Clinical trial NCT02804815: Add-Aspirin: A Trial Assessing the Effects of Aspirin on Disease Recurrence and Survival After Primary Therapy in Common Non Metastatic Solid Tumours
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
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE3
Conditions: Cancer
Breast Cancer
Prostate Cancer
Colorectal Cancer
Gastro-oesophageal Cancer
Keywords: Aspirin
prostate
colorectal
breast
gastro-oesophageal
recurrence
Lead sponsor: University College, London
Sponsor class: OTHER
First posted: 2016-06-17
Enrollment: 11000
Sex: ALL
Minimum age (years): 16
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: OTHER

Brief 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.

Detailed 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.

Eligibility criteria: 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.

Primary outcomes:
measure: Overall Survival
timeFrame: 10 years follow up
measure: Invasive disease-free survival (IDFS)
timeFrame: 6 years follow up
measure: Disease-free survival (DFS)
timeFrame: 6 years follow up
measure: Overall survival
timeFrame: 5 years follow up
measure: Biochemical recurrence-free survival (bRFS)
timeFrame: 5 years follow up
Secondary outcomes:
measure: Adherence
timeFrame: 5 years follow up
measure: Number of participants with serious haemorrhage (grade 3 or above) as measured by CTCAE V4.0. Data will be collected on case report forms.
timeFrame: 5 years follow up
measure: Number of participants with treatment-related (active drug and placebo) cardiovascular events as assessed by CTCAE v4.0
timeFrame: 5 years follow up
measure: Number of participants with second malignancies as assessed by case report form
timeFrame: 5 years follow up
measure: Number of participants that show a decline in cognition and extent of decline as assessed by the Montreal Cognitive Assessment (MoCA)
timeFrame: 5 years follow up
Other outcomes:
Locations:
city: Cork
country: Ireland
facility: Bon Secours Hospital
city: Cork
country: Ireland
facility: Cork University Hospital
city: Dublin
country: Ireland
facility: Beaumont Hospital
city: Dublin
country: Ireland
facility: Mater Misericordiae University Hospital
city: Dublin
country: Ireland
facility: Mater Private Hospital
city: Dublin
country: Ireland
facility: St Luke's Hospital
city: Dublin
country: Ireland
facility: St Vincent's Hospital
city: Dublin
country: Ireland
facility: Tallaght University Hospital
city: Galway
country: Ireland
facility: University College Hospital Galway
city: Limerick
country: Ireland
facility: University Hospital Limerick
city: Sligo
country: Ireland
facility: Sligo University Hospital
city: Waterford
country: Ireland
facility: University Hospital Waterford
city: Ashford
country: United Kingdom
facility: William Harvey Hospital
city: Aylesbury
country: United Kingdom
facility: Stoke Mandeville Hospital
city: Bangor
country: United Kingdom
facility: Ysbyty Gwynedd
city: Barnstaple
country: United Kingdom
facility: North Devon District Hospital
city: Basildon
country: United Kingdom
facility: Basildon Hospital
city: Bedford
country: United Kingdom
facility: Bedford Hospital
city: Blackpool
country: United Kingdom
facility: Victoria Hospital
city: Bodelwyddan
country: United Kingdom
facility: Glan Clwyd Hospital
city: Boston
country: United Kingdom
facility: Pilgrim Hospital
city: Brighton
country: United Kingdom
facility: Royal Sussex County Hospital
city: Bristol
country: United Kingdom
facility: Bristol Haematology & Oncology Centre
city: Bury St Edmunds
country: United Kingdom
facility: West Suffolk Hospital
city: Bury
country: United Kingdom
facility: Fairfield Hospital
city: Canterbury
country: United Kingdom
facility: Kent and Canterbury Hospital
city: Cardiff
country: United Kingdom
facility: University Hospital of Wales
city: Cardiff
country: United Kingdom
facility: Velindre Hospital
city: Carlisle
country: United Kingdom
facility: Cumberland Infirmary
city: Cheltenham
country: United Kingdom
