| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
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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.1.3 | Condition being studied is a rare disease | Yes |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| To further characterize the safety profile of single agent SEL24/MEN1703 |
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| E.2.2 | Secondary objectives of the trial |
To assess anti-leukemic activity of single agent SEL24/MEN1703
To evaluate the PK profile of SEL24/MEN1703 and its metabolites, as appropriate.
Evaluation of CYP2D6 phenotyping will be carried out. Results will be reported separately. Left over sample aliquots may be analyzed for metabolite identification purposes. |
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| E.2.3 | Trial contains a sub-study | Yes |
| E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
Pharmacodynamics
The PD activity of SEL24/MEN1703 will be assessed by changes between
pre- and post-treatment levels of relevant biomarkers e.g. pS6 in
peripheral blood by using flow cytometry.
Genetic profile of AML cells
The genetic profile of AML cells of each patient will be performed by
using Next Generation Sequencing and/or qRT-PCR. The mutational
status of patients before and after treatment with SEL24/MEN1703 will
be assessed by the analysis of a panel of relevant AML mutated genes in
bone marrow.
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| E.3 | Principal inclusion criteria |
1. Patient with diagnosis of AML (i.e. ≥20% blasts in bone marrow or peripheral blood) harboring IDH1 or IDH2 mutation (as per local
assessment).
2. Provide written informed consent prior to Screening.
3. Male or female patients, age ≥18 years old.
4. Patient has no standard therapeutic options available (including IDH inhibitors where approved) and has:
a) Relapsed AML unsuitable for intensive chemotherapy;
b) Primary refractory AML unsuitable for intensive chemotherapy;
Clarification note: Patients naïve to IDH inhibitor are eligible ONLY if no IDH inhibitors are approved/available in the country/site where they are
enrolled.
Clarification note: patients are eligible regardless of their AML genetic and/or molecular aberrations, if any. However, patients with AML harboring druggable mutations for whom an approved targeted therapy is available (eg FLT3-ITD and/or FLT3-TKD) are eligible ONLY if they have already received such approved targeted therapy
5. ECOG Performance Status 0, 1 or 2.
6. Adequate organ function at Screening, including:
a) Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤2.5X the upper limit of normal (ULN);
b) Total bilirubin ≤2X ULN;
c) Creatinine clearance ≥40 mL/min (Cockcroft-Gault formula)
d) Left ventricular ejection fracture (LVEF) ≥40% as per local assessment practice.
7. A female of childbearing potential, defined as any female who has experienced menarche and who has not undergone successful surgical sterilization or is not postmenopausal (i.e. has serum follicle stimulating hormone level ≥30 IU/L in the absence of hormone replacement therapy, or complete absence of menses for at least 12 consecutive months which is not due to medication), must have a negative pregnancy test within 7 days prior to receiving study drug.
8. Sexually active male or female patients of childbearing potential may be enrolled providing that:
Female:
-Agrees to use an effective method of birth control that both results in a Pearl index < 1 and is considered highly effective as defined by the Clinical Trial Facilitation Group (e.g. combined estrogen and progestogen containing hormonal contraception, progestogen-only hormonal contraception, intrauterine device, intrauterine hormone-releasing system, vasectomized partner, total sexual abstinence or bilateral tubal occlusion)*.
-Undergoes a pregnancy test at Day 1 of each treatment cycle and after the end of relevant systemic exposure (30 days from the last study drug administration).
Male:
-Agrees to use an effective contraceptive method (condom) during treatment and until the end of relevant systemic exposure. Females of childbearing potential that are partners of male study participants have to observe the same birth control indications that apply to female participants.
* Hormonal contraceptives are allowed as pre-clinical evaluation of SEL24/MEN1703 confirmed a low interaction between SEL24/MEN1703 and the most common active principles used for this purpose.
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| E.4 | Principal exclusion criteria |
1. Received anti-cancer treatments (including cytotoxic chemotherapy, radiotherapy, hormonal therapy, biologic, immunotherapy or investigational drugs) within 14 days or 5 half-lives (whichever is longer) before the first dose of study drug.
2. Prior treatment with a PIM inhibitor.
3. Hyperleukocytosis (leukocytes >30 x109/L) immediately prior to the first dose of study drug and/or clinical concerns of leukostasis.
Note: Patients may undergo leukapheresis according to routine practice before the first dose of study drug; where hydroxyurea is used prior to receiving study drug, it may be continued up to Cycle 1, Day 21, although Investigators are asked to stop treatment prior to the first dose of study drug or before Day 7, wherever possible.
4. Clinically significant active central nervous system (CNS) leukemia.
Note: Previously treated and controlled CNS leukemia and ongoing standard CNS prophylaxis (e.g. with intrathecal cytarabine) is acceptable.
