A Phase I/II Study of SEL24 in Patients With Acute Myeloid Leukemia
Phase: PHASE1
Conditions: Acute Myeloid Leukemia
Sponsor: Menarini Group

CLINICAL STUDY PROTOCOL 
A Phase I/II Study of SEL24 
in Patients with Acute Myeloid Leukemia 
Protocol No: 
CLI24-001 
Nickname: 
DIAMOND-01 
Version No: 
V13.0 
Version Date: 
27 June 2022 
IND No:  
128902 
EudraCT No:  
2019-000941-10 
MENARINI RICERCHE S.P.A. 
10, Via Tito Speri 
Pomezia (Rome), 00071 
Italy 
The information contained in this document, especially unpublished data, is confidential 
communication from Menarini Ricerche S.p.A.. Acceptance of this document constitutes the 
agreement of the recipient that this information will not be disclosed to others without written 
authorization from Menarini Ricerche S.p.A., except to the extent necessary for Ethics 
Committee/Institutional Review Board procedures and to obtain written informed consent from 
those persons to whom test drug may be administered.
NCT #: NCT03008187

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CLI24-001 V13.0 Final 27JUN2022                                                                                                                         2 of 108 
Protocol Version Summary: 
 
Protocol 
Version: 
Version Date:  
Comments:  
Version 12 
20 April 2021 
Submitted to FDA and all RAs and ECs/IRB. 
Approved by AIFA and ISS, URPL, AEMPS and 
FDA. 
Version 11.3 
1 July 2020 
Submitted to FDA on 13Jul2020 (SN 0033, no 
comments received) and to US sites. Approved by 
AIFA and ISS and Italian sites 
Version 11.2 
10 June 2020 
Approved by URPL, AEMPS and Polish/Spanish 
sites 
Version 11.1 
24 March 2020 
Submitted to FDA on 2Apr2020 (SN 0032), AIFA, 
ISS, URPL, AEMPS and to all sites 
Version 11.0 
21 February 2020 
FDA only; this version was not submitted to the 
investigative sites 
Version 10.2 
05 August 2019 
Submitted to FDA on 9Aug2019 (SN 0028) and to all 
sites 
Version 10.1 
14 June 2019 
FDA only; this version was not submitted to the 
investigative sites 
Version 10.0 
21 May 2019 
FDA only; this version was not submitted to the 
investigative sites 
Version 9.0 
25 February 2019 
FDA only; this version was not submitted to the 
investigative sites 
Version 8.0 
26 April 2018 
Submitted to FDA on 11May2018 (SN 0011) and to 
all sites 
Version 7.0 
06 December 2017 
Approved by the FDA on 15Dec2017 and submitted 
to all sites 
Version 6.0 
21 November 2017 
FDA only; this version was not submitted to the 
investigative sites.  
Version 5.0 
19 April 2017 
Version issued to amend exclusion criteria and 
prohibited medication, submitted to all sites 
Version 4.0 
27 July 2016 
The initial protocol submitted to all sites, under 
which patient enrollment commenced in March 
2017.  
 

Menarini Ricerche S.p.A.
DIAMOND-O1
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0-.< .   
PROTOCO  APPROVAL SIGNATURES
Spoiisor s Approvai:
This stiidy will be conducted in compliance with Inter ational Conference on Harmonis tion (ICH)
gLiidelines on Good Clinical Practice (GCP), thè Declaration of Helsinki (with amendments), and in
accoi dancc with locai legai and regiilatory requirements.
This protocol has been approved by Menarini Ricerche S.p.A.
Mena ini Ricerche S.p.A.
MENARINI RICERCHE S.p.A.
10, Via Tito Speri
Pomezi  (Rome), 00071
Italy
Tel:+39 055 56809990
Fax:+39 055 5680597
Date:
CL124-00I V13.0 Final 27JUN2022
3ofl08

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CLI24-001 V13.0 Final 27JUN2022                                                                                                                         4 of 108 
Investigator’s Approval: 
I have read this protocol and agree that it contains all the necessary details for carrying out this study. I 
will conduct the study as described and will complete the study within the time designated. I verify that 
I am suitably qualified by education, scientific and medical training and experience to conduct the study. 
Documentation of my qualifications and professional affiliations are contained in my up-to-date 
curriculum vitae provided to the Sponsor. 
 
I will provide the supplied copies of the protocol, including future protocol amendments, and all 
information relating to non-clinical, and clinical experience when available (e.g. in updated editions of 
the Investigator’s Brochure), to all staff in my unit involved in the conduct of this study. I will discuss 
this material with them to ensure that they are fully conversant with the investigational medicinal product 
and study design, and that they will handle the data and information generated in the study confidentially. 
 
I will conduct the study in accordance with Good Clinical Practice, the Declaration of Helsinki, and the 
moral, ethical and scientific principles that justify medical research. The study will be conducted in 
accordance with the relevant laws and regulations relating to clinical studies and the protection of 
patients. All patients will be informed comprehensively about the nature of the study and will give their 
written consent to participate before entry into the study. They will be informed that they may withdraw 
from the study at any time. I will use only the information sheet and consent form approved by the 
Sponsor and the Ethics Committee/Institutional Review Board for this study. I will supply the Sponsor 
with any material written by myself (e.g. summary of study) which is given to the Ethics 
Committee/Institutional Review Board in support of the application. 
 
Where applicable, the patient information contained in clinic records, reports and manuscripts will be 
transcribed to the case report forms (the case report form may be the original source document for 
specified items). Either I or an appointed person will attest to the authenticity of the data and accuracy 
and completeness of the transcription by signing the case report form. I agree to the audit and monitoring 
procedures that involve verification of such study records against original records. Should it be requested 
by government regulatory agencies, I will make available additional background data from my records, 
and where allowed, from the hospital or institution where the study was conducted.  
 
I understand that the case report forms and other data pertinent to this study are the property of Menarini 
Ricerche S.p.A. and are confidential. I will supply Menarini Ricerche S.p.A. (or their delegates) with 
the study data in such a way that the patient cannot be personally identified. 
 
 
Investigator:  
__________________________      
___________________ 
 
 
 
Signature 
 
 
 
   
Date 
 
Print Name: 
 
________________________________________________________ 
 
Institution Name:  
________________________________________________________ 
 
Institution Address: 
________________________________________________________ 

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CLI24-001 V13.0 Final 27JUN2022                                                                                                                         5 of 108 
OTHER CONTACT INFORMATION 
Full contact details for each Investigational site, the Sponsor (including appropriate medical monitor 
contact number), and key coordinating and operational personnel will be maintained in the Trial Master 
File (TMF) and in each Site Study File. 
 
 
 
 

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CLI24-001 V13.0 Final 27JUN2022                                                                                                                         6 of 108 
PROTOCOL SYNOPSIS 
 
Protocol No:  
CLI24-001 
 
Study Title:  
A Phase I/II Study of SEL24 in Patients with Acute Myeloid Leukemia 
 
SEL24/MEN1703 Investigational Product: 
 
SEL24/MEN1703 will be supplied as drug substance powder in a gelatin capsule (non-formulated API 
in capsule), as well as formulated drug product in a gelatin capsule. Details of the Investigational Product 
provided during Part 1 are reported in Table 3. Formulated drug only will be provided for Part 2.  
 
Phase of Development:  
Phase I/II 
 
Number of Sites: 
 
Five sites in Part 1. Approximately additional 10-15 sites may be added as required to meet the 
recruitment needs of the study in Part 2. 
 
Number of Patients:  
Twenty-five evaluable patients were enrolled in Part 1 (dose escalation). 
In Part 2, the first expansion cohort (“all-comers”) 23 unselected relapsed or refractory AML patients 
have been enrolled. An additional expansion cohort (“IDH mutants”) will enroll approximately 20 
relapsed or refractory AML patients harboring an IDH mutation (either IDH1 or IDH2). 
 
Table 1: Part 1 Study Objectives and Endpoint (Assessment) 
Objective 
Endpoint (Assessments) 
Primary: 
 
• To estimate the MTD or MAD and determine 
the RD of SEL24/MEN1703 for Part 2 
• DLT evaluation at the end of one treatment 
cycle for each dose level 
Secondary: 
 
• To assess the safety and tolerability of 
SEL24/MEN1703  
• The number and frequency of AEs, safety 
laboratory, vital signs and ECG assessments 
• To 
assess 
anti-leukemic 
activity 
of 
SEL24/MEN1703  
• 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  
• To 
evaluate 
the 
PK 
profile 
of 
SEL24/MEN1703 and its metabolites as 
appropriate 
• Assessment of PK variables, including Cmax, 
AUC and t½ 
Exploratory: 
 
• To assess the PD activity of SEL24/MEN1703 
• To assess the genetic profile of AML cells 
• Flow cytometry assessment of relevant 
biomarkers (e.g. pS6)  

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Objective 
Endpoint (Assessments) 
• Analysis of relevant mutations in peripheral 
blasts and bone marrow by using Next 
Generation Sequencing and/or qRT-PCR 
Table 2: Part 2 Study Objectives and Endpoint (Assessment) 
Objective 
Endpoint (Assessments) 
Primary: 
 
• To further characterize the safety profile of 
single agent SEL24/MEN1703  
• The number and frequency of AE, safety 
laboratory, vital signs and ECG assessments 
Secondary: 
 
• To assess anti-leukemic activity of single 
agent SEL24/MEN1703  
• 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, OS , 
transfusion 
conversion 
rate, 
transfusion 
maintenance rate, HSCT rate 
• To 
evaluate 
the 
PK 
profile 
of 
SEL24/MEN1703 and its metabolites, as 
appropriate 
• Assessment of PK variables, including Cmax, 
AUC and t½ 
Exploratory: 
 
• To assess the PD activity of SEL24/MEN1703 
• To assess the genetic profile of AML cells 
• Flow cytometry assessment of relevant 
biomarkers (e.g. pS6) 
• Analysis of relevant mutations in peripheral 
blasts and bone marrow by using Next 
Generation Sequencing and/or qRT-PCR 
 
Study Design: 
This is a Phase I/II, open-label, multi-center, dose escalation study to estimate the MTD (or MAD) of 
SEL24/MEN1703 in patients with AML. At the end of Part 1 a RD of SEL24/MEN1703 has to be 
selected for further evaluation in Part 2. In Part 2 the safety and anti-leukemic activity of 
SEL24/MEN1703 will be further assessed in the study population.  
SEL24/MEN1703 is taken orally once daily (QD) for 14 consecutive days over a 21-day treatment cycle.  
 
NOTE: At the time this protocol Version 12.0 is running, Part 1 has been completed. Procedures 
to be followed along Part 1 are reported below for completeness 
 
Part 1 was initially designed with an accelerated titration design (ATD) for the first 4 cohorts. The study 
design has then been revised to follow a 3+3 design from Cohort 2 (50mg) onwards in order to assess 
for DLT, adverse events and adequate PK profile data from at least 3 patients in each dose level (see 
Table 3). Patients will be enrolled to cohorts in a sequential fashion following the dosing regimen and 
will be observed for safety and tolerability during Cycle 1, prior to permitting dose escalation to the next 
dose level (cohort). From Cohort 4 onwards there will be a mandated recruitment interval of at least 7 
days for each patient enrolled.  
 

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Should a patient experience a toxicity which qualifies as a DLT during Cycle 1 in any cohort, that cohort 
will be expanded to enroll up to a maximum of 6 patients to further assess for toxicity prior to considering 
the next dosing step.  
 
Cohort 4 (100mg) repeated twice due to the introduction of a new formulated SEL24/MEN1703 IMP. 
To distinguish between the original cohort and the repeat cohort at the same dose level, the repeat cohort 
is named Cohort 4F.  
 
No recruitment interval is applied in the Cohort 4F where formulated SEL24/MEN1703 IMP is 
introduced, as this dose level has already been explored with the non-formulated SEL24/MEN1703 API 
in capsules. Upon the successful completion of the repeat Cohort 4F with the formulated IMP, the study 
will progress to the next Cohort 4b and onwards, according to the study design, using SEL24/MEN1703 
formulated IMP only. In particular it has been shown that, overall, PK disposition of SEL24/MEN1703 
(absorption, distribution and elimination) following the administration of formulated IMP is in line with 
that observed with non-formulated IMP. This evidence further supports that no dose adjustment is 
warranted with formulated IMP. 
 
Patients who commenced dosing with the non-formulated SEL24/MEN1703 API in capsules and who 
are still on treatment, will continue receiving this formulation until treatment withdrawal per protocol.  
 
Recruitment and dose escalation for each cohort in Part 1 is described in Table 3. 
 
Table 3: Patients exposure along Dose Escalation Steps 
Cohort 
Dose Level 
Patients treated 
with  
non-formulated 
IMP 
Patients treated 
with Formulated 
IMP 
Patients who 
experienced DLT 
1 
25 mg 
2* 
0 
1 
2 
50 mg 
3 
0 
0 
3 
75 mg 
3 
0 
0 
4 
100 mg 
3 
0 
0 
4F 
100 mg 
0 
3 
0 
4b 
125 mg 
0 
7* 
1 
5 
150 mg 
3 
1 
3  
* One patient not DLT evaluable  
 
In Part 1, according to a 3+3 design, the MTD is defined as the highest dose at which no more than 1 in 
up to 6 patients experience a DLT during Cycle 1. In Cohort 5, provided the MTD is not exceed with 
125 mg and to further characterize the safety profile of MEN1703, up to 4 additional patients will be 
treated at 150 mg formulated IMP according to a Bayesian modified toxicity probability interval (mTPI) 
with a target toxicity rate ≤ 25%. Should none of these 4 patients experience a DLT, higher dose levels 
may be considered and will be subject to a protocol amendment. 
 

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The DMC consisting of the Principal Investigator at each site, plus the Medical Monitor and Sponsor 
representatives, will review all safety data available during Cycle 1 for each cohort and assess for DLT 
during Part 1 of the study. Experts in the evaluation of PK and PD data may participate in the DMC 
meetings to help inform the next dose escalation step. Further details of DMC procedures/participants 
in the different parts of the study are reported in the ad-hoc charter. 
 
The dose escalation rules to be followed during Part 1 of the study are described in Table 4. 
 
Table 4: Part 1 Dose Escalation Rules  
No. of evaluable patients  
with DLT at a given dose level 
Dose escalation rules 
0 
Proceed to next dose level 
≥2 
Dose escalation will be stopped. This dose level will be declared 
the MAD (highest dose administered). Additional patients will 
be entered at the previously highest dose level with <33% 
DLTs, to a maximum of 6, if less than 6 patients were treated 
previously at that dose. 
NOTE: at the 150 mg dose, additional 4 patients will be tested 
targeting ≤ 25% toxicity rate as described above. 
1 
Proceed to enter 6 patients at the dose level: 
- if no further patients experience DLT, proceed to the next 
dose level 
- if 1 or more of the additional patients enrolled suffer DLT, 
then dose escalation is stopped, and this dose is declared the 
MAD which has exceeded the MTD. Additional patients will 
be entered at the previously highest dose level with <33% 
DLTs, to a maximum of 6, if less than 6 patients were treated 
previously at that dose 
- confirmation that a dose level exceeds the MTD may be 
obtained before completing enrollment of 6 patients 
≤1 out of 6 at highest dose level 
administered 
This is generally the MTD/RD. At least 6 patients must be 
entered at the proposed recommended dose level for Part 2.  
 
In addition to DLT evaluation, there will be ongoing assessment of all adverse events (AEs) and serious 
adverse events (SAEs), 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. Note that where the DMC is concerned about 
any safety signal in the study e.g. a trend in Grade 2 events, they may recommend a cohort is expanded 
to evaluate up to 6 patients, in order to explore this safety signal further. 
The highest SEL24/MEN1703 dose level considered to be well tolerated, and to have optimal PK and 
PD characteristics, will be called the RD and will be selected for further evaluation in Part 2. 

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Part 2 foresees the enrollment of patients to be treated at the RD (identified in Part 1 based on 
recommendation by the DMC) in the expansion cohorts defined below: 
- 
The expansion cohort in 20 unselected relapsed or refractory AML patients patients (“all-
comers”)  
NOTE: At the time this protocol version 12.0 is running, the expansion cohort in “all-
comers”AML patients has been already completed with 23 patients enrolled. 
- 
An additional expansion cohort (“IDH mutants”) will enroll approximately 20 relapsed or 
refractory AML patients harboring an IDH mutation (either IDH1 or IDH2).  
The evaluable patients treated at the RD in Part 1 or in Part 2 may be also retrospectively included in 
exploratory safety/efficacy pooled analysis, including patients with comparable inclusion criteria.  
Considering that IDH inhibitors are approved/available only in some of the participating countries, it is 
anticipated that the study will enroll both IDH inhibitor pre-treated and IDH inhibitor naïve patients. For 
this reason, the recruitment will aim to have a balanced distribution across the two sub-populations to 
explore the differences in SEL24/MEN1703 activity between pre-treated and IDH inhibitor naïve 
patients, if any. 
Retrospective correlations between the clinical activity of SEL24/MEN1703 and relevant disease 
markers (e.g. CD25 expression, FLT3 mutational status, IDH1/IDH2 mutational status, others) may be 
included in the statistical analysis plan. 
 
In both Parts of the study, the criteria for retreatment described in Section 4.4 must be met prior to 
proceeding to administer a further cycle of treatment. 
 
Dose Limiting Toxicity: 
DLT events for dose escalation decisions will be assessed to the end of Cycle 1 for each patient in each 
cohort, except in the case of protracted neutropenia in the absence of active AML, where evaluation of 
the event must be conducted over 42 days. Ongoing safety events beyond Cycle 1 will be reviewed 
across all cohorts during the study to help inform dose escalation decisions. 
 
AEs will be graded according to the National Cancer Institute Common Terminology Criteria for 
Adverse Events (NCI CTCAE) V4.03. The AEs listed below will be considered as DLT unless they are 
clearly and incontrovertibly attributable to the underlying disease or to an extraneous cause: 
 
• 
Grade 5 toxicity  
• 
Grade 4 neutropenia lasting ≥42 days from the start of the therapy cycle in absence of 
evidence of active AML (<5% blasts)  
• 
Grade 3 or 4 non-hematologic toxicity, except:  
o 
Alopecia;  

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o 
Grade 3 fatigue, asthenia, anorexia, fever, or constipation; 
o 
Grade 3 nausea, vomiting, or diarrhea not requiring tube feeding, TPN, or 
hospitalization; 
o 
Infection, bleeding, or other expected direct complications of cytopenia due to active 
leukemia; 
o 
Grade 3 or 4 electrolyte imbalances that respond to correction i.e. return to ≤Grade 2, 
within 48 hours (h) from correction’s onset; 
o 
Grade 3 increase in aspartate aminotransferase (AST) and/or, alanine aminotransferase 
(ALT) and/or alkaline phosphatase (ALP) recovering ≤Grade 2 within 7 days. 
 
Only clinically significant abnormalities in laboratory findings, physical examination, vital signs, 
weight or ECG (see Section 7.2) will be considered for DLT assessment, according to the protocol 
definition. 
 
Inclusion/Exclusion Criteria: 
 
Inclusion Criteria 
Patients are eligible to be included in study if they meet all of the following 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. 
 
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) (see Appendix B); 
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 are eligible providing that: 

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CLI24-001 V13.0 Final 27JUN2022                                                                                                                         12 of 108 
 
Female: 
- 
Agrees to use an effective method of birth control as applicable per local law 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 with a final test to be taken 
when no relevant drug systemic exposure is expected (i.e. 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. 
 
Exclusion Criteria 
Patients are not eligible to be included in study if they meet any of the following 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.  

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CLI24-001 V13.0 Final 27JUN2022                                                                                                                         13 of 108 
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. 
 
IMP Administration and Duration of Treatment: 
SEL24/MEN1703 will be taken orally once daily for 14 consecutive days over a 21-day treatment cycle. 
 
Patients must be informed that a SEL24/MEN1703 photosensitivity/phototoxicity effect cannot be 
excluded. For this reason, patients should minimize or avoid exposure to natural or artificial sunlight 
(tanning beds or UVA/B treatment) during the entire study period. If patients need to be outdoors when 
taking SEL24/MEN1703, they should wear loose-fitting clothes that protect skin from sun exposure and 
discuss other sun protection measures with the investigator. If a sunburn like reaction or skin eruption 
occurs, patients should contact the investigator. 
 
Throughout the study, treatment with SEL24/MEN1703 may continue until the occurrence of one of the 
following events, whichever comes first: 

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CLI24-001 V13.0 Final 27JUN2022                                                                                                                         14 of 108 
 
• 
Patient withdrawal of consent. 
• 
Disease progression.  
Note: Patients with disease progression may continue to receive SEL24/MEN1703, if in the 
opinion of the Investigator, they remain clinically stable and may be deriving potential 
clinical benefit from SEL24/MEN1703 and it is not considered detrimental to the patient to 
continue study treatment. 
• 
Treatment delay of more than 2 weeks for reasons other than toxicity (see Section 4.4). 
• 
Occurrence of an unacceptable toxicity (see Section 4.4). 
• 
Requirement for treatment with prohibited medication (see Section 6.9.2). 
• 
Treatment non-compliance.  
Note: Treatment non-compliance will be based on patient enquiry and SEL24/MEN1703 
capsule count on return of used IMP to pharmacy. In Part 1, it will be defined as missing 
more than 2 doses in a 14-day dosing schedule in Cycle 1. After Cycle 1 and throughout 
Part 2, treatment compliance will be assessed on a case-by-case basis.   
• 
Study non-compliance. 
Note: Each patient’s continued willingness to attend study visits and undergo study 
assessments will be assessed on a case-by-case basis.  
• 
Investigator decision that it is in the patient’s best interest to withdraw from the study. 
 
Continuation of the study treatment may be discussed between the Investigator and the Sponsor on a 
case by case basis. The DMC may also advise on the suitability of an individual patient to continue to 
receive study treatment.  
 
Study Assessments: 
Safety 
Adverse events, clinical chemistry, hematological, coagulation, lipid profile and urinalysis parameters 
will be assessed. All clinical AEs and laboratory abnormalities will be graded according to NCI CTCAE 
V4.03. DLT, SAEs and AEs leading to treatment discontinuations will be determined. 
 
Patients will also undergo regular physical examination, vital sign, ECG and urinalysis assessments. 
 
Disease assessment 
Disease assessment will involve evaluation of leukemic blast proportion in the bone marrow. 
Hematologic parameters from the routine local assessments including blast percentage (where 
applicable), absolute neutrophil count (ANC), platelet count, and other relevant parameters such as 
transfusion dependence will also contribute to this assessment. Evaluation of disease status will be 
performed at the time-points described in the Schedule of Study Assessment (Table 5). To note, disease 
assessment must be performed as soon as the peripheral lab results become consistent with an objective 
response. Disease assessment will also include an aliquot of bone marrow aspirate/biopsy that will be 
centrally stored for future analysis (e.g. minimal residual disease), if any. 
In case bone marrow aspirate/biopsy is consistent with CRi or better response, but still a minimal 
percentage of peripheral blasts is detected, the response assessment can be postponed up to 2 weeks and 
will be based on repeated peripheral blood results and last bone marrow aspiration results. 

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Transfusion conversion rate and transfusion maintenance rate  
Starting from Protocol V12.0, information about transfusion dependency will be collected and evaluated 
among study endpoints. For the purpose of defining transfusion conversion rate and transfusion 
maintenance rate, transfusion status (independent Vs. dependent) at baseline period and post-baseline 
period are defined as follows for subjects who took at least one dose of study drug: 
 
Baseline transfusion status: 
• Baseline period is defined as the period from 28 days prior to the first dose to 28 days post first 
dose (C2D7). For subjects who are on treatment <28 days, baseline period is from 28 days prior 
to the first dose (in the event that this information is not available the ICF signature date will be 
exploited as baseline period start) until the end of treatment.  
• Subjects are classified as baseline transfusion independent if there is no red blood cells (RBC) 
or platelet transfusions within the baseline period; otherwise, the subject is to be considered as 
baseline transfusion dependent. 
Post-baseline transfusion status: 
• Post-baseline period is defined as the period from 29 days post first dose (day after C2D7) until 
last dose. 
• For subjects who are on treatment ≥84 days (C5D1 or more), subjects are classified post-baseline 
transfusion independent if there is one consecutive 56 days period without any RBC or platelet 
transfusion in the post-baseline period. 
• For subjects who are on treatment >28 days (beyond C2D7) but <84 days (up to C4D21), post-
baseline transfusion status is not evaluable. 
• Otherwise, the subject is considered post-baseline transfusion dependent. 
Both transfusion conversion rate and maintenance rate apply to subjects who have evaluable post-
baseline transfusion status.  
Transfusion conversion rate is defined as the number of subjects who were transfusion dependent at 
baseline period but become transfusion independent at post-baseline period divided by the total number 
of subjects who were transfusion dependent at baseline period. Transfusion maintenance rate is defined 
as the number of subjects who were transfusion independent at baseline period and still maintain 
transfusion independent at post-baseline period divided by the total number of subjects who were 
transfusion independent at baseline period. 
 
Allogeneic hematopoietic stem cell transplant (HSCT) rate 
Allogeneic HSCT rate is defined as the percentage of subjects undergoing allo-SCT during the study 
period. MRD status will be recorded immediately prior to the transplant and after the procedure 
whenever a bone marrow aspirate/biopsy will be collected (recommended every 2 months unless 
differently indicated by the treating physician based on actual patient’s parameters). 
In the event a patient undergoes allogeneic HSCT, the following information will be recorded: a) date 
of transplant; b) HLA match type (HLA-identical sibling, syngeneic, HLA-matched other relative, HLA-

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mismatched relative, Unrelated donor); c) source of stem cells (Bone marrow, peripheral blood, cord 
blood, others); d) conditioning regimen (myeloablative, non-myeloablative). 
Pharmacokinetics 
The PK profile of SEL24/MEN1703 and its metabolites (as appropriate) will be evaluated by analysis 
of concentration levels in plasma. Evaluation of CYP2D6 phenotyping will be carried out. Results will 
be reported separately. Blood sampling will be performed as described in the Schedule of Study 
Assessment (Table 5). Left over sample aliquots may be analyzed for metabolite identification purposes. 
The results of the metabolite identification analysis will be reported separately. 
 
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. Blood sampling for this 
assessment will be performed as described in the Schedule of Study Assessment (Table 5). Left over 
sample aliquots may be used for future biomarker analysis which is relevant to the development of 
SEL24/MEN1703 in AML. 
 
Genetic profile of AML cells 
The genetic profile of AML cells of each patient will be performed at the time-points described in the 
Schedule of Study Assessment (Table 5) 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. Left over sample aliquots and 
aliquots of bone marrow aspirates/biopsy may be used for future biomarker analysis which is relevant 
to the development of SEL24/MEN1703 in AML.  
 
