A Phase I/II Study of NMS-03592088, a FLT3, KIT and CSF1R Inhibitor, in Patients With Relapsed or Refractory AML or CMML
Phase: PHASE1
Conditions: Acute Myeloid Leukemia (AML), Chronic Myelomonocytic Leukemia (CMML)
Sponsor: Nerviano Medical Sciences

NMS-03592088 
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Version 9_28 February 2024 
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A Phase I/II Study of NMS-03592088, a FLT3, KIT and CSF1R 
Inhibitor, in Patients with Relapsed or Refractory AML or CMML 
Sponsor: 
Nerviano Medical Sciences, S.r.l. 
Therapeutic Area: 
Oncology 
Substance Identifier: 
NMS-03592088 
Protocol Number: 
MKIA-088-001 
EudraCT Number: 
2018-002793-47 
Status: 
Final 
Protocol Version Number 
9 
Including Amended Information as per: 
Amendment No. 
Date 
Countries 
Sites 
1 
29 May 2019 
Italy 
All 
2 
24 April 2020 
Italy 
All 
3 
28 September 2020 
Italy 
All 
NA 
27 August 2021 
Spain 
All 
4 
27 August 2021 
Italy 
All 
5 
20 April 2022 
Italy, Spain 
All 
6 
21 January 2023 
All 
All 
6.1 
17 March 2023 
France 
Not implemented 
6.2 
31 March 2023 
France 
All 
NA 
18 October 2023 
Italy, Spain, France 
All 
7 
28 February 2024 
EU Countries 
All 
This document contains confidential information belonging to the Sponsor. Except as may be 
otherwise agreed to in writing, by accepting or reviewing these materials, you agree to hold such 
information in confidence and not to disclose it to others (except where required by applicable 
law), nor to use it for unauthorized purposes. In the event of actual or suspected breach of this 
obligation, the Sponsor should be promptly notified. 
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SPONSOR REFERENCES AND APPROVAL 
 
Sponsor Name: 
Nerviano Medical Sciences, S.r.l. 
Sponsor Address: 
Viale Pasteur, 10 
20014 Nerviano (Milan) 
Italy 
 
 
 
 
 
Sponsor Statistician: 
 
Nerviano Medical Sciences, S.r.l. 
 
 
 
 
 
 
 
 
Sponsor 
Representative: 
 
Nerviano Medical Sciences, S.r.l. 
Sponsor Medical 
Expert: 
 
Nerviano Medical Sciences, S.r.l. 
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INVESTIGATOR’ SIGNATURE 
 
 
Title 
A Phase I/II Study of NMS-03592088, a FLT3, KIT and CSF1R 
Inhibitor, in Patients with Relapsed or Refractory AML or CMML 
Protocol Number 
MKIA-088-001 
Version Number 
9 
Date 
28 February 2024 
 
 
 
I declare I’ll carry out the study in accordance with the referenced protocol, the ICH E6 R2 
(Good Clinical Practices), Declaration of Helsinki and in accordance to local legal and regulatory 
requirements. 
 
 
 
 
Investigator's Name 
 
Investigator's Title 
Investigational Site Name 
 
 
Investigational Site Address 
 
 
Investigator' Signature 
 
Date 
  
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TABLE OF CONTENTS 
1. SUMMARY ...........................................................................................................................9 
2. ABBREVIATIONS AND DEFINITIONS OF TERMS ......................................................58 
3. BACKGROUND INFORMATION AND STUDY RATIONALE .....................................62 
3.1. INTRODUCTION .........................................................................................................62 
3.2. Disease background .......................................................................................................62 
3.3. Target Background.........................................................................................................65 
3.4. NMS-03592088..............................................................................................................67 
3.4.1. Pharmacology ..........................................................................................................68 
3.4.2. Safety Pharmacology ...............................................................................................69 
3.4.3. Nonclinical Pharmacokinetics .................................................................................69 
3.4.4. Drug-drug Interactions .............................................................................................70 
3.4.5. Toxicology ...............................................................................................................71 
3.4.6. Study Rationale ........................................................................................................72 
4. TRIAL OBJECTIVES AND ENDPOINTS .........................................................................74 
4.1. Objectives ......................................................................................................................74 
4.1.1. Primary Objective ....................................................................................................74 
4.1.2. Secondary Objectives (Phase I and II): ....................................................................74 
 
4.2. Endpoints .......................................................................................................................75 
4.2.1. Primary Endpoint .....................................................................................................75 
4.2.2. Secondary Endpoints (Phase I and Phase II) ...........................................................75 
 
5. TRIAL DESIGN AND DESIGN RATIONALE .................................................................77 
5.1. Starting Dose ..................................................................................................................79 
5.2. Phase I ............................................................................................................................79 
5.3. Definition of DLT ..........................................................................................................81 
5.3.1. DLT window ............................................................................................................82 
5.3.2. Patient replacement ..................................................................................................82 
5.4. Definition of MTD and RP2D .......................................................................................82 
5.5. Phase II...........................................................................................................................83 
6. PATIENT SELECTION ......................................................................................................84 
6.1. Patient Inclusion Criteria ...............................................................................................84 
6.2. Patient Exclusion Criteria ..............................................................................................85 
7. SCHEDULE OF EVENTS ..................................................................................................87 
8. ENROLLMENT PROCEDURES ........................................................................................88 
9. TREATMENT ......................................................................................................................90 
9.1. Study Products Description............................................................................................90 
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9.1.1. Drug Preparation and Dispensing ............................................................................90 
9.1.2. Patient Education & Information .............................................................................91 
9.1.3. Procedure for Handling Drug Spills ........................................................................92 
9.1.4. Storage and Stability ................................................................................................92 
9.1.5. Source of Drug .........................................................................................................92 
9.1.6. Drug Accountability.................................................................................................92 
9.2. Treatment Administration ..............................................................................................93 
9.2.1. Treatment Dose and Schedule .................................................................................93 
9.2.2. Duration of Treatment..............................................................................................94 
9.2.3. Dose Modifications ..................................................................................................95 
9.2.3.1. Re-treatment Criteria and Cycle Delay .............................................................95 
9.2.3.2. Dose Reductions and Interruptions ....................................................................95 
9.2.4. Extension Treatment ................................................................................................97 
9.2.5. Overdose and Medication Error Instructions ...........................................................97 
9.2.6. Unblinding ...............................................................................................................98 
9.2.7. Assessment and Management of Potential Neurologic Toxicity .............................98 
9.2.7.1. Background ........................................................................................................98 
9.2.7.2. Patient management ...........................................................................................99 
9.2.7.3. Dose Modifications ..........................................................................................100 
9.2.8. Tumor Lysis Syndrome..........................................................................................100 
9.2.9. Differentiation Syndrome ......................................................................................101 
9.2.10. Concomitant Medications and Other Therapy .....................................................101 
9.2.10.1. Antiemetics Support ......................................................................................101 
9.2.10.2. Antidiarrheal Support ....................................................................................101 
9.2.10.3. Hematopoietic Support ..................................................................................102 
9.2.10.4. Antiacids ........................................................................................................102 
9.2.10.5. Other Permitted Concomitant Medications ...................................................102 
9.2.10.6. Other Anticancer or Experimental Therapy ..................................................103 
9.2.10.7. Phototoxicity Prevention ...............................................................................103 
9.2.10.8. Potential interactions with other medicinal products ....................................103 
10. PATIENT WITHDRAWAL FROM STUDY PARTICIPATION ..................................105 
11. ASSESSMENTS ..............................................................................................................107 
11.1. Timing of Assessments ..............................................................................................107 
11.2. Disease Assessments ..................................................................................................107 
11.2.1. Immunophenotyping, Cytogenetic and Molecular Characterization ...................107 
11.2.2. Detection  of FLT3-ITD or D835/I836 mutations ...............................................107 
11.3. Efficacy Assessments.................................................................................................108 
11.3.1. Laboratory Assessments: Hematology ................................................................108 
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11.3.2. Disease Assessments: Bone Marrow Aspirate/Biopsy ........................................108 
11.3.3. Clinical evaluation of Extramedullary Disease....................................................109 
11.3.4. Definition of the response ....................................................................................109 
11.4. Outcomes Research Assessments ..............................................................................109 
11.5. Safety Assessments ....................................................................................................109 
11.5.1. Adverse Event Assessment ..................................................................................110 
11.5.1.1. Definition of Adverse Events ........................................................................110 
11.5.1.2. Unexpected Adverse Event ...........................................................................112 
11.5.1.3. Eliciting Adverse Event Information .............................................................112 
11.5.1.4. Adverse Event Reporting Period ...................................................................112 
11.5.1.5. Adverse Event Follow Up after the End of the Reporting Period .................112 
11.5.1.6. Relationship to the Investigational Medicinal Product ..................................113 
11.5.1.7. Reporting Requirements ................................................................................113 
11.5.1.8. Recording Adverse Events in the Case Report Forms ..................................114 
11.5.1.9. Grading of Adverse Event Severity ...............................................................115 
11.5.1.10. Exposure In Utero ........................................................................................116 
11.5.2. Laboratory Safety Assessments ...........................................................................117 
11.5.3. Other Safety Assessments ....................................................................................120 
11.6. Other Assessments .....................................................................................................122 
11.6.1. Pharmacokinetic Assessments .............................................................................122 
11.6.1.1. Blood Sampling in Phase I ............................................................................122 
11.6.1.2. Blood Sampling in Phase II ...........................................................................127 
11.6.1.3. Urine Sampling ..............................................................................................129 
11.6.1.4. Bioanalytical method in plasma and urine ....................................................129 
11.6.2. Translational Research .........................................................................................130 
11.6.2.1. DNA extraction for genomic analysis ...........................................................130 
11.6.2.2. NGS Analysis of FLT3 and other selected genes ..........................................130 
11.6.3. Biomarker assessment ..........................................................................................130 
11.6.3.1. PIA analysis for FLT3 pathway .....................................................................130 
11.6.3.2. Circulating CSF1 analysis .............................................................................131 
12. STATISTICAL METHODS ............................................................................................132 
12.1. Sample Size Calculation ............................................................................................132 
12.2. Definition of Analyzed Study Populations ................................................................133 
12.3. Analyses .....................................................................................................................133 
12.3.1. Study Conduct and Patient Disposition ...............................................................133 
12.3.2. Baseline Characteristics .......................................................................................134 
12.3.3. Treatment Administration/Compliance ...............................................................134 
12.3.4. Efficacy Analyses ................................................................................................134 
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12.3.5. Outcomes Research Analyses ..............................................................................137 
12.3.6. Safety Analyses ....................................................................................................137 
12.3.7. Analyses of Other Endpoints ...............................................................................138 
12.3.7.1. Molecular Features in Biological Samples ....................................................138 
12.3.7.2. Pharmacokinetics ...........................................................................................138 
12.3.7.3. Relationship of corrected QT changes to treatment exposure .......................139 
12.3.7.4. Translational Research ..................................................................................139 
12.4. Interim Analysis Plan .................................................................................................139 
12.4.1. Futility Analysis ...................................................................................................139 
12.4.2. Safety Analysis ....................................................................................................140 
12.5. Data Monitoring Committee ......................................................................................142 
13. END OF THE TRIAL ......................................................................................................143 
14. QUALITY CONTROL AND QUALITY ASSURANCE ...............................................143 
15. DATA HANDLING AND RECORD KEEPING ............................................................144 
15.1. Electronic Case Report Forms (eCRFs) .....................................................................144 
15.2. Record Retention .......................................................................................................144 
15.3. Confidentiality of Clinical Trial or Study Documents ...............................................144 
16. ETHICS ............................................................................................................................146 
16.1. Institutional Review Board (IRB)/Independent Ethics Committee (IEC) .................146 
16.2. Ethical Conduct of the Trial .......................................................................................146 
16.2.1. Serious Breaches ..................................................................................................146 
16.3. Informed Consent Process .........................................................................................147 
16.4. Personal Data Protection ............................................................................................147 
17. SPONSOR DISCONTINUATION CRITERIA ..............................................................148 
18. DISSEMINATION AND PUBLICATION OF RESULTS .............................................148 
19. REFERENCES .................................................................................................................149 
 
TABLES 
Table 1.  Recommended Dose Modification Criteria* for Treatment-Related Toxicity Observed 
During or Prior a Treatment Cycle ...........................................................................96 
Table 2. Drug-induced Tremors and Corresponding Neurologic Signs ................................98 
Table 3. Drugs to avoid .......................................................................................................100 
Table 4. Grading of Adverse Event Severity  for Events not reported in the CTCAE Version 5.0
 ................................................................................................................................116 
Table 5. PK Blood Sample Collection for Schedule A (Phase I: Dose Escalation) ............123 
Table 6. PK Blood Sample Collection for Schedule A (Phase I: Dose Expansion) ............123 
Table 7. PK Blood Sample Collection for Schedule B (Phase I: Dose Escalation) ............124 
Table 8. PK Blood Sample Collection in the backfill cohorts (Phase I) .............................125 
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Table 9. PK Blood Sample Collection in the backfill cohort for food effect investigation (Phase 
I) .............................................................................................................................126 
Table 10. PK Blood Sample Collection Schema (Phase II -all patients) ............................128 
Table 11. Estimated 95% Confidence Intervals for Assumed CRc Rates at Interim Analysis for 
Futility ....................................................................................................................132 
Table 12. Safety Boundaries for Toxicity Monitoring ........................................................142 
Table 13. Examples of clinical inhibitors for CYP-mediated metabolism ..........................166 
Table 14. Examples of clinical inducers for CYP-mediated metabolism ...........................167 
 
