Study to Evaluate the Safety and Tolerability of EP0042

Study Overview
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Brief Summary
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A research study looking at a new treatment for patients with advanced cancer, to investigate different doses of the experimental study drug, EP0042, in order to determine a dose, which is safe, well-tolerated and likely to be effective in treating AML (acute myeloid leukaemia).

Official Title
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A Modular, Multipart, Multi-arm, Open-label, Phase I/IIa Study to Evaluate the Safety and Tolerability of EP0042 Alone and in Combination With Anti-cancer Treatments in Patients With Advanced Malignancies

Conditions
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Acute Myeloid Leukemia, Chronic Myelomonocytic Leukemia, Myelodysplastic Syndromes

Intervention / Treatment
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* Drug: EP0042


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: General: Male or female patients aged ≥ 18 years of age, at the time of informed consent, with histological or cytological confirmation of an advanced malignancy Ability to understand and provide written informed consent before any study-specific procedures, sampling, or analyses, including access to archival tumour tissue Ability to swallow and retain oral medication Sufficient life expectancy to allow the patient to complete at least 1 cycle (28 days) of the treatment period. ECOG Performance Status of 0, 1 or 2 at Screening In the opinion of the investigator, all other relevant medical conditions must be well-managed and stable for at least 28 days prior to first administration of study drug Part A (escalation phase) only: Patients with pathologically confirmed/documented AML or MDS, as defined by the 2017 European LeukaemiaNet (ELN) recommendations, or CMML, as defined by World Health Organization (WHO) criteria, who have relapsed from or are refractory to previous therapy Part B (Expansion cohort patients) only: Patients with pathologically confirmed/documented AML, as defined by the 2017 European LeukaemiaNet (ELN) recommendations, who either decline or are unsuitable for standard therapy, or who are refractory to, or have relapsed after, initial treatment, with no more than 3 prior lines of therapy. A prior line of therapy is defined as: Treatment to induce remission with anthracycline/cytarabine (eg '3+7' daunorubicin 60 mg/m2 [3 days/cycle] plus cytarabine 100-200 mg/m2 [7 days/cycle], +/-midostaurin mylotarg and including CPX-351, FLAG-ida or similar intensive regimens). Low dose cytarabine or hypomethylating agents (azacitidine or decitabine) Treatment with single agent FLT3 inhibitors (quizartinib, gilteritinib, crenolanib) for relapsed disease Transplantation (allogeneic) in active disease. The following is not considered a prior line of therapy: Consolidation cycles including those with midostaurin or mylotarg or quizartinib Transplantation (allogeneic) given during remission. Other prior treatments may be discussed with the Medical Monitor for consideration. Approximately 20 evaluable patients will be included with FLT-3 ITD AML and approximately 10 evaluable patients with FLT-3 wild type AML, both confirmed by local laboratories within 28 days prior to dosing Contraception: Female patients should either be of non-child-bearing potential or must agree to use highly effective methods of contraception from Screening until 6 months following administration of the last dose of study drug Male patients must use double barrier contraception from enrolment through treatment and for 6 months following administration of the last dose of study drug Exclusion Criteria: Patients with any of the following will not be included in the study: Disease Under Study and Prior Anticancer Treatment: Suspected brain and/or leptomeningeal metastases that are symptomatic or untreated or that require current therapy Acute promyelocytic leukaemia (FAB:M3) Systemic anti-cancer therapy for the disease under study within 4 weeks of the first dose of study treatment. (Concomitant hydroxyurea is acceptable and will be permitted throughout the screening period and during first 2 cycles of study treatment) Ongoing toxic manifestations of previous treatments that have not reduced to at least 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. Transplantation (allogeneic or autologous) within last 90 days, or on active immunosuppressive therapy for graft versus host disease in last 2 weeks Laboratory Parameters Patient with any out-of-range laboratory values defined as shown below. Haematology evaluations must be performed ≥7 days from any blood or blood product transfusion and ≥14 days from any dose of hematologic growth factor. Serum creatinine > 1.5 x upper limit of normal (ULN) and/or creatinine clearance (calculated using Cockcroft-Gault formula, or measured) < 50 mL/min Inadequate liver function as demonstrated by serum bilirubin ≥3 times the upper limits of normal range (ULN) or alanine aminotransferase (ALT) ≥3 times the ULN or aspartate aminotransferase (AST) ≥3 times the ULN or AST or ALT ≥5 times the ULN in the presence of liver involvement by leukaemia Medical History and Concomitant Medications: Confirmed QTcF > 470 msec on screening ECG or congenital long QT syndrome 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 may receive hydroxyurea throughout the screening period and during the first 2 cycles of study treatment. Any evidence of severe or uncontrolled systemic or current unstable or uncompensated respiratory or cardiac conditions which makes it undesirable for the patient to participate in the study or which could jeopardize patient safety Current refractory nausea and vomiting, malabsorption syndrome, disease significantly affecting gastrointestinal (GI) function, re-section of the stomach, extensive small bowel re-section 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. Known history of human immunodeficiency virus infection (HIV) (testing is not required), active hepatitis B virus (HBV) or hepatitis C virus (HCV) infection. Testing for HBV or HCV status is not necessary unless clinically indicated or the patient has a history of HBV or HCV infection Hypersensitivity to EP0042 or D -α-Tocopherol polyethylene glycol succinate (TPGS) Malignant disease other than that being treated in this study, with the following exceptions: Malignancies that were treated curatively and have not recurred within 2 years prior to study treatment Completely resected basal cell and squamous cell skin cancers Any malignancy considered to be indolent and that has never required therapy Completely resected carcinoma in situ of any type 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 Any major surgical procedure (in the investigator's judgement) within 2 weeks of the first dose of study drug (minimally invasive procedures such as bronchoscopy, tumour biopsy, insertion of a central venous access device, and insertion of a feeding tube are not considered major surgery and are not exclusionary) Patients with a history of, or currently suffering from, severe psychiatric diseases such as mania, manic depression or psychoses 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)

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: EP0042<br> | Drug: EP0042<br>* EP0042 Oral 20 mg 50 mg capsules<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of dose-limiting toxicities (DLTs) from the first dose through the end of the DLT observation period. | Incidence of dose-limiting toxicities (DLT) | First cycle of treatment (28 Days) |