration within 8 wks of last therapy.

• Participants may receive endocrine therapy and trastuzumab. All ER positive patients should be planned to undergo at least 5 yrs of adjuvant endocrine therapy.

COLORECTAL COHORT INCLUSION CRITERIA

• Histologically confirmed stage II or III adenocarcinoma of the colon or rectum and patients who have undergone resection of liver metastases with clear margins and no residual metastatic disease

• Patients with synchronous tumours if one of the tumours is at least stage II or III

• Serum CEA ideally =1.5 x upper limit of normal

• Have undergone curative (R0) resection with clear margins

• Timing of entry:

• If no adjuvant treatment: registration within 12 wks of definitive surgery achieving clear margins

• Following adjuvant treatment: registration within 8 wks of last therapy GASTROOESOPHAGEAL COHORT INCLUSION CRITERIA

• Patients with histologically confirmed adenocarcinoma, adenosquamous carcinoma or squamous cell cancer of the oesophagus, gastrooesophageal junction or stomach

• Have undergone curative (R0) resection with clear margins or primary chemoRT given with curative intent

• Timing of entry:

• Following surgery without adjuvant treatment: registration within 12 wks of the definitive surgery achieving clear margins

• Following primary chemoRT or surgery with adjuvant treatment: registration within 8 wks of last therapy

PROSTATE COHORT INCLUSION CRITERIA

• Men with histologically confirmed node negative nonmetastatic adenocarcinoma of the prostate

• Have undergone curative treatment, either:

• Radical prostatectomy

• Radical RT

• Intermediate or high risk according to D'Amico classification Depending on the curative treatment pathway, participant must additionally satisfy the following (a) Prostatectomy patients

• Open, laparoscopic or robotic radical prostatectomy

• Men treated with immediate adjuvant RT

• Men receiving adjuvant hormone therapy planned for a maximum duration of 3 yrs

• Timing of entry:

• If no adjuvant RT: registration within 12 wks of definitive surgery and PSA at =6 weeks postsurgery must be <0.1ng/ml

• Following adjuvant RT: registration within 8 wks of delivery of final fraction of RT

• Men treated with salvage RT following a rise in PSA

• Men randomised to RADICALSHD (ISRCTN 40814031) provided all other eligibility criteria are met (b) Radical RT patients

• Men receiving neoadjuvant and/or adjuvant hormone therapy planned for a maximum duration of 3yrs

• Timing of registration within 8wks from completion of RT (c) Salvage RT patients after previous Radical Prostatectomy

• Men treated with salvage RT following a rise in PSA

• Men receiving neoand/ or adjuvant hormone therapy planned for a maximum of 3yrs

COMMON EXCLUSION CRITERIA

• Current or previous regular use of aspirin (at any dose) or current use of another NSAID for any indication.

• A past history of adverse reaction or hypersensitivity to NSAIDs, celecoxib, aspirin or other salicylates or sulphonamides, including asthma, that is exacerbated by use of NSAIDs.

• Current use of anticoagulants.

• Current or longterm use of oral corticosteroids. The treating physician should make the clinical decision whether a patient has been exposed to longterm therapy.

• Active or previous peptic ulceration

• Previous gastrointestinal bleeding except where the cause of the bleeding has been surgically removed.

• Active or previous history of inflammatory bowel disease.

• History of moderate or severe renal impairment, with eGFR<45ml/min/1.73m2.

• Previous invasive or noninvasive malignancy except:

• DCIS where treatment consisted of resection alone. Prostate cancer initially treated with prostatectomy and now being treated with salvage radiotherapy following a rise in PSA.

• Cervical carcinoma in situ where treatment consisted of resection alone.

• Basal cell carcinoma where treatment consisted of resection alone or radiotherapy.

• Superficial bladder carcinoma where treatment consisted of resection alone.

• Other cancers where the patient has been diseasefree for =15 years.