APPENDICES 
Appendix 1. ECOG Performance Status .............................................................................156 
Appendix 2. Response Criteria in AML .............................................................................157 
Appendix 2.1. Response Criteria in AML according to ELN 2022.................................158 
Appendix 2.2. Response Criteria in AML according to ELN 2017.................................159 
Appendix 3. Response criteria in CMML ...........................................................................160 
Appendix 4. European Consensus on Grading Bone Marrow Fibrosis ..............................162 
Appendix 5. Proposed criteria for measurement of disease progression in adult CMML ..163 
Appendix 6. Drugs That May Prolong QT .........................................................................164 
Appendix 7. Inhibitors and inducers for CYP-mediated metabolism. ................................166 
Appendix 8. Recommended Birth Control Methods ..........................................................168 
 
 
 
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1. SUMMARY 
 
Therapeutic Area: 
Oncology 
Product: 
NMS-03592088 
Indication: 
Acute Myeloid Leukemia (AML) and Chronic Myelomonocytic Leukemia (CMML)  
Protocol Number: 
MKIA-088-001 
Title of Study: 
A Phase I/II Study of NMS-03592088, a FLT3, KIT and CSF1R Inhibitor, in Patients 
with Relapsed or Refractory AML or CMML  
Background Information and Study Rationale 
NMS-03592088 is a potent inhibitor of the kinase activity of FLT3, CSF1R and KIT showing high preclinical 
efficacy in target driven tumors, also in the presence of resistance mutations.  
All three targets of NMS-03592088 are relevant in different settings of hematologic malignancies and solid 
tumors. 
FLT3, CSF1R and KIT play an important role in Acute Myeloid Leukemia (AML). In particular, FLT3 is 
mutated in ~ 30% of AML. Midostaurin, a multikinase inhibitor with activity on FLT3, was approved as first-
line therapy of FLT3-mutant AML in combination with chemotherapy and gilteritinib, a more selective FLT3 
inhibitor, was approved as monotherapy for the treatment of FLT3- positive relapsed/refractory AML patients, 
confirming the validity of the target. In addition, a few additional selective FLT3 inhibitors are undergoing 
clinical development. Although the introduction of midostaurin as additional therapy for newly diagnosed FLT3-
mutant AML and of gilteritinib for relapsed/refractory FLT3-mutant AML patient led to significant 
improvements in outcome for FLT3-mutant AML patients, the medical need, especially for older patients and 
patients who relapse after an initial response, remains high. In addition, the emergence of secondary FLT3 
mutations during the course of therapy with FLT3 inhibitors raises new challenges toward effective therapy in 
this subset of AML.  
c-KIT mutations are reported in 17%-46% of patients with a defined AML subtype known as core binding factor 
AML (CBF-AML). These patients have a higher relapse rate and shorter event-free survival/overall survival than 
those without c-KIT mutation. 
Finally, CSF1R is expressed in AML blasts and there is emerging evidence suggesting a potential therapeutic 
role for CSF1R blockade in AML. CSF1R is expressed in Chronic Myelomonocytic Leukemia (CMML) and 
CMML cells have shown sensitivity to the drug in vitro. Therefore, CSF1R represents a putative target in this 
disease, which lacks an effective standard of care and thus represents a high medical need. The FLT3 pathway is 
also activated in a small CMML subset. 
NMS-03592088I is the corresponding hemioxalate salt formulated for oral administration and it has been 
selected for clinical development in patients with hematological malignancies and solid tumors. 
The compound demonstrated strong anti-proliferative activity against FLT3-dependent human tumor cell lines, 
harboring different types of mutation. 
 
. Notably, compared to other FLT3 inhibitors in 
clinical development in AML, NMS-03592088 is the most potent FLT3 inhibitor in the preclinical setting, also 
in the presence of drug resistance mutations. In fact, 
 
 than comparators. On the contrary, it 
 
 
 
NMS-3592088 has demonstrated antitumor activity in a KIT-dependent model, resistant to imatinib.  
 
 
 
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Therapeutic Area: 
Oncology 
Product: 
NMS-03592088 
Indication: 
Acute Myeloid Leukemia (AML) and Chronic Myelomonocytic Leukemia (CMML)  
Protocol Number: 
MKIA-088-001 
Title of Study: 
A Phase I/II Study of NMS-03592088, a FLT3, KIT and CSF1R Inhibitor, in Patients 
with Relapsed or Refractory AML or CMML  
NMS-03592088 was proven to have an acceptable safety profile in preclinical models and to cross the blood 
brain-barrier
 
 
 
 
  
The potent activity of NMS-03592088 on FLT3-ITD and its mutants as well as the inhibitory activity of KIT and 
CSF1R along with a favorable pharmacological and safety profile support the clinical development of the 
compound in the proposed hematological malignancies.  
This is a first in human study of NMS-03592088 focused on hematological malignancies, with a Phase I dose 
escalation in AML and CMML patients followed by a Phase II in FLT3mut AML patients.  
As of 15 January 2023, cut-off date, the IB has been updated with safety, PK and anti-blast activity.  A trend of 
 
 
 
 
 
 
 
 
.  Full safety, PK, anti-leukemic blast activity, population PK model, 
exposure relationship to blasts and safety trends are presented in the IBv5 [55].  In summary, 
 
 
   The current protocol provides exposure caps relative to safety 
trends to ensure reasonable dosing (see Section 9.2.1 and IBv5 [55]). 
Trial Objectives and Endpoints 
Primary Objective: 
Phase I  
• 
To determine the maximum tolerated dose (MTD) or maximum administered dose (MAD) and the 
recommended Phase II dose (RP2D) of NMS-03592088 administered orally once daily for 21 consecutive 
days followed by 7 days of rest in a 28 day cycle (Schedule A) or once daily for 28 consecutive days 
(Schedule B) in adult patients with selected hematologic malignancies who have exhausted standard 
treatment options or for whom standard therapy is considered unsuitable.  
Phase II   
• 
To explore the antitumor activity of NMS-03592088 in FLT3-ITD mut AML. 
Secondary Objectives (Phase I and II): 
• 
To define the safety profile and tolerability of NMS-03592088; 
• 
To evaluate pharmacokinetics (PK) of NMS-03592088 and its metabolites NMS-03593860 and 
NMS-03603422 in plasma and, limited to Phase I, also in urine; 
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Therapeutic Area: 
Oncology 
Product: 
NMS-03592088 
Indication: 
Acute Myeloid Leukemia (AML) and Chronic Myelomonocytic Leukemia (CMML)  
Protocol Number: 
MKIA-088-001 
Title of Study: 
A Phase I/II Study of NMS-03592088, a FLT3, KIT and CSF1R Inhibitor, in Patients 
with Relapsed or Refractory AML or CMML  
• 
To assess any preliminary evidence of clinical efficacy of NMS-03592088 (Phase I). 
 
  
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Primary Endpoints: 
Phase I 
• 
Drug related first-cycle dose limiting toxicities (DLTs). 
Phase II   
• 
FLT3-ITD mut AML: Composite Complete Remission (CRc) Rate, i.e. Complete Remission (CR) + 
Complete Remission with Incomplete Hematologic Recovery (CRi), as defined by the Investigators based 
on the 2022 European LeukemiaNet (ELN) recommendations [6]. 
Secondary Endpoints (Phase I and II): 
• 
Overall safety profile of NMS-03592088 characterized by type, frequency, severity (graded using the 
National Cancer Institute Common Terminology Criteria for Adverse Events [NCI CTCAE] Version 5.0), 
timing and relationship to study therapy of adverse events, and laboratory and ECG abnormalities; 
• 
Plasma pharmacokinetic profile and corresponding parameters of NMS-03592088 and its metabolites NMS-
03593860 and NMS-03603422;  
• 
Renal clearance and fraction of NMS-03592088 and its metabolites NMS-03593860 and NMS-03603422 
excreted in urine (only Phase I); 
Secondary efficacy endpoints include: Best Response by category, Overall Survival (OS), Time to Response 
(TTR), Duration of Response (DoR), Event-Free Survival (EFS) and Relapse-free Survival (RFS) as defined by 
the ELN recommendations [6, 7]  and disease specific International Working Group criteria [56]  and proportion 
of patients bridged to hemopoietic stem cell transplantation (HSCT). For AML and in Phase II only: Complete 
Remission (CR) Rate, Complete Remission and Complete Remission with Partial Hematologic Recovery 
(CR/CRh) Rate, CR/CRh/CRi rate and Overall Response Rate (ORR: CRc + CRh + MLFS + PR) as defined by 
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Therapeutic Area: 
Oncology 
Product: 
NMS-03592088 
Indication: 
Acute Myeloid Leukemia (AML) and Chronic Myelomonocytic Leukemia (CMML)  
Protocol Number: 
MKIA-088-001 
Title of Study: 
A Phase I/II Study of NMS-03592088, a FLT3, KIT and CSF1R Inhibitor, in Patients 
with Relapsed or Refractory AML or CMML  
the 2022 ELN recommendations [6][7];  rate of conversion from transfusion-dependence to transfusion-
independence. 
 
 
 
 
  
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
. 
Study Design and Methods 
Study Design 
This is an open-label Phase I/II, first-in-human (FIH), non-randomised, multi-center study to explore tolerability, 
safety and antitumor activity of NMS-03592088 in adult patients with selected hematologic malignancies who 
have exhausted standard treatment options or for whom standard therapy is considered unsuitable. 
 
 
  
Phase I: Dose Escalation 
 
 
 
 
 
 
 
 
  
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Therapeutic Area: 
Oncology 
Product: 
NMS-03592088 
Indication: 
Acute Myeloid Leukemia (AML) and Chronic Myelomonocytic Leukemia (CMML)  
Protocol Number: 
MKIA-088-001 
Title of Study: 
A Phase I/II Study of NMS-03592088, a FLT3, KIT and CSF1R Inhibitor, in Patients 
with Relapsed or Refractory AML or CMML  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Starting Dose 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Dosing Schedule 
 
 
  
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
   
 
Phase I: Dose-Escalation 
The dose escalation schema will be as follows: 
For Schedule A, in the initial dose-escalation phase, defined as early accelerated phase, 100% dose escalations 
will be applied as per modified accelerated titration design [57]. The rapid escalation phase is intended to reduce 
the number of patients exposed to low study drug levels that might have lower probability of providing benefit to 
patients. The accelerated phase will stop when one patient experiences first cycle DLT or 2 patients at any dose 
level experience non-DLT NCI CTCAE Grade 2 drug-related toxicity during the first cycle.  
At this point, the subsequent dose-escalation phase of the study will start and dose will be escalated by ≤ 50% 
incremental steps. At the time of protocol amendment #3, testing of Schedule A is ongoing with ≤50% dose 
increments.  Since Schedule B will start while Schedule A is ongoing, a dose escalation with ≤ 50 % increments 
will be adopted since the beginning. 
After the completion of each cohort, available safety and PK data will be reviewed and will form the basis for 
the next dose level decided jointly by the Investigators and the Sponsor.  
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Therapeutic Area: 
Oncology 
Product: 
NMS-03592088 
Indication: 
Acute Myeloid Leukemia (AML) and Chronic Myelomonocytic Leukemia (CMML)  
Protocol Number: 
MKIA-088-001 
Title of Study: 
A Phase I/II Study of NMS-03592088, a FLT3, KIT and CSF1R Inhibitor, in Patients 
with Relapsed or Refractory AML or CMML  
At each dose level, a minimum of 3 patients will be included. 
If 0/3 patient experiences first cycle DLT, the next cohort will start one dose level higher. 
If 1/3 patient experiences first cycle DLT, up to three more patients will receive the study medication at the same 
dose level; if 1/6 experiences first cycle DLT the next cohort will start one dose level higher. 
If ≥2/3 or ≥2/6 patients experience DLTs in the first cycle of treatment, the MTD is considered to have been 
exceeded. At this point Sponsor and Investigators may request to evaluate three more patients at the previous 
dose level (if only 3 patients were previously treated at that prior dose) or to explore an intermediate dose level 
(not yet tested) in order to more precisely define the MTD. Evaluation of safety profile and exposure in patients 
treated in the study will guide the selection of the intermediate dose level. 
The first two patients in each cohort should be treated with at least two weeks of delay between the first and the 
second patient. In absence of 1st cycle DLT in the first patient, the third patient can be enrolled at any time. In 
presence of 1st cycle DLT in the first patient, the third patient can be enrolled only after the second patient has 
completed the first cycle without DLT. In case a cohort needs to be expanded to more than three patients, the 
additional patients can be enrolled simultaneously. 
If a patient fails to receive at least 70% of the treatment in the first cycle for reasons other than treatment-related 
toxicities, or if a patient is not assessed for DLTs, an additional patient must be enrolled at the same dose level. 
A patient may also be replaced if, under particular circumstances (e.g. due to noncompliance), the assessment of 
DLTs is not possible as judged jointly by the Investigators and the Sponsor. 
For each dosing schedule, intra-patient dose escalation can be applied only for individual patients for whom the 
Investigator believes this is in the patient’s best interest based on a risk/benefit evaluation and in agreement with 
the Sponsor. In this case, the patient should have already received 2-3 cycles of treatment at the assigned dose 
level with no relevant toxicities and the higher dose level applied should already be proven to be safe. 
In backfill cohorts patients may be enrolled simultaneously. 
Definition of Dose Limiting Toxicity (DLT): 
For the purpose of this study, DLT is defined as any grade ≥3 non-hematologic toxicity occurring in the first 
cycle of treatment for which 
 
 
 
