Conditions: Recurrent Adult Acute Myeloid Leukemia Acute Myeloid Leukemia, in Relapse
Keywords: Acute Myeloid Leukemia AML Relapsed Refractory MEN1112 Monoclonal antibody
Allocation: NA | Intervention model: SEQUENTIAL
Enrollment: 71
Healthy volunteers: no

Brief summary:
The purpose of this study is to assess the safety of MEN1112, given as intravenous infusion, in patients with relapsed or refractory AML. Pharmacokinetics, clinical activity and potential immunogenicity of MEN1112 will be evaluated as well.

Detailed description:
This trial is designed as an open label, non randomised, dose escalation and cohort expansion, first administration to human study to be conducted in approximately 20 European sites. The study is aiming to identify the Dose Limiting Toxicity (DLT) and Maximum Tolerated Dose (MTD), to assess the pharmacokinetics and to determine the clinical activity and potential immunogenicity of MEN1112, administered as IV infusion for two 21-day cycles.

Approximately 100 male and female ≥ 18 years-old patients, with a documented diagnosis of relapsed or refractory AML (not M3 FAB subtype), will be treated in the study, which consists of two steps.

Step 1 is the dose escalation phase according to a 3+3 patients cohort design. Incremental mg/Kg doses will be tested. Briefly, MEN1112 doses are to be administered to 3 patients; if no DLT is observed in a cohort of 3 DLT evaluable patients at a given dose level, the next cohort of 3 new patients will be treated with the next higher dose. In case of DLT occurrence by one of the three patients at any dose, the cohort will be expanded to 6 DLT evaluable patients at the same dose level. If two or more patients at a given dose level exhibit DLT, the dose escalation phase will be concluded as the MTD will be identified as one dose level below the one at which ≥ 2 DLT out of 6 treated patients occur.

Step 2 is the cohort expansion phase which will include patients treated at the MTD or the maximum dose level judged to be tolerable.

In each study Step, patients will be given two induction cycles of MEN1112 followed by a four-week End of Treatment period and a Follow-up period. In Step 1 and Step 2, DLT and MTD will be assessed when MEN1112 is given as a 'one shot' infusion (first group of patients) for all doses as well as a 'ramp up' administration to be infused in 3 days for the first two doses in Cycle 1 (second group of patients).

Along the study period, adverse events, changes in hematology/serum biochemistry parameters and bone marrow treatment response will represent the major clinical findings to be monitored on regular basis. The individual experimental clinical phase will last up to 6 months (except for female patients of childbearing potential that will undergo monthly pregnancy test until 6 months from the last study drug administration) encompassing approx. 40 planned visits at site, including Screening,Treatment, End of Treatment, Follow-up period and the End of Study visit.

Arms:
arm 1: Dose escalation will occur using a standard 3+3 dose escalation approach, beginning in dose level I with dose cohorts and rules for escalation

Interventions: intervention 1: MEN1112
Intervention descriptions: intervention 1: Intravenous infusion of MEN1112 pro/Kg body weight dose will be administered for two 21-day cycles; MEN1112 dose is administered as' one shot infusion' (first group of patients) and as a dose to be infused in 3 days for the first two doses in Cycle 1 (second group of patients).

Two treatment cycles will be followed by a 4-week End of Treatment Period and a Follow-up period. The individual treatment/observation period is six months (except for female patients of childbearing potential that will undergo monthly pregnancy test until 6 months from the last study drug administration).

Protocol document:
Prot_SAP_000.pdf: 
NCT: 02353143
 
Date: 04 November 2019 






Clinical Trial Protocol 
EudraCT No.:  2014-002433-59 
 
Study Code: ARMY-1 
 Final Version 7.0, 04 November 2019 
 
 
 
 
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PRINCIPAL INVESTIGATOR’S STATEMENT 
 
My signature below documents my agreement with the contents of this clinical trial protocol titled 
“First in man study with MEN1112, a CD157 targeted monoclonal antibody, in relapsed or 
refractory Acute Myeloid Leukemia” - Final Version 7.0, 04 November 2019 - with regard to the 
execution of the study and the required documentation/data collection. I agree to comply with this 
clinical trial protocol in its entirety and with the International Conference of Harmonisation (ICH) 
guidelines for Good Clinical Practice (GCP). 
 
Principal Investigator  
Signature 
Date 
............................................................. ............................................................. .............................. 
 (printed name) 
 
 
 
 


Clinical Trial Protocol 
EudraCT No.:  2014-002433-59 
 
Study Code: ARMY-1 
 Final Version 7.0, 04 November 2019 
 
 
 
 
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2. PROTOCOL SYNOPSIS 
 
Study Title 
 
Sponsor Code  
Nick name/Acronym 
First in man study with MEN1112, a CD157 targeted monoclonal 
antibody, in relapsed or refractory Acute Myeloid Leukemia. 
ARMY-1 
ARMY - Anti CD157 Receptor Monoclonal AntibodY 
Phase 
Phase I 
Indication 
Acute Myeloid Leukemia (AML). 
No. of sites & countries 
Approximately 20 EU sites. 
Investigational Medicinal 
Product 
MEN1112 (5.0 mg/mL) concentrate for solution for infusion. 
Design 
(see also § 2.1) 
Open label, 3+3 dose escalation and cohort expansion, multicentre, 
phase I study. 
Treatment 
(see also § 2.1) 
Step 1 (dose escalation phase): In protocol versions from 1.0 to 4.1 
n=3 Dose Limiting Toxicity (DLT) evaluable patients per cohort 
(expanded to n=6 DLT evaluable patients in case of DLT occurrence, 
with the exception of cohort 0.3 mg/kg which was expanded to n=6 
DLT evaluable patients regardless of DLT occurrence) were treated 
with MEN1112 at escalating doses of 0.1, 0.3, 0.6, 1.0, 1.7, and 2.5 
mg/kg using “one-shot” infusions. 
Starting from protocol version 6.1/6.2, n=3 Dose Limiting Toxicity 
(DLT) evaluable patients per cohort (expanded to n=6 DLT evaluable 
patients in case of DLT occurrence) will be treated with MEN1112 at 
escalating doses of 1.7, 2.0, 3.0, 5.0 mg/kg per each dose cohort 
using a modified schedule of administration that will include a 
“ramp-up” approach at Cycle 1. Additional intermediate dose levels 
may be explored, under a 3+3 design, upon recommendation of the 
independent Data Safety Monitoring Board (iDSMB) that will be 
appointed to guide dose escalation decisions in place of the Cohort 
Review Committee (CRC) that was appointed for this role up to 
Protocol Version 4.1. 
 
 
 


Clinical Trial Protocol 
EudraCT No.:  2014-002433-59 
 
Study Code: ARMY-1 
 Final Version 7.0, 04 November 2019 
 
 
 
 
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Step 2 (cohort expansion phase): Under Protocol Version 4.1, two 
patients experienced DLTs at the dose level of 2.5 mg/kg using the 
“one-shot” schedule of administration in Cycle 1. Therefore, the 1.7 
mg/kg dose level was defined as the maximum tolerated dose (MTD) 
for the schedule of administration encompassing the “one-shot” 
infusion since Cycle 1; as a consequence, the expansion phase was 
opened to enrol up to 25 patients with MEN1112 given as “one-shot” 
infusions since Cycle 1. 
Starting from protocol version 6.1/6.2, up to 30 patients will be 
treated with MEN1112 given at the MTD identified in Step 1 using 
the “ramp-up” approach during Cycle 1. The iDMSB, already 
implemented for Step 1, will also be appointed to assess the data 
collected during the Step 2 of the study. 
Up to Protocol Version 4.1, MEN1112 was administered by 
intravenous “one-shot” weekly infusions for two 21-day cycles, 
followed by “one-shot” monthly infusions in patients demonstrating 
clinical benefit (as per Investigator’s judgement) as long as such 
benefit was maintained. Starting from protocol version 6.1/6.2, 
MEN1112 will be administered for two 21-day cycles; the first two 
infusions of Cycle 1 will be given using a “3-day ramp-up” schedule 
of administration, i.e. the complete MEN1112 dose will be split in 
three days. Starting from the third infusion of Cycle 1 onwards, 
MEN1112 will be administered as “one-shot” infusions. The 
treatment plan by dose level will be therefore as following: 
DOSE LEVEL 
CYCLE 1  
CYCLE 2 
1.7 mg/kg 
Visit 1/Day 1: 0.1 mg/kg  
Visit 2/Day 2: 0.6 mg/kg 
Visit 3/Day 3: 1.0 mg/kg 
Visit 8/Day 8: 0.1 mg/kg 
Visit 9/Day 9: 0.6 mg/kg  
Visit 10/Day 10: 1.0 mg/kg 
Visit 12/Day 15: 1.7 mg/kg 
Visit 16/Day 22: 1.7 mg/kg 
Visit 20/Day 29: 1.7 mg/kg 
Visit 24/Day 36: 1.7 mg/kg 






Clinical Trial Protocol 
EudraCT No.:  2014-002433-59 
 
Study Code: ARMY-1 
 Final Version 7.0, 04 November 2019 
 
 
 
 
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Working Group (IWG criteria, 2003) following at least 1 cycle 
of cytotoxic chemotherapy (or hypomethylating agents if 
unsuitable for cytotoxic chemotherapy) and unlikely, as per 
Investigator’s judgement, to achieve CR/CRi with further 
cytotoxic chemotherapy (or hypomethylating agents if 
unsuitable for cytotoxic chemotherapy). 
3. White Blood Cells (WBC) count ≤ 10 x 109/L at Visit 1/ Day 
1; hydroxyurea is allowed to lower WBC count. 
4. Eastern Cooperative Oncology Group (ECOG) performance 
status of 0 to 2 at Visit 1/Day 1. 
5. Life expectancy of at least 2 months. 
6. Adequate renal and hepatic laboratory assessments: 
- 
Aspartate 
aminotransferase 
(AST), 
alanine 
aminotransferase (ALT) and alkaline phosphatase (ALP) 
≤3.0 × Upper Limit of Normal (ULN), unless considered 
due to leukemic organ involvement. 
- 
Total Bilirubin ≤2.0 × ULN. 
- 
Serum creatinine ≤2.0 × ULN. 
7. A female of childbearing potential may be enrolled providing 
she: 
− has a negative pregnancy test during screening period and  
− is routinely using an effective method of birth control that 
both results in a Pearl index < 1 and is considered highly 
effective as defined by the Clinical Trial Facilitation Group 
(e.g. combined estrogen and progestogen containing 
hormonal contraception, associated with inhibition of 
ovulation, intrauterine device, total sexual abstinence or  
bilateral tubal occlusion) until 6 months from the last study 
drug administration 
− undergoes a monthly pregnancy test until 6 months from the 
last study drug administration. 
8. Able to give written informed consent before any study related 
procedure. 
NOTE: Inclusion criteria will be evaluated during the Screening 


Clinical Trial Protocol 
EudraCT No.:  2014-002433-59 
 
Study Code: ARMY-1 
 Final Version 7.0, 04 November 2019 
 
 
 
 
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Period, with the exception of inclusion criteria 3 and 4, which will be 
evaluated at Visit 1/Day 1; inclusion criteria 5 and 6 will be re-
evaluated prior to the first study drug administration (Visit 1/Day 1). 
Exclusion criteria 
Patients will not be eligible to participate in the study if they meet 
ANY of the following exclusion criteria: 
1. Acute promyelocytic leukaemia (French-American-British 
[FAB] M3 classification).  
2. Active central nervous system involvement. 
3. Haematopoietic stem cell transplantation (HSCT) performed 
within 3 months prior to Screening Period. Patients with prior 
allogeneic HSCT performed more than 3 months prior to 
Screening Period are eligible with Medical Monitor approval. 
4. Active infection requiring intravenous antibiotics. 
5. Life-threatening illnesses other than AML, uncontrolled 
medical conditions or organ system dysfunction which, in the 
investigator's opinion, could compromise the patient's safety 
or interfere with the patient’s ability to comply with the study 
activities. 
6. Anti-tumour therapy within 14 days of study Visit 1/Day 1, 
excluding hydroxyurea. 
7. Prior participation in an investigational study (procedure or 
device) within 21 days of study Visit 1/Day 1. 
8. Major surgery within 28 days of study Visit 1/Day 1. 
9. Radiotherapy within 28 days prior to study Visit 1/Day 1 or 
scheduled along the study conduct. 
10. Known history of human immunodeficiency virus (HIV) or 
active infection with hepatitis C virus (HCV) or hepatitis B 
virus (HBV). 
11. Known hypersensitivity to MEN1112 excipients.   
12. Other active malignancies. History of malignancy in the last 
12 months (except basal cell or squamous cell skin cancer or 
carcinoma in situ of the cervix or breast or non-melanoma 
skin cancer). 
13. Pregnant or breast-feeding women. 


Clinical Trial Protocol 
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Study Code: ARMY-1 
 Final Version 7.0, 04 November 2019 
 
 
 
 
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NOTE: Exclusion criteria will be evaluated during the Screening 
Period, with the exception of exclusion criteria 6, 7, 8 and 9, which 
will be evaluated at Visit 1/Day 1; exclusion criteria 4 and 5 will be 
re-evaluated prior to the first study drug administration (Visit 1/Day 
1). 
Study procedures and 
assessments 
(see also § 2.2) 
PRIOR to any study procedures, written Informed Consent shall be 
obtained by the patient. 
Screening Period (Day -7 to 0) 
 Check of Inclusion/Exclusion Criteria 
 Demographic data collection 
 Medical and medication general history 
 AML history, i.e. date of onset of AML, relapsed or 
refractory status following the last AML treatment, de 
novo or secondary AML status, number and category of 
previous AML treatments (including autologous and 
allogeneic HSCT), and duration of last CR (for relapsed 
patients), and disease features when available (i.e. AML 
karyotype, NPM1 and/or FLT3-ITD mutational status, 
FAB subtype)  
 Physical examination, including vital signs (i.e. blood 
pressure [BP], heart rate [HR], breathing rate [BR], body 
temperature [T]) 
 Weight measurement 
 Performance Status (PS) evaluation  
 12-lead Electrocardiogram (ECG) 
 Blood sampling and urine collection for safety lab tests, 
including pregnancy test (if applicable) 
 Blood sampling for anti-HIV antibodies, anti- Hepatitis B 
core Antigen (anti-HBcAg) antibodies, Hepatitis B Virus-
Deoxyribonucleic acid (HBV-DNA), Hepatitis C Virus-
Ribonucleic acid (HCV-RNA) 
 
 
 
 
 




Clinical Trial Protocol 
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 Final Version 7.0, 04 November 2019 
 
 
 
 
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 Tumour lysis syndrome (TLS) risk assessment (see 
Appendix I: TLS Manual for Investigator) 
 TLS prophylaxis (see Appendix I: TLS Manual for 
Investigator) 
 Premedication (see §8.4.2)  
 
Study drug administration 
 Study drug administration, given as a 6h infusion with 
constant infusion rate 
 Blood sampling for safety lab test at following time points 
after start of infusion: 2h, 4h, 8h, 12h 
 Vital signs every 15 minutes during the first hour of study 
drug administration and then at the same time points of  
blood sampling for safety lab test 
 12-lead ECG at the end of infusion 
 Blood sampling for PK 
 (at the end of 
infusion and 6h after the end of infusion) 
 Recording of AEs and change in concomitant medications 
 
Visit 2/Day 2 (one day after the completion of Visit 1) and Visit 
3/Day 3 (one day after the completion of Visit 2) 
Prior to study drug administration 
 Physical examination, including vital signs 
 PS evaluation 
 12-lead ECG 
 Blood sampling for safety lab test 
 Blood sampling for PK 
 (pre-infusion) 
 Recording of AEs and change in concomitant medications  
 TLS prophylaxis (see Appendix I: TLS Manual for 
Investigator) 
 Premedication (see §8.4.2)  
Study drug administration 
 Study drug administration, given as 6h infusion with 
constant infusion rate 


Clinical Trial Protocol 
EudraCT No.:  2014-002433-59 
 
Study Code: ARMY-1 
 Final Version 7.0, 04 November 2019 
 
 
 
 
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 Blood sampling for safety lab test at the following time 
points after start of infusion: 2h, 4h, 8h, 12h 
 Vital signs every 15 minutes during the first hour of study 
drug administration and then at the same time points of  
blood sampling for safety lab test 
 12-lead ECG at the end of infusion 
 Urine collection at the end of infusion (ONLY at Visit 
3/Day 3) 
 Blood sampling for PK 
 at the end of 
infusion, 6h after the end of infusion (ONLY at Visit 
2/Day 2), 14h after the end of infusion (ONLY at Visit 
3/Day 3) 
 Recording of AEs and change in concomitant medications 
 
Visit 4/Day 4 one day after the completion of the entire first 
“ramp-up” 
 Physical examination, including vital signs 
 PS evaluation 
 Blood sampling for safety lab test  
 
 
 Blood sampling for PK 
 24h after the 
end of last “ramp-up” dosing infusion 
 Bone marrow aspirate for morphologic assessment, 
 
 
  
 Recording of AEs and change in concomitant medications 
 
Visit 5-6/Day 5-6, at one and two days after Visit 4, respectively 
 Blood sampling for PK 
 (44h and 68h 
after the end of last “ramp-up” dosing infusion) 
 Recording of AEs and change in concomitant medications 
 
Visit 8/Day 8 (five days after the completion of Visit 3), Visit 
9/Day 9 (one day after the completion of Visit 8) and Visit 10/Day 




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Visit 12/Day 15 (five days after Visit 10), first “one-shot” infusion 
Prior to study drug administration 
 Physical examination, including vital signs 
 Weight measurement  
 PS evaluation 
 Blood sampling for safety lab test  
NOTE: Check that WBC count is ≤ 10 x 109/L; 
hydroyxurea is allowed to lower WBC count. 
 Blood sampling for PK 
 (pre-infusion) 
 Recording of AEs and change in concomitant medications  
 TLS prophylaxis (see Appendix I: TLS Manual for 
Investigator) 
 Premedication (see §8.4.2)  
Study drug administration 
 Study drug administration, given as a 6h infusion with 
constant infusion rate 
 Blood sampling for safety lab test at the following time 
points after start of infusion: 2h, 4h, 8h, 12h 
 Vital signs every 15 minutes during the first hour of study 
drug administration, after then at the same time points of 
blood sampling for safety lab test 
 Blood sampling for PK 
 (at the end of 
infusion) 
 Recording of AEs and change in concomitant medications  
 
Visit 13-15/Day 16-18, one, two and three days after Visit 12 
 Physical examination including vital signs 
 PS evaluation 
 Blood sampling for safety lab test (at 24h, 48h and 72 h 
after start of infusion) 
 Recording of AEs and change in concomitant medications 
 
CYCLE 2  


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EudraCT No.:  2014-002433-59 
 
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Visit 16/Day 22, seven days after Visit 12 
Prior to study drug administration 
 Physical examination including vital signs  
 Weight measurement 
 PS evaluation  
 Blood sampling for safety lab test 
 
  
 Blood sampling for PK 
 (pre-infusion) 
 Bone marrow aspirate for morphologic assessment, 
 
 
 
 Recording of AEs and change in concomitant medications  
 Premedication (see §8.4.2)  
Study drug administration 
 Study drug administration, given as a 6h infusion with 
constant infusion rate 
 Vital signs every 15 minutes during the first hour  of study 
drug administration and at 15 minutes after end of 
infusion 
 Blood sampling for PK 
 (at the end of 
infusion) 
 Recording of AEs and change in concomitant medications 
 
Visit 17-19/Day 23-25, one, two and three days after the 
completion of Visit 16, respectively 
 Physical examination including vital signs 
 PS evaluation 
 Blood sampling for safety lab test  
 Recording of AEs and change in concomitant medications 
 
Visit 20/Day 29, seven days after the completion of Visit 16 
Prior to study drug administration 
 Physical examination including vital signs  
 Weight measurement 


Clinical Trial Protocol 
EudraCT No.:  2014-002433-59 
 
Study Code: ARMY-1 
 Final Version 7.0, 04 November 2019 
 
 
 
 
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 PS evaluation  
 Blood sampling for safety lab test 
 Blood sampling for PK 
 (pre-infusion) 
 Recording of AEs and change in concomitant medications  
 Premedication (see §8.4.2)  
Study drug administration 
 Study drug administration, given as a 6h infusion with 
constant infusion rate 
 Vital signs every 15 minutes during the first hour of study 
drug administration and at 15 minutes after end of 
infusion 
 Blood sampling for PK 
 at the end of 
infusion 
 Recording of AEs and change in concomitant medications 
 
Visit 21-23/Day 30-32, one, two and three days after the 
completion of Visit 20, respectively) 
 Physical examination including vital signs 
 PS evaluation 
 Blood sampling for safety lab test  
 Recording of AEs and change in concomitant medications 
 
Visit 24/Day 36, seven days after the completion of Visit 20 
Prior to study drug administration 
 Physical examination including vital signs  
 Weight measurement 
 PS evaluation  
 Blood sampling for safety lab test  
 Blood sampling for PK 
 (pre-infusion) 
 Recording of AEs and change in concomitant medications 
 Premedication (see §8.4.2) 
Study drug administration 
 Study drug administration, given as a 6h infusion with 
constant infusion rate 


Clinical Trial Protocol 
EudraCT No.:  2014-002433-59 
 
Study Code: ARMY-1 
 Final Version 7.0, 04 November 2019 
 
 
 
 
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 Vital signs every 15 minutes during the first hour of study 
drug administration and at 15 minutes after end of 
infusion 
 Blood sampling for PK 
 (at the end of 
infusion and at 1h and 6h after the end of infusion) 
 Recording of AEs and change in concomitant medications 
 
Visit 25-27/Day 37-39, one, two and three days after the 
completion of Visit 24, respectively 
 Physical examination including vital signs 
 PS evaluation 
 Blood sampling for safety lab test including pregnancy 
test (only at Visit 27, if applicable) 
 Blood sampling for PK 
 (24h, 48h and 
72h after the end of infusion) 
 Recording of AEs and change in concomitant medications 
 
Visit 28-29/Day 40-41, one and two days after Visit 27, 
respectively 
 Blood sampling for PK 
 (96h and 120h  
after the end of infusion) 
 Recording of AEs and change in concomitant medications 
 
Visit 30/Day 42, the day after Visit 29 
 Physical examination including vital signs 
 PS evaluation 
 Blood sampling for safety lab test  
 
 
 Blood sampling for PK 
 (144h after the 
end of infusion) 
 Bone marrow aspirate for morphologic assessment, 
 
 
 
 Recording of AEs and change in concomitant medications 


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 Final Version 7.0, 04 November 2019 
 
 
 
 
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NOTES:  
• During Cycle 1, under the “ramp-up” dosing scheme, an 
administration visit will encompass the three “ramp-up” 
infusions (to be split in up to four days, in case of specific 
infusion-related toxicities, see §8.4.7) to complete the 
administration of MEN1112. 
• Prior to start MEN1112 infusion, results of the safety lab tests 
(including hepatic function tests) should be duly checked by 
the Investigator to confirm that eligibility criteria are met 
(Visit 1/Day 1, prior of infusion) or no treatment 
withdrawal/dose interruption criteria are met (any subsequent 
infusion).  
• One of the following adjustments is allowed: 
o +1 day for any “ramp-up” administration visit in case 
of WBC count >10x109/L on the first day of such 
visit, in order to lower the WBC count using 
hydroxyurea. This is applicable also to the “one-shot” 
infusion visit of Cycle 1 (Visit 12/Day 15). 
o + 1 day for each study drug administration visit (i.e. 
first “ramp-up” and “one-shot” administration visit).  
• In case of study visit re-schedule due to infusion related 
toxicities (see §8.4.7), WBC count recovery, or any other 
reasons, the interval of 5 days (Cycle 1) or 7 days (Cycle 2) 
between the end of any study drug administration visit and 
the start of the following one should be guaranteed. 
• Moreover, at each infusion during the study conduct, in case 
of interruption due to drug-related toxicities: 
o The infusion duration will be prolonged 
 
 using a constant infusion rate; 
this infusion duration will then be applied to every 
subsequent infusions. 
o In case the interruption lasts >24 hours, the safety 
assessments will be repeated when the infusion is 
resumed according to the time-points scheduled for 


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the original visit. 
o If any interruption occurs during Cycle 1 and the 3rd 
infusion of Cycle 2, blood sampling for PK 
 
 will also be taken at the time of each 
infusion interruption and just before each infusion 
resumption. 
• During Cycle 1, under the “ramp-up” dosing scheme, prior to 
start each administration visit WBC count should be ≤ 10 x 
109/L. In case the “ramp-up” administration visit is split due 
to infusion-related toxicities, WBC count should be ≤ 10 x 
109/L also prior to start the second part of the “ramp-up” 
administration visit.  
• During Cycle 1, patients must be treated and monitored as in-
patients up to at least 24 hours after each study drug 
administration visit. 
 
 
 
 
  
• As the consumption of fibrinogen is a marker of disseminated 
intravascular coagulation, the investigator shall carefully 
monitor the fibrinogen decrease rate and consider prompt 
treatment with fresh frozen plasma even in the presence of 
fibrinogen values within normal range. 
 