facility: Cheltenham General Hospital
city: Coventry
country: United Kingdom
facility: University Hospital Coventry and Warwickshire
city: Darlington
country: United Kingdom
facility: Darlington Memorial Hospital
city: Dartford
country: United Kingdom
facility: Darent Valley Hospital
city: Edinburgh
country: United Kingdom
facility: Western General Hospital
city: Edmonton
country: United Kingdom
facility: North Middlesex Hospital
city: Exeter
country: United Kingdom
facility: Royal Devon and Exeter Hospital
city: Gateshead
country: United Kingdom
facility: Queen Elizabeth Hospital
city: Glasgow
country: United Kingdom
facility: The New Victoria Hospital
city: Greenock
country: United Kingdom
facility: Inverclyde Royal Hospital,
city: Harlow
country: United Kingdom
facility: Princess Alexandra Hospital
city: Harrow
country: United Kingdom
facility: Northwick Park Hospital
city: High Wycombe
country: United Kingdom
facility: Wycombe Hospital
city: Huntingdon
country: United Kingdom
facility: Hinchingbrooke Hospital
city: Inverness
country: United Kingdom
facility: Raigmore Hospital
city: Ipswich
country: United Kingdom
facility: Ipswich Hospital
city: Keighley
country: United Kingdom
facility: Airedale General Hospital
city: Kidderminster
country: United Kingdom
facility: Kidderminster General Hospital
city: Kingston
country: United Kingdom
facility: Kingston Hospital
city: Lancaster
country: United Kingdom
facility: Royal Lancaster Infirmary
city: Lincoln
country: United Kingdom
facility: Lincoln County Hospital
city: London
country: United Kingdom
facility: Royal Marsden Hospital
city: London
country: United Kingdom
facility: St George's Hospital
city: Luton
country: United Kingdom
facility: Luton & Dunstable Hospital
city: Maidstone
country: United Kingdom
facility: Maidstone Hospital
city: Manchester
country: United Kingdom
facility: Christie Hospital
city: Manchester
country: United Kingdom
facility: North Manchester General Hospital
city: Manchester
country: United Kingdom
facility: Wythenshawe Hospital,
city: Margate
country: United Kingdom
facility: Queen Elizabeth The Queen Mother Hospital
city: Milton Keynes
country: United Kingdom
facility: Milton Keynes University Hospital
city: Northallerton
country: United Kingdom
facility: Friarage Hospital
city: Northampton
country: United Kingdom
facility: Northampton General Hospital
city: Nuneaton
country: United Kingdom
facility: George Eliot Hospital
city: Oldham
country: United Kingdom
facility: Royal Oldham Hospital
city: Paisley
country: United Kingdom
facility: Royal Alexandra Hospital
city: Portsmouth
country: United Kingdom
facility: Queen Alexandra Hospital
city: Reading
country: United Kingdom
facility: Royal Berkshire Hospital
city: Redditch
country: United Kingdom
facility: Alexandra Hospital
city: Redhill
country: United Kingdom
facility: East Surrey Hospital
city: Romford
country: United Kingdom
facility: Queen's Hospital
city: Salisbury
country: United Kingdom
facility: Salisbury District Hospital
city: Sheffield
country: United Kingdom
facility: Weston Park Hospital
city: Stevenage
country: United Kingdom
facility: Lister Hospital
city: Sutton-in-Ashfield
country: United Kingdom
facility: King's Mill Hospital
city: Sutton
country: United Kingdom
facility: Royal Marsden
city: Swansea
country: United Kingdom
facility: Singleton Hospital
city: Swindon
country: United Kingdom
facility: Great Western Hospital
city: Truro
country: United Kingdom
facility: Royal Cornwall Hospital
city: Weston Super Mare
country: United Kingdom
facility: Weston General Hospital
city: Whitehaven
country: United Kingdom
facility: West Cumberland Hospital
city: Wigan
country: United Kingdom
facility: Royal Albert Edward Infirmary
city: Worcester
country: United Kingdom
facility: Worcestershire Royal Hospital
city: Wrexham
country: United Kingdom
facility: Wrexham Maelor Hospital
Study officials:
affiliation: MRC CTU at UCL
name: Ruth Langley
role: STUDY_DIRECTOR
References: