<clinical_study>
  <!-- This xml conforms to an XML Schema at:
    https://clinicaltrials.gov/ct2/html/images/info/public.xsd -->
  <required_header>
    <download_date>ClinicalTrials.gov processed this data on September 20, 2023</download_date>
    <link_text>Link to the current ClinicalTrials.gov record.</link_text>
    <url>https://clinicaltrials.gov/ct2/show/NCT03794596</url>
  </required_header>
  <id_info>
    <org_study_id>CFT/sp123</org_study_id>
    <secondary_id>2018-004121-80</secondary_id>
    <secondary_id>16_DOG02_289</secondary_id>
    <secondary_id>017NovCC1079</secondary_id>
    <nct_id>NCT03794596</nct_id>
  </id_info>
  <brief_title>A Proof of Concept, Window Trial of the IMmunological Effects of AveLumab and Aspirin in Triple-Negative Breast Cancer</brief_title>
  <acronym>IMpALA</acronym>
  <official_title>A Proof of Concept, Window Trial of the IMmunological Effects of AveLumab and Aspirin in Triple-Negative Breast Cancer</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>The Christie NHS Foundation Trust</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>University of Manchester</agency>
      <agency_class>Other</agency_class>
    </collaborator>
  </sponsors>
  <source>The Christie NHS Foundation Trust</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
    <is_fda_regulated_drug>No</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
    <is_us_export>No</is_us_export>
  </oversight_info>
  <brief_summary>
    <textblock>
      This research is being done because the investigators are looking for new and better ways to&#xD;
      treat a type of breast cancer called triple negative breast cancer. This type of breast&#xD;
      cancer can be more difficult to treat than other types of breast cancer as it does not&#xD;
      respond to drugs such as hormonal therapies. One type of treatment that looks promising is&#xD;
      immunotherapy using new drugs called immune checkpoint inhibitors.&#xD;
&#xD;
      Immune checkpoints help to regulate the immune system and can stop the immune system from&#xD;
      attacking cancer cells. Immune checkpoint inhibitors block this 'off-switch' and aim to help&#xD;
      the immune system control the cancer. These drugs have been very effective in other cancers&#xD;
      such as melanoma and are now being tested in breast cancer.&#xD;
&#xD;
      In this study patients will receive an immune checkpoint inhibitor called avelumab. Half the&#xD;
      patients on the study will also receive aspirin tablets for approximately 18 days as the&#xD;
      investigators wish to compare the effects of avelumab alone versus in combination with&#xD;
      aspirin.&#xD;
&#xD;
      Patients will attend hospital approximately five times in order to complete all necessary&#xD;
      study assessments. The first visit screens patients for suitability, after which a baseline&#xD;
      visit will collect the first of two breast tissue biopsies. At the third visit a single dose&#xD;
      of Avelumab will be given via an infusion (a drip in the forearm). Patients will then return&#xD;
      approximately two weeks later for a second breast tissue biopsy before having a final follow&#xD;
      up visit another two weeks later. Blood and urine samples will be taken at various visits&#xD;
      throughout the study to help us learn more about the effects these treatments may have on the&#xD;
      immune system and on breast cancer cells.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      TNBC is an aggressive subtype of breast cancer associated with poor survival and new&#xD;
      treatments are needed. A key feature of cancer is its ability to go undetected by the immune&#xD;
      system. Recent developments in cancer research have identified immune checkpoints as a&#xD;
      possible treatment option as they seem to promote an anti-tumour immune response.&#xD;
&#xD;
      Some breast cancers have considerable cancer cell infiltration, which has been associated&#xD;
      with better prognosis. This is where white blood cells have permeated the cancer cell and&#xD;