END of TREATMENT 
Visit 31-34/Day 43/50/57/64, one week, two weeks, three weeks 
and four weeks after Visit 24, respectively 
 Blood sampling for PK 
 
 Blood sampling for immunogenicity assessment (ONLY 
at Visit 34) 
 Recording of AEs and change in concomitant medications 
NOTE: During the End of Treatment, a time-frame of + 1 day is 
allowed at any visit, however the scheduled time of the following 


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visits should be maintained. 
 
FOLLOW-UP PERIOD 
Visit 35-38/Day 65/85/121/149, one, twenty-nine, fifty-seven and 
eighty-five days after Visit 34, respectively 
 Physical examination, including vital signs  
 PS evaluation 
 Blood sampling for safety lab test including pregnancy 
test (if applicable) 
 Bone marrow aspirate for morphologic assessment on 
Visit 35 and Visit 37 only in patients showing peripheral 
blood labs consistent with CR/CRi/ Partial Remission 
(PR) 
 Recording of AEs and change in concomitant medications 
NOTES:  
- 
To serve the best interest of the patients, for those 
achieving at least a partial remission, the Sponsor 
commits to consider providing MEN1112 to allow the 
prosecution of the infusions at the frequency 
recommended by the iDSMB on an individual basis 
and after discussion with the treating Investigator and 
the Medical Monitor. In this case, premedication and 
safety assessments will resemble those already 
described for study drug administration visits, unless 
differently advised by the iDSMB. 
- 
During Follow-up Period, a time-frame of + 2 days 
each is allowed at any visit, however the scheduled 
time of the following visits should be maintained. 
 
END OF STUDY 
End of Study Visit (180 days after Visit 1/Day 1) 
 Physical examination and vital signs 
 PS evaluation 
 Blood sampling for safety lab test including pregnancy 


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Study Code: ARMY-1 
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test (if applicable) 
 
 
 Bone marrow aspirate for morphologic assessment, 
 
 
  
 Recording of AEs and change in concomitant medications 
NOTES:  
• 
At the End of Study Visit, a time-frame of + 5 days is 
allowed. 
• All patients shall undergo the End of Study Visit at the 
scheduled date or at the time of study withdrawal. 
Unscheduled assessments showing disease progression 
and leading to patient’s withdrawal can replace the End of 
Study Visit provided that all assessment/procedures 
scheduled for this visit are completed. 
• In case the patient is discontinued from the study within 
the treatment period, the End of Study Visit bone marrow 
aspirate is highly recommended to be performed. 
 
Blood safety lab tests will be performed at the local laboratory and 
will 
include: 
albumin, 
alkaline 
phosphatase, 
Alanine 
Aminotransferase (ALT), AST, Blood Urea Nitrogen (BUN)/Urea, 
serum creatinine, uric acid, sodium, chloride, potassium, phosphorus, 
calcium, 
total 
bilirubin, 
direct 
bilirubin, 
Gamma-Glutamyl 
Transpeptidase (GGT), glucose, Lactate Dehydrogenase (LDH), total 
proteins, prothrombin time and/or prothrombin activity, International 
Normalized Ratio (INR), partial thromboplastin time, fibrinogen, D-
dimer, amylase, platelets, Red Blood Cells (RBC), Mean Corpuscular 
Volume (MCV), haemoglobin, haematocrit, WBC with differential 
(absolute and %) and Beta Human Chorionic Gonadotropine (ß-
HCG) (if applicable).  
Urinalysis will be performed at the local laboratory and will include: 
pH, density, proteins, glucose, ketones, nitrite, RBC, WBC, epithelial 
cells, casts, bacteria, yeast and crystals. 


Clinical Trial Protocol 
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PK 
 will be performed centrally (see § 10.1.2 for 
details) and will include pharmacokinetic analysis 
 
 
 
 
GENERAL NOTES: 
• 
For each safety lab test, blood sampling for PK 
 
(except for those to be collected at the end of infusion) 
and for vital signs, a window of +/- 5% of the required time 
interval is allowed. 
• The total dose calculated for the first study drug administration 
can be applied also for the following ones providing that actual 
patient’s weight is within ±10% of the weight measured prior 
to the first study drug administration; otherwise, the total dose 
to be given shall be calculated based on the weight measured 
at the corresponding visit.  
• 
Any effort aimed at preserving patient’s safety and/or further 
clarifying an adverse event is recommended, including 
unscheduled assessments (e.g. additional safety lab sampling, 
additional 
safety 
lab 
parameters). 
The 
anonymized 
documentation of the above unscheduled assessment shall be 
then provided to the Sponsor. 
• 
It is strongly recommended not to start the treatment on the 
day prior to -or on- weekends/holidays, unless the treatment is 
deemed not deferrable by the Investigator in view of the 
specific patient’s clinical situation. In such case, the site shall 
anyway guarantee the actual availability of site personnel as 
well as the actual feasibility of ALL study procedures as 
required by the protocol. 
Study Endpoints 
 
 
 
 
Primary Endpoints 
• Identification of DLT defined as an adverse event occurring 
during the first treatment cycle, judged to be related to 
MEN1112 and meeting any of the following criteria:  
• Grade 3 non-haematological toxicity lasting more 


Clinical Trial Protocol 
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than 7 days  
• Grade ≥ 4 non-haematological toxicity.  
Note: Common complications of AML (in particular infections, 
bleedings, fatigue) will not contribute to DLT assessment.  
 Identification of MTD defined as one dose level below the 
Maximum Administered Dose (i.e. one dose level below the 
one at which ≥ 2 DLTs out of 6 treated patients occur). 
Secondary Endpoints 
 Complete remission (CR) rate at any time point, where CR is 
defined 
as: 
bone 
marrow 
blasts 
<5%, 
absence 
of 
extramedullary disease, absolute neutrophil count >1 x 109/L 
and platelet count > 100 x 109/L. 
 Composite complete remission (CRc) rate at any time point, 
defined as the proportion of patients having either CR or CRi  
(where CRi is defined as: all criteria for CR except residual 
thrombocytopenia [platelets <100 x 109/L] and/or neutropenia 
[absolute neutrophil count <1 x 109/L]). 
 Best response rate, defined as the best observed response at 
any time point between CR, CRi and partial remission ([PR]: 
all haematological criteria for CR with bone marrow blasts 5-
25% and decrease of pre-treatment bone marrow blast 
percentage by at least 50%). 
 Duration of CRc: number of days between the date of CR/CRi  
achievement and the date of the last assessment confirming 
CR/CRi. 
 Overall Survival (OS), defined as the number of days between 
the first study drug administration and death from any cause. 
 Correlation of baseline characteristics with clinical activity of 
MEN1112. 
 
 
 
 
 
 
 




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that the patients no-DLT evaluable during the dose escalation phase 
will be replaced, and assuming a drop-out rate of 30%, up to 
approximately 60 patients will be treated with MEN1112. This 
number might be higher in case additional intermediate dose levels 
will be investigated.  
Analysis Populations 
 Safety population: all patients receiving study drug. 
 DLT population:  
 
 
 
 
 
 
 
 
 
 
 
 
  
Starting from protocol version 6.1/6.2 and following 
amendments: 
- 
All patients receiving at least 80% of the scheduled study 
drug administration during the first treatment cycle and with 
a safety follow-up of at least 6 days after the last 
administered dose or having experienced a DLT.  
 Efficacy population: all patients completing the first treatment 
cycle and having a post-cycle peripheral blood lab test and bone 
marrow aspirate.  
 PP population: all patients of the efficacy population excluding 
patients who experience major protocol violation(s). 
 PK population: all patients receiving the study treatment and 
with reliable drug assay data relevant for the PK parameter of 
interest. 


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Statistical analysis 
All study variables (with the exception of PK variables) will be 
presented by dose-cohort and overall, by using the appropriate 
descriptive statistics according to the variable nature, unless 
otherwise specified: 
 Continuous variables: number of non-missing observations, 
arithmetic mean, standard deviation (SD), minimum, median, 
maximum. 
 Categorical variables: number of non-missing observations and 
column percentages (N, %). 
 Time to event variables: number of non-missing observations, 
number and percentage of censored observations, 1st quartile, 
median and its 95% Confidence Interval (CI), 3rd quartile, 
Kaplan-Meier survival curves and event rate every 28 days. 
 
The behaviour over time of study variables will be summarised by 
treatment cohort and overall as follows: 
 Continuous variables: descriptive statistics for each time point and 
for the absolute/percentage differences to baseline.  
 Discrete variables: descriptive statistics for each time point and 
shift tables to baseline. 
 
Pharmacokinetic Analysis 
The PK analysis will be run on the PK population. All PK variables 
(i.e. serum concentrations and parameters) will be summarized by 
cohort using the following descriptive statistics: 
• Number of non-missing observations (N) 
• Arithmetic mean and its 90% CI, SD, coefficient of variation 
(CV%) and standard error (SE)  
• Geometric mean (GM) and its 90% CI and GM CV%  
• Minimum, median, maximum  
The concentration of MEN1112 will be summarized for each scheduled 
sampling time point using descriptive statistics. Individual serum 
concentration data versus time will be presented in a data listing and 
visualized as individual concentration-time plots. 


Clinical Trial Protocol 
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Clinical Trial Protocol 
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2.1 
SCHEMATIC STUDY DESIGN  
 
 
 
 
 
 
Study treatment outline 
 
Starting from protocol version 6.1/6.2, MEN1112 will be administered for two 21-day cycles; the first two infusions of 
Cycle 1 will be given using a “3-day ramp-up” schedule of administration, i.e. the complete MEN1112 dose will be 
split in three days. Starting from the third infusion of Cycle 1 onwards, MEN1112 will be administered as “one-shot” 
infusion: 
 
 
DX= Day of treatment administration or follow-up 
VY= Visit on Day X (example V8 on Day 8 of treatment administration) 


Clinical Trial Protocol 
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                                     Final Version 7.0, 04 November 2019 
 
 
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2.2 
STUDY FLOW-CHART 
 
 
Prior to any study procedures, written informed consent shall be obtained by the patient. 
 
 
PROCEDURE 
STUDY VISITS/DAYS 
Screening  
Period 
Day -7 to 
Day 0 
TREATMENT PHASE - CYCLE 1* 
TREATMENT PHASE - CYCLE 2* 
END OF 
TREATMENT ** 
FOLLOW-UP 
PERIOD*** 
End of 
Study**** 
Visit 
1 
Day 
1 
Visit 
2-3 
Day 
2-3 
Visit 
4 
Day 
4 
Visit5-6 
Day 5-6 
Visit 
8-10  
Day 
8-10 
Visit 
11  
Day 
11 
Visit 
12 
Day 
15 
Visit 
13-
15 
Day 
16-
18 
Visit 
16 
Day 
22 
Visit 
17-19 
Day 
23-25 
Visit 
20 
Day 
29 
Visit 
21-23 
Day 
30-32 
Visit 
24 
Day 
36 
Visit 
25-27 
Day 
37-39 
Visit 
28-29 
Day 
40-41 
Visit 30 
Day 42 
Visit 31-34 
Day 43/50/57/64 
Visit 35-38 
Day 65/85/121/149 
EoS Visit 
Incl./Excl. 
criteria 
Xa 
Xa 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history 
and AML 
history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical 
examination 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
X 
X 
PS evaluation b 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
X 
X 
Vital signs  
X 
Xc 
Xc 
X 
 
Xc 
X 
Xc 
X 
Xd 
X 
Xd 
X 
Xd 
X 
 
X 
 
X 
X 
Weight 
measurement 
X 
X 
 
 
 
Xe 
 
X 
 
X 
 
X 
 
X 
 
 
 
 
 
 
12-Lead ECG  
X 
X f 
X f 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Safety Lab 
Testsg 
X 
Xh 
Xi 
X 
 
Xh, 
i 
X 
Xh  
X 
X 
X 
X 
X 
X 
X 
 
X 
 
X 
X 
Blood sampling  
X j, k, l, n, 
m 
 
 
Xn 
 
 
 
 
 
Xn 
 
 
 
 
 
 
Xn 
Xk 
 
Xn 
Bone marrow 
aspirate  
Xo 
 
 
Xo 
 
 
 
 
 
Xo 
 
 
 
 
 
 
Xo 
 
Xp 
Xo 
Pregnancy Test 
q 
X 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
X 
X 
Urinalysis  
X 
Xr 
Xr 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 




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h 
= Check of WBC count  ≤10 X 109 L prior to the first “ramp-up” study drug administration (Visit 1/Day 1, Visit 8/Day 8) and at Visit 12/Day 15; 
hydroxyurea is allowed to lower WBC count. 
i 
= In case the “ramp-up” administration visit is split due to infusion-related toxicities, WBC count should be ≤ 10 x 109/L also prior to start the second 
part of the “ramp-up” administration visit. 
j
.  
k = Blood sampling for immunogenicity assessment to be collected during the Screening Period (Day -7 to Day 0) and at Visit 34. 
l = 
 
m = Blood sampling for anti-HIV antibodies, anti-HBcAg antibodies, HBV-DNA, HCV-RNA to be tested according to local standard procedures ONLY in 
case results of laboratory tests for have not been performed within 3 months prior to Screening Period. 
n = Blood sampling for CD157 receptor occupancy assessment. 
o = Bone marrow aspirate for morphologic assessment, 
. In case the patient is 
discontinued from the study within the treatment period, the End of Study Visit bone marrow aspirate is highly recommended to be performed. 
p = Bone marrow aspirate for morphologic assessment to be performed ONLY at Visit 35, and Visit 37 in case peripheral blood labs are consistent with 
CR/CRi/PR.  
q = Pregnancy test (if applicable) will be performed locally during the Screening Period, Visit 11, Visit 27, Visit 35, Visit 36, Visit 37, Visit 38 and End of 
Study Visit; female patients of childbearing potential are required to undergo a monthly pregnancy test until 6 months from last study drug administration. 
r = Urinalysis will be performed at Visit 1/Day 1 pre-infusion and at the end of Visit 3/Day 3 infusion. 
s = Timings of each blood sampling for PK & exploratory tests are listed in Appendix II: Timings of Blood sampling for PK & exploratory tests. If any 
interruption occurs during Cycle 1 and the 3rd infusion of Cycle 2, blood sampling for PK & exploratory tests will also be taken at the time of each infusion 
interruption and just before each infusion resumption. 
t = Recording and active follow-up of AEs will be performed from Informed Consent signature to the End of Study Visit or 70 days after last study drug 
administration whichever occurs last. 
 
* = One of the following adjustments is allowed: 
− 
+1 day for any “ramp-up” administration visit in case of WBC count >10x109/L on the first day of such visit, in order to lower the WBC count using hydroxyurea. This is 
applicable also to the “one-shot” infusion visit  of Cycle 1 (Visit 12/Day 15). 
− 
+ 1 day for each study drug administration visit (i.e. first “ramp-up” and “one-shot” administration visit). 
In case of study visit re-schedule due to infusion related toxicities, WBC count recovery, or any other reasons, the interval of 5 days (Cycle 1) or 7 days (Cycle 2) between the end 
of any study drug administration visit and the start of the following one should be guaranteed. 
** = During the End of Treatment, a time-frame of + 1 day is allowed at any visit, however the scheduled time of the following visits should be maintained. 
*** = During Follow-up Period, a time-frame of + 2 days each is allowed at any visit, however the scheduled time of the following visits should be maintained.  
- To serve the best interest of the patients, for those achieving at least a partial remission, the Sponsor commits to consider providing MEN1112 to allow the prosecution of the 
infusions at the frequency recommended by the iDSMB on an individual basis and after discussion with the treating Investigator and the Medical Monitor. In this case, 
premedication and safety assessments will resemble those already described for study drug administration visits, unless differently advised by the iDSMB. 


Clinical Trial Protocol 
EudraCT No.: 2014-002433-59 
 
                                                              Study Code: ARMY-1 
                                     Final Version 7.0, 04 November 2019 
 
 
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**** = At the End of Study Visit, a time-frame of + 5 days is allowed. 




Clinical Trial Protocol 
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Laboratories involved in the study are provided in section 8.5.1.1. Further details will be addressed in 
the specific Laboratory Manual. 
 


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4. TABLE OF CONTENTS 
 
1. 
SIGNATURES ................................................................................................................................................................ 2 
2. 
PROTOCOL SYNOPSIS ................................................................................................................................................ 4 
2.1 
Schematic Study Design ...................................................................................................................................... 29 
2.2 
Study flow-chart ................................................................................................................................................... 30 
3. 
INVESTIGATORS AND STUDY ADMINISTRATIVE STRUCTURE ..................................................................... 34 
4. 
TABLE OF CONTENTS .............................................................................................................................................. 36 
4.1 
Glossary ............................................................................................................................................................... 39 
5. 
ETHICAL AND LEGAL ASPECTS ............................................................................................................................ 42 
5.1 
General Aspects ................................................................................................................................................... 42 
5.2 
Independent Ethics Committee and Legal Requirements..................................................................................... 42 
5.3 
Patient Information and Declaration of Consent .................................................................................................. 42 
5.4 
Patient Insurance .................................................................................................................................................. 43 
5.5 
Documentation of Study-related Data and Record Retention .............................................................................. 43 
5.6 
Confidentiality ..................................................................................................................................................... 44 
5.7 
Protocol Modifications ......................................................................................................................................... 44 
5.8 
Study Commencement ......................................................................................................................................... 44 
5.9 
Patient’s Safety .................................................................................................................................................... 44 
5.10 
Data Property/Publication Policy ......................................................................................................................... 45 
5.11 
Data Protection ..................................................................................................................................................... 45 
5.11.1 
General Principles on Personal Data Compliance ....................................................................................... 45 
5.11.2 
Acknowledgment......................................................................................................................................... 46 
5.11.3 
Data Controllers and Data Processors ......................................................................................................... 46 
5.11.4 
Duties of the Parties involved in the Performance of the Study .................................................................. 47 
5.11.5 
Archiving of the clinical trial master file and patients’ personal data ......................................................... 49 
5.11.6 
Data Breach ................................................................................................................................................. 49 
5.11.7 
Information Notice in Personal Data Protection and Pseudonymisation ..................................................... 51 
5.11.8 
Genetic Data ................................................................................................................................................ 52 
5.11.9 
Transfer of patients’ data outside the European Union ............................................................................... 53 
5.11.10 
Exercise of patients’ data privacy rights ...................................................................................................... 53 
5.11.11 
Future research ............................................................................................................................................ 54 
6. 
BACKGROUND INFORMATION .............................................................................................................................. 55 
6.1 
Acute Myeloid Leukaemia ................................................................................................................................... 55 
6.2 
The Investigational Product: Men1112 ................................................................................................................ 58 
6.2.1 
Physical, Chemical and Pharmaceutical Properties and Formulation .............................................................. 58 
6.2.2 
Non-Clinical Data ............................................................................................................................................ 58 
6.2.3 
Rationale for a Phase I Study and Selection of a Safe Starting Dose .............................................................. 62 
6.2.4 
Clinical Experience .......................................................................................................................................... 62 
6.3 
Risk Benefit Assessment ...................................................................................................................................... 65 
7. 
STUDY OBJECTIVES ................................................................................................................................................. 69 
7.1 
Primary objectives ................................................................................................................................................ 69 
7.2 
Secondary objectives ............................................................................................................................................ 69 
7.3 
 70 
8. 
INVESTIGATIONAL PLAN ........................................................................................................................................ 70 
8.1 
Overall Study Design and Plan Description ......................................................................................................... 70 
8.2 
Selection of Study Population .............................................................................................................................. 71 
8.2.1 
Inclusion criteria .............................................................................................................................................. 71 
8.2.2 
Exclusion criteria ............................................................................................................................................. 72 
8.2.3 
Withdrawal of patients from therapy or assessment ........................................................................................ 72 
8.3 
Identity of the Investigational Product ................................................................................................................. 73 
8.3.1 
Description of Investigational Medicinal Product ........................................................................................... 73 
8.3.2 
Packaging, labelling, and storage..................................................................................................................... 74 
8.3.3 
Drug accountability ......................................................................................................................................... 75 
8.3.4 
Destruction of surplus medication ................................................................................................................... 75 


Clinical Trial Protocol 
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8.4 
Treatment administration- frequency and duration of application ....................................................................... 76 
8.4.1 
TLS risk assessment and prophylaxis .............................................................................................................. 76 
8.4.2 
Premedication .................................................................................................................................................. 76 
8.4.3 
Step 1 Dose escalation method and cohort management ................................................................................. 76 
8.4.4 
Step 2- Cohort expansion ................................................................................................................................. 78 
8.4.5 
Treatment regimen and duration ...................................................................................................................... 78 
8.4.6 
Treatment compliance...................................................................................................................................... 80 
8.4.7 
Dosage modification and management of infusion toxicities .......................................................................... 81 
8.4.8 
Concomitant Medication.................................................................................................................................. 86 
8.5 
Study Procedures and Assessments...................................................................................................................... 86 
8.5.1 
Study Procedures ............................................................................................................................................. 86 
8.5.2 
Assessment of Safety ....................................................................................................................................... 96 
8.5.3 
Pharmacokinetic Evaluation .......................................................................................................................... 102 
8.5.4 
Pharmacokinetic and Safety Endpoints ......................................................................................................... 105 
8.6 
Management and Reporting of Adverse Events ................................................................................................. 107 
8.6.1 
Reporting of Serious Adverse Events to the Sponsors................................................................................... 107 
8.6.2 
Management of Suspected Unexpected Serious Adverse Reactions and other relevant safety issues ........... 108 
8.6.3 
Management of Non-Serious Adverse Events (NSAES) and/or Laboratory Abnormalities ......................... 109 
8.6.4 
Annual Safety Reporting ............................................................................................................................... 109 
8.6.5 
Breaking of the Randomisation Code ............................................................................................................ 110 
8.6.6 
Serious and Non-Serious Adverse Event Follow-Up..................................................................................... 110 
8.7 
Management of Positive Pregnancy Test ........................................................................................................... 110 
8.8 
Independent Data Safety Monitoring Board ...................................................................................................... 110 
9. 
STATISTICAL METHODS AND DETERMINATION OF SAMPLE SIZE ............................................................ 112 
9.1 
Determination of Sample Size ........................................................................................................................... 112 
9.2 
Analysis Populations .......................................................................................................................................... 112 
9.3 
Statistical Analysis ............................................................................................................................................. 112 
9.3.1 
Descriptive statistics ...................................................................................................................................... 112 
9.3.2 
Efficacy Analysis ........................................................................................................................................... 113 
9.3.3 
Pharmacokinetic Analyses ............................................................................................................................. 113 
9.3.4 
Safety analysis ............................................................................................................................................... 114 
9.3.5 
Data Imputations ............................................................................................................................................ 114 
9.4 
Protocol Violations and Data Review Meeting .................................................................................................. 114 
9.5 
Statistical Analysis Plan ..................................................................................................................................... 114 
10. 
DATA QUALITY MANAGEMENT ..................................................................................................................... 115 
10.1 
Data Collection .................................................................................................................................................. 115 
10.1.1 
Case Report Forms .................................................................................................................................... 115 
10.1.2 
Central Laboratory/Examination data ....................................................................................................... 115 
10.1.3 
Data capture systems versions and validation documentation ................................................................... 116 
10.2 
Clinical Data Management ................................................................................................................................. 116 
10.3 
Source Data ........................................................................................................................................................ 116 
10.4 
Quality Control/Quality Assurance .................................................................................................................... 117 
10.4.1 
Study Monitoring ...................................................................................................................................... 117 
10.4.2 
Quality Assurance ..................................................................................................................................... 117 
11. 
PREMATURE TERMINATION OF THE WHOLE STUDY ............................................................................... 117 
12. 
END OF CLINICAL TRIAL AND ARCHIVING ................................................................................................. 118 
12.1 
Archiving of Electronic Documentation/Data .................................................................................................... 118 
13. 
References .............................................................................................................................................................. 119 
14. 
Appendices ............................................................................................................................................................. 122 
14.1 
Appendix I: TLS Manual for Investigator .......................................................................................................... 122 
1. 
Risk assessment for tumor lysis syndrome (TLS) ....................................................................................................... 124 
2. 
TLS diagnostic criteria ................................................................................................................................................ 125 
3. 
Prophylaxis of TLS ...................................................................................................................................................... 126 
4. 
Treatment of established TLS ...................................................................................................................................... 127 
5. 
References ................................................................................................................................................................... 129 
14.2 
Appendix II: Timings of Blood sampling for PK & exploratory tests ............................................................... 130 
14.3 
Appendix III: Timings of safety blood sampling ............................................................................................... 131 


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14.4 
Appendix IV: Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0. Published: May 28, 
2009 (v4.03: June 14, 2010). U.S.Department Of Health And Human Services - National Institutes of Health - National 
Cancer Institute ................................................................................................................................................................ 132 
 


