A Proof of Concept, Window Trial of the IMmunological Effects of AveLumab and Aspirin in Triple-Negative Breast Cancer

TNBC is an aggressive subtype of breast cancer associated with poor survival and new treatments are needed. A key feature of cancer is its ability to go undetected by the immune system. Recent developments in cancer research have identified immune checkpoints as a possible treatment option as they seem to promote an anti‐tumour immune response. Some breast cancers have considerable cancer cell infiltration, which has been associated with better prognosis. This is where white blood cells have permeated the cancer cell and infiltrated the infected cell in an attempt to 'cure' the infected cell. Greater immune‐sensitivity is thought to correlate with greater cancer cell infiltration therefore researchers are looking at ways in which immune‐sensitivity can be improved. One approach is to target inflammation that is known to play a major role in cancer development and progression. Certain proteins can often be abnormally expressed in many cancers. In preclinical models the investigators recently demonstrated that the presence of certain cancer cell‐derived proteins is critical for the growth of tumours formed by melanoma, colorectal and breast mouse cancer cell lines. In the mouse preclinical trials it indicated that by blocking the cancer cells ability to produce these proteins was associated with a marked shift in the inflammatory profile. To test this theory, this study will use aspirin as the chosen protein inhibitor and it is speculated that the addition of aspirin might enhance the efficacy of the immune checkpoint blockade, avelumab. TRIAL AIMS & DESIGN The aim of this trial is to determine whether aspirin enhances the efficacy of avelumab by promoting a greater anti‐cancer immune response. This is a multi‐centre study recruiting patients with confirmed TNBC from across four trial sites within the United Kingdom. It is anticipate that 50 participants will need to be screened in order to successfully enrol 42 patients onto the trial. Patients will be randomly assigned to one of two arms:‐ ‐ 21 patients into Arm A: Avelumab + Proton Pump Inhibitor (PPI) ‐ 21 patients into Arm B: Avelumab + Aspirin + PPI Visit windows have been used to aid visit planning in the hope that most research appointments can take place in line with patients' ordinary care visits so as to reduce any burden inflicted on the patient. Adverse events (AEs) and Serious Adverse Events (SAEs) will be collected from the time of randomisation and will continue to be collected up until Visit 5 (Follow up Visit B). All post biopsy treatment will be at the discretion of the subject's treating physician per local standard of care. PATIENT IDENTIFICATION & SCREENING The study will be conducted as a multi‐centre trial consisting of four NHS secondary care out‐paints clinics from across the United Kingdom. Each site has been chosen for their expertise in oncology and their ability to identify patients for the trial directly from their clinics with each centre treating between 20 to 40 patients per annum; this pool of patients will constitute the source of recruitment in the study, PIC sites may also be used. Potential participants will be identified by the Principal Investigators multi‐disciplinary team following recent diagnosis of TNBC. The multidisciplinary team shall be trained on the study protocol and required to sign the trial delegation and training log in advance of working on the trial or identifying participants. Potential participants will have at least 24 hours to read the patient information and decide if they would like to participate in the study. Participants must have the capacity to provide fully informed consent. Participants must not participate in any other therapeutic trials whilst on study treatments, however once all study treatments as specified by trial schema are completed, participation in further studies will not be affected. The estimated duration of participation for a participant is up to 10 weeks. Each subject will be asked to complete 5 study visits. After successfully completing a Screening Visit (Visit 1), each