| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Acute myeloid leukaemia (AML), Chronic myelomonocytic leukaemia (CMML) and Myelodysplastic syndrome (MDS) |
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| E.1.1.1 | Medical condition in easily understood language |
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| 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 | 21.1 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10000880 |
| E.1.2 | Term | Acute myeloid leukaemia |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 21.1 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10028533 |
| E.1.2 | Term | Myelodysplastic syndrome |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 21.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10054350 |
| E.1.2 | Term | Chronic myelomonocytic leukemia |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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| 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 |
Core Primary Objectives:
1. To investigate the safety and tolerability of EP0042 given alone or in combination with anti-cancer treatments.
Module 1 Primary Objectives:
1. To investigate the safety and tolerability of EP0042 given as a monotherapy in patients with relapsed or refractory (R/R) AML (AML, MDS or CMML).
Module 2 Primary Objectives:
1. Part A: To evaluate the safety, tolerability, of EP0042 + a Bcl-2 inhibitor (venetoclax) in patients with R/R FLT3 wildtype (WT) AML.
2. Part B: To evaluate the safety, tolerability, of EP0042 in combination with a Bcl-2 inhibitor (venetoclax) + a hypomethylating agent (azacitidine) in patients with R/R FLT3 WT or newly diagnosed AML. |
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| E.2.2 | Secondary objectives of the trial |
Core Secondary Objectives:
1. To characterizse the pharmacokinetics (PK) of EP0042, given alone or in combination with anti-cancer treatments, after a single dose and at steady state after multiple dosing.
2. To assess the biological and anti-tumor activity of EP0042, given alone or in combination with anticancer treatments.
Module 1 Secondary Objectives:
1. To characterizse the (PK) of EP0042, given as a monotherapy, after a single dose and at steady state after multiple dosing.
2. To assess the efficacy of EP0042, given as a monotherapy in patients with relapsed or refractory AML (and MDS or CMML).
Module 2 Secondary Objectives:
1. To characterize the PK of EP0042 + combination agent(s), after a single dose and at steady state after multiple dosing.
2. To assess the efficacy of EP0042 + combination agent(s) in patients with AML.
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Core Inclusion Criteria:
1. Male or female patients aged ≥ 18 years of age, at the time of informed consent, with histological or cytological confirmation of leukemia.
2. Ability to understand and provide written informed consent before any study-specific procedures, sampling, or analyses, including access to archival tumor tissue.
3. Ability to swallow and retain oral medication. |
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| E.4 | Principal exclusion criteria |
Core Exclusion Criteria:
1. Suspected brain and/or leptomeningeal metastases that are symptomatic or untreated or that require current therapy.
2. Ongoing toxic manifestations of previous treatments that have not reduced to at least Common Terminology Criteria for Adverse Events (CTCAE) Grade 1. Exceptions to this are alopecia or certain Grade 2 treatment related toxicities, which in the opinion of the Investigator should not exclude the patient.
3. Creatinine clearance (calculated using Cockcroft-Gault formula, or measured) < 50 mL/min.
4. Receiving an investigational anti-cancer treatment concurrently or within 14 days or five half-lives of either the parent drug or any active metabolite prior to the start of treatment with EP0042. Patients with AML may receive hydroxyurea throughout the screening period and during the first 2 cycles of study treatment in the first module (FIH study).
5. Current refractory nausea and vomiting, malabsorption syndrome, disease significantly affecting gastrointestinal (GI) function, resection of the stomach, extensive small bowel resection that is likely to affect absorption, symptomatic inflammatory bowel disease, partial or complete bowel obstruction, or gastric restrictions and bariatric surgery such as gastric bypass.
6. Known active hepatitis B virus (HBV) or hepatitis C virus (HCV) infection per institutional protocol. Testing for HBV or HCV status is not necessary unless clinically indicated or the patient has a history of HBV or HCV infection.