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4.1 
GLOSSARY 
 
ADA 
Anti-Drug Antibodies 
ADCC 
Antibody-Dependent Cell-mediated Cytotoxicity 
ADL 
Activities of Daily Living 
ADP 
Adenosine DiPhosphate 
ADR 
Adverse Drug Reaction 
AE 
Adverse Event 
ALP 
Alkaline Phosphatase 
ALT 
Alanine Aminotransferase 
AML 
Acute Myeloid Leukaemia 
AST 
Aspartate Aminotransferase 
ATL 
Adult T leukaemia/lymphoma 
AUC 
Area Under Curve 
%AUCex 
Percentage of AUC(0-∞) obtained by extrapolation 
AUC(0-t) 
AUC from time 0 until the last quantifiable concentration 
AUC(0-∞) 
AUC from time 0 until infinity 
AUC(0-7days) 
AUC from time 0 until 7th day 
AUMC(0-∞) 
Area under the first moment curve from zero to infinity 
BLLOQ 
Below the Lower Limit of Quantification 
BP 
Blood Pressure 
BR 
Breathing Rate 
BUN 
Blood Urea Nitrogen 
CA 
Competent Authority 
CDC 
Complement Dependent Cytotoxicity 
CHO 
Chinese Hamster Ovary 
CI 
Confidence Interval 
CL 
Systemic Clearance 
Clast 
Last quantifiable serum concentration values 
CLL 
Chronic Lymphocytic Leukaemia 
Cmax 
Maximum serum Concentration 
CR 
Complete Remission 
CRc 
Composite Complete Remission 
CRC 
Cohort Review Committee 
CRi 
Complete Remission with incomplete blood count recovery 
CRF 
Case Report Form 
CRO 
Contract Research Organization 
CRS 
Cytokine Release Syndrome 
Ctrough 
Pre-dose serum concentration 
CV 
Coefficient of variation 
DA 
Daunorubicin plus cytosine Arabinoside 
DLT 
Dose Limiting Toxicity 
DNA 
Deoxyribonucleic acid 
DRM 
Data Review Meeting 
DSM 
Drug Safety Manager 
DSUR 
Development Safety Update Report 
EC 
Ethics Committee 
ECG 
Electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group  
e-CRF 
electronic Case Report Form 
EDC 
Electronic Data Capture  
ELN 
European Leukemia Net prognostic system 
EU 
European Union 


Clinical Trial Protocol 
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FAB 
French American British 
 
 
 
 
FLT3 
Fms-Like Tyrosine kinase 3 
GCP 
Good Clinical Practice 
GGT 
Gamma-Glutamyl Transpeptidase 
GM 
Geometric Mean 
GMP 
Good Manufacturing Practice 
GPI 
GlycosylPhosphatIdylinositol 
h 
hour 
HBcAg 
Hepatitis B core antigen 
HBV 
Hepatitis B Virus 
HCV 
Hepatitis C Virus 
HED 
Human Equivalent Dose 
HEENT 
Head, Eyes, Ears, Nose and Throat 
HIV 
Human Immunodeficiency Virus 
HR 
Heart Rate 
HSCT 
Haematopoietic Stem Cell Transplantation 
IB 
Investigator’s Brochure 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonisation 
ID 
Identity 
iDSMB 
Independent Data Safety Monitoring Board 
IEC 
Independent Ethics Committee 
IFN 
InterFeroN 
IL 
Interleukin 
IMP 
Investigational Medicinal Product 
INR 
International Normalized Ratio 
IRB 
Institutional Review Board 
ITD  
Internal Tandem Duplication 
IV 
Intravenous 
IWG 
International Working Group 
ke 
Apparent terminal elimination rate constant 
LDH 
Lactate Dehydrogenase 
LLOQ 
Lower Limit of Quantification 
MAD 
Maximum Administered Dose 
MBH 
Menarini Biotech 
MCV 
Mean Corpuscular Volume 
MLL 
Mixed Lineage Leukemia  
MoAB 
Monoclonal Antibody 
MRT 
Mean Residence Time 
MTD 
Maximum Tolerating Dose 
NHL 
Non Hodgkin Lymphoma 
NHP 
Non-Human Primate 
NK 
Natural Killer 
NOAEL 
No Observed Adverse Effect Level 
NPM1 
Nucleophosmin 
OS 
Overall Survival 
PD 
Pharmacodynamics 
pH 
Potential of Hydrogen 
PD 
Pharmacodynamics 
PK 
Pharmacokinetics 
PR 
Partial Remission 
PS 
Performance Status 


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QA 
Quality Assurance 
RBC 
Red Blood Cells 
RNA 
Ribonucleic Acid 
Ro 
Accumulation Ratio 
RR 
Respiratory Rate 
SADR 
Serious Adverse Drug Reaction 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SD 
Standard Deviation 
SDST 
Study Drug Safety Team 
SE 
Standard Error 
SIV 
Site Initiation Visit 
SmPC 
Summary of Product Characteristics 
SOP 
Standard Operating Procedure 
ß-HCG 
Human Chorionic Gonadotropine 
SST 
Serum-Separating Tube 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
T 
Body Temperature 
t1/2  
Terminal serum half-life 
tlast 
Time to Clast 
TESS 
Treatment Emergent Sign and Symptoms 
TK 
ToxicoKinetic 
TLS 
Tumor Lysis Syndrome 
TMF 
Trial Master File 
tmax 
Time to Cmax 
TNF 
Tumour Necrosis Factor 
ULN 
Upper Limit of Normal 
Vd 
Volume of distribution 
Vss 
Volume of distribution at steady state 
WBC 
White Blood Cells 
WHO 
World Health Organization 


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5. ETHICAL AND LEGAL ASPECTS 
 
5.1 
GENERAL ASPECTS 
This study will be carried out in compliance with the study protocol, the recommendations on 
biomedical research on human subjects of the Declaration of Helsinki, ICH-GCP Guidelines, EU 
regulations in force (EU Directive 2001/20 of April 4, 2001, as amended), and national requirements 
of the participating countries. Furthermore, the study will be conducted in agreement with Sponsor or 
CRO’s Standard Operating Procedures (SOP) requirements as agreed. The agreed SOPs are listed in 
the project management plan and monitoring plan of the study. All clinical work conducted under this 
protocol is subject to GCP rules. This includes audit/inspections by the Sponsor and/or its delegate 
(e.g. CRO), and/or by national/international Health Authority representatives at any time. All 
Investigators must agree to the audit/inspection of the study site, facilities, and of study-related 
records by the Health Authority representatives and/or by the Sponsor, and/or its delegates, which 
must be performed in accordance with national laws concerning personal data protection. 
 
5.2 
INDEPENDENT ETHICS COMMITTEE AND LEGAL REQUIREMENTS 
Before starting the study in a study site, study protocol and relevant documentation must be submitted to 
and approved by the Institutional Review Board/Ethics Committees (IRB/ECs) and the Competent 
Authorities (CAs) of the participating countries.  
In addition, all local national legal requirements for the conduct of a clinical study have to be followed 
prior to the start of the study. 
The CAs and IRB/ECs of the participating countries will be informed about any changes in the study 
protocol, the end of the study, or the premature study termination as appropriate and within the requested 
time period. 
 
5.3 
PATIENT INFORMATION AND DECLARATION OF CONSENT 
Before any study-related procedures may be performed, informed consent must be obtained from the 
patient by means of a signed declaration. 
The Informed Consent Form (ICF) must be approved in the corresponding local language and in 
accordance with local laws and regulations by the IRB/ECs prior to be submitted to the patient.  
In the patient information leaflet, patients will be given information and fully comprehensive explanation 
in easily understandable terms of the study procedures, regarding the benefits, restrictions, discomforts, 
and risks in taking part in the study, the properties of the Investigational Medicinal Product (IMP), the 
method of assignment to treatments, and any medically accepted and readily available treatment other 
than the IMP.  


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Patients will also be informed about the measures taken to ensure their confidentiality according to the 
pertinent legislation.  
After being duly informed and interviewed by the Investigator, the patient freely has to date and sign an 
ICF before being enrolled into the study and before undergoing any study procedure. The Investigator 
must store the original of the signed ICF in the Investigator’s File, and the patient will be provided with a 
copy of it. 
The process of obtaining informed consent shall be documented in the patient source documents. 
If a protocol amendment would affect the terms of the ICF, it will be revised to reflect the protocol 
change and submitted to IRB/EC for approval. The Investigator will ensure that this new consent form is 
signed by all patients subsequently entered in the study and those currently in the study, before the 
changes take effect on their participation in the trial.  
 
5.4 
PATIENT INSURANCE 
For patients participating in the study, Menarini Ricerche S.p.A. has stipulated an insurance policy in 
accordance with local regulatory requirements. 
Details on the insurance in accordance with national requirements will be made available to patients in 
the ICF and/or provided as a separate document.  
A copy of the insurance certificate will be provided to each Investigator and will be filed in the 
Investigator’s File at the sites and in the study’s Trial Master File (TMF). 
 
5.5 
DOCUMENTATION OF STUDY-RELATED DATA AND RECORD RETENTION  
It is the responsibility of the Investigator to document all study related data for each patient in a case 
report form (CRF). For this study, an e-CRF will be used. The Investigator has to guarantee the accuracy 
of the documented data and has to comment any missing or spurious data. 
In addition to the e-CRF the Investigator will maintain adequate records that fully document the 
participation of the patient in the clinical study including the study assessments (patient source data 
documentation). Details on the source data documentation are provided in section 10.3. 
As required by EU Regulation 536/2014, the Investigator will keep essential documents at least 25 years 
after the end of the clinical trial. Patients’ data (e.g.: e-CRFs, lab data) have to be archived for the same 
period of time. These documents should be retained for a longer period however, if required by the 
applicable regulatory requirements or by an agreement with the Sponsor. No study documents should be 
destroyed without prior written agreement between Sponsor and Investigator. Patients’ records have to be 
archived according to national law requirements. Should the Investigator wish moving the study record to 
another location, he/she must notify the Sponsor in writing.  
 


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5.6 
CONFIDENTIALITY 
By signing the study protocol, the Investigator affirms that any information provided by the Sponsor will 
be maintained in confidence, and that such information will be divulged to IRB/ECs or CAs only under 
an appropriate understanding of confidentiality with such a committee or institution. 
In order to maintain the patient’s confidentiality, all data collected by the Investigator will be recorded 
pseudonymously in the e-CRF. Patient’s data will be identified by a unique patient number.  
The Investigator agrees that within national regulatory restrictions and ethical considerations, 
representatives of the Sponsor, any regulatory agency, and IRB/ECs may consult study source documents 
in order to verify data in the e-CRF. Patient medical records pertinent to the study will be reviewed by the 
study monitor to assure adequate source documentation, accuracy, and completeness of e-CRFs. The 
review will be conducted in accordance with relevant SOPs and with strict adherence to professional 
standards of confidentiality, GCP, and the relevant data protection legislation. 
 
5.7 
PROTOCOL MODIFICATIONS 
The protocol must be read thoroughly by everybody whom the information therein concerns and the 
instructions must be exactly followed. 
Changes in the study protocol will require a protocol amendment. Such amendments will be agreed upon 
and approved in writing by all signatories of the protocol. If amendments are substantial, i.e. are likely to 
have an impact on the safety of the patients, or to change the interpretation of the scientific documents in 
support of the conduct of the study, or if they are otherwise significant, the IRB/ECs and the CAs in the 
participating countries have to approve these amendments before implementation.  
Changes which have no significant impact on medical or scientific validity of the study will be agreed 
upon and approved in writing by all signatories of the protocol and the IRB/ECs will be notified of this 
protocol amendment. 
Any substantial amendments of the protocol will be integrated in an updated study protocol. The 
Principal Investigator must ensure full compliance with the updated study protocol. 
 
5.8 
STUDY COMMENCEMENT 
The study can commence in an individual study site only after all prerequisites are fulfilled according to 
GCP/ICH guidelines, any local regulatory requirements, and the Sponsor’s/CRO’s SOPs. 
 
5.9 
PATIENT’S SAFETY 
If any event(s) related to the conduct of the study or the development of the IMP affects the safety of the 
study participants, the Sponsor and the Investigator will take appropriate urgent safety measures to 
protect the patients against any immediate hazard. The CAs and IRB/ECs will be informed forthwith 
about these new events and the measures taken. 


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5.10 DATA PROPERTY/PUBLICATION POLICY 
All data generated in the study (e.g. e-CRFs, the structured data files in the clinical database system, the 
results of the statistical evaluation, and medical interpretation as well as the final clinical study report) are 
the property of Menarini Ricerche S.p.A. 
It is intended that study design and main results will be published on www.clinicaltrials.gov. In 
addition, the results of the study may be published as scientific literature. Results may also be used in 
submissions to CAs and IRB/ECs. The conditions mentioned below are intended only to protect 
confidential commercial information (patents, etc.), and not to restrict publication. 
All information concerning MEN1112 (such as patent applications, formulae, manufacturing 
processes, basic scientific data, or formulation information supplied to the Investigator by Menarini 
Ricerche S.p.A. and not previously published) are considered confidential by Menarini Ricerche 
S.p.A. and will remain the sole property of Menarini Ricerche S.p.A. The Investigator agrees not to 
use it for other purposes without written consent from Menarini Ricerche S.p.A. 
Menarini Ricerche S.p.A. will use the information obtained in this clinical study in connection with 
the development of MEN1112 and therefore may disclose it to other Investigators or concerned CAs 
and IRB/ECs in the European Union or abroad. In order to allow for the use of information derived 
from this clinical study, the Investigator has an obligation to provide Menarini Ricerche S.p.A. with 
complete test results and all data recorded during this study. 
Prior to submitting the results of this study for publication or presentation, the Investigator will allow 
Menarini Ricerche S.p.A. at least 30-day time to review and comment upon the publication 
manuscript. Menarini Ricerche S.p.A. will provide any manuscript of the results of this study at least 
30 days before publishing to the authors for a complete review. In accordance with generally 
recognised principles of scientific collaboration, co-authorship with any Menarini Ricerche S.p.A. 
personnel will be discussed and mutually agreed upon before submission of a manuscript to a 
publisher. 
It is agreed, that the results of the study will not be submitted for presentation, abstract, poster 
exhibition, or publication by the Investigator until Menarini Ricerche S.p.A. has reviewed/commented 
and agreed to any publication. 
 
5.11 DATA PROTECTION 
5.11.1 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 applicable law on 


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personal data protection 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. 
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 
fulfilment of patients’ privacy rights. 
5.11.2 Acknowledgment 
The Site, the Principal investigator, the Centralised Laboratories, the CRO as well as their appointed 
staff and service providers acknowledge that:  
(a) the performance of the study will imply processing of sensitive personal data; 
(b) personal data processing is regulated by the applicable 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. In particular, it is hereby 
acknowledged that being the Sponsor a company incorporated under Italian law, it has to 
mandatorily comply with Italian legal provisions on data protection: therefore the Site, the 
Principal investigator, the Centralised Laboratories, the CRO shall cooperate with the Sponsor 
to allow the fulfilment of such obligations; 
(c) 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 Principal 
investigator, the Centralised Laboratories, the CRO. 
5.11.3 Data Controllers and Data Processors  
The Sponsor, the Site, the Principal 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 
Principal investigator will act as data processors respectively of the Sponsor and of Site. Before the 
beginning of the study, the Site will instruct in writing Principal Investigator as its data processor.  
However, if specific local laws or regulations mandate a different definition of the privacy roles, the 
Sponsor, the Site, the Principal investigator and the CRO will implement the relevant legal 
instruments (e.g. if pursuant to the local laws  the Site is a data processor of the Sponsor, a Data 
Processing Agreement will be finalised; if pursuant to the local laws Sponsor and Site are join 
controllers, a Joint Controllership Agreement will be finalised). 


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5.11.4 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, 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 Principal investigator, the Sponsor, the CRO and the Centralised Laboratories 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) 
DATA SAFETY. The Site and/or the Principal Investigator shall adopt all the necessary 
measures to prevent or minimise the risks of theft, fire, flooding, partial or total loss, accidental 
disclosure or illegal/unauthorised access to patient’s data or Sponsor’s proprietary confidential 
information. To this extent, before the beginning of the study, the Site and/or the Principal 
Investigator shall ensure that the actual measures they have implemented are fit-for-purpose and law-
compliant, and in particular: 
- In order to minimise the risk of unauthorized access and theft, the hardware on which patients’ 
personal data are stored shall be placed in a restricted-access area, accessible only to those 
individuals who need to retrieve the patients’ personal data included in the database for 
professional purposes; the same safeguards shall be put in place for non-electronic databases; 
- Any electronic database containing the patients’ personal data shall be password-protected by 
means of a strong password. Systems shall be set so that passwords must be updated at least every 
three months and feature at least 8 characters, with upper-case and lower-case recognition, 
containing at least three "special" characters, such as upper case letters [A-Z], lower case letters [a-
z], numbers [0-9], symbols [!, #, $, etc.] or other special characters [Á, ë, ö, etc.]. Passwords shall 
not include elements which may easily be associated with the assignee or information regarding 
him/her, such as name and year of birth (e.g. “johnbrown80”) or easily predictable strings of 
characters (e.g. “qwerty”, “12345”, “admin”, “user”, etc.);  
- Adequate cryptographic protection measures shall be put in place for data “at rest” and “in transit” 
(these include, for example, file system or database cryptography, or any other equivalent IT 
measure which renders data unintelligible to those who are not authorised to access them);  
- High level security measures shall be implemented also on the files or databases which contain the 
“key” to match the patients’ personal data (i.e. name, surname, etc.) with their respective “Patient 
IDs” (as defined at point (iv) below); 


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- Backup processes and other measures that ensure rapid restoration of business critical systems shall 
be implemented; 
- Updated Antivirus and firewall programs shall be installed on the IT devices. 
The Site shall regularly test and update the measures listed above.  
The Site shall, upon request from the Sponsor and/or the CRO, provide detailed written information 
about the measures listed above.  
The CRO shall ensure that the selected sites for the study have implemented the above listed 
measures.  
(ii) TRANSMISSION OF DATA. All the parties that transfer data through internet and/or to the 
centralised database(s) used to process study’s data or to generate statistical analyses shall implement 
secure protocols based on cryptographic standards which make data unintelligible to unauthorized 
individuals. 
(iii) 
SECURITY OF THE CENTRALISED DATA BASE. The centralised database held by the 
Sponsor shall have the following safeguards in place:  
− Appropriate authentication methods, which differentiate between different users according to 
their respective roles so as to ensure that access to a specific set of subjects' data is permitted 
exclusively to those for whom access to such data is essential in the context of their work for 
the study; 
− Appropriate measures to ensure that the authentication credentials are periodically updated 
(i.e.  password change); 
(iv) 
PSEUDONYMIZATION. All personal data that may allow identification of the patients 
involved in the study shall be adequately dissociated from the other data pertaining to the study 
(“pseudo-anonymization” process). The Principal Investigator shall adequately dissociate the 
identification data of patients from the data pertaining to the study by linking results to an 
alphanumerical code [“Patient ID”], whose format shall not make it possible to identify the patient 
directly or indirectly, so as to ensure that only anonymous data are transmitted to the Sponsor, the 
Centralised Laboratories and /or the CRO. Site/Principal Investigator shall securely store a separate 
list (e.g.: identification log) with the identification code, together with all signed informed consents, in 
accordance with the security measures as defined above.  
As outlined below, samples shall only be stored for as long as strictly necessary for the study’s 
performance for a maximum of 10 years from the date of the Last Subject Last Visit before 
destruction. Biological samples and any other examination (e.g. X-ray, ECG) shall bear Patient ID, 
and in no case will they bear other information that may lead to the direct or indirect identification of 
the patient, especially when, in accordance with this protocol, samples shall be forwarded and shared 
outside the clinical Site (e.g. in case of centralized reading or local laboratory analysis).  


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(v) 
TRAINING. The parties shall ensure that any personnel involved in the study have received 
proper training on data protection issues. 
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 Ethics Committees 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 Principal Investigator, the CRO and the 
Centralised Laboratories undertake to adopt all the necessary activities to overcome such remarks to 
assure the full compliance with the data protection laws. 
5.11.5 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 Principal 
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 trial. However, medical records and the 
identification code list (i.e. the list that where the Patient ID is linked to the patients’ identification 
data such as name and surname), including the relevant patients’ personal data, shall be archived in 
accordance with the national laws of the country where the study is performed.   
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. 
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 (see § 3) as responsible person 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. 
5.11.6 Data Breach  
Data Breach is an incident regarding personal data security and 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 Site, Sponsor, CRO, Principal Investigator, etc.; 
data loss is when the data may still exist, but the Site, Sponsor, CRO, Principal Investigator etc. has 
lost control or access to it, or no longer has it in their possession; damage is where personal data has 
been altered, corrupted, or is no longer complete; data unavailability is where, following a data 


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incident (such as a network outage, a natural or man-made disaster, etc.) personal data become 
temporarily inaccessible to the Site, Sponsor, CRO, Principal Investigator, etc. 
Anomalous Event is an event that is not part of the standard operational scope of an infrastructure, 
network or service and which affects, or is likely to affect, personal data; this may include theft or loss 
of IT devices and other physical events (e.g. an unauthorised access to a locked storage room 
containing paper files with personal data), and/or electronic/IT anomalies (e.g. cyber-attacks, default 
or hacking of cloud services), which may, in any way, entail loss, unavailability, alteration, theft, copy 
or dissemination of personal data.   
Whoever becomes aware in any way of an Anomalous Event and/or of a Data Breach 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 an Anomalous Event 
and/or of a Data Breach) inform the Study Manager (see § 3), the sponsor’s Data Protection Officer, 
who may be contacted 
the Site and the CRO (details of this latest are included 
in the separate Operational Contact List) and shall provide the following information: 
(i) Anomalous  Event / Data Breach Type (e.g. data loss, unauthorized access, loss of company device, 
etc.);  
(ii) Person or source that first reported the Anomalous Event/ Data Breach; 
(iii) Date and Time when the person who first reported the Anomalous Event / Data Breach became 
aware of it; 
(iv) Anomalous Event / Data Breach Date and Time (actual or presumed); 
(v) Place (specify if actual or alleged) where the Anomalous Event / Data Breach  occurred; 
(vi) Anomalous Event / Data Breach Description;  
(vii) Indicate the source of the Anomalous Event / 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 Anomalous Event/Data Breach (if 
relevant); 
(x) Number of data subjects 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. 


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For Data Breach affecting personal data of patients enrolled within the European Union, Sponsor and 
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; 
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. 
5.11.7 Information Notice in Personal Data Protection and Pseudonymisation  
Prior to patients’ enrolment in the study, the Principal 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 Principal Investigator is responsible for archiving 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 (e.g. to perform the study and /or for pharmacovigilance 
purposes and/or to register new medicines, any future research), 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 
§ 5.11.11; 
(vi) The pseudonymisation procedure and scope; 
(vii) Who can access patients’ data and under what circumstances. In the context of this study, 
only coded data will be forwarded to the Sponsor, to other companies belonging to the 
Sponsor’s group, Sponsor’s licensors-licensees or to third parties acting on behalf of the 
Sponsor, including the CRO. However, European Medical Regulatory Authorities, the 
European Medicines Agency, the Insurance Company and the Sponsor (and its delegates), may 
inspect the study files to ensure that the results of the study have been properly recorded, as 
well as for scientific research, pharmacovigilance, safety and insurance purposes: this may 


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require matching personal code with patient’s data and identity. Moreover, patients’ data can 
be disclosed in an aggregate or pseudonymised form in scientific publications; 
(viii) The period of data retention/storage as defined in § 5.11.4 above, including the storage of the 
biological sample; 
(ix) To which entities/countries outside the EU patients’ data will be transmitted (The updated list 
of foreign countries is 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 
;  
(xiii) In case of genetic data processing, any possible finding, also with regard to unexpected 
findings that might be disclosed on account of the processing of the genetic data. 
5.11.8 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. 
- 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. 
- The measures to keep patients’ identification data separated from biological materials and genetic 
information are indicated in § 5.11.4 and 5.11.5. 
- 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. 


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- 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). 
5.11.9 Transfer of patients’ data outside the European Union 
The study performance entails transferring patients’ personal data (coded data) outside the EU. To this 
extent, the Sponsor, the Site, the Principal Investigator, the Centralised Laboratories, 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. 
5.11.10 Exercise of patients’ data privacy rights 
Each study patient has the right to contact the Sponsor, Site, Principal Investigator, Centralised 
Laboratories and 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, namely: knowing whether or not any data 
referring to his/her is being processed in the context of the study; accessing his/her data; verifying the 
data’s content, origin, exactness, location (including, where applicable, the non EU countries where 
the data might be); obtaining a copy of the data including their transmission to another entity indicated 
by the patient; asking that the data are supplemented, updated, amended; in the circumstances set forth 
by the law, asking that the processing of data is restricted, that data are anonymised or frozen; 
opposing 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 as inappropriate. 


