Clinical Trials /

Epigenetic Modulation of the immunE Response in GastrointEstinal Cancers (EMERGE)

NCT03812796

Description:

A multicenter phase II non-randomised trial assessing the efficacy of domatinostat (4SC-202) plus avelumab in patients with GI cancer

Related Conditions:
  • Adenocarcinoma of the Gastroesophageal Junction
  • Colorectal Adenocarcinoma
  • Esophageal Adenocarcinoma
  • Gastric Adenocarcinoma
Recruiting Status:

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Epigenetic Modulation of the immunE Response in GastrointEstinal Cancers (EMERGE)
  • Official Title: Epigenetic Modulation of the immunE Response in GastrointEstinal Cancers (EMERGE)

Clinical Trial IDs

  • ORG STUDY ID: CCR 4745
  • NCT ID: NCT03812796

Conditions

  • Cancer
  • GI Cancer

Interventions

DrugSynonymsArms
Domatinostat4SC-202Domatinostat plus Avelumab
AvelumabDomatinostat plus Avelumab

Purpose

A multicenter phase II non-randomised trial assessing the efficacy of domatinostat (4SC-202) plus avelumab in patients with GI cancer

Detailed Description

      During this phase II randomised trial patients with microsatellite stable colorectal or
      gastroesophageal cancer which has previously been treated with chemotherapy will be treated
      with domatinostat plus avelumab.
    

Trial Arms

NameTypeDescriptionInterventions
Domatinostat plus AvelumabExperimentalThis is a multicentre open-label, phase II non-randomised clinical trial domatinostat plus avelumab (two separate cohorts in phase IIB part of trial).
  • Domatinostat
  • Avelumab

Eligibility Criteria

        Inclusion Criteria

        i. Male/female patients aged ≥18 years ii. Histologically confirmed gastric,
        gastro-oesophageal junction or oesophageal adenocarcinoma (referred to as oesophagogastric
        adenocarcinoma (OGA) in this protocol) or colorectal adenocarcinoma (referred to as CRC in
        this protocol) iii. Agrees to undergo biopsies for translational endpoints iv. Tumour must
        be mismatch repair proficient assessed using a validated test such as immunohistochemistry
        for mismatch repair proteins or microsatellite instability testing v. Tumours should be
        advanced and inoperable or metastatic vi. Patients must have received at least one prior
        chemotherapy treatment for their cancer, have no established treatment option, or decides
        against an established treatment option.

        vii. Adequate bone marrow function:

          1. Absolute neutrophil count (ANC) ≥1.5 x109/L

          2. White blood count >3x109/L

          3. Platelets ≥100x109/L

          4. Haemoglobin (Hb) ≥9g/dl (can be post-transfusion) viii. Adequate renal function:
             Creatinine Clearance o ≥30ml/min is required. This may be calculated as per local
             practice, if calculated CrCl is <60ml/min then EDTA is required to demonstrate CrCl of
             ≥30ml/min If available, the EDTA clearance should always take precedence over the
             creatinine clearance.

        ix. Adequate liver function

        a. Serum bilirubin ≤1.5x ULN b. ALT/AST ≤2.5x ULN or ALT/AST ≤5x ULN if metastatic disease
        to liver x. Adequate coagulation profile

          1. International Normalised Ratio (INR) < 1.5

          2. Activated Prothrombin Time (APTT) < 1.5xULN xi. Patients on oral anticoagulation are
             advised to change to low molecular weight heparin prior to study entry to be eligible
             xii. ECOG performance status 0-1 xiii. Patient is fit to undergo all protocol
             investigations and receive all protocol treatment based on the assessment oncology
             clinics xiv. Signed and dated informed consent document indicating that the patient
             (or legally acceptable representative) has been informed of all the pertinent aspects
             of the trial prior to enrolment.

        xv. Willingness and ability to comply with the protocol for the duration of the study
        including scheduled visits, examinations, investigations and treatment plans xvi. Pregnancy
        must be excluded with a negative serum pregnancy test, within 7 days before initiation of
        therapy, if the risk of conception exists. Sexually active female patients must be
        surgically sterile or be postmenopausal or must agree to use highly effective contraception
        which must be used for 10 days before the negative pregnancy test. Sexually active male
        patients must be surgically sterile or must agree to use highly effective contraception,
        i.e. methods with a failure rate of <1% per year (see section 6.4 for full definition and
        examples of highly effective contraception). Highly effective contraception must be agreed
        to be used throughout the study and for 30 days after last avelumab treatment if risk of
        conception exists. Female patients of child-bearing potential should be strictly advised to
        use a highly effective contraceptive measure, from the time of screening to 30 days after
        the last dose of trial treatment. If the patient uses a hormonal contraceptive method, the
        patient's partner should additionally use a condom. Male patients with partners of child
        bearing potential should be strictly advised to use barrier contraception in addition to
        having their partner use another method of contraception during the trial and for three
        months after the last dose. Male patients should also be advised to abstain from sexual
        intercourse with pregnant or lactating women, or to use condoms.

