Advanced gastrooesophageal and colorectal cancer MedDRA version: 20.0 Level: PT Classification code 10009944 Term: Colon cancer System Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) MedDRA version: 20.0 Level: LLT Classification code 10042080 Term: Stomach cancer System Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) MedDRA version: 21.0 Level: PT Classification code 10030137 Term: Oesophageal adenocarcin
Conditions
Interventions
Product Name: Domatinostat
Product Code: Domatinostat
Pharmaceutical Form: Tablet
INN or Proposed INN: (E)-N-(2-aminophenyl)-3-(1-(4-(1-methyl-1H-pyrazol-4-yl)-phenylsulfonyl)-1H-pyrrol-3-yl)-acryl
proposed INN: domatinostat
CAS Number: 1186222-89-8
Current Sponsor code: 4SC-202
Other descriptive name: None
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 100mg
Sponsors
The Royal Marsden NHS Foundation Trust
Eligibility
Sex/Gender
All
Inclusion 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: a. Absolute neutrophil count (ANC) =1.5 x109/L b. White blood count >3x109/L c. Platelets =100x109/L d. 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 a. International Normalised Ratio (INR) < 1.5 b. 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 3 monthsafter 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 3 months after the last dose of trial treatment. 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. xvii) Measurable disease
Exclusion criteria
Exclusion criteria: Patients are not eligible for the trial if any of the exclusion criteria below are met: 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: a. Brain metastases that have been treated locally and are clinically stable for at least 2 weeks prior to enrolment b. 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) c. Subjects must be either off steroids or on a stable or decreasing dose of 110bpm) e. Patients with a marked baseline prolongation of QT/QTc interval, e.g., repeated demonstration of a QTc interval >450 msec (Grade 1 NCI-CTCAE); Long-QT-Syndrome (QTcF is applicable) 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
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: This trial is designed to evaluate the safety and efficacy of administering Domatinostat a histone deacetylate lysine-specific demethylase inhibitor plus avelumab, an anti-PD-L1 monoclonal antibody in patients with advanced bowel, stomach or oesophageal adenocarcinoma who have been previously treated with chemotherapy. This trial is in 2 stages: the first stage (Phase IIA, safety run-in) will establish a safe and tolerated dose of Domatinostat in combination with avelumab and the second stage (Phase IIB, efficacy) will assess the efficacy of this combination therapy in achieving radiological response according to RECIST 1.1 criteria. ;Secondary Objective: Assess safety and side effects of Domatinostat plus avelumab and impact on survival and disease control in trial population. To assess the effect of each drug on the cancer cells in biopsies. To assess the effect of therapy on survival. ;Primary end point(s): Primary Objective is to assess the efficacy of the addition of Domatinostat to avelumab therapy in patients with previously treated advanced OGA and CRC. Outcome measures: ORR according to RECIST 1.1 measured using CT imaging. Timepoint(s) of evaluation of this outcome measure is best response at 6 months. ;Timepoint(s) of evaluation of this end point: Primary endpoint of the main study is objective response. This will be assessed on CT every 6 weeks. Response will be best response assessed at any timepoint. | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): Toxicity and safety Progression free survival Overall survival Translational endpoints;Timepoint(s) of evaluation of this end point: Toxicity and safety will be assessed throughout study on an ongoing basis Survival will be assessed on an ongoing basis Translational endpoints will be based on biopsy and plasma samples at baseline, C1 and C4. | — |
Countries
United Kingdom
Contacts
Public ContactMiss Claire Saffery
The Royal Marsden NHS Foundation Trust
Outcome results
None listed