Statistical Methods: 
This is a preliminary study with a limited number of patients, which is being performed primarily to 
assess safety. The sample size for this study was determined for both clinical and statistical study design 
considerations. 
 
Part 1 of the study ran according to the standard “3+3” design.1,2. At the 150 mg dose cohort, up to 4 
additional patients were to be treated with formulated IMP according to a Bayesian modified toxicity 
probability interval (mTPI) with a target toxicity rate ≤ 25%. Safety data have been reviewed prior to 
progress with additional cohort at higher dose and wereto be subject to a protocol amendment. 
 
Part 2 permits further evaluation of the safety and tolerability of the RD of SEL24/MEN1703 in the 
expansion cohorts defined above. 
 
Statistical analysis will be performed through descriptive statistics only and separately for the two 
different cohorts (“all-comers” and “IDH-mutant”). 
The evaluable patients treated at the RD in Part 1 or in Part 2 may be also retrospectively included in 
exploratory safety/efficacy pooled analysis, including patients with comparable inclusion criteria. 
 
On-going safety will be assessed regularly by the DMC during Part 2 and at a minimum when 6 new 
patients have been dosed (to end Cycle 1) or every 2 months, whichever comes first. No dose escalation 
steps will be permitted in Part 2. 

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Demographic data will be displayed, and summary statistics will be used to describe the study 
population. 
 
Safety data will be tabulated for all patients. Laboratory parameters and adverse events will be included. 
Adverse events will be tabulated by body system, severity and relation to therapy. 
 
Anti-leukemia activity data will be tabulated. 
 

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Table 5: Schedule of Study Assessments (14 days SEL24/MEN1703 treatment in 21-day cycles) 
Cycle 
Screening  
≤28-days 
Cycle 1  
Cycle 2 
Cycle 3 
onwards 
Final 
Study 
Visit17 
Follow 
Up18 
Visit 
D1 
D2 
D3&4 
D7 
(±1) 
D14 
(±1) 
D15 
D17 
D19 
D1 (±2) 
D7 
(±1) 
D14 
(±1) 
D1 
(±2) 
D14 
(±1) 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion checks 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
FSH and/or Pregnancy test1 
X 
X 
 
 
 
 
 
 
 
X 
 
 
X 
 
X 
 
ECOG PS 
X 
 
 
 
 
 
 
 
 
X 
 
 
X 
 
X 
 
Vital signs2 
X 
X 
 
 
 
 
 
 
 
X 
 
 
X 
 
X 
 
Physical examination3 
X 
X 
 
 
 
 
 
 
 
X 
 
 
X 
 
X 
 
Clinical chemistry4 
X 
X 
X 
X 
X 
X 
 
 
 
X 
X 
X 
X 
X 
X 
 
Hematology4 
X 
X 
X 
X 
X 
X 
 
 
 
X 
X 
X 
X 
X 
X 
 
Coagulation4 
X 
X 
X 
X 
X 
X 
 
 
 
X 
X 
X 
X 
 
X 
 
Lipid profile4 
X 
X 
 
 
 
X 
 
 
 
X 
 
X 
X 
 
X 
 
Peripheral blasts5 
X 
X 
 
 
 
X 
 
 
 
 
 
X 
 
X 
X 
 
Urinalysis 
X 
X 
 
 
 
 
 
 
 
X 
 
 
X 
 
X 
 
Electrocardiogram6  
X 
X 
 
 
X 
 
 
 
 
X 
 
 
X 
 
X 
 
Echocardiogram (or MUGA scan) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Bone marrow aspirate/biopsy7 
X 
 
 
 
 
 
 
 
 
 
 
 
(X)§ 
 
(X) 
 
Disease evaluation8 
 
 
 
 
 
 
 
 
 
 
 
 
(X)§ 
 
(X) 
 
The genetic profile of AML cells9 
X 
 
 
 
 
 
 
 
 
 
 
 
(X)§ 
 
(X) 
 
PD biomarker blood sampling10 
X 
X 
 
 
 
X 
 
 
 
X 
 
X 
X§ 
X§ 
 
 
CYP2D6 phenotyping11 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CD25 Expression12 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Mutational Status13  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
AML Karyotypic analysis 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Adverse events 
 
X 
X 
X 
X 
X 
 
 
 
X 
X 
X 
X 
X 
X 
 
Concomitant medication 
X 
X 
X 
X 
X 
X 
 
 
 
X 
X 
X 
X 
X 
X 
 
Transfusion status 
X 
X 
X 
X 
X 
X 
 
 
 
X 
X 
X 
X 
X 
X 
 
SEL24/MEN1703 administration14 
  
X - once daily dosing for 14 consecutive days in 21-day cycles 
  
  
PK sampling (blood)15 
  
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
PK (urine collection)16 
  
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Follow-up assessments 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
General instructions: 
• 
Informed Consent must be obtained using the current version of the PIS/ICF prior to commencing Screening. 

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• 
On dosing days, assessments should be performed prior to SEL24/MEN1703 dosing unless specified otherwise; tolerance windows for specific assessments are 
described below. 
• 
(X) denotes an optional sample; please refer to Footnotes.  
• 
X§ denotes a sample not taken at every cycle; please refer to Footnotes. 
• 
Additional assessments may be performed as clinically indicated. 
 
Footnotes:  
1 
A pregnancy test is required within 7 days prior to receiving study drug. Pregnancy test may be alternatively carried out at C1D1 visit prior to first SEL24/MEN1703 
administration; results of the test should be available prior to receiving study drug. Additionally, a pregnancy test is required on the first day of each study cycle 
and at the Final Study Visit. If the Final Study Visit is performed before 30 days has elapsed from the last study drug administration, the pregnancy test shall be 
postponed when 30 days (+7 d tolerance) from the last study drug intake is elapsed (i.e. when no relevant drug systemic exposure is expected). A negative pregnancy 
test may be confirmed by urine or blood test. Where a urine test is positive or equivocal, a blood test must be performed to confirm the result. Patients requiring 
confirmation of post-menopausal status will have FSH levels assessed at Screening. 
2 
Vital signs include temperature, systolic blood pressure, diastolic blood pressure, heart rate and respiratory rate. 
3 
Physical examination includes height and weight at Screening and only weight at the start of each cycle. After Screening, further assessments may be symptom-
directed. 
4 
For complete list of Clinical chemistry, Hematology, Coagulation, and Lipid profile parameters please refer to Appendix E. Coagulation parameters may be assessed 
from the Hematology sample. Should a patient develop coagulation abnormalities at any point during the study, a comprehensive evaluation of coagulation 
abnormalities will be performed immediately which may include, but not be limited to repeat PT/INR, APTT, fibrinogen, D-dimer, plus a peripheral blood smear, 
thrombin time, to be evaluated by the Investigator in conjunction with the patient’s medical history, a physical examination and concomitant medication review. 
Repeat testing may be performed as clinically indicated, which may include additional parameters or time-points (please also refer to Appendix E). 
5 
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. This assessment may be performed from the Hematology sample. 
6 
At C1 D1, the electrocardiogram assessment will be carried out pre-dose and at 4-6 h post dose. 
7 
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. In case of AML relapse following response to SEL24/MEN1703, a bone marrow aspirate/biopsy is highly recommended, whenever 
possible. Time-points described as (X)§ are recommended every 2 cycles, but not mandatory. Patients may not have the FSV assessment performed where they 
already have had a bone marrow assessment in the last month or have progressive disease. A bone marrow differential will be performed locally. An aliquot of 
bone marrow aspirate/biopsy will be centrally stored for future analysis (e.g. minimal residual disease), if any. Please refer to the Lab Manual for full details on 
bone marrow aspirates/biopsy collection, time-points, processing, storage and shipment. 
8 
Disease evaluation will be performed at every time-point (excluding Screening) where a bone marrow aspirate/biopsy is taken.  
9 
Bone marrow aspirate/biopsy taken during the study will be tested centrally for the genetic profile of AML cells. Please refer to the Lab Manual for full details on 
sample collection, time-points, processing, storage and shipment. 
10 
Blood sampling for PD biomarker assessments will be taken at Screening, C1 D1 pre-dose, C1 D1 2-6h post-dose, C1 D14 2-6h post-dose, C2 D1 pre-dose, C2 D14 
2-6h post-dose, C3 D1 pre-dose, C3 D14 2-6h post-dose. All sample times are approximate and every effort should be made to take the samples as close to the 
specified time given and, where relevant, contemporaneously with blood sampling for PK assessments. For the C1 D1and D14 a ±30 min window is allowed. Please 
refer to the Lab Manual for full details on PD biomarker sample collection, time-points, processing, storage and shipment. 

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11 
CYP2D6 phenotyping will be assessed centrally on a blood sample collected at Screening. 
12 
CD25 expression will be assessed centrally on an aliquot of blood sample for PD biomarker assessment taken at Screening. 
13 
Mutational status (including at least FLT3 and IDH mutations) will be assessed locally at Screening. 
14 
SEL24/MEN1703 will be given once daily on D1-14 over 21-day treatment cycles. Doses shall be taken on an empty stomach (at least 2 hours after and 1 hour 
before eating). 
15 
Blood samples for plasma PK analysis will be taken at C1 D1 pre-dose, 0.5, 1, 2, 4, 6, 8, 10-14 and 24 h (C1 D2 pre-dose), C1 D7 at 4 and 8 h post dose, C1 D14 (or 
last day of dosing in cycle) pre-dose, 0.5, 1, 2, 4, 6, 8, 10-14 and 24 h (C1 D15), 72 h (C1 D17), 120 h (C1 D19), C2 D1 pre-dose (-1 d tolerance), D7 and 14 (or last 
day of dosing in cycle) at 2-6 h post dose, C3 onwards D1 pre-dose (-1 d tolerance) and D14 (or last day of dosing in each cycle) at 2-6 h post dose (-2 d tolerance). 
All sample times are approximate, and every effort should be made to take the samples as close to the specified time given and, where relevant, contemporaneously 
with blood sampling for PD biomarker assessments. For the C1 D1, D2, D7 and D14 a ±5 min window is allowed, for the C1 last day of dosing 24 h (C1D15), 72 h 
(C1D17) and 120 h (C1D19) samples, a ±2 h window is allowed. Please refer to the Lab Manual for full details on sample collection, time-points, processing, storage 
and shipment. 
16 
Part 1 only. Urine collection for PK analysis will be collected from the first dose of SEL24/MEN1703 until immediately prior to the second dose. Please refer to the 
Lab Manual for full details on sample collection, time-points, processing, storage and shipment. 
17 
Final study assessments to be conducted up to 30 d (+/-2 d) from last dose of SEL24/MEN1703. Adverse events and concomitant medications must be assessed to 
30 d from last dose of SEL24/MEN1703. Other assessments may be carried out between 7-30 d from last dose.  
18 
An assessment of each patient’s disease status and AML-related medications administered will be made approximately every 3 months from last dose of 
SEL24/MEN1703 for up to 1 year (or until End of Study, whichever occurs first) regardless of the initiation of additional treatments to determine date of progression 
(where appropriate) and survival status. 
 

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TABLE OF CONTENTS 
1. 
INTRODUCTION ........................................................................................................................................ 29 
1.1. 
ACUTE MYELOID LEUKEMIA .......................................................................................................... 29 
1.2. 
SEL24/MEN1703 ..................................................................................................................................... 29 
1.3. 
NON-CLINICAL STUDIES WITH SEL24/MEN1703 .......................................................................... 30 
1.4. 
RATIONALE FOR SEL24/MEN1703 STARTING DOSE SELECTION AND DOSE ESCALATION 
PLAN 33 
1.5. 
SAFETY GUIDANCE INFORMATION FOR INVESTIGATORS ..................................................... 35 
2. 
STUDY OBJECTIVES ................................................................................................................................ 37 
3. 
SELECTION CRITERIA ............................................................................................................................ 39 
3.1. 
INCLUSION CRITERIA ........................................................................................................................ 39 
3.2. 
EXCLUSION CRITERIA ....................................................................................................................... 40 
3.3. 
DEFINITION OF EVALUABLE PATIENT AND REPLACEMENT OF PATIENTS ....................... 41 
3.4. 
REASONS FOR WITHDRAWAL OF PATIENT FROM STUDY ...................................................... 41 
3.5. 
SCREEN-FAILURE PATIENT AND PROCEDURES FOR RE-SCREENING ................................. 42 
3.6. 
PROCEDURES FOR PATIENT DISCONTINUATION ...................................................................... 42 
3.7. 
STUDY OR SITE TERMINATION ....................................................................................................... 43 
4. 
STUDY DESIGN .......................................................................................................................................... 44 
4.1. 
PART 1 ..................................................................................................................................................... 44 
4.2. 
PART 2 ..................................................................................................................................................... 47 
4.3. 
DLT CRITERIA ...................................................................................................................................... 48 
4.4. 
CRITERIA FOR RE-TREATMENT AND DOSE MODIFICATION RULES .................................... 49 
4.5. 
INTRA-PATIENT DOSE ESCALATION ............................................................................................. 51 
5. 
STUDY SCHEDULE ................................................................................................................................... 53 
5.1. 
SCHEDULE OF STUDY ASSESSMENTS ............................................................................................ 53 
5.2. 
VOLUME OF BLOOD SAMPLING ...................................................................................................... 58 
5.3. 
DESCRIPTION OF STUDY INTERVENTIONS AND ASSESSMENTS ............................................ 58 
5.3.1. 
MEDICAL HISTORY ............................................................................................................................. 58 
5.3.2. 
PREGNANCY AND FSH TEST ............................................................................................................. 59 
5.3.3. 
ECOG PERFORMANCE STATUS ....................................................................................................... 59 
5.3.4. 
VITAL SIGNS ......................................................................................................................................... 59 
5.3.5. 
PHYSICAL EXAMINATIONS .............................................................................................................. 59 
5.3.6. 
CLINICAL CHEMISTRY, HEMATOLOGY, COAGULATION, LIPID PROFILE AND 
URINALYSIS ........................................................................................................................................................ 60 
5.3.7. 
PERIPHERAL BLASTS ......................................................................................................................... 60 
5.3.8. 
ELECTROCARDIOGRAMS ................................................................................................................. 60 

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5.3.9. 
ECHOCARDIOGRAM ........................................................................................................................... 60 
5.3.10. 
BONE MARROW ASSESSMENT .................................................................................................... 61 
5.3.11. 
DISEASE EVALUATION .................................................................................................................. 61 
5.3.12. 
PD BIOMARKERS ............................................................................................................................. 61 
5.3.13. 
GENETIC PROFILE OF AML CELLS ............................................................................................ 61 
5.3.14. 
PK SAMPLING .................................................................................................................................. 62 
5.3.15. 
CYP2D6 PHENOTYPING ................................................................................................................. 62 
5.3.16. 
CD25 EXPRESSION .......................................................................................................................... 62 
5.3.17. 
MUTATIONAL STATUS................................................................................................................... 62 
5.3.18. 
AML KARYOTYPIC ANALYSIS ..................................................................................................... 62 
5.3.19. 
TRANSFUSION STATUS .................................................................................................................. 62 
6. 
STUDY MEDICATION AND ADMINISTRATION ................................................................................. 64 
6.1. 
LABELING OF SEL24/MEN1703 .......................................................................................................... 64 
6.2. 
SEL24/MEN1703 STARTING DOSE AND DURATION OF TREATMENT ON STUDY ................. 64 
6.3. 
STORAGE OF SEL24/MEN1703 ........................................................................................................... 65 
6.4. 
BLINDING AND PROCEDURES FOR UN-BLINDING THE STUDY .............................................. 65 
6.5. 
PROVISION AND REPLACEMENT OF SEL24/MEN1703 ................................................................ 65 
6.6. 
DRUG ACCOUNTABILITY .................................................................................................................. 65 
6.7. 
TREATMENT ALLOCATION .............................................................................................................. 66 
6.8. 
DOSING INSTRUCTIONS ..................................................................................................................... 66 
6.9. 
PERMITTED AND RESTRICTED CONCOMITANT MEDICATIONS ........................................... 67 
6.9.1. 
ACCEPTABLE CONCOMITANT MEDICATIONS ............................................................................ 67 
6.9.2. 
ANTIBACTERIAL AND ANTIFUNGAL PROPHYLAXIS ................................................................ 68 
6.9.3. 
POTENTIAL FOR DRUG-DRUG INTERACTIONS ........................................................................... 68 
7. 
ADVERSE EVENTS AND REPORTING REQUIREMENTS .................................................................. 70 
7.1. 
ASSESSMENT OF SAFETY .................................................................................................................. 70 
7.2. 
ADVERSE EVENT DEFINITION ......................................................................................................... 70 
7.3. 
IMPORTANCE OF ADVERSE EVENT REPORTING ....................................................................... 71 
7.4. 
EVALUATING ADVERSE EVENTS .................................................................................................... 71 
7.5. 
SEVERITY .............................................................................................................................................. 71 
7.6. 
SERIOUS ADVERSE EVENTS ............................................................................................................. 71 
7.6.1. 
EXCEPTIONS TO SAE REPORTING .................................................................................................. 73 
7.7. 
OTHER IMPORTANT EVENTS FOR IMMEDIATE REPORTING ................................................. 74 
7.7.1. 
EXPOSURE DURING PREGNANCY OR LACTATION .................................................................... 74 
7.7.2. 
MISUSE AND OVERDOSE ................................................................................................................... 75 
7.7.3. 
DOSE LIMITING TOXICITY ............................................................................................................... 75 

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7.7.4. 
INVESTIGATIONAL PRODUCT COMPLAINTS .............................................................................. 76 
7.8. 
RELATIONSHIP..................................................................................................................................... 76 
7.9. 
UNEXPECTED ADVERSE EVENTS .................................................................................................... 77 
7.10. 
REPORTING SERIOUS ADVERSE EVENTS ..................................................................................... 77 
7.11. 
REPORTING OF SERIOUS ADVERT EVENTS TO REGULATORY AUTHORITY ..................... 77 
7.12. 
FOLLOW UP INFORMATION ON A SAE .......................................................................................... 79 
8. 
DATA EVALUATION ................................................................................................................................. 80 
8.1. 
DATA MONITORING COMMITTEE .................................................................................................. 80 
8.2. 
POPULATIONS ...................................................................................................................................... 80 
8.3. 
COMPLETION OF THE STUDY .......................................................................................................... 81 
8.4. 
STATISTICAL CONSIDERATIONS .................................................................................................... 81 
8.4.1. 
MISSING DATA/DISCONTINUATION ............................................................................................... 81 
8.5. 
DEMOGRAPHIC, MEDICAL HISTORY, PRIOR MEDICATION AND OTHER BASELINE 
CHARACTERISTICS .......................................................................................................................................... 81 
8.6. 
STUDY TREATMENT ........................................................................................................................... 82 
8.7. 
CONCOMITANT MEDICATION ......................................................................................................... 82 
8.8. 
METHODS FOR ASSESSMENT OF SAFETY PARAMETERS......................................................... 82 
8.9. 
METHODS FOR ASSESSMENT OF ANTI-LEUKEMIC ACTIVITY ............................................... 82 
8.10. 
METHODS FOR ASSESSMENT OF PK DATA .................................................................................. 83 
8.11. 
METHODS FOR ASSESSMENT OF PD DATA ................................................................................... 83 
8.12. 
METHODS FOR ASSESSMENT OF THE GENETIC PROFILE OF AML CELLS ......................... 84 
8.13. 
ESTIMATED SAMPLE SIZE ................................................................................................................ 84 
9. 
QUALITY ASSURANCE ............................................................................................................................ 84 
9.1. 
DATA RECORDING / MONITORING OF THE STUDY AND REGULATORY COMPLIANCE .. 84 
9.2. 
STUDY MONITORING.......................................................................................................................... 85 
9.3. 
CLINICAL STUDY AUDIT ................................................................................................................... 85 
9.4. 
CLINICAL STUDY REPORT ................................................................................................................ 85 
9.5. 
DATA RETENTION AND AVAILABILITY ........................................................................................ 86 
9.6. 
CURRICULA VITAE AND FINANCIAL DISCLOSURE OF INVESTIGATORS ............................ 86 
9.7. 
PROTOCOL MODIFICATIONS ........................................................................................................... 86 
10. 
ETHICS REVIEW/INFORMED CONSENT/ETHICAL CONSIDERATIONS ...................................... 87 
10.1. 
ETHICAL CONDUCT OF THE STUDY .............................................................................................. 87 
10.2. 
INFORMED CONSENT ......................................................................................................................... 87 
10.3. 
PATIENT PARTICIPATION CARD ..................................................................................................... 88 
10.4. 
INSURANCE ........................................................................................................................................... 89 
10.5. 
INSTITUTIONAL REVIEW BOARD/INDEPENDENT ETHICS COMMITTEE ............................. 89 

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10.6. 
PATIENT PRIVACY .............................................................................................................................. 89 
11. 
DATA CONFIDENTIALITY AND PUBLICATION POLICY ................................................................. 90 
12. 
DATA PROTECTION ................................................................................................................................. 90 
12.1. 
GENERAL PRINCIPLES ON PERSONAL DATA COMPLIANCE................................................... 90 
12.2. 
ACKNOWLEDGMENT ......................................................................................................................... 90 
12.3. 
DATA CONTROLLERS AND DATA PROCESSORS ......................................................................... 91 
12.4. 
DUTIES OF THE PARTIES INVOLVED IN THE PERFORMANCE OF THE STUDY .................. 91 
12.5. 
ARCHIVING OF THE CLINICAL TRIAL MASTER FILE AND PATIENTS’ PERSONAL DATA
 
93 
12.6. 
DATA BREACH ...................................................................................................................................... 94 
12.7. 
INFORMATION NOTICE ON PERSONAL DATA PROTECTION AND PSEUDONYMISATION95 
12.8. 
GENETIC DATA .................................................................................................................................... 95 
12.9. 
TRANSFER OF PATIENTS’ DATA OUTSIDE THE EUROPEAN UNION ...................................... 96 
12.10. 
EXERCISE OF PATIENTS’ DATA PRIVACY RIGHTS................................................................ 97 
12.11. 
FUTURE RESEARCH ....................................................................................................................... 97 
13. 
END OF CLINICAL TRIAL AND ARCHIVING ...................................................................................... 98 
13.1. 
ARCHIVING OF ELECTRONIC DOCUMENTATION/DATA .......................................................... 98 
 
 
 
 
 

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List of Tables 
Table 1: Part 1 Study Objectives and Endpoint (Assessment) ....................................................................................6 
Table 2: Part 2 Study Objectives and Endpoint (Assessment) ....................................................................................7 
Table 3: Patients exposure along Dose Escalation Steps.............................................................................................8 
Table 4: Part 1 Dose Escalation Rules........................................................................................................................9 
Table 5: Schedule of Study Assessments (14 days SEL24/MEN1703 treatment in 21-day cycles) ........................... 18 
Table 6: Human rationale based on dog toxicology studies ...................................................................................... 34 
Table 7: Human dose rationale based on rat toxicology studies ................................................................................ 34 
Table 8: CLI24-001 Patient Disposition up to clinical hold (all patients treated with non-formulated IMP) .............. 34 
Table 9: CLI24-001 Patient Disposition ................................................................................................................... 35 
Table 10: Dose Modification of SEL24/MEN1703 for Non-hematologic Toxicity ................................................... 50 
Table 11: Dose Modification of SEL24/MEN1703 for Hematologic Toxicity .......................................................... 51 
Table 12: Composition of SEL24/MEN1703 for oral use ......................................................................................... 64 
Table 13: Contact details for SAE reporting............................................................................................................. 77 
Table 14: Pharmacokinetic Parameters .................................................................................................................... 83 
 
 
List of Figures 
Figure 1: Cohort expansion and dose escalation plan ............................................................................................... 47 
Figure 2: Sample patient participation card .............................................................................................................. 89 
 
 

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LIST OF ABBREVIATIONS 
 
AE 
adverse event 
ADHD 
attention deficit hyperactivity disorder 
ALT 
alanine aminotransferase 
AML 
acute myeloid leukemia 
ANC 
absolute neutrophil count 
API 
active pharmaceutical ingredient 
AST 
aspartate aminotransferase 
ATC 
anatomical therapeutic chemical 
AUC 
area under the curve 
AUC0-∞ 
AUC from time zero to infinity 
AUC0-t 
AUC from time zero to time t 
BID 
twice daily dosing 
BCRP 
breast cancer resistance protein 
BSA 
body surface area 
BUN 
blood urea nitrogen 
CD25 
cluster of differentiation 25; gene coding for the alpha chain of 
Interleukin 2 receptor protein 
cDNA 
complementary deoxyribonucleic acid 
cGMP 
current Good Manufacturing Practice 
CI 
confidence interval 
CIOMS 
Council for International Organizations of Medical Sciences 
CL 
plasma clearance 
Cmax 
maximum plasma concentration 
CNS 
central nervous system 
COVID-19 
Coronavirus disease 2019 
CR 
complete response/remission 
CRA 
Clinical Research Associate 
CRF 
Case Report Form 
CRi 
complete remission with incomplete blood count recovery 
CRh 
complete remission with partial hematologic recovery 
CRO 
contract research organization 
CTCAE 
common terminology criteria for adverse events 
DLT 
dose limiting toxicity 
DMC 
Data Monitoring Committee 
DoR 
duration of response 
EC 
European Community 
EC 
Ethics Committee 
ECG 
electrocardiogram 
ECI 
events of clinical interest 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
electronic Case Report Form 
EGFR 
epidermal growth factor receptor 
EDC 
electronic data capture 

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EFS 
event-free survival 
EU 
European Union 
FDA 
(US) Food and Drug Administration 
FIH 
first-in-human 
FLT3 
Fms-like tyrosine kinase 3; a gene coding for FMS-like tyrosine kinase-3 
FPI 
first patient in 
FSH 
follicle-stimulating hormone 
FSV 
final study visit 
GALT 
gut associated lymphoid tissue 
GCP 
Good Clinical Practice 
GMP 
Good Manufacturing Practice 
GPCR 
G-protein-coupled receptors 
GVHD 
Graft versus Host Disease 
HBV 
hepatitis B virus 
HCV 
hepatitis C virus 
hERG 
human ether-a-go-go-related gene 
HIV 
human immunodeficiency virus 
HMA 
hypomethylating agents 
HNSTD 
highest non-severely toxic dose 
HSCT 
hematopoietic stem cell transplant 
I.V. 
intravenous(ly) 
IB 
Investigator’s Brochure 
IC50 
half maximal inhibitory concentration 
ICF 
informed consent form 
ICH 
IDH 
International Conference on Harmonisation  
Isocitrate DeHydrogenase 
IMP 
investigational medicinal product 
IND 
investigational new drug 
IRB 
Institutional Review Board 
ITD 
internal tandem duplication 
IWRS 
interactive web response system 
LDH 
lactate dehydrogenase 
LPO 
last patient out 
LVEF 
left ventricular ejection fraction 
MAD 
maximum administered dose 
MRD 
minimal residual disease 
MLFS 
morphologic leukemic-free state 
ms 
millisecond(s) 
MTD 
maximum tolerated dose 
MUGA 
multi-gated acquisition 
NCI  
National Cancer Institute  
NOAEL 
no observed adverse effect level 
NYHA 
New York Heart Association 
ORR 
objective (or overall) response rate 
OS 
overall survival 