      infiltrated the infected cell in an attempt to 'cure' the infected cell. Greater&#xD;
      immune-sensitivity is thought to correlate with greater cancer cell infiltration therefore&#xD;
      researchers are looking at ways in which immune-sensitivity can be improved.&#xD;
&#xD;
      One approach is to target inflammation that is known to play a major role in cancer&#xD;
      development and progression. Certain proteins can often be abnormally expressed in many&#xD;
      cancers. In preclinical models the investigators recently demonstrated that the presence of&#xD;
      certain cancer cell-derived proteins is critical for the growth of tumours formed by&#xD;
      melanoma, colorectal and breast mouse cancer cell lines. In the mouse preclinical trials it&#xD;
      indicated that by blocking the cancer cells ability to produce these proteins was associated&#xD;
      with a marked shift in the inflammatory profile. To test this theory, this study will use&#xD;
      aspirin as the chosen protein inhibitor and it is speculated that the addition of aspirin&#xD;
      might enhance the efficacy of the immune checkpoint blockade, avelumab.&#xD;
&#xD;
      TRIAL AIMS &amp; DESIGN&#xD;
&#xD;
      The aim of this trial is to determine whether aspirin enhances the efficacy of avelumab by&#xD;
      promoting a greater anti-cancer immune response. This is a multi-centre study recruiting&#xD;
      patients with confirmed TNBC from across four trial sites within the United Kingdom. It is&#xD;
      anticipate that 50 participants will need to be screened in order to successfully enrol 42&#xD;
      patients onto the trial. Patients will be randomly assigned to one of two arms:-&#xD;
&#xD;
        -  21 patients into Arm A: Avelumab + Proton Pump Inhibitor (PPI)&#xD;
&#xD;
        -  21 patients into Arm B: Avelumab + Aspirin + PPI&#xD;
&#xD;
      The estimated duration of participation for a participant is up to 10 weeks. Each subject&#xD;
      will be asked to complete 5 study visits. After successfully completing a Screening Visit&#xD;
      (Visit 1), each eligible subject will attend for a Baseline Visit (Visit 2) and will be&#xD;
      randomly assigned to treatment ARM A or ARM B. As part of the baseline visit subjects will&#xD;
      have their first of two breast tumour biopsies. All subjects will commence their PPI&#xD;
      following the baseline visit, those subjects randomised to ARM B will also commence their&#xD;
      Aspirin at this time. At visit 3 all subjects will receive their Avelumab infusion. At Visit&#xD;
      4 (Follow up Visit A) each subject will undergo their second research biopsy and further&#xD;
      research blood sampling this will be the first of two follow up visits, with Visit 5 (Follow&#xD;
      up Visit B) concluding the patients participation.&#xD;
&#xD;
      Visit windows have been used to aid visit planning in the hope that most research&#xD;
      appointments can take place in line with patients' ordinary care visits so as to reduce any&#xD;
      burden inflicted on the patient.&#xD;
&#xD;
      Adverse events (AEs) and Serious Adverse Events (SAEs) will be collected from the time of&#xD;
      randomisation and will continue to be collected up until Visit 5 (Follow up Visit B). All&#xD;
      post biopsy treatment will be at the discretion of the subject's treating physician per local&#xD;
      standard of care.&#xD;
&#xD;
      PATIENT IDENTIFICATION &amp; SCREENING&#xD;
&#xD;
      The study will be conducted as a multi-centre trial consisting of four NHS secondary care&#xD;
      out-paints clinics from across the United Kingdom. Each site has been chosen for their&#xD;
      expertise in oncology and their ability to identify patients for the trial directly from&#xD;
      their clinics with each centre treating between 20 to 40 patients per annum; this pool of&#xD;
      patients will constitute the source of recruitment in the study, PIC sites may also be used.&#xD;
&#xD;
      Potential participants will be identified by the Principal Investigators multi-disciplinary&#xD;
      team following recent diagnosis of TNBC. The multidisciplinary team shall be trained on the&#xD;