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Each study patient is free to withdraw from the study at any time. In such case, each study patient may 
ask the Sponsor, the Site, the Principal Investigator, the Centralised Laboratories, 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.  
Specific rights in relation to the processing of genetic data apply. Please refer to § 5.11.8.  
If the Site, the Principal Investigator, the Centralised Laboratories, and/or the CRO receive a request 
for data privacy rights exercise, the concerned recipient shall immediately inform the Sponsor DPO by 
e-mail at
 
The request shall be fulfilled within the term set forth by the applicable privacy laws (normally 30 
days). The Sponsor, the Site, the Principal Investigator, the Centralised Laboratories, and the CRO 
shall implement adequate organisational measures to reply to patients within the above mentioned 
deadline. 
5.11.11 
Future research  
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 drugs.  
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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6. BACKGROUND INFORMATION 
 
6.1 
ACUTE MYELOID LEUKAEMIA 
Acute myeloid leukaemia (AML) is predominantly a disease of the elderly, with an age-adjusted 
incidence rate of 3 to 4/100 000 in Western countries (1-3) and the median age at diagnosis of 
approximately 70 years (3-5). 
It is now recognized that AML is a highly heterogeneous disease or set of diseases in terms of 
morphology, cytochemistry, immunophenotype, cytogenetics, and molecular abnormalities (either 
mutations or gene overexpression) of the leukemic cell population. Since the morphology of the 
leukemic cells (blasts) in the bone marrow may not be sufficient to determine lymphoid or myeloid 
origin, cytochemistry and/or immunophenotyping is an essential part of the diagnosis. Chromosomal 
abnormalities occur in 50% to 60% (6-7) of patients and are highly prognostic for the outcome of 
first-line therapy and also after relapse, and are widely used to assess the treatment strategy in 
individual cases. 
Recently, molecular characterization has added a further layer of prognostic insight within the 
cytogenetic strata, and in particular patients harboring some mutations (particularly those related to 
FLT3 IDH1 and IDH2) have molecularly targeted approach available. 
AML is an aggressive disease that is rapidly fatal without specific therapy, and achievement of CR is 
a prerequisite for long-term survival. Curative treatment was not available until the late 1960s, when 
chemotherapy with Daunorubicin plus cytosine Arabinoside (DA) was introduced (8-9). The 
combination of an anthracycline, usually given over 3 days and cytarabine given over seven days (the 
so called 7+3 regimen) can induce CR in the majority of AML patients and in a proportion with 
favourable prognostic factors. A long-term survival is possible after appropriate post-remission 
therapy. Although numerous drugs have been tested either in monotherapy or in combination, no 
alternative induction regimens have proven to be more effective. Therefore, 7+3 remains the 
cornerstone of AML induction treatment, with the addition of Midostaurin in FLT3 mutated patients. 
Newly diagnosed patients who are unfit for standard induction chemotherapy are treated with non-
intensive options, basically the hypomethylating agents (HMAs) Decitabine and Azacitidine or low-
dose Cytarabine; recent data have shown that the addition of the BCL-2 inhibitor Venetoclax to the 
above agents or that of the hedgehog pathway inhibitor Glasdegib to low dose Cytarabine do improve 
the outcome of the single agent front line treatment (10-12). Venetoclax and Glasdegib, in 
combination with HMAs/LDAC or LDAC, respectively, have been approved by the US FDA for the 
front-line treatment of AML patients who are unfit for standard induction chemotherapy.  
Since all patients will eventually relapse (usually within a matter of weeks) after responding to 
induction treatment alone, post-remission therapy is essential to achieve long term disease control. 
This can take the form of high dose consolidation chemotherapy (10-16) or in suitable patients’ 


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allogeneic haematopoietic stem cell transplantation (allo-HSCT). Both of them can reduce the risk of 
relapse and improve long term disease control. In general, however, allo-HSCT offers the best 
possibility of increasing overall survival and can be curative in a minority of patients with the most 
favourable prognostic features (17-19).   
Overall therefore, post remission therapy can prolong the period of time patients remain in remission 
following initial induction therapy, although long term survival is only achieved in 40% to 50% and 
10% to 15% of younger and older patients, respectively (20). Furthermore, post-remission therapy is 
associated with a significant and debilitating burden of toxicity and also a treatment related mortality 
of 10-15 % within the first two months of therapy. 
Whilst a minority experience long lasting disease control, the vast majority of patients in remission 
(approximately 80 per cent) will eventually relapse again and most of these will do so within six to 
twelve months of achieving a complete response. Furthermore, approximately 30 per cent of AML 
patients will fail to respond to induction therapy at all and, hence, demonstrate refractory disease from 
the outset. 
Relapsed or refractory AML is an exceptionally intractable disease state and, if untreated, the overall 
survival is only about eight to ten weeks. 
The treatment of AML at disease relapse or in refractory patients is highly unsatisfactory as 
demonstrated by the lack of any widely accepted standard of care approach. In general, salvage 
treatment consists of either high dose Cytarabine or combination regimens such as FLAG-IDA 
(Idarubicin, Fludarabine, Cytarabine and GCSF) or MEC (Mitoxantrone, Etoposide and Cytarabine), 
followed by allo-HSCT when possible for those patients achieving an initial remission. For specific 
subsets of AML patients (i.e. those harboring FLT3, IDH1 or IDH2 mutations), the US FDA has 
approved targeted treatments at disease relapse, yet the medical need in this indication remains largely 
unmet. 
For those patients not receiving HSCT, responses to salvage therapy are dismal, with a median overall 
survival of about seven months at best. Even after HSCT, outcomes are significantly inferior to those 
of patients in first remission. 
Hence, new effective approaches are urgently needed and inclusion in clinical investigational trials of 
novel experimental agents (such as the current study of the anti-CD157 antibody MEN1112) is still 
one of the best options for such patients. 
Bst1/CD157, a GlycosylPhosphatIdylinosotol (GPI)-anchored transmembrane protein of 318 amino 
acids belonging to the Adenosine DiPhosphatase (ADP)-ribosyl cyclase family (21) previously 
described as bone marrow stromal antigen-1 (Bst-1) (22), is expressed on monocytes, granulocytes 
and macrophages matured in vitro (23) and it has been identified as a novel antigen expressed on 
AML blasts. Two separate studies demonstrated that the prevalence of the Bst1/CD157 expression on 
blast cells was almost 100% in peripheral and bone marrow blood samples obtained from AML 


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patients, either at the disease diagnosis or relapse (for the details of both studies, refer to the 
Investigator’s Brochure). 
Like CD33 (a cell surface target which has formed the basis of a number of antibody approaches to 
AML), Bst-1/CD157 is a cell surface antigen expressed on blasts and normal blood cells such as 
granulocytes and monocytes but, differently from CD33, it is not internalized. Hence, it represents a 
valuable antigen to be targeted by antibodies such as MEN1112, a humanized de-fucosylated 
monoclonal antibody (MoAb) which has shown activity against leukemic cells lines and ex vivo 
primary AML blasts. 
In the context of haematological diseases, the therapeutic efficacy of MoAbs targeting surface 
antigens and acting through Antibody Dependent Cell-mediated Cytotoxicity (ADCC) has been 
proven in Non-Hodgkin’s Lymphomas (NHLs) and Chronic Lymphocytic Leukaemia (CLL) with the 
approval of first generation antibodies such as rituximab and alemtuzumab. However, this approach 
has as yet been unsuccessful in AML. In part, this may be due to the fact that earlier strategies 
targeting CD33 may have been sub-optimal, due to a partial internalization and shedding of CD33, 
making it an inappropriate antigen for targeting by MoAbs acting through ADCC. 
Furthermore, it is now widely recognized that the core fucose of Fc-linked oligosaccharides greatly 
affects the ADCC efficacy of therapeutic antibodies, with the removal of fucose markedly enhancing 
the ADCC through improved FcγRIIIa binding without altering antigen binding (24); ADCC 
enhancement technology is, therefore, expected to play a key role in the development of next-
generation therapeutic antibodies with improved clinical efficacy. This may be particularly relevant in 
the context of AML, as the disease is characterized by an impairment of immune effector cells mainly 
involved in ADCC such as NK cells, monocytes and macrophages, thus making ADCC less effective 
(24-28). Therefore, the use of new generation of Fc engineered MoAbs such as MEN1112 could be 
expected to show significantly greater clinical efficacy than has been seen with antibodies of an 
earlier era. Indeed, Mogamulizumab, a new defucosylated MoAb, has shown to be active in Adult T 
leukaemia/lymphoma (ATL) (29-30) and was approved in Japan for the treatment of 
relapsed/refractory ATL. Compared to earlier antibody approaches in AML, MEN112 therefore 
possesses significant potential advantages in terms of both novelty of the leukaemic target and also 
structural superiority of the antibody construct. The current trial is intended to explore the extent to 
which these pre-clinical points of differentiation translate into clinical efficacy in patients with 
advanced AML who lack any existing established treatment options. 
 
 
 
 
 


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6.2 
THE INVESTIGATIONAL PRODUCT: MEN1112 
 
6.2.1 Physical, Chemical and Pharmaceutical Properties and Formulation 
MEN1112 is a recombinant humanized antibody originated by engineering of a murine monoclonal 
antibody raised against the Bst1/CD157 antigen. 
 
 
 
 
 
MEN1112 drug substance is a solution containing the recombinant humanized antibody MEN1112 
dissolved in a buffered and isotonic saline solution. 
 
 
 
 
 
The drug product MEN1112 consists of 10 mL of a sterile 
 solution containing 5.0 mg 
monoclonal antibody/mL in single-use glass vials as concentrate for solution for infusion. 
 
 
For drug product administration, the required volume of MEN1112 5.0 mg/mL concentrate for 
solution for infusion will be withdrawn from the vials and administered as IV infusion over 6 hours in 
250 mL sterile 0.9 % sodium chloride solution.  
 
6.2.2 Non-Clinical Data 
 
6.2.2.1 
Non Clinical Pharmacology 
 
6.2.2.1.1 Mechanism of Action – in vitro 
MEN1112 is a defucosylated humanized monoclonal antibody directed against Bst1/CD157. The 
Bst1/CD157 antigen shows an extremely low mRNA expression profile in healthy tissues, but it is 
highly expressed in monocytes, CD33+ cells and leukaemia cell lines. MEN1112 exhibits high and 
specific affinity for the Bst1/CD157 antigen in the range of 0.4-1 nM. After binding to Bst1/CD157 
expressed on cell surface, MEN1112 is poorly internalized remaining localized at the cell membrane, 
making the targeting of Bst1/CD157 suitable for an ADCC approach. ADCC is one of the major 
clinical mechanisms of action of therapeutic antibodies against cell surface targets expressed on 
tumour cells. The antibody uses patients’ innate immune cells (NK, monocytes, and macrophages) to 
kill target antigen-positive tumour cells. The activity is primarily triggered by: 1) a direct interaction 
of the Fc domain of the antibody with the corresponding FcγR receptors (CD16A) expressed on 
effector immune cells; 2) the interaction of the antigen binding domain of the Fab portion of 
MEN1112 with Bst1/CD157 expressed on blasts of AML. The defucosylation of Fc in MEN1112 
should enhance ADCC potency allowing also the interaction with low affinity (158 F) allele of 


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CD16A. 
 
 
 
 
 
Indeed, MEN1112 promotes very efficiently ADCC in a concentration dependent manner on various 
cell lines expressing Bst1/CD157. 
However, MEN1112 has per se no antiproliferative/proliferative activities and it is not able to mediate 
complement-dependent cytotoxicity (CDC). 
 
6.2.2.1.2 Translational Research 
Flow cytometric studies on human healthy donor whole blood using MEN1112 confirmed that 
Bst1/CD157 is highly expressed on neutrophils/monocytes, while eosinophils showed only a low-
moderate expression of the antigen. 
To evaluate prevalence of Bst1/CD157 antigen in primary human AML cells, extensive ex vivo 
investigations with patient-derived samples were conducted. Xenotransplantation studies are 
commonly employed and they are a useful approach to study the efficacy of anticancer therapeutics. 
However, translational research, that takes into consideration the heterogeneity of cancer, can add 
important information for the development of targeted therapies. In particular, it has been 
demonstrated, for AML, that mouse xenografts cannot represent the clonal architecture of leukaemia. 
However, primary samples of human AML tissue can be extremely useful for compound activity 
profiling and they reflect individual patient disease biology. 
Two different studies, performed by flow cytometry, demonstrated that: 1) Bst1/CD157 is expressed 
in nearly 100% of AML patient samples analyzed (including samples at primary diagnosis or at 
relapse) both in bone marrow and in peripheral blood; 2) Bst1/CD157 expression levels varied to 
some degree between samples by intensity.  
Similar results were also obtained in the bone marrow of AML patients.  
Moreover, the expression of Bst1/CD157 on the compartment with a high percentage of leukemic 
stem cells was analyzed in 20 AML samples. Bst1/CD157 was expressed in 20/20 patients in the 
leukemic stem cell subpopulation of patient samples.   
The correlation of Bst1/CD157 expression to FAB classification and cytogenetic markers was 
analyzed and the level of expression for Bst1/CD157 was found to vary to some degree between the 
different FAB subtypes, in particular the antigen is significantly higher in FAB M4/M5 compared to 
the other subtypes. When evaluating for cytogenetic prognostic markers, a significantly higher 
expression of Bst1/CD157 was observed in patients with Mixed Lineage Leukemia (MLL) 
rearrangements. For NPM1 and FLT-ITD mutations, no significant correlation could be shown. 






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6.2.3 Rationale for a Phase I Study and Selection of a Safe Starting Dose 
In order to identify the starting dose for the first administration in humans, a repeat-dose toxicity 
study by i.v. administration has been carried out in Cynomolgus monkey (§ 6.2.2.3.1). 
 
 
 
 
 
 
 
 
 
 
 
6.2.4 Clinical Experience 
This is the first in human study with MEN1112. The data and information related to the ARMY-1 
study described in this section and in its respective paragraphs are included in the MEN1112 
Investigator’s Brochure (IB).  
 
6.2.4.1 
Patient disposition and reasons for withdrawal 
As of 28 March 2019 (data cut-off date, unclean data) a total of 57 patients have been screened in the 
ARMY-1 study, 47 of whom have been treated, all using the “one-shot” schedule of administration, as 
tabulated below. Patient disposition at the cut-off date is provided below: 
 
 


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Table 1: Patient disposition in the ARMY-1 study 
Number of Patients 
Cohort 
0.1 mg/kg 
N=4 
Cohort 
0.3 mg/kg 
N=7 
Cohort 
0.6 mg/kg 
N=6 
Cohort 
1.0 mg/kg 
N=8 
Cohort 
1.7 mg/kg 
N=17* 
Cohort 
2.5 mg/kg 
N=5 
Overall 
N=47 
Screened 
7 
8 
7 
10 
20 
5 
57 
Screening failure 
3 
1 
1 
2 
3 
0 
10 
Safety population 
4/(100.0%) 
7/(100.0%) 
6/(100.0%) 
8/(100.0%) 
17/(100.0%) 
5/(100.0%) 
47/(100.0%) 
DLT population 
3/(75.0%) 
6/(85.7%) 
6/(100.0%) 
7/(87.5%) 
7/(41.2%) 
5/(100.0%) 
34/(72.3%) 
Efficacy population 
2/(50.0%) 
4/(57.1%) 
5/(83.3%) 
4/(50.0%) 
5/(29.4%) 
2/(40.0%) 
22/(46.8%) 
Early withdrawal 
4/(100.0%) 
7/(100.0%) 
6/(100.0%) 
8/(100.0%) 
10/(58.8%) 
5/(100.0%) 
40/(85.1%) 
 
Note: Percentages calculated using the total number of patients enrolled as the denominator 
* Includes 8 patients treated in the Step 2 of the study, all using the “one-shot” schedule 
 
The majority of patients were early withdrawn from the study. The most frequently reported reason 
for withdrawal from study were disease progression and Investigator judgement (29.8% and 21.3%, 
respectively).   
6.2.4.2 
Overview of safety 
Using the “one-shot” schedule of administration, treatment-related TESS occurred in the majority 
(95.7%) of study patients: 44.7% and 36.2% of patients experienced grade ≥ 3 treatment-related TESS 
and treatment-related serious TESS, respectively; the incidence of grade ≥ 3 treatment-related TESS 
was clearly increased in the Cohort 2.5 mg/kg, in which all patients experienced such events; the 2.5 
mg/kg dose level also retained the highest incidence of treatment-related serious TESS (60%). 
Moreover, in this latter dose level, 2 out of 5 patients experienced DLT events, hence leading to the 
stop of the dose escalation phase as well as to the definition of the immediately lower dose level, 
namely 1.7 mg/kg, as the MTD. Treatment-related deaths occurred in two patients overall (4.3%), one 
in Cohort 1.0 mg/kg and one in Cohort 1.7 mg/kg. 
 
 
 
 
. Treatment-related TESS leading to 
temporary study drug administration interruption occurred in 63.8% of study patients; although there 
is not a clear dose-relationship for such events, the highest incidence was found in the 2.5 mg/kg dose 
level. The incidence of TESS leading to temporary study drug administration interruption and 
reported as serious ranged between 0 and 25.0% through all the cohorts, without a clear dose trend.  
The most frequently reported treatment-related grade < 3 TESS across all cohorts were infusion-
related reaction (38.3% of patients), disseminated intravascular coagulation (17.0%), chills (14.9%) 
and pyrexia (12.8%); while for the latter two types of TESS there was no dose trend, the incidence of 
disseminated intravascular coagulation was clearly higher in Cohort 2.5 mg/kg - 60.0% of patients 
experiencing such TESS - than in all the previous cohorts (0-17.6% of patients reported to experience 
such TESS). With regard to infusion related reaction, the highest incidence (75.0%) was found at the 
0.1 mg/kg dose level, which however was run using the one hour infusion duration and without the 
standardized 
premedication 
encompassing 
the 
mandatory 
use 
of 
dexamethasone 
and 




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The most frequently reported grade ≥ 3 treatment related TESS were those pertaining to the Blood and 
lymphatic system disorders and Investigations by System Organ Class, both occurring in 21.3% of 
study patients. TESS pertaining to Blood and lymphatic system disorders did not show a clear dose 
trend; with regard to TESS pertaining to Investigations, the incidence of these events was clearly 
higher in the cohort 2.5 mg/kg than in any other dose level. The only grade ≥ 3 treatment related 
TESS reported in at least 10% of patients in any cohort was febrile neutropenia (10.6% of all study 
patients, without clear dose trend). 
6.2.4.3 
Overview of clinical pharmacokinetics 
MEN1112 serum concentrations from Cohort 0.1 mg/kg to Cohort 1.7 mg/kg of ARMY-1 study were 
measured and an interim PK analysis was performed for 38 subjects after a single IV infusion and for 
8 subjects after six consecutive IV infusions. The pharmacokinetics of MEN1112 in human were 
characterised by a dose-dependent behaviour after both single and repeat dose administration, as 
shown by a more than proportional increase in AUC0-inf in the dose-range 0.1-2.5 mg/kg. MEN1112 
was slowly cleared from the body, with a mean half-life ranging from 10.8 to 41.8 hr and from 12.8 to 
146.4 hr after single and repeat dose, respectively. The values obtained for volume of distribution at 
steady state were similar to total blood volume (i.e. 5 L). Estimates of clearance were also low (0.02 - 
0.9 L/hr) and in the range of those reported for other monoclonal antibodies. The magnitude of inter-
individual variability in MEN1112 disposition is large in the explored dose-range of 0.1-2.5 mg/kg. 
 
6.3 
RISK BENEFIT ASSESSMENT 
The medical need for AML and MDS is yet highly unmet and new treatments are urgently needed for 
either disease.  
MEN1112 is a defucosylated Monoclonal Antibody with high affinity binding to Bst1/CD157 antigen, 
which is expressed at high prevalence on both AML and MDS cells.  
Due to its ability to deplete AML and MDS blasts, even in the presence of low NK cells percentage, 
MEN1112 is considered to have the potential to represent a new targeted therapeutic opportunity in 
both AML and MDS patients. the single agent activity of MEN1112 is under clinical investigation in 
patients with relapsed or refractory AML in the ARMY-1 trial. In this trial, the MTD of the “one-
shot” administration schedule has been identified at 1.7 mg/kg following the occurrence of two DLT 
events in two patients treated at 2.5 mg/kg dose level 
 
. The Sponsor therefore performed an in-depth review of the safety 


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profile of MEN1112, with a particular focus on the four patients 
 
 who, throughout the study, experienced DLT events that clearly started during the infusion 
and that were characterized by increased transaminases, with or without severe coagulation 
derangements and multiorgan failure 
 A panel of widely acknowledged AML 
experts was also called to advice on the pathophysiology of the above events as well as on the next 
steps for the prosecution of the clinical development of MEN1112 in AML. The experts concluded 
that the pathophysiology of the severe events observed so far in the above patients may involve 
cytokine storm and/or monocytic-macrophage activation, as well as massive lysis of target cells and 
that, to possibly prevent the occurrence of such events or limiting their severity, general safety 
measures should be applied. Based on the experience with other compounds (e.g. Blinatumomab, 
Venetoclax) and on the fact that the above toxicities did develop either at the first or the second dose 
during the first cycle of treatment, a “ramp-up” approach during Cycle 1 was concluded to be the 
most appropriate one. Therefore, the dose escalation will be resumed from the 1.7 mg/kg dose level 
(i.e. from the MTD achieved using the “one shot” schedule per Protocol V4.1), under the 3+3 design 
and using a “ramp-up” approach during the first two MEN1112 administrations of Cycle 1. If no DLT 
occurs, additional dose levels will be explored at 2.0 mg/kg, 3.0mg/kg and 5.0mg/kg. 
 
 
 
  
Additional intermediate dose levels may be also explored, under a 3+3 design, upon recommendation 
of the iDSMB that will be appointed to guide dose escalation decisions. In addition, as the clinical 
data collected so far are not sufficient to adequately design a maintenance treatment phase, starting 
from protocol version 6.1/6.2 the study will no longer encompass a maintenance phase, which is 
replaced by a follow-up period for safety and efficacy assessments. To serve the best interest of the 
patients, for those achieving at least a partial response according to protocol-defined criteria, the 
Sponsor commits to consider providing MEN1112 to allow the prosecution of the infusions at the 
frequency recommended by the iDSMB on an individual basis and after discussion with the treating 
Investigator and the Medical Monitor. 
A mechanistic Target-Mediated Drug Disposition (TMDD) population PK model has been developed 
from free circulating MEN1112 concentration from ARMY-1 study (MEN1112-PK-01). The TMDD 
model was used in simulation to explore different “ramp-up” dosing schedule scenarios. Upon the 
aforementioned PK modelling simulations, a 3-day “ramp-up” approach was chosen. The “ramp-up” 
dosing escalation and the whole treatment plan will thus be as following:  
 
 
 






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cohort, and will take-over the same applicable roles and responsibilities previously assigned to the 
Cohort Review Committee. The iDMSB will review the safety, efficacy and PK data collected with 
the “ramp-up” schedule, and the Sponsor will follow the iDSMB recommendation for any dose 
escalation decision.  
 
 
 
 
  
     
Although neither complete nor partial responses have been documented so far in the ARMY-1 study, 
four patients – two of whom treated at the MTD dose level identified with the “one-shot” schedule of 
administration, namely 1.7 mg/kg –  showed signs of a treatment-induced TLS, which represents a 
potential sign for potent antileukemic activity. Overall, these data support to continue the investigation 
of the clinical activity of MEN1112 given as single agent in AML patients with relapsed/refractory 
disease, and to investigate the new administration schedule (“ramp-up”) aiming at exploring 
additional dose levels in the ARMY-1 study following the iDSMB recommendation for any dose 
escalation decision. 
Therefore, considering a) the fair tolerability of MEN1112 at the MTD dose level (1.7 mg/kg) 
identified using  the “one-shot” schedule, b) the possibility to further increase the MTD dose level by 
the mean of the new “ramp-up” schedule, c) the implementation of an iDSMB, as well as d) the 
potentially promising antitumour activity of MEN1112 (as proven by the four reported TLS cases, two 
of which at the 1.7 mg/kg dose level using the “one-shot” schedule), and eventually e) its potential 
use in combination studies using the “ramp-up” schedule of administration, the risk-benefit is 
assessed to be in favour of continuing MEN1112 clinical investigation and development as above 
described. 
7. STUDY OBJECTIVES 
 
7.1 
PRIMARY OBJECTIVES 
To identify the DLT and MTD of MEN1112 when given intravenously during Cycle 1 in patients with 
relapsed or refractory AML. 
 
7.2 
SECONDARY OBJECTIVES 
The following will be assessed/determined: 
• Safety and tolerability of MEN1112. 
• Pharmacokinetic profile after single and repeat doses of MEN1112 following IV 


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administration. 
• Potential of MEN1112 immunogenicity. 
• Clinical activity of MEN1112. 
• Correlation of baseline patient’s and disease characteristics with clinical activity of MEN1112 
 
 
 
 
 
 
 
 
 
 
 
8. INVESTIGATIONAL PLAN 
 
8.1 
OVERALL STUDY DESIGN AND PLAN DESCRIPTION 
In protocol versions from 1.0 to 4.1 n=3 Dose Limiting Toxicity (DLT) evaluable patients per cohort 
(expanded to n=6 DLT evaluable patients in case of DLT occurrence, with the exception of cohort 0.3 
mg/kg which was expanded to n=6 DLT evaluable patients regardless of DLT occurrence) were 
treated with MEN1112 at escalating doses of 0.1, 0.3, 0.6, 1.0, 1.7, and 2.5 mg/kg using “one-shot” 
infusions. 
Starting from protocol version 6.1/6.2, n=3 Dose Limiting Toxicity (DLT) evaluable patients per 
cohort (expanded to n=6 DLT evaluable patients in case of DLT occurrence) will be treated with 
MEN1112 at escalating doses of 1.7, 2.0, 3.0, 5.0 mg/kg per each dose cohort using a modified 
schedule of administration that will include a “ramp-up” approach at Cycle 1. Additional 
intermediate dose levels may be explored, under a 3+3 design, upon recommendation of the 
independent Data Safety Monitoring Board (iDSMB) that will be appointed to guide dose escalation 
decisions in place of the Cohort Review Committee (CRC) that was appointed for this role up to 
Protocol Version 4.1. 
 