7. Patients with active human immunodeficiency virus infection (HIV) infection (testing is not required). Patients living with HIV will be eligible if they have CD4+ T-cell count ≥ 350 cells/μL, no history of AIDS-defining opportunistic infections in the past 12 months, and can be managed on a regimen consistent with this protocol's permitted concomitant medications
8. Malignant disease other than that being treated in this study, with the following exceptions:
a. Malignancies that were treated curatively and have not recurred within 2 years prior to study treatment.
b. Completely resected basal cell and squamous cell skin cancers.
c. Any malignancy considered to be indolent and that has never required therapy.
d. Completely resected carcinoma in situ of any type.
9. Any medical condition that would, in the investigator’s judgment, prevent the patient’s participation in the clinical study due to safety concerns, compliance with clinical study procedures, or interpretation of study results.
10. Any major surgical procedure (in the investigator’s judgement) within 2 weeks of the first dose of study drug.
11. Pregnant, likely to become pregnant, or lactating women (where pregnancy is defined as the state of a female after conception and until the termination of gestation).
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| E.5 End points |
| E.5.1 | Primary end point(s) |
Module 1 Primary Endpoints:
1. Incidence of DLT, adverse events (AEs), serious adverse events (SAEs) and changes in laboratory parameters, physical examination, vital signs and electrocardiograms (ECGs).
Module 2 Primary Endpoints:
1. Incidence of DLTs, AEs, SAEs and changes in laboratory parameters, physical examination, vital signs and electrocardiograms. |
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
DLTs, AEs and SAEs are evaluated from consent to 30 days after last study dose. Haematological Safety laboratory measurements are taken at every visit while on treatment and at follow up.
Chemistry and Coagulation Safety Laboratory measurements are taken at every visit in Cycle 1 and every other visit (Days 1 and 15) while on treatment cycles and at follow up.
Physical examinations are carried out every visit in Cycle 1 then on Day 1 of every other cycle while on treatment and at follow up.
Vitial signs are taken at every visit in Cycle 1 and every other visit (Days 1 and 15) while on treatment cycles and at follow up.
ECGs are are taken at every visit in Cycle 1 and Days 1 and 15 at Cycle 2. Then every cycle after cycle 2 on Day 1 while on treatment and 15 measurements pre-dose. |
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| E.5.2 | Secondary end point(s) |
Module 1 Secondary Endpoints:
1. Plasma PK parameters (AUClast, AUCinf, Cmax and/or Cmin, Tmax, t1/2, CL/F, V/F and/or Vz/F) after single and multiple doses
2. Best overall response (BOR)
3. Duration of response (DOR)
4. Overall survival (OS)
Module 2 Secondary Endpoints:
1. Plasma PK parameters (AUClast, AUCinf, Cmax and/or Cmin, Tmax, t1/2, CL/F, V/F and/or Vz/F) of EP0042 and combination agents after single and multiple doses.
2. BOR
3. DOR
4. Event free survival (EFS)
5. Relapse free survival (RFS)
6. OS
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
Blood samples for PK analyses will be taken Cycle 1 Day 1 Pre-dose, 0.5, 1, 2, 4, 6, 8, 12 and 24-hours post dose. Samples also taken on Cycle 1 Day 8, 15 and 22 (to be taken pre-dose, or during the visit if no dose is administered) and Cycle 2 Day 1 pre-dose.
Best Overall Response and Duration of Response will be calculated on the response criteria given at day 1 of each cycle from cycle 2 onwards. |
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| 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 | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | Yes |
| E.6.11 | Pharmacogenomic | Yes |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | Yes |
| E.6.13.1 | Other scope of the trial description |
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| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | Yes |
| E.7.1.1 | First administration to humans | Yes |
| 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 | 2 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 6 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Australia |
| United Kingdom |
| United States |
| Netherlands |
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| E.8.7 | Trial has a data monitoring committee | No |
| 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
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| 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 | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 3 |
| 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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