• Any other physical condition which is associated with increased risk of aspirinrelated morbidity or, in the opinion of the Investigator, makes the patient unsuitable for the trial, including but not limited to severe asthma, haemophilia and other bleeding diatheses, macular degeneration and patients with a highrisk of mortality from another cause within the trial treatment period.

• Known glucose6phosphate dehydrogenase deficiency.

• LFTs greater than 1.5x the upper limit of normal unless agreed with TMG.

• Anticipated difficulties in complying with trial treatment or followup schedules.

• <16 years old.

• Participants in other treatment trials where this has not been agreed in advance by both trial teams.

BREAST COHORT EXCLUSION CRITERIA

• Metastatic or bilateral breast cancer.

COLORECTAL COHORT EXCLUSION CRITERIA • Proven (or clinically suspected) metastatic disease (patients who have undergone resection of liver metastases with clear margins and no residual metastatic disease are eligible).

GASTROOESOPHAGEAL COHORT EXCLUSION CRITERIA

• Proven (or clinically suspected) metastatic disease.

PROSTATE COHORT EXCLUSION CRITERIA

• Biopsy proven or radiologically suspected nodal involvement, or distant metastases from prostate cancer.

• Adjuvant hormone therapy planned for >3 years.

Related Conditions & MeSH terms

• Breast Cancer
• Cancer
• Colorectal Cancer
• Gastro-oesophageal Cancer
• Prostate Cancer
• Recurrence

Intervention

Drug:
• Aspirin 100mg
Aspirin 100mg
• Aspirin 300mg
Aspirin 300mg
• Placebo 100mg
Placebo 100mg
• Placebo 300mg
Placebo 300mg