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PBMC 
peripheral blood mononuclear cells 
PD 
pharmacodynamic(s) 
PD 
progressive disease 
PIM 
proviral integration site for Moloney murine leukemia virus; a 
serine/threonine protein kinase (a proto-oncogene) 
PIS 
patient information sheet 
PK 
pharmacokinetic(s) 
PS 
performance score 
QD 
once daily 
QTc 
corrected Q wave T wave interval 
RD 
recommended dose 
RFS 
relapse-free survival 
s.c. 
subcutaneous(ly) 
SAE 
serious adverse event 
SAP 
Statistical Analysis Plan 
SEL24/MEN1703 
a dual kinase inhibitor targeting PIM (PIM1, PIM2, PIM3) and FLT3 
kinases; also referred to as SEL24-B489 or SEL24-1289 (free base 
forms) and SEL24-B489A and SEL24-1289A (hydrochloride salt of 
SEL24-B489 or SEL24-1289) 
SSRI 
selective serotonin reuptake inhibitor 
SDSU 
Study Drug Safety Unit 
SUSAR 
suspected unexpected serious adverse reaction 
t½ 
half-life 
tmax 
time to reach maximum concentration 
TMF 
Trial Master File 
TPN 
total parenteral nutrition 
ULN 
upper limit of normal 
USA 
United States of America 
VF 
ventricular fibrillation 
Vss 
volume of distribution at steady state 
VT 
ventricular tachycardia 
λz 
individual estimate of the terminal elimination rate constant 
 
 

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1. INTRODUCTION
1.1. Acute Myeloid Leukemia
Acute myeloid leukemia (AML), a malignancy of a myeloid precursor cell, is an extremely 
aggressive malignancy; patients treated with supportive care alone have a median survival of 2.5 
months1. In the United States it was estimated that there would be approximately 14,500 new cases 
of AML in 20132, in the European Union (EU), annual incidence is on the order of 20,000 new 
cases3. AML represents approximately 25% of all adult leukemias as measured by the incidence 
rate4. Despite significant recent advances in the treatment of many cancers, the mainstay of initial 
treatment of AML was developed nearly 40 years ago as a combination of cytosine arabinoside 
(ara-C or cytarabine) with an anthracycline (this combination is known as ‘7+3’), and remains the 
standard of care. Approximately 60% to 70% of adults with AML can be expected to attain a CR 
following appropriate induction therapy; however, over half of these patients will subsequently 
relapse and only about 25% of adults with AML can be expected to survive 3 or more years and 
be cured. Patients who fail to achieve a CR with current standard therapy have very poor prognosis. 
In patients who relapse within 6 months of attaining CR (regardless of age), the prognosis remains 
particularly poor. Some patients who have had a prolonged period of CR may respond a second 
time to standard therapy (cytarabine plus an anthracycline, ‘7+3’), but for patients who are 
refractory to this regimen, there are no therapies that have been shown to prolong survival. 
AML is primarily a disease of older adults and the median age of patients at diagnosis is 65 years. 
Age plays a key role in the prognosis of AML; 5-year survival of patients younger than 45 is over 
50%, but drops to less than 5% for patients older than 65 years4. There are several factors that 
contribute to this survival disparity based on age. Firstly, older patients exhibit a worse 
performance status than younger patients, often due to intercurrent medical conditions. Secondly, 
AML in older patients is more frequently associated with unfavorable cytogenetics, which implies 
a greater degree of genetic damage and drug resistance. Finally, older AML patients exhibit a 
higher frequency of multi-drug resistance (mdr) expression, which also contributes to drug 
resistance5. These aspects of AML in the elderly are reflected in several key outcomes: compared 
with patients 55 years and younger, patients aged 65 to 75 years have lower rates of CR (39% vs. 
64%); higher rates of mortality within 30-days after induction (23% vs. 3%); and lower overall 
median survival times (6.9 months vs. 18.8 months)5. Given these poor outcomes, many older 
patients are not considered to be candidates for aggressive remission induction therapy, may now 
receive combination treatments such as low dose cytarabine with either venetoclax or glasdegib or 
a hypomethylating agent (azacitidine/azacytidine or decitabine) with venetoclax. 
Although specific treatments are available for patients with AML harboring specific mutations, 
relapsed or refractory AML remains one of the largest unmet needs in medicine, particularly in 
patients that have already failed target salvage options, where any. 
1.2. SEL24/MEN1703 
Menarini Ricerche S.p.A (hereinafter referred to as Menarini) is developing a dual kinase inhibitor 
targeting PIM (PIM1, PIM2, PIM3) and FLT3 kinases, named SEL24/MEN1703.  

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Fms-like tyrosine kinase 3 internal tandem duplication (FLT3-ITD) is one of the most common 
genetic lesions in AML and is associated with a poor long-term prognosis6. Although FLT3 
tyrosine kinase inhibitors are now approved for commercial use, the medical need in FLT3 mutated 
AML patients is still largely unmet, particularly – though not limited - in patients with relapsed or 
refractory disease. PIM (proviral integration site for Moloney murine leukemia virus) kinases are 
thought to be major drivers of the resistance phenotype and their inhibition in relapsed samples 
restores cell sensitivity to FLT3 inhibitors7. Thus, simultaneous PIM and FLT3 inhibition 
represents a promising strategy in AML therapy. 
 
1.3. Non-Clinical Studies with SEL24/MEN1703 
SEL24/MEN1703, a potent PIM and FLT3-ITD dual activity inhibitor, demonstrates significantly 
broader activity in AML cell lines and primary AML blasts, irrespective of FLT3 status, than 
selective FLT3-ITD or PIM inhibitors. 
 
In vitro studies and in vivo nonclinical pharmacology studies in mouse leukemia human xenograft 
models have been conducted to evaluate the anticancer potential of SEL24/MEN1703. Evaluation 
of SEL24/MEN1703 by enzymatic assay and biomarker studies shows that it exhibits potent 
activity on PIM kinase isoforms comparable with AZD1208, and slightly lower activity than 
quizartinib for the FLT3 mutant. 
 
SEL24/MEN1703 demonstrates strong cytotoxic effects in AML cell lines, independently of FLT3 
status, in contrast to quizartinib and AZD1208, which show more narrow therapeutic potential. 
 
The unique mechanism of inhibiting both PIM and FLT3 kinases translates into potent effects in 
in vivo models. SEL24/MEN1703 shows anticancer effects in subcutaneous xenografts AML 
models and is superior to quizartinib and AZD1208, depending on the genetic background of 
mutations. Nonclinical pharmacology study results suggest that SEL24/MEN1703 may offer a 
comprehensive approach to targeting the PIM/FLT3 axis in AML patients and that the activity can 
be further enhanced by combination with standard chemotherapy. 
 
In vitro and in vivo safety pharmacology studies have been conducted. In vitro studies included 
nuclear receptor binding studies, hERG inhibition and hERG tail currents recorded from 
transfected HEK293 cells. An in vivo GLP study has been conducted in male Beagle dogs to 
evaluate the effects on cardiovascular and neurobehavioral functions. 
 
SEL24/MEN1703 was tested on a panel of G-protein-coupled receptors (GPCRs) and other 
receptors. The compound was tested at the high concentration of 10 µM. Three receptors were 
identified as inhibited more than 85% (NK1, 5HT2B, and sigma). Both receptors were tested for 
agonistic and antagonistic activity of SEL24/MEN1703. No agonistic activity was detected.  
 
Results of evaluation of hERG currents indicated that for SEL24/MEN1703, the hERG IC50 was 
3.561 µM. For the positive control, E-4031, the mean hERG inhibition was 88.5%. In addition, 
SEL24/MEN1703 inhibited hERG tail current in HEK293 cells stably transfected with hERG 
cDNA with an estimated IC50 value of 2.5 µM. 
 

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In a GLP safety pharmacology study in the dog, the effect of SEL24/MEN1703 at doses of 5, 10 
and 20 mg/kg on arterial blood pressure, heart rate, lead II ECG intervals, core body temperature 
and on neurobehavioral functions was assessed in conscious telemetered Beagle dogs. After the 
administration of SEL24/MEN1703 at these doses, no effect was noted on arterial blood pressure, 
heart rate, lead II ECG intervals and core body temperature. The evaluation of neurobehavioral 
parameters, both direct and remote, did not show changes compared with vehicle at any dose level. 
 
Pharmacokinetic studies have been performed in mouse, rat, and dog. The pharmacokinetic profile 
of SEL24/MEN1703 obtained in vivo in mice, rats and dogs confirmed good bioavailability and a 
favorable profile for oral administration. In vivo efficacious doses as low as 25 mg/kg twice daily 
(BID) in the mouse leads to complete biomarker response in tumor and spleen including inhibition 
of phosphorylation of the classical PIM target S6 (Ser235/236 and Ser240/244). According to 
PK/PD modelling analysis based on MOLM16 cell line xenograft data performed with the aim to 
investigate the exposure-response relationship between plasma SEL24/MEN1703 concentration 
and inhibition of S6 (Ser235/236) phosphorylation, the IC50 is expected at a plasma concentration 
of approximately 800 ng/mL. A dose of 25 mg/kg QD in rat reaches therapeutic plasma levels of 
biomarker inhibition and administration of 100 mg/kg QD in rat leads to approximately 3 times 
higher compound concentration in plasma than the predicted therapeutic level. Pharmacokinetic 
studies confirmed that QD administration is sufficient to maintain therapeutic exposure in rats. In 
another study, bioavailability was evaluated in fasted as well as non-fasted female Sprague Dawley 
rats. Good absolute bioavailability (calculated from AUC0-t), i.e., higher than 70%, was shown for 
both conditions after oral administration in an aqueous solution formulation; however, the non-
fasted state showed slightly higher oral bioavailability than the fasted state (76.2% vs. 70.2%). 
 
Non-GLP repeat-dose toxicity studies have been conducted in rat and dog and GLP repeat-dose 
studies have been carried out in rat and dog. The non-GLP studies confirmed the therapeutic index 
and lack of any toxicology findings at therapeutic doses by clinical pathology and histopathology. 
These studies also demonstrated that adverse effects observed at higher doses are completely or 
partially reversible in a follow-up recovery period. 
 
A non-GLP 10-day twice daily oral gavage toxicity study in rats established that the severely toxic 
dose resulting in 10% lethality (STD10) for SEL24/MEN1703 administered twice daily (12 h ± 1 
h apart) was between 50 and 100 mg/kg/day under those experimental conditions. 
 
In a two-week repeat-dose followed by a two-week recovery period study in rats, the highest dose 
level of 80 mg/kg/day induced mortality and severe clinical signs after at least 10 days of daily 
administration in relation to kidney and liver toxicity. At 20 and 40 mg/kg/day given for two weeks, 
SEL24/MEN1703 induced adverse dose-related degeneration/regeneration (tubulonephrosis) in 
the kidney, and bile duct hyperplasia in the liver. The dose level of 20 mg/kg/day was expected to 
be a no observed adverse effect level (NOAEL) with sufficient plasma exposure. However, based 
on kidney and liver adverse pathological changes observed at all doses in both sexes, no NOAEL 
or STD10 could be established under these experimental conditions. 
 
A GLP two-cycle study of two-week oral repeat-doses followed by a four-week recovery period 
was conducted in rats in which SEL24/MEN1703 was administered orally to Crl:CD(SD) rats once 

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daily for two cycles of 14 days separated by one week of treatment withdrawal. Rats were treated 
at doses of 0 (vehicle), 10, 25 and 50 mg/kg/day (as parent). At 25 mg/kg/day, SEL24/MEN1703-
related findings were observed in the thymus and sternum-bone marrow from males and females, 
and in the liver, adrenals and mammary gland from males only; at 50 mg/kg/day, 
SEL24/MEN1703-related findings were observed in thymus, sternum bone-marrow, kidneys, liver 
and adrenals from both sexes, and in male (prostate and seminal vesicles) and female (ovaries, 
vagina, cervix and uterus) reproductive tracts. Overall, males were more affected in terms of 
incidence and severity compared to females, and the liver (degenerative and proliferative changes 
in the intra and extra-hepatic biliary system), kidney (renal degenerative/ necrotic changes of the 
proximal tubule), and male/female reproductive tract (endocrine disruption) findings were 
considered adverse at 50 mg/kg/day. These findings were sometimes associated to clinical 
pathology and organ weight changes; furthermore, clinical observations (mainly piloerection) and 
decreases in the body weight/body weight gain and food consumption were also observed at 50 
mg/kg/day at the end of each treatment cycle. Based on the pathology findings, the NOAEL is 
considered to be 25 mg/kg/day, which corresponds to mean Cmax and AUC0-24 values of 570 ng/mL 
and 8950 ng.hr/mL in males and to mean Cmax and AUC0-24 values of 579 ng/mL and 7920 
ng.hr/mL in females after two cycles of 14 days treatment separated by one week of treatment 
withdrawal. 
 
In a non-GLP dose range-finding and oral repeat-dose toxicity study in the Beagle dog, it was 
determined that the lowest dose of 10 mg/kg was well-tolerated when administered for 10 days. 
The next higher dose of 30 mg/kg demonstrated clear toxicity and is considered not suitable for 
studies of longer duration. The highest dose of 60 mg/kg necessitated early kill of both male and 
female dogs and was clearly beyond the maximum tolerated dose.  
 
A GLP two-cycle 14-day oral repeat-dose toxicity study was conducted in Beagle dogs followed 
by a four-week treatment-free recovery period. SEL24/MEN1703 was administered orally to 
Beagle dogs QD for 2 cycles of 14 days separated by one week of treatment withdrawal at the 
doses of 0 (vehicle), 5, 10 and 20 mg/kg/day. Treatment resulted in severe clinical signs, marked 
limp of the right and/or left hind limb, reduction of proprioceptive reflex, reduction in body weight 
and food consumption in animals at 20 mg/kg/day leading to early termination of one male and 
two females. Microscopic findings in the gall bladder, liver, stomach, small intestine (duodenum, 
jejunum, ileum), kidneys, lymphoid organs/tissue (thymus, spleen-white pulp, mandibular and 
mesenteric lymph nodes, Gut Associated Lymphoid Tissue (GALT)), hematopoietic tissue 
(sternum-bone marrow) and prostate were variably observed in surviving and premature decedents 
at 20 mg/kg/day and in the gall bladder, liver, lymphoid organs/tissue (thymus, spleen-white pulp, 
mandibular and GALT), and male reproductive system (prostate, testes, epididymis) at 10 
mg/kg/day with a partial recovery in the gall bladder and liver and with no recovery in the male 
reproductive system. In one male, after the second cycle treatment, at 10 mg/kg limping of the left 
hind limb was observed. Based on these results the NOAEL is considered to be 5 mg/kg/day which 
corresponded to mean Cmax and AUC0--24 values of 485 ng/mL and 5850 ng.hr/mL in males and to 
mean Cmax and AUC0--t values of 556 ng/mL and 6730 ng.hr/mL in females after two cycles of 14 
days of treatment.  
 

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The drug interaction potential of SEL24/MEN1703 has been characterized in detail in an extensive 
range of in vitro drug interaction studies as outlined in the FDA Guidance for Industry: Drug 
Interaction Studies-Study Design, Data Analysis, Implications for Dosing, and Labeling 
Recommendations (Draft Guidance, February 2012) and in the EMA Guideline on the 
investigation of drug interactions (June 21, 2012). These studies indicate that SEL24/MEN1703 
may inhibit CYP2D6 and act as a substrate for CYP2D6 and BCRP.   
 
Please refer to the current edition of the Investigator’s Brochure for further information on the non-
clinical studies with SEL24/MEN1703. 
 
1.4. Rationale for SEL24/MEN1703 Starting Dose Selection and Dose Escalation Plan 
The first-in-human (FIH) starting dose for the clinical study in patients with AML was derived 
based on data accumulated from preclinical non-GLP and GLP repeat oral dose toxicology studies 
with SEL24/MEN1703 conducted in rats and dogs. The dog was the more sensitive species and 
the observations from the repeat dose dog GLP toxicology study form the basis for the rationale 
for the FIH starting dose.  
 
This FIH study initially employed an accelerated dose escalation design for the first 4 cohorts, in 
which the starting dose was 25 mg in the first cohort (1 patient, in the absence of unacceptable 
toxicity), followed by a dose of 50, 75 and 100 mg in Cohorts 2, 3 and 4, respectively (1 patient 
per cohort, in the absence of unacceptable toxicity). Thereafter, dose escalation was to proceed 
according to a conventional 3 + 3 design with successive cohorts having dose increments of 50% 
or less. 
 
The 25, 50, 75 and 100 mg doses in humans were supported by the non-clinical toxicology findings 
in animals. Rats and dogs were administered daily doses of SEL24/MEN1703 for two 14-day 
cycles with one week rest between treatment cycles, followed by a 28-day treatment-free recovery 
period. This treatment regimen mimics that to be utilized in the first-in-human clinical study in 
patients with AML. 
 
Doses of 10, 25 and 50 mg/kg (human equivalent dose [HED] of 60, 150 and 300 mg/m2, 
respectively) were administered to rats with no significant toxicity findings. Since no MTD was 
achieved, the rat was considered the less sensitive species. 
 
Doses of 5, 10 and 20 mg/kg (HED of 100, 200 and 400 mg/m2, respectively) were administered 
to dogs. The dog was considered the more sensitive species since the 20 mg/kg SEL24/MEN1703 
dose resulted in severe clinical signs leading to early termination of 3 out of 12 animals.  
 
Following a four-week recovery period, SEL24/MEN1703-related findings were reversible in all 
dose groups. Based on the findings in dogs, the NOAEL was 5 mg/kg and the highest non-severely 
toxic dose (HNSTD) was 10 mg/kg.  
 
As shown in the tables below, the HED of the NOAEL in dogs is 170 mg, based on a human BSA 
of 1.7 m2. Per the ICH S9 guidance, an appropriate human starting dose would be 50 mg, which is 
1/6th the HNSTD in dogs. This study commenced with a lower starting dose of 25 mg. Doses of 25 

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mg through 100 mg remain well below the HED of the NOAEL in dogs and are also below the 
NOAEL and the lowest safe dose tested in rats.  
 
Table 6: Human rationale based on dog toxicology studies 
SEL24/MEN1703 dose level in 
dogs (mg/kg/d) 
Human equivalent dose 
(HED) 
HED in mg, 
based on 1.7 m2 BSA 
5 (NOAEL) 
100 mg/m2/d 
170 mg 
10 (HNSTD) 
200 mg/m2/d 
340 mg 
20 (toxic dose) 
400 mg/m2/d 
680 mg 
 
Table 7: Human dose rationale based on rat toxicology studies 
SEL24/MEN1703 dose level in 
rats  
(mg/kg/d) 
Human equivalent dose 
(HED) 
HED in mg, 
based on 1.7 m2 BSA 
10 (safe dose) 
60 mg/m2/d 
102 mg 
25 (NOAEL) 
150 mg/m2/d 
255 mg 
50 (safe dose with reversible 
SEL24/MEN1703-related 
findings) 
300 mg/m2/d 
510 mg 
 
The first patient to be treated with SEL24/MEN1703 commenced dosing on 15 March 2017. As of 
06 October 2017, eight patients had been dosed with SEL24/MEN1703 at the dose levels described 
in Table 8. 
 
Table 8: CLI24-001 Patient Disposition up to clinical hold (all patients treated with non-formulated IMP) 
Cohort  
1 
2 
3 
4 
5 
SEL24/MEN1703 
Dose Level 
25 mg 
50 mg 
75 mg 
100 mg 
150 mg 
N 
2* 
1 
1 
1 
3 
DLT 
1 
0 
0 
0 
2 
*One patient not included in the dose-determining population 
 
Accelerated titration design had continued through to Cohort 4. At the 150 mg dose level (the first 
cohort to be enrolled following the 3+3 design), DLTs were reported in 2 patients (another patient 
experienced a DLT event at 25 mg dose level). The occurrence of these two events meeting the 
DLT definition at the 150 mg dose level led to an adjustment of the dose escalation plan for this 
study, whereby SEL24/MEN1703 was more thoroughly evaluated following a “3+3” design.  
 

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The subsequent restarting dose level of 50 mg (Cohort 2) following a 3+3 design was selected, 
also supported by the PK data obtained that far during the CLI24-001 study: the total (AUC) and 
maximum (Cmax) exposure of SEL24/MEN1703 observed in the patients were within, or slightly 
exceeding the toxicological coverage established in dog at the dose of 5 mg/kg, which was defined 
as the HNSTD. After single and repeat dose administration of SEL24/MEN1703 25 mg and 50 
mg, Cmax and AUC(0-t) observed in human were more than 11 and 9 times lower than those observed 
in dogs at the HNSTD, respectively. Overall, the PK results obtained that far in human confirmed 
that SEL24/MEN1703 exposure at 25 mg and 50 mg is below 1/6 of the exposure obtained at the 
HNSTD defined in dog (i.e. the most sensitive toxicological species). Moreover, it is noted that 
the dog is a relevant species also from a metabolic point of view, with the M3 metabolite similarly 
identified as the main metabolite in human and canine plasma. In a dedicated 10-day toxicology 
study in the dog (treated at 10, 30 and 60 mg/kg), the parent drug and the M3 metabolite were 
measured in plasma: the presence of M3 metabolite was confirmed and, at 10 mg/kg, it was double 
and one third compared to parent drug in the male and female animals, respectively. 
As of today, 48 patients were dosed with SEL24/MEN1703 at the doses levels described in Table 
9, including 30 patients treated at the RD of 125 mg: 
Table 9: CLI24-001 Patient Disposition 
Cohort 
1 
2 
3 
4 
4F 
4b 
5 
SEL24/MEN1703 Dose Level 
25 
mg 
50 
mg 
75 
mg 
100 
mg 
100 mg 
formulated 
125 
mg 
150 
mg 
Number patients treated with non-formulated 
IMP 
2* 
3 
3 
3 
0 
0 
3 
Number patients treated with Formulated IMP 
0 
0 
0 
0 
3 
30* 
1 
DLT 
1 
0 
0 
0 
0 
1 
3 
*One patient not included in the dose-determining population
Since 3 patients (out of 4) treated at 150 mg experienced DLT, the 125 mg dose level, already 
shown to be tolerable in 6 DLT evaluable patients, was determined to be the RD.  
1.5. Safety Guidance Information for Investigators 
Throughout the study, Investigators should refer to the current edition of the Investigator’s 
Brochure (IB) for a full review of the potential risks associated with treatment with 
SEL24/MEN1703 and details of expected AEs. 
Based on available safety data, administration of SEL24/MEN1703 may be associated with the 
potential risk of fatal thrombosis and severe hepatotoxicity. In addition, hypophosphatemia has 
occurred at the 25, 50, 75, and 150 mg dose levels. Please refer to Section 6.9.1 for further guidance 
on the management of this latter event.  
No other particular risks have been identified for SEL24/MEN1703 according to available clinical 
data. Nevertheless, results from non-clinical data do not allow to exclude the potential phototoxic 
effect of MEN1703. To this end, new safety measures - Inclusion of photosensitivity/phototoxicity 

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preventive measures – have been implemented in previous Clinical Trial Protocol Versions 11.2 
and 11.3. Please refer to Section 6.8 for further guidance on the prevention and management of 
this event. 
 
Risk Benefit Assessment for COVID-19 pandemic 
There is currently an outbreak of respiratory disease (COVID-19) caused by a novel coronavirus 
SARS-CoV-2 that was first detected in Wuhan City, Hubei Province, China in 2019. This new 
virus has rapidly spread across the globe causing the World Health Organization (WHO) to declare 
a pandemic situation on March 12, 2020. In response to the pandemic, the health authorities have 
issued recommendations on the further conduct of clinical studies. Accordingly, 
risk assessments of involvement in the trial with added challenges due to COVID-19 and mitigation 
measures need to be taken into consideration in all clinical studies to protect subjects, site staff and 
the society as a whole. 
In this phase I/II clinical trial for heavily pre-treated relapsed or refractory AML patients the 
eligibility will be evaluated by the treating physician/PI after individual assessment that the clinical 
benefit of the investigational product will outweigh the risk of contracting the SARS-CoV-2 
infection without compromising the safety of the subjects. 
 
Measures to mitigate the additional risks caused by COVID-19 are: 
• Current national laws and local recommendations for prevention of pandemic will be 
strictly adhered. 
• Subjects will be encouraged to strictly follow local mitigation recommendations (e.g. social 
distancing, use of mask, etc.). 
• Access to clinical site will be granted according to local COVID-19 control measures. 
• Based on the local circumstances, to be reassessed on an ongoing basis, additional measures 
will be considered for implementation including: 
o Interruption or slowing down of recruitment of new trial participants; 
o Postponement of activation of sites that have not yet been initiated; 
o Transfer of trial participants to investigational sites away from risk zones, or closer 
to their home; 
o IMP re-distribution among sites, in case of shortage of study drug; 
o Safety laboratory tests to be performed at local laboratory or participant’s home, in 
case the trial participants cannot reach the site; 
o Remote consent could be collected (when applicable as per local policy). 
 
 

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CLI24-001 V13.0 Final 27JUN2022                                                                                                               37 of 108 
2. STUDY OBJECTIVES 
 
Table 1: Part 1 Study Objectives and Endpoint (Assessment) 
Objective 
Endpoint (Assessments) 
Primary: 
 
• To estimate the MTD or MAD and 
determine the RD of SEL24/MEN1703 for 
Part 2 
• DLT evaluation at the end of one treatment 
cycle for each dose level 
Secondary: 
 
• To assess the safety and tolerability of 
SEL24/MEN1703  
• The number and frequency of AEs, safety 
laboratory, vital signs and ECG assessments 
• To 
assess 
anti-leukemic 
activity 
of 
SEL24/MEN1703  
• 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  
• To 
evaluate 
the 
PK 
profile 
of 
SEL24/MEN1703 and its metabolites as 
appropriate 
• Assessment of PK variables, including Cmax, 
AUC and t½ 
Exploratory: 
 
• To 
assess 
the 
PD 
activity 
of 
SEL24/MEN1703 
• To assess the genetic profile of AML cells 
• Flow cytometry assessment of relevant 
biomarkers (e.g. pS6) 
• Analysis of relevant mutations in peripheral 
blasts and bone marrow by using Next 
Generation Sequencing and/or qRT-PCR 
 
Table 2: Part 2 Study Objectives and Endpoint (Assessment) 
Objective 
Endpoint (Assessments) 
Primary: 
 
• To further characterize the safety profile of 
single agent SEL24/MEN1703  
• The number and frequency of AE, safety 
laboratory, vital signs and ECG assessments 
Secondary: 
 
• To assess anti-leukemic activity of single 
agent SEL24/MEN1703  
• 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, OS , 
transfusion conversion rate, transfusion 
maintenance rate, HSCT rate 
• To 
evaluate 
the 
PK 
profile 
of 
SEL24/MEN1703 and its metabolites, as 
appropriate 
• Assessment of PK variables, including Cmax, 
AUC and t½ 
Exploratory: 
 
• To 
assess 
the 
PD 
activity 
of 
SEL24/MEN1703 
• Flow cytometry assessment of relevant 
biomarkers (e.g. pS6)  

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CLI24-001 V13.0 Final 27JUN2022                                                                                                               38 of 108 
Objective 
Endpoint (Assessments) 
• To assess the genetic profile of AML cells 
• Analysis of relevant mutations in peripheral 
blasts and bone marrow by using Next 
Generation Sequencing and/or qRT-PCR 

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3. SELECTION CRITERIA
3.1. Inclusion Criteria
Patients are eligible to be included in study if they meet all of the following 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 inhibitors are eligible ONLY if no IDH inhibitors 
are approved/available in the country/site where they are enrolled. 
5.
ECOG Performance Status 0, 1 or 2.
6.
Adequate organ function at Screening, including:
e) Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤2.5X the
upper limit of normal (ULN);
f)
Total bilirubin ≤2X ULN;
g)
Creatinine clearance ≥40 mL/min (Cockcroft-Gault formula) (see Appendix B);
h)
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 potentialare eligible providing
that:
Female:
-
Agrees to use an effective method of birth control as applicable per local law 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: 

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- 
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. 
 
3.2. Exclusion Criteria 
Patients are not eligible to be included in study if they meet any of the following 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. 

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CLI24-001 V13.0 Final 27JUN2022                                                                                                               41 of 108 
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. 
 
3.3. Definition of Evaluable Patient and Replacement of Patients 
In Part 1 Cycle 1, a patient must have received at least 12 of their 14 doses of SEL24/MEN1703 
within the required 14-day treatment period in order to be evaluable. If a patient is withdrawn from 
the study for reasons other than a DLT-associated event before the end of the first treatment cycle, 
the patient must be replaced so that the required number of patients in the cohort is evaluable for 
the dose escalation decision. Patients who withdraw from the study or discontinue treatment after 
completion of the first treatment cycle will not be replaced.  
 
In Part 2, patients may be replaced if they are not considered evaluable for safety (all patients who 
received at least a dose of SEL24/MEN1703). Patients in Part 2 may also be replaced if they 
received one or more administrations of SEL24/MEN1703 without having one post-treatment bone 
marrow disease assessment. 
In this latter event, patients may be replaced only if the hematology assessments performed on 
peripheral blood shall not indicate a clear disease progression. 
 
3.4. Reasons for Withdrawal of Patient from Study 
Throughout the study, treatment with SEL24/MEN1703 may continue until the occurrence of one 
of the following events, whichever comes first: 
 
• 
Patient withdrawal of consent. 
• 
Disease progression.  
Note: Patients with disease progression may continue to receive SEL24/MEN1703, if 
in the opinion of the Investigator, they remain clinically stable and may be deriving 

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CLI24-001 V13.0 Final 27JUN2022                                                                                                               42 of 108 
potential clinical benefit from SEL24/MEN1703 and it is not considered detrimental 
to the patient to continue study treatment. 
• 
Treatment delay of more than 2 weeks for reasons other than toxicity (see Section 4.4). 
• 
Occurrence of an unacceptable toxicity (see Section 4.4). 
• 
Requirement for treatment with prohibited medication (see Section 6.9.3). 
• 
Treatment non-compliance.  
Note: Treatment non-compliance will be based on patient enquiry and 
SEL24/MEN1703 capsule count on return of used investigational medical product 
(IMP) to site. In Part 1 it will be defined as missing more than 2 doses in a 14-day 
dosing schedule in Cycle 1. After Cycle 1 and throughout Part 2, treatment compliance 
will be assessed on a case-by-case basis (see also Section 4.4).   
• 
Study non-compliance. 
Note: Each patient’s continued willingness to attend study visits and undergo study 
assessments will be assessed on a case-by-case basis.  
• 
Investigator decision that it is in the patient’s best interest to withdraw from the study. 
 
Where appropriate (e.g. in the case of disease progression), continuation of the study treatment 
will be discussed between the Investigator and the Sponsor on a case by case basis. The DMC may 
also advise on the suitability of an individual patient to continue to receive study treatment. 
 
Patients who experience a DLT will be permitted to receive further treatment with 
SEL24/MEN1703 according to the dose modification criteria described in Section 4.4. 
 
3.5. Screen-failure patient and procedures for re-screening 
Screen-failure patient is defined as any patient who does not meet eligibility criteria required for 
study participation or for whom the time window between Screening and C1D1 is longer than 28 
days.  
 
Any patient who has screen-failed may be re-screened at a later date should it be determined the 
patient meets eligibility (e.g. out of range lab value). Re-screening patients will be registered in 
IWRS with a new screening number and they must sign a new consent form if the first dose of 
study drug is given more than 28 days after having signed the first consent form. 
 
3.6. Procedures for Patient Discontinuation 
If a patient withdraws from the study prior to study completion, the reason for withdrawal should 
be sought and recorded in the patient file and the electronic Case Report Form (eCRF). Every effort 
will be made to complete the Final Study Visit. 
 
The Final Study Visit will be performed up to 30 days after the last dose of SEL24/MEN1703. 
Unscheduled assessments showing disease progression and leading to subject’s withdrawal can 
replace the Final Study Visit provided that all assessment/procedures scheduled for this visit are 
completed.  
After the Final Study Visit, all subjects evaluable for efficacy will be followed for survival/disease 
status according to local practice (a visit or a telephone call) every 3 months from last dose of 

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CLI24-001 V13.0 Final 27JUN2022                                                                                                               43 of 108 
SEL24/MEN1703 for up to 1 year (or until End of Study, whichever occurs first), regardless of the 
initiation of additional treatments. 
 
In the case of a temporary or permanent clinical hold, procedures will be put in place to 
communicate this to patients and advice provided to sites on how to complete patient eCRFs. 
 
3.7. Study or Site Termination 
If the Sponsor or their representatives, Investigator, or Competent Authority officials discover 
conditions during the study that indicate that the study or site involvement should be terminated, 
this action may be taken after appropriate consultation with the Sponsor and the Investigator. 
Conditions that may warrant termination of the study or involvement of a study site include, but 
are not limited to: 
 
• 
The discovery of an unexpected, serious, or unacceptable risk to patients enrolled in 
the study. 
• 
The decision on the part of the Sponsor to suspend or discontinue testing, evaluation, 
or development of the study drug. 
• 
Failure of the Investigator(s) to comply with pertinent clinical study regulations. 
• 
Submission of knowingly false information from the research facility to the Sponsor, 
study monitor, or Competent Authority. 
• 
Insufficient adherence to protocol requirements. 
 
In any case, the study will end with the Final Study Visit of the last subject who discontinues the 
study treatment.. For safety monitoring, all serious adverse events (SAEs) with a suspected causal 
relationship to the study treatment that occur after the End of Study must be recorded and notified 
to the Sponsor. 
 
Study termination and follow-up will be performed in accordance with applicable local regulations. 
 
 

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4. STUDY DESIGN
This is a Phase I/II, open-label, multi-center, dose escalation study to estimate the MTD (or MAD)
of SEL24/MEN1703 in patients with AML. At the end of Part 1 a RD of SEL24/MEN1703 will
be selected for further evaluation in Part 2. In Part 2 the safety and anti-leukemic activity of
SEL24/MEN1703 will be further assessed in the study population.
The starting dose will be 25 mg SEL24/MEN1703 taken orally QD for 14 consecutive days over a
21-day treatment cycle. In both parts of the study, the criteria for retreatment described in Section
4.4 must be followed prior to proceeding to administer a further cycle of treatment.
4.1. Part 1 
At the time this protocol Version 12.0 is running, Part 1 has been completed; procedures are 
reported below for completeness. 
Part 1 was initially designed with an ATD for the first 4 cohorts. The study design has then been 
revised to follow a 3+3 design from Cohort 2 (50mg) onwards in order to assess for DLT, adverse 
events, and adequate PK profile data from at least 3 patients in each dose level (see Table 
3).Patients will be enrolled to cohorts in a sequential fashion following the dosing regimen and 
will be observed for safety and tolerability during Cycle 1, prior to permitting dose escalation to 
the next dose level (cohort). From Cohort 4 onwards there will be a mandated recruitment interval 
of at least 7 days for each patient enrolled. 
Should a patient experience a toxicity which qualifies as a DLT during Cycle 1 in any cohort, that 
cohort will be expanded to enroll up to a maximum of 6 patients to further assess for toxicity prior 
to considering the next dosing step.  
Cohort 4 (100mg) is repeated twice due to the introduction of a new formulated SEL24/MEN1703 
IMP. 
To distinguish between the original cohort and the repeat cohort at the same dose level, the repeat 
cohort is named Cohort 4F.  
No recruitment interval is applied in the cohort 4F where formulated SEL24/MEN1703 IMP is 
introduced, as this dose level has already been explored with the non-formulated SEL24/MEN1703 
API in capsules. Upon the successful completion of the repeat cohort with the formulated IMP, the 
study will progress to the next Cohort 4b and onwards, according to the study design, using 
SEL24/MEN1703 formulated IMP only. In particular, it has been shown that, overall, PK 
disposition of SEL24/MEN1703 (absorption, distribution and elimination) following the 
administration of formulated IMP is in line with that observed with non-formulated IMP. This 
evidence further supports that no dose adjustment is warranted with formulated IMP. 
Patients who commenced dosing with the non-formulated SEL24/MEN1703 API in capsules and 
who are still on treatment, will continue receiving this formulation until treatment withdrawal per 
protocol.  

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CLI24-001 V13.0 Final 27JUN2022                                                                                                               45 of 108 
Recruitment and dose escalation for each cohort in Part 1 is described in Table 3. 
 
Table 3: Patients exposure along Dose Escalation Steps 
Cohort 
Dose Level 
Patients treated 
with  
non-formulated 
IMP 
Patients treated / 
to be treated with  
Formulated IMP 
Patients who 
experienced DLT 
1 
25 mg 
2* 
0 
1 
2 
50 mg 
3 
0 
0 
3 
75 mg 
3 
0 
0 
4 
100 mg 
3 
0 
0 
4F 
100 mg 
0 
3 
0 
4b 
125 mg 
0 
7* 
1 
5 
150 mg 
3 
1 
3 
* One patient not DLT evaluable  
 
In Part 1, according to a 3+3 design, the MTD is defined as the highest dose at which no more than 
1 in up to 6 patients experience a DLT during Cycle 1. In Cohort 5, up to 4 additional patients will 
be treated at 150 mg formulated IMP according to a Bayesian modified toxicity probability interval 
(mTPI) with a target toxicity rate ≤ 25%. Should none of these 4 patients experience a DLT, higher 
dose levels may be considered and will be subject to a protocol amendment. 
 
The DMC consisting of the Principal Investigator at each site, plus the Medical Monitor and 
Sponsor representatives, will review all safety data available during Cycle 1 for each cohort and 
assess for DLT during Part 1 of the study (see Section 4.3). Experts in the evaluation of the PK 
and PD data may participate in the DMC meetings to help inform the next dose escalation step. 
 
The dose escalation rules to be followed during Part 1 of the study are described in Table 4. 

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CLI24-001 V13.0 Final 27JUN2022                                                                                                               46 of 108 
Table 4: Part 1 Dose Escalation Rules 
No. of evaluable patients  
with DLT at a given dose level 
Dose escalation rules 
0 
Proceed to next dose level 
≥2 
Dose escalation will be stopped. This dose level will be 
declared the MAD (highest dose administered). Additional 
patients will be entered at the previously highest dose 
level with <33% DLTs, to a maximum of 6, if less than 6 
patients were treated previously at that dose. 
NOTE: at the 150 mg dose, additional 4 patients will be 
tested targeting ≤ 25% toxicity rate as described above. 
1 
Proceed to enter 6 patients at the dose level: 
- if no further patients experience DLT, proceed to the 
next dose level 
- if 1 or more of the additional patients suffer DLT, then 
dose escalation is stopped, and this dose is declared the 
MAD which has exceeded the MTD. Additional 
patients will be entered at the previously highest dose 
level with <33% DLTs, to a maximum of 6, if less than 
6 patients were treated previously at that dose 
- confirmation that a dose level exceeds the MTD may be 
obtained before completing enrollment of 6 patients 
≤1 out of 6 at highest dose level 
This is generally the MTD/RD. At least 6 patients must be 
entered at the recommended dose level for Part 2.  
 
In addition to DLT evaluation, there will be ongoing assessment of all AE and SAEs, changes in 
laboratory values (clinical chemistry, hematology, urinalysis, lipid profiles) and ECGs as further 
measures of safety and tolerability. All safety parameters will continue to be assessed beyond Cycle 
1. Note that where the DMC is concerned about any safety signal in the study e.g. a trend in Grade 
2 events, they may recommend a cohort is expanded to evaluate up to 6 patients, in order to explore 
this safety signal further. 
 
The schematic below (Figure 1) provides a summary of cohort expansion and dose escalation plan 
for the protocol based on safety data evaluation. 

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CLI24-001 V13.0 Final 27JUN2022                                                                                                               47 of 108 
Figure 1: Cohort expansion and dose escalation plan 
 
 
 
 
The highest SEL24/MEN1703 dose level considered to be well tolerated and to have optimal PK 
and PD characteristics, will be called the RD and will be selected for further evaluation in Part 2. 
 
4.2. Part 2 
Part 2 is designed to enroll patients at the RD identified in Part 1 based on recommendation by the 
DMC. 
 
Part 2 foresees the enrollment of patients to be treated at the RD (identified in Part 1 based on 
recommendation by the DMC) in the expansion cohorts defined below: 

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- 
The expansion cohort in 20 unselected relapsed or refractory AML patients patients (“all-
comers”)  
NOTE: At the time this protocol version 12.0 is running the expansion cohort in “all-
comers”AML patients has been already completed with 23 patients enrolled. 
- 
An additional expansion cohort (“IDH mutants”) will enroll approximately 20 relapsed or 
refractory AML patients harboring an IDH mutation (either IDH1 or IDH2). 
The evaluable patients treated at the RD in Part 1 or in Part 2 may be also retrospectively included 
in exploratory safety/efficacy pooled analysis, including patients with comparable inclusion 
criteria. 
Considering that IDH inhibitors are approved/available only in some of the participating countries, 
it is anticipated that the study will enroll both IDH inhibitor pre-treated and IDH inhibitor naïve 
patients. For this reason, the recruitment will aim to have a balanced distribution across the two 
sub-populations to explore the differences in SEL24/MEN1703 activity between pre-treated and 
IDH inhibitor naïve patients, if any. 
Retrospective correlations between the clinical activity of SEL24/MEN1703 and relevant disease 
markers (e.g. CD25 expression, FLT3 mutational status, IDH1/IDH2 mutational status, others) 
may be included in the statistical analysis plan. 
Subjects who have a suitable donor and achieve a response allowing them to undergo 
hematopoietic stem cell transplant (HSCT) per each institution’s assessment can undergo HSCT 
without leaving the study. However, SEL24/MEN1703 should be stopped and a preHSCT visit 
should be performed prior to starting the conditioning regimen for HSCT. SEL24/MEN1703 can 
be resumed after stem cell transplantation if all the following conditions are met:  
• Subject is between 30 - 60 days post HSCT  
• Subject has had successful engraftment as demonstrated by absolute neutrophil count 
(ANC) ≥ 500/mm3 and platelets ≥ 20000/mm3 without transfusions  
• Subject does not have ≥ grade 2 acute graft-versus-host disease  
• Subject is in CR, CRi, CRh 
Those subjects resuming treatment will follow the procedures listed under subsequent Cycle 3 Day 
1 in the Assessments Schedule. Subjects who do not resume SEL24/MEN1703 will be followed 
for the applicable endpoints’ assessment.  
Finally, MRD status will be recorded immediately prior to the transplant and after the procedure 
whenever a bone marrow aspirate/biopsy will be collected (recommended every 2 months unless 
differently indicated by the treating physician based on actual patient’s parameters). 
 
4.3. DLT Criteria 
DLT events for dose escalation decisions will be assessed to the end of Cycle 1 for each patient in 
each cohort, except in the case of protracted neutropenia in the absence of active AML, where 
evaluation of the event must be conducted over 42 days. Ongoing safety events beyond Cycle 1 
will be reviewed across all cohorts during the study to help inform dose escalation decisions.  

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CLI24-001 V13.0 Final 27JUN2022                                                                                                               49 of 108 
 
AEs will be graded according to the NCI CTCAE V4.03. The AEs listed below will be considered 
as DLT unless they are clearly and incontrovertibly attributable to the underlying disease or to an 
extraneous cause:  
 
• 
Grade 5 toxicity 
• 
Grade 4 neutropenia lasting ≥42 days from the start of the therapy cycle in absence of 
evidence of active AML (<5% blasts)  
• 
Grade 3 or 4 non-hematologic toxicity, except:  
o 
Alopecia;  
o 
Grade 3 fatigue, asthenia, anorexia, fever, or constipation; 
o 
Grade 3 nausea, vomiting, or diarrhea not requiring tube feeding, TPN, or 
hospitalization; 
o 
Infection, bleeding, or other expected direct complications of cytopenias due to 
active leukemia; 
o 
Grade 3 or 4 electrolyte imbalances that respond to correction i.e. return to 
≤Grade 2, within 48 hours (h) from correction’s onset; 
o 
Grade 3 increase in aspartate aminotransferase (AST) and/or, alanine 
aminotransferase (ALT) and/or alkaline phosphatase (ALP) recovering ≤Grade 
2 within 7 days. 
 
Only clinically significant abnormalities in laboratory findings, physical examination, vital signs, 
weight or ECG (see Section 7.2) will be considered for DLT assessment, according to the protocol 
definition. 
 
Please refer to Section 7.7.3 for details of how to report DLT events. 
 
4.4. Criteria for Re-treatment and Dose Modification Rules 
The following sections describe the requirements for proceeding with treatment with 
SEL24/MEN1703 from Cycle 2 onwards, and the protocol rules for dose modification due to 
toxicity.  
 
From Cycle 2 onwards, each patient’s liver and renal function tests must return to the values 
required for entry into the study (Section 3.1) or better, in order to continue treatment in the next 
cycle. This requirement may be achieved by following a dose delay as described below.  
 
In the case of SEL24/MEN1703-related non-hematologic toxicity, the dose modification rules to 
be followed in both parts of the study are presented in Table 10. No more than two dose reductions 
for toxicity will be permitted before withdrawal of study treatment. 
 
 

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Table 10: Dose Modification of SEL24/MEN1703 for Non-hematologic Toxicity 
CTCAE Grade 
Occurrence of 
Specified 
Event 
SEL24/MEN1703 Dose Modification 
≤Grade 2 
(tolerable) 
Any 
Maintain patient’s starting dose if toxicity can be 
tolerated  
Grade 2 
intolerable  
  
1st  
Delay treatment by up to 2 weeks; 
- 
If toxicity resolved, re-start at same dose level 
- 
If toxicity not resolved, re-start at dose level 
below* 
 
2nd 
 
If at patient’s starting dose, delay treatment by up to 2 
weeks; 
- 
If toxicity resolved, re-start at dose level 
below* 
 
If at dose level below patient’s starting dose; 
- 
Discontinue permanently  
3rd 
Discontinue permanently 
Grade 3 
 
1st  
Delay treatment by up to 2 weeks; 
- 
If toxicity resolved, re-start at dose level 
below*/** 
- 
If toxicity not resolved, permanently 
discontinue** 
2nd 
Discontinue permanently** 
Grade 4 
Any 
Discontinue permanently** 
*dose reductions lower than 25 mg are not possible 
**patients with Grade 3 or 4 electrolyte imbalances that respond to correction i.e. return to ≤Grade 2, within 48 h 
from correction’s onset may re-start at the same dose level; if the event occurs a 2nd time, the patient must re-start at 
the dose level below; if the event occurs a 3rd time, they must be permanently discontinued. 
 
After Cycle 1, in case of hematologic toxicity the bone marrow status will guide the initiation of 
the next cycle according to Table 11 (NOTE: bone marrow examination may not be performed in 
case peripheral labs indicate persistence of disease):  
 

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Table 11: Dose Modification of SEL24/MEN1703 for Hematologic Toxicity 
Bone marrow status 
SEL24/MEN1703 Dose Modification 
No remission 
Next cycle may commence immediately 
Remission 
Next cycle may commence once peripheral count recovery has 
been achieved 
Hypocellular 
(<5% cellularity without 
evidence of leukemia 
blasts) 
Next cycle may not commence until peripheral counts recover 
•
Once peripheral counts recover, start SEL24/MEN1703 at
same dose level if recovery by Day 42
•
If peripheral count recovery occurs beyond Day 42, then
a one dose level reduction of SEL24/MEN1703 for
subsequent treatment cycles should be implemented, once
peripheral counts recover
Achieved CR or CRi, 
with G3 or 4 hematologic 
toxicity 
(e.g. febrile neutropenia) 
Consider one dose level reduction of SEL24/MEN1703 for 
subsequent treatment cycles, once peripheral counts recover 
The Investigator may determine the resumption of next treatment cycle based on clinical 
judgement. Deviations from the above guidelines are permitted to ensure safety and serve the best 
interest of the patient according to the assessment and judgement of the Investigator. The reason 
for deviating from the guidelines should be documented in source documents. 
Dosing may be withheld in the presence of non-drug related Grade 3 or 4 adverse event if the 
Investigator feels that it is unsafe to continue the administration of SEL24/MEN1703. 
In general, a patient who requires more than two dose reductions will be removed from the study 
unless, in the opinion of the investigator, the patient is experiencing a clinical benefit defined as 
achieving CR, CRi, CRh, PR or stable disease without unacceptable toxicities. In such cases, a 
decision regarding the continuation of treatment with SEL24/MEN1703 and further dose 
reductions will be made on an individual basis in consultation with the medical monitor and the 
justification will be recorded in the source documents. All dose modifications will be captured in 
the eCRF. 
Patients will be monitored for compliance throughout the study and may be withdrawn if 
considered to be non-compliant (see Section 3.4). In Part 1 (from Cycle 2 onwards only) and in 
Part 2, an extended treatment delay e.g. of up to 14 days, may be permitted on one occasion, either 
before commencing a new treatment cycle or during a treatment cycle, for reasons unrelated to 
SEL24/MEN1703 toxicity where the Investigator considers the treatment delay to be exceptional 
and that it remains in the patient’s best interests to continue with SEL24/MEN1703. 
4.5. Intra-patient Dose Escalation  
In Part 1, intra-patient dose escalation will be permitted per patient at the discretion of the 
Investigator, and in consultation with the DMC. The selected dose for the escalation step must 

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have been confirmed as well-tolerated (i.e. patients must have been evaluated to the end of Cycle 
1, and the dose level does not exceed the MTD). The patients must also have completed 2 or more 
cycles of treatment at their starting dose without experiencing any DLT or its equivalent. Intra-
patient Dose Escalation is not permitted in Part 2. 
 

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5. STUDY SCHEDULE
The study consists of a Screening period, Treatment cycles, a Final Study Visit, plus Follow-up
Assessments. Informed consent must be obtained using the current version of the Patient
Information Sheet (PIS)/Informed Consent Form (ICF) prior to commencing Screening. Patients
will attend the clinic for Screening assessments up to a maximum of 28 days before receiving the
first dose of SEL24/MEN1703. Due to the nature of the disease being studied, it is likely that
Screening assessments will in practice be carried out over a shorter time period. The Final Study
Visit assessments will occur up to 30 days after the patient has discontinued SEL24/MEN1703
study treatment. A final AE and concomitant medication review must take place 30 days after the
last dose of SEL24/MEN1703. Follow up assessments will be conducted, wherever possible,
every 3 months after the Final Study Visit regardless of initiation of additional treatments for up
to 1 year (or until End of Study, whichever occurs first).
The following sections provide a detailed listing of study assessments by visit. A summary of this 
information is also provided in Schedule of the Study Assessment (Table 5). 
Patients will be required to visit the study sites for each study visit. Permitted tolerance windows 
for specific study visits and assessments may apply and are described in the Schedule of Study 
Assessment (Table 5) and in its footnotes. Where these are applied, the same tolerance windows 
may also be used for the entire study visit and all other assessments scheduled to be conducted at 
that visit. 
5.1. Schedule of Study Assessments 
Each section below provides a summary of study assessments described by visit.  
Please also refer to the Schedule of Study Assessments (Table 5) and associated footnotes. 
Informed Consent must be obtained using the current version of the PIS/ICF prior to commencing 
Screening. On dosing days, assessments should be performed prior to SEL24/MEN1703 dosing 
unless specified otherwise. Additional assessments may be conducted as clinically indicated. 
Where possible, patients will be followed up every 3 months for up to 1 year from their Final Study 
Visit regardless of initiation of additional treatments to check for disease progression and survival 
status. This assessment may be made by telephone interview or performed during the patient’s 
routine clinic visits following completion of participation in the study. If the patient is lost to 
follow-up public databases can also be searched. 
The following list of assessments is based on 14 days of SEL24/MEN1703 treatment in 21-day 
cycles, further details, including possible exceptions for samples to be collected, are reported in 
the Schedule of Study Assessments (Table 5) and its footnotes. 
Screening (up to a maximum of 28 days prior to first dose of SEL24/MEN1703) 
∼
Demographics
∼
Medical history
∼
Inclusion/exclusion check
∼
FSH/Pregnancy testing (as appropriate; pregnancy test to be conducted within 7 days of
the first SEL24/MEN1703 administration)
∼
ECOG PS

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∼ Vital signs 
∼ Physical examination 
∼ Clinical chemistry 
∼ Hematology 
∼ Coagulation 
∼ Lipid profile 
∼ Peripheral blasts 
∼ Urinalysis 
∼ ECG  
∼ Echocardiogram (or MUGA scan, if this is preferred standard, local cardiac assessment) 
∼ Bone marrow aspirate/biopsy (local bone marrow differential to be performed) 
∼ Genetic profile of AML cells (bone marrow) 
Note: An aliquot of bone marrow aspirates/biopsy will be used 
∼ PD biomarkers (blood) 
∼ CYP2D6 phenotyping (blood) 
∼ CD25 expression (blood) 
Note: An aliquot of blood taken for PD biomarker will be used 
∼ Mutational status 
∼ AML Karyotypic analysis 
∼ Transfusion status 
∼ Concomitant medication 
 
Cycle 1, Day 1 
∼ Vital signs 
∼ FSH/Pregnancy testing 
∼ Physical examination 
∼ Clinical chemistry 
∼ Hematology 
∼ Coagulation 
∼ Lipid profile 
∼ Peripheral blasts  
∼ Urinalysis 
∼ ECG (pre-dose and 4-6 h post dose) 
∼ PD biomarkers (blood; pre-dose, 2-6h post dose) 
∼ Adverse events 
∼ Transfusion status 
∼ Concomitant medication 
∼ PK profile sampling (blood; pre-dose, 0.5, 1, 2, 4, 6, 8, 10-14 h post dose) 
∼ PK (urine; Part 1 only) 
 
Cycle 1, Day 2 
∼ Clinical chemistry 
∼ Hematology 

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∼ Coagulation 
∼ Adverse events 
∼ Transfusion status 
∼ Concomitant medication 
∼ PK sampling (blood; 24 h post C1 D1 dose/C1 D2 pre-dose) 
∼ PK (urine; collect to immediately before D2 dose, Part 1 only) 
 
Cycle 1, Days 3 and 4 
∼ Clinical chemistry 
∼ Hematology 
∼ Coagulation 
∼ Adverse events 
∼ Transfusion status 
∼ Concomitant medication 
 
Cycle 1, Day 7 
∼ Clinical chemistry 
∼ Hematology 
∼ Coagulation 
∼ ECG 
∼ Adverse events 
∼ Transfusion status 
∼ Concomitant medication 
∼ PK sampling (blood; 4 h and 8 h post dose) 
 
Cycle 1, Day 14 
∼ Clinical chemistry 
∼ Hematology 
∼ Coagulation 
∼ Lipid profile 
∼ Peripheral blasts 
∼ PD biomarkers (blood; 2-6h post dose) 
∼ Adverse events 
∼ Transfusion status 
∼ Concomitant medication 
∼ PK profile sampling (blood; pre-dose, 0.5, 1, 2, 4, 6, 8, 10-14 h post dose) 
 
Note: PD and PK sampling times are relative to last dose in C1. 
 
