| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Patients with advanced mismatch repair proficient oesophagogastric cancer |
|
| E.1.1.1 | Medical condition in easily understood language |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Digestive System Diseases [C06] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 21.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10071114 |
| E.1.2 | Term | Metastatic gastric adenocarcinoma |
| E.1.2 | System Organ Class | 100000004864 |
|
| 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 |
| The trial is designed to evaluate the safety and efficacy of administering DKN-01, a Wnt inhibitor, plus atezolizumab, an anti-PDL1 monoclonal antibody in patients with advanced 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 DKN-01 in combination with atezolizumab 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 |
- To assess safety and side effects of DKN-01 plus atezolizumab and impact of survival and disease control in trial population
- To assess the effect of each drug on the cancer cells in biopsies.
- To asess the effect of therapy on survival. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Signed Informed Consent Form
2. Male or female patients age ≥18 years at time of signing Informed Consent Form
3. Ability to comply with the study protocol, in the investigator's judgment
4. Histologically or cytologically confirmed advanced or metastatic gastroesophageal adenocarcinoma. Patients with HER2 positive cancer are permitted after having received HER2 targeted therapy in first line as per Standard of Care
5. Disease progression during or following treatment with one or two lines of treatment for advanced disease, one of which must have been a platinum and fluoropyrimidine combination.
6. Measurable, or non-measurable but evaluable, disease per RECIST v1.1
7. Evidence of tumor mismatch repair proficiency and/or MSI stability must be documented through testing of a representative tumor tissue specimen using immunohistochemistry for MMR proteins or MSI testing. Local testing or historical results of archival tumour tissue is satisfactory for trial entry
8. ECOG 0-1
9. Life expectancy > 3 months as per physician judgement
10. Adequate hematologic and end-organ function, defined by the following laboratory test results obtained within 14 days prior to initiation of study treatment:
- ANC greater ≥ 1.5 x 109/L without granulocyte colony-stimulating factor support
- Lymphocyte count ≥ 0.5 x109/L
- Platelet count ≥ 100 x 109/L without transfusion
- Hemoglobin ≥ 90 g/L (9 g/dL) (patients may be transfused to meet this criterion)
- AST, ALT, and alkaline phosphatase (ALP) ≤ 2.5 x upper limit of normal (ULN), with the following exceptions:
i. Patients with documented liver metastases: AST and ALT ≤ 5 x ULN
ii. Patients with documented liver or bone metastases: ALP ≤ 5 x ULN
iii. Serum bilirubin ≤ 1.5 x ULN with the following exception:
- Patients with known Gilbert disease: serum bilirubin level ≤ 3 x ULN
- Serum creatinine ≤ 1.5 x ULN or Creatinine clearance (CrCl) ≥ 50 mL/min (calculated using the Cockcroft-Gault formula)
- Serum albumin ≥ 25 g/L (2.5 g/dL)
11. For patients not receiving therapeutic anticoagulation: INR or aPTT ≤ 1.5 x ULN
12. For patients receiving therapeutic anticoagulation: stable anticoagulant regimen
13. Negative hepatitis B surface antigen (HBsAg) test at screening
14. Negative total hepatitis B core antibody (HBcAb) test at screening, or positive total HBcAb test followed by quantitative hepatitis B virus (HBV) DNA ≤ 500 IU/mL at screening
15. Negative hepatitis C virus (HCV) antibody test at screening, or positive HCV antibody test followed by a negative HCV RNA test at screening
16. Tumour is amenable to safe repeated biopsies and patient agrees to undergo biopsies for translational endpoints.
17. In patients who are receiving anticoagulation, stopping anticoagulation for biopsies must be deemed safe by the treating team.
28. Tumours should be advanced and inoperable or metastatic
29. Patients on oral anticoagulation are required to change to low molecular weight heparin prior to study entry to be eligible. In patients who are receiving anticoagulation, stopping anticoagulation for biopsies must be deemed safe by the treating team.
30. Patient is fit to undergo all protocol investigations and receive all protocol treatment based on the assessment oncology clinics
31. Willingness and ability to comply with the protocol for the duration of the study including scheduled visits, examinations, investigations and treatment plans
32. Pregnancy must be excluded with a negative serum pregnancy test, within 7 days before initiation of therapy, if the risk of conception exists.