 
  
 
Step 2 (cohort expansion phase): Under Protocol Version 4.1, two patients experienced DLTs at the 
dose level of 2.5 mg/kg using the “one-shot” schedule of administration in Cycle 1. Therefore, the 1.7 
mg/kg dose level was defined as the maximum tolerated dose (MTD) for the schedule of 
administration encompassing the “one-shot” infusion since Cycle 1; as a consequence, the expansion 
phase was opened to enrol up to 25 patients with MEN1112 given as “one-shot” infusions since 
Cycle 1.  


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Starting from protocol version 6.1/6.2, up to 30 patients will be treated with MEN1112 given at the 
MTD identified in Step 1 using the modified schedule of treatment, i.e. encompassing the “ramp-up” 
approach during Cycle 1. The iDMSB, already implemented for Step 1 will also be appointed to 
assess the data collected during the Step 2 of the study. See section 8.4.5 for the treatment plan details. 
Starting from protocol version 6.1/6.2, Cycle 1 and Cycle 2 will constitute the Treatment period, 
followed by a 4-week End of Treatment period and a Follow-up period. During the Follow-up periods, 
only safety and/or efficacy assessments are scheduled; however, to serve the best interest of the 
patients, for those achieving at least a partial response according to protocol-defined criteria, the 
Sponsor commits to consider providing MEN1112 to allow the prosecution of the infusions at the 
frequency recommended by the iDSMB on an individual basis and after discussion with the treating 
Investigator and the Medical Monitor.   
8.2 
SELECTION OF STUDY POPULATION 
The study population of this phase I trial will consist of relapsed or refractory AML patients who meet 
all of the inclusion criteria and none of the exclusion criteria, providing written informed consent. 
 
8.2.1 Inclusion criteria 
Inclusion criteria will be evaluated during Screening Period, with the exception of inclusion criteria 3 
and 4, which will be evaluated at Visit 1/Day 1; inclusion criteria 5 and 6 will be re-evaluated prior to 
the first study drug administration (Visit 1/Day 1). 
1. Male or female patients aged ≥ 18 years. 
2. Documented definitive diagnosis of AML (according to World Health Organization (WHO) 
criteria, 2008) that is relapsed /refractory to standard treatment, for which no standard therapy 
is available or the patient refuses standard therapy. For the purpose of this study, refractory 
AML is defined as following:  
Failure to achieve CR/CRi (IWG criteria, 2003) following at least 1 cycle of cytotoxic 
chemotherapy (or hypomethylating agents if unsuitable for cytotoxic chemotherapy) and 
unlikely, as per Investigator’s judgement, to achieve CR/CRi with further cytotoxic 
chemotherapy (or hypomethylating agents if unsuitable for cytotoxic chemotherapy). 
3. WBC count ≤ 10 x 109/L at Visit 1; hydroxyurea is allowed to lower WBC count. 
4. ECOG performance status of 0 to 2 at Visit 1/Day 1. 
5. Life expectancy of at least 2 months. 
6. Adequate renal and hepatic laboratory assessments: 
- 
AST, ALT, ALP ≤3.0 × ULN, unless considered due to leukemic organ involvement. 
- 
Total Bilirubin ≤2.0 × ULN. 
- 
Serum creatinine ≤2.0 × ULN. 


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7. A female of childbearing potential may be enrolled providing she: 
- 
has a negative pregnancy test during screening period and  
- 
is routinely using an effective method of birth control that both results in a Pearl index < 1 
and is considered highly effective as defined by the Clinical Trial Facilitation Group (e.g. 
combined estrogen and progestogen containing hormonal contraception, associated with 
inhibition of ovulation, intrauterine device, total sexual abstinence or bilateral tubal 
occlusion) until 6 months from the last study drug administration 
- 
undergoes a monthly pregnancy test until 6 months from the last study drug administration. 
8. Able to give written informed consent before any study related procedure. 
 
8.2.2 Exclusion criteria 
Exclusion criteria will be evaluated during Screening Period, with the exception of exclusion criteria 
6, 7, 8 and 9, which will be evaluated at Visit 1/Day 1; exclusion criteria 4 and 5 will be re-evaluated 
prior to the first study drug administration (Visit 1/Day 1). 
1. Acute promyelocytic leukaemia (FAB M3 classification).  
2. Active central nervous system involvement. 
3. Haematopoietic stem cell transplantation (HSCT) performed within 3 months prior to 
Screening Period. Patients with prior allogeneic HSCT performed more than 3 months prior to 
Screening Period are eligible with Medical Monitor approval. 
4. Active infection requiring intravenous antibiotics. 
5. Life-threatening illnesses other than AML, uncontrolled medical conditions or organ system 
dysfunction which, in the investigator's opinion, could compromise the patient's safety or 
interfere with the patient’s ability to comply with the study activities. 
6. Anti-tumour therapy within 14 days of study Visit 1, excluding hydroxyurea. 
7. Prior participation in an investigational study (procedure or device) within 21 days of study 
Visit 1. 
8. Major surgery within 28 days of study Visit 1/Day 1. 
9. Radiotherapy within 28 days prior to study Visit 1 or scheduled along the study conduct. 
10. Known history of HIV or active infection with HCV or HBV. 
11. Known hypersensitivity to MEN1112 excipients.   
12. Other active malignancies. History of malignancy in the last 12 months (except for basal cell 
or squamous cell skin cancer or carcinoma in situ of the cervix or breast or non-melanoma skin 
cancer). 
13. Pregnant or breast-feeding women. 
 
8.2.3 Withdrawal of patients from therapy or assessment 


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Participation in the study is strictly voluntary and patients have the right to withdraw from the study 
at any time without explanation. This will not affect his/her rights for future medical care. Treatment 
should be discontinued also if this is in the best interest of the patient upon Investigator judgement 
and/or in case of any of the following:  
• Non-compliance of the patient or investigator with the protocol 
• Disease progression  
• DLTs  
• Infusion toxicities requiring permanent treatment discontinuation (see §8.4.7)  
• Treatment-related grade 3 not haematological toxicity lasting more than 7 days occurring after 
the first cycle, excluding common complications of AML (in particular infections, bleedings, 
fatigue) 
• Treatment-related grade ≥ 4 not haematological toxicity occurring after the first cycle, 
excluding common complications of AML (in particular infections, bleedings, fatigue) 
• Life threatening related Serious Adverse Event (SAE) 
• Patient receives other treatment for AML (including HSCT) 
• Occurrence of pregnancy 
The Investigator is ultimately responsible for the safety and well-being of the patients and, if at any 
time during the study it is believed that the constraints of this protocol are detrimental to the patient’s 
health, the patient may be withdrawn from the study.  
Withdrawal of a patient must be notified to the study monitor, the reason(s) of withdrawal should be 
documented in the e-CRF and follow-up should be reported. For patients who withdraw from study, 
End of Study Visit has to be performed at the time of withdrawal. 
If a patient prematurely terminates the study, data already collected will be used and analysed for the 
purpose of the study. In regard to biological samples already collected, in case of Informed Consent 
withdrawal, the patient may choose if samples not yet analysed, shall be analysed or destroyed. 
 
8.3 
IDENTITY OF THE INVESTIGATIONAL PRODUCT  
 
8.3.1 Description of Investigational Medicinal Product 
The drug product MEN1112 5.0 mg/mL concentrate for solution for infusion consists of 10 mL of a 
 solution containing 5.0 mg MoAB/mL as concentrate for solution for infusion 
 
 
 
.  
Composition: 
Ingredient 
 
Quality 
Function 
MEN1112 
Internal Specification API 




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store the IMP in the respective national language. The label of the IMP center box is multilingual and 
reports the contents of the center box (quantity and unique numbers of vials) and the instructions how 
to administer and store the IMP in the respective national language. 
Storage: 
. The IMP must be 
kept in a secure area, out of reach and sight of children and inaccessible to unauthorised individuals.  
 
8.3.3 Drug accountability 
Upon receipt of all IMP, study site personnel or the designated pharmacist will open the shipment 
package, verify the contents as stated on the enclosed shipping form, and confirm the receipt by filling 
in and sending the form “Handing over and delivery receipt of Investigational Medicinal Product” 
 
 
The Investigator will be responsible for documenting the dispensing of the IMP to the patient by 
entering the unique vial number in the source documents and in the e-CRF. 
The amount of administered drug product will be documented by the Investigator in the source 
documents and in the e-CRF in order to allow drug accountability. 
In addition, the sites will maintain paper drug accountability forms to document dispensed IMP per 
patient. The peel-off labels of the vials will be stuck on these paper drug accountability forms. 
 
 
 
 
The infusion solution must be kept in a secured area, 
inaccessible to any unauthorised individuals. 
 
8.3.4 Destruction of surplus medication 
Throughout the study course and at the end of the study, all remaining IMP will be reconciled under 
the responsibility of the Investigator at the site. 
 
. In case the return is not possible, the 
IMP can be destroyed locally, provided that the order for destruction is authorised by the Sponsor. 


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8.4 
TREATMENT ADMINISTRATION- FREQUENCY AND DURATION OF APPLICATION 
 
8.4.1 TLS risk assessment and prophylaxis 
At the first “ramp-up” dose (Visit 1/Day 1), prior to study drug administration, TLS risk shall be 
assessed (see Appendix I: TLS Manual for Investigator for details) and, during Cycle 1, TLS 
prophylaxis has to be given prior to each study drug administration, as detailed in the TLS Manual for 
Investigator. 
 
8.4.2 Premedication  
On the first day of each “ramp-up” administration visit (i.e. Visits 1 and 8/Days 1 and 8), as well as 
on each ”one shot” administration visit, premedication shall consist of: 
• Dexamethasone 8 mg (os or IV) at 12 hours prior to the start of infusion 
• Dexamethasone 8 mg (os or IV) to be repeated at 3 hours prior to the start of infusion 
• Methylprednisolone 100 mg IV at 1-2 h prior to the start of infusion 
• An antihistaminic and an antipyretic agent at 30 to 60 minutes prior to the start of infusion 
On the second and the third day of each “ramp-up” administration visit (Visit 2, 3, 9 and 10/Day 2, 3, 
9 and 10), premedication shall consist of:  
• Methylprednisolone 100 mg IV at 1-2 h prior to the start of infusion 
• An antihistaminic and an antipyretic agent at 30 to 60 minutes prior to the start of infusion  
In case the “ramp-up” administration visit is stopped due to infusion-related toxicities: 
• If “ramp-up” is resumed after ≥2 days, the premedication at “ramp-up” resumption should 
follow the whole scheme above, i.e. with dexamethasone on the day of “ramp-up” 
resumption and without dexamethasone on the following “ramp-up” day(s), if any. 
• If “ramp-up” is resumed the day after the interruption, premedication without dexamethasone 
should be given on the day of “ramp-up” resumption and on the following “ramp-up” day(s), 
if any. 
• If “ramp-up” is resumed on the same day of interruption, no additional premedication is 
needed at “ramp-up” resumption. 
8.4.3 Step 1 Dose escalation method and cohort management 
MEN1112 doses are to be administered to cohorts of 3 patients each. If no Dose-Limiting Toxicity 
(DLT) is observed in a cohort of three patients at a given dose level, the next cohort of 3 new patients 


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will be treated with the next higher dose. If a DLT is experienced by one of the three patients at any 
dose, three additional patients will be treated at the same dose level. 
If two or more patients at a given dose level exhibit DLTs, this dose will be defined as the MAD. The 
MTD is defined as one dose level below the MAD, i.e. one dose level below the one at which ≥ 2 
DLTs out of 6 treated patients occur.  
In protocol versions from 1.0 to 4.1 n=3 Dose Limiting Toxicity (DLT) evaluable patients per cohort 
(expanded to n=6 DLT evaluable patients in case of DLT occurrence, with the exception of cohort 0.3 
mg/kg which was expanded to n=6 DLT evaluable patients regardless of DLT occurrence) were 
treated with MEN1112 at escalating doses of 0.1, 0.3, 0.6, 1.0, 1.7, and 2.5 mg/kg using “one-shot” 
infusions. 
Starting from protocol version 6.1/6.2, n=3 Dose Limiting Toxicity (DLT) evaluable patients per 
cohort (expanded to n=6 DLT evaluable patients in case of DLT occurrence) will be treated with 
MEN1112 at escalating doses of 1.7, 2.0, 3.0, 5.0 mg/kg per each dose cohort using a modified 
schedule of administration that will include a “ramp-up” approach at Cycle 1. Additional 
intermediate dose levels may be explored, under a 3+3 design, upon recommendation of the 
independent Data Safety Monitoring Board (iDSMB) that will be appointed to guide dose escalation 
decisions in place of the Cohort Review Committee (CRC) that was appointed for this role up to 
Protocol Version 4.1. 
 
 
. 
8.4.3.1 
Dose-level escalation assessment  
In place of the Cohort Review Committee (CRC), which was appointed to guide dose escalation 
decisions up to Protocol Version 4.1, starting from Protocol Version 6.1/6.2, the decision as to 
whether, or how, to proceed through the dose levels during Step 1 are guided by the iDMSB which 
will be comprised of independent AML experts. 
The iDSMB will meet by telephone to review the latest safety, PK and Pharmacodynamics (PD) (if 
any) data prior to dose-escalation to a subsequent cohort, and at any time if needed. Appropriate 
representatives of the Sponsor and the coordinating CRO will also attend and minute the meeting. 
Decisions of the iDMSB will be documented and sent to the sites.  
The iDSMB is empowered to:  
• Review the safety data from the first cycle of each cohort during the dose escalation phase of 
the study and make dose-escalation (or de-escalation) decisions according to the protocol or 
making adjustments, as needed. AEs occurring in Cycle 2 which meet the definition of a DLT 
or are considered clinically significant may also be considered in making dose escalation 
decisions. 


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• Consider other AEs, or possible trends in AEs, during the dose escalation phase which may 
provide relevant information for the dose escalation. 
• Confirm the MTD or the maximum dose judged to be tolerable for evaluation in Step 2. 
• Review safety data for additional patients recruited at the MTD or the maximum dose judged 
to be tolerable (at least every 2 months). 
• Recommend future dose level and dose schedule administration during the study conduct; 
advise on premedication, concomitant medication and on any individual patient dose 
adjustments. 
Roles and responsibilities of iDSMB as well as meeting schedule and format of information will be 
set forth in a separate iDSMB Charter prior to start administrating the drug to the first patient under 
protocol version 6.1/6.2.  
8.4.4 Step 2- Cohort expansion 
Under Protocol Version 4.1, two patients experienced DLTs at the dose level of 2.5 mg/kg using the 
“one-shot” schedule of administration in Cycle 1. Therefore, the 1.7 mg/kg dose level was defined as 
the maximum tolerated dose (MTD) for the schedule of administration encompassing the “one-shot” 
infusion since Cycle 1; as a consequence, the expansion phase was opened to enrol up to 25 patients 
with MEN1112 given as “one-shot” infusions since Cycle 1.  
Starting from protocol version 6.1/6.2, up to approximately 30 patients will be treated with MEN1112 
given at the MTD identified in Step 1 using the modified schedule of treatment, i.e. encompassing the 
“ramp-up” approach during Cycle 1. In place of the CRC, which was appointed to assess the data 
collected during Step 2 up to Protocol Version 4.1, under Protocol Version 6.1/6.2 and following 
amendments the iDMSB, already implemented in Step 1 will be appointed also to assess the data 
collected during the Step 2 of the study.   
8.4.5 Treatment regimen and duration 
MEN1112 is to be administered intravenously for two treatment cycles.  
Up to Protocol Version 4.1, MEN1112 was administered by intravenous “one-shot” weekly infusions 
for two 21-day cycles, followed by “one-shot” monthly infusions in patients demonstrating clinical 
benefit (as per Investigator’s judgement) as long as such benefit was maintained. Starting from 
protocol version 6.1/6.2, MEN1112 will be administered for two 21-day cycles; the first two infusions 
of Cycle 1 will be given using a “3-day ramp-up” schedule of administration, i.e. the complete 
MEN1112 dose will be split in three days. Starting from the third infusion of Cycle 1 onwards, 
MEN1112 will be administered as “one-shot” infusions. The treatment plan by dose level will be 
therefore as following: 
 
 




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The total dose calculated for the first study drug administration can be applied also for the following 
ones providing that actual patient’s weight is within ±10% of the weight measured prior to the first 
study drug administration. Otherwise, the total dose to be given shall be calculated based on the 
weight measured at the corresponding visit.   
The individual study period (including the follow-up) is six months (except for female patients of 
childbearing potential, who will be required to undergo a monthly pregnancy test until 6 months from 
the last study drug administration). 
8.4.6 Treatment compliance 
The assessment of patients’ compliance to IMP administration is not required as the investigational 
drug is infused at site by the Investigator. 


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8.4.7 Dosage modification and management of infusion toxicities 
No dose adjustment is allowed.  
The following instructions are provided for the management of infusion toxicities: 
 
Toxicity 
CTCAE v.4.03 
Grade (duration) 
Occurrence 
Action on MEN1112 infusion 
Action for toxicity 
Cytokine release 
storm  and/or 
Tumor lysis 
syndrome 
3 (≤7 days) 
First (during “ramp-
up” administration) 
Interrupt MEN1112 until resolved to grade 
0, then: 
- If ≤20% of the ramp-up infusion dose (i.e. 
≤50 mL of the total 250 mL infusion 
solution) was missed, restart MEN1112 at 
the next scheduled study drug 
administration.  
- If >20% (i.e. >50 mL of the total 250 mL 
infusion solution) of the ramp-up infusion 
was missed, as soon as feasible (upon 
resolution to grade 0) restart MEN1112 to 
complete the residual ramp-up dose (e.g. 
if the dose was interrupted when 120 mL 
of the second ramp-up dose had been 
administered, complete the second ramp-
up dose with 130 mL of infusion solution, 
then administer the full 250 mL infusion 
solution of the third ramp-up dose on the 
day after). If the infusion cannot be 
completed within 24 hours from dilution, 
a new infusion solution shall be prepared. 
If applicable, postpone the next scheduled 
study drug administration (i.e. the first 
infusion of the following 3-day ramp-up 
Tumor lysis syndrome (TLS)1:  
• Consider multidisciplinary approach with 
involvement of nephrologists and intensive 
care physicians.  
• Potassium must not be added to the 
hydration fluid.  
• In the absence of contraindications, it is 
recommended rasburicase at a dose of 0·2 
mg/kg/day (duration determined according 
to the clinical response) 
• Symptomatic hypocalcaemia is 
recommended to be treated with a short 
infusion of calcium gluconate   
• In patients with potassium levels ≥6 mmol/l 
or with ≥ 25% increase from baseline,  
cardiac monitoring is recommended 
• Intractable fluid overload, hyperkalaemia, 
hyperuricaemia, hyperphosphataemia or 


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Toxicity 
CTCAE v.4.03 
Grade (duration) 
Occurrence 
Action on MEN1112 infusion 
Action for toxicity 
dosing) to ensure an interval of 5 days 
between any study drug administration is 
guaranteed.  
hypocalcaemia are indications for renal 
dialysis.  
• Consider intensive care unit admittance for 
severe (grade 3-4) TLS cases 
Cytokine release storm2: paracetamol and high 
dose steroids (dexamethasone) are 
recommended. Consider intensive care unit 
admittance for severe (grade 3-4) cases 
Disseminated intravascular coagulation 
(DIC)3:  
• 
In patients with DIC and active bleeding, it 
is recommended the  use of platelet 
transfusion to maintain the platelet count 
above 50x109/L  
• 
In patients with DIC and active bleeding, it 
is suggested transfusion of fresh frozen 
plasma (15–30 mL kg-1) with careful 
clinical monitoring to decide on dose 
adjustments.  
• 
In actively bleeding cases with persistently 
low fibrinogen values (below 1.5 g L-1) 
despite these supportive measures, it is  
suggested transfusion of two pools of 
cryoprecipitate (whenever available) or 
fibrinogen concentrate 
3 (≤7 days) 
First (during “one 
shot” administration) 
Interrupt MEN1112 until resolved to grade 
0, then: 
- If ≤20% of the infusion (i.e. ≤50 mL of 
the total 250 mL infusion solution) dose 
was missed, restart MEN1112 at the next 
scheduled study drug administration. 
- If >20% (i.e. >50 mL of the total 250 mL 


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Toxicity 
CTCAE v.4.03 
Grade (duration) 
Occurrence 
Action on MEN1112 infusion 
Action for toxicity 
infusion solution) of the infusion was 
missed, as soon as feasible (upon 
resolution to grade 0) restart MEN1112 to 
complete the residual dose (e.g. if the dose 
was interrupted when 120 mL had been 
administered, complete the dose with 130 
mL of infusion solution). If the infusion 
cannot be completed within 24 hours from 
dilution, a new infusion solution shall be 
prepared. If applicable, postpone the next 
scheduled study drug administration to 
ensure an interval of 7 days between any 
study drug administration is guaranteed. 
• 
Routine use of tranexamic acid is not 
recommended. If therapy-resistant 
bleeding dominates the picture in 
hyperfibrinolytic DIC, tranexamic acid 
may be considered 
• 
It is recommended regular clinical and 
laboratory surveillance of the patient, to 
detect the development of complications 
including organ failure, and to ensure the 
underlying condition is being adequately 
treated 
• 
Consider intensive care unit admittance for 
severe (grade 3-4) cases 
Infusion related reaction (IRR)4: 
• 
Stop the administration of medication 
• 
Maintain the i.v. access and assess the 
patients level of consciousness 
• 
Position: - In the case of hypotension, the 
patient should be placed in the 
Trendelenburg position. - In the case of 
respiratory distress, sitting up. - If 
unconscious, in recovery position. 
• 
Administrate oxygen, if needed  
3 (≤7 days) 
Second 
Discontinue MEN1112 permanently 
3 (>7 days) 
Any 
4 (any) 
Any 
Elevated 
transaminase(s), 
disseminated 
intravascular 
coagulation, 
and/or other 
clinically 
relevant (as 
determined by 
treating 
physician) 
adverse 
reactions 
3 (≤7 days) 
First 
Interrupt MEN1112 until the toxicity 
improves to grade ≤1, then follow the 
instructions provided above for grade 3 
cytokine release storm/tumor lysis 
syndrome lasting ≤7 days at the first 
occurrence (either during ramp-up or one 
shot administration, as applicable). 
3  (≤7 days) 
Second 
Discontinue MEN1112 permanently 
3 (>7 days) 
Any 
4 (any) 
Any 
Any 
2 
Any 
Interrupt MEN1112 until the toxicity 
improves to grade ≤1, then follow the 
instructions provided above for grade 3 
cytokine release storm/tumor lysis 


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Toxicity 
CTCAE v.4.03 
Grade (duration) 
Occurrence 
Action on MEN1112 infusion 
Action for toxicity 
syndrome lasting ≤7 days at the first 
occurrence (either during ramp-up or one 
shot administration, as applicable) 
• 
In case of anaphylaxis: 
o It is recommended to administer adrenaline 
(0.01 mg/kg  intramuscularly); this can be 
repeated every 5–15 min. Failure of a 
prompt response should be followed by 
administration of i.v. adrenaline 
o Fluid resuscitation: a rapid infusion of 1–2 
litres of normal saline at a rate of 5–10 
mL/kg in the first 5 min is recommended.  
o Vasopressors: dopamine (400 mg in 500 
mL of 5% dextrose water) administered at 
2–20 mg/kg/min and titrated to increase 
systolic blood pressure might be required if 
adrenaline and fluid resuscitation have 
failed 
to 
alleviate 
hypotension. 
Vasopressin and norepinephrine may also 
be used in anaphylaxis that is unresponsive 
to adrenaline 
o Antihistamines: the combined use of H1 
and H2 antagonists is superior to the use of 
either alone.  Diphenhydramine (1–2 
mg/kg or 25–50 mg) may be given slowly 
i.v. in combination with ranitidine (50 mg) 
i.v. over 5 min  
o Corticosteroids: effective in preventing 
biphasic reactions, but not critical in the 
management of anaphylaxis. If given, the 
Any 
1 
Any 
At Investigator’s discretion, either continue 
the scheduled infusion or interrupt it until 
the toxicity is resolved; in this latter case 
follow the instructions provided above for 
grade 3 cytokine release storm/tumor lysis 
syndrome lasting ≤7 days at the first 
occurrence (either during ramp-up or one 
shot administration, as applicable).   