Cycle 1, Day 15 
∼ PK sampling (blood; 22-26 h post C1 D14 dose) 
 
Note: PK sampling times are relative to last dose in C1. 

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Cycle 1, Day 17 
∼ PK sampling (blood; 70-74 h post C1 D14 dose) 
 
Note: PK sampling time is relative to last dose in C1. 
 
Cycle 1, Day 19 
∼ PK sampling (blood; 118-122 h post C1 D14 dose) 
 
Note: PK sampling time is relative to last dose in C1. 
 
Cycle 2, Day 1 
∼ ECOG PS 
∼ Vital signs 
∼ FSH/Pregnancy testing 
∼ Physical examination 
∼ Clinical chemistry 
∼ Hematology 
∼ Coagulation 
∼ Lipid profile 
∼ Urinalysis 
∼ ECG  
∼ PD biomarkers (blood; pre-dose) 
∼ Adverse events 
∼ Transfusion status 
∼ Concomitant medication 
∼ PK sampling (blood; pre-dose) 
 
Cycle 2, Day 7 
∼ Clinical chemistry 
∼ Hematology 
∼ Coagulation 
∼ Adverse events 
∼ Transfusion status 
∼ Concomitant medication 
∼ PK sampling (blood; 2-6 h post dose) 
 
Cycle 2, Day 14 
∼ Clinical chemistry 
∼ Hematology 
∼ Coagulation 
∼ Lipid profile 
∼ Peripheral blasts 

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∼ PD biomarkers (blood; 2-6 h post dose) 
∼ Adverse events 
∼ Transfusion status 
∼ Concomitant medication 
∼ PK sampling (blood; 2-6 h post dose) 
 
Cycle 3 onwards, Day 1 
∼ ECOG PS 
∼ Vital signs 
∼ FSH/Pregnancy testing 
∼ Physical examination 
∼ Clinical chemistry 
∼ Hematology 
∼ Coagulation 
∼ Lipid profile 
∼ Urinalysis 
∼ ECG  
∼ Bone marrow aspirate/biopsy (mandatory as soon as peripheral lab results become 
consistent with an objective response and at Cycle 3; recommended every 2 cycles 
thereafter) 
∼ Disease evaluation (optional; recommended every 2 cycles) 
∼ Genetic profiling (bone marrow, recommended every 2 cycles) 
Note: An aliquot of bone marrow aspirates/biopsy will be used 
∼ PD biomarkers (blood; pre-dose) 
∼ Adverse events 
∼ Transfusion status 
∼ Concomitant medication 
∼ PK sampling (blood; pre-dose) 
 
Cycle 3 onwards, Day 14 
∼ Clinical chemistry 
∼ Hematology 
∼ Peripheral blasts 
∼ PD biomarkers (blood; 2-6 h post dose) 
∼ Adverse events 
∼ Transfusion status 
∼ Concomitant medication 
∼ PK sampling (blood; 2-6 h post dose) 
 
Final Study Visit 
∼ ECOG PS 
∼ Vital signs 

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∼ FSH/Pregnancy testing (if Final Study Visit is performed after at least 30 days from last 
study drug administration; otherwise this test shall be postponed when 30 days have elapsed 
from last study drug administration  
∼ Physical examination 
∼ Clinical chemistry 
∼ Hematology 
∼ Coagulation 
∼ Lipid profile 
∼ Peripheral blasts 
∼ Urinalysis 
∼ ECG  
∼ Bone marrow aspirate/biopsy (optional; as required) 
∼ Disease evaluation (optional; as required) 
∼ Genetic profiling (bone marrow; optional, as required) 
Note: An aliquot of bone marrow aspirates/biopsy will be used 
∼ Adverse events 
∼ Transfusion status 
∼ Concomitant medication 
 
Follow-Up 
∼ Follow-up assessments (a visit or a telephone call, as per local practice) 
 
IMPORTANT NOTE: in addition to the optional time points above described, bone marrow 
aspirate/biopsy is mandatory at Screening and as soon as the peripheral lab results become 
consistent with an objective response. 
 
5.2. Volume of Blood Sampling 
Total blood volumes required during study participation will be provided in PIS/ICF provided to 
each patient. The Lab Manual will also describe the unit and total blood volumes and provide 
examples based on various durations on study. Efforts will be made to limit PK and PD blood-
letting during the study where on-going data analysis during the study suggests redundancy in 
sampling. Any such reductions in requirements for PK and PD blood sampling will be described 
and updated in the Lab Manual. 
 
5.3. Description of Study Interventions and Assessments 
Details of the procedures to be followed for specified study assessments are provided. Additional 
assessments may be carried out as clinically indicated. 
 
5.3.1. Medical history 
There will be a baseline assessment of medical history conducted at Screening to confirm eligibility 
and to record significant medical history and concurrent illnesses in the eCRF. Concurrent illnesses 
recorded at Screening, that worsen in severity or frequency from this baseline assessment during 
the study, should be recorded and reported as AEs (see Section 7). 

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All prior therapy for the treatment of AML must be recorded in eCRF including, but not limited 
to, start date, stop date and best response. 
 
5.3.2. Pregnancy and FSH test 
Female patients of reproductive potential will have a pregnancy test carried out at Screening. This 
test must be carried out within 7 days prior to first SEL24/MEN1703 administration. Alternatively, 
pregnancy test may be performed at C1D1 and results should be available prior to receiving study 
treatment. Additionally, a pregnancy test is required on the first day of each study cycle and after 
relevant systemic exposure can be reasonably excluded (30 days from the last study drug 
administration). A urine test is acceptable; however, where a urine test is positive or equivocal, a 
blood test must be performed to confirm the result. Patients confirmed as pregnant will be excluded 
from participation in the clinical study.  
 
Please refer to Section 7.7.1 for further instructions on the management of a positive urine test 
during the study conduct. 
 
Female patients who require documented confirmation of post-menopausal status will have their 
follicle-stimulating hormone (FSH) levels assessed at Screening. When post-menopausal status is 
not confirmed, patients will be required to undergo pregnancy testing per protocol to confirm 
suitability to proceed.  
 
5.3.3. ECOG performance status 
ECOG PS will be assessed at the times given in the Schedule of Study Assessment (Table 5). 
Details of the ECOG PS categories are presented in Appendix A. Patients must be confirmed as 
ECOG PS 0, 1 or 2 at Screening in order to be eligible for study participation. 
 
5.3.4. Vital signs 
Vital sign parameters will be taken at the times given in the Schedule of Study Assessment (Table 
5). The date and time of collection will be recorded in the source data and on the eCRF. 
 
Vital sign parameters will consist of measurements of temperature, resting heart rate, seated blood 
pressure and respiratory rate.  
 
5.3.5. Physical examinations 
A physical examination, including measurement of weight, will be taken at the times given in the 
Schedule of Study Assessment (Table 5). The patient’s height will be measured at Screening. The 
patient’s weight will also be assessed at Screening and at the start of every cycle. Height and body 
weight will be obtained while the patient is wearing light clothing (without shoes). 
 
A full physical examination will include assessment of the following categories: head, eyes, ears, 
nose, throat, heart, lungs, abdomen, skin, musculoskeletal, extremities, neurological, lymph nodes, 
and ‘other’. After the Screening assessment, the physical examination may be reduced to a 
symptom-directed assessment.  
 
 

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5.3.6. Clinical chemistry, hematology, coagulation, lipid profile and urinalysis 
Blood and urine samples for determination of clinical chemistry, hematology, coagulation, lipid 
profile and urinalysis parameters will be taken at the times given in the Schedule of Study 
Assessment (Table 5). The date and time of collection will be recorded in the source data and on 
the CRF. 
 
All testing will be performed at each site’s local laboratory. Patients should be asked to follow 
local guidance for fasting prior to the lipid profile assessment. At time points where coagulation 
testing is performed, these parameters may be assessed from the hematology sample. Should a 
patient develop coagulation abnormalities at any point during the study, a comprehensive 
evaluation of coagulation abnormalities will be immediately performed which may include, but 
not be limited to repeat PT/INR, APTT, fibrinogen, D-dimer, plus a peripheral blood smear, 
thrombin time. These abnormalities have to be evaluated by the Investigator in conjunction with 
the patient’s medical history, physical examination and concomitant medication review. Repeat 
testing may be performed as clinically indicated, which may include additional parameters or time-
points. Additional tests will be performed as required to rule out other etiologies. 
 
Copies of laboratory accreditation certificates and reference ranges will be obtained from each 
study site prior to the analysis of their first patient sample. 
 
The laboratory variables to be measured are described in Appendix E. 
 
Results from the hematology test panel will contribute to each patient’s disease assessment (see 
Section 5.3.11). 
 
5.3.7. Peripheral blasts 
Assessment of peripheral blasts will be part of the hematology panel at the time-points specific in 
the Schedule of Study Assessment (Table 5). 
 
Results from these assessments will contribute to each patient’s disease assessment (see  
Section 5.3.11). 
 
5.3.8. Electrocardiograms  
A resting 12-lead ECG will be performed at the times given in the Schedule of Study Assessment 
(Table 5).  
 
All 12-lead ECGs should be recorded while the patient is in the supine position. ECGs will be 
recorded at 25 mm/sec. All efforts should be made to ensure that an identical ECG machine is used 
to collect traces for individual patients. The Investigator or designated physician will review the 
ECG results.  
 
5.3.9. Echocardiogram 
An echocardiography assessment will be performed at Screening with follow up assessments as 
clinically indicated. This cardiac assessment may be performed by a MUGA scan if this is the 
standard, local method used.   

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5.3.10. Bone marrow assessment 
A bone marrow aspirate (or biopsy where obtaining an aspirate is not possible), will be taken at 
the times specified in the Schedule of Study Assessment (Table 5). A local bone marrow 
differential assessment, to determine the % of different bone marrow cellular subpopulations, 
including the % leukemic blasts, will be conducted at Screening. In addition to the optional time 
points reported in the Schedule of Study Assessment, bone marrow assessment is mandatory at 
Screening and as soon as the peripheral lab results become consistent with an objective response. 
Bone marrow aspirates/biopsy will be tested for the genetic profile of AML cells (see Section 
5.3.13). An aliquot of bone marrow aspirate/biopsy will be centrally stored for future analysis (e.g. 
minimal residual disease), if any.  
 
Results from these assessments will contribute to each patient’s disease assessment (see  
Section 5.3.11).  
 
5.3.11. Disease evaluation 
Evaluation of disease status will be performed at the time-points described in the Schedule of Study 
Assessment (Table 5), according to the AML Response Criteria in Appendix D. 
 
Disease assessment will involve evaluation of leukemic blast proportion in the bone marrow. 
Hematologic parameters from the routine local assessments including blast percentage (where 
applicable), platelet count, and other relevant parameters such as transfusion dependence will also 
contribute to this assessment. 
To note, disease assessment must be performed as soon as the peripheral lab results become 
consistent with an objective response. Disease assessment will also include an aliquot of bone 
marrow aspirate/biopsy that will be centrally stored for future analysis (e.g. minimal residual 
disease), if any. In case bone marrow aspirate/biopsy is consistent with CRi or better response but 
still a minimal percentage of peripheral blasts is detected, the response assessment can be 
postponed up to 2 weeks and will be based on repeated peripheral blood results and last bone 
marrow aspiration results. 
 
5.3.12. PD biomarkers 
Evaluation of PD biomarkers will be performed at the time-points described in Schedule of Study 
Assessment (Table 5). 
 
The PD activity of SEL24/MEN1703 will be assessed by changes between pre- and post-treatment 
levels of p-Ser235/6 S6 and other relevant biomarkers as appropriate, in peripheral blood by using 
flow cytometry. 
 
5.3.13. Genetic profile of AML cells 
The genetic profile of AML cells will be performed at the time-points described in the Schedule 
of Study Assessment (Table 5) 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. Left over sample aliquots 

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and aliquots of bone marrow aspirates/biopsy may be used for future biomarker analysis which is 
relevant to the development of SEL24/MEN1703 in AML. 
Full details of sample collection and handling for these samples will be described in Lab Manual 
for the study. 
 
5.3.14. PK sampling  
Evaluation of the levels of SEL24/MEN1703 and its metabolites (as appropriate) will be performed 
at the time-points described in the Schedule of Study Assessment (Table 5). The PK profile of 
SEL24/MEN1703 and its metabolites, as appropriate, will be evaluated by analysis of 
concentration levels in plasma. Evaluation of CYP2D6 phenotyping will be carried out (see Section 
5.3.15). Results will be reported separately. In Part 1 ONLY, urine samples will also be collected 
from the first dose of SEL24/MEN1703 until immediately prior to the second dose for PK analysis. 
 
Nominal PK blood sampling times should be adhered to as closely as possible. It is essential that 
the actual time and date of collection of each blood sample be recorded in the patient’s records and 
in the eCRF. 
 
Full details of sample collection and handling for these samples will be described in the Lab 
Manual for the study. Left over sample aliquots could be analyzed for metabolite identification 
purposes. The results of the metabolite identification analysis will be reported separately. 
 
5.3.15. CYP2D6 phenotyping 
As SEL24/MEN1703 may both inhibit and act as a substrate for Cytochrome P450 enzyme 
CYP2D6, patients will be assessed for their CYP2D6 phenotype. A blood sample collected during 
Screening will be used for this assessment. 
 
5.3.16. CD25 Expression 
An aliquot of PD sample collected during Screening will be used for this assessment. 
 
5.3.17. Mutational Status 
AML mutational status will be assessed locally at Screening. 
 
5.3.18. AML Karyotypic Analysis 
AML Karyotype analysis will be performed locally at Screening. 
 
5.3.19. Transfusion Status  
Need for blood transfusion will be recorded as concomitant medication during patient participation 
to the study. In particular, information on blood transfusion occurred from 28 days prior to the first 
dose of SEL24/MEN1703 to the Final Study Visit will be collected to define transfusion 
conversion rate and transfusion maintenance rate. 
Transfusion status (independent Vs. dependent) at baseline period and post-baseline period are 
defined as follows for subjects who took at least one dose of study drug: 
 
Baseline transfusion status: 

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• Baseline period is defined as the period from 28 days prior to the first dose to 28 days post 
first dose (C2D7). For subjects who are on treatment <28 days, baseline period is from 28 
days prior to the first dose (in the event that this information is not available the ICF 
signature date will be exploited) until the end of treatment.  
• Subjects are classified as baseline transfusion independent if there is no red blood cells 
(RBC) or platelet transfusions within the baseline period; otherwise, the subject is to be 
considered as baseline transfusion dependent. 
 
Post-baseline transfusion status: 
• Post-baseline period is defined as the period from 29 days post first dose (day after C2D7) 
until last dose. 
• For subjects who are on treatment ≥84 days (C5D1 or more), subjects are classified post-
baseline transfusion independent in the event of 56 consecutive days without any RBC or 
platelet transfusion within post-baseline period 
• For subjects who are on treatment >28 days (C2D7) but <84 days (C4D21), post-baseline 
transfusion status is not evaluable 
• Otherwise, the subject is considered post-baseline transfusion dependent. 
Both transfusion conversion rate and maintenance rate apply to subjects who have evaluable post-
baseline transfusion status.  
Transfusion conversion rate is defined as the number of subjects who were transfusion dependent 
at baseline period but become transfusion independent at post-baseline period divided by the total 
number of subjects who were transfusion dependent at baseline period. Transfusion maintenance 
rate is defined as the number of subjects who were transfusion independent at baseline period and 
still maintain transfusion independent at post-baseline period divided by the total number of 
subjects who were transfusion independent at baseline period. 
 
 
 

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6. STUDY MEDICATION AND ADMINISTRATION
The Quality Control Standards and requirements for SEL24/MEN1703 study medication are
described in separate release protocols/Certificate of Analysis.
SEL24/MEN1703 IMP will be supplied as gelatin capsules containing 25 and 100 mg 
SEL24/MEN1703 API (free base) (not-formulated API in capsule) and gelatin capsules containing 
25 and 100 mg API (free base) as formulated drug product (formulated drug product in capsule), 
respectively. Details of the Investigational Product provided during Part 1 are reported in Table 3. 
Formulated drug only will be provided for Part 2.  
The drug product used until the implementation of protocol amendment V8.0 is API directly filled 
by weight in capsules, which is a suitable procedure for small scale batches in early development 
stages. However, this formulation and manufacturing process are not suitable for later clinical 
phases and for industrial scale production for commercial purposes. Therefore, a formulation of 
drug product has been developed to guarantee a standardized manufacturing process. 
Table 12: Composition of SEL24/MEN1703 for oral use 
Active components 
25 mg capsules: 25 mg SEL24/MEN1703 (free base) 
100 mg capsules: 100 mg SEL24/MEN1703 (free base) 
Excipients 
 
 
Stability 
Stability testing of SEL24/MEN1703 is on-going and the IMP shelf-
life will be extended as appropriate during the course of the clinical 
study 
Storage and handling 
API in capsules: SEL24/MEN1703 IMP (API in capsules) must be 
stored at controlled room temperature [20-25 ºC (68-77 ºF)]. The 
bottles should be stored protected from light 
Formulated drug product in capsules: Do not store the 
SEL24/MEN1703 IMP (formulated drug product in capsules) above 
25 °C (77 °F). Do not freeze. Store in the original package 
Please refer to the current version of the IB for additional information on the physical, chemical 
and pharmaceutical properties of SEL24/MEN1703. 
6.1. Labeling of SEL24/MEN1703 
The IMP SEL24/MEN1703 will be labelled in compliance with the current valid international and 
corresponding national requirements. The label will report instructions on how to administer and 
store the SEL24/MEN1703 IMP in local language of the respective study country. 
6.2. SEL24/MEN1703 Starting Dose and Duration of Treatment on Study 
The starting dose of SEL24/MEN1703 will be 25 mg, taken orally once daily for 14 consecutive 
days over a 21-day treatment cycle. The cohort dose may be escalated by an increase in the daily 
dose level during the study based on the dose escalation rules. 

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Reasons for withdrawal from the study and SEL24/MEN1703 treatment are described in  
Section 3.4.  
 
Continuation of the study treatment may be discussed between the Investigator and the Sponsor on 
a case-by-case basis. The DMC may also advise on the suitability of an individual patient to 
continue to receive study treatment.  
 
Patients who experience a DLT will be permitted to receive further treatment with 
SEL24/MEN1703 according to the dose modification rules described in Section 4.4. 
 
6.3. Storage of SEL24/MEN1703 
SEL24/MEN1703 will be shipped to the site and must be stored at the site in a secure location 
under controlled room temperature conditions. Do not store SEL24/MEN1703 IMP (formulated 
drug product in capsules) above 25 °C (77 °F). 
 
Detailed instructions for the storage of dispensed IMP at home will be provided to every patient 
enrolled in the clinical study. 
 
6.4. Blinding and Procedures for Un-blinding the Study 
This is an open-label study, and there are no procedures for blinding and un-blinding. 
 
6.5. Provision and Replacement of SEL24/MEN1703 
Sufficient doses of SEL24/MEN1703 medication will be supplied. Where clinical supplies (or 
packaging) are apparently damaged on receipt or considered unfit for use by the study site, the 
Sponsor (or their delegate) must be notified immediately. Where required, clinical study supplies 
will be replaced. Further details on the handling of SEL24/MEN1703 at site will be described in 
the Pharmacy Manual.  
 
6.6. Drug Accountability 
The Investigator is obliged to keep sufficient documentation of the delivery, use and destruction 
or return of unused, used or partially used IMP. The documentation must include dates, quantities, 
patient numbers, batch numbers or other identification number. The Investigator may assign some 
or all of the Investigator’s duties for drug accountability to an appropriate pharmacist. Roles and 
responsibilities of site staff will be recorded in the Investigator Site File. 
 
The Investigator should maintain records that document adequately that the patients have been 
administered the doses specified in the protocol and reconcile all SEL24/MEN1703 received for 
the study. The local study monitor will be responsible for checking the drug accountability records 
maintained by the site during the monitoring visits. 
 
The medication provided for this study is for use only as directed in the protocol. It is the 
Investigator and their institution’s responsibility to establish a system for handling study drug so 
as to ensure that: 
 
• 
deliveries of SEL24/MEN1703 are correctly received by a responsible person; 

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• 
such deliveries are recorded; 
• 
study treatments are handled and stored safely and properly as stated on the label; 
• 
study drug is only dispensed to study patients in accordance with the protocol; and 
• 
any unused study drug is destroyed locally or returned for destruction in liaison with 
the study monitor. 
 
Throughout the study, it must be possible to reconcile delivery records with records of usage and 
any destroyed/returned stock of SEL24/MEN1703. To help with compliance checks, records of 
usage should include the identification of the patient to whom the study treatment was dispensed 
and the quantity and date of dispensing, plus all unused supplies at the end of each treatment cycle. 
Patients will be asked to maintain a dosing diary and bring it with them to study visits to support 
reconciliation and compliance checks. This record is in addition to any drug accountability 
information recorded on the eCRF. Any discrepancies must be accounted for on the appropriate 
forms. Certificates of delivery and return must be signed by the responsible pharmacist, and copies 
retained in the Pharmacy File. 
 
The return or destruction of unused drug will be conducted after written approval by the Sponsor, 
with appropriate documentation and drug accountability procedures completed following 
destruction. 
 
6.7. Treatment Allocation 
In order to ensure that the appropriate numbers of patients are enrolled to each cohort in Part 1 and 
in Part 2, and that enrolment to the study is appropriately controlled, on identifying a potential 
study patient, the Investigator is required to register a patient in the study. Patients will be 
registered in the study by using the Interactive Web Response System (IWRS) automated patient 
registration system (see the Study Operations Manual for specific instructions). 
Prior to registration of Screening in IWRS and any study-specific evaluations being performed, all 
patients must have given written informed consent for the study. Patients must have completed the 
Screening evaluations and must meet all of the eligibility requirements listed in Section 3 prior to 
being registered in the system as enrolled. Study drug will be assigned through the IWRS.  
 
There will be regular communication with the sites during the study, in addition to the Cohort 
Review Meetings to ensure that Investigators are aware of enrolment status on the study and of 
suitable times for patient enrolment. 
 
6.8. Dosing Instructions 
Patients will be instructed to take their assigned SEL24/MEN1703 dose at regular intervals in the 
morning on dosing days, swallowed with water or an alternative drink. Doses shall be taken on an 
empty stomach (at least 2 hours after and 1 hour before eating). Patients will be asked to record 
the exact time they take each dose, how many capsules they take, what they have eaten and drunk, 
and when, before and after each dose in their dosing diary (see Section 6.6). Patients enrolled once 
the DMC has approved the introduction of the formulated SEL24/MEN1703 will be instructed to 
take the assigned number of capsules, following the same dosing instructions. 
 

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Patients will be instructed not to make up missed doses or vomited doses. Full details of dosing 
instructions will be provided to patients in the PIS. 
 
Patients must be informed that a SEL24/MEN1703 photosensitivity/phototoxicity effect cannot be 
excluded. For this reason, patients should minimize or avoid exposure to natural or artificial 
sunlight (tanning beds or UVA/B treatment) during the entire study period. If patients need to be 
outdoors when taking SEL24/MEN1703, they should wear loose-fitting clothes that protect skin 
from sun exposure and discuss other sun protection measures with the investigator. If a sunburn 
like reaction or skin eruption occurs, patients should contact the investigator. 
 
6.9. Permitted and Restricted Concomitant Medications 
Medications specifically prohibited in the exclusion criteria (Section 3.2) are not allowed during 
the ongoing study. If there is a clinical indication for any medication specifically prohibited during 
the study, discontinuation from study therapy may be required. The Investigator should discuss 
any questions regarding this with the assigned Medical Monitor for the study. The final decision 
on any supportive therapy or vaccination rests with the Investigator and/or the patient's primary 
physician. However, the decision to continue the patient on study treatment requires agreement 
from the Medical Monitor. 
 
Note that use of erythropoiesis stimulating agents and growth factors during Cycle 1 is prohibited. 
Beyond Cycle 1, their use should be avoided; however, their use may be discussed with the Medical 
Monitor on a case-by-case basis. 
 
6.9.1. Acceptable concomitant medications 
All treatments that the Investigator considers necessary for their patient’s welfare may be 
administered at their discretion in keeping with the standards of medical care. All concomitant 
medication will be recorded on the eCRF including all prescription, over-the-counter, herbal 
supplements, pre-medications, intravenous medications or transfusions. Note that the assessment 
of red cell transfusions will be part of the disease assessment criteria (see Section 5.3.11). If 
changes occur during the study period, documentation of drug dosage, frequency, route, and date 
may also be included on the eCRF. All concomitant medications the patient received within 30 
days before the first dose of SEL24/MEN1703 and 30 days after the last dose of SEL24/MEN1703 
should be recorded. Concomitant medications administered after 30 days from the last dose of 
SEL24/MEN1703 should be recorded for SAEs and any Events of Clinical Interest (ECIs) as 
defined in Section 7.10. 
 