Female patients of childbearing potential 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 from time of consent to enter the WAKING study. |
|
| E.4 | Principal exclusion criteria |
1. Any contraindication or known hypersensitivity reaction to any of the study drugs
2. Persisting toxicity relating to prior therapy of >grade 1 CTCAE version 5.0 except alopecia of any grade and neuropathy ≤ grade 2, or other grade ≤2 not constituting a safety risk based on investigators judgement
3. Any prior treatment with immunotherapy including anti-PD-1or PD-L1 therapy.
4.Active or untreated CNS metastases are excluded. Patients with treated and asymptomatic CNS metastases are eligible, if they meet all of the following:
a. Evaluable or measurable disease outside the CNS
b. No metastases to midbrain, pons, medulla, or within 10 mm of the optic nerves and chiasm
c. No history or evidence of intracranial haemorrhage or spinal cord haemorrhage
d. No evidence of clinically significant vasogenic oedema
e. Not on corticosteroids for ≥ 2 weeks; anti-convulsants at a stable dose are allowed.
f. No evidence of clinical and radiographic disease progression in the CNS ≥ 3 weeks after radiotherapy or surgery.
5. Known severe hypersensitivity reactions to monoclonal antibodies (Grade ≥ 3 NCI CTCAE v 5.0), any history of anaphylaxis.
6. Any Immunodeficiency disorders
7.Patients with another active malignancy or a prior malignancy within the past 5 years are excluded, except patients with completely resected cutaneous melanoma (early stage), basal cell carcinoma, cutaneous squamous cell carcinoma, cervical carcinoma in-situ, breast carcinoma in-situ, and localized prostate cancer are eligible.
8. History of autoimmune disease except for the following:
- Patients with autoimmune hypothyroidism on a stable dose of thyroid replacement hormone are eligible
- Patients with controlled type 1 diabetes mellitus on a stable dose of insulin regimen are eligible
- Patients with eczema, psoriasis, lichen simplex chronicus, or vitiligo with dermayologic manifestations only (e.g. patients with psoriatic arthritis) are permitted provided that they meet the following conditions:
- Patients with psoriasis must have a baseline ophthalmologic exam to rule out ocular manifestations
- Rash must cover less than 10% of body surface area
- Disease is well controlled at baseline and only requiring low−potency topical steroids (e.g., hydrocortisone 2.5%, hydrocortisone butyrate 0.1%, flucinolone 0.01%, desonide 0.05%, aclometasone dipropionate 0.05%)
- No acute exacerbations of underlying condition within the last 12 months (not requiring PUVA [psoralen plus ultraviolet A radiation], methotrexate, retinoids, biologic agents, oral calcineurin inhibitors, or high-potency or oral steroids)
16. History of idiopathic pulmonary fibrosis, organizing pneumonia, bronchiolitis obliterans, drug-induced pneumonitis, or idiopathic pneumonitis Patients with radiation pneumonitis within the radiation field are eligible.
17. Prior organ transplantation, including allogeneic transplant
18. Significant infection requiring systemic therapy:
a. HIV infection
b. Active tuberculosis infection
c. Severe infections within 2 weeks prior to Cycle 1 Day 1
d. Received oral or IV antibiotics within 2 weeks prior to Cycle 1 Day 1
e. Patients receiving prophylactic antibiotics (e.g., for prevention of urinary tract
f. infection or chronic obstructive pulmonary disease) are eligible
g. Active or chronic viral hepatitis B or C infection
i. Patients with hepatitis B virus (HBV) infection are eligible if test for hepatitis B
1. surface antigen (HBsAg) and HBV DNA are negative
ii. Patients with hepatitis C virus (HCV) infection are eligible if polymerase chain
reaction (PCR) test for HCV RNA is negative.
14. Known positive tests for human immunodeficiency virus (HIV) infection or known acquired immunodeficiency syndrome
|
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Phase IIA safety run in: inform safe and tolerable dose for efficacy phase
Phase IIB efficacy phase: Objective Response rate (CR or PR as their best overall response during treatment) according to RECIST1.1 criteria (additional iRECIST criteria will be used in a sensitivity analysis).
|
|
| 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 | No |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | No |
| 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 | 4 |
| 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 ‘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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