 
Hematological adverse events will not be considered as DLTs. However, prolonged myelosuppression defined as 
grade 4 neutropenia (ANC<500 mm3) for more than 21 days off therapy in the absence of evidence of active 
leukemia in the bone marrow or peripheral blood will be considered as a DLT. 
. 
DLTs will be classified according to NCI CTCAE version 5.0. 
Definition of MTD and RP2D 
The MTD may or may not be determined and is defined as the dose level at which 0/3, 0/6 or 1/6 patients 
experience DLT in the first cycle of treatment with the next higher dose having at least 2/3 or 2/6 patients 
encountering DLT. Effectively, the MTD is the highest dose level associated with the cohort at which < 33% of 
patients experience a first cycle DLT. RP2D is no higher than MTD relative to dose or exposure but may be 
selected if MTD is not determined and is chosen based on PK, anti-blast activity, biomarkers and safety 
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Therapeutic Area: 
Oncology 
Product: 
NMS-03592088 
Indication: 
Acute Myeloid Leukemia (AML) and Chronic Myelomonocytic Leukemia (CMML)  
Protocol Number: 
MKIA-088-001 
Title of Study: 
A Phase I/II Study of NMS-03592088, a FLT3, KIT and CSF1R Inhibitor, in Patients 
with Relapsed or Refractory AML or CMML  
considerations among other features. 
This dose may be the dose recommended for further investigations. 
Phase I: Dose-Expansion and Backfill 
For each schedule, once the MTD or MAD is identified and safety and PK data have been reviewed by the 
Investigators and the Sponsor and are considered adequate, a maximum of 10 additional patients will be enrolled 
and treated at the MTD or MAD to further characterize the safety and tolerability profile of NMS-03592088 and 
to better define the  recommended dose and the schedule for the Phase II portion of the study. In the dose 
expansion and in the backfill cohorts the Sponsor may restrict the enrollment to AML FLT3 positive patients 
and/or to patients with specific prior lines or therapies.  Up to 4 backfill cohorts of up to 14 patients each may 
enroll at doses and schedules no higher than RP2D or exposure equivalent and may include the following:  1) 
first cycle at reduced dose/exposure relative to RP2D to collect additional PK, matched PK/ECG for standard 
E14 update exposure/QTc, biomarkers, and anti-cancer activity followed by subsequent cycle up to RP2D or 
exposure equivalent; 2) food effect with first cycle no higher than RP2D or equivalent exposure followed by 
subsequent cycle with standard meal on day 1 of cycle 2 only.  The exposure cap described above will be 
followed. 
Phase II:  Expansion Cohorts 
Once the RP2D and schedule of NMS-03592088 have been selected, the exploratory Phase II portion of the 
study will be opened for enrollment and will consist of two parallel cohorts: 
- Cohort 1 (40 patients with a futility analysis at 10 patients): patients with AML FLT3 Internal Tandem 
Duplication (ITD) mutation as assessed by central laboratory, who have failed standard of care including 
venetoclax and gilteritinib based therapies. Dose and schedule will be within the defined exposure cap rule (see 
above).  The enrollment in this cohort may be restricted to patients with specific prior lines/therapies and/or 
mutations, based on Sponsor decision. 
- Cohort 2 (40 patients with a futility analysis at 10 patients): patients with AML FLT3 Internal Tandem 
Duplication (ITD) mutation as assessed by central laboratory, who have failed standard of care.  Dose and 
schedule will be within the defined exposure cap rule (see above).  The cohort may be restricted to patients with 
specific prior lines/therapies and/or mutations, based on Sponsor decision.  
The Sponsor will control the patient assignment to cohorts and may stop or pause cohorts in any phase or part of 
the study based on safety, efficacy or strategic reasons (note: while finalizing this document, the Sponsor has 
termporarily restricted cohort 2 to include patients with AML FLT3 Internal Tandem Duplication (ITD) mutation 
(as assessed by central laboratory) who have failed standard of care including intensive induction chemotherapy 
in first line of treatment and Gilteritinib based therapy in any line of prior treatments)  
Dose modification: See Section 9.2.3. 
Treatment Duration 
Patients may continue on study treatment until disease progression, unacceptable toxicity, investigator decision, 
withdrawal of consent by the patient or other discontinuation criteria detailed in Section 10 are met.  
Sample Size Determination 
 
 
 
 
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Therapeutic Area: 
Oncology 
Product: 
NMS-03592088 
Indication: 
Acute Myeloid Leukemia (AML) and Chronic Myelomonocytic Leukemia (CMML)  
Protocol Number: 
MKIA-088-001 
Title of Study: 
A Phase I/II Study of NMS-03592088, a FLT3, KIT and CSF1R Inhibitor, in Patients 
with Relapsed or Refractory AML or CMML  
 
 
  
 
 
 
 
 
 
 
 
Table 1 shows the estimated 2-sided 95% CI for assumend CRc rates at interim analyses for futility. 
Table 1 Estimated 95% Confidence Intervals for Assumed CRc Rates at Interim Analysis 
Number of 
Treated Patients 
Number of 
Patients Who 
Achieve 
Response 
Observed 
CRc Rate 
(%) 
Lower Bound 
Exact 95% CI 
(%) 
Upper Bound 
Exact 95% CI 
(%) 
Half-Width 
of CI (%) 
10 
1 
10.00 
0.25 
44.50 
22.13 
10 
2 
20.00 
2.52 
55.61 
26.55 
10 
3 
30.00 
6.67 
65.25 
29.29 
 
Overall, considering both parts of the study, a maximum of approximately 180 patients is expected. 
Statistical Methods 
Descriptive statistics and patients’ data listings will be used in the characterization of patients’ disposition, 
demographic and baseline characteristics, treatment exposure and safety variables. Analyses by treatment cohort 
and dose schedule will be provided for treatment exposure and safety variables. Additional analyses will be 
performed by treatment period (ie cycle 1 vs. cycles >1), if appropriate, for adverse events, and selected 
hematological and biochemical tests. Adverse events, hematological and biochemical toxicity will be classified 
according to the NCI CTCAE (version 5.0). The MedDRA (Medical Dictionary for Regulatory Activities) 
dictionary (version 21.0) will be used to code the reported adverse events. The anti-tumor activity will be 
assessed by considering the objective tumor responses defined according to the ELN recommendations for the 
AML population [6, 7] whereas for CMML patients the tumor response evaluation will be made according to 
disease specific IWG criteria [56]. All efficacy data will be documented in individual patients’ data listings. 
Untreated patients will be identified and described separately. For the Phase II portion of the trial a futility 
analysis will be performed for each cohort after at least 10 evaluable patients at the same dose level are observed 
for at least 3 cycles (ongoing enrollment up to 10 more treated patients may continue while analysis is being 
performed) such that if at least one responder (i.e. one CR or CRi) is observed then the full cohort may proceed.  
Time-matched, replicate ECGs and PK samples will be used to explore for concentration-corrected QT interval 
responses. Such analyses will be further described in a separate analysis plan.  
For further details see Section 12.3. 
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Therapeutic Area: 
Oncology 
Product: 
NMS-03592088 
Indication: 
Acute Myeloid Leukemia (AML) and Chronic Myelomonocytic Leukemia (CMML)  
Protocol Number: 
MKIA-088-001 
Title of Study: 
A Phase I/II Study of NMS-03592088, a FLT3, KIT and CSF1R Inhibitor, in Patients 
with Relapsed or Refractory AML or CMML  
Interim Analysis   
 
 
 
 
 
 
 
 
 
 
 
    
 
 
 
Safety analysis: 
During the Phase II part of the trial, the rate of drug-related toxicities namely grade 4 non-hematological adverse 
events, 
 with systemic and/or bulbar impairment or prolonged grade 4 neutropenia leading 
to withdrawal and drug-related deaths will be monitored on an ongoing basis and sequential boundaries will be 
used to monitor rates of these events. 
The analyses will include the first 20 treated patients of each cohort. The safety boundaries are developed using 
Pocock method, and they are based on a per patient count.  
In addition, empirical safety stopping rules will be applied in each cohort beyond the 20 patients treated up to 
last treated patients.  
For further details see Section 12.4.2. 
Patient Selection 
Patients must meet all of the following inclusion criteria to be eligible for enrollment into the study.  
Inclusion Criterion for Phase I and Backfill 
1) 
 
 
 
  
 
 
 
Inclusion Criteria for Phase II 
2) Patients with confirmed diagnosis of AML as defined by the 2022 ELN recommendations positive for 
FLT3-ITD mutation in the BM or PB as determined by central laboratory test performed at study entry. 
Patients with very rapidly proliferative disease who, in the opinion of the Investigator, cannot wait for the 
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Therapeutic Area: 
Oncology 
Product: 
NMS-03592088 
Indication: 
Acute Myeloid Leukemia (AML) and Chronic Myelomonocytic Leukemia (CMML)  
Protocol Number: 
MKIA-088-001 
Title of Study: 
A Phase I/II Study of NMS-03592088, a FLT3, KIT and CSF1R Inhibitor, in Patients 
with Relapsed or Refractory AML or CMML  
central laboratory results can be enrolled based on a local test performed at study entry. Patients with an 
allelic ratio ≥ 0.05 will be considered to have FLT3ITD-mutated disease. Patients positive for FLT3- D835 
or I836 mutations will not be eligible. 
3) Patients must have failed standard of care including venetoclax and gilteritinib based therapies (cohort 1) or 
standard of care (cohort 2).  
The enrollment in each cohort may be restricted to patients with specific prior lines/therapies and/or 
mutations, based on Sponsor decision. 
Inclusion Criteria applying to both Phase I and Phase II 
4) Adult (age  18 years) patients 
5) ECOG performance status  2 
6) The interval from prior antitumor treatment to time of NMS-03592088 administration should be at least 2 
weeks for any agents other than hydroxyurea. 
7) All acute toxic effects (excluding alopecia) of any prior therapy must have resolved to NCI CTCAE version 
5.0 Grade ≤ 1 
8) Adequate hepatic function, as defined by serum transaminases (i.e., AST/ALT)  2.5 x ULN, ALP  2.5 x 
ULN and total bilirubin  1.5 x ULN unless abnormality considered due to Gilbert’s syndrome in which 
case the limit is 2 mg/dL). 
9) Adequate renal function, as defined by an estimated glomerular filtration rate (eGFR) ≥ 45 mL/min as 
calculated by the BSA-unadjusted Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) 
equation, *  
 (eGFR (mL/min)= eGFR (mL/min/1.73 m2) x [BSA (m2)/1.73] 
where  
eGFR (mL/min/1.73 m2) = 141 x  min(Scr/κ,1)α x max(Scr/κ, 1)-1 209 x 0.993Age x 1.018 [if female] x 1.159 
[if African American] 
10) Patients must use highly effective contraception (for reference, see 0). Female patients must be surgically 
sterile or be postmenopausal or must agree to the use of highly effective contraception during the period of 
therapy and in the following 208 days after discontinuation of study treatment. Since NMS-03592088 has 
potential induction of CYP3A4, WOCBP must be advised that hormonal contraceptives might lose efficacy 
and must use alternate form of highly effective contraception.  Male patients must be surgically sterile or 
must agree to use highly effective contraception during the period of therapy and in the following 118 days 
after discontinuation of study treatment. 
11) Capability to swallow capsules intact (without chewing, crushing, or opening) 
12) Willingness and ability to comply with scheduled visits, treatment plan, laboratory tests and other study 
indications or procedures 
13) Signed and dated IEC or IRB-approved informed consent form indicating that the patient is aware of the 
neoplastic nature of his/her disease and has been informed of the procedures to be followed, the 
investigational nature of the therapy, potential benefits, side effects, discomforts, risks and alternative 
treatments. 
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Therapeutic Area: 
Oncology 
Product: 
NMS-03592088 
Indication: 
Acute Myeloid Leukemia (AML) and Chronic Myelomonocytic Leukemia (CMML)  
Protocol Number: 
MKIA-088-001 
Title of Study: 
A Phase I/II Study of NMS-03592088, a FLT3, KIT and CSF1R Inhibitor, in Patients 
with Relapsed or Refractory AML or CMML  
Patient Exclusion Criteria applying to both Phase I and Phase II:  
The presence of any of the following will exclude a patient from study enrollment: 
1) Current enrollment in another interventional clinical study unless currently only participating in the  
survival follow up part   
2) Diagnosis of acute promyelocytic leukemia or BCR-ABL-positive leukaemia 
3) Currently active second malignancy, except for adequately treated basal or squamous cell skin cancer 
and/or cone biopsied in situ carcinoma of the cervix uteri and/or superficial bladder cancer. 
4) Patients with known leukemia involvement of CNS.  
5) Hematopoietic stem cell transplantation (HSCT) within 3 months of treatment start and/or persistent non-
hematologic toxicities of Grade ≥2 related to the transplant 
6) Active acute or chronic graft versus host disease (GVHD) requiring immunosuppressive treatment 
7) Patients with QTcF interval ≥ 480 milliseconds or with risk factors for torsade de pointes (e.g., uncontrolled 
heart failure, uncontrolled hypokalemia, history of prolonged QTc interval or family history of long QT 
syndrome). For patients receiving treatment with concomitant medications known to prolong the QTc 
interval, replacement with another treatment needs to be considered. If replacement or discontinuation is not 
clinically feasible, a careful risk/benefit evaluation should be performed prior to enrollment. 
8) Pregnancy. All female patients with reproductive potential must have a negative pregnancy test (serum or 
urine) within the screening period prior to start of study drug.  
9) Breast-feeding or planning to breast feed during the study or within 3 months after study treatment.   
10) Known hypersensitivity to any of the components of the NMS-03592088 drug product. 
11) Any of the following in the previous 6 months: myocardial infarction, unstable angina, coronary/peripheral 
artery bypass graft, symptomatic congestive heart failure, cerebrovascular accident or transient ischemic 
attack, pulmonary embolism, deep vein thrombosis 
12) Known active, life threatening or clinically significant uncontrolled systemic infection. 
13) Known human immunodeficiency virus (HIV) or acquired immunodeficiency syndrome (AIDS)-related 
illness.  
14) Active Hepatitis B Virus (HBV) or Hepatitis C Virus (HCV) C infection.  
15) Known active gastrointestinal disease (e.g., Crohn’s disease, ulcerative colitis, or short gut syndrome) or 
other malabsorption syndromes or gastric/intestinal resection that would impact on drug absorption. 
16) Known active gastrointestinal ulcer. 
17) Other severe acute or chronic medical or psychiatric condition or laboratory abnormality that may increase 
the risk associated with study participation or study drug administration or may interfere with the 
interpretation of study results and, in the judgment of the Investigator, would make the patient inappropriate 
for entry into this study or could compromise protocol objectives in the opinion of the Investigator and/or 
the Sponsor. 
18) Known diagnosis of myasthenia gravis or any known history of MG autoantibodies at screening window 
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Therapeutic Area: 
Oncology 
Product: 
NMS-03592088 
Indication: 
Acute Myeloid Leukemia (AML) and Chronic Myelomonocytic Leukemia (CMML)  
Protocol Number: 
MKIA-088-001 
Title of Study: 
A Phase I/II Study of NMS-03592088, a FLT3, KIT and CSF1R Inhibitor, in Patients 
with Relapsed or Refractory AML or CMML  
19) Concomitant anticoagulant use that is not already stabilized therapeutically 
20) Subjects under legal protection or unable to express their consent; subjects deprived of liberty; subjects who 
are not members or not beneficiaries of a social security scheme. 
21) Signs or symptoms of myasthenia gravis or stroke during screening 
22) Concomitant medications with the potential to cause de novo myasthenia gravis, worsening of myasthenia 
gravis or cause myasthenia gravis-like symptoms as in https://myasthenia-gravis.com/clinical/drugs-
vaccines-to-avoid (also see 9.2.7.2.1 for a corresponding list) 
23) Uncontrolled hypertension, atrial fibrillation or flutter, ventricular arrhythmia or receiving treatment for 
cardiac rhythm disorder or diabetes that is not adequately controlled 
Schedule of Events 
The tables and the related footnotes, reported in the next pages, summarize information on the timing of study 
assessments for: 
Phase I (Dose Escalation and Dose Expansion): Schedule A 
Phase I (Dose Escalation and Dose Expansion and Backfill): Schedule B 
Phase II 
 