eligible subject will attend for a Baseline Visit (Visit 2) and will be randomly assigned to treatment ARM A or ARM B. As part of the baseline visit subjects will have their first of two breast tumour biopsies. All subjects will commence their PPI following the baseline visit, those subjects randomised to ARM B will also commence their Aspirin at this time. At visit 3 all subjects will receive their Avelumab infusion. At Visit 4 (Follow up Visit A) each subject will undergo their second research biopsy and further research blood sampling this will be the first of two follow up visits, with Visit 5 (Follow up Visit B) concluding the patients participation. At the screening visits the following data will be collected:‐ ‐ Informed consent ‐ Demographics ‐ Medical history ‐ Concomitant medication ‐ Complete Physical examination ‐ Vital Signs ‐ 12‐lead Electrocardiograph (ECG) ‐ ECOG performance status ‐ Blood tests:‐ ‐ Biochemistry: AST or ALT, LDH, Alk Phos, total bilirubin, sodium, potassium, urea, creatinine, total protein, albumin, adjusted calcium ‐ Haematology: FBC: Hb, Platelets, ANC, WBC, Lymphocytes, basophils, eosinophils ‐ Thyroid Function: Free T4, TSH ‐ Urinalysis ‐ Pregnancy testing ‐ Optional: Microbiome samples kit dispensation (Stool sample, Saliva sample, Nasal Swab) ‐ Baseline tumour assessment BASELINE VISIT The following assessments will be conducted at the time of this visit: ‐ Adverse Events ‐ Concomitant medication ‐ Vital Signs ‐ ECOG performance status ‐ Eligibility ‐ Randomisation ‐ Research Bloods (Circulating tumour DNA (CtDNA); Plasma for Cytokine Analysis; PBMC extraction for immunophenotyping) ‐ Mid‐stream Urine sample for prostaglandin ‐ Optional: Microbiome samples kit collection (Stool sample, Saliva sample, Nasal Swab) ‐ Breast Tissue Biopsy ‐ Pre‐treatment dispensation (Arm A: PPI OR Arm B: PPI + aspirin) ‐ Diary card training and dispensation ‐ Pre‐treatment Reminder Telephone call ‐ TREATMENT & FOLLOW UP VISITS Visit 3: I.V visit The following assessments will be conducted at the time of this visit: ‐ Assessment of Adverse Events ‐ Concomitant medication ‐ Vital Signs ‐ *Laboratory tests *(Biochemistry, Haematology and Urinalysis only if screening labs were >14 day prior to visit 3) ‐ **Pregnancy testing **(only if screen pregnancy test was >14days prior to day Visit 3) ‐ Microbiome samples kit dispensation only (Stool, Saliva, Nasal Swab ) ‐ Mid‐stream Urine sample for prostaglandin ‐ Diary card ‐ Pre‐treatment compliance check (Arm A: PPI, Arm B: PPI + aspirin) ‐ Avelumab (10mg/kg i.v.) Visit 4: Follow up A The following assessments will be conducted at the time of this visit ‐ Adverse Events ‐ Concomitant medication ‐ Research Bloods (CtDNA); Plasma for Cytokine Analysis; Immunophenotyping) ‐ Microbiome sample kit collection (Stool sample, Saliva sample, Nasal Swab) ‐ Mid‐stream Urine sample for prostaglandin ‐ Breast Tumour Biopsy ‐ Diary card ‐ Pre‐treatment compliance check (Arm A: PPI, Arm B: PPI + aspirin) Visit 5: Follow up B The following assessments will be conducted at the time of this visit: ‐ Adverse Events ‐ Concomitant medication ‐ Symptom Directed Physical examination ‐ Vital Signs (BP, HR, Sp02, Temp) ‐ ECOG performance status ‐ Laboratory blood tests ‐ Biochemistry: AST or ALT, LDH, Alk Phos, total bilirubin, sodium, potassium, urea, creatinine, total protein, albumin, adjusted calcium ‐ Haematology: FBC ‐ Hb, Platelets, ANC, WBC, Lymphocytes, basophils, eosinophils ‐ Thyroid Function: Free T4, TSH ‐ Urinalysis ‐ Research Bloods (CtDNA); Plasma for Cytokine Analysis; Immunophenotyping) SAFETY REVIEW An Independent Trial Steering Committee (TSC) and Data Monitoring Committee (IDMC) is being formed and will review trial safety data as a combined committee group. TRANSLATIONAL RESEARCH With consent the following samples will be collected from patients and held by the Manchester Cancer Research Centre (MCRC) biobank: ‐ Microbiome samples ‐ Research blood samples ‐ Breast Tissue Biopsies The MCRC biobank holds a generic research tissue bank ethics approval under their HTA license and will release the samples for relevant research, subject to approval by the Biobank's Access Committee.