Sites should follow their institutional guidelines for treating hypophosphatemia, including 
administration of oral or I.V. phosphate supplements. Phosphate supplements should be started the 
same day any ≥Grade 3 hypophosphatemia is detected. Patients should be retested no less than 
every 24 hours, until phosphate levels are ≤Grade 2. SEL24/MEN1703 treatment may be reinstated 
per the retreatment guidelines provided in Section 4.4. Lower grade abnormalities should be 
monitored and corrected as soon as possible. Additional assessments should be carried out as 
clinically indicated. 
 

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6.9.2. Antibacterial and antifungal prophylaxis  
Patients with grade 4 neutropenia should receive both antibacterial and antifungal prophylaxis 
according to institutional guidelines, as long as grade 4 neutropenia persists. Commonly used 
prophylactic agents (fluoroquinolones, azoles), with the exception of isavuconazole (not allowed, 
being a BCRP inhibitor) are not contraindicated, however careful clinical monitoring is 
recommended pending the clinical evaluation of potential for drug-drug interactions. 
 
6.9.3. Potential for drug-drug interactions 
Non-clinical drug interaction studies indicate that SEL24/MEN1703 may inhibit CYP2D6, and act 
as a substrate for CYP2D6 and BCRP. Between discontinuation of the following agents and the 
first administration of SEL24/MEN1703 (see Exclusion Criterion 16), a 7-day washout period, or 
a period corresponding to 4-5 half-lives of the agents, is therefore mandated: 
 
• 
sensitive CYP2D6 substrates 
• 
CYP2D6 substrates with a narrow therapeutic range 
• 
strong or moderate CYP2D6 inhibitors 
• 
BCRP inhibitors 
 
In addition, any drug which is a CYP2D6 substrate, a strong or moderate inhibitor of CYP2D6, or 
a BCRP inhibitor should not be administered concomitantly with SEL24/MEN1703 during the 
study. If a patient requires a drug in these categories, the Investigator should explore the use of an 
alternative therapeutic treatment/agent. If this is not possible, SEL24/MEN1703 should be 
discontinued and a 7 day washout period allowed before administration of the required therapeutic 
agent commences. Following discontinuation of SEL24/MEN1703 for this reason, treatment with 
SEL24/MEN1703 cannot re-start once treatment with the CYP2D6 substrate, or inhibitor of 
CYP2D6 or BCRP has stopped. Examples of relevant drugs to consider are provided below. 
 
CYP2D6 substrates: 
• 
Sensitive CYP2D6 substrates: atomoxetine, desipramine, dextromethorphan, 
metoprolol, 
nebivolol, 
perphenazine, 
thioridazine, 
tolterodine, 
venlafaxine, 
nortriptyline 
• 
CYP2D6 substrate with narrow therapeutic range: thioridazine 
 
CYP2D6 inhibitors: 
• 
Strong 
CYP2D6 
inhibitors: 
quinidine, 
fluoxetine, 
paroxetine, 
bupropion, 
dacomitinibm, ecstasy, terbinafine 
• 
Moderate CYP2D6 inhibitors: AMD070, cinacalcet, moclobemide, mirabegron, 
duloxetine, dronedarone, eliglustat, tipranavir/ritonavir, fluvoxamine, cimetidine 
 
BCRP inhibitors: 
• 
Representative BCRP inhibitors: cyclosporine, elacridar (GF120918), eltrombopag, 
gefitinib, curcumin, isavuconazole 
 

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Please refer to Appendix F for a (not-exhaustive) list of CYP2D6 substrates, CYP2D6 inhibitors 
and BCRP inhibitors. 
 
 

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7. ADVERSE EVENTS AND REPORTING REQUIREMENTS
7.1. Assessment of Safety
All patients who have received at least one dose of SEL24/MEN1703 will be considered evaluable 
for safety. All AEs and SAEs will be collected from the time the patient gives informed consent 
up to and including the 30 day follow up (Final Study Visit). There will be a baseline medical 
condition review taken at Screening. Events, other than the primary disease under evaluation, that 
worsen in severity or frequency from this baseline assessment during the study, should be recorded 
and reported as AEs. 
7.2. Adverse Event Definition 
An AE is defined as any new untoward medical occurrence or worsening of a pre-existing medical 
condition in a patient or clinical investigation patient administered a medicinal product and which 
does not necessarily have a causal relationship with this treatment. An AE can therefore be any 
unfavorable and unintended sign (including a clinically significant abnormal laboratory finding, 
for example), symptom, or disease temporally associated with the use of a medicinal 
(investigational) product, whether or not considered related to the IMP. 
The definition covers also medication errors and uses outside what was foreseen in the protocol, 
including misuse and abuse of the product (see chapter 7.7.2). 
Adverse events include: 
•
worsening (change in nature, severity, or frequency) of conditions present at the start
of the study;
•
intercurrent illness;
•
drug interactions;
•
experiences related or possibly related to concomitant medications;
•
clinically significant abnormal laboratory values or shifts from baseline; and
•
clinically significant abnormalities in physical examination, vital signs, weight, or
ECG.
The Investigator must record all the available information concerning any non-serious AE (whether 
or not deemed related to the study treatment) in the corresponding section of the eCRF-AE pages, 
within 5 calendar days after the first knowledge of the occurrence of the event  
Progression of the disease under study (i.e. AML) will not be captured as an AE. 
Surgical procedures or other therapeutic interventions themselves are not AEs, but the condition 
for which the surgery/intervention is required is an AE and should be documented accordingly. 
Planned surgical measures and the condition(s) leading to these measures are not AEs, if the 
condition(s) was (were) known before the period of observation and did not worsen during study. 
In the latter case, the condition should be reported as medical history. 

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7.3. Importance of Adverse Event Reporting 
Timely and complete reporting of safety information is very important to assist in the identification 
of any untoward medical occurrence, thereby ensuring: 
 
• 
the safety of study patients; 
• 
a greater understanding of the overall safety profile of the investigational drug; 
• 
recognition of any dose-related investigational drug toxicity; 
• 
appropriate modification of study protocols; 
• 
improvements in study design or procedures as required; and 
• 
adherence to required ethical and regulatory requirements for clinical study conduct. 
 
7.4. Evaluating Adverse Events 
Following the patient’s written consent to participate in the study, all AEs should be collected. All 
identified AEs must be recorded and described on the appropriate AE page of the eCRF, except 
for those events occurring prior to the first dose of study medication, which should be recorded on 
the Medical History eCRF page (unless related to the study procedures performed prior to dosing 
; in this case they have to be reported as an AE). Where known, the diagnosis of illness or disorder 
should be recorded, rather than listing individual symptoms.  
 
The following information should be captured for all AEs: date of onset and resolution, severity of 
the event (see definitions in Section 7.5), assessment whether the event was serious or non-serious, 
Investigator's opinion of the relationship to IMP (see definitions in Section 7.8) treatment required 
for the AE, action taken with IMP, and information regarding resolution/outcome. 
 
7.5. Severity 
All AEs (including SAEs) are to be accurately recorded on the AE page of the patient’s eCRF. 
Each event will be graded for severity using the classifications of NCI CTCAE v4.03 (see 
Appendix C). For events not addressed in the NCI CTCAE v4.03, classifications the following 
grading will apply: 
 
• 
Mild (Grade 1) - Mild; asymptomatic or mild symptoms; clinical or diagnostic 
observations only; intervention not indicated.  
• 
Moderate (Grade 2) - Moderate; minimal, local or noninvasive intervention 
indicated; limiting age-appropriate instrumental activity of daily living. 
• 
Severe (Grade 3) - Severe or medically significant but not immediately life-
threatening; hospitalization or prolongation of hospitalization indicated; 
disabling; limiting self-care activity of daily living. 
• 
Life-threatening (Grade 4) - Life-threatening consequences; urgent 
intervention indicated. 
• 
Death (Grade 5) - Related to adverse event. 
 
7.6. Serious Adverse Events 
An SAE is defined as any untoward medical occurrence that at any dose causes or qualifies as the 
following: 

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• 
Results in death. 
• 
Is life-threatening: 
o 
“Life-threatening” means that the patient was at immediate risk of death at the 
time of the SAE; it does not refer to an SAE that hypothetically might have 
caused death if it were more severe. 
• 
Requires hospitalization or prolongation of existing hospitalization: 
o 
This means that hospital inpatient admission or prolongations of hospital stay 
were required for the treatment of the SAE or that they occurred as a 
consequence of the event. 
o 
Visits to a hospital by ambulance or to the emergency room without admission 
will not be regarded as hospitalization unless the event fulfills any other of the 
serious criteria. 
• 
Results in persistent or significant disability or incapacity: 
o 
“Persistent or significant disability or incapacity” means a permanent or 
significant and substantial disruption of a person’s ability to carry out normal 
life functions. 
• 
Is a congenital anomaly or birth defect. 
• 
Is an important medical event: 
o 
Medical and scientific judgment should be exercised in deciding whether 
expedited reporting is appropriate in situations where none of the outcomes listed 
above occurred. Important medical events that may not be immediately life-
threatening or result in death or hospitalization but may jeopardize the patient or 
may require intervention to prevent one of the other outcomes listed in the 
definition above should also usually be considered serious. Examples of such 
events include allergic bronchospasm requiring intensive treatment in an 
emergency room or at home, blood dyscrasias, or convulsions that do not result 
in inpatient hospitalization, or the development of drug dependency or drug 
abuse. 
 
Note-1: These characteristics/consequences have to be considered at the time the event occurs. 
For example, regarding a life-threatening event, this refers to an event in which the subject was at 
risk of death at the time of the event; it does not refer to an event which hypothetically might have 
caused death if it were more severe.  
Any other AE/ADR which is not included in the above definitions will be considered as non 
serious. 
 
Note-2: Hospitalization lasting less than 24 hours or pre-planned hospitalization for diagnostic 
procedures or medical intervention shall not qualify as SAE. 
 
 
For the purposes of this study, specified events considered to be expected in this patient population 
and during 
leukemia 
therapy 
will 
not require 
to 
be reported 
as 
SAEs 
(see  
Section 7.6.1). 

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All patients with SAEs must be followed up for outcome until it is considered resolved, returns to 
baseline, is chronically ongoing, stabilized, or is otherwise explained by the Investigator. 
 
If the Investigator detects a SAE in a study patient after the end of the period of observation and 
considers the event possibly related to prior study treatment or procedures, they should 
immediately (within 24 hours of awareness) contact the Sponsor to determine how this event 
should be documented and reported. For screening failure patients, SAEs detected after SF 
declaration will be recorded only if the event is considered as possibly related to study procedures. 
 
7.6.1. Exceptions to SAE reporting 
For this study, the following events will be considered to be expected events in this population and 
during leukemia therapy other than SEL24/MEN1703 (e.g. myelosuppression and events 
secondary to disease) and should not be reported to the Sponsor as serious events unless the 
Investigator considers any of these events to be clinically concerning and of unusual manifestation 
with regard to severity, duration, frequency, outcome or other characteristics of the event. It is 
important to note that these events (with the exception of progression of AML), still need to be 
captured as AEs on the AE eCRF and will be reviewed by the DMC in aggregate with all 
cumulative safety data. 
 
Expected events during leukemia therapy are: 
 
• 
Myelosuppression due to disease or leukemia therapy :  
o 
febrile or infection episodes. 
o 
epistaxis or bleeding except for catastrophic CNS or pulmonary hemorrhage. 
o 
anemia, neutropenia, lymphopenia, thrombocytopenia, leukopenia, leukocytosis. 
• 
Events due to underlying disease:  
o 
symptoms associated with anemia: 
∼ 
fatigue. 
∼ 
weakness. 
∼ 
shortness of breath. 
o 
electrolyte abnormalities (sodium, potassium, bicarbonate, CO2, magnesium). 
o 
chemistry abnormalities (LDH, phosphorus, calcium, BUN, protein, albumin, 
uric acid, alkaline phosphatase, glucose). 
o 
coagulation abnormalities. 
o 
disease specific therapy (induction, maintenance, salvage, or stem cell therapy). 
o 
alopecia. 
o 
bone, joint, or muscle pain. 
o 
liver function test abnormalities associated with infection or disease progression. 
o 
disease progression. 
• 
General therapy events:  
o 
events attributed to the use, placement and/or insertion of catheters. 
o 
renal failure associated with tumor lysis syndrome or antibiotic/antifungal 
therapy. 

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o
rash due to antibiotic use.
•
Hospitalization for the management of any of the above expected events.
Abnormal hematologic or clinical chemistry values, not considered to be clinically significant, will 
not be recorded on the adverse event eCRF, although all values will be recorded on the hematology 
and clinical chemistry laboratory eCRFs. 
7.7. Other Important Events for Immediate Reporting 
In addition to the above criteria, AEs meeting either of the below criteria, although not serious per 
ICH definition, are reportable to the Sponsor in the same timeframe as SAEs to meet certain local 
requirements and the study needs.  
•
a new cancer (that is not a condition of the study);
•
a reported pregnancy or lactation after receipt of study treatment and for up to 30
days from last dose;
•
an overdose (defined as any dose of SEL24/MEN1703 which is more than the
assigned dose for that patient); or
•
an AE which qualifies as a DLT during Cycle 1 for patients in Part 1 (see Section
7.7.3).
Such events must be reported within 24 hours to the Sponsor via the eCRF. Once the information 
is saved in the eCRF, a notification e-mail will be automatically generated and sent to the Sponsor’s 
Study Drug Safety Unit (SDSU). Only in case of breakdown of the eCRF System, the specific 
paper report form, provided to the sites, will be used. In such case, the Investigator will be 
responsible for sending the corresponding paper form and inserting the data in eCRF as soon as 
the system works again. The reporting procedures can be found in the SAE report form completion 
manual distributed to the sites.  
7.7.1. Exposure during pregnancy or lactation 
Although pregnancy and lactation are not considered AEs, it is the responsibility of 
Investigators or their designees to report any pregnancy or lactation in a patient 
(spontaneously reported to them) or pregnancy in a patient’s partner that occurs during the 
study. 
Pregnancies and lactations that occur in patients after the ICF is signed but before starting 
study treatment must be reported by the Investigator if they cause the patient to be excluded 
from the study. Pregnancies and lactations that occur in a study patient or a pregnancy in a 
patient’s partner from the time of first study treatment through to 30 days following 
cessation of SEL24/MEN1703 study treatment must be reported by the Investigator. All 
reported pregnancies must be followed to the completion or termination of the pregnancy. 
If the pregnancy continues to term, the outcome (health of infant) must also be reported. 
Such events must be reported within 24 hours to the Sponsor. 

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Pregnancy and lactation will be reported to the Sponsor via EDC. ONLY if the eCRF 
system does not work, the specific paper report form (Pregnancy Exposure Report form) 
will be completed and sent to the Sponsor by email or fax (see Section 7.7). The “Pregnancy 
Exposure Report” form will be distributed to the sites to be used for this purpose. The 
outcome of the reported pregnancies will be always notified to the Sponsor using the 
Pregnancy Exposure Report form. If the pregnancy results in an abnormal outcome 
(miscarriage or new-born with congenital abnormality and/or stillbirth), this will be 
recorded in the eCRF as a SAE and managed as described in Section 7.10. The reporting 
procedures can be found in the SAE report form completion manual distributed to the sites.  
 
7.7.2.  
Misuse and overdose 
Both misuse and overdose issues should be reported to the Sponsor’s SDSU within the 
same timelines as a SAE, even if they may not result in an adverse outcome (see Section 
7.7). In the event of overdose, the patient should be observed closely for signs of toxicity. 
Appropriate supportive treatment should be provided if clinically indicated. 
 
For the purpose of this protocol, an overdose is any dose of SEL24/MEN1703 which is 
more than the assigned dose level for that patient. The corresponding information should 
be entered on the overdose page in the eCRF no later than 24 hours of awareness by the 
site. Once the page is completed and saved by the staff involved in the study, an alert 
notification will be automatically sent to the Sponsor. ONLY if the eCRF system does not 
work or if the eCRF is not available, the paper CRF-AE report form shall be used and sent 
to the Sponsor by email. 
The reporting procedures are described in detail in the SAE report form completion manual 
distributed to the sites. 
In addition, if an AE (serious o non-serious) is associated with an overdose, it will be 
recorded on the AE page in the e-CRF, recording the overdose details. 
 
If the pharmacy discovers that an overdose has or may have been administered, they should 
immediately contact the Investigator and Sponsor (or their delegate). 
 
7.7.3.  
Dose limiting toxicity 
DLT events for dose escalation decisions will be assessed at the end of Cycle 1 (and on 
Day 42 in the case of protracted neutropenia in the absence of active AML), for each patient 
in each cohort and should be reported within 24 hours of the Investigator or their study 
team first becoming aware of the event. The AEs listed below will be considered as DLT 
unless they are clearly and incontrovertibly attributable to the underlying disease or to an 
extraneous cause:  
  
• 
Grade 5 toxicity  
• 
Grade 4 neutropenia lasting ≥42 days from the start of the therapy cycle in 
absence of evidence of active AML (<5% blasts) 
• 
Grade 3 or 4 non-hematologic toxicity, except:  
o 
Alopecia;  
o 
Grade 3 fatigue, asthenia, anorexia, fever, or constipation; 

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o 
Grade 3 nausea, vomiting, or diarrhea not requiring tube feeding, TPN, or 
hospitalization; 
o 
Infection, bleeding, or other expected direct complications of cytopenias 
due to active leukemia; 
o 
Grade 3 or 4 electrolyte imbalances that respond to correction i.e. return to 
≤Grade 2, within 48 hours (h) from correction’s onset; 
o 
Grade 3 increase in aspartate aminotransferase (AST) and/or, alanine 
aminotransferase (ALT) and/or alkaline phosphatase (ALP) recovering 
≤Grade 2 within 7 days. 
 
Only clinically significant abnormalities in laboratory findings, physical examination, 
vital signs, weight or ECG (see Section 7.2) will be considered for DLT assessment, 
according to the protocol definition. 
 
7.7.4. Investigational product complaints 
Pharmaceutical technical complaints associated with the investigational product must be reported 
to the Sponsor immediately. The same reporting timelines as for SAEs apply.  
 
7.8. Relationship 
All AEs (including SAEs) will be assessed for the relationship of the AE to the study drug using 
the following standard definitions (for DLT events assessment for dose escalation decision please 
specifically refer to the above chapter 7.7.3): 
 
• Not Related: The event or laboratory test abnormality (AE), with a time to drug 
intake with an unreasonable relationship and or non-plausibility and/or the 
existence of a clear alternative explanation.  
• Unlikely related - The event or laboratory test abnormality (AE), with a time to 
drug intake that makes a relationship improbable (but not impossible). Disease or 
other drugs provide plausible explanations. 
• Possibly related - The event or laboratory test abnormality (AE) has a reasonable 
time relationship to the drug intake, but it could also be explained by disease or 
other drugs. Information on drug withdrawal (dechallenge) may be lacking or 
unclear. 
• Probably related - The event or laboratory test abnormality (AE) has a reasonable 
time relationship to the drug intake, it is unlikely to be attributed to a concurrent 
disease or other drugs and it follows a clinically reasonable response on withdrawal 
(dechallenge). Rechallenge (AE reappearance after drug reintroduction) is not 
required to fulfil this definition. 
• Definitely related - The event or laboratory test abnormality (AE) has a plausible 
time relationship to the drug intake and it cannot be explained by a concurrent 
disease or other drugs. The response to withdrawal of the drug (dechallenge) should 
be plausible (pharmacologically, pathologically). The event must be definitive 
pharmacologically or phenomenologically (i.e. an objective and specific medical 
disorder or a recognised pharmacological phenomenon), using a satisfactory 
rechallenge procedure if necessary. 

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Please also refer to supporting information provided in Appendix C. The relationship of the study 
treatment to an AE will be determined by the Investigator and subsequently reviewed by the 
Medical Monitor. 
 
For reporting and data analysis purposes, AEs reported with a causality assessment of “Definitely”, 
“Probably”, and “Possibly” are to be considered as “having a reasonable causal relationship” to 
study drug. In case of disagreement between the Investigator and the Sponsor’s Medical Monitor, 
the more conservative assessment will determine the reportability of the case. 
 
7.9. Unexpected Adverse Events 
The Sponsor will assess all SAEs whether they are expected or unexpected. An unexpected AE is 
any adverse drug event, the outcome, specificity, or severity of which is not consistent with that 
included in the Reference Safety Information chapter of the current IB. 
 
7.10. 
Reporting Serious Adverse Events 
Adverse events classified as serious require expeditious handling and reporting to the assigned 
Sponsor’s Study Drug Safety Unit (SDSU) to comply with regulatory requirements, except for 
SAEs meeting the “exceptions to SAE reporting” definition (see Section 7.6.1).  
 
For any SAE that occurs while a patient is on-study; within 30 days of the last study drug 
administration, regardless of any opinion as to the relationship of the SAE to the study drug; or if 
any SAE that the Investigator considers as related to the study drug occurs later than 30 days after 
the last study drug administration, the Sponsor’s SDSU must be notified immediately (within 24 
hours of becoming aware of the event). 
The procedure for reporting is via eCRF. Once the event is entered and saved on the AE page in 
the eCRF, an automatic alert notification will be sent to the Sponsor’s SDSU. ONLY in case of 
eCRF system unavailability, the paper CRF-AE report form can be completed and the PDF sent to 
the Sponsor’s SDSU by email to meet the reporting timelines. As soon as the eCRF works again, 
the event should be recorded in the eCRF by the Investigator without further delay. 
The Sponsor’s SDSU and the SDSM contact details are listed below. 
 
Table 13: Contact details for SAE reporting 
SAE Facsimile Transmission: sdsu@menarini.es 
SDSM: 
 
SDSM E-mail Contact: 
 
SDSM Phone: 
 
SDSM Mobile 
 
 
7.11. 
Reporting of Serious Advert Events to Regulatory Authority 
The Sponsor has appointed the centralized Study Drug Safety Unit (SDSU) team as responsible 
for the management of AEs from all the sites in compliance with the applicable regulatory 

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requirements (including SAEs and SUSARs management) and all safety communications to be 
submitted to the sites, RAs and ECs accordingly to the procedures described in the corresponding 
study Safety Management Plan (SMP). 
In addition, the Sponsor shall ensure that all relevant information about any SUSAR, will be 
expeditiously reported to the CAs (including EudraVigilance Clinical Trial Module), and to ECs 
if applicable (as per country-specific requirements) with the following deadlines after the first 
knowledge, intended as the day when the Sponsor’s receives the notification of the SUSAR or the 
monitor is aware of it: 
• 
Fatal and life-threatening unexpected cases, no later than 7 days; 
• 
Other unexpected serious cases, no later than 15 days. 
 
The Sponsor shall ensure that all relevant new information and supporting documentation that 
subsequently become available will be also expeditly reported as follow-up information no later 
than 15 days after the first knowledge for all cases. 
The following safety issues will be subject to expedited management for the identification of 
possible necessary actions: 
• 
SAEs associated with the study procedures; 
• 
Potential clinically significant findings emerging from non-clinical studies; 
• 
An anticipated end or suspension for safety reasons of another study with the same 
study treatment. 
 
When appropriate and applicable as per local regulatory requirements, the Sponsor will arrange 
the adequate information also to the Investigators. The Sponsor (through the SDSU) will distribute 
the validated CIOMS I form to the investigators (via e-mail) with a safety letter. 
For the US, the Investigator must ensure the study team is aware and comply with any additional 
local reporting requirements. For all SAEs that are related and unexpected, the Sponsor will assign 
a case number to be used in all future correspondence regarding the event and can provide an IND 
Safety Reports in MedWatch form or CIOMS form describing the event, for the Investigators to 
report to their Institutional Review Board (IRB)/ Ethics Committee (EC) or other committee (as 
per local requirements). Other SAEs (i.e. expected or unrelated SAEs) should be reported per the 
relevant institution’s procedures (if required). 
Where required, submission of Safety Updates by the Investigator to Competent Authorities should 
be handled according to local regulations. Otherwise, periodic safety reports to the regulatory 
agencies will be handled by the Sponsor (or their delegate). These safety updates will also include 
SAEs that do not require expedited reporting to the authorities. 
In addition, a periodic line-listing of SUSARs occurred with SEL24/MEN1703 is to be reported to 
European Investigators (as per country requirements) every 6 months by the Sponsor SDSU. 
Periodically (at least annually), the IB will be updated to include new and relevant safety 
information. Until such time that an AE becomes identified in the IB, it should be considered 
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7.12. 
Follow Up Information on a SAE 
 
After the End of Study Visit, the Investigator is not requested to actively follow-up the patient 
unless ongoing SAEs are present. However, if after the end of the study, the Investigator becomes 
aware of any SAEs with a suspected causal relationship to the study treatment, this SAE should be 
duly reported to the Sponsor and recorded in the eCRF if still available. If the eCRF is not available 
anymore, the paper CRF SAE form will be used as a backup.  
 
Collection of complete information concerning SAEs is extremely important. Thus, follow-up 
information that becomes available as the SAE evolves, as well as supporting documentation (e.g. 
hospital discharge summaries and/or autopsy reports), should be collected subsequently, if not 
available at the time of the initial report, and immediately sent using the same procedure as the 
initial SAE report. The original SAE form must be kept on file at the study site. The Sponsor will 
also review SAE reports for missing information and open queries to the site for resolution as 
appropriate. 
 
Appropriate diagnostic tests should be performed and therapeutic measures, if indicated, should be 
instituted. Appropriate consultation and follow-up evaluations should be carried out by the 
Investigator (or designee). A SAE is followed until it is considered resolved, returns to baseline, is 
chronically ongoing, stabilized, or is otherwise explained by the Investigator.  
 
 
 
 
 

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8. DATA EVALUATION
8.1. Data Monitoring Committee
The DMC consists of the Principal Investigators (or their representatives), the Medical Monitor, 
and Sponsor representatives. It may also include invited experts (such as a PK or PD data expert). 
During Part 1 the DMC will meet by telephone (or in person if possible) to review safety data from 
the first treatment cycle of the current cohort under evaluation. The DMC will also convene 
periodically during Part 2, after every 2 months or a further 6 patients have been enrolled 
(whichever comes first), to consider ongoing safety and tolerability at the RD. They will also 
consider PK and PD data as available and on-going safety data from prior cohorts. Appropriate 
representatives of the Sponsor and the coordinating personnel will also attend and minute the 
meeting. Decisions of the DMC will be documented, filed in the eTMF, and will be distributed to 
all study sites. 
Further details on the composition of the DMC, as well as the process for data review and decision 
making, are described in the DMC charter for this study.  
The DMC will: 
•
review the safety data from the first cycle of treatment for each cohort during Part 1
and make dose-escalation decisions;
•
consider other AEs, or possible trends in AEs, during Part 1 which may inform dose
escalation decisions or selection of the RD for Part 2;
•
confirm the MTD or MAD and select the RD for further evaluation in Part 2;
•
review the safety data package for Part 1; perform on-going assessment of safety, anti-
leukemic activity, PK and PD data in Part 2;
•
support the implementation of supportive care guidelines during the study, by ongoing
review of AEs and need for treatment delays; consider these data both for DLT
evaluation, possible need for dose modification for individual patients, or
recommendation for withdrawal (see Section 3.4).
8.2. Populations 
Two populations for analysis are considered: 
The dose determining set will consist of all patients in each cohort that have completed one cycle 
of treatment and patients that discontinued earlier due to a DLT occurring in this period. This 
population will be used for the dose escalation Part 1. 
For all other objectives, the safety set consisting of all patients that have received at least one dose 
of SEL24/MEN1703 will be used. Patients will be also be categorized by cohort and by dose level 
received. 
For some objectives (e.g. anti-leukemic or PD activity), a subgroup of patients of the safety set 
with respective baseline and post-baseline measurements will be used. 