      study protocol and required to sign the trial delegation and training log in advance of&#xD;
      working on the trial or identifying participants. Potential participants will have at least&#xD;
      24 hours to read the patient information and decide if they would like to participate in the&#xD;
      study. Participants must have the capacity to provide fully informed consent. Participants&#xD;
      must not participate in any other therapeutic trials whilst on study treatments, however once&#xD;
      all study treatments as specified by trial schema are completed, participation in further&#xD;
      studies will not be affected.&#xD;
&#xD;
      At the screening visits the following data will be collected:-&#xD;
&#xD;
        -  Informed consent&#xD;
&#xD;
        -  Demographics&#xD;
&#xD;
        -  Medical history&#xD;
&#xD;
        -  Concomitant medication&#xD;
&#xD;
        -  Complete Physical examination&#xD;
&#xD;
        -  Vital Signs&#xD;
&#xD;
        -  12-lead Electrocardiograph (ECG)&#xD;
&#xD;
        -  ECOG performance status&#xD;
&#xD;
        -  Blood tests:-&#xD;
&#xD;
             -  Biochemistry: AST or ALT, LDH, Alk Phos, total bilirubin, sodium, potassium, urea,&#xD;
                creatinine, total protein, albumin, adjusted calcium&#xD;
&#xD;
             -  Haematology: FBC: Hb, Platelets, ANC, WBC, Lymphocytes, basophils, eosinophils&#xD;
&#xD;
             -  Thyroid Function: Free T4, TSH&#xD;
&#xD;
             -  Urinalysis&#xD;
&#xD;
        -  Pregnancy testing&#xD;
&#xD;
        -  Optional: Microbiome samples kit dispensation (Stool sample, Saliva sample, Nasal Swab)&#xD;
&#xD;
        -  Baseline tumour assessment&#xD;
&#xD;
      BASELINE VISIT&#xD;
&#xD;
      The following assessments will be conducted at the time of this visit:&#xD;
&#xD;
        -  Adverse Events&#xD;
&#xD;
        -  Concomitant medication&#xD;
&#xD;
        -  Vital Signs&#xD;
&#xD;
        -  ECOG performance status&#xD;
&#xD;
        -  Eligibility&#xD;
&#xD;
        -  Randomisation&#xD;
&#xD;
        -  Research Bloods (Circulating tumour DNA (CtDNA); Plasma for Cytokine Analysis; PBMC&#xD;
           extraction for immunophenotyping)&#xD;
&#xD;
        -  Mid-stream Urine sample for prostaglandin&#xD;
&#xD;
        -  Optional: Microbiome samples kit collection (Stool sample, Saliva sample, Nasal Swab)&#xD;
&#xD;
        -  Breast Tissue Biopsy&#xD;
&#xD;
        -  Pre-treatment dispensation (Arm A: PPI OR Arm B: PPI + aspirin)&#xD;
&#xD;
        -  Diary card training and dispensation&#xD;
&#xD;
        -  Pre-treatment Reminder Telephone call&#xD;
&#xD;
        -  TREATMENT &amp; FOLLOW UP VISITS&#xD;
&#xD;
      Visit 3: I.V visit&#xD;
&#xD;
      The following assessments will be conducted at the time of this visit:&#xD;
&#xD;
        -  Assessment of Adverse Events&#xD;
&#xD;
        -  Concomitant medication&#xD;
&#xD;
        -  Vital Signs&#xD;
&#xD;
        -  *Laboratory tests *(Biochemistry, Haematology and Urinalysis only if screening labs were&#xD;
           &gt;14 day prior to visit 3)&#xD;
&#xD;
        -  **Pregnancy testing **(only if screen pregnancy test was &gt;14days prior to day Visit 3)&#xD;
&#xD;
        -  Microbiome samples kit dispensation only (Stool, Saliva, Nasal Swab )&#xD;
&#xD;
        -  Mid-stream Urine sample for prostaglandin&#xD;
&#xD;
        -  Diary card - Pre-treatment compliance check (Arm A: PPI, Arm B: PPI + aspirin)&#xD;
&#xD;
        -  Avelumab (10mg/kg i.v.)&#xD;
&#xD;
      Visit 4: Follow up A The following assessments will be conducted at the time of this visit&#xD;
&#xD;
        -  Adverse Events&#xD;
&#xD;
        -  Concomitant medication&#xD;
&#xD;
        -  Research Bloods (CtDNA); Plasma for Cytokine Analysis; Immunophenotyping)&#xD;
&#xD;
        -  Microbiome sample kit collection (Stool sample, Saliva sample, Nasal Swab)&#xD;
&#xD;
        -  Mid-stream Urine sample for prostaglandin&#xD;
&#xD;
        -  Breast Tumour Biopsy&#xD;
&#xD;
        -  Diary card - Pre-treatment compliance check (Arm A: PPI, Arm B: PPI + aspirin)&#xD;