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Toxicity 
CTCAE v.4.03 
Grade (duration) 
Occurrence 
Action on MEN1112 infusion 
Action for toxicity 
dosing 
of 
i.v. 
corticosteroids 
is 
recommended to be equivalent to 1–2 
mg/kg of (methyl)prednisolone every 6 h 
o For bradycardia, it is recommended 
atropine 600 µg i.v. 
Elevated transaminases: it is recommended to 
rule out possible alternative/contributing 
causes. For grade 3 or 4 events, monitoring of 
liver function tests is recommended to be 
carried out on a daily basis. 
1 Adapted from Coiffier et al, J Clin Oncol. 2008 Jun 1;26(16):2767-78 and from Jones et al, Br J Haematol. 2015 Jun;169(5):661-71 
2 Adapted from Frey  and Porter, Hematology Am Soc Hematol Educ Program. 2016 Dec 2;2016(1):567-572 
3 Adapted from Thachil et al, J Thromb Haemost2015;13: 671–5. 
4 Adapted from Rosellò et al, Ann Oncol (2017) 28 (suppl 4): iv100–iv118 
 
In case an infusion is interrupted due to drug-related toxicities (not meeting permanent treatment withdrawal criteria), when the infusion is 
resumed and/or at all subsequent infusions, the infusion duration shall be prolonged to 8 hours (total infusion time), using a constant infusion rate. 
In case of grade 3 or 4 Cytokine Release Syndrome (CRS), it is recommended to consider the use of high dose corticosteroids. Intensive-care 
supportive therapy should be considered for severe or life-threatening CRS, tumour lysis syndrome and/or disseminated intravascular coagulation. 


 
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8.4.8 Concomitant Medication 
During the study, patients are not allowed to receive: 
• Any other investigational agent. 
• Any active agent in AML setting (hydroxyurea is allowed throughout the whole duration of 
the first induction cycle in case of need for WBC count reduction). 
Concomitant and prior (i.e. within 30 days before enrolment) medications shall be carefully 
checked since the use of the above reported medications may represent an exclusion criterion and 
make the patient ineligible to participate in the study. Furthermore, the regular and occasional use 
of any concomitant medication has to be recorded starting from Screening until the End of Study 
Visit.  
 
8.5 
STUDY PROCEDURES AND ASSESSMENTS 
 
8.5.1 Study Procedures  
Approximately 40 study visits are scheduled for screening, treatment and for assessment of safety, 
efficacy and pharmacokinetics as depicted in the study flow chart (see §2.2) and summarised below.  
The End of Study Visit is scheduled 180 days after Visit 1/Day 1.  
Written Informed Consent has to be obtained PRIOR to performing any study assessment, as 
described below: 
 
Screening Period (Day -7 to 0) 
 Check of Inclusion/Exclusion Criteria 
 Demographic data collection 
 Medical and medication general history 
 AML history, i.e. date of onset of AML, relapsed or refractory status following the last 
AML treatment, de novo or secondary AML status, number and category of previous 
AML treatments (including autologous and allogeneic HSCT), and duration of last CR 
(for relapsed patients), and disease features when available (i.e. AML karyotype, NPM1 
and/or FLT3-ITD mutational status, FAB subtype)  
 Physical examination, including vital signs (i.e. blood pressure [BP], heart rate [HR], 
breathing rate [BR], body temperature [T]) 
 Weight measurement 
 Performance Status (PS) evaluation  
 12-lead ECG 
 Blood sampling and urine collection for safety lab tests, including pregnancy test (if 
applicable) 
 Blood sampling for anti-HIV antibodies, anti-HBcAg antibodies, HBV-DNA, HCV-
RNA 
 
 




 
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 12-lead ECG at the end of infusion 
 Blood sampling for PK 
 
 (at the end of infusion, and 6h after the end 
of infusion) 
 Recording of AEs and change in concomitant medications 
 
Visit 2/Day 2(one day after the completion of Visit 1) and Visit 3/Day 3 (one day after the 
completion of Visit 2) 
Prior to study drug administration 
 Physical examination, including vital signs 
 PS evaluation 
 12-lead ECG 
 Blood samplingfor safety lab test 
 Blood sampling for PK 
 (pre-infusion) 
 Recording of AEs and change in concomitant medications 
 TLS prophylaxis (see Appendix I: TLS Manual for Investigator) 
 Premedication (see §8.4.2)  
Study drug administration 
 Study drug administration, given as 6h infusion with constant infusion rate 
 Blood sampling for safety lab test at the following time points after start of infusion: 2h, 
4h, 8h, 12h 
 Vital signs every 15 minutes during the first hour of study drug administration and then 
at the same time points of  
blood sampling for safety lab test 
 12-lead ECG at the end of infusion 
 Urine collection at the end of infusion (ONLY at Visit 3) 
 Blood sampling for PK 
 at the end of infusion, 6h after the end of 
infusion (ONLY at Visit 2), 14h after the end of infusion (ONLY at Visit 3) 
 Recording of AEs and change in concomitant medications 
 
Visit 4/Day 4, one day after the completion of the entire first “ramp-up” 
 Physical examination, including vital signs 
 PS evaluation 
 Blood sampling for safety lab test  
 
 
 Blood sampling for PK 
 24h after the end of last “ramp-up” dosing 
infusion 
 Bone marrow aspirate for morphologic assessment, 
 
  


 
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 Recording of AEs and change in concomitant medications 
 
Visit 5-6/Day 5-6, one and two days after Visit 4, respectively 
 Blood sampling for PK 
 (44h and 68h after the end of last “ramp-up” 
dosing infusion) 
 Recording of AEs and change in concomitant medications 
 
Visit 8/Day 8 (five days after the completion of Visit 3), Visit 9/Day 9 (one day after the 
completion of Visit 8) and Visit 10/Day 10 (one day after the completion of Visit 9), second 3-
day “ramp-up” administration 
Prior to study drug administration 
 Physical examination, including vital signs 
 Weight measurement (ONLY at Visit 8/Day 8) 
 PS evaluation 
 Blood sampling for safety lab test  
NOTE: Check that WBC count is ≤ 10 x 109/L (ONLY at Visit 8/Day 8); hydroxyurea 
is allowed to lower WBC count. 
 Blood sampling for PK 
 (pre-infusion) 
 Recording of AEs and change in concomitant medication  
 TLS prophylaxis (see Appendix I: TLS Manual for Investigator)  
 Premedication (see §8.4.2) 
Study drug administration 
 Study drug administration, given as a 6h infusion with constant infusion rate 
 Blood sampling for safety lab test at the following time points after start of infusion: 2h, 
4h, 8h, 12h 
 Vital signs every 15 minutes during the first hour of study drug administration, after then 
at the same time points of blood sampling for safety lab test 
 Blood sampling for PK 
at the end of infusion) 
 Recording of AEs and change in concomitant medications 
 
Visit 11/Day 11, one day after the completion of the entire second “ramp-up” 
 Physical examination, including vital signs 
 PS evaluation 
 Blood sampling for safety lab test including pregnancy test, if applicable 
 Recording of AEs and change in concomitant medications 
 
Visit 12/Day 15, five days after Visit 10, first “one-shot” infusion 
Prior to study drug administration 




 
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Study drug administration 
 Study drug administration, given as a 6h infusion with constant infusion rate 
 Vital signs every 15 minutes during the first hour of study drug administration and at 15 
minutes after end of infusion 
 Blood sampling for PK 
 (at the end of infusion) 
 Recording of AEs and change in concomitant medications 
 
Visit 17-19/ Day 23-25, one, two and three days after the completion of Visit 16, respectively 
 Physical examination including vital signs 
 PS evaluation 
 Blood sampling for safety lab test  
 Recording of AEs and change in concomitant medications 
 
Visit 20/Day 29, seven days after the completion of Visit 16 
Prior to study drug administration 
 Physical examination including vital signs  
 Weight measurement 
 PS evaluation  
 Blood sampling for safety lab test  
 Blood sampling for PK 
 (pre-infusion) 
 Recording of AEs and change in concomitant medication  
 Premedication (see §8.4.2)  
Study drug administration 
 Study drug administration, given as a 6h infusion with constant infusion rate 
 Vital signs every 15 minutes during the first hour of study drug administration and at 15 
minutes after end of infusion 
 Blood sampling for PK 
 at the end of infusion 
 Recording of AEs and change in concomitant medications 
 
Visit 21-23/Day 30-32, one, two and three days after the completion of Visit 20, respectively 
 Physical examination including vital signs 
 PS evaluation 
 Blood sampling for safety lab test  
 Recording of AEs and change in concomitant medications 
 
Visit 24/Day 36, seven days after the completion of Visit 20 
Prior to study drug administration 
 Physical examination including vital signs  


 
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 Weight measurement 
 PS evaluation  
 Blood sampling for safety lab test  
 Blood sampling for PK 
 (pre-infusion) 
 Recording of AEs and change in concomitant medications  
 Premedication (see §8.4.2)  
Study drug administration 
 Study drug administration, given as a 6h infusion with constant infusion rate 
 Vital signs every 15 minutes during the first hour of study drug administration and at 15 
minutes after end of infusion 
 Blood sampling for PK 
 (at the end of infusion and at 1h and 6h after 
the end of infusion) 
 Recording of AEs and change in concomitant medications 
 
Visit 25-27/Day 37-39, one, two and three days after the completion of Visit 24, respectively 
 Physical examination including vital signs 
 PS evaluation 
 Blood sampling for safety lab test including pregnancy test (only at Visit 27, if 
applicable) 
 Blood sampling for PK 
 (24h, 48h and 72h after the end of infusion) 
 Recording of AEs and change in concomitant medications 
 
Visit 28-29/Day 40-41, one and two days after Visit 27, respectively 
 Blood sampling for PK 
 (96h and 120h after the end of infusion) 
 Recording of AEs and change in concomitant medications 
 
Visit 30/Day 42, the day after Visit 29 
 Physical examination including vital signs 
 PS evaluation 
 Blood sampling for safety lab test  
 
 
 Blood sampling for PK 
 (144h after the end of infusion) 
 Bone marrow aspirate for morphologic assessment,
 
 
 Recording of AEs and change in concomitant medications 
 
NOTES:  




 
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treatment with fresh frozen plasma even in the presence of fibrinogen values within normal 
range. 
 
END of TREATMENT 
Visit 31-34/Day 43/50/57/64, one week, two weeks, three weeks and four weeks after Visit 24, 
respectively) 
 Blood sampling for PK 
 
 Blood sampling for immunogenicity assessment (ONLY at Visit 34) 
 Recording of AEs and change in concomitant medications 
NOTE: During the End of Treatment, a time-frame of + 1 day is allowed at any visit, however the 
scheduled time of the following visits should be maintained. 
 
FOLLOW-UP PERIOD 
Visit 35-38/Day 65/85/121/149, one, twenty-nine, fifty-seven and eighty-five days after Visit 34, 
respectively 
 Physical examination, including vital signs 
 PS evaluation 
 Blood sampling for safety lab test including pregnancy test (if applicable) 
 Bone marrow aspirate for morphologic assessment on Visit 35 and Visit 37 only in 
patients showing peripheral blood labs consistent with CR/CRi/PR 
 Recording of AEs and change in concomitant medications. 
NOTES:  
- 
To serve the best interest of the patients, for those achieving at least a partial remission, 
the Sponsor commits to consider providing MEN1112 to allow the prosecution of the 
infusions at the frequency recommended by the iDSMB on an individual basis and after 
discussion with the treating Investigator and the Medical Monitor. In this case, 
premedication and safety assessments will resemble those already described for study 
drug administration visits, unless differently advised by the iDSMB. 
- 
During Follow-up Period, a time-frame of + 2 days each is allowed at any visit, 
however the scheduled time of the following visits should be maintained. 
 
END OF STUDY 
End of Study Visit (180 days after Visit 1/Day 1) 
 Physical examination and vital signs 
 PS evaluation 
 Blood sampling for safety lab test including pregnancy test (if applicable) 
 
  


 
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 Bone marrow aspirate for morphologic assessment,
 
 
 Recording of AEs and change in concomitant medications 
NOTES:  
• 
At the End of Study Visit, a time-frame of + 5 days is allowed. 
• All patients shall undergo the End of Study Visit at the scheduled date or at the time of 
study withdrawal. Unscheduled assessments showing disease progression and leading to 
patient’s withdrawal can replace the End of Study Visit provided that all 
assessment/procedures scheduled for this visit are completed.  
• In case the patient is discontinued from the study within the treatment period, the End of 
Study Visit bone marrow aspirate is highly recommended to be performed. 
 
GENERAL NOTES: 
• 
For each safety lab test, blood sampling for PK 
 
 (except for those to be 
collected at the end of infusion) and for vital signs, a window of +/- 5% of the required time 
interval is allowed. 
• 
The total dose calculated for the first study drug administration can be applied also for the 
following ones providing that actual patient’s weight is within ±10% of the weight measured 
prior to the first study drug administration; otherwise, the total dose to be given shall be 
calculated based on the weight measured at the corresponding visit. 
• 
Any effort aimed at preserving patient’s safety and/or further clarifying an adverse event is 
recommended, including unscheduled assessments (e.g. additional safety lab sampling, 
additional safety lab parameters). The anonymized documentation of the above unscheduled 
assessment shall be then provided to the Sponsor. 
• 
It is strongly recommended not to start the treatment on the day prior to -or on- 
weekends/holidays, unless the treatment is deemed not deferrable by the Investigator in view 
of the specific patient’s clinical situation. In such case, the site shall anyway guarantee the 
actual availability of site personnel as well as the actual feasibility of ALL study procedures 
as required by the protocol. 
8.5.1.1 
Sample Analyses 
In order to perform safety, pharmacokinetics, immunogenicity, 
,
 
 
 
 from approximately 4 
mL to 90 mL (this highest volume taken only during the administration visits of Cycle 1) of whole 
blood volume needs to be collected per visit.   
 
  


 
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Details on samples collection, handling and shipment will be provided in separate Laboratory 
Manuals. 
Bone marrow morphologic assessment will be performed on bone marrow blood smears. 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 Bone marrow morphologic assessment will be performed locally. 
 
 
 
 
 
 
8.5.2 Assessment of Safety  
Safety and tolerability endpoints will be derived from the following measurements/evaluations: 
 
Incidence, severity, seriousness, and treatment related causality of TESS. 
 
Frequency of clinically significant changes in: 
− 
Physical examination and vital signs 
− 
PS Evaluation 
− 
Safety laboratory tests 
− 
12-lead-ECG.  
8.5.2.1 
Medical History 


 
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Complete medical history will be collected during the Screening Period in order to obtain all the 
information necessary to confirm the study inclusion and exclusion criteria. 
General medical history shall include all the diseases (excluding AML) and conditions, either 
chronic or not, which are needed to assess the compliance with inclusion/exclusion criteria and 
those which are relevant according to the Investigator. 
The AML specific medical history will include: date of onset of AML, relapsed or refractory status 
following the last AML treatment, de novo or secondary AML status, number and category of 
previous AML treatments (including auto- and allo-HSCT, if any), duration of the last CR/CRi 
(relapsed patients), AML karyotype (if available), NPM1 mutational status (if available), FLT3-ITD 
mutational status (if available), FAB subtype (if available) and previous patient’s participation in 
clinical trials (if any).  
General medical history shall be collected starting from 30 days prior to screening. 
AML specific medical history shall be collected starting from AML onset date. 
8.5.2.2 
Physical Examinations and Vital signs  
A complete physical examination will be performed at each study visit from Screening to End of 
Study Visit, except at Visit 5-6, Visit 28-29 and during the End of Treatment period; it includes a 
general appearance observation and a complete exam of the following body systems/areas: Head, 
Eyes, Ears, Nose and Throat (HEENT)/Neck, Lymph Nodes, Thyroid, Abdomen, Skin, 
Cardiovascular, Respiratory, Gastrointestinal, Neurological and Musculoskeletal/Extremities.  
Vital signs will be recorded throughout the study at each visit except at Visit 5-6, Visit 28-29/ and 
during the End of Treatment period. At each study drug administration during Cycle 1, vital signs 
should be measured prior to study drug administration and following the same time points of blood 
sampling for safety lab tests (see 14.3). At Cycle 2, they should be measured prior to study drug 
administration, every 15 minutes during the first hour of study drug administration and 15 minutes 
after the end of infusion. The following parameters will be measured: 
 
Heart rate (HR, beats / min) 
 
Blood pressure (BP, systolic and diastolic, mmHg) 
 
Breathing rate (BR, breaths / min) 
 
Body temperature (T, °C). 
8.5.2.3 
Weight measurement 
Body weight (to the nearest 0.1 kilogram [kg] in indoor clothing, but without shoes) will be 
measured during screening period and at study drug administration visits (during Cycle 1 only prior 
to the first “ramp-up” dose and at Visit 12/Day 15). 
8.5.2.4 
PS evaluation 
Performance Status evaluation will be performed throughout the study at each visit except at Visit 
5-6, Visit 28-29 and during End of Treatment period. The ECOG scale will be used.  
 


 
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8.5.2.5 
12-Lead ECG 
12-Lead ECGs will be performed locally, using standard equipment available at the study sites, 
during Screening Period and at Visit 1/Day 1, Visit 2/Day 2 and Visit 3/Day 3 (prior to and at the 
end of the study drug infusion).  
Standard 12-Lead ECG will be performed at rest in the supine position. All ECG print-outs should 
be identified with patient number, year of birth and gender, as well as with the date and time of 
recording. All print-outs should be assessed, dated and signed by the Investigator and stored in the 
patient’s record. 
8.5.2.6 
Clinical laboratory evaluation 
Safety laboratory assessments will be performed at each study visit except at Visit 5-6, Visit 28-29 and 
during End of Treatment. Pregnancy test will be performed, if applicable, during Screening Period, at 
Visit 11, at Visit 27, at Visits 35-38 and at the End of Study Visit. In addition, female patients of 
childbearing potential are required to undergo a monthly pregnancy test until 6 months from the last 
study drug administration. Urinalysis will be assessed prior to and at the end of the first “ramp-up”  
administration visit (Visit 1/Day 1, Visit 2/Day 2 and Visit 3/Day 3). The assessment of anti-HIV 
antibodies, anti-HBcAg antibodies, HBV-DNA and HCV-RNA will be performed ONLY during the 
Screening Period. Safety tests will be performed by the local laboratory of participating sites in order 
to ensure prompt patient management. For the same reason, tests for anti-HIV antibodies, anti-HBcAg 
antibodies, HBV-DNA and HCV-RNA will be performed by the local laboratory of participating sites 
according to local standard procedures. Results of laboratory tests for anti-HIV antibodies, anti-
HBcAg antibodies, HBV-DNA, HCV-RNA which have been performed within 3 months prior to 
Screening Period in the context of the standard patient’s management (either in the local lab or in a 
different lab, provided that they comply with local standard procedures) can be reported in the e-CRF 
under Screening Period procedures. In such case, there is no need to repeat the above mentioned tests. 
Laboratory values have to be transcribed into the e-CRF, except for the urinalysis where only the 
judgment will be reported; the Sponsor will be provided by the site laboratories with the currently 
valid version of the respective normal ranges (any update of reference ranges needs to be notified on 
an ongoing basis). 
The lab print-outs should be identified with the patient number. All print-outs should be dated and 
signed by the Investigator and stored in the patient’s record. Any out of range value shall be 
clinically assessed by the Investigator. 
The volume of blood to be drawn for each battery of safety lab tests will amount to approximately 
15 mL.  
The following tests will be performed: 
 
 
 
 
 


 
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Table 3: Serum, Blood and Urine Sample Analyte Listing 
SERUM CHEMISTRY 
SERUM VIROLOGY 
HAEMATOLOGY 
URINALYSIS 
Creatinine 
Anti-HIV antibodies 
Haemoglobin 
pH 
Uric acid 
Anti-HBcAg 
antibodies 
Haematocrit 
Density 
Potassium 
HBV-DNA 
RBC count 
 
Phosphorus 
HCV-RNA 
Platelet count 
MCV 
 
Calcium 
 
WBC count and 
differential (absolute and 
%): 
 
Nitrite 
BUN/Urea 
 
neutrophil 
Protein 
Albumin 
 
lymphocyte 
Glucose 
Alkaline phosphatase 
 
eosinophil 
Ketones 
Glucose 
 
basophil 
RBC 
Total proteins 
 
monocytes 
WBC 
Total bilirubin and Direct 
bilirubin 
 
blasts 
Epithelial cells 
ALT and AST 
 
 
Casts 
LDH 
 
 
Bacteria 
GGT 
 
 
Yeast 
INR 
 
 
Crystals 
Prothrombin time and/or 
prothrombin activity 
Partial thromboplastin time 
Fibrinogen 
D-dimer 
Amylase 
 
 
 
Sodium 
 
 
 
Chloride 
 
 
 
Beta-HCG (if applicable) 
 
 
 
 
8.5.2.7 
 Adverse Events/Serious Adverse Events – Definitions 
 
8.5.2.7.1 Adverse Event (AE) 
An AE is any untoward medical occurrence in a patient (or a clinical investigation subject), 
receiving a medicinal product and which does not necessarily have a causal relationship with the 
treatment. An AE can, therefore, be any unfavourable and unintended sign (including an abnormal 
clinically significant laboratory finding), symptom, or disease temporally associated with the use of 
a medicinal (investigational) product, whether or not related to the medicinal (investigational) 
product. 
8.5.2.7.2 Adverse Drug Reaction (ADR) 
All untoward and unintended responses to an Investigational Medicinal Product (IMP) related to 
any dose administered. The definition covers also medication errors and uses outside what is 
foreseen in the protocol, including misuse and abuse of the product. The definition implies a 
‘reasonable possibility of a causal relationship between the event and the IMP. This means that 
there are facts (evidence) or arguments to suggest a causal relationship.  


 
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8.5.2.7.3 Intensity (severity) of an Adverse Event / Adverse Drug Reaction 
  
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 14.4). 
The highest intensity grade reached in a given cycle should be reported in the e-CRF: 
- 
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. 
 
NOTE: In case of an AE/ADR consisting of a laboratory abnormality, its intensity (severity) 
should be ranged based on the level of abnormality of the out –of-range value and/or its 
interference on patient ability to perform daily routine activities, as above defined. A severe AE, 
as defined by the above grading scale, is NOT the same as serious AE which is defined in 
§8.5.2.7.4. 
* Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0. Published: May 28, 2009 (v4.03: June 14, 
2010). U.S.DEPARTMENT OF HEALTH AND HUMAN SERVICES National Institutes of Health National Cancer 
Institute (please refer to Appendix IV). 
 
8.5.2.7.4 Serious Adverse Event (SAE) / Serious Adverse Drug Reaction 
(SADR) 
Any untoward medical occurrence or effect that at any dose: 
 
results in death. 
 
is life-threatening. 
 
NOTE: the term life-threatening in the definition of “serious” refers to an event in which the 
patient 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. 
 
 
requires patient hospitalisation or prolongation of existing hospitalisation. 
 
results in persistent or significant disability/incapacity. 
 
is a congenital anomaly/birth defect. 
 
is an ‘important medical event’ that may jeopardise the patient or may require an 
intervention to prevent one of the above characteristics/consequences. 
 


 
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NOTE: Hospitalisation lasting less than 24 hours or pre-planned hospitalisation for medical 
intervention, such as chemotherapy administration, shall not qualify as SAE.  
 
Any other AE/ADR which is not included in the above definitions will be considered as non-
serious. 
The Investigator should also promptly report all the SAEs to the Sponsor’s Drug Safety Manager 
(DSM, see §8.6).  
8.5.2.7.5 Unexpected Adverse Drug Reaction  
An ADR, the nature or intensity of which is not consistent with the applicable product ‘safety 
reference information (e.g. IB for an unauthorised investigational product or summary of product 
characteristics (SmPC) for an authorised product).  
Any other ADR which is not included in the above definition will be considered as expected. 
 
NOTE: In this study, the reference document is the MEN1112 IB, last version approved..  
8.5.2.7.6 Algorithm for Causality Assessment of Adverse Events 
The causality (causal relationship to the study drug) of AEs will be assessed based on the following 
algorithm: 
1. Certainly related: An AE, including a laboratory test abnormality assessed as CS, is considered 
certainly related to a drug when it occurs in a plausible time relation to the administration of the 
drug, and which cannot be explained by concurrent disease or other drugs or chemicals. The 
response to withdrawal of the drug (de-challenge) should be clinically plausible. The event must be 
definitely related, pharmacologically or phenomenologically, using a satisfactory re-challenge 
procedure if necessary. 
2. Probably related: An AE, including a laboratory test abnormality assessed as CS, is considered 
probably related to a drug when it occurs in a reasonable time relation to the administration of the 
drug, is unlikely to be attributed to concurrent disease or other drugs or chemicals, and which 
follows a clinically reasonable response on withdrawal (de-challenge). Re-challenge information 
(AE reappearance after drug reintroduction) is not required to fulfil this definition. 
3. Possibly related: An AE, including a laboratory test abnormality assessed as CS, is considered 
possibly related to a drug when it occurs in a reasonable time relation to the administration of the 
drug, or it could also be explained by concurrent disease or other drugs or chemicals. Information 
on drug withdrawal (de-challenge) may be lacking or unclear. 
4. Unlikely related: An AE, including a laboratory test abnormality assessed as CS, is considered 
unlikely related to a drug when other drugs, chemicals or underlying disease provide plausible 
explanations and/or the temporal relation to the administration of the drug makes a causal relation 
improbable. 