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2. ABBREVIATIONS AND DEFINITIONS OF TERMS 
AchR 
Acetylcholine receptor 
AE 
Adverse Event 
AIDS 
Acquired immunodeficiency syndrome 
AKT 
AKR mouse thymoma kinase 
ALP 
Alkaline phosphatase  
ALT 
Alanine aminotransferase 
AML 
Acute myeloblastic leukemia 
AST 
Aspartate aminotransferase 
ASXL1 
Additional Sex combs Like 1 
AUC 
Area under the plasma concentration vs time curve up to infinite 
time   
AUC 0-24 
Area under the concentration-time curve from time zero to 24h 
BCR-ABL 
Breakpoint cluster region-Abelson 
BM 
Bone Marrow 
BP 
Blood pressure 
BSA 
Body Surface Area 
CB 
Clinical Benefit 
CBF-AML 
Core Binding Factor AML 
CBR 
Clinical Benefit rate 
CCR 
Complete Cytogenetic Remission 
CE 
Capillary Electrophoresis 
CEBPA 
CCAAT/Enhancer-Binding Protein Alpha 
CDK-EPI 
Chronic Kidney Disease Epidemiology Collaboration 
CI 
Confidence Interval 
C-KIT 
Stem cell factor receptor / Hardy-Zuckerman 4 feline sarcoma viral 
oncogene 
Cmax 
Maximum serum/plasma drug concentration 
CMML 
Chronic Myelomonocytic Leukemia 
CNS 
Central Nervous System 
CPK 
Creatine PhosphoKinase 
CR 
Complete Remission 
CRc 
Composite Complete Remission Rate 
CRh 
Complete Remission with Partial Hematologic Recovery 
CRi 
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CSF1 
Colony stimulating factor-1   
CSF1R 
Colony stimulating factor-1 receptor  
CV 
Coefficient of Variation 
CYP 
Cytochrome  
CYP1A2, 3A4 
Cytochrome P-450, 1A subfamily 2 enzyme, 3A subfamily 4 
enzyme 
CYP2B6 
Cytochrome P-450, 2B subfamily 6 enzyme 
CYP2C8, 2C9, 
2C19 
Cytochrome P-450, 2C subfamily 8 enzyme, 2C subfamily 9 
enzyme, 2C subfamily 19 enzyme 
CYP2D6 
Cytochrome P-450, 2D subfamily 6 enzyme 
DDI 
Drug-Drug Interaction 
DLT/s 
Dose limiting toxicity/ies  
DNA 
Deoxyribonucleic Acid 
DoR 
Duration of Respnse 
ECG 
Electrocardiogram 
ECOG-PS 
Eastern Cooperative Oncology Group Performance Status 
eCRF 
Electronic Case Report Form 
ELN 
European LeukemiaNet 
EMD 
Extramedullary disease 
ES 
(specific for)  Spain 
FACS 
Fluorescence-Activated Cell Sorting 
FIH 
First in Human 
FLT3 
Fms-like tyrosine kinase 3 
FR 
(specific for) France 
FU 
Follow-up 
GIST 
Gastrointestinal Stromal Tumors 
GLP 
Good Laboratory Practices 
GVHD 
Graft versus host disease 
Hb 
Hemoglobin 
HBV 
Hepatitis B Virus 
HCV 
Hepatitis C Virus 
hERG 
Human ether-a-go-go-related gene 
HIV 
Human immunodeficiency virus 
HNSTD 
Highest Non-Severely Toxic Dose 
HR 
Hazard ratio 
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HSCT 
Hemopoietic stem cell transplantation 
IC50 
Concentration for 50% inhibition 
ICH E6 R2 
Integrated addendum of International Conference on 
Harmonization  E6(R1) 
IEC 
Independent Ethics Committee 
IL-3 
Interleukine-3 
IRB 
Institutional Review Board 
IT 
(specific for) Italy 
ITD 
Internal tandem duplication 
IWG 
International Working Group 
JAK 
Janus kinase 
KIT 
Tyrosine-protein kinase Kit or CD117 
LDH 
Lactate Dehydrogenase 
MAD 
Maximum Administered Dose 
MAPK 
Mitogen-activated protein kinase 
MedRA 
Medical Dictionary for Regulatory Activities 
MLFS 
Morphologic Leukemia-free State 
MR 
Marrow Response 
mRNA 
Messenger RNA (RiboNucleic Acid) 
MTD 
Maximum tolerated dose 
MuSK 
Muscle-specific kinase 
NCI CTCAE 
National Cancer Institute Common Terminology Criteria for 
Adverse Events 
NGS 
Next Generation Sequencing 
NPM1 
Nucleophosmin  
NOAEL 
No observed adverse effect level 
NOEL 
No observed effect level 
ORR 
Overall response rate 
OS 
Overll survival 
PB 
Peripheral Blood 
PCR 
Polymerase Chain Reaction 
PD 
Pharmacodynamics 
PD-1 
Programmed Death-1 
PI3K 
Phosphatidylinositol 3-kinase 
PIA 
Plasma inhibitory activity 
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PK 
Pharmacokinetics 
PLT  
Platelets 
PR 
Partial Remission 
QTcF 
QT interval using Fridericia standard 
RAF 
Rapidly accelerated fibrosarcoma oncogene 
RAS 
Rat sarcoma oncogene 
RBC 
Red blood cells 
RFS 
Relapse-free Survival 
RP2D 
Recommended Phase II dose 
RUNX1 
Runt-related transcription factor 1  
SD 
Standard Deviation 
SGOT 
Serum Glutamic-Oxaloacetic Transaminase 
SGPT 
Serum Glutamic Pyruvic Transaminase 
SRSF2 
Serine and Arginine Rich Splicing Factor 2 
STAT 
Signal transducers and activators of transcription 
STD10 
Severely Toxic Dose in 10% of the animals 
TAM 
Tumor Associated Macrophage 
TKD 
Tyrosine Kinase Domain 
TET2 
Tet methylcytosine dioxygenase 2  
TP53 
Tumor Protein 53 
TTR 
Time to Response 
ULN 
Upper Limit of Normality 
WBC 
White blood cell 
WHO 
World Health Organization 
WOCBP 
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3. BACKGROUND INFORMATION AND STUDY RATIONALE 
3.1. INTRODUCTION 
NMS-03592088 is a potent inhibitor of the kinase activity of FLT3, CSF1R and KIT. The 
compound is formulated for oral administration and it was selected for clinical investigation 
in patients with hematological malignancies and solid tumors.  
 
 
 
