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

Sponsor

University College, London (Other)

Overall Status

Recruiting

CT.gov ID

NCT02804815

Collaborator

(none)

11,000

Enrollment

Locations

Arms

132

Duration (Months)

134.1

Patients Per Site

Patients Per Site Per Month

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Cancer Breast Cancer Prostate Cancer Colorectal Cancer Gastro-oesophageal Cancer	Drug: Aspirin 100mg Drug: Aspirin 300mg Drug: Placebo 100mg Drug: Placebo 300mg	Phase 3

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.

Study Design

Study Type:

Interventional

Anticipated Enrollment :

11000 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

Triple (Participant, Care Provider, Investigator)

Primary Purpose:

Other

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 Start Date :

Oct 1, 2015

Anticipated Primary Completion Date :

Oct 1, 2026

Anticipated Study Completion Date :

Oct 1, 2026

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: Aspirin 100mg Aspirin 100mg	Drug: Aspirin 100mg Aspirin 100mg
Placebo Comparator: Placebo 100mg 100mg Placebo	Drug: Placebo 100mg Placebo 100mg
Active Comparator: Aspirin 300mg Aspirin 300mg	Drug: Aspirin 300mg Aspirin 300mg
Placebo Comparator: Placebo 300mg 300mg Placebo	Drug: Placebo 300mg Placebo 300mg

Outcome Measures

Primary Outcome Measures

Overall Survival [10 years follow up]
Overall survival of all cohorts combined
Invasive disease-free survival (IDFS) [6 years follow up]
IDFS in the breast cancer cohort
Disease-free survival (DFS) [6 years follow up]
DFS in the colorectal cancer cohort
Overall survival [5 years follow up]
Overall survival in the gastro-oesophageal cancer cohort
Biochemical recurrence-free survival (bRFS) [5 years follow up]
bRFS in the prostate cancer cohort

Secondary Outcome Measures

Adherence [5 years follow up]
Patient-reported compliance (via diary card) will be assessed during the run-in period
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]
Number of participants with treatment-related (active drug and placebo) cardiovascular events as assessed by CTCAE v4.0 [5 years follow up]
Number of participants with second malignancies as assessed by case report form [5 years follow up]
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]

Eligibility Criteria

Criteria

Ages Eligible for Study:

16 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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:

ER negative
HER2 positive
Grade 3
Lymphovascular invasion present
Age <35
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.

Contacts and Locations

Locations

	Site	City	Country
1	Bon Secours Hospital	Cork	Ireland
2	Cork University Hospital	Cork	Ireland
3	Beaumont Hospital	Dublin	Ireland
4	Mater Misericordiae University Hospital	Dublin	Ireland
5	Mater Private Hospital	Dublin	Ireland
6	St Luke's Hospital	Dublin	Ireland
7	St Vincent's Hospital	Dublin	Ireland
8	Tallaght University Hospital	Dublin	Ireland
9	University College Hospital Galway	Galway	Ireland
10	University Hospital Limerick	Limerick	Ireland
11	Sligo University Hospital	Sligo	Ireland
12	University Hospital Waterford	Waterford	Ireland
13	William Harvey Hospital	Ashford	United Kingdom
14	Stoke Mandeville Hospital	Aylesbury	United Kingdom
15	Ysbyty Gwynedd	Bangor	United Kingdom
16	North Devon District Hospital	Barnstaple	United Kingdom
17	Basildon Hospital	Basildon	United Kingdom
18	Bedford Hospital	Bedford	United Kingdom
19	Victoria Hospital	Blackpool	United Kingdom
20	Glan Clwyd Hospital	Bodelwyddan	United Kingdom
21	Pilgrim Hospital	Boston	United Kingdom
22	Royal Sussex County Hospital	Brighton	United Kingdom
23	Bristol Haematology & Oncology Centre	Bristol	United Kingdom
24	West Suffolk Hospital	Bury St Edmunds	United Kingdom
25	Fairfield Hospital	Bury	United Kingdom
26	Kent and Canterbury Hospital	Canterbury	United Kingdom
27	University Hospital of Wales	Cardiff	United Kingdom
28	Velindre Hospital	Cardiff	United Kingdom
29	Cumberland Infirmary	Carlisle	United Kingdom
30	Cheltenham General Hospital	Cheltenham	United Kingdom
31	University Hospital Coventry and Warwickshire	Coventry	United Kingdom
32	Darlington Memorial Hospital	Darlington	United Kingdom
33	Darent Valley Hospital	Dartford	United Kingdom
34	Western General Hospital	Edinburgh	United Kingdom
35	North Middlesex Hospital	Edmonton	United Kingdom
36	Royal Devon and Exeter Hospital	Exeter	United Kingdom
37	Queen Elizabeth Hospital	Gateshead	United Kingdom
38	The New Victoria Hospital	Glasgow	United Kingdom
39	Inverclyde Royal Hospital,	Greenock	United Kingdom
40	Princess Alexandra Hospital	Harlow	United Kingdom
41	Northwick Park Hospital	Harrow	United Kingdom
42	Wycombe Hospital	High Wycombe	United Kingdom
43	Hinchingbrooke Hospital	Huntingdon	United Kingdom
44	Raigmore Hospital	Inverness	United Kingdom
45	Ipswich Hospital	Ipswich	United Kingdom
46	Airedale General Hospital	Keighley	United Kingdom
47	Kidderminster General Hospital	Kidderminster	United Kingdom
48	Kingston Hospital	Kingston	United Kingdom
49	Royal Lancaster Infirmary	Lancaster	United Kingdom
50	Lincoln County Hospital	Lincoln	United Kingdom
51	Royal Marsden Hospital	London	United Kingdom
52	St George's Hospital	London	United Kingdom
53	Luton & Dunstable Hospital	Luton	United Kingdom
54	Maidstone Hospital	Maidstone	United Kingdom
55	Christie Hospital	Manchester	United Kingdom
56	North Manchester General Hospital	Manchester	United Kingdom
57	Wythenshawe Hospital,	Manchester	United Kingdom
58	Queen Elizabeth The Queen Mother Hospital	Margate	United Kingdom
59	Milton Keynes University Hospital	Milton Keynes	United Kingdom
60	Friarage Hospital	Northallerton	United Kingdom
61	Northampton General Hospital	Northampton	United Kingdom
62	George Eliot Hospital	Nuneaton	United Kingdom
63	Royal Oldham Hospital	Oldham	United Kingdom
64	Royal Alexandra Hospital	Paisley	United Kingdom
65	Queen Alexandra Hospital	Portsmouth	United Kingdom
66	Royal Berkshire Hospital	Reading	United Kingdom
67	Alexandra Hospital	Redditch	United Kingdom
68	East Surrey Hospital	Redhill	United Kingdom
69	Queen's Hospital	Romford	United Kingdom
70	Salisbury District Hospital	Salisbury	United Kingdom
71	Weston Park Hospital	Sheffield	United Kingdom
72	Lister Hospital	Stevenage	United Kingdom
73	King's Mill Hospital	Sutton-in-Ashfield	United Kingdom
74	Royal Marsden	Sutton	United Kingdom
75	Singleton Hospital	Swansea	United Kingdom
76	Great Western Hospital	Swindon	United Kingdom
77	Royal Cornwall Hospital	Truro	United Kingdom
78	Weston General Hospital	Weston Super Mare	United Kingdom
79	West Cumberland Hospital	Whitehaven	United Kingdom
80	Royal Albert Edward Infirmary	Wigan	United Kingdom
81	Worcestershire Royal Hospital	Worcester	United Kingdom
82	Wrexham Maelor Hospital	Wrexham	United Kingdom