 
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5. Not related: An AE, including a laboratory test abnormality assessed as CS, is considered not 
related to the use of a drug in case of existence of a clear alternative explanation and/or 
unreasonable temporal relationship, and/or non plausibility. 
6. Unassessable/unclassifiable: The relationship between drug and AE, including a laboratory test 
abnormality assessed as CS, is considered unassessable/unclassifiable when a report, suggesting an 
AE, cannot be judged because information is insufficient or contradictory and cannot be 
supplemented or verified. 
An AE in which the relationship is ranked 1, 2, 3 or 6 is defined as an ADR. AEs ranked 4 or 5 are 
not considered as ADRs. 
8.5.2.8 
Monitoring and Recording of Adverse Events 
The Investigator is responsible for the detection and documentation of events meeting the definition 
of AE, as provided in this protocol (see § 8.5.2.7.1). 
All AEs, whether or not thought to be drug related, must be actively followed-up and recorded by 
the Investigator (or designee) in the source documents and in the appropriate section of the e-CRF 
throughout the whole study duration, starting from the Informed Consent signature to the End of 
Study Visit or 70 days after last study drug administration whichever occurs last.   
NOTE: An AE will be considered as ‘Treatment-Emergent Signs and Symptoms (TESS)’ if it 
occurs for the first time or if it worsens in terms of seriousness or severity after the first study drug 
intake (Visit 1). 
8.5.3  Pharmacokinetic Evaluation 
Blood samples for MEN1112 serum concentration measurements will be taken during Treatment 
phase and End of Treatment as depicted in § 14.2. If any interruption occurs during Cycle 1 and the 
3rd infusion of Cycle 2 (i.e. where the PK is evaluated), blood sampling for PK & exploratory tests 
will be taken at the time of each infusion interruption and just before each infusion resumption. 
 
 
 
 
Cmax 
Maximum observed serum concentration. 
tmax 
Time to Cmax. 
Clast 
Last quantifiable serum concentration. 
tlast 
Time to Clast. 
Ctrough 
Pre-dose serum concentration. 
Cavg 
AUC from dose time to τ (i.e. dosing interval) divided by τ 


 
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ke 
Apparent terminal elimination rate constant, estimated by log-
linear regression analysis on serum concentrations visually 
assessed to be on the terminal log-linear phase. 
t½ 
The terminal serum half-life, calculated according to the 
following equation:  
ek
t
693
.0
2
/
1
=
                   
AUC(0-t) 
 
Area under the serum concentration-time curves from time zero 
(pre-dose) to the time of the last quantifiable concentration, 
calculated by means of the linear-log trapezoidal method. 
AUC(0-∞) 
Area under the serum concentration-time curve from time zero to 
infinity, calculated according to the following equation:                     
e
last
t)
(0
k
C
AUC
AUC
+
=
−
∞)
−
(0
 
%AUCex 
The percentage of AUC(0-∞) obtained by extrapolation calculated 
as follows: 
100
(%)
⋅
−
=
∞
−
−
∞
−
)
(0
)
t
(0
)
(0
ex
AUC
AUC
AUC
AUC
  
CL 
Systemic clearance, calculated according to the following 
equation:   
 
AUC
Dose
CL
)
-
(0 ∞
=
 
Vss 
Volume of distribution at steady state, calculated according to 
the following equation:  
MRT
CL
Vss
⋅
=
  
Vd 
Volume of distribution based on the terminal phase, calculated 
according to the following equation:  
 
AUC
k
Dose
V
e
d
)
-
(0 ∞
⋅
=
                    
AUMC(0-∞) 
The area under the first moment curve from zero to infinity 
calculated using the equation: 
(
)
2
1
1
i
1
0
1
-
0
)
(
2
e
e
i
i
i
n
i
i
i
k
Clast
k
Clast
tlast
t
C
t
C
t
t
AUMC
+
⋅
+
+
-
=
+
+
-
=
+
∞
∑
+
t∙Ct
λz + 
Ct
λz2 +
t∙Ct
λz + 
Ct
λz2 +
𝑡𝑡∙𝐶𝐶𝑡𝑡
λ𝑧𝑧+ 
𝐶𝐶𝑡𝑡
λ𝑧𝑧2 
MRT 
Mean residence time (for drug given with a constant infusion rate over 
a period Tinf) was calculated as: 
(
)
2
T
-
AUC
AUMC
MRT
inf
)
-
(0
0
∞
∞
-
=
 
Ro 
Accumulation ratio calculated as: 
|
1
|
1
τ
ek
e
Ro
−
−
=
 
 


 
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PK parameters will be calculated, as data permit, following each of the three doses of the first 
“ramp-up” administration visit during Cycle 1 and following the third “one-shot” administration 
visit during Cycle 2.  
The following PK variables will be assessed following the 1st and 2nd dose of the first “ramp-up” 
administration visit during Cycle 1: 
• Cmax, tmax, Ctrough, Cavg, AUC(0-t) 
The following PK variables will be assessed following the 3rd dose of the first “ramp-up” 
administration visit during Cycle 1:  
• Cmax, tmax, Ctrough, Cavg, Clast, tlast, AUC(0-t), AUC(0-∞), %AUCex, ke, t1/2, CL, Vss, Vd, AUMC(0-
∞), MRT. 
Total AUC following the first “ramp-up” administration visit during Cycle 1 will be calculated as 
the sum of AUC(0-t) related to each dose.  
The following pharmacokinetic variables will be assessed following the 3rd “one-shot” 
administration visit during Cycle 2:  
• Cmax, tmax, Ctrough, Cavg, Clast, tlast, AUC(0-t), AUC(0-∞), %AUCex, ke, t1/2, CL, Vss, Vd, AUMC(0-
∞), MRT, accumulation ratio (Ro). 
 
Actual PK sampling times will be used in the derivation of PK parameters. Alternatively, it is also 
acceptable to consider the planned sampling times if they do not deviate by more than 5% from the 
actual. Planned sampling times may be used as a replacement for unknown or missing actual times. 
The calculation of the parameters listed above and others will depend upon the results of the drug 
concentration assay and the duration of drug infusions. 
For the calculation of individual pharmacokinetic parameters, values Below the Lower Limit Of 
Quantification (BLLOQ) will be handled as follows: 
1. BLLOQ values located before the tmax of their affiliating curve will be transformed to zero. 
2. If a BLLOQ value located after the tmax falls between two quantifiable concentrations, it will 
be omitted from the pharmacokinetic analysis.  
3. If, within a dosing interval, two or more BLLOQ values occur in succession after 
quantifiable concentrations, the profile will be deemed to have terminated at the first 
BLLOQ value and any subsequent concentrations in that dosing interval will be omitted 
from the non-compartmental analysis.  
4. In some circumstances, when a pharmacokinetic rationale exists, BLLOQ values may be set 
to some other values, e.g., half of the Lower Limit of Quantification (LLOQ). 
Concentrations reported as >LLOQ at time zero, when the subject has not previously been dosed, 
will be set to zero. 
 
 
 


 
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8.5.4 Pharmacokinetic and Safety Endpoints 
 
8.5.4.1 
Primary Endpoints 
• Identification of DLT defined as an adverse event occurring during the first treatment cycle, 
judged to be related to MEN1112 and meeting any of the following criteria:  
• Grade 3 non-haematological toxicity lasting more than 7 days  
• Grade ≥ 4 non-haematological toxicity.  
Note: Common complications of AML (in particular infections, bleedings, fatigue) will not 
contribute to DLT assessment.   
• Identification of MTD defined as one dose level below the Maximum Administered Dose 
(i.e. one dose level below the one at which ≥ 2 DLTs out of 6 treated patients occur). 
 
8.5.4.2 
Secondary Endpoints 
• Immunogenicity Evaluation Criteria: Incidence of anti-MEN1112 autoantibodies. 
• Clinical Evaluation Criteria: 
 Complete remission (CR) rate at any time point, where CR is defined as: bone 
marrow blasts <5%, absence of extramedullary disease, absolute neutrophil count >1 
x 109/L and platelet count > 100 x 109/L.  
 Composite complete remission (CRc) rate at any time point, defined as the 
proportion of patients having either CR or CRi (where CRi is defined as: all criteria 
for CR except residual thrombocytopenia [platelets <100 x 109/L] and/or neutropenia 
[absolute neutrophil count <1 x 109/L]). 
 Best response rate, defined as the best observed response at any time point between 
CR, CRi and partial remission ([PR]: all haematologic criteria for CR with bone 
marrow blasts 5-25% and decrease of pre-treatment bone marrow blast percentage by 
at least 50%). 
 Duration of CRc: number of days between the date of CR/CRi achievement and the 
date of the last assessment confirming CR/CRi. 
 Overall Survival (OS), defined as the number of days between the first study drug 
administration and death from any cause. 
 Correlation of baseline characteristics with clinical activity of MEN1112. 
 
 
  
 
 
 
 
 
 
 
 
8.5.4.4 
Safety Endpoints 


 
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 Incidence, severity, seriousness and treatment related causality of Treatment 
Emergent Signs and Symptoms (TESSs).  
 Frequency of clinically significant abnormalities in physical examination, safety 
laboratory tests, vital signs and 12-Lead ECG. 
 
8.5.4.5 
Pharmacokinetic Endpoints 
PK parameters will be calculated, as data permit, following each of the three doses of the first 
“ramp-up” administration visit during Cycle 1 and following the third “one-shot” administration 
visit during Cycle 2.  
The following PK variables will be assessed following the 1st and 2nd dose of the first “ramp-up” 
administration visit during Cycle 1: Cmax, tmax, Ctrough, Cavg, AUC(0-t). 
The following PK variables will be assessed following the 3rd dose of the first “ramp-up” 
administration visit during Cycle 1: Cmax, tmax, Ctrough, Cavg, Clast, tlast, AUC(0-t), AUC(0-∞), %AUCex, 
ke, t1/2, CL, Vss, Vd, AUMC(0-∞), MRT. Total AUC following the first “ramp-up” administration 
visit during Cycle 1 will be calculated as the sum of AUC(0-t) related to each dose.  
The following pharmacokinetic variables will be assessed following the 3rd “one-shot” 
administration visit during Cycle 2: Cmax, tmax, Ctrough, Cavg, Clast, tlast, AUC(0-t), AUC(0-∞), %AUCex, 
ke, t1/2, CL, Vss, Vd, AUMC(0-∞), MRT, accumulation ratio (Ro).  




 
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be provided to the Sponsor’s SDSM by email no later than 24 hours after they become known by 
the Investigator. 
 
8.6.2 Management of Suspected Unexpected Serious Adverse Reactions and 
other relevant safety issues 
For each SAE, assessment of seriousness (according to § 8.5.2.7.4), causality (according to 
§8.5.2.7.6) will be provided by both, the reporting Investigator and the Sponsor. The assessment of 
expectedness (according to §8.5.2.7.5) will be done by the Sponsor. 
 
NOTE: The causality assessment given by the Investigator will not be downgraded by the Sponsor. 
If the Sponsor disagrees with the Investigator’s causality assessment, the opinions of both, the 
Investigator and the Sponsor, will be provided. 
 
SUSARs (Suspected Unexpected Serious Adverse Reaction) are AEs which, cumulatively: 
− have a reasonable possibility of causal relationship to the IMP 
− are serious  
− are unexpected 
The Sponsor will ensure that all SUSARs occurred during the study are reported on an expedited 
basis (7 days or 15 days) to the concerned national CAs and ECs, according to European and/or 
country-specific legal requirements: 
- For fatal and life-threatening SUSARs: the Sponsor should report at least the minimum 
information, as soon as possible, and in any case no later than 7 days after being made aware of 
the case. If the initial report is incomplete, the Sponsor is to submit a completed report based on 
the initial information within an additional 8 days.  
- SUSARs which are not fatal and not life-threatening are to be reported within 15 days. 
- The clock for expedited initial reporting (day zero) starts as soon as the information containing 
the minimum reporting criteria has been received by the Sponsor (or the Sponsor’s delegate). 
- If significant new information on an already reported case is received by the Sponsor, the clock 
starts again at day zero (i.e. the date of receipt of new information). This information should be 
reported as a follow-up report within 15 days. 
The Sponsor will also inform all investigators. Whenever practicable, the information will be 
aggregated in a 6 monthly cumulative ‘line listing’ of SUSARs (with a brief safety assessment 
report), as required, per country regulations. 
Apart from SUSARs, the following safety issues will be subjected 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; 


 
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• 
An anticipated end or suspension for safety reasons of another study with the 
same study drug. 
8.6.3 Management of Non-Serious Adverse Events (NSAES) and/or Laboratory 
Abnormalities 
The Investigator must record all the available information concerning any NSAE (whether or not 
deemed related to the investigational drug) in the corresponding section of the eCRF: eCRF-AE pages, 
within 5 calendar days after the first knowledge of the occurrence of the event. 
When relevant, e-CRF pages concerning medical history, concomitant medication and laboratory test 
will also be retrieved by the Sponsor’s SDSM. 
In addition, during the clinical study, abnormalities in laboratory tests (newly occurring after ICF 
signature or worsening of previously known abnormalities), which are considered clinically 
significant by the Investigator (such as values significantly above or under normal range or which 
require an intervention or diagnostic tests, or which may result in the IMP discontinuation), should 
be reported as AEs. Furthermore, all abnormalities in laboratory values should be collected and 
reviewed by Sponsor on a monthly basis. 
8.6.4 Annual Safety Reporting 
Once a year throughout the clinical trial, the Sponsor will provide the concerned national CAs and 
ECs with a safety report (Development Safety Update Report, DSUR), taking into account all new 
safety information received during the reporting period.  


 
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8.6.5 Breaking of the Randomisation Code 
Not applicable. 
8.6.6 Serious and Non-Serious Adverse Event Follow-Up 
After the End of Study Visit or 70 days after last study drug administration whichever occurs last, 
the Investigator is not requested to actively follow-up the patient unless ongoing SAEs or non-
serious AEs of special interest (as per CRC/iDSMB indication) are present. However, if the 
Investigator becomes aware of any SAE with a suspected causal relationship to the IMP after the 
end of the study, the Investigator shall, without undue delay, report the SAE to the Sponsor. 
These SAEs should be also recorded in the e-CRF as far as it is available. If the e-CRF is not 
available, the paper SAE form will be used as a backup.  
Patients who have discontinued the treatment for any reason will be followed up for at least 10 
weeks after the last drug dose, or until recovery from all toxic effects or longer in case of expected 
delayed toxicity. 
 
8.7 
MANAGEMENT OF POSITIVE PREGNANCY TEST 
Pregnancy tests will be performed, if applicable, during Screening Period, at Visit 11, at Visit 27, at 
Visits 35-38 and at the End of Study Visit. In addition, female patients of childbearing potential are 
required to undergo a monthly pregnancy test until 6 months from the last study drug 
administration. Pregnant women are excluded from the enrollment onto the study. In case a patient 
becomes pregnant during the study period, she shall be discontinued from treatment and the 
pregnancy followed up until the outcome.  
The Investigator is expected to record in the provided “Pregnancy Exposure Report Form” any case 
of pregnancy occurring in a female patient participating in the study, during the treatment and until 
6 months from the last study drug administration. The mentioned form will be sent by e-mail to the 
Sponsor’s DSM within 5 calendar days after being made aware of the pregnancy. The “Pregnancy 
Exposure Report Form” is distributed to the sites to be used for this purpose. 
The Investigator is requested to follow up each case of pregnancy exposure until the completion or 
termination of the pregnancy. If the pregnancy continues to term, the “Pregnancy Exposure Report 
Form” must be completed with the outcome (health status of the newborn infant) and sent to the 
Sponsor’s SDSM again within 5 days after the outcome is known. If the pregnancy results in an 
abnormal outcome (miscarriage or new-born with congenital abnormality and/or stillbirth), in 
addition to completing the “Pregnancy Exposure Report Form”, this will be recorded in the e-CRF as 
a SAE and managed as above described in § 8.6.1. 
 
8.8 
INDEPENDENT DATA SAFETY MONITORING BOARD  
Starting from protocol version 6.1/6.2, an independent Data Safety Monitoring Board (iDMSB) 
made by a panel of independent AML experts is introduced. In the Step 1, the iDSMB will be 


 
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responsible to review dose escalation data and make dose escalation decisions; moreover, the 
iDSMB will review and assess the data collected during the Step 2 of the study.  
Roles and responsibilities of the iDSMB are detailed in a separate DSMB Charter. 
 


 
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9. STATISTICAL METHODS AND DETERMINATION OF SAMPLE SIZE 
 
9.1 
DETERMINATION OF SAMPLE SIZE 
Due to the nature of the study, no formal sample size calculation is applicable. 
 
  
Starting from protocol version 6.1/6.2, up to approximately 6 DLT evaluable patients per dose level 
will be treated with MEN1112 during the dose escalation phase, while up to approximately 30 
patients will be treated in the cohort expansion phase. Considering that the patients no-DLT 
evaluable during the dose escalation phase will be replaced, and assuming a drop-out rate of 30%, 
up to approximately 60 patients will be treated with MEN1112. This number might be higher in 
case additional intermediate dose levels will be investigated.  
 
9.2 
ANALYSIS POPULATIONS 
The following analysis populations will be considered in the statistical analysis: 
 Safety population: all patients receiving study drug. 
 DLT population:  
 
 
 
 
 
 
 
 
  
Starting from protocol version 6.1/6.2 and following amendments: 
 All patients receiving at least 80% of the scheduled study drug administration during the 
first treatment cycle and with a safety follow-up of at least 6 days after the last 
administered dose or having experienced a DLT.   
 Efficacy population: all patients completing the first treatment cycle and having a post-cycle 
peripheral blood lab test and bone marrow aspirate. 
 PP population: all patients of the efficacy population excluding patients who experience major 
protocol violation(s).  
 PK population: all patients receiving the study treatment and with reliable drug assay data 
relevant for the PK parameter of interest. 
 
9.3 
STATISTICAL ANALYSIS 
 
9.3.1 Descriptive statistics 


 
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All study variables (with the exception of PK variables) will be presented by cohort, dose and 
overall, by using the appropriate descriptive statistics according to the variable nature, unless 
otherwise specified: 
 Continuous variables: number of non-missing observations, arithmetic mean, standard deviation 
(SD), minimum, median, maximum. 
 Categorical variables: number of non-missing observations and column percentages (N, %). 
 Time to event variables: number of non-missing observations, number and percentage of 
censored observations, 1st quartile, median and its 95% CI, 3rd quartile, Kaplan-Meier survival 
curves and event rate every 21 days. 
 
The behaviour over time of study variables will be summarised by cohort and overall as follows: 
 Continuous variables: descriptive statistics for each time point and for the absolute/percentage 
differences to baseline.  
 Discrete variables: descriptive statistics for each time point and shift tables to baseline. 
 
The Overall Survival (OS) is calculated as: 
• In case of all-cause death: 
OS = date of death – date of first study drug administration + 1.  
• In case of censored information not for drop-out: 
OS = date of end of observation period (i.e. study end / end of survival follow-up) – date of 
first study drug administration + 1.  
• In case of censored information for drop-out: 
OS = Last date known alive – date of first study drug administration + 1. 
 
9.3.2  Efficacy Analysis 
Efficacy analyses will be performed only through descriptive statistics. 
 
9.3.3 Pharmacokinetic Analyses 
The PK analysis will be run on the PK population. All PK variables (i.e. serum concentrations and 
parameters) will be summarized by cohort using the following descriptive statistics: 
• Number of non-missing observations (N), 
• Arithmetic mean and its 90% CI, SD, coefficient of variation (CV%) and standard error 
(SE),  
• Geometric mean (GM) and its 90% CI and GM CV%,  
• Minimum, median, maximum. 
The concentration of MEN1112 will be summarized for each scheduled sampling time point (see 
Appendix II: Timings of Blood sampling for PK 
) using descriptive statistics. 
Individual serum concentration data versus time will be presented in a data listing and visualized as 


 
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individual concentration-time plots. Additional analyses, if deemed appropriate, will be described in 
the statistical analysis plan. 
For descriptive statistics, BLLOQ concentrations at time zero, when the subject has not previously 
been dosed, will be set to zero. All other BLLOQ values will be substituted by ½ LLOQ value 
before the calculation of the summary statistics.  
 
9.3.4 Safety analysis 
Safety and toxicity will be evaluated on the safety population by means of descriptive statistics 
during each study phase. Summary statistics (counts, %) will report the incidence of the AEs by 
CTC toxicity grade, dose level, cycle of therapy, relationship to study drug and overall. Counts and 
percentages will be produced for the results of the ECG, laboratory values, vital signs, physical 
examination, all classified as Normal/Abnormal NCS/Abnormal CS by dose level and therapy 
cycle. 
Descriptive statistics will also be produced for the extent of exposure, overall drug(s) 
administration, drug(s) administration by dose(s) level, and dose(s) delay by dose(s) level. 
 
9.3.5 Data Imputations 
The missing values will not be imputed because, for all the analyses, an observed-cases approach 
will be applied. 
 
9.4 
PROTOCOL VIOLATIONS AND DATA REVIEW MEETING 
Categories of protocol violations will be defined and will be integrated in the statistical analysis. 
For the primary efficacy analysis, a Data Review Meeting (DRM) will take place at the end of the 
study in order to evaluate and accept the data management report, discuss remaining issues 
(outstanding queries, unresolved errors) and to confirm and approve relevant protocol violations. 
After this final DRM has taken place and the database is considered cleaned, the database will be 
locked. 
 
9.5 
STATISTICAL ANALYSIS PLAN 
The SAP will be finalised before the lock of the study database. The SAP will describe in detail 
study endpoints and the statistical analyses, including the statistical analysis of the primary endpoint 
to be performed, including also additional endpoints and analyses not planned in the protocol. In 
case changes of the original primary endpoint or of the original primary analyses occur during the 
study, these changes will be the subject of a substantial protocol amendment.  
Minor deviations (e.g. not involving changes in the primary endpoint and analysis) which might 
occur during the study will be detailed only in the SAP. All statistical analyses not pre-specified and 
run after data lock will be considered additional/exploratory analyses.  


 
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10. DATA QUALITY MANAGEMENT 
 
10.1 DATA COLLECTION 
Data collection activities will be carried out under the responsibility of the Sponsor. Patient data 
will be collected using an Electronic Data Capture system (EDC see §10.1.1). Patients will be 
identified by the patient study identification number (patient ID), assigned during the Screening 
Period.  
  
 
 
 
 
 
Data will be collected, processed, evaluated, reviewed and stored in anonymous form in accordance 
with applicable data protection regulations. 
10.1.1 Case Report Forms 
Clinical data collected during the study at sites will be recorded in an electronic Case Report Form 
(e-CRF) using 
, which is a validated system. The Sponsor will be responsible for 
developing the e-CRF based on this study protocol and to review and perform the user acceptance 
test of the e-CRF in order to ensure protocol adherence.  
The e-CRF will be made available to the study personnel by means of the 
 The 
accounts will be individual and password-protected.  
The Investigator or designee will be responsible for entering study data into the e-CRF in 
accordance to the e-CRF Completion Guidelines provided by the Sponsor. In order to improve the 
quality of data collection and cleaning, data shall be entered into the e-CRF as closely as possible to 
the time when they become available and in any case within 5 working days. 
The e-CRF data will not be considered as source data. The definition of the source data can be 
found in section 10.3. 
Investigators will ensure the accuracy, completeness and consistency of data entered electronically 
signing the e-CRF using a personal password. An audit trail within the system will track all changes 
made to the data. 
10.1.2 Central Laboratory/Examination data 
The following Central Laboratories will be used during the study: 
 
• 
 
 
 


 
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10.1.3 Data capture systems versions and validation documentation 
Versions of EDC system could change during the study. The Sponsor will maintain a list of the data 
capture system versions used and the validation documentation of each version. The list and the 
validation documentation will be provided to the site at the Site Initiation Visit (SIV) and will be 
updated at any EDC version change. 
10.2 CLINICAL DATA MANAGEMENT 
Data Management will be carried out under the responsibility of the Sponsor.  
e-CRF data will be electronically verified through the use of automatic and manual checks. 
Discrepancies in the data will be resolved by means of electronic queries. Data will be frozen after 
source data verification by the Monitor, and they will be locked by the Data Managers when all 
activities for the trial, including medical and safety revision of the data, are complete and no more 
entries are expected.  
Data from sources other than e-CRF will be provided to the Data Manager on an agreed scheduled 
basis. The Data Manager has the responsibility to reconcile data captured in the e-CRF with 
external data sources. Discrepancies found in the reconciliation of the data will be addressed by 
means of queries.  
A clear overview of all clinical data management activities will be given in the Data Management 
Plan. 
10.3 SOURCE DATA 
Source data are defined as all data in original records and certified copies of original records of 
clinical findings, observations or other activities in a clinical trial that are necessary for the 
reconstruction and evaluation of the trial. 
Original documents and data records include, but are not limited to, hospital/patients’ medical 
records, laboratory notes, ECG records, patients’ evaluation checklists, pharmacy dispensing 
records. 
Study sites will also maintain paper drug accountability forms for the IMP to document dispensed 
and returned IMP per patient. 