Locations

Country	Name	City	State
Ireland	Bon Secours Hospital	Cork
Ireland	Cork University Hospital	Cork
Ireland	Beaumont Hospital	Dublin
Ireland	Mater Misericordiae University Hospital	Dublin
Ireland	Mater Private Hospital	Dublin
Ireland	St Luke's Hospital	Dublin
Ireland	St Vincent's Hospital	Dublin
Ireland	Tallaght University Hospital	Dublin
Ireland	University College Hospital Galway	Galway
Ireland	University Hospital Limerick	Limerick
Ireland	Sligo University Hospital	Sligo
Ireland	University Hospital Waterford	Waterford
United Kingdom	William Harvey Hospital	Ashford
United Kingdom	Stoke Mandeville Hospital	Aylesbury
United Kingdom	Ysbyty Gwynedd	Bangor
United Kingdom	North Devon District Hospital	Barnstaple
United Kingdom	Basildon Hospital	Basildon
United Kingdom	Bedford Hospital	Bedford
United Kingdom	Victoria Hospital	Blackpool
United Kingdom	Glan Clwyd Hospital	Bodelwyddan
United Kingdom	Pilgrim Hospital	Boston
United Kingdom	Royal Sussex County Hospital	Brighton
United Kingdom	Bristol Haematology & Oncology Centre	Bristol
United Kingdom	Fairfield Hospital	Bury
United Kingdom	West Suffolk Hospital	Bury St Edmunds
United Kingdom	Kent and Canterbury Hospital	Canterbury
United Kingdom	University Hospital of Wales	Cardiff
United Kingdom	Velindre Hospital	Cardiff
United Kingdom	Cumberland Infirmary	Carlisle
United Kingdom	Cheltenham General Hospital	Cheltenham
United Kingdom	University Hospital Coventry and Warwickshire	Coventry
United Kingdom	Darlington Memorial Hospital	Darlington
United Kingdom	Darent Valley Hospital	Dartford
United Kingdom	Western General Hospital	Edinburgh
United Kingdom	North Middlesex Hospital	Edmonton
United Kingdom	Royal Devon and Exeter Hospital	Exeter
United Kingdom	Queen Elizabeth Hospital	Gateshead
United Kingdom	The New Victoria Hospital	Glasgow
United Kingdom	Inverclyde Royal Hospital,	Greenock
United Kingdom	Princess Alexandra Hospital	Harlow
United Kingdom	Northwick Park Hospital	Harrow
United Kingdom	Wycombe Hospital	High Wycombe
United Kingdom	Hinchingbrooke Hospital	Huntingdon
United Kingdom	Raigmore Hospital	Inverness
United Kingdom	Ipswich Hospital	Ipswich
United Kingdom	Airedale General Hospital	Keighley
United Kingdom	Kidderminster General Hospital	Kidderminster
United Kingdom	Kingston Hospital	Kingston
United Kingdom	Royal Lancaster Infirmary	Lancaster
United Kingdom	Lincoln County Hospital	Lincoln
United Kingdom	Royal Marsden Hospital	London
United Kingdom	St George's Hospital	London
United Kingdom	Luton & Dunstable Hospital	Luton
United Kingdom	Maidstone Hospital	Maidstone
United Kingdom	Christie Hospital	Manchester
United Kingdom	North Manchester General Hospital	Manchester
United Kingdom	Wythenshawe Hospital,	Manchester
United Kingdom	Queen Elizabeth The Queen Mother Hospital	Margate
United Kingdom	Milton Keynes University Hospital	Milton Keynes
United Kingdom	Friarage Hospital	Northallerton
United Kingdom	Northampton General Hospital	Northampton
United Kingdom	George Eliot Hospital	Nuneaton
United Kingdom	Royal Oldham Hospital	Oldham
United Kingdom	Royal Alexandra Hospital	Paisley
United Kingdom	Queen Alexandra Hospital	Portsmouth
United Kingdom	Royal Berkshire Hospital	Reading
United Kingdom	Alexandra Hospital	Redditch
United Kingdom	East Surrey Hospital	Redhill
United Kingdom	Queen's Hospital	Romford
United Kingdom	Salisbury District Hospital	Salisbury
United Kingdom	Weston Park Hospital	Sheffield
United Kingdom	Lister Hospital	Stevenage
United Kingdom	Royal Marsden	Sutton
United Kingdom	King's Mill Hospital	Sutton-in-Ashfield
United Kingdom	Singleton Hospital	Swansea
United Kingdom	Great Western Hospital	Swindon
United Kingdom	Royal Cornwall Hospital	Truro
United Kingdom	Weston General Hospital	Weston Super Mare
United Kingdom	West Cumberland Hospital	Whitehaven
United Kingdom	Royal Albert Edward Infirmary	Wigan
United Kingdom	Worcestershire Royal Hospital	Worcester
United Kingdom	Wrexham Maelor Hospital	Wrexham

Sponsors (1)

Lead Sponsor	Collaborator
University College, London

Countries where clinical trial is conducted

Ireland,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Overall Survival	Overall survival of all cohorts combined	10 years follow up
Primary	Invasive disease-free survival (IDFS)	IDFS in the breast cancer cohort	6 years follow up
Primary	Disease-free survival (DFS)	DFS in the colorectal cancer cohort	6 years follow up
Primary	Overall survival	Overall survival in the gastro-oesophageal cancer cohort	5 years follow up
Primary	Biochemical recurrence-free survival (bRFS)	bRFS in the prostate cancer cohort	5 years follow up
Secondary	Adherence	Patient-reported compliance (via diary card) will be assessed during the run-in period	5 years follow up
Secondary	Number of participants with serious haemorrhage (grade 3 or above) as measured by CTCAE V4.0. Data will be collected on case report forms.		5 years follow up
Secondary	Number of participants with treatment-related (active drug and placebo) cardiovascular events as assessed by CTCAE v4.0		5 years follow up
Secondary	Number of participants with second malignancies as assessed by case report form		5 years follow up
Secondary	Number of participants that show a decline in cognition and extent of decline as assessed by the Montreal Cognitive Assessment (MoCA)		5 years follow up