&#xD;
      Visit 5: Follow up B&#xD;
&#xD;
      The following assessments will be conducted at the time of this visit:&#xD;
&#xD;
        -  Adverse Events&#xD;
&#xD;
        -  Concomitant medication&#xD;
&#xD;
        -  Symptom Directed Physical examination&#xD;
&#xD;
        -  Vital Signs (BP, HR, Sp02, Temp)&#xD;
&#xD;
        -  ECOG performance status&#xD;
&#xD;
        -  Laboratory blood tests&#xD;
&#xD;
             -  Biochemistry: AST or ALT, LDH, Alk Phos, total bilirubin, sodium, potassium, urea,&#xD;
                creatinine, total protein, albumin, adjusted calcium&#xD;
&#xD;
             -  Haematology: FBC - Hb, Platelets, ANC, WBC, Lymphocytes, basophils, eosinophils&#xD;
&#xD;
             -  Thyroid Function: Free T4, TSH&#xD;
&#xD;
             -  Urinalysis&#xD;
&#xD;
        -  Research Bloods (CtDNA); Plasma for Cytokine Analysis; Immunophenotyping)&#xD;
&#xD;
      SAFETY REVIEW An Independent Trial Steering Committee (TSC) and Data Monitoring Committee&#xD;
      (IDMC) is being formed and will review trial safety data as a combined committee group.&#xD;
&#xD;
      TRANSLATIONAL RESEARCH With consent the following samples will be collected from patients and&#xD;
      held by the Manchester Cancer Research&#xD;
&#xD;
      Centre (MCRC) biobank:&#xD;
&#xD;
        -  Microbiome samples&#xD;
&#xD;
        -  Research blood samples&#xD;
&#xD;
        -  Breast Tissue Biopsies&#xD;
&#xD;
      The MCRC biobank holds a generic research tissue bank ethics approval under their HTA license&#xD;
      and will release the samples for relevant research, subject to approval by the Biobank's&#xD;
      Access Committee.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Withdrawn</overall_status>
  <why_stopped>
    IP breach&#xD;
  </why_stopped>
  <start_date type="Anticipated">September 2019</start_date>
  <completion_date type="Anticipated">February 28, 2021</completion_date>
  <primary_completion_date type="Anticipated">February 28, 2021</primary_completion_date>
  <phase>Phase 2</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Randomized</allocation>
    <intervention_model>Parallel Assignment</intervention_model>
    <intervention_model_description>Patients will be randomly assigned to one of two arms:-&#xD;
21 patients into Arm A: Avelumab + Proton Pump Inhibitor (PPI)&#xD;
21 patients into Arm B: Avelumab + Aspirin + PPI</intervention_model_description>
    <primary_purpose>Treatment</primary_purpose>
    <masking>Single (Outcomes Assessor)</masking>
    <masking_description>Laboratory staff and the blinded statistician will remain blinded to trial treatment arm</masking_description>
  </study_design_info>
  <primary_outcome>
    <measure>Mean combined gene expression of COX-2 tumour-promoting genes</measure>
    <time_frame>7 weeks</time_frame>
    <description>Mean combined gene expression of COX-2 tumour-promoting genes, in samples taken post treatment</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Post treatment tumour infiltrating lymphocytes (TIL)</measure>
    <time_frame>7 weeks</time_frame>
    <description>Post treatment tumour infiltrating lymphocytes (TIL) assessed by IHC using standardised methodology (Salgado et al., 2015)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Mean combined gene expression of the elements of the denominator of the COX-2 ratio</measure>
    <time_frame>7 weeks</time_frame>
    <description>Mean combined gene expression of the elements of the denominator of the COX-2 ratio, in samples taken post treatment.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>The post treatment COX-2 ratio</measure>
    <time_frame>7 weeks</time_frame>
    <description>The post treatment COX-2 ratio (a ratio of mean expression of 9 tumour-promoting to 15 tumour-inhibitory genes)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Safety and tolerability assessed by grade 3-4 AEs and SAEs</measure>
    <time_frame>7 weeks</time_frame>