5. Patients who have undergone major surgery within 1 month prior to first dose of study drug.
6. Hematopoietic stem cell transplant within 4 months of first dose of study drug.
7. Requires systemic immune-modulating therapy (regardless of dose) for the prophylaxis or treatment of GVHD.
8. Evidence of ongoing and uncontrolled systemic bacterial, fungal, or viral infection, with the exception of patients with documented Grade CTCAE ≤2 infections with evidence of improvement or without evidence of worsening infection.
9. Known positive serology for human immunodeficiency virus (HIV).
10. Ongoing drug-induced liver injury, known chronic active hepatitis C (HCV) infection, known chronic active hepatitis B (HBV) infection, alcoholic liver disease, non-alcoholic steatohepatitis, primary biliary cirrhosis, extrahepatic obstruction cause by cholelithiasis, cirrhosis of the liver, or portal hypertension. Participants with history of chronic HBV and HCV infection are eligible if disease is stable and sufficiently controlled as per investigator's judgment.
11. Ongoing drug-induced pneumonitis.
12. Ongoing inflammatory bowel disease.
13. Pregnancy or breastfeeding.
14. Concurrent participation in another therapeutic clinical study.
15. Ongoing toxicity from any prior anti-cancer therapy that has not resolved to Grade 1 or less prior to the first dose of study drug.
16. Received an agent known to be a sensitive CYP2D6 substrate or a CYP2D6 substrate with a narrow therapeutic range, a strong or moderate CYP2D6 inhibitor, or a BCRP inhibitor within 7 days or a period corresponding to 4-5 half-lives of the agent, prior to the first dose of study drug.
17. Cardiac dysfunction defined as myocardial infarction within 6 months of study entry, New York Heart Association (NYHA) Class III or IV heart failure, uncontrolled dysrhythmias or poorly controlled angina.
18. Are receiving any active treatment for thrombosis.
19. History of serious ventricular arrhythmia (e.g. VT or VF, ≥3 beats in a row), or QT interval corrected for heart rate (QTc) ≥480 ms.
Note: QTc values up to 500 ms will be acceptable where patient’s medical history e.g. bundle branch block, is known to cause mild QTc prolongation and the condition is well controlled.
20. Any disease, syndrome or condition which may affect significantly drug intake via oral route.
21. Any other prior or current medical condition, intercurrent illness, surgical history, physical or 12- lead electrocardiogram (ECG) findings, laboratory abnormalities, or extenuating circumstance (e.g. alcohol or drug addiction) that, in the investigator’s opinion, could jeopardize patient safety or interfere with the objectives of the study. |
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| E.5 End points |
| E.5.1 | Primary end point(s) |
| The number and frequency of AE, safety laboratory, vital signs and ECG assessments |
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
There will be ongoing assessment of all adverse events (AEs), changes in laboratory values (clinical chemistry, hematology, coagulation, lipid profile, and urinalysis) and electrocardiograms as further measures of safety and tolerability. All safety parameters will continue to be assessed beyond Cycle 1.
Vital Signs- Screening, Day 1 of Cycle 1-Cycle2-Cycle 3; Final Study Visit
ECG- Sreeining, Day 1&Day 7 of Cycle 1; Day 1 of Cycle2-Cycle3; Final Study Visit. |
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| E.5.2 | Secondary end point(s) |
- Assessment of bone marrow and peripheral blast % and other assessments of clinical benefit including ORR (CR, CRi, CRh and MLFS),
PR rate, DoR, RFS, EFS and OS, transfusion conversion rate, transfusion maintenance rate, HSCT rate.
- Assessment of PK variables, including Cmax, AUC and t½
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
Bone marrow aspirate/biopsy shall be taken at the following time points: at Screening, either as soon as peripheral lab results become consistent with an objective response or at C3 D1 whichever comes first, at a recommended frequency of every 2 cycles thereafter e.g. C5 D1, C7 D1, etc. (-2 d tolerance) or as clinically indicated, at relapse and FSV.
Assessment of blasts in peripheral blood will be carried out at Screening, C1 D1 pre-dose, C1 onwards at D14 (or last day of dosing in each cycle; -2 d tolerance from C3 onwards), and FSV.
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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 | No |
| 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 | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| 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 | Yes |
| 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 | 8 |
| 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 |
| United States |
| Italy |
| Poland |
| Spain |
|
| 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
|
End of Study is defined 6 months after first treatment administration to the last subject or as soon as all enrolled patients completed the
treatment/follow up period, whichever occurs first.
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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 | 1 |
| E.8.9.1 | In the Member State concerned months | 6 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 1 |
| E.8.9.2 | In all countries concerned by the trial months | 9 |
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