 
This first in human study of NMS-03592088 is a Phase I dose finding/Phase II study in 
patients with AML and CMML. 
3.2. Disease background 
Acute myeloid leukemia 
Acute myeloid leukemia (AML) is the most common type of acute leukemia in adults and 
represents 36% of all leukemias in adults and children [1]. The American Cancer Society 
estimates 19,520 new cases of AML and 10,670 deaths from AML in the United States in 
2018. (https://www.cancer.org/cancer/acute-myeloid-leukemia/about/key-statistics.html or 
https://seer.cancer.gov/statfacts/html/amyl.html). Similarly, over 18,000 new cases are 
expected in the European Union, considering a reported crude incidence rate of 3.62 per 
100,00 people [2]. AML is primarily a disease of elderly, with a median age at diagnosis of 
68 years.  
After many years the backbone of standard therapy for AML remains chemotherapy, a 
combination of cytarabine- and anthracycline-based regimens, with allogeneic stem cell 
transplantation for eligible candidates. Elderly patients are often unable to tolerate these 
regimens and carry a particularly poor prognosis. Individuals over the age of 65 are in fact 
more likely to present with an adverse cytogenetic-risk profile, less likely to respond to 
chemotherapy and often more susceptible to treatment-related toxicities. Thus, an optimal 
approach to elderly patients with AML has not been established.  
Despite good initial response to conventional induction therapy, AML relapse is common, 
contributing to a 5-year survival rate of only 27.4% 
(https://seer.cancer.gov/statfacts/html/amyl.html). 
AML is a biologically and clinically heterogeneous disease. In the majority of cases, it 
appears as a de novo malignancy in previously healthy individuals, but it can arise in 
patients with an underlying hematological disorder, or as a consequence of prior 
chemo/radiotherapy for another malignancy [3]. Regardless of its etiology, the pathogenesis 
of AML involves the abnormal proliferation and differentiation of a clonal population of 
myeloid stem cells that displace the normal hematopoietic system. Genetic mutations are 
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identified in more than 97% of cases, often in the absence of any large chromosomal 
abnormality [4, 5]. The prognostic relevance of specific mutations and karyotypes is 
becoming more and more recognized and is reflected in the 2017 revision [7].and in the 
latest 2022 revision of the AML classification of the European LeukemiaNet (ELN) [6]. 
Some of these mutations, such as those involving the FMS-like tyrosine kinase 3 (FLT3) 
gene, have an impact on disease pathophysiology, prognosis and treatment strategy. 
FLT3 mutations occur in approximately 30% of AMLs, and is associated with a lower 
complete remission (CR) rate, higher induction death rate, increased risk of relapse, and 
adverse disease-free survival (DFS), event-free survival, and overall survival (OS) [8 -13]. 
Because of its association with poor outcomes, detection of the FLT3 mutation classifies 
any newly diagnosed AML as poor risk.The majority of FLT3-mutated AML patients carry 
an internal tandem duplication (ITD) mutation in the FLT3 gene, which leads to 
uncontrolled cellular proliferation, survival, and differentiation through constitutive 
activation of FLT3 [14].  
While in the 2017 ELN recommendation the FLT3ITD allelic ratio and NPM1 mutational 
status were considered for ELN risk stratification that classified AML patients with wild-
type NPM1 and FLT3ITD with high allelic ratio (≥ 0.5) into adverse risk cathegory [7], in 
the 2022 revision of the ELN recommendations [6], the FLT3-ITD allelic ratio is no longer 
considered in the risk classification and all AML with FLT3-ITD are now categorized in the 
intermediate-risk group, regardless of the allelic ratio or presence of NPM1 mutation. The 
rationale for this change refers to methodological issues with standardizing the assay to 
measure the FLT3-ITD allelic ratio, the modifying impact of midostaurin-based therapy on 
FLT3-ITD without NPM1 mutation, and the increasing role of MRD in treatment decisions 
[6]. 
However, the prognostic impact of the ITD of FLT3 (FLT3ITD) is reported to depend on 
the allelic ratio in the literature, with high FLT3ITD allelic ratio (>0.5) in the absence of a 
nucleophosmin (NPM1) mutation carrying a dismal prognosis [15, 16, 17].  
Mutations in the tyrosine kinase domain (TKD) of FLT3 are less frequent (7%) and their 
prognostic relevance is less well defined) [18].  
AML carrying t(8;21)(q22;q22) and inv(16)/t(16;16)(p13;q22) is classified as French-
American-British (FAB) AML subtype M2 or monocytic with eosinophilic differentiation 
(M4Eo) by morphology and as core binding factor (CBF)-AML according to pathogenesis. 
CBF-AML accounts for approximately 15% of AML and frequently harbors c-KIT mutation 
(17∼46%). c-KIT mutated CBF-AML patients usually have higher baseline white blood cell 
count, higher relapse rate and shorter event free survival/overall survival after conventional 
chemotherapy than those without c-KIT mutation. 
In addition to FLT3 and NPM1 other genes such as CEBPA, RUNX1, ASXL1 and TP53 are 
also frequently mutated in AML and included in the ELN classification. The assessment of 
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their mutational status can be useful to better interpret patient outcome after treatment with 
NMS-03592088.  
The recognition of the key role of FLT3 mutations has led to intensive research around this 
target, resulting in the approval of the first FLT3 inhibitor, midostaurin, in 2017. Approval 
was based on a randomized, double-blind, placebo-controlled trial in 717 patients with 
previously untreated FLT3mut AML [19]. This trial randomized patients aged 18 to 59 
years to either placebo or midostaurin during induction and consolidation chemotherapy 
followed by continuous daily midostaurin for up to 12 cycles and demonstrated a 
statistically significant improvement in overall survival (OS) for patients receiving 
midostaurin compared with those on the placebo-containing arm (HR 0.77, p=0.016). 
In addition, a more selective FLT3 inhibitor, gilteritinib, was approved in 2018 in US and 
2019 in EU as monotherapy for treatment as of adult patients who have relapsed or 
refractory acute myeloid leukaemia (AML) with a FLT3 mutation. The approval was based 
on results from the Phase 3 ADMIRAL trial, which investigated gilteritinib versus salvage 
chemotherapy in patients with relapsed or refractory FLT3 positive AML. The study showed 
a significantly longer overall survival (OS) in patients treated with gilteritinib (median OS 
9.3 months) than those who received salvage chemotherapy (median OS 5.6 months) [20].  
Additional selective FLT3 inhibitors  in clinical development have reported encouraging 
results in AML patients [19,21,22,23]. However, activity of FLT3 selective inhibitors 
appears to be limited by the appearance of resistance mutations. 
Although the introduction of midostaurin as additional therapy for newly diagnosed 
FLT3mut AML and gilteritinib for relapsed/refractory FLT mut AML patient led to 
significant improvements in outcomes for FLT3-mutant AML patients, the medical need, 
especially for older patients and patients who relapse after an initial response remains high. 
In addition, the emergence of secondary FLT3 mutations during the course of therapy with 
FLT3 inhibitors raises new challenges toward effective therapy in this subset of AML. 
Chronic myelomonocytic leukemia 
Chronic myelomonocytic leukemia (CMML) is a clonal hematopoietic stem cell disorder 
with overlapping features of myelodysplastic syndromes and myeloproliferative neoplasms. 
The median age at CMML diagnosis is 71-74 years, with a male preponderance. Incidence 
of CMML has increased in US from 0.5/100,000 to 0.6/100,000 population from 2000 to 
2011 [24].  
Gene mutations are seen in >90% of patients, with common abnormalities involving 
epigenetic regulators (TET2 and ASXL1), spliceosome components (SRSF2) and cell 
signaling (oncogenic RAS). 
Many different prognostic models have been proposed, some of them incorporate molecular 
abnormalities. The Mayo Molecular Model, for example, considers  the presence of 
nonsense or frameshift  ASXL1 mutations, together with absolute monocyte count, 
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hemoglobin, platelet count and presence of circulating immature myeloid cells and stratifies 
CMML patients in 4 risk groups with median survivals from 16 months (high risk) to 97 
months (low risk) [25]. Furthermore, the presence of FLT3ITD was also found in CMML 
patients and may represent an independent negative prognostic factor for these patients [26].  
Rates of leukemic transformation vary among different series reported in literature. 
However, most studies quote an incidence of 20 % over 3 -5 years. [27].  
Median survival post- blast transformation is short, 4.7 months, and 5-year survival is only 
6%. Survival is longer with allogeneic stem cell transplant (14.4 months vs. 4.3 months for 
chemotherapy vs. 0.9 months for supportive care) [28].  
Hypomethylating agents remain the most commonly used therapeutic intervention for 
CMML patients. Standard induction chemotherapy should be considered for all eligible 
patients who develop blast transformation. The impact of mutations on patients undergoing 
therapy is still unclear [29]. 
Therefore, the response rate and survival following therapy is suboptimal and the role of 
allogeneic hematopoietic cell transplantation in CMML remains controversial. Younger 
patients should be considered for transplant. Older patients are best suited for clinical trials 
[29]. 
3.3. Target Background 
FLT3, CSF1R and KIT are members of the class III receptor tyrosine kinase family 
characterized by an extracellular domain with five immunoglobulin-like loops, a 
transmembrane region and a cytoplasmic domain containing not only the kinase domain 
(divided in two regions), but also an auto-inhibitory juxtamembrane (JM) domain that docks 
with the kinase domain to stabilize a catalytically inactive conformation.  
All three targets play an important role in AML, while CSF1R and FLT3 are relevant for 
CMML. 
FLT3 has a crucial role in normal hematopoiesis while its expression in adults is restricted 
to CD34+ hematopoietic stem/progenitor cells, brain, placenta, and gonads. Activation of 
FLT3 by FLT3-ligand promotes the normal growth of early progenitor cells. FLT3 is 
expressed in AML cells of most patients and mutations of the FLT3 gene are one of the 
most common acquired genetic lesions [30].  
FLT3 mutations can be detected in ~30% of AML patients, and also in 5-10% of patients 
with myelodysplastic syndrome [31]. There are two types of somatic FLT3 genetic 
mutations: internal tandem duplications (ITDs) in the juxta-membrane domain, which are by 
far the most frequent, and point mutations in the activation loop of the tyrosine kinase 
domain. ITD mutations are any elongation or shortening of the JM domain of FLT3 due to 
additions or deletions of amino acids that result in the constitutive activation of FLT3. The 
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presence of FLT3ITD mutations is associated with a poor clinical outcome in patients with 
AML. Point mutations in the activation loop of the kinase domain (FLT3TKD) involve the 
aspartic acid D835 residue leading to an activated configuration and transformation of 
myeloid cells. D835 mutations are missense mutations that result in substitution of tyrosine, 
histidine, valine, glutamic acid or asparagine for aspartic acid at amino acid 835 of FLT3. 
These mutations have been reported in ~7% of patients with AML. TKD mutations, unlike 
ITD mutations, have an uncertain prognostic significance in AML. Both types of FLT3 
mutations cause ligand-independent activation of the receptor and activation of downstream 
signaling pathways. Mutant FLT3 provides survival advantage to leukemic cells because it 
causes activation of three major intracellular signalling pathways: PI3K/AKT; 
RAS/RAF/MAPK and JAK/STAT [32]. 
In conclusion, interfering with the FLT3 signalling represents a specific and effective means 
of blocking tumor cell proliferation in AML. However, despite encouraging results seen 
with midostaurin and other agents (gilteritinib, quizartinib, crenolanib), responses to FLT3 
inhibitors are usually transient due to the emergence of resistance mutations. These are point 
mutations in the FLT3ITD kinase domain, generally confined to the D835 and F691 
residues [33,34]. The different FLT3 kinase inhibitors either approved or in development 
have distinct inhibitory potencies against the different resistance mutations [35,36]. In 
particular, the F691 mutation originally identified as one of the most frequent resistance 
mutations to quizartinib has also been identified in patients treated with crenolanib and 
gilteritinib, suggesting that this so called “gatekeeper mutation” represents a common 
resistance mechanism, thus resulting in an unmet medical need in the clinical setting [33, 
36,37]. 
The FLT3 pathway may also play a role in CMML Introduction of an internal tandem 
duplication (ITD) mutation in the endogenous murine Flt3 locus resulted in the generation 
of a murine model which closely resembles human CMML [38]. Genomic analysis of a 
large series of primary patient samples led to the identification of a subset of FLT3ITD 
positive CMML [38,39,40].  
 
 
 
 
 
The CSF1 receptor (CSF1R) has been shown to polarize macrophages towards an 
immunosuppressive and tumor-promoting phenotype. Thus, the CSF1–CSF1R axis has been 
extensively investigated in solid tumors and is paradigmatic of the tumor-associated 
macrophages (TAM)–cancer cell interaction. High CSF1 or CSF1R expression levels in the 
tumor or peritumoral tissue have been associated with poor patient survival in different 
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malignancies, such as lymphoma, breast cancer, and hepatocellular carcinoma [41, 42, 43, 
44].  
Treatment with CSF1R has been shown to induce upregulation of circulating CSF1 ligand, 
which can be used as a pharmacodynamics biomarker of CSF1R inhibition [45]. 
CSF1R is a key regulator for monocyte differentiation from progenitors of the bone marrow 
and also determines monocyte activation and migration [46 ]. CSF1 and/or CSF1R gene are 
expressed in AML blasts, with a 30% of cases with co-expression of both genes and 30% of 
cases where neither gene is expressed [47]. Presence of CSF1R mutations is also reported as 
rare event in AML, mainly in the extracellular domain, that could lead to constitutive 
activation of the receptor. These mutations are not associated with FLT3 or c-KIT mutation 
[48].   
Recent experimental evidence suggests a potential therapeutic role of CSF1R blockade in 
AML [49]), probably by interfering with microenvironmental support [43,50]. Furthermore, 
also CMML blasts express high level of CSF1R (A. Rambaldi, unpublished observation).  
NMS-03592088 was shown to strongly inhibit CSF1R in biochemical assays (Ki= 4.5 nM) 
as well as in cellular assays, including cells from CMML patients, and in vivo.  
KIT is a receptor tyrosine kinase expressed on a wide variety of cell types and normally 
activated by stem cell factor. Signalling by KIT plays an important role in erythropoiesis, 
lymphopoiesis, mast cell development and function, megakaryopoiesis, gametogenesis and 
melanogenesis.  Hematopoietic stem cells, multipotent progenitors and common myeloid 
progenitors, but also early T lineage progenitors and thymocytes express high levels of KIT. 
KIT is mutated in 8.0% of acute myeloid leukemia (COSMIC). Oncogenic KIT mutations 
occur primarily in core binding factor (CBF) AML [51], which constitutes 5-8 % of all 
AML cases [53,54,52]. Expression levels of both KIT mRNA and proteins are much higher 
in CBFL, with either wild type or mutant KIT, than in leukemia cells negative for CBF 
rearrangement [54]. The prognostic significance of cKIT mutations remains to be 
established [53, 52]. 
NMS-03592088 inhibits wild type KIT with a Ki of 7.7 nM and has high activity against 
KIT activating mutations (e.g. V559D) and secondary mutations (e.g. V654A and T670I), 
confirmed both in cells, including KIT-mutated AML cells, and in xenograft tumors in vivo. 
3.4. NMS-03592088 
 
 
 
 
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The following sections present a summary of the preclinical studies; detailed information is 
presented in the Investigator Brochure [55]. 
3.4.1. Pharmacology 
 
 
  
 
 
 
 
  
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
   
 
 
 
  
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3.4.2. Safety Pharmacology 
 
 
 
 
   
 
  
 
 
 
 
 
 
 
 
 
 
. 
3.4.3. Nonclinical Pharmacokinetics 
 
 
 
 
 
 
 
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3.4.4. Drug-drug Interactions 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
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3.4.5. Toxicology 
 
 
  
 
 
 
 
  
 
 
 
 
 
  
 
 
 
  
  
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
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3.4.6. Study Rationale 
 
 
 
 
 
 
  
 
 
 
 
  
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4. TRIAL OBJECTIVES AND ENDPOINTS 
4.1. Objectives 
4.1.1. Primary Objective 
Phase I  
To determine the maximum tolerated dose (MTD) or maximum administered dose 
(MAD) and the recommended Phase II dose (RP2D) of NMS-03592088 administered 
orally once daily for 21 consecutive days followed by 7 days of rest in a 28 days cycle 
(Schedule A) or once daily for 28 consecutive days (Schedule B) in adult patients with 
selected hematologic malignancies who have exhausted standard treatment options or 
for whom standard therapy is considered unsuitable.  
Phase II   
• To explore the antitumor activity of NMS-03592088 in FLT3-ITD mut AML. 
4.1.2. Secondary Objectives (Phase I and II): 
• To define the safety profile and tolerability of NMS-03592088; 
• To evaluate pharmacokinetics (PK) of NMS-03592088 and its metabolites 
NMS-03593860 and NMS-03603422 in plasma and, limited to Phase I, also in urine; 
• To assess any preliminary evidence of clinical efficacy of NMS-03592088 (Phase I). 
 
  
 
 
  
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
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4.2. Endpoints  
4.2.1. Primary Endpoint 
Phase I 
• Drug related first-cycle dose limiting toxicities (DLTs). 
Phase II   
• FLT3-ITD mut AML: Composite Complete Remission (CRc) Rate, i.e. Complete 
Remission (CR) + Complete Remission with Incomplete Hematologic Recovery (CRi), 
as defined by the 2022 ELN recommendations [6]; 
 
4.2.2. Secondary Endpoints (Phase I and Phase II) 
• Overall safety profile of NMS-03592088 characterized by type, frequency, severity 
(graded using the National Cancer Institute Common Terminology Criteria for Adverse 
Events [NCI CTCAE] Version 5.0), timing and relationship to study therapy of adverse 
events, and laboratory and ECG abnormalities; 
• Plasma pharmacokinetic profile and corresponding parameters of NMS-03592088 and 
its metabolites NMS-03593860 and NMS-03603422;  
• Renal clearance and fraction of NMS-03592088 and its metabolites NMS-03593860 and 
NMS-03603422 excreted in urine (only Phase I); 
• Secondary efficacy endpoints include: Best Response by category, Overall Survival 
(OS), Time to Response (TTR), Duration of Response (DoR), Event-Free Survival 
(EFS) and Relapse-free Survival (RFS) as defined by the ELN recommendations [6, 7]  
and disease specific International Working Group criteria [56] and proportion of patients 
bridged to hemopoietic stem cell transplantation (HSCT). For AML and in Phase II 
only: Complete Remission (CR) Rate, Complete Remission and Complete Remission 
with Partial Hematologic Recovery (CR/CRh) Rate, (CR/CRh/CRi) rate and Overall 
Response Rate (ORR: CRc + CRh + MLFS + PR) as defined by the 2022 ELN 
recommendations [6]. Rate of conversion from transfusion-dependence to transfusion 
independence. 
 