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Patients who were screened but did not receive any treatment will be listed and will not be part of 
any summary table. 
 
8.3. Completion of the Study 
The study will be completed when all patients have completed their Final Study Visit assessment. 
On completion of the study, data will be reconciled and the database will be locked for analysis.  
 
Study start is defined by First Patient In (FPI) i.e. when the first patient receives the first dose of 
study drug. Study Completion is defined by Last Patient Out (LPO) of the study i.e. when the last 
patient enrolled in the study has completed the last dose of study drug or discontinued for any 
reason and been followed up to the Final Study Visit.  
End of Study is defined as the Final Study Visit of the last subject who discontinues the study 
treatment. 
 
An addendum (or addenda) to the Clinical Study Report will be generated as required to report any 
data obtained during the Follow-up Assessments. 
 
8.4. Statistical Considerations 
Detailed statistical analysis information will be provided separately in the Statistical Analysis Plan 
(SAP). The SAP will detail all data handling rules, including the management of missing values 
and the handling of data for withdrawn patients. The SAP will also outline protocol deviation 
criteria. Any deviations to the planned analyses specified or populations defined within the SAP 
will be justified in writing and presented within the final clinical study report. 
 
The clinical database lock will occur after all data are reconciled (i.e. “cleaned”) for all patients 
who participate in both Part 1 and Part 2. A single clinical study report will be generated for this 
study. The SAP will be finalized and signed before the database is locked.  
 
In all tables, listings and figures the dose-escalating cohorts will be reported from the lowest to the 
highest dose.  Part 1 will be reported together with Part 2. Where appropriate, those patients who 
received the same dose in Part 1 or Part 2 in both cohorts may be combined and summarized, as 
well as being summarized separately. The same is valid for the two cohorts, “all-comers” and 
“IDH-mutants” patients. 
 
8.4.1. Missing data/discontinuation 
Due the dose escalation design of the study no missing imputation of missing values will be done 
for the primary objective. Reasons for discontinuation of the study and the study treatment will be 
listed and summarized. 
 
8.5. Demographic, Medical History, Prior Medication and Other Baseline Characteristics 
Demographic characteristics, medical history, prior medication and other baseline data will be 
listed and summarized using descriptive statistics for continuation data and contingency tables for 
categorical data. Prior medication will be summarized by ATC terms. 
 

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8.6. Study Treatment 
The number of doses of SEL24/MEN1703 by cycle and over entire study period will be listed and 
summarized using descriptive statistics. The time of study drug administration until last treatment 
received will be listed and presented by descriptive statistics.  
 
8.7. Concomitant Medication 
Concomitant medication and significant non-drug therapies after the start of study treatment will 
be listed and summarized by ATC term in contingency tables. 
 
8.8. Methods for Assessment of Safety Parameters 
All safety and tolerability assessments will be based on the safety analysis set, which is defined as 
all patients who have received at least one dose of study medication.  
 
No formal statistical analysis will be performed on safety data. 
 
Vital signs, resting 12-lead ECGs, clinical chemistry, hematology, coagulation, lipid profile, and 
urinalysis data will be listed by cohort, dose and time-point.  
 
The number and percentage of patients experiencing one or more AEs will be summarized by 
cohort, dose, relationship to study drug, and severity. AEs will be coded using MedDRA 
terminology. AEs that have missing onset dates will be considered to be treatment-emergent, unless 
the stop date is known to be prior to the first administration of the study medication. 
 
SAEs and DLTs will also be presented separately. 
 
8.9. Methods for Assessment of Anti-Leukemic Activity 
No formal statistical analysis will be performed on anti-leukemic parameters.  
 
Anti-leukemic activity data will be collected throughout Part 1 and Part 2 and will summarized by 
cohort, by dose and overall. In Part 2 response may be summarized and an exact 95% confidence 
interval (CI) calculated.  
 
Measures of anti-leukemic activity will include: 
 
• 
Changes in pre- and post-treatment levels of leukemic blasts in the peripheral blood 
and/or bone marrow; 
• 
Duration of response (DoR); 
• 
Relapse-free survival (RFS); 
• 
Event-free survival (EFS); 
• 
Overall Survival (OS) 
• 
Transfusion conversion rate; 
• 
Transfusion maintenance rate; 
• 
HSCT rate. 
 

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Where possible disease assessment will be evaluated according to the response criteria in AML6. 
(see Appendix D).  
 
8.10. 
Methods for Assessment of PK Data 
The analysis plan for PK assessment for SEL24/MEN1703 in the study will be described in the 
SAP. Pharmacokinetic parameters will be estimated for each patient using a fully validated version 
of WinNonlin 8.0 (PhoenixTM, Pharsight®) or equivalent. The following parameters will be 
derived, where appropriate, from the individual plasma concentration versus time profiles of 
SEL24/MEN1703 and its metabolites. PK analysis in urine will be described separately. 
 
Table 14: Pharmacokinetic Parameters 
Parameter 
Definition 
Cmax 
The maximum observed concentration. 
tmax 
The time at which Cmax was apparent. 
AUC0-t 
The area under the concentration versus time curve from time zero to the sampling 
time at the last quantifiable concentration (Ct) at tlast (the time of the last quantifiable 
concentration) calculated by the linear trapezoidal rule. 
λz 
The apparent terminal rate constant, estimated using the negative slope of the least 
square regression analysis of the log concentration versus time data for the terminal 
linear portion of the curve. 
t1/2 
The apparent terminal half-life, calculated from Ln 2 / λz. 
AUC0-∞ 
The area under the concentration-time curve estimated from time zero to infinity as the 
sum of the 2 areas: AUC0-t and AUCextrap, where AUCextrap is calculated as Ct/λz. 
CL 
The systemic clearance calculated as: Dose/AUC0-∞. 
Vss 
The apparent volume of distribution at steady state calculated as: 
Dose/AUC × (AUMC/UC0-∞ - t1/2). 
 
Additional PK parameters may be calculated as appropriate.  
 
8.11. 
Methods for Assessment of PD Data 
The Sponsor will exploit flow cytometry for the analysis of relevant biomarkers (e.g. pS6). Since 
such investigation is of exploratory nature, the Sponsor may choose to prepare separate analysis 
plan and report for the PD analysis. 
 

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8.12. 
Methods for assessment of the genetic profile of AML cells 
The Sponsor will exploit Next Generation Sequencing and/or qRT-PCR to analyze the genetic 
profile of AML cells. Since such investigation is of exploratory nature, the Sponsor may choose to 
prepare separate analysis plan and report for this analysis. 
8.13. 
Estimated Sample Size 
After completion of Part 1 (dose escalation) and definition of RD, approximately 40 evaluable 
patients are to be enrolled in the Part 2, namely 20 patients in the ‘all comers’ and 20 patients in 
the IDH mutated patients cohort . .  
The study Part 1 was initially designed with an accelerated titration design for the first 4 cohorts, 
then a 3+3 design had to be followed from the former fifth cohort (150 mg dose level) onwards. 
However, following the occurrence of 2 DLTs at the 150 mg dose level, one of which resulted in 
a fatal treatment-related outcome, the study design has then been revised to follow a 3+3 design 
from Cohort 2 onwards in order to assess for DLT, adverse events, and adequate PK profile data 
from at least 3 patients in each dose level from 50 mg onwards. The final number of patients treated 
in Part 1 will therefore be dependent upon the number of cohorts (dose levels) investigated, as well 
as the number of cohort expansions. 
In Part 1 a conventional algorithm will be used to identify the MTD or MAD, escalating on 0/3 or 
1/6 DLTs, and de-escalating if 2 or more patients with DLTs are encountered. The MTD will be 
the highest dose level at which 0 or 1 of 6 patients experience a DLT, with the next higher dose 
having at least 2 of 3 or 2 of 6 patients experiencing a DLT. At the 150 mg dose cohort, up to 4 
additional patients will be treated with formulated IMP according to a Bayesian modified toxicity 
probability interval (mTPI) with a target toxicity rate ≤ 25%. 
Part 2 of the study further evaluates safety and tolerability of SEL24/MEN1703 in AML population 
where there is rationale to treat. The expansion cohort in ‘all comers’ has already enrolled 23 
unselected AML patients. An additional expansion cohort (“IDH mutants”) will enroll 
approximately 20 relapsed or refractory AML patients harboring an IDH mutation (either IDH1 or 
IDH2). 
Considering that IDH inhibitors are approved/available only in some of the participating countries, 
it is anticipated that the study will enroll both IDH inhibitor pre-treated and IDH inhibitor naïve 
patients. For this reason, the recruitment will aim to have a balanced distribution across the two 
sub-populations to explore the differences in SEL24/MEN1703 activity between pre-treated and 
IDH inhibitor naïve patients, if any. 
9. QUALITY ASSURANCE
9.1. Data recording / Monitoring of the Study and Regulatory Compliance
The project manager, or their designee, will make an initiation site visit to each institution to review 
the protocol and its requirements with the Investigator(s), inspect the drug storage area, and fully 
inform the Investigator of his/her responsibilities and the procedures for assuring adequate and 

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correct documentation. During the initiation site visit the electronic case report forms (eCRFs) and 
other pertinent study materials will be reviewed with the Investigator’s site staff. During the course 
of the study, the monitor will make regular site visits in order to review protocol compliance, 
examine eCRFs and individual patient’s medical records and assure that the study is being 
conducted according to pertinent regulatory requirements. All eCRF entries will be verified with 
source documentation. The review of medical records will be done in a manner to assure that 
patient confidentiality is maintained. 
 
All eCRF data will be collected using an eCRF within a fully validated and CFR 21 Part 11–
compliant Electronic data capture system. The Investigator’s site staff will be responsible for 
entering study data into the eCRF in accordance to the eCRF Completion Guidelines provided by 
Sponsor.  All data shall be entered into the eCRF by the Investigator’s site staff as closely as 
possible to the time when they become available and not later than 10 business days. These data 
will then be source-data verified and reviewed by the Clinical Research Associates (CRAs) before 
data cleaning by Data Management is performed. All queries will be raised and resolved within 
the electronic data capture system. During entry, programmatic checking of the data will be 
performed and, once saved into the database, more complex programmatic checks will also be 
performed. During the conduct of the study, all system users will have real-time access to the data. 
The level of access to the data and study privileges will be determined by their user role.  
 
After all queries have been resolved, the SAP approved and signed, and any summary/analysis 
populations approved, the database will be locked and the data released for summary and analysis. 
All summary and analysis of the data will be performed using appropriate version of SAS® and 
WinNonLin 8.0, or equivalent. 
 
9.2. Study Monitoring 
Study Monitors will be responsible for the monitoring of the study.  
 
The Study Monitor will review the progress of the study on a regular basis to ensure adequate and 
accurate data collections. Monitoring site visits to review eCRF, patient case notes, administrative 
documentation, including the Investigator Site 
File, and frequent telephone/e-mail 
communications with site will be performed throughout the study. 
 
At each study monitoring visit, the Investigator will make available all records pertaining to the 
study. To allow sufficient time to assemble documentation for the Study Monitor, monitoring visits 
will be confirmed in advance of planned visits. 
 
9.3. Clinical Study Audit 
The Sponsor, Sponsor representative or external regulatory agency may at any time during or after 
completion of the study conduct a GCP audit. Prior notice will be given to each site selected for 
audit in advance of a planned audit. 
 
9.4. Clinical Study Report 
The results of the study will be presented in an integrated Clinical Study Report according to ICH 
guidelines. 

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9.5. Data Retention and Availability 
The Investigator is required to maintain copies of all essential study documentation, including the 
Investigator Site File, a disc containing all eCRF data (including the full audit trail and all data 
queries), signed informed consent forms, and records for the receipt and disposition of study 
medications, must be retained for at least 25 years after the end of the clinical study, unless other 
EU laws require archiving for a longer period.  These documents should be retained for a longer 
period, however, if required by the applicable regulatory requirements or by an agreement with the 
Sponsor. It is the responsibility of the Sponsor to inform the investigator/institution as to when 
these documents no longer need to be retained. 
 
During the study, the Investigator must make study data accessible to the Study Monitors, the 
Sponsor (or a third-party auditor assigned by the Sponsor), and relevant IEC/IRBs and Regulatory 
Agencies. A file for each patient must be maintained that includes the signed informed consent 
form and all source documentation related to that patient. The Investigator must ensure the 
availability of source documents from which the information in the eCRF was derived. 
 
9.6. Curricula Vitae and Financial Disclosure of Investigators  
All Principal Investigators will be required to provide a current signed and dated curriculum vitae, 
a completed FDA Form 1572 (required in the USA; in the EU, if applicable) and a financial 
disclosure statement (required in the USA; in the EU, if applicable). All Sub-investigators will be 
required to provide a current curriculum vitae and a financial disclosure statement. 
 
9.7. Protocol Modifications 
No modification of the protocol should be implemented without the prior written approval of the 
Sponsor. Any such changes which may affect a patient’s treatment or informed consent, especially 
those increasing potential risks, must receive prior approval by the IRB/IEC. The exception to this 
is where modifications are necessary to eliminate an immediate hazard to study patients, or when 
the change involves only logistical or administrative aspects of the study (e.g. change in monitor, 
change in telephone number). Other administrative revisions which may impact the clinical portion 
of a study will be duly reported to the IRB/IEC by the Principal Investigator. 
 
 

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10. ETHICS REVIEW/INFORMED CONSENT/ETHICAL CONSIDERATIONS
The Investigator will obtain written informed consent from each patient, or their authorized 
representative, participating in the study. The form must be signed, witnessed and dated. The 
informed consent form will contain all the Essential Elements of Informed Consent set forth in 
21 CFR, Part 50, the ICH Guideline for Good Clinical Practice, and the terms of the Declaration 
of Helsinki, the US Health Insurance Portability and Accountability Act regulations (HIPAA), the 
US Common Rule (45 CFR 46.116) , the EU Regulations 536/2014 and 679/2016 as applicable. 
Copies of the signed document should be given to the patient and filed in the Investigator’s study 
file, as well as the patient’s medical record if in conformance with the institution’s Standard 
Operating Procedures (SOPs) and the applicable Laws and Regulations.  
The final study protocol and patient informed consent form will be approved by the appropriate 
IEC/IRB for each investigational site. Approval will be received in writing before initiation of the 
study. 
Changes to the protocol during the study will be documented as amendments. Depending on the 
contents of the amendment and local legal requirements, the amendment will be submitted for 
approval to the relevant IEC/IRBs and to the relevant competent authorities prior to 
implementation. Exceptions are cases of changes made to protect patient safety, which will be 
implemented immediately. 
If an amendment substantially alters the study design, increases the potential risk to the patients, 
affects the treatment of the patient, or might otherwise influence the willingness of the patient to 
participate in the study, then the information sheet must be revised and submitted to the relevant 
IEC/IRB and, where necessary, to the relevant competent authorities, for review and approval. 
When a patient is currently undergoing study procedures and is affected by the amendment, then 
the patient must be asked to consent again using the new information sheet. 
10.1. 
Ethical Conduct of the Study 
The study will be conducted in accordance with ICH GCP, the Declaration of Helsinki, the 
European Union Clinical Trials Directive 2001/20/EC, the EU Clinical Trials Regulation 536/2014 
when it will come into force, the GCP Directive 2005/28/EC, the requirements of local IEC/IRB, 
and the US Code of Federal Regulations, Title 21 CFR Part 50. Relevant updates to these 
regulations will be implemented as they come into force. 
10.2. 
Informed Consent 
The principles of informed consent in the Declaration of Helsinki and GCP guidelines will be 
implemented before any protocol-specific procedures or interventions are carried out.  
All patients will be informed that their participation is voluntary and that they can cease 
participation at any time without necessarily giving a reason and without any penalty or loss of 
benefits to which they are entitled.  

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With the help of the information sheet the patient will be informed about the IMP(s) and anticipated 
effects and the reason, design, and implication of the study. The patient must give consent to 
participate prior to enrolment in the study. This consent must be given in writing. The Investigator 
who conducts the informed consent discussion must also sign. The Investigator may delegate this 
responsibility to a suitably qualified member of the study team (e.g. Sub-Investigator) if permitted 
by local regulations. This delegation of responsibility must be recorded in the Study File. By giving 
signed consent, the patient will confirm that his or her participation is voluntary and that he or she 
will follow the instructions of the Investigator and answer the questions asked. Signatures must be 
personally dated. 
 
The signed and dated consent form will be securely kept by the Investigator. Prior to participation 
in the study, the patient should receive a copy of the signed and dated written informed consent 
form.  
 
The consent form and information sheet must include all elements required by law, local 
regulations, GCP and ICH guidelines including consent to allow the Sponsor, Sponsor 
representative, or external regulatory auditor to review the patient’s medical records. This gives 
permission to examine, analyze, verify, and reproduce any records and reports that are important 
to the evaluation of the study.  
 
Any party with direct access must take all adequate reasonable precautions within the constraints 
of the applicable regulatory requirement(s) to maintain the confidentiality of the patients’ identities 
and Sponsor’s proprietary information. It is the CRA’s responsibility to verify that each patient has 
consented, in writing, to direct access and that the documents are safely archived. 
 
10.3. 
Patient Participation Card 
A study participation card will be offered to sites for use by each patient on the study. The card 
will indicate that he or she is participating in a clinical study and give the name and contact details 
of the Sponsor and the Investigator/study site. If used, the patient will be asked to retain this card 
while participating in the study and show it to any other medical practitioners consulted during this 
time. Patients will be advised to contact the Investigator/study site if there are any questions. A 
sample patient participation card is shown below. Use of Patient Participation cards is optional. 
Relevant contact information will always be provided in the patient information sheet. 
 

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Figure 2: Sample patient participation card 
 
Dear Patient,  
 
Please inform any physician you are going to 
visit during the course of the study that you are 
participating in a clinical trial by presenting 
this contact card. 
 
Please carry this card with you at all times until 
the end of the study. 
 
Patient Name: ...................................................... 
is participating in an open-label trial and is 
receiving 
an 
investigational 
product, 
SEL24/MEN1703, a novel PIM and FLT3 kinase 
inhibitor. 
 
 
Study Contact Card: Clinical Trial CLI24-
001 
A Phase I/II Study of SEL24 in Patients with 
Acute Myeloid Leukemia 
 
In the case that additional medications must be 
prescribed, you need more information about the 
clinical trial, or there is a worsening condition of 
the patient, please contact the treating study 
physician: 
 
Name: 
.......................................................................  
 
Phone: 
 
10.4. 
Insurance 
Appropriate insurance for this study will be arranged by the Sponsor of the clinical study, in 
accordance with the regulatory requirements of the countries involved. 
Details on the insurance company will be provided as a separate document upon patient’s request, in 
accordance with national requirements. 
A copy of the country-specific insurance certificate will be held in the TMF and in the Investigator 
Site File. 
 
10.5. 
Institutional Review Board/Independent Ethics Committee 
The study will not be initiated without approval of the IRB/IEC and compliance with all 
administrative requirements of the governing body of the institution. This protocol, consent 
procedures, and any amendments must be approved by the IRB/IEC in compliance with current 
regulations of the FDA and the EU as applicable and in accordance with ICH GCPs. A letter of 
approval will be sent to the Sponsor prior to initiation of the study and when any subsequent 
modifications are made. The IRB/IEC will be kept informed about the progress of the study as well 
as of any serious and unexpected adverse events by the Investigator, CRO, or the Sponsor, as 
required by national regulations.  
 
10.6. 
Patient Privacy  
In order to maintain patient confidentiality, all case report forms, study reports and 
communications relating to the study will identify patients by an assigned patient number; patients 
should not be identified by name and/or date of birth. In accordance with local, national or federal 
regulations, the Investigator will allow the Sponsor or their designee personnel access to all 
pertinent medical records in order to verify the data gathered on the case report forms and to audit 
the data collection process. Regulatory agencies may also request access to all study records, 
including source documentation for inspection. Clinical information will not be released without 
the written permission of the patient as outlined in the patient consent form. 

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11. DATA CONFIDENTIALITY AND PUBLICATION POLICY
The original eCRFs and all data generated during the clinical study are the property of the Sponsor. 
It is intended that the study design and main results will be published on www.clinicaltrials.gov 
and on other applicable country specific websites (e.g., https://www.clinicaltrialsregister.eu). 
In addition, all information regarding SEL24/MEN1703 and the Sponsor’s operations (e.g. patent 
applications, formulas, manufacturing processes, basic scientific data, or formulation information) 
supplied by the Sponsor to the Investigator and not previously published is considered confidential. 
This confidential information remains the sole property of the Sponsor and shall not be disclosed 
to others without the written consent of the Sponsor. The Investigator agrees to use this information 
only to perform this study and will not use it for other purposes, including publications and 
presentations, without the Sponsor’s written consent.  
Any proposed publication or presentation (including a manuscript, abstract, or poster) for 
submission to a journal or scientific meeting should be sent to the Sponsor for review prior to 
submission. Publication of the results will not include confidential information without the 
permission of the Sponsor. The full terms of confidentiality, intellectual property and publication 
policy are described in the current Clinical Trial Agreement between the Sponsor and the Site. 
The Sponsor may announce quality assured summary data in order to comply with Financial 
Regulatory Authorities, while ensuring, so far as possible, that such announcements will not 
compromise the Investigators ability to publish the data in appropriate scientific forums. 
12. DATA PROTECTION
12.1. 
General Principles on Personal Data Compliance
All clinical trial information shall be recorded, processed, handled, and stored in such a way that 
it can be accurately reported, interpreted and verified; at the same time, the confidentiality of 
records and of the personal data of the patients shall remain protected in accordance with the 
Laws and Regulation on personal data protection from time to time applicable such as the EU 
General Data Protection Regulation 679/2016 and the EU Regulation on clinical trials on 
medicinal products for human use 536/2014 or the US Health Insurance Portability and 
Accountability Act regulations (HIPAA), the US Common Rule (45 CFR 46.116). 
This section defines the appropriate technical and organisational measures that shall be 
implemented to protect information and personal data processed against unauthorised or 
unlawful access, disclosure, dissemination, alteration, or destruction or accidental loss as well 
as to assure the fulfillment of patients’ privacy rights. 
12.2. 
Acknowledgment 
The Site, the Investigator, the Central Lab and the CRO as well as their appointed staff and 
service providers acknowledge that: 
(i) the performance of the study will imply processing of sensitive personal data;

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(ii) personal data processing is regulated by the applicable U.S. Federal, European (i.e. the 
EU General Data Protection Regulation 679/2016 and the EU Regulation on clinical 
trials on medicinal products for human use 536/2014 ) and local laws (i.e. the laws of the 
country where the study is conducted) as well as by the Sponsor’s national legislation.; 
(iii)strict compliance with the applicable data protection laws and this section of the protocol 
is deemed by the Sponsor as an essential condition of collaboration with the Site, the 
Investigator, the Central Lab and the CRO. 
 
12.3. 
Data Controllers and Data Processors 
The Sponsor, the Site, the Investigator and the CRO acknowledge that according to the 
applicable privacy laws, Sponsor and Site will act as independent data controllers while CRO 
and the Investigator will act as data processors respectively of the Sponsor and of the Site. Before 
the beginning of the study, the Site will instruct in writing Investigator as its data processor as 
required by the applicable laws and regulations. However, if specific local laws or regulations 
mandate a different definition of the privacy roles, the Sponsor, the Site, the Investigator and the 
CRO will implement the relevant legal instruments. 
 
12.4. 
Duties of the Parties involved in the performance of the study 
Collection and use of patients’ personal data (i.e. subjects' data), including their biological 
samples, will be carried out in full respect of the provisions of the information notices submitted 
to patients in the ICF, as well as the privacy rights, the fundamental freedoms and the dignity of 
data subjects. All the parties involved in this study undertake to adopt adequate measures to 
warrant that data will always be processed securely and in compliance with privacy laws. 
The Site, the Investigator, the Sponsor, the CRO and the Central Lab as well as their appointed 
staff and service providers, each in its respective remit and within the limits of their specific role 
in the study, shall implement the following safety measures (physical, logical, organizational, 
technical, electronic, I.T. etc) to ensure adequate protection of the personal data of the patients 
involved in the study. In particular: 
(i) 
 
 
 
 
 
 
 
 
  

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All actions related to the implementation of the afore mentioned measures shall be 
provided by the Sponsor, the Site and/or the CRO to the competent authorities (including 
data protection authorities) and IRB/IEC if and when requested. If such authorities or the 
Sponsor consider the implementation of the afore mentioned measures insufficient to 
guarantee an adequate level of protection of the patients’ personal data, the Site, the 
Investigator, the CRO and the Central Lab undertake to adopt all the necessary activities 
to overcome such remarks to assure the full compliance with the data protection laws. 
 
12.5. 
Archiving of the clinical trial master file and patients’ personal data 
Unless other EU laws require archiving for a longer period, the Sponsor, the Site and the 
Investigator shall archive the content of the clinical trial master file, including the relevant 
patients’ personal data, for at least 25 years after the end of the clinical study. However, medical 
records shall be archived in accordance with the national laws of the country where the study is 
performed. The patient code pairing list (i.e. the list that where the patient number is linked to 
the patients’ identification data such as name and surname), shall be archived care of the 
Investigator. 
U.S. Federal laws require that an Investigator maintain all study records for the indication under 
investigation for two years following the date a Product Licensing Application is approved or, 
if no application is to be filed or if the application is not approved for such indication, until two 
years after the investigation is discontinued and the FDA is notified. 
The content of the clinical trial master file shall be archived in a way that ensures that it is readily 
available and accessible, upon request, to the competent authorities. Should the Investigator wish 
to move the study record to another location, he/she must notify the Sponsor in writing. No study 
documents should be destroyed without prior written agreement between the Sponsor and 
Investigator. 
Any transfer of ownership of the content of the clinical trial master file shall be documented. 
The new owner shall undertake the responsibilities set out in this protocol. 
The Sponsor appoints the Study Manager as responsible person/s for archives. Access to 
archives shall be restricted to those individuals. 
The media used to archive the content of the clinical trial master file shall be such that the content 
remains complete and legible throughout the period referred to in the first paragraph. Any 
alteration to the content of the clinical trial master file shall be traceable. 
 