    <description>Safety and tolerability assessed by grade 3-4 AEs and SAEs. In addition, grade 2 renal toxicity AEs (creatinine rise) and grade 2 gastrointestinal toxicity AEs (duodenal perforation, dyspepsia, oesophageal haemorrhage, dysphagia, oesophageal pain, oesophageal perforation, oesophagitis).</description>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">0</enrollment>
  <condition>Breast Cancer</condition>
  <arm_group>
    <arm_group_label>(Arm A) Avelumab + PPI</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>21 patients into Arm A: Avelumab + Proton Pump Inhibitor (PPI)</description>
  </arm_group>
  <arm_group>
    <arm_group_label>(Arm B) Avelumab + Aspirin + PPI</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>21 patients into Arm B: Avelumab + Aspirin + PPI</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Avelumab</intervention_name>
    <description>Colourless odourless aqueous solution for infusion at dose of 10mg/kg</description>
    <arm_group_label>(Arm A) Avelumab + PPI</arm_group_label>
    <arm_group_label>(Arm B) Avelumab + Aspirin + PPI</arm_group_label>
    <other_name>Bavencio</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Aspirin</intervention_name>
    <description>300mg tablets</description>
    <arm_group_label>(Arm B) Avelumab + Aspirin + PPI</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Lansoprazole (Proton Pump Inhibitor)</intervention_name>
    <description>300mg capsule</description>
    <arm_group_label>(Arm A) Avelumab + PPI</arm_group_label>
    <arm_group_label>(Arm B) Avelumab + Aspirin + PPI</arm_group_label>
    <other_name>Lansoprazole</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          1. Written informed consent, willing and able to comply with the trial protocol for the&#xD;
             duration of the trial including all treatments and scheduled biopsies.&#xD;
&#xD;
          2. Female patients, age 18 and over&#xD;
&#xD;
          3. Histologically confirmed triple negative invasive breast cancer as defined as&#xD;
             oestrogen receptor (ER) negative, progesterone receptor (PgR) negative (if available,&#xD;
             otherwise PgR unknown), (as defined by Allred score 0- 2 or &lt;1% of tumour cells&#xD;
             positive for stain) and HER2 negative (immunohistochemistry 0/1+ or negative by in&#xD;
             situ hybridization) as determined by local laboratory. Have previously untreated,&#xD;
             non-metastatic TNBC with a tumour amenable to multiple biopsies including a T stage of&#xD;
             at least T2. Note multifocal primary tumours are allowed providing at least one tumour&#xD;
             meets the criteria above. All biopsies should be obtained from the same tumour.&#xD;
&#xD;
          4. Have previously untreated, non-metastatic TNBC with a tumour amenable to multiple&#xD;
             biopsies including a T stage of at least T2. Note multifocal primary tumours are&#xD;
             allowed providing at least one tumour meets the criteria above. All biopsies should be&#xD;
             obtained from the same tumour.&#xD;
&#xD;
          5. ECOG performance status 0/1&#xD;
&#xD;
          6. Women of childbearing potential (WOCBP), defined as not surgically sterilized or not&#xD;
             post-menopausal for at least 24 months if age ≤55 years or 12 months if age &gt;55 years,&#xD;
             must have a negative serum or urine pregnancy test (minimum sensitivity 25 IU/L or&#xD;
             equivalent units of HCG) within 14 days prior to the start of either IMP study&#xD;
             treatment (Avelumab, and Aspirin if applicable).&#xD;
&#xD;
          7. Adequate organ function:-&#xD;
&#xD;
               1. Adequate Hepatic function:&#xD;
&#xD;
                    -  AST and ALT &lt;2.5x ULN&#xD;
&#xD;
                    -  Alkaline phosphatase ≤2 x ULN&#xD;
&#xD;
                    -  Total Bilirubin within normal range i.e. ≤1.5 x ULN. If AST/ALT and Alkaline&#xD;
                       phosphatase are within normal limits then isolated elevation of bilirubin to&#xD;
                       3≤ ULN and a presumptive diagnosis of Gilbert's syndrome is permitted.&#xD;
&#xD;
               2. Adequate organ function as defined by:&#xD;
&#xD;