 
 
 
 
  
 
 
 
 
  
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5. TRIAL DESIGN AND DESIGN RATIONALE  
This is an open-label Phase I/II, first-in-human (FIH), multi-centric trial in sequential 
cohorts of patients with relapsed or refractory hematologic malignancies who have 
exhausted standard treatment options or for whom standard therapy is considered unsuitable.  
The study will be conducted in two parts: a Phase I dose escalation part including patients 
with AML and CMML and a Phase II exploratory study with interim analyses for futility 
and safety comprising two parallel cohorts of AML FLT3-ITD mutated patients that are 
more likely to respond to the drug.  
NMS-03592088 will be administered as home-based treatment. 
For the diagnosis and response assessment of AML patients the ELN 2017 Guidelines [7] 
have been followed up to the approval of amendment 6, after which ELN 2022 were 
implemented [6]. 
 
 
 
 
 
 
 
 
 
Dose escalations will be decided jointly between the Investigators and the Sponsor.  
 
 
 
  
 
 
 
 
 
 
  
 
  
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5.1. Starting Dose  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
5.2. Phase I 
Dosing of the drug will be based on 
 
  
The dose escalation schema will be as follows. 
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DLTs will be classified according to CTCAE version 5.0. 
5.3.1. DLT window 
 
 
 
 
 
 
 
 
5.3.2. Patient replacement 
During the first cycle of the dose-escalation part in Phase I, patients who meet any of the 
following criteria will not permit the DLT evaluation and therefore will be replaced: 
• did not receive at least 70% of cycle study drug, unless treatment was stopped for a 
drug-related toxicity, 
• did not undergo a first-cycle DLT assessment. 
A patient may also be replaced if, under particular circumstances (e.g. due to   
noncompliance), the assessment of DLTs is not possible as judged jointly by the 
Investigators and the Sponsor.  
5.4. Definition of MTD and RP2D 
The MTD may or may not be determined and is defined as the dose level at which 0/3, 0/6 
or 1/6 patients experience DLT in the first cycle of treatment with the next higher dose 
having at least 2/3 or 2/6 patients encountering DLT. Effectively, the MTD is the highest 
dose level associated with the cohort at which < 33% of patients experience a first cycle 
DLT.   
RP2D is no higher than MTD relative to dose or exposure but may be selected if MTD is not 
determined and is chosen based on PK, anti-blast activity, biomarkers and safety 
considerations among other features. 
This dose may be the dose recommended for further investigations. 
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5.5. Phase II 
Once the RP2D and schedule of NMS-03592088 have been selected and communicated to 
sites, the exploratory Phase II portion of the study with interim analysis for futility and 
safety will be opened for enrollment and will consist of two parallel cohorts: 
Cohort 1 (40 patients with a futility analysis at 10 patients): patients with AML FLT3 
Internal Tandem Duplication (ITD) mutation as assessed by central laboratory, who have 
failed standard of care including venetoclax and gilteritinib based therapies. Dose and 
schedule will be within the defined exposure cap rule defined in section 9.2.1).  The 
enrollment in this cohort may be restricted to patients with specific prior lines/therapies 
and/or mutations, based on Sponsor decision. 
Cohort 2 (40 patients with a futility analysis at 10 patients): patients with AML FLT3 
Internal Tandem Duplication (ITD) mutation as assessed by central laboratory, who have 
failed standard of care. Dose and schedule will be within the defined exposure cap rule 
defined in section (refer to section 9.2.1).  The cohort may be restricted to patients with 
specific prior lines/therapies and/or mutations, based on Sponsor decision. 
The Sponsor will control the patient assignment to cohorts and may stop or pause cohorts in 
any phase or part of the study based on safety, efficacy or strategic reasons. The sponsor 
have also the possibility to explore additional phase II cohorts upon protocol amendment 
based on restriction of patient population and/or additional dose regimens within the 
described cap of exposure. The same criteria for futility analysis will apply on such cohorts. 
For the FLT3-ITD mutated AML group, the main endpoint in the Phase II will be the 
Composite Complete Remission Rate (CRc), defined as the proportion of patients who 
achieved a Complete Remission (CR) or Complete Remission with Incomplete Recovery 
(CRi). See Section 11.2 for all details.  
For the safety analysis, the rate of drug-related unacceptable toxicities and drug-related 
deaths will be monitored on ongoing basis using sequential boundaries.  
The analyses will include all treated patients of each cohort of the Phase II portion.  
All details are reported in Section 12.4.2. 
For statistical considerations, see Section 12. 
 
 
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6. PATIENT SELECTION 
This clinical trial can fulfill its objectives only if appropriate patients are enrolled.  The 
following eligibility criteria are designed to select patients for whom protocol treatment is 
considered appropriate.  All relevant medical and non-medical conditions should be taken 
into consideration when deciding whether this protocol is suitable for a particular patient.  
Prospective approval of protocol deviations to recruitment and enrolment criteria, also 
known as protocol waivers or exemptions, is not permitted. 
6.1. Patient Inclusion Criteria 
Patients must meet all of the following inclusion criteria to be eligible for enrollment into 
the study. Some specific inclusion criteria apply only to Phase I and backfill or Phase II of 
the study.  
Phase I and backfill: 
1. Patients with relapsed/refractory disease who have failed standard therapy or are 
unsuitable for standard treatment, with one the following confirmed diagnosis: 
• AML as defined by the European LeukemiaNet (ELN) recommendations [6, 7].  
In backfill cohorts, sponsor may require specific FLT3 mutations in the BM or PB as 
determined by central and/or local laboratory test performed at study entry. The 
enrolment could also be restricted to specific prior lines/therapies. 
Phase II: 
2. Patients with confirmed diagnosis of AML as defined by the 2022 ELN 
recommendations [6] positive for FLT3-ITD mutation in the BM or PB as determined by 
central laboratory test performed at study entry. Patients with very rapidly proliferative 
disease who, in the opinion of the Investigator, cannot wait for the central laboratory 
results can be enrolled based on a local test performed at study entry. Patients with an 
allelic ratio ≥ 0.05 will be considered to have FLT3-ITD- mutated disease. Patients 
positive for FLT3- D835 or I836 mutations will  not be eligible. 
3. Patients must have failed standard of care including venetoclax and gilteritinib based 
therapies (cohort 1) or standard of care (cohort 2).  
The enrollment in each cohort may be restricted to patients with specific prior 
lines/therapies and/or mutations, based on Sponsor decision. 
Both Phase I and Phase II 
4. Adult (age  18 years) patients 
5. ECOG performance status  2 
6. The interval from prior antitumor treatment to time of NMS-03592088 administration 
should be at least 2 weeks for any agents other than hydroxyurea. 
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7.  All acute toxic effects (excluding alopecia) of any prior therapy must have resolved to 
NCI CTCAE version 5.0 Grade ≤1 
8. Adequate hepatic function, as defined by serum transaminases (i.e., AST/ALT)  2.5 x 
ULN, ALP  2.5 x ULN and total bilirubin  1.5 x ULN unless abnormality considered 
due to Gilbert’s syndrome (in which case the limit is 2 mg/dL). 
9. Adequate renal function, as defined by serum creatinine  1.5 x ULN and an estimated 
glomerular filtration rate (eGFR)  ≥ 45 mL/min as calculated by the BSA-unadjusted 
Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation, *  
 eGFR (mL/min)= eGFR (mL/min/1.73 m2) x [BSA (m2)/1.73] 
where 
eGFR (mL/min/1.73 m2) = 141 x  min(Scr/κ,1)α x max(Scr/κ, 1)-1.209 x 0.993Age x 1.018 
[if female] x 1.159 [if African American]  
10. Patients must use highly effective contraception (for reference, see Appendix 0). Female 
patients must be surgically sterile or be postmenopausal or must agree to the use of 
highly effective contraception during the period of therapy and in the following 208 days  
after discontinuation of study treatment. Since NMS-03592088 has potential induction 
of CYP3A4 WOCBP must be advised that hormonal contraceptives might lose efficacy 
and must use alternate form of highly effective contraception. Male patients must be 
surgically sterile or must agree to use highly effective contraception during the period of 
therapy and in the following 118 days  after discontinuation of study treatment. 
11. Capability to swallow capsules intact (without chewing, crushing, or opening) 
12. Willingness and ability to comply with scheduled visits, treatment plan, laboratory tests 
and other study indications or procedures 
13. Signed and dated IEC or IRB-approved informed consent form indicating that the 
patient is aware of the neoplastic nature of his/her disease and has been informed of the 
procedures to be followed, the investigational nature of the therapy, potential benefits, 
side effects, discomforts, risks and alternative treatments. 
 
6.2. Patient Exclusion Criteria 
The presence of any of the following will exclude a patient from study enrollment: 
1. Current enrollment in another interventional clinical study unless currently only 
participating in the survival follow up part. 
2. Diagnosis of acute promyelocytic leukemia or BCR-ABL-positive leukaemia 
3. Currently active second malignancy, except for adequately treated basal or squamous 
cell skin cancer and/or cone biopsied in situ carcinoma of the cervix uteri and/or 
superficial bladder cancer. 
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4. Patients with known leukemia involvement of CNS  
5. Hematopoietic stem cell transplantation (HSCT) within 3 months of treatment start 
and/or persistent non-hematologic toxicities of Grade ≥2 related to the transplant 
6. Active acute or chronic graft versus host disease (GVHD) requiring immunosuppressive 
treatment 
7. Patients with QTcF interval ≥ 480 milliseconds or with risk factors for torsade de 
pointes (e.g., uncontrolled heart failure, uncontrolled hypokalemia, history of prolonged 
QTc interval or family history of long QT syndrome). For patients receiving treatment 
with concomitant medications known to prolong the QTc interval, replacement with 
another treatment needs to be considered. If replacement or discontinuation is not 
clinically feasible, a careful risk/benefit evaluation should be performed prior to 
enrollment.  
8. Pregnancy. All female patients with reproductive potential must have a negative 
pregnancy test (serum or urine) within the screening period prior to start of study drug.  
9. Breast-feeding or planning to breast feed during the study or within 3 months after study 
treatment.  
10. Known hypersensitivity to any of the components of the NMS-03592088 drug product. 
11. Any of the following in the previous 6 months: myocardial infarction, unstable angina, 
coronary/peripheral artery bypass graft, symptomatic congestive heart failure, 
cerebrovascular accident or transient ischemic attack, pulmonary embolism, deep vein 
thrombosis 
12. Known active, life threatening or clinically significant uncontrolled systemic infection. 
13. Known human immunodeficiency virus (HIV) or acquired immunodeficiency syndrome 
(AIDS)-related illness  
14. Active Hepatitis B Virus (HBV) or Hepatitis C Virus (HCV) C infection.  
15. Known active gastrointestinal disease (e.g., Crohn’s disease, ulcerative colitis, or short 
gut syndrome) or other malabsorption syndromes that would impact on drug absorption. 
16. Known active gastrointestinal ulcer 
17. Other severe or chronic medical or psychiatric condition or laboratory abnormality that 
may increase the risk associated with study participation or study drug administration or 
may interfere with the interpretation of study results and, in the judgment of the 
Investigator, would make the patient inappropriate for entry into this study or could 
compromise protocol objectives in the opinion of the Investigator and/or the Sponsor. 
18. Known diagnosis of myasthenia gravis or any known history of MG autoantibodies at 
screening window 
19. Concomitant anticoagulant use that is not already stabilized therapeutically. 
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20. Subjects under legal protection or unable to express their consent; subjects deprived of 
liberty; subjects who are not members or not beneficiaries of a social security scheme 
21. Signs or symptoms of myasthenia gravis or stroke during screening 
22. Concomitant medications with the potential to cause de novo myasthenia gravis, 
worsening of myasthenia gravis or cause myasthenia gravis-like symptoms as in 
https://myasthenia-gravis.com/clinical/drugs-vaccines-to-avoid (also see 9.2.7.2.1 for a 
corresponding list) 
23. Uncontrolled hypertension, atrial fibrillation or flutter, ventricular arrhythmia or 
receiving treatment for cardiac rhythm disorder or diabetes that is not adequately 
controlled. 
7. SCHEDULE OF EVENTS  
 
 
 