 
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Source data should be held available for inspection by Sponsor representatives for the study or other 
authorised persons, such as auditors and inspectors of Regulatory Authorities.  
Direct access to source data is defined as permission to examine, analyse, verify and reproduce any 
records and reports that are important for evaluation of a clinical trial. Any party allowed direct 
access to study source data and documents should take all reasonable precautions within the 
constraints of the applicable regulatory requirements to maintain the confidentiality of patient 
identity and sponsor proprietary information.  
Data that are derived from the source documents should be consistent with the source documents 
and discrepancies, if any, should be explained in writing.  
All the original documentation pertinent to the study procedures must be available for review in 
each patient’s record. 
10.4 QUALITY CONTROL/QUALITY ASSURANCE 
10.4.1 Study Monitoring 
This trial will be monitored in accordance with the ICH Note for Guidance on Good Clinical 
Practice. Monitoring and will be carried out by the CRO, 
 
The site monitor will perform visits to the trial sites during the study 
conduct. At each monitoring visit, the facilities, study drug, storage conditions for immunogenicity, 
 and blood sampling for PK 
, storage area, e-CRF, patient’s 
source data, and all other study documentation will be inspected/reviewed by the site monitor for 
adherence to the protocol and Good Clinical Practice. At each site visit, the monitor will review the 
e-CRFs for completion and accuracy. Accuracy will be checked by performing source data 
verification that is a direct comparison of entries made onto the e-CRFs against the appropriate 
source documentation. Any resulting discrepancies will be reviewed with the Investigator and 
his/her staff. 
The Investigator agrees to allow access to all study related materials needed for the proper review of 
study conduct and to assist the monitor during the monitoring visits and during the data cleaning 
process. Monitoring procedures require that 100% of data are source data verified, particularly 
focusing on informed consents, adherence to inclusion/exclusion criteria, drug accountability, 
documentation of SAEs and the proper recording of efficacy and safety measurements. 
All monitoring activities will be described in detail in the study-specific Monitoring Plan. 
10.4.2 Quality Assurance 
Independent study audit(s) and/or inspection(s) may take place at any time during or after the trial. 
The Independent audits/inspections can be carried by the Quality Assurance (QA) Department of 
the CRO, the independent Sponsor QA, or a Competent Authority. At all times, the confidentiality 
of patient related documents will be maintained. 
11. 
PREMATURE TERMINATION OF THE WHOLE STUDY 


 
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The whole trial may be discontinued at the discretion of the Sponsor in the event of any of the 
following: 
 New information leading to unfavourable risk-benefit judgement of the investigational products 
due to: 
- 
Occurrence of clinically significant unknown AEs or unexpectedly high severity or 
incidence of known AEs 
- 
New evidence of unfavourable safety or efficacy findings (from clinical or non-clinical 
examinations, e.g. toxicology) 
 The Sponsors decision that continuation of the trial is unjustifiable for medical or ethical 
reasons 
 Discontinuation of development of the IMP. 
Competent Authorities and IRB/IECs will be informed about the discontinuation of the trial in 
accordance with applicable regulations. 
12. END OF CLINICAL TRIAL AND ARCHIVING 
The clinical trial 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. 
12.1 ARCHIVING OF ELECTRONIC DOCUMENTATION/DATA  
Duplicate electronic media 
 containing 
the patient data in PDF format (i.e. e-CRFs) for each site will be prepared by the Sponsor or a delegate 
for archiving purposes. 
 
 
 
  
Patient data relevant for each site will be distributed to the Investigator, who has to confirm the receipt 
of the material, verify whether the provided electronic media represent a copy of data generated during 
the study and sign a dedicate form provided by the Sponsor, the signed form has to be collected and 
archived at the Sponsor TMF. 
 
 In addition, the Sponsor is responsible for creating 
2 electronic media 
 containing an integrated 
 
database with all study data (e.g.: e-CRF, central laboratory); 
 
 
Investigators and the Sponsor will be also responsible for refreshing their electronic media 
 to ensure long term archiving of files/data. 


 
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13. REFERENCES 
1. Cancer Incidence in Sweden 2006. National Board of Health and Welfare. 
http://wwwsocialstyrelsense/NR/rdonlyres/AAD7CA00-CCE3-4E3EB998-
1450BD7FB4A1/9428/20074216pdf. Accessed July 3, 2008. 
2. National 
Cancer 
Institute, 
Surveillance 
Epidemiology 
and 
End 
Results. 
http://wwwseercancergov/aststats/selectionsphp?run&output_2&data_1&statistic_1&year_2
00802&race_1&sex_1&age 1&series_cancer&cancer_96#Output. Accessed July 3, 2008. 
3. Phekoo KJ, Richards MA, Moller H, Schey SA. The incidence and outcome of myeloid 
malignancies in 2112 adult patients in southeast England. Haematologica. 2006;91:1400-
1404. 
4. Estey E, Dohner H. Acute myeloid leukaemia. Lancet. 2006;368:1894-1907. 
5. Juliusson G, Billstrom R, Gruber A, et al. Attitude towards remission induction for elderly 
patients with acute myeloid leukaemia influences survival.  Leukaemia. 2006;20:42-47. 
6. Slovak M, Kopecky K, Cassileth PA, et al: Karyotypic analysis predicts outcome of 
preremission and postremission therapy in adult acute myeloid leukaemia: A Southwest 
Oncology Group/ Eastern Cooperative Oncology Group Study. Blood 96:4075-4083, 2000. 
7. Grimwade D, Walker H, Oliver F, et al: The importance of diagnostic cytogenetics on 
outcome in AML: Analysis of 1,612 patients entered into the MRC AML: 10 Trial. Blood 
92:2322-2333, 1998. 
8. Ellison RR, Holland JF, Weil M, et al. Arabinosyl. cytosine: a useful agent in the treatment 
of acute leukaemia in adults. Blood. 1968;32:507-523. 
9. Boiron M, Weil M, Jacquillat C, et al. Daunorubicin in the treatment of acute myelocytic 
leukaemia. Lancet. 1969;1:330-333. 
10. Di Nardo et al, Blood 2019 133:7-17 
11. Wei et al, Blood 2017 130:890 
12. https://www.onclive.com/web-exclusives/fda-approves-glasdegib-for-frontline-aml 
13. Burnett AK. Treatment of acute myeloid leukaemia in younger patients. Best Pract Res Clin 
Haematol. 2001;14:95-118. 
14. Mayer RJ, Davis RB, Schiffer CA, et al. Intensive postremission chemotherapy in adults 
with acute myeloid leukaemia: Cancer and Leukaemia Group B. N Engl J Med. 
1994;331:896-903. 
15. Schiller G, Gajewski J, Territo M, et al. Long-term outcome of high-dose cytarabine-based 
consolidation chemotherapy for adults with acute myelogenous leukemia. Blood. 
1992;80:2977-2982. 
16. Ribeiro RC, Razzouk BI, Pounds S, Hijiya N, Pui CH, Rubnitz JE. Successive clinical trials 
for childhood acute myeloid leukaemia at St Jude Children’s Research Hospital, from 1980 
to 2000. Leukaemia. 2005;19:2125-2129. 


 
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17. Zittoun RA, Mandelli F, Willemze R, et al. Autologous or allogeneic bone marrow 
transplantation compared with intensive chemotherapy in acute myelogenous leukaemia: 
European Organization for Research and Treatment of Cancer (EORTC) and the Gruppo 
Italiano Malattie Ematologiche Maligne dell’Adulto (GIMEMA) Leukaemia Cooperative 
Groups. N Engl J Med. 1995;332:217-223. 
18. Wahlin A, Markevarn B, Golovleva I, Nilsson M. Improved outcome in adult acute myeloid 
leukaemia is almost entirely restricted to young patients and associated with stem cell 
transplantation. Eur J Haematol. 2002;68:54-63. 
19. Cornelissen JJ, van Putten WL, Verdonck LF, et al. Results of a HOVON/SAKK donor 
versus nodonor analysis of myeloablative HLA-identical sibling stem cell transplantation in 
first remission acute myeloid leukaemia in young and middleaged adults: benefits for 
whom? Blood. 2007;109:3658-3666. 
20. Burnett AK. The treatment of AML: current status and novel approaches. Haematology. 
2005; 10[suppl 1]:50-53. 
21. Ortolan  E,  Vaisitti T and Aydin S. Evolution and Function of the ADP Ribosyl 
Cyclase/CD38 Gene Family in Physiology and Pathology.  Physiol Rev.; 88: 841-86, 2008.  
22. Kaisho T, Ishikawa J, Oritani K, Inazawa J, Tomizawa H,  Muraoka O,  Ochi T, and Hirano 
T.  BST-1, a surface molecule of bone marrow stromal cell lines that facilitates pre-B-cell 
growth.  PNAS , 91: 5325-5329, 1994. 
23. Okuyama Y, Ishihara K, Kimura N, Hirata Y, Sato K, Itoh M, Ok LB, Hirano T. Human 
BST-1 expressed on myeloid cells functions as a receptor molecule. Biochem Biophys Res 
Commun. ; 228(3):838-45, 1996.  
24. Satoh M, Iida S, Shitara K. Non-fucosylated therapeutic antibodies as next-generation 
therapeutic antibodies. Expert Opin Biol Ther. 2006;6:1161–1173.  
25. Ho X, Fook-Chong S, Linn YC. Natural killer cell receptor repertoire is comparable 
amongst newly diagnosed acute myeloid leukaemia of different French-American-British 
subtypes, risk categories and chemosensitivities. Leuk Lymphoma. 2014 Feb;55(2):342-8. 
26. Lion E, Willemen Y, Berneman ZN et al. Natural killer cell immune escape in acute 
myeloid leukaemia. Leukaemia. 2012 Sep;26(9):2019-26. 
27. Stringaris K, Sekine T, Khoder A, et al. Leukaemia-induced phenotypic and functional 
defects in natural killer cells predict failure to achieve remission in acute myeloid 
leukaemia. Haematologica. 2014 May;99(5):836-47. 
28. Fauriat C, Just-Landi S, Mallet F, et al. Deficient expression of NCR in NK cells from acute 
myeloid leukaemia: Evolution during leukaemia treatment and impact of leukaemia cells in 
NCRdull phenotype induction. Blood. 2007;109(1):323- 330. 
29. Kazuhito Yamamoto, Atae Utsunomiya, Kensei Tobinai, Kunihiro Tsukasaki Phase I Study 
of KW-0761, a Defucosylated Humanized Anti-CCR4 Antibody, in Relapsed Patients With 


 
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Adult T-Cell Leukaemia-Lymphoma and Peripheral T-Cell Lymphoma J Clin Oncol 2010:  
28:1591-1598. 
30. Takashi Ishida, Tatsuro Joh, Naokuni Uike, Kazuhito Yamamoto Defucosylated Anti-CCR4 
Monoclonal Antibody (KW-0761) for Relapsed Adult T-Cell Leukaemia-Lymphoma: A 
Multicenter Phase II Study J Clin Oncol  2012: 30:837-842. 
 


 
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14. APPENDICES 
 
14.1 APPENDIX I: TLS MANUAL FOR INVESTIGATOR 
 
 
 
 
 
 
 
 
 
 
 
 
Tumour Lysis Syndrome (TLS) Manual for Investigator 
 
for ARMY-1 Clinical Study 
 
 
 
 
First in man study with MEN1112, a CD157 targeted 
monoclonal antibody, in relapsed or refractory Acute 
Myeloid Leukemia 
 
 


 
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Table of Content 
 
1. 
Risk assessment for tumor lysis syndrome (TLS) ............. Errore. Il segnalibro non è definito. 
2. 
TLS diagnostic criteria ...................................................... Errore. Il segnalibro non è definito. 
3. 
Prophylaxis of TLS ............................................................ Errore. Il segnalibro non è definito. 
4. 
Treatment of established TLS............................................ Errore. Il segnalibro non è definito. 
5. 
References ......................................................................... Errore. Il segnalibro non è definito. 


 
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1. RISK ASSESSMENT FOR TUMOR LYSIS SYNDROME (TLS) 
Patients due to receive the first cycle of treatment with MEN1112 should have a risk assessment for 
tumour lysis syndrome (TLS) according to the following algorithm: 
 
Figure adapted from Cairo M, Coiffier B, Reiter A and Younes A on behalf of the TLS Expert Panel. British Journal of 
Haematology 2010. 
Important Note:   
 Patients with LRD are intermediate-risk for TLS when renal dysfunction and/or renal involvement 
is present; 
 Patients with IRD are high-risk for TLS when renal dysfunction and/or renal involvement is 
present OR when uric acid, phosphate and/or potassium levels are > ULN 
Legend. WBC= White Blood Count, LDH=Lactate Dehydrogenase, ULN= Upper Limit of Normal, 
LRD= Low Risk Disease, IRD= Intermediate Risk Disease, HRD= High Risk Disease. 
Important note: Although neither French-American-British subtype nor cytogenetics are included in 
the TLS risk assessment algorithm, it is worth considering that AML inv(16) / t(16;16) and the M4Eo 
cases are prone to demonstrate fulminant TLS under treatment, some of which have been reported to 
be fatal even despite optimal clinical patient management. Such TLS, which in other AML are usually 
only seen with very high peripheral blood counts, may show up in AML M4 inv(16) / t(16;16) 
patients even with low peripheral tumor cell counts, which is suspected to be linked to a very high 
fragility/sensitivity of the tumor cells to lysis/cell death induction. In this respect it is worth recalling 
that in the first in human ARMY study, a fulminant TLS leading to disseminated intravascular 
coagulation and consequent cerebral haemorrhage was the most likely cause for the fatal treatment-
related case occurred in patient 
, who was indeed affected by relapsed AML M4 Eo with 
t(16;16). 
 




 
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3. PROPHYLAXIS OF TLS 
LRD 
IRD 
HRD 
Hydration 
Hydration 
Hydration 
± Allopurinol 
Allopurinol 
Rasburicase 
 
Important Note: 
 Any patient with renal impairment or allergic to allopurinol should be considered for rasburicase 
despite their risk assignment based on tumor features, though those with low risk disease can often 
be managed using hydration alone 
 Rasburicase should be avoided in patients with glucose-6-phosphate dehydrogenase (G6PD) 
deficiency. Such patients should be treated with fluids and allopurinol and monitored carefully 
 
 
Hydration: The exact fluid volume required is not known but it seems reasonable to aim for 3 L/24 h, 
provided individual tolerability. Urinary output shall be carefully monitored. Alkalinization is not 
recommended.  
 
Allopurinol: The standard recommended dosing schedule for allopurinol in prevention of TLS is 200–
400 mg/m2/day in 1–3 divided doses for adults, up to a maximum of 800 mg daily. In practice, most 
adult haematologists simply use 300 mg/day and, for the most part, this is effective but it may be 
prudent to increase the dose of allopurinol or, preferably, switch to rasburicase in the presence of 
deteriorating biochemical or clinical markers. Allopurinol doses may need to be adjusted in renal 
failure. 
 
 
Rasburicase: Although the licensed dose of rasburicase is 0,2 mg/kg/day, a number of publications 
have explored lower doses and shorter courses of therapy. Taking these into account, and 
pragmatically considering available vial sizes, it has been recommend that, in the absence of 
established clinical or laboratory TLS, TLS can be prevented in the majority of adult patients using a 
single fixed dose of 3 mg rasburicase. It is essential to closely monitor for biochemical and clinical 
markers of TLS and if there is evidence of any progression then the dose should be repeated daily 
until markers of TLS have entirely returned to normal. In patients with a prior history of glucose-6-
phosphate dehydrogenase (G6PD) deficiency, rasburicase is contraindicated and allopurinol should be 
utilized instead of rasburicase. 


 
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4. TREATMENT OF ESTABLISHED TLS 
Management of this condition requires a multidisciplinary approach including haematologists, 
nephrologists and intensive care physicians. The following topics need to be addressed: 
 
Fluid balance: There are no trials that demonstrate a particular rate of fluid delivery to be better than 
another but recent reports suggest 3 L/m2 every 24 hours would be reasonable in adults, with the aim 
of maintaining a urine output of > 100 ml/m2/h for older patients. Urine output should be measured at 
least hourly and a formal assessment of fluid balance should be undertaken at least 6 hourly. Care 
should be taken to document all fluid losses, such as vomiting or diarrhoea. Elderly patients and those 
with pre-existing cardiac and renal disease are at particular risk of fluid overload. Whilst furosemide 
0.5 mg/kg intravenously can be a useful emergency treatment, the drug may promote tubular uric acid 
deposition and is likely to be less efficacious in the presence of renal tubular blockade. The presence 
of significant fluid overload requires nephrology advice. Alkalinization of the urine is not 
recommended. 
 
Management of hyperuricaemia: Rasburicase is the drug of choice. Any patient who has been on 
allopurinol as a prophylactic measure should be switched to rasburicase if they develop clinical TLS, 
the exceptions being patients who have had previous allergic reactions to rasburicase and those in 
whom it is contraindicated due to G6PD deficiency. In those patients allopurinol should be continued 
but renal dialysis is more likely to be required. The standard recommended dose of rasburicase is 0.2 
mg/kg/day given as a 30-min infusion. The current European Medicines Agency and US Food and 
Drug Administration recommendations include daily dosing for up to 5 days. Whilst there are some 
data to support short duration of rasburicase or reduced dose therapy in the context of prophylaxis 
there are no data, beyond those of the licensing authority, to guide dosing in the setting of established 
TLS. It seems reasonable to recommend rasburicase 0.2 mg/kg/day be given for 3–7 days with careful 
monitoring of electrolytes. 
 
Management of hyperphosphataemia and hypocalcaemia: If the above measures do not prevent 
significant hyperphosphataemia, it can be hard to control phosphate levels other than by dialysis. The 
temporary use of aluminium hydroxide 50–150 mg/kg/day has been described but is slow to act and 
poorly tolerated, thus is not routinely recommended in this setting. Asymptomatic hypocalcaemia 
should not be treated as treatment can precipitate further calcium phosphate deposition in the kidneys. 
If corrected calcium levels drop below ≤1.75 mmol/L or there has been a 25% drop from baseline, 
then cardiac monitoring is recommended. Symptomatic hypocalcaemia (e.g. cardiac arrhythmia, 
seizure or tetany) should be treated with calcium gluconate in the standard doses for adults and 
children. The aim is to treat the symptoms but not to normalize the biochemical parameters. 
 
Hyperkalaemia: It is recommended that patients with potassium levels ≥6 mmol/L or having 
experienced a 25% increase in potassium level from baseline should be offered cardiac monitoring. A 
potassium level ≥7 mmol/L constitutes a medical emergency and dialysis is likely to be required 
urgently. Effects of standard measures are temporary and dialysis is often required. Acute 
cardiotoxicity should be treated with a short infusion of calcium gluconate with continuous cardiac 
monitoring. Nebulized or intravenous salbutamol can be effective, as can intravenous infusion of 
insulin and glucose. Both strategies increase movement of potassium from the extracellular to the 
intracellular space. 


 
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Renal dialysis: When the measures described have failed to prevent renal deterioration and significant 
fluid overload, hyperkalaemia, hyperuricaemia, hyperphosphataemia or hypocalcaemia have 
developed, renal dialysis is indicated. Peritoneal dialysis is not recommended for this indication 
because clinical improvement is slower than with other forms of dialysis. There are no major trials 
comparing haemodialysis with haemofiltration or other extracorporeal therapies and all approaches 
appear to be effective. Given the continuous release of metabolites into the blood in the setting of 
TLS, some groups have suggested that daily dialysis may be the best strategy. In patients who are 
haemodynamically compromised, continuous renal replacement therapy can be helpful. Dialysis 
should continue until there is adequate recovery of renal function and urine output. 
 
Important note: Any additional safety test is allowed when required to properly guide TLS 
prophylaxis/management and/or as per Investigator's judgment. 


 
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5. REFERENCES 
• Jones GL, Will A, Jackson GH, et al. Guidelines for the management of tumour lysis syndrome in 
adults and children with haematological malignancies on behalf of the British Committee for 
Standards in Haematology. Br J Haematol. 2015 Jun;169(5):661-71 
• Cairo MS, Coiffier B, Reiter A, et al. Recommendations for the evaluation of risk and prophylaxis 
of tumour lysis syndrome (TLS) in adults and children with malignant diseases: an expert TLS 
panel consensus. Br J Haematol. 2010 May;149(4):578-86 
• Cairo MS, Bishop M. Tumour lysis syndrome: new therapeutic strategies and classification. Br J 
Haematol. 2004 Oct;127(1):3-11 
• Seftel MD, Bruyere H, Copland M, et al. Fulminant tumour lysis syndrome in acute myelogenous 
leukaemia with inv(16)(p13;q22). Eur J Haematol. 2002 Oct;69(4):193-9 
• Hijiya N, Metzger ML, Pounds S, et al. Severe cardiopulmonary complications consistent with 
systemic inflammatory response syndrome caused by leukemia cell lysis in childhood acute 
myelomonocytic or monocytic leukemia. Pediatr Blood Cancer. 2005 Jan;44(1):63-9.  
• Dombret H, Hunault M, Faucher C, et al. Acute lysis pneumopathy after chemotherapy for acute 
myelomonocytic leukemia with abnormal marrow eosinophils. Cancer. 1992 Mar 15;69(6):1356-
61.) 


 
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14.2 APPENDIX II: TIMINGS OF BLOOD SAMPLING FOR PK & EXPLORATORY TESTS 
 
 
STUDY VISIT 
NR. Blood sampling 
for PK & exploratory 
tests 
TIMING 
 
CYCLE 1 
 
1, 2 
3 each Visit 
Pre-infusion 
At the end of infusion 
6 h after the end of infusion 
3 
3 
Pre-infusion 
At the end of infusion 
14 h after the end of infusion 
4 
1 
24 h after the end of last ramp-up 
dosing infusion 
5 
1 
44 h after the end of last ramp-up 
dosing infusion 
6 
1 
68 h after the end of last ramp-up 
dosing infusion 
8, 9, 10 
2 each Visit 
Pre-infusion 
At the end of infusion 
12 
2 
Pre-infusion 
At the end of infusion 
CYCLE 2 
16 
2 
Pre-infusion 
At the end of infusion 
20 
2 
Pre-infusion 
At the end of infusion 
24 
4 
Pre-infusion 
At the end of infusion 
1 h after the end of infusion 
6 h after the end of infusion 
25 
1 
24 h after the end of infusion 
26 
1 
48 h after the end of infusion 
27 
1 
72 h after the end of infusion 
28 
1 
96 h after the end of infusion 
29 
1 
120 h after the end of infusion 
30 
1 
144 h after the end of infusion 
End of Treatment 
31 
1 
1 week after the end of infusion 
32 
1 
2 weeks after the end of infusion 
33 
1 
3 weeks after the end of infusion 
34 
1 
4 weeks after the end of infusion 
 
NOTE: If any interruption occurs during Cycle 1 and the 3rd infusion of Cycle 2, blood sampling for PK & exploratory 
tests will also be taken at the time of each infusion interruption and just before each infusion resumption. 
 
 
 
 
 
 
 
 


 
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14.3 APPENDIX III: TIMINGS OF SAFETY BLOOD SAMPLING 
 
 
 
STUDY VISIT 
NR. SAFETY 
SAMPLES 
TIMING 
SCREENING 
1 
N/A 
CYCLE 1 
1, 2, 3 
5 each Visit 
Pre-infusion 
2h after the start of infusion 
4h after the start of infusion  
8h after the start of infusion 
12h after the start of infusion 
4 
1 
One day after the completion of the entire first 
ramp-up 
8, 9, 10 
5 each Visit 
Pre-infusion 
2h after the start of infusion 
4h after the start of infusion 
8h after the start of infusion 
12h after the start of infusion 
11 
1 
One day after the completion of the entire 
second ramp-up 
12 
5  
Pre-infusion 
2 h after the start of infusion 
4 h after the start of infusion 
8h after the start of infusion 
12 h after the start of infusion 
13, 14, 15 
1 each Visit 
24 h after the start of infusion 
48h after the start of infusion 
72 h after the start of infusion 
CYCLE 2 
16 
1 
Pre-infusion 
17 
1 
N/A 
18 
1 
N/A 
19 
1 
N/A 
20 
1 
Pre-infusion 
21 
1 
N/A 
22 
1 
N/A 
23 
1 
N/A 
24 
1 
Pre-infusion 
25 
1 
N/A 
26 
1 
N/A 
27 
1 
N/A 
30 
1 
N/A 
FOLLOW-UP 
PERIOD 
35-38 
1 
N/A  
End of study 
1 
N/A 
 
 


Clinical Trial Protocol 
EudraCT No.: 2014-002433-59 
 
Study Code: ARMY-1 
Final Version 7.0, 04 November 2019 
 
 
Confidential 
Menarini Ricerche S.p.A. 
Page 132 of 132 
 
 
 
 
14.4 APPENDIX IV: COMMON TERMINOLOGY CRITERIA FOR ADVERSE EVENTS 
(CTCAE) VERSION 4.0. PUBLISHED: MAY 28, 2009 (V4.03: JUNE 14, 2010). 
U.S.DEPARTMENT OF HEALTH AND HUMAN SERVICES - NATIONAL INSTITUTES OF 
HEALTH - NATIONAL CANCER INSTITUTE