        Exclusion Criteria

        i. Any contraindication or known hypersensitivity reaction to any of the study drugs ii.
        Persisting toxicity relating to prior therapy of >grade 1 CTCAE version 4.03 except
        alopecia of any grade and neuropathy ≤ grade 2, or other grade ≤2 not constituting a safety
        risk based on investigators judgement iii. Any prior treatment with immunotherapy including
        anti-PD-1or PD-L1 therapy or other immunomodulatory drugs.

        iv. All subjects with brain metastases, except those meeting the following criteria:

          1. Brain metastases that have been treated locally and are clinically stable for at least
             2 weeks prior to enrolment

          2. No ongoing neurological symptoms that are related to the brain localization of the
             disease (sequelae that are a consequence of the treatment of the brain metastases are
             acceptable)

          3. Subjects must be either off steroids or on a stable or decreasing dose of <10mg daily
             prednisone (or equivalent)

        v. Known severe hypersensitivity reactions to monoclonal antibodies (Grade ≥ 3 NCI CTCAE v
        4.0), any history of anaphylaxis, or uncontrolled asthma (i.e., 3 or more features of
        partially controlled asthma) vi. Patients who have received chemotherapy or radiotherapy
        for a previous malignancy in the past 3 years.

        vii. Any immunodeficiency disorder viii. Any active, known or suspected autoimmune disease
        that might deteriorate when receiving immunostimulatory agent, with the following
        exceptions:

          1. Patients with diabetes type I, vitiligo, psoriasis, hypo- or hyperthyroid disease not
             requiring immunosuppressive treatment are eligible

          2. Patients requiring hormone replacement with corticosteroids are eligible if the
             steroids are administered only for the purpose of hormonal replacement and at doses
             ≤10mg (or equivalent) of prednisolone per day

          3. Administration of steroids through a route known to result in minimal systemic
             exposure (topical, intranasal, intra-ocular, intra-articular or inhalation) are
             acceptable. Steroids as pre-medication for hypersensitivity reactions e.g. CT contrast
             are also acceptable.

        ix. Prior organ transplantation, including allogeneic stem-cell transplantation x. Active
        infection requiring systemic therapy xi. History of inflammatory bowel disease xii.
        Patients with a history of interstitial lung disease or radiological evidence of pulmonary
        fibrosis xiii. Cerebrovascular disease (including transient ischaemic attacks (TIA) and
        strokes) within the previous 6 months xiv. Cardiovascular diseases as follows:

          1. Myocardial infarction within the previous 6 months

          2. Unstable angina

          3. Congestive heart failure ≥NYHA Classification Class II

          4. Serious cardiac arrhythmia requiring medication (for example, ventricular tachycardia,
             supraventricular tachycardia or atrial fibrillation with a resting heart rate >
             110bpm) xv. Current signs or symptoms of any other severe progressive or uncontrolled
             hepatic, haematologic, gastrointestinal, endocrine, respiratory or cardiac disease,
             which in the opinion of the investigator, might impair the subject's tolerance of
             trial treatment or procedures.

        xvi. Major surgery, major trauma or open biopsy within 28 days prior to registration (not
        including staging laparoscopy) xvii. Evidence of bleeding diathesis or coagulopathy xviii.
        Active non-healing wound, ulcer or bone fracture requiring therapy xix. Known positive
        tests for human immunodeficiency virus (HIV) infection or known acquired immunodeficiency
        syndrome, hepatitis A or C virus, acute or chronic active hepatitis B infection xx. Use of
        live attenuated vaccine within 28 days of initiation of study therapy, or anticipation that
        a live attenuated vaccine will be required during the study xxi. Current lactation
        (patients that discontinue breastfeeding may be eligible) xxii. Other severe acute or
        chronic medical conditions or psychiatric conditions including recent (within the past
        year) or active suicidal ideation or behaviour; or laboratory abnormalities that may
        increase the risk associated with study participation or study treatment administration or
        may interfere with the interpretation of study results and, in the judgment of the
        investigator, would make the patient inappropriate for entry into this study.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Safety run-in phase: To establish a safe and tolerable dose of domatinostat in combination with avelumab for use in the main (Phase IIB efficacy) phase of the trial
Time Frame:The DLT period is 28 days following the first treatment with domatinostat and avelumab
Safety Issue:
Description:Progression through dosing levels will be determined by the occurrence of dose limiting toxicities in the study population.

Secondary Outcome Measures

Measure:Number of patients with adverse events (according to NCI-CTCAE version 4) as a measure of safety and tolerability
Time Frame:Up to 90 days after last dose
Safety Issue:
Description:Safety of domatinostat and avelumab will be assessed by summarizing adverse events as a proportion
Measure:Progression free survival according to RECIST 1.1
Time Frame:upto 2 years
Safety Issue:
Description:PFS will be summarized using Kaplan Meier methods, presenting median survival with 95% confidence intervals. PFS is defined as the time from day of first treatment to disease progression or death from any cause. Patients without an event will be censored on day of last radiological follow up
Measure:Overall survival
Time Frame:upto 2 years
Safety Issue:
Description:OS will be summarized using Kaplan Meier methods, presenting median survival with 95% confidence intervals. OS is defined as the time from say of first treatment to death from any cause. Alive patients will be censored at the last follow up date
Measure:Disease control rate
Time Frame:At 6 and 12 months on treatment
Safety Issue:
Description:The proportion of patients with best disease control (CR, PR or SD) at 6 months and 12 months from initiation of combination treatment will be presented with a 95% confidence interval
Measure:Duration of objective response according to RECIST 1.1
Time Frame:upto 2 years
Safety Issue:
Description:DoOR will be summarized using Kaplan Meier methods. DoOR is defined as the time between the initial response to treatment and subsequent disease progression or relapse. Patients without an event will be censored on day of last radiological assessment

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Royal Marsden NHS Foundation Trust

Last Updated