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8. ENROLLMENT PROCEDURES 
Patients considered suitable for study will be informed about study, both verbally and by 
written information. The patients will be given ample time for reading the information 
provided and to ask others’ opinion. The patients who will participate into the study will 
sign and date the informed consent form (ICF) before starting any trial related procedures; 
the Investigator will also sign and date the form.  
After the signature of the ICF, a screening number will be centrally assigned to the patient, 
allowing the screening process for eligibility to begin. All screening evaluations must be 
completed and reviewed to confirm that potential participants meet all eligibility criteria. 
The investigator will maintain a screening log to record details of all participants screened 
and to confirm eligibility or record reasons for screening failure, as applicable. 
Upon completion of the screening evaluation, patients meeting all the eligibility criteria will 
be enrolled and, for the Phase I portion of the study, the Sponsor will assign the dose level 
and schedule.  The enrollment number will be centrally assigned and maintained throughout 
all the study duration. Patients who do not meet all the eligibility criteria will be declared 
screening failure. Screening and enrollment numbers will be centrally managed by the 
Sponsor or designee (details reported in the Study Manual).  
In order to obtain the screening number and the patient number for each patient, the 
Investigator will enter the information required in an online application made available to 
the centers by the Sponsor (details reported in the Study Manual).  
Eligibility confirmation is automatically notified to the Sponsor/or delegate by e-mail. The 
assignment of the screening and enrollment numbers will be provided within one working 
day and will be automatically notified to the site by e-mail. 
In case of the web site is not available because of any reason, the Investigator will fill in a 
registration/enrollment form and fax it to Sponsor or designee. Specific details concerning 
the enrollment procedure are reported in the Study Manual. Eligibility of a patient is a 
responsibility of the Investigator. Verification of the confirmed eligibility will be performed 
by the Sponsor or authorized personnel delegated by the Sponsor during the course of the 
study. 
No study drug will be dispensed to a patient until the entire registration process is 
completed. It is recommended to start the treatment within 1-4 days from patient enrollment. 
For the Phase I portion of the study, the Sponsor or designee will notify all the participant 
sites of the inclusion of a new patient and will inform them of the next possible enrollment 
date. Clinical safety from all cycles as well as the PK data available will be reviewed prior 
to escalating to the next dose level of both schedules. Dose escalations will be decided 
jointly between the Investigators and the Sponsor after data review. 
For the starting dose and dose escalation rules, see Sections 5.1 and 5.2. 
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For the backfill cohorts and the Phase II portion of the study, following the ICF signature, in 
order to get the patient’s screening number, the Investigator will provide the basic 
information required in the clinical data management system made available by the Sponsor. 
The assigned screening number will be sequential within the site where the patient has been 
recruited. 
Upon completion of the screening evaluation, the Investigator will enter relevant 
information in the clinical data management system, confirming or not patient’s eligibility. 
Patients meeting all the eligibility criteria will be enrolled. The assigned enrollment number 
will be sequential regardless of the center where the patient has been recruited. Enrollment 
will be competitive among the participating sites. 
At any time, enrollment may be restricted to patients with specific prior lines/therapies 
and/or mutations, based on Sponsor decision. 
The Sponsor will control the patient assignment to cohorts and may stop or pause cohorts in 
any phase or part of the study based on safety, efficacy or strategic reasons. 
Further details on the above procedures, including the notifications from Investigator to 
Sponsor and vice versa, are reported in the general module of the Study Manual. 
 
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9. TREATMENT  
Only qualified personnel familiar with procedures that minimize undue exposure to 
themselves and to the environment should undertake the preparation, handling, and safe 
disposal of chemotherapeutic agents. 
9.1. Study Products Description  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
9.1.1. Drug Preparation and Dispensing 
NMS-03592088 will be administered as home-based treatment. Site personnel must ensure 
that patients clearly understand the directions for self-medication. The Investigator (or 
delegate) will dispense to the patient the doses of NMS-03592088 covering no more than 
one cycle at a time. The daily doses will be made out of a number of capsules according to 
the dose level (in mg/day) at which the patient has been assigned for a given cycle, without 
adjustment for body size (flat dose).  
In Schedule A, at each cycle, patients will take the assigned daily dose for 21 consecutive 
days (from Day 1 to Day 21). No drug should be given for the subsequent 7 days (i.e. Days 
22-28), to ensure a 7-day resting period.  
In Schedule B, at each cycle, patients will take the assigned daily dose for 28 consecutive 
days (i.e., from Day 1 to Day 28), with no resting period. 
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The dose and schedule in Phase II or backfill cohorts may be adapted to a loading/ 
maintenance regimen. Initially, NMS-03592088 will be administered, on Cycle 1, at 360 
mg/day (loading dose) for 5 consecutive days, followed by 150 mg/day (maintenance dose) 
for 23 consecutive days. The same maintenance dose (150 mg/day) will be administered 
from Cycle 2 onwards, unless dose modifications are needed based on the toxicities 
observed. Additional dosing may be explored in the Phase II or backfill as long as dosing or 
expected exposures are no higher than escalation-cleared exposure equivalents that  that 
haves been studied for safety and tolerability adequately during escalation.  
The study medication has to be stored under refrigerated conditions (between 2°C and 8 °C 
or 36°-46°F), out of the reach and sight of children. Patients should be instructed to keep 
their medication in the bottles provided and not transfer it to any other containers. 
9.1.2. Patient Education & Information 
All patients will receive their doses of NMS-03592088 together with a patient’s diary, 
which includes also the instructions relevant to drug administration. The site personnel 
handling the study medication must ensure that patients fully understand that the treatment 
period (cycle) comprises 28 days (4 weeks), consisting in 21 consecutive days of daily 
administration followed by a 7-day resting period (Schedule A) or 28 consecutive days of 
daily drug administration (Schedule B). 
Additionally, the patients should be informed: 
• to take NMS-03592088 every day as prescribed by their doctor. 
• to take NMS-03592088 at the same time each day ,generally 1 hour before breakfast, 
with a glass of plain water; water is allowed during fasting period. For the food effect 
sub-study the sponsor will define the standard meal in the study manual. 
• In the rare event that the patient forgets to take NMS-03592088 at the usual time, to take 
it as soon as possible within 2 hours from the usual time, in fasting condition or 
otherwise to skip the dose and in any case record the events on the patient’s diary.  
• if the patient misses one day, to take the usual planned daily dose the next day, if 
scheduled. The prescribed daily dose of NMS-03592088 should not be doubled and the 
number of capsules missed and the reason should be tracked in the patient’s diary. 
• if vomiting occurs during or after having taken the daily dose, not to take extra capsules 
that day and to take the usual planned daily dose the next day, if scheduled. The daily 
prescribed dose of NMS-03592088 should not be doubled and the events should be 
recorded in the patient’s diary. 
• to adhere to the principles of safe handling and storage of the study medication. 
Breaking/crushing or opening the capsules must be avoided. In such cases, record of the 
broken capsules should be kept in the patient’s diary. In case of opening of the capsules, 
avoid contact or inhalation. In case of skin contact, the patient should be instructed to 
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wash the affected area with plenty of water or soap and water. In case of eye-contact, the 
patient should be instructed to rinse thoroughly with plenty of water and seek medical 
advice as soon as possible. 
• to return all packaging (bottles and single cartons) as well as not-taken capsules (if any) 
and the patient diary to the site personnel. 
These instructions should be given to the patient at the pre-treatment visit and restated on 
subsequent visits, in particular when a new drug supply is provided. 
9.1.3. Procedure for Handling Drug Spills 
Precautions for drug handling of cytotoxic agents should be followed for NMS-03592088. 
In case of opening of the capsules, avoid contact or inhalation. In case of skin contact, the 
affected area should be washed with plenty of water or soap and water. Any contaminated 
clothing should be removed. In case of eye-contact, rinse thoroughly with plenty of water. 
Seek medical advice as soon as possible. 
9.1.4. Storage and Stability 
 
 
 
 
 
 
 
 
 
9.1.5. Source of Drug 
 
 
 
9.1.6. Drug Accountability 
NMS-03592088 must not be used outside the context of this protocol. Under no 
circumstances should the Investigator or site personnel supply study product to other 
Investigators or clinics, or allow the supplies to be used other than as directed by this 
protocol.  
In this protocol the study drug may be administered to patient, according to the selected 
schedule, until the criteria for withdrawal as detailed in Section 10 are met. Drug 
accountability should continue to be performed until the patient’s last dose of NMS-03592088. 
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Adequate records on receipt, use, return, loss, or other disposition of medication must be 
maintained and electronically captured in the dedicated eCRF page. If needed, specific drug 
accountability forms supplied by the Sponsor or designee or computer records used by the 
pharmacy at the investigational site, and agreed with the Sponsor or designee, can be also 
used to provide drug accountability information. In either case, information describing study 
drug supplies and their disposition, patient by patient, must be provided, signed by the 
Investigator (or the pharmacist or other person who dispensed the drug) and collected by the 
study monitor. Requisite data includes relevant dates, quantities, batches or code numbers, 
and patient identification for patients who received study drug. At the end of the study, after 
verification by the study monitor and upon authorization of the Sponsor, the unused study 
drug may be destroyed at the site as dictated by the appropriate standard procedures of the 
participating institution. Destruction must be documented. Alternatively, all unused product 
will be returned to the Sponsor or Manufacturer on behalf of the Sponsor. If disposed 
locally, all used bottles and containers of study product should be discarded according to the 
standard institutional policy. 
9.2. Treatment Administration 
9.2.1. Treatment Dose and Schedule  
 
 
 
  
  
 
 
 
  
 
 
 
   
 
 
 
 
 
 
 
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9.2.2. Duration of Treatment  
Patients may continue on study treatment until disease progression, unacceptable toxicity, 
investigator decision, withdrawal of consent by the patient or other discontinuation criteria 
detailed in Section 10 are met. Note:  If patient is clinically stable and has observation of 
blasts reduction or suspected disease stabilization in the judgment of the investigator the 
investigator may continue dosing after an adverse event taking into account dose 
modification in section 9.2.3. 
A participant patient is considered to have completed the study if he/she has completed all 
phases of the study including the last scheduled procedure as shown in the Schedule of 
Events in Section 1. 
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9.2.3. Dose Modifications  
Adverse events that are intolerable or severe will be managed by treatment interruption 
and/or dose reduction depending on the circumstance. Dose reductions and delay will be 
based on adverse events at least possibly related to the study drug. 
Dose modifications may occur during a cycle or at the start of a new cycle. All dose 
modifications for the start of a new cycle should be based on the most severe toxicity 
observed in the previous cycle. In the event of multiple toxicities, the dose modification 
should be based on the worst toxicity observed (according to the NCI CTCAE v 5.0).  
Any modifications to the NMS-03592088 dose should be documented in the eCRF. 
9.2.3.1. Re-treatment Criteria and Cycle Delay 
For a patient with non- hematological toxicities, a new cycle of treatment may begin when 
toxicities (except for alopecia) are ≤ Grade 1or have recovered to pre-treatment status. If 
these conditions are not met, treatment should be delayed for 1 week and up to a maximum 
of 2 weeks, to allow for recovery. If, after this period, toxicities do not recover to the pre-
defined level, patient will be withdrawn from the study unless the patient is demonstrating 
clinical benefit as agreed by the Investigator and Sponsor. 
9.2.3.2. Dose Reductions and Interruptions 
If a patient experiences a DLT during Cycle 1, the patient should be discontinued from the 
study, unless the patient is demonstrating clinical benefit and can continue the treatment at a 
reduced dose, as agreed by the Investigator and Sponsor. If a patient experiences a non-
hematological adverse event meeting DLT criteria after Cycle 1, administration of NMS-
03592088 should be held until the drug related toxicity has resolved to Grade ≤1 or baseline 
grade. Upon resolution of the toxicity, the patient should restart study drug at the next lower 
dose level depending on the severity and type of toxicity observed and after discussion with 
Sponsor or designee.  If the patient experiences persistent Grade 4 myelosuppression in the 
absence of disease progression, dose reduction can be considered starting from Cycle 3.  
 
 
France specific: In case of G4 non hematological toxicity reoccurrence, NMS-03592088 
must be permanently discontinued. 
Suggested dose reduction and interruption or discontinuation criteria are described in 
Table 1 and are provided as guidance to the Investigators. 
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Table 1.  Recommended Dose Modification Criteria* for Treatment-Related Toxicity 
Observed During or Prior a Treatment Cycle 
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9.2.4. Extension Treatment  
Not applicable. 
9.2.5. Overdose and Medication Error Instructions 
There are no known antidotes for NMS-03592088 overdose. In the case of an overdose 
clinical care must monitor for both acute and long-term effects. The Sponsor 
Pharmacovigilance should be notified immediately (i.e. within 24 hours) according to 
procedures described in part 11.5.1.7. Study monitor should be also contacted to discuss the 
details of any overdose. 
Medication errors are reportable irrespective of the presence of an associated AE/SAE, 
including: 
• Medication errors involving patient exposure to the product, 
• Potential medication errors or uses outside of what is foreseen in the protocol that do or 
do not involve the participating patient. 
Whether or not the medication error is accompanied by an AE, as determined by the 
Investigator, the medication error and, if applicable, any associated adverse event(s) must be 
captured on an adverse event (AE) eCRF page (refer to Safety Assessments, Section 11.5, 
for further details).  
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9.2.6. Unblinding 
Not applicable. 
9.2.7. Assessment and Management of Potential Neurologic Toxicity 
9.2.7.1. Background 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   
 
 
 
 
Table 2. Drug-induced Tremors and Corresponding Neurologic Signs 
© 2002 The Cleveland Clinic Foundation 
 
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9.2.7.2. Patient management 
 
 
 
 
 
 
 
 
. 
 
  
 
 
 
 
  
 
 
  
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
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Table 3. Drugs to avoid  
9.2.7.3. Dose Modifications 
Criteria for dose adjustments and interruptions are reported in Table 1. 
9.2.8. Tumor Lysis Syndrome  
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
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9.2.9. Differentiation Syndrome  
Differentiation syndrome (DS) is a potentially fatal complication of effective leukemia 
treatments, initially reported in patients with acute promyelocytic leukemia undergoing 
induction therapy with all-trans retinoic acid (ATRA) or arsenic trioxide [64]. 
DS has been described in patients with AML receiving novel targeted therapeutics including 
IDH inhibitors and FLT3 tyrosine kinase inhibitors. While frequency of the event has been 
reported to be 14%-19% for IDH inhibitors [65;66], the event is much less frequent with 
FLT3 inhibitors (1% for gilterinib (Xopata®) [67]. Terminal myeloid differentiation of bone 
marrow blasts in association with a clinical DS has also been reported in patients treated 
with quizartinib [68]. 
 