                    -  Bone marrow function: Hb ≥100g/L&#xD;
&#xD;
                    -  Absolute neutrophil count ≥1.5 x 109/L&#xD;
&#xD;
                    -  Platelets ≥100 x 109/L&#xD;
&#xD;
                    -  Hemoglobin &gt;9 g/dL&#xD;
&#xD;
                    -  Renal function: Creatinine ≤1.5 x ULN OR &gt; 50ml/min using the&#xD;
                       Cockcroft-Gault formula (appendix 4).&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
        Patients meeting any of the following criteria must not be enrolled in the study:&#xD;
&#xD;
          1. Prior systemic anti-cancer treatment (immune therapy, targeted therapy, vaccine&#xD;
             therapy, or investigational treatment) for triple negative breast cancer.&#xD;
&#xD;
          2. Current use of a prohibited medication as described in section 7.11.&#xD;
&#xD;
          3. Malignancy within the last 5 years except: adequately treated non-melanoma skin&#xD;
             cancer; curatively treated in situ cancer of the cervix, ductal carcinoma in situ&#xD;
             (DCIS); stage 1, grade I endometrial carcinoma.&#xD;
&#xD;
          4. Has received a live vaccine within 30 days of the first dose of study treatment.&#xD;
&#xD;
             NB Seasonal influenza vaccines are generally inactivated flu vaccines and are allowed;&#xD;
             intranasal influenza vaccines (eg FluMist®) are live attenuated vaccines and are not&#xD;
             allowed.&#xD;
&#xD;
          5. Contraindications to aspirin dosing including hypersensitivity to aspirin (eg known&#xD;
             aspirin sensitive asthma; history of peptic ulcer disease, gastric bleeding or&#xD;
             cerebrovascular haemorrhages; haemorrhagic diathesis.&#xD;
&#xD;
          6. Evidence of distant metastases apparent prior to randomisation. Patients who are&#xD;
             diagnosed with distant metastases during the course of the study can complete study&#xD;
             procedures if willing to do so.&#xD;
&#xD;
          7. Significant cardiovascular disease including a history of myocardial infarction, acute&#xD;
             coronary syndrome or coronary angioplasty/stenting/bypass grafting within the last 6&#xD;
             months or clinically significant congestive heart failure.&#xD;
&#xD;
          8. Any other serious or unstable pre-existing medical conditions (aside from malignancy&#xD;
             exceptions specified above), psychiatric disorders, or other conditions that in the&#xD;
             opinion of the investigator could interfere with the patient's safety, obtaining&#xD;
             informed consent, or compliance with study procedures.&#xD;
&#xD;
          9. Known Human Immunodeficiency Virus (HIV), Hepatitis B Virus (HBV), or Hepatitis C&#xD;
             Virus (HCV) infection (patients with laboratory evidence of cleared or chronic (not&#xD;
             active) HBV and HCV infection will be permitted).&#xD;
&#xD;
         10. Patients with active, known or suspected autoimmune disease. Patients with type 1&#xD;
             diabetes mellitus, hypothyroidism only requiring hormone replacement, skin or&#xD;
             rheumatological disorders (such as vitiligo, psoriasis, rheumatoid arthritis or&#xD;
             alopecia) not requiring systemic treatment, or conditions not expected to recur in the&#xD;
             absence of an external trigger will be permitted to enrol. Autoimmune conditions such&#xD;
             as ulcerative colitis that have been definitively treated (e.g. with total colectomy)&#xD;
             will be permitted to enrol but should be discussed with the CI.&#xD;
&#xD;
         11. Patients with a condition requiring systemic treatment with either corticosteroids&#xD;
             (&gt;10 mg daily prednisone equivalent) or other immunosuppressive medications within 14&#xD;
             days of study drug administration. Inhaled or topical steroids and adrenal replacement&#xD;
             steroid doses &gt; 10 mg daily prednisone equivalent are permitted in the absence of&#xD;
             active autoimmune disease.&#xD;
&#xD;
         12. Patients with interstitial lung disease that is symptomatic or may interfere with the&#xD;
             detection or management of suspected drug-related pulmonary toxicity.&#xD;
&#xD;
         13. Patients unable to swallow orally administered medication and patients with&#xD;
             gastrointestinal disorders likely in to interfere with absorption of the trial&#xD;
             medication.&#xD;
&#xD;
         14. Females who are pregnant or breast-feeding.&#xD;
&#xD;
         15. Active infection requiring systemic treatment.&#xD;
&#xD;
         16. Current or previous regular use of aspirin (at any dose) or current use of another&#xD;
             NSAID for any indication (see appendix IV for list of medications not permitted in the&#xD;
             trial). Regular aspirin use is defined as taking aspirin more than twice in any given&#xD;
             week for more than 4 consecutive weeks. Current NSAID use is defined as taking any&#xD;
             NSAID for more than a week in the preceding month. If investigators feel that this&#xD;
             definition may unfairly exclude a participant, this can be discussed with the CI/MCTU&#xD;
             and a case by case decision will be made.&#xD;
&#xD;
         17. Known immediate or delayed hypersensitivity reaction or idiosyncrasy to drugs&#xD;
             chemically related to the study treatments.&#xD;
      </textblock>
    </criteria>
    <gender>Female</gender>
    <gender_based>Yes</gender_based>
    <gender_description>Female patients, age 18 and over</gender_description>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Anne Armstrong</last_name>
    <role>Principal Investigator</role>
    <affiliation>The Christie NHS Foundation Trust</affiliation>
  </overall_official>
  <verification_date>July 2019</verification_date>
  <study_first_submitted>November 22, 2018</study_first_submitted>
  <study_first_submitted_qc>January 4, 2019</study_first_submitted_qc>
  <study_first_posted type="Actual">January 7, 2019</study_first_posted>
  <last_update_submitted>July 19, 2019</last_update_submitted>
  <last_update_submitted_qc>July 19, 2019</last_update_submitted_qc>
  <last_update_posted type="Actual">July 22, 2019</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>The Christie NHS Foundation Trust</investigator_affiliation>
    <investigator_full_name>Rachel Cox</investigator_full_name>
    <investigator_title>Non CI _Project manager</investigator_title>
  </responsible_party>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Breast Neoplasms</mesh_term>
    <mesh_term>Triple Negative Breast Neoplasms</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Aspirin</mesh_term>
    <mesh_term>Avelumab</mesh_term>
    <mesh_term>Lansoprazole</mesh_term>
    <mesh_term>Dexlansoprazole</mesh_term>
    <mesh_term>Proton Pump Inhibitors</mesh_term>
  </intervention_browse>
  <patient_data>
    <sharing_ipd>No</sharing_ipd>
  </patient_data>
  <!-- Results have not yet been posted for this study                                          -->
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT03794596
org study id: CFT/sp123
secondary id: 2018-004121-80
secondary id: 16_DOG02_289
secondary id: 017NovCC1079
nct id: NCT03794596
lead sponsor: 
collaborator: 
has dmc: Yes
is fda regulated drug: No
is fda regulated device: No
is us export: No
This research is being done because the investigators are looking for new and better ways to
      treat a type of breast cancer called triple negative breast cancer. This type of breast
      cancer can be more difficult to treat than other types of breast cancer as it does not
      respond to drugs such as hormonal therapies. One type of treatment that looks promising is
      immunotherapy using new drugs called immune checkpoint inhibitors.

      Immune checkpoints help to regulate the immune system and can stop the immune system from
      attacking cancer cells. Immune checkpoint inhibitors block this 'off-switch' and aim to help
      the immune system control the cancer. These drugs have been very effective in other cancers
      such as melanoma and are now being tested in breast cancer.

      In this study patients will receive an immune checkpoint inhibitor called avelumab. Half the
      patients on the study will also receive aspirin tablets for approximately 18 days as the
      investigators wish to compare the effects of avelumab alone versus in combination with
      aspirin.

      Patients will attend hospital approximately five times in order to complete all necessary
      study assessments. The first visit screens patients for suitability, after which a baseline
      visit will collect the first of two breast tissue biopsies. At the third visit a single dose
      of Avelumab will be given via an infusion (a drip in the forearm). Patients will then return
      approximately two weeks later for a second breast tissue biopsy before having a final follow
      up visit another two weeks later. Blood and urine samples will be taken at various visits
      throughout the study to help us learn more about the effects these treatments may have on the
      immune system and on breast cancer cells.
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

      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.

      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.

      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.
allocation: Randomized
intervention model: Parallel Assignment
intervention model description: 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
primary purpose: Treatment
masking: Single (Outcomes Assessor)
masking description: Laboratory staff and the blinded statistician will remain blinded to trial treatment arm
measure: Mean combined gene expression of COX-2 tumour-promoting genes
time frame: 7 weeks
description: Mean combined gene expression of COX-2 tumour-promoting genes, in samples taken post treatment
measure: Post treatment tumour infiltrating lymphocytes (TIL)
time frame: 7 weeks
description: Post treatment tumour infiltrating lymphocytes (TIL) assessed by IHC using standardised methodology (Salgado et al., 2015)
measure: Mean combined gene expression of the elements of the denominator of the COX-2 ratio
time frame: 7 weeks
description: Mean combined gene expression of the elements of the denominator of the COX-2 ratio, in samples taken post treatment.
measure: The post treatment COX-2 ratio
time frame: 7 weeks
description: The post treatment COX-2 ratio (a ratio of mean expression of 9 tumour-promoting to 15 tumour-inhibitory genes)
measure: Safety and tolerability assessed by grade 3-4 AEs and SAEs
time frame: 7 weeks
description: Safety and tolerability assessed by grade 3-4 AEs and SAEs. In addition, grade 2 renal toxicity AEs (creatinine rise) and grade 2 gastrointestinal toxicity AEs (duodenal perforation, dyspepsia, oesophageal haemorrhage, dysphagia, oesophageal pain, oesophageal perforation, oesophagitis).
arm group label: (Arm A) Avelumab + PPI
arm group type: Experimental
description: 21 patients into Arm A: Avelumab + Proton Pump Inhibitor (PPI)
arm group label: (Arm B) Avelumab + Aspirin + PPI
arm group type: Experimental
description: 21 patients into Arm B: Avelumab + Aspirin + PPI
intervention type: Drug
intervention name: Avelumab
description: Colourless odourless aqueous solution for infusion at dose of 10mg/kg
arm group label: (Arm A) Avelumab + PPI
arm group label: (Arm B) Avelumab + Aspirin + PPI
other name: Bavencio
intervention type: Drug
intervention name: Aspirin
description: 300mg tablets
arm group label: (Arm B) Avelumab + Aspirin + PPI
intervention type: Drug
intervention name: Lansoprazole (Proton Pump Inhibitor)
description: 300mg capsule
arm group label: (Arm A) Avelumab + PPI
arm group label: (Arm B) Avelumab + Aspirin + PPI
other name: Lansoprazole
criteria: 
gender: Female
gender based: Yes
gender description: Female patients, age 18 and over
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Anne Armstrong
role: Principal Investigator
affiliation: The Christie NHS Foundation Trust
responsible party type: Principal Investigator
investigator affiliation: The Christie NHS Foundation Trust
investigator full name: Rachel Cox
investigator title: Non CI _Project manager
mesh term: Breast Neoplasms
mesh term: Triple Negative Breast Neoplasms
mesh term: Aspirin
mesh term: Avelumab
mesh term: Lansoprazole
mesh term: Dexlansoprazole
mesh term: Proton Pump Inhibitors
sharing ipd: No