| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Advanced gastrooesophageal and colorectal cancer |
|
| E.1.1.1 | Medical condition in easily understood language |
| Gastric, oesophageal and bowel cancer which cannot be cured by surgery and which has been treated before with chemotherapy |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10009944 |
| E.1.2 | Term | Colon cancer |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10042080 |
| E.1.2 | Term | Stomach cancer |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 21.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10030137 |
| E.1.2 | Term | Oesophageal adenocarcinoma |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| 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. |
|
| E.2.2 | Secondary objectives of the trial |
| 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. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal 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 (a least one target lesion) by RECIST 1.1 |
|
| E.4 | Principal 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 <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:
a. Patients with diabetes type I, vitiligo, psoriasis, hypo- or hyperthyroid disease not requiring immunosuppressive treatment are eligible
b. 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
c. 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:
a. Myocardial infarction within the previous 6 months
b. Unstable angina
c. Congestive heart failure ≥NYHA Classification Class II
d. Serious cardiac arrhythmia requiring medication (for example,
ventricular tachycardia, supraventricular tachycardia or atrial fibrillation with a resting heart rate > 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 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
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.
xxiii) Patients unable to swallow orally administered medication |
|
| E.5 End points |
| E.5.1 | 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.
|
|
| E.5.1.1 | 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. |
|
| E.5.2 | Secondary end point(s) |
Toxicity and safety
Progression free survival
Overall survival
Translational endpoints |
|
| E.5.2.1 | 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. |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | No |
| E.8.1.1 | Randomised | No |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 10 |
| E.8.5 | The trial involves multiple Member States | No |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | No |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.7 | Trial has a data monitoring committee | Yes |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
The study end date is deemed to be the date of last data capture. Patient follow up will continue until death to evaluate the survival endpoint of the trial.
The ‘end of trial notification’ will be submitted to the relevant regulatory authorities (e.g. UK MHRA) and ethics committees within 90 days by the sponsor. Following the submission of the end of trial notification to the MHRA and REC, the sponsor should ensure that end of trial report is submitted within 12 months of this notification. |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 3 |
| E.8.9.1 | In the Member State concerned months | 0 |
| E.8.9.1 | In the Member State concerned days | 1 |
| E.8.9.2 | In all countries concerned by the trial years | 0 |
| E.8.9.2 | In all countries concerned by the trial months | 0 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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