 
  
Symptoms of DS are non-specific and may include fever, weight gain, edema, hypotension, 
rash, renal dysfunction, malaise, dyspnea and pleural and/or pericardial effusions, in 
addition to marked neutrophil-predominant leukocytosis. DS was reported to occur as early 
as 1 day and up to 5 months after initiation of treatment with IDH inhibitors. Prompt 
identification of early signs and symptoms and intervention are essential to avoid serious 
complications. Therapeutic intervention may include oral hydroxyurea to mitigate 
leukocytosis and steroid therapy, as appropriate.  
9.2.10. Concomitant Medications and Other Therapy 
All concomitant medications and other therapies must be recorded in the eCRF. Directives 
for supportive care are outlined below. 
9.2.10.1. Antiemetics Support 
In Phase I (dose escalation), emesis prophylaxis is not allowed in Cycle 1, until nausea 
and/or vomiting have been clearly identified as study-medication expected adverse events. 
In the subsequent cycles, if needed, prophylactic therapy is allowed using institutional 
guidelines for treatment and/or published guidelines 69,70. 
9.2.10.2. Antidiarrheal Support 
Treatment with antidiarrheal drugs is recommended once the onset of the earliest signs of 
diarrhea is present. Loperamide or other antidiarrheal agents used by the Institution might be 
started at the occurrence of Grade 1 diarrhea (increase of < 4 stools per day over baseline; 
mild increase in ostomy output compared to baseline). Recommendation for Loperamide use 
should be taken in the following manner: 4 mg at the first onset of diarrhea, then 2 mg every 
2 hours. This therapy should continue for 12 hours after the last liquid stool. Patients may 
take loperamide 4 mg every 4 hours during the night. In no instance should loperamide be 
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administered for more than 48 consecutive hours because of the risk of paralytic ileus. 
Patients should be instructed to refer to the center in case of diarrhea lasting > 24 hours 
despite optimal supportive care or diarrhea with fever. 
The patients should contact the Investigator or the study nurse if they experience diarrhea 
for the first time during the treatment; black or bloody stools; symptoms of dehydration such 
as lightheadedness, dizziness, or faintness; an inability to take liquids by mouth due to 
nausea and vomiting; or an inability to get diarrhea under control with loperamide within 
24 h. In addition to loperamide, the patients should be provided with an antibiotic therapy as 
per institutional guidelines. Patients should be instructed to refer immediately to the center 
in case of occurrence of these symptoms. Patients with colitis/ileus, neutropenic fever or 
infection should also be hospitalized promptly for IV antibiotic therapy. 
9.2.10.3. Hematopoietic Support 
In Phase I prophylactic use of G-CSF or initiation of erythropoietin in Cycle 1 is not 
recommended, but may be instituted in Cycle ≥2 in patients who are having difficulty with 
severe neutropenia or anemia. 
Patients who have been treated for  4 weeks with erythropoietin prior to the first cycle may 
continue on the existing treatment. 
Patients with neutropenic fever or infection should be hospitalized promptly for IV 
antibiotic therapy and may receive therapeutic CSFs as appropriate. 
Red blood cell and platelet transfusions should be administered as warranted. 
9.2.10.4. Antiacids 
Patients using H2-receptor antagonists must take them between at least 12 hours before and 
2 hours after a dose of NMS-03592088, antiacids between at least 4 hours before and 2 
hours after a dose, to avoid any potential effect on NMS-03592088 absorption.   
Proton pump inhibitors (PPI) are allowed if administered between at least 10 hours before 
and 1 hour after the dose. Sponsor might opt to restrict further PPI use. 
9.2.10.5. Other Permitted Concomitant Medications 
 
 
 
 
 
 
 
 
 
 
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9.2.10.6. Other Anticancer or Experimental Therapy 
 
 
 
 
 
9.2.10.7. Phototoxicity Prevention 
  
 
 
 
 
 
 
 
 
 
 
9.2.10.8. Potential interactions with other medicinal products 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
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10. PATIENT WITHDRAWAL FROM STUDY PARTICIPATION 
Patients may withdraw from the study at any time at their own request, or they may be 
withdrawn at any time at the discretion of the Investigator or Sponsor for safety, behavioral, 
or administrative reasons.  
If a patient does not return for a scheduled visit, every effort should be made to contact 
him/her. In any circumstance, every effort should be made to document patient outcome, if 
possible. The Investigator should inquire about the reason for withdrawal, requests the 
patient to return for a final visit, if applicable, and follow-up with the patient regarding any 
unresolved adverse events. 
If the patient withdraws from the study and also withdraws consent for disclosure of future 
information, no further evaluations should be performed and no additional data should be 
collected. The Sponsor may retain and continue to use any data collected before such 
withdrawal of consent. 
Patients may continue with therapy with the study medication unless any of the following 
occurs: 
• 
Disease progression or relapse at any time; 
Note: If patient is clinically stable and has observation of blasts reduction or suspected 
disease stabilization in the judgment of the investigator the patient may continue with 
dosing after an adverse event taking into account dose modification in section 9.2.3;  
Note: Patient must discontinue treatment for failure to achieve at least partial response 
after 9  cycles 
• 
Global deterioration of health status requiring discontinuation;  
• 
First-cycle DLT, unless the patient is demonstrating clinical benefit and can continue the 
treatment at a reduced dose, as agreed by the Investigator and Sponsor; 
• 
 with systemic and/or bulbar impairment 
• 
Unacceptable study drug-related toxicities incompatible with continuation of treatment 
with NMS-03592088 according to the judgment of the Investigator, even at a reduced 
dose;  
• 
Change in the patient’s medical status (including pregnancy) such that the Investigator 
believes that patient safety may be compromised or that it would be in the best patient’s 
interest to stop treatment; 
• 
Treatment delay for >14 days due to treatment related non-hematologic toxicity unless 
the patient is demonstrating clinical benefit as agreed by the Investigator and Sponsor; 
• 
The patient becomes eligible for hemopoietic stem cell transplantation (HSCT) 
• 
Substantial deviation from specified inclusion or exclusion criteria or non-compliance 
by the patient with protocol requirements; 
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• 
Investigator's decision; 
• 
Patient’s refusal to continue study treatment; 
• 
Patient lost to follow up; 
• 
Death; 
• 
Study terminated by Sponsor. 
Patient will be withdrawn from the study in case of: 
• 
Withdrawal of consent; 
• 
Patient lost to follow up; 
• 
Death; 
• 
Study terminated by Sponsor. 
Data to be collected for the end of study treatment/withdrawal are described in the Schedule 
of Events, reported in Section 1. 
Patients will be followed for at least 28 days after the last dose of study drug for adverse 
events and for 18 months from patient’s first study drug dose for survival status. 
 
 
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11. ASSESSMENTS  
11.1. Timing of Assessments 
Schedule of Events, reported in Section 1, summarizes information on the timing of 
assessments to be performed during Phase I and Phase II portions of the study. Protocol 
waivers or exemptions are not allowed. 
Procedures conducted as part of the participant’s routine clinical management (e.g., bone 
marrow aspirate or biopsy) and obtained before signing of the Informed Consent Form may 
be utilized for screening or baseline purposes provided the procedures met the protocol-
specified criteria and were performed within the time frame defined in the Schedule of 
Events. 
11.2. Disease Assessments 
Peripheral blood and/or bone marrow aspirate/biopsy will be collected for cytogenetic 
molecular and phenotypic characterization of the disease at the study entrance, during 
treatment, as applicable, and at the end of treatment. 
11.2.1. Immunophenotyping, Cytogenetic and Molecular Characterization 
 
 
 
 
 
 For further details regarding antigens to be 
assessed by FACS, please refer to Study Manuals. 
11.2.2. Detection  of FLT3-ITD or D835/I836 mutations  
 
  
 
 
 
  
 
 
 
 
 
 
 
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11.3. Efficacy Assessments 
Efficacy assessments will be based on analysis of full blood count, bone marrow aspirate or 
biopsy and, for patients with extramedullary disease, on clinical examination and/or 
imaging, as appropriate. 
11.3.1. Laboratory Assessments: Hematology 
Hematology should include hemoglobin, RBC, PLT, WBC with differential counts 
(neutrophils, lymphocytes, monocytes, eosinophils, and basophils) and blast cells. It should 
be done at screening and at the same day when bone marrow samples are obtained for the 
disease assessment (see Section 1, Schedule of Events). 
11.3.2. Disease Assessments: Bone Marrow Aspirate/Biopsy  
A bone marrow aspirate/biopsy obtained from hipbone or from another appropriate site, will 
be performed: 
• During Phase I, at screening and at the end of treatment, regardless of when the patient 
discontinues the study. During treatment at Day 1 on Cycle 2, 3 and then at every even 
subsequent cycle. If a bone marrow aspirate or biopsy has been collected within 7-days 
of the nominal date (excluding the screening sample) it need not to be repeated. 
• During Phase II, at screening and at the end of treatment, regardless of when the patient 
discontinues the study. During treatment at Day 1 on Cycles 2, 3, 4, 6, 8 and then every 
three subsequent cycles. For AML patients who achieve a CR, CRh or CRi collection of 
bone marrow aspirate or biopsy sample will be repeated 1 month after achievement of 
the first remission, to confirm response. If a bone marrow aspirate or biopsy has been 
collected within 7-days of the nominal date (excluding the screening sample) it need not 
be repeated. 
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• At Investigator’s discretion 
Throughout the clinical study, bone marrow and/or blood samples collected at screening and 
at the end of treatment will be used also for centralized NGS analysis and biomarkers 
expression evaluation. For further details on these evaluations see Section 11.6.2 and the 
Study Manuals. 
11.3.3. Clinical evaluation of Extramedullary Disease  
For all patients, clinical evidence of extramedullary disease (EMD) will be collected, in the 
eCRF, in terms of presence/absence of the disease. The site of involvement will also be 
reported in the eCRF.During the study, the EMD status will be clinically evaluated at 
screening, during the physical examinations performed on treatment, at the same times of 
disease evaluation, at the end of treatment and at Investigator’s discretion . 
In the presence of EMD, lesions must be followed by imaging and/or other clinical 
evaluations, and the choice of methods is at the Investigator’s discretion. For CMML 
patients, splenomegaly should always be assessed using CT or MRI scan (3-D ultrasound 
will be acceptable if other aforementioned scans are not available within the allotted 
timeframes of the intra-study evaluation). 
11.3.4. Definition of the response 
The response to treatment will be evaluated:  
• For AML patients, following criteria as defined by the  ELN recommendations [6, 7]. 
For reference, see Appendix 2; 
• For CMML patients, following the International Working Group criteria [56]. For 
reference see Appendix 3, Appendix 4 and Appendix 5. 
11.4. Outcomes Research Assessments 
Not applicable. 
11.5. Safety Assessments   
Safety assessments include collection of AEs, SAEs, triplicate 12-lead ECGs, vital sign 
measurements, physical examinations and safety laboratory tests. These will be performed 
periodically at baseline, during treatment and at End of Treatment (and/or at Investigators’ 
discretion). 
Assessment of adverse events will include type, incidence, severity (graded by the National 
Cancer Institute [NCI] Common Terminology Criteria for Adverse Events [CTCAE], 
Version 5.0), timing, seriousness, and relatedness. 
Baseline signs and symptoms will be recorded at baseline and then reported as adverse 
events during the trial if they worsen in severity or increase in frequency. 
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11.5.1. Adverse Event Assessment  
11.5.1.1. Definition of Adverse Events 
11.5.1.1.1. Adverse Event 
According to ICH definition and EU directive (2001/20/EC), an AE is defined as any 
untoward medical occurrence in a patient or a clinical trial patient administered a medicinal 
product and which does not necessarily have to have a causal relationship with the use of the 
product. An adverse event can therefore be any unfavorable and unintended sign (e.g. an 
abnormal laboratory finding), symptom, or diagnosis temporally associated with the use of a 
medicinal product, whether or not considered related to the medicinal product. 
Any untoward medical occurrence, which occurs outside the period of patient follow-up 
defined in the protocol, is not considered an AE. Symptoms or medically significant 
laboratory or instrumental (e.g., by electrocardiography) abnormalities of a pre-existing 
condition should not be considered an AE. However, occurrence of new symptoms, 
laboratory or instrumental abnormalities, as well as worsening of pre-existing ones, is 
considered AEs. 
11.5.1.1.2. Serious Adverse Events 
A serious adverse event (SAE) is an adverse event that falls into one or more of the 
following categories:  
• Results in death; 
• Is life-threatening, i.e., an event which, in the view of the Investigator, placed the patient 
at risk of death at the time of event (it does not include an event which hypothetically 
might have caused death if it were more severe); 
• Requires inpatient hospitalization or prolongation of existing hospitalization; 
• Results in persistent or significant disability/incapacity, where disability is defined as a 
substantial disruption of a person’s ability to conduct normal life functions, either 
reported or defined as per clinical judgment; 
• Is a congenital anomaly/birth defect (if exposure to product just before conception or 
during pregnancy resulted in an adverse outcome in the child); 
• Is any other important medical event, i.e., may not result in death, be life-threatening, or 
require hospitalization, but based upon appropriate medical judgment, it may jeopardize 
the patient and may require medical or surgical intervention to prevent one of the 
outcomes listed in the points above. Examples of such events include allergic 
bronchospasm requiring intensive treatment in an emergency room or at home, and 
blood dyscrasias or convulsions that do not result in inpatient hospitalization. 
A non-serious adverse event is any adverse event that does not meet the criteria listed above 
or the outcome cannot be determined with the information provided. 
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Each adverse event has to be classified by the Investigator as serious or