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12.6. 
Data Breach 
Data Breach is data breach of security leading to the accidental or unlawful destruction, loss, 
alteration, unauthorised disclosure of, or access to, personal data transmitted, stored or otherwise 
processed. In particular: destruction of personal data is where the data no longer exists, or no 
longer exists in a form that is of any use to the Sponsor, Site, CRO and Investigator etc.; data 
loss is when the data may still exist, but the Sponsor, Site, CRO and Investigator etc. has lost 
control or access to it, or no longer has it in its possession; damage is where personal data has 
been altered, corrupted, or is no longer complete; data unavailability is where, following a data 
incident (such as a network outage, a natural or man- made disaster, etc.), personal data become 
temporarily inaccessible to the Sponsor, Site, CRO and Investigator etc. 
Whoever becomes aware in any way of a Data Breach (see definitions above) affecting the 
patients’ personal data and/or personal data collected in the context of the study, shall, as 
appropriate, immediately (and in any case no later than 24 hours from the knowledge of a Data 
Breach) inform the study manager, the Sponsor’s Data Protection Officer, who may be contacted 
at dpo@menarini.com, the Site and the CRO at privacy@medpace.com and shall provide the 
following information if known: 
(i) Data Breach Type (e.g. data loss, unauthorized access, loss of company device, etc.); 
(ii) Person or source that first reported the Data Breach; 
(iii)Date and Time when the person who first reported the Data Breach became aware of it; 
(iv) Data Breach Date and Time (actual or presumed); 
(v) Place (specify if actual or alleged) where the Data Breach occurred ; 
(vi) Data Breach Description; 
(vii) Indicate the source of the Data Breach (e.g. I.P. source) - (if relevant); 
(viii) Indicate 
the 
affected 
infrastructure/system/application/cloud/software/hardware/ 
database and their location; 
(ix) List or describe the processing/storage systems affected by the Data Breach (if relevant); 
(x) Number of data patients involved (if known); 
(xi) Amount of allegedly breached data; 
(xii) Other relevant information. 
 
Once all the above information have been provided, the Sponsor and/or the Site should have a 
reasonable degree of certainty that a security incident has occurred that has led to personal data 
being compromised. 
Then, as appropriate, Sponsor and Site, each one in its respective remit, shall manage the Data 
Breach in accordance with the applicable data protection regulations. 
For Data Breach affecting personal data of patients enrolled within the European Union, Sponsor 
and the Site autonomously or jointly -depending on the circumstances and their privacy 
responsibilities as defined by the Regulation 679/2016- shall: 
1. collect the necessary evidence and information; 
2. categorise the breach; 
3. determine the risk probability and level to the rights and freedom of the concerned patients; 

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4. identify and put in place appropriate remedies to minimise the impact of the Data Breach; 
5. determine the notification and communication duties vis à vis the competent supervisory 
authority and/or the concerned patients. 
 
12.7. 
Information notice on personal data protection and pseudonymisation 
Prior to patients’ enrolment in the study, the Investigator and/or the Site (including their 
personnel) shall provide each patient with adequate, law-compliant “information notices and 
consent forms to process personal data” as included in the ICF (or, as the case may be, through 
a separate, specific form) provided by the Sponsor or delegated CRO and shall collect his/her 
written consent to the processing of personal data according to the actual performance conditions 
in which the study is carried out. The Investigator is responsible to archive the signed ICF in 
accordance with the security measures described above. 
Among other things, the ICF (or the separate form) shall inform patients about: 
(i) the applicable data protection legislation; 
(ii) what kind of data shall be collected during the study listing them in detail or by category; 
(iii)the purpose of data processing (for the performance of the study and/or for 
pharmacovigilance purposes and/or to register new medicines) and the legal basis; 
(iv) whether granting the consent(s) to process personal data is a necessary or an optional 
condition to take part in the study; 
(v) the use of data for future scientific researches/secondary use of data (if any). Please refer 
to Section 12.11; 
(vi) the pseudonymisation procedure and scope; 
(vii) who can access patients’ data and under what circumstances (Investigator and Site for the 
study conduction, Sponsor for analysis of data, regulatory authorities for registration of 
new medicine and/or for inspections, and the central lab. The complete list will be available 
upon request); 
(viii) the period of data retention/storage as defined in Section 12.5 above, including the storage 
of the biological sample; 
(ix) to which entities/countries outside the EU patients’ data will be transmitted (including US). 
The complete list will be available upon request; 
(x) patients’ data protection rights as defined by the EU General Data Protection Regulation 
679/2016; 
(xi) Data Controllers/Data Processors and the relevant contact details; 
(xii) Sponsor’s Data Protection Officer contacts (dpo@menarini.com); 
(xiii) in case of genetic data processing the possible findings, also with regard to unexpected 
findings that might be disclosed on account of the processing of the genetic data. 
 
12.8. 
Genetic Data 
- 
The collection of genetic data for performing genetic tests and screening shall be limited 
to the personal and family information that is absolutely indispensable for performing the study. 
- 
If genetic data are processed in the context of the study for pregnancy follow-up purposes 
(pharmacovigilance) only (i) the collection of genetic data for performing genetic tests and 

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screening shall be limited to the personal and family information that is absolutely indispensable 
for pregnancy follow-up; (ii) the source, nature and mechanism for samples taking and storage 
will be under the pregnant health care provider and its local procedures; genetic data shall be 
processed pursuant to the applicable pharmacovigilance laws and regulations; genetic data shall 
be communicated/transmitted using high security standard. The provisions below shall be 
implemented as applicable from time to time. 
- 
The source, nature and mechanisms for samples taking and storage will be under the site 
and its local procedures. 
- 
Without prejudice to applicable laws and regulations, the protocol shall be subject to 
confidentiality obligations that will assure the secrecy of the data for at least one year after the 
conclusion of the [study - use the same protocol terminology/definitions]. 
- 
The measures to keep patients’ identification data separated from biological materials and 
genetic information are reported in Section 12.4 and Section 12.5. 
- 
Access to the premises where genetic data are stored shall be controlled by security staff 
and/or electronic devices also based on biometrics. Any person admitted after closing time, on 
whatever grounds, shall have to be identified and their data recorded 
- 
Preservation, use, and transportation of biological samples shall be carried out in such a 
manner as to also ensure their quality, integrity, availability and traceability. 
- 
Genetic data shall be transmitted electronically by certified electronic mail after encrypting 
and digitally signing the information to be transmitted. Web application-based communication 
channels may be used if they rely on secure communication protocols and they can guarantee 
the digital identity of the server providing the service as well as of the client station from which 
the data are accessed by means of digital certificates issued by a certification authority in 
pursuance of the law. 
- 
Electronically processed genetic data may be accessed provided that authentication 
systems are based on tokens/devices. 
- 
Genetic data and biological samples contained in lists, registers and/or databases shall be 
processed with encryption techniques and/or by means of identification codes and/or any other 
techniques that can make them temporarily unintelligible also to the persons authorised to access 
them. 
- 
In order to minimise the risks of accidental disclosure and/or unlawful/unauthorised access, 
patients’ identities will be disclosed only when strictly necessary (e.g. to prevent a physical 
prejudice).  
- 
Genetic and medical data will be processed separately from any other personal data that 
can identify the patients directly. 
- 
The ICF will detail the possible findings regarding genetic data, also with regard to 
unexpected findings that might be disclosed as result of the test / elaboration of genetic data; 
- 
The ICF will detail whether the data subject is allowed to limit the scope of communication 
of his/her genetic data and the transfer of biological samples, including their possible use for 
additional purposes; 
- 
The ICF will detail the retention period of genetic data and biological samples (if different 
from the general retention period of other data processed in the context of the study). 
 
12.9. 
Transfer of patients’ data outside the European Union 
The study performance entails transferring patients’ personal data (coded pseudonymized data) 

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outside the EU. To this extent, the Sponsor, the Site, the Investigator, the Central Lab and the 
CRO, undertake to export such data in compliance with adequate safeguards/legal basis as 
required by the Regulation 679/2016 including the Commission Decisions, the Standard 
Contract Clauses, the Privacy Shield, patients’ specific consent. The updated list of foreign 
countries is available upon request. 
12.10. Exercise of patients’ data privacy rights 
Each study patient has the right to contact the Sponsor, the Site, the Investigator, the Central Lab 
and the CRO to exercise the rights afforded to the patient by the law, including the afforded ones 
under articles 15 to 22 of Regulation (EU) 2016/679, as from to time to time applicable and 
compatible with the study. Namely: knowing whether or not any data referring to his/her is being 
processed in the context of the study; access his/her data; verify the data’s content, origin, 
exactness, location (including, where applicable, the non EU countries where the data might be); 
obtain a copy of the data including their transmission to another entity indicated by the patient; 
ask that the data are supplemented, updated, amended; in the circumstances set forth by the law, 
ask that the processing of data is restricted, that data are anonymised or frozen; oppose to the 
processing of his/her data for legitimate reasons. Each patient has the right to lodge a complaint 
with his/her local supervisory authority and/or to notify to the Data Protection Officer any use 
of his/her personal data the patient regards as inappropriate. 
Each study patient is free to withdraw at any time from the study. In such case, each study patient 
may ask the Sponsor, the Site, the Investigator, the Central Lab and the CRO to destroy/delete 
his/her personal data including his/her biological samples, unless they have been permanently 
anonymised, thus preventing any further processing or analysis of his/her data. However, data 
and results of tests that may have been used to determine the results of the study shall not be 
deleted, to avoid altering or impairing altogether the results of the study. Please refer to Section 
12.8. 
If the Site, the Investigator, the Central Lab and the CRO receives a request for data privacy 
rights exercise, the concerned recipient shall immediately inform the Sponsor DPO by email at 
dpo@menarini.com 
The request shall be fulfilled within the term set forth by the applicable privacy laws (normally 
30 days). The Sponsor, the Site, and the Investigator, the Central Lab and the CRO shall 
implement adequate organisational measures to reply to patients within the above mentioned 
deadline. 
12.11. Future research 
Upon IRB/IECs and regulatory agencies approvals received, with patients’ optional and 
additional consent, the Sponsor and/or the Site may use the data collected during the course of the 
study for further medical and scientific research purposes. These may include, for example: 
retrospective clinical studies; clinical studies pertaining to the patients’ pathology/medical 
condition(s) or similar conditions; studies which compare the data of this Study with those from 
other sources to identify the factors involved in a disease; registration of new medicines. 
In the context of these additional research activities, patients’ data will be processed, pseudonymised 
and transferred abroad and may be shared with future research partners.

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13. END OF CLINICAL TRIAL AND ARCHIVING 
The study will end with the collection and analysis of study data and the issue of the clinical study 
report. All essential documents will be archived by the Sponsor according to the relevant SOP. 
 
13.1. 
Archiving Of Electronic Documentation/Data  
As described in Section 12.5, duplicate electronic media such as CDs/DVDs (1 for routine access 
and 1 for back-up) containing the patient data in PDF format (i.e., eCRFs) for each site will be 
prepared by the Sponsor or a delegate for archiving purposes. The electronic media, of not re-
printable type, will be appropriately labelled recording the files/data included. The files should 
contain at least the eData copy clearly reporting the system name, study code and the eCRF 
version used; for eCRF data also the electronic signature and the associated audit trails have to 
be included. The Investigator should verify whether the provided electronic media represent a 
complete copy of eCRFs generated during the study. The Investigator has to confirm the receipt 
and correctness of the material by signing a dedicate form provided by the Sponsor, the signed 
form has to be collected and archived in the TMF. Investigators will be also responsible for 
electronic media refreshment approximately every 7 years to ensure long term archiving of 
files/data. Two copies of the same electronic media prepared for the sites or cumulative 
electronic media with the same content will be archived by the Sponsor and refreshed 
approximately every 7 years to ensure long term archiving of files/data. In addition the Sponsor 
is responsible to create 2 electronic media (1 for routine access and 1 for back-up) containing an 
integrated SAS database with all study data (e.g., eCRF, central laboratory), with appropriate 
refreshment procedures. 
 
 
 
 

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APPENDIX A: EASTERN COOPERATIVE ONCOLOGY GROUP PERFORMANCE 
SCORE 
 
Grade 
ECOG Performance Score8 
0 
Fully active. Able to carry on all pre-disease performance without restriction. 
1 
Restricted in physically strenuous activity but ambulatory and able to carry out work 
of a light or sedentary nature (e.g. light house work, office work). 
2 
Ambulatory and capable of all self-care but unable to carry out any work activities. 
Up and about more than 50% of waking hours. 
3 
Capable of only limited self-care, confined to bed or chair more than 50% of waking 
hours. 
4 
Completely disabled. Cannot carry on any self-care. Totally confined to bed or chair. 
5 
Dead. 
  
 

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APPENDIX B: CREATININE CLEARANCE ALGORITHM 
 
Creatinine clearance should be calculated using the Cockcroft-Gault Formula9, which is given 
below: 
  
CrCl = (140 - Age) x Mass (in kilograms) x (0.85 if Female) 
 
72 x serum Creatinine (in mg/dL) 
 
 
 
 

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APPENDIX C: SUPPORTING INFORMATION FOR ASSESSMENT OF ADVERSE 
EVENTS 
 
National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) 
v4.03 can be found at the website of the National Cancer Institute.  
http://evs.nci.nih.gov/ftp1/CTCAE 
 
The following table provides supporting information to assess the relationship of AEs with study 
(test) drug. 
1 
Not related 
This category applies to those adverse events which, after careful consideration, are 
clearly and incontrovertibly due to extraneous causes (disease, environment, etc.). 
2 
Unlikely 
(must have two) 
In general, this category can be considered applicable to those adverse events which, 
after careful medical consideration at the time they are evaluated, are judged to be 
unrelated to the test drug. An adverse event may be considered unlikely if or when: 
1. It does not follow a reasonable temporal sequence from administration of the test 
drug. 
2. It could readily have been produced by the patient’s clinical state, environmental or 
toxic factors, or other modes of therapy administered to the patient. 
3. It does not follow a known pattern of response to the test drug. 
4. It does not reappear or worsen when the drug is readministered. 
3 
Possibly 
(must have two) 
This category applies to those adverse events for which, after careful medical 
consideration at the time they are evaluated, a connection with the test drug 
administration appears unlikely but cannot be ruled out with certainty. An adverse 
event may be considered possibly related if or when: 
1. It follows a reasonable temporal sequence from administration of the test drug. 
2. It could not readily have been produced by the patient’s clinical state, environmental 
or toxic factors, or other modes of therapy administered to the patient. 
3. It follows a known pattern of response to the test drug. 
4 
Probably 
(must have three) 
This category applies to those adverse events for which, after careful medical 
consideration at the time they are evaluated, are felt with a high degree of certainty to 
be related to the test drug. An adverse event may be considered probably related if or 
when: 
1. It follows a reasonable temporal sequence from administration of the test drug. 
2. It could not be reasonably explained by the known characteristics of the patient’s 
clinical state, environmental or toxic factors, or other modes of therapy administered 
to the patient. 
3. It disappears or decreases on cessation or reduction in dose. There are important 
exceptions when an adverse event does not disappear upon discontinuation of the drug, 
yet drug-relatedness clearly exists (e.g., bone marrow depression, fixed drug eruptions, 
tardive dyskinesia).  
4. It follows a known pattern of response to the test drug. 
5 
Definitely 
(must have all) 
This category applies to those adverse events which, the Investigator feels are 
incontrovertibly related to test drug. An adverse event may be assigned an attribution 
of definitely related if or when: 
1. It follows a reasonable temporal sequence from administration of the test drug. 
2. It could not be reasonably explained by the known characteristics of the patient’s 
clinical state, environmental or toxic factors, or other modes of therapy administered 
to the patient. 
3. It disappears or decreases on cessation or reduction in dose with re-exposure to drug. 
(Note: this is not to be construed as requiring re-exposure of the patient, however, a 
category of definitely related can only be used when a recurrence is observed.)  
4. It follows a known pattern of response to the test drug. 

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APPENDIX D: AML RESPONSE CRITERIA 
 
Category 
Definition 
Comment 
Response# 
CR without minimal residual 
disease (CRMRD-) 
If studied pretreatment, CR with 
negativity for a genetic marker 
by RT-qPCR, or CR with negativity 
by MFC 
Sensitivities vary by marker tested, 
and by method 
used; therefore, test used and 
sensitivity of the 
assay should be reported; analyses 
should be done 
in experienced laboratories 
(centralized diagnostics) 
Complete remission (CR) 
Bone marrow blasts <5%; absence 
of circulating blasts and 
blasts with Auer rods; absence of 
extramedullary disease; 
ANC ≥1.0 x 109/L (1000/µL); 
platelet count ≥100 x 109/L 
(100 000/µL) 
MRD+ or unknown 
CR with incomplete 
hematologic recovery 
(CRi) 
Bone marrow blasts <5%; absence 
of circulating blasts and 
blasts with Auer rods; absence of 
extramedullary disease with 
incomplete recovery of peripheral 
blood counts (ANC < 1.0 × 109/L 
[1000/µL] or platelet 
count < 100 × 109/L [100 000/µL]) 
 
 
CR with partial hematologic 
recovery (CRh)10, 11 
Bone marrow blasts <5%; absence 
of circulating blasts and 
blasts with Auer rods; absence of 
extramedullary disease with partial 
recovery of peripheral blood counts 
(ANC > 0.5 × 109/L [500/µL] and 
platelet count > 50 × 109/L [50 
000/µL]) 
 
Morphologic leukemia-free 
state (MLFS) 
Bone marrow blasts <5%; absence 
of blasts with Auer rods; 
absence of extramedullary disease; 
no hematologic recovery 
required 
Marrow should not merely be 
“aplastic”; at least 200 
cells should be enumerated or 
cellularity should be 
at least 10% 
Partial remission (PR) 
All hematologic criteria of CR; 
decrease of bone marrow blast 
percentage to 5% to 25%; and 
decrease of pretreatment 
bone marrow blast percentage by at 
least 50% 
Especially important in the context 
of phase 1-2 clinical 
trials 
Treatment failure 
 

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Primary refractory disease 
No CR or CRi after 2 courses of 
intensive induction treatment; 
excluding patients with death in 
aplasia or death due to 
indeterminate cause 
Regimens containing higher doses 
of cytarabine are generally 
considered as the best option 
for patients not responding to a first 
cycle of 7+3; the 
likelihood of responding to such 
regimens is lower 
after failure of a first 
Death in aplasia 
Deaths occurring ≥7 d following 
completion of initial treatment 
while cytopenic; with an aplastic or 
hypoplastic bone marrow 
obtained within 7 d of death, 
without evidence of persistent 
leukemia 
 
Death from indeterminate 
cause 
Deaths occurring before completion 
of therapy, or <7 d 
following its completion; or deaths 
occurring ≥7 d following 
completion of initial therapy with 
no blasts in the blood, but no 
bone marrow examination available 
 
Response criteria for clinical trials only 
 
 
Stable disease 
 
 
Absence of CRMRD-, CR, CRi, PR, 
MLFS; and criteria for PD not met 
Period of stable disease should last 
at least 3 mo 
Progressive disease (PD)*,† 
Evidence for an increase in bone 
marrow blast percentage 
and/or increase of absolute blast 
counts in the blood: 
• 
>50% increase in marrow 
blasts over baseline (a 
minimum 15% point 
increase is required in 
cases with <30% blasts at 
baseline; or persistent 
marrow blast percentage of 
>70% over at least 3 mo; 
without at least a 100% 
improvement in ANC to an 
absolute level (>0.5 x 
109/L [500/µL], and/or 
platelet count to >50 x 
109/L [50 000/µL] 
nontransfused); or 
• 
>50% increase in 
peripheral blasts (WBC x 
% blasts) to >25 x 109/L 
(>25 000/µL) (in the 
absence of differentiation 
syndrome)†; or 
Category mainly applies for older 
patient given low intensity or 
single-agent “targeted therapies” in 
clinical trials. 
In general, at least 2 cycles of a 
novel agent should be administered. 
Some protocols may require blast 
increase in 2 consecutive marrow 
assessments at least 4 wk apart; the 
date of progression should then be 
defined as of the first observation 
date. 
Some protocols may allow transient 
addition of hydroxyurea to lower 
blast counts. 
“Progressive disease” is usually 
accompanied by a decline in ANC 
and platelets and increased 
transfusion requirement and decline 
in performance status or increase in 
symptoms. 

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• 
New extramedullary 
disease 
 
Relapse 
Hematologic relapse 
(after CRMRD-, CR, CRi, CRh) 
Bone marrow blasts ≥5%; or 
reappearance of blasts in the 
blood; or development of 
extramedullary disease 
 
Molecular relapse 
(after CRMRD-) 
If studied pretreatment, 
reoccurrence of MRD as assessed 
by 
RT-qPCR or by MFC 
Test applied, sensitivity of the 
assay, and cutoff values used must 
be reported; analyses should be 
done in 
experienced laboratories 
(centralized diagnostics) 
 
Table adapted from Döhner H, et al 20176 
 
Footnotes 
ANC, absolute neutrophil count; IDH, isocitrate dehydrogenase; MLFS, morphologic leukemia-free state; WBC, white 
blood cell. 
*The authors acknowledge that this new provisional category is arbitrarily defined; the category aims at harmonizing 
the various definitions used in different clinical trials. 
†Certain targeted therapies, for example, those inhibiting mutant IDH proteins, may cause a differentiation syndrome, 
that is, a transient increase in the percentage of bone marrow blasts and an absolute increase in blood blasts; in the 
setting of therapy with such compounds, an increase in blasts may not necessarily indicate PD.# In case bone marrow 
aspirate/biopsy is consistent with CRi or better but still a minimal percentage of peripheral blasts is detected, the 
response assessment can be postponed up to 2 weeks and will be based on repeated peripheral blood results and last 
bone marrow aspiration results. 
 

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APPENDIX E: LOCAL LABORATORY PARAMETERS 
 
Clinical Chemistry 
Hematology, including Coagulation* 
Calcium 
Red cell count 
Total protein 
Mean corpuscular volume 
Albumin 
Hemoglobin, free hemoglobin 
Total bilirubin and direct bilirubin 
Hematocrit 
Alanine transaminase (ALT, SGPT) 
Absolute reticulocyte count 
Aspartate transaminase (AST, SGOT) 
Platelet count 
Lactate dehydrogenase (LDH) 
White blood cells 
Alkaline phosphatase 
Leukocyte differential count (% or absolute) 
Glucose (random) 
International normalized ratio or prothrombin time 
Sodium 
Activated partial thromboplastin time  
Potassium 
Fibrinogen 
Bicarbonate 
D-dimer 
Chloride 
Urinalysis  
Magnesium 
Glucose 
Urea = Blood urea nitrogen 
Protein 
Creatinine 
Bilirubin 
Phosphate 
Ketones 
Uric acid 
Blood 
C-reactive protein 
pH 
Lipid profile 
Specific gravity (microscopic exam when indicated) 
Triglycerides 
HCG (female pre-menopausal patients; at Screening) 
Cholesterol 
FSH (female menopausal patients; at Screening) 
Low-density lipoprotein (LDL) 
 
High-density lipoprotein (HDL) 
 
*Additional coagulation parameters will be performed in patients who develop coagulation 
abnormalities during the study treatment; in these patients, additional parameters and time-points 
for coagulation assessment may be performed as clinically indicated to ensure a comprehensive 
evaluation of coagulation abnormalities. 
 
This is the full testing panel to be carried out by sites; any exceptions due to local testing 
restrictions must be notified to Sponsor to ensure safety assessment is not jeopardized. The lipid 
panel describes the minimum assessments to be tested. Local sites may also report (calculate) other 
parameters as standard, such as very low-density lipoprotein (VLDL) or the cholesterol/HDL 
ratio. 

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APPENDIX F: List of Relevant CYP2D6 Substrates, CYP2D6 Inhibitors, and BCRP 
Inhibitors 
 
INN/General  
Brand name (not exclusive) 
Indication 
CYP2D6: SENSITIVE SUBSTRATES* OR SUBSTRATES WITH NARROW THERAPEUTIC RANGE** 
atomoxetine 
Strattera 
ADHD 
desipramine 
Norpramin 
Depression 
dextromethorphan 
Robitussin 
Cough 
metoprolol 
Lopressor, Toprol 
Beta blocker 
nebivolol 
Bystolic 
Beta blocker 
perphenazine 
same 
Antipsychotic/schizophrenia 
thioridazine 
same 
Antipsychotic/schizophrenia 
tolterodine 
Detrol 
Incontinence  
venlafaxine 
Effexor 
Depression/anxiety 
nortriptyline 
Aventyl 
Depression 
CYP2D6: STRONG INHIBITORS 
bupropion 
Wellbutrin, Zyban 
Smoking cessation/depression 
dacomitinib 
same 
EGFR inhibitor  
ecstasy 
same 
-- 
fluoxetine 
Prozac 
SSRI 
paroxetine 
Paxil 
SSRI 
quinidine 
-- 
Antiarrhythmic  
terbinafine 
Lamisil 
Antifungal (skin) 
CYP2D6: MODERATE INHIBITORS 
AMD070 
-- 
-- 
cinacalcet 
Sensipar 
Calcium reduction 
dronedarone 
Multaq 
Antiarrhythmic 
duloxetine 
Cymbalta 
Nerve pain/depression 
eliglustat 
Cerdelga 
Gaucher disease 
mirabegron 
Myrbetriq 
Overactive bladder 
moclobemide 
Amira 
Depression/anxiety 
 
 
 
tipranavir/ritonavir 
-- 
HIV 
fluvoxamine 
Luvox 
Obsessive-compulsive disorder 
cimetidine 
Tagamet 
Histamine H2 receptor antagonist 
BCRP: INHIBITORS  
cyclosporine 
Sandimmune 
Immunosuppressant 
elacridar (GF120918) 
-- 
-- 
eltrombopag 
Promacta, Revolade 
Thrombocytopenia 
gefitinib 
Iressa 
EGFR inhibitor 
Curcumin 
- 
- 
isavuconazole 
Cresembra 
Antifungal (systemic) 
*  Sensitive CYP substrates refers to drugs whose plasma AUC values have been shown to increase 5-fold or higher when co-
administered with a known CYP inhibitor.  
** CYP substrates with narrow therapeutic range refers to drugs whose exposure-response relationship indicates that small increases 
in their exposure levels by the concomitant use of CYP inhibitors may lead to serious safety concerns (e.g., Torsades de Pointes). 
CYP2D6 substrates and inhibitors obtained from the University of Washington, School of Pharmacy Drug Interaction 
Database Program (updated July 2016); 
BCRP inhibitors obtained from the FDA website;  

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Isavuconazole added by the Sponsor, being its potential use relevant to the study population for antifungal prohylaxis 
and its potential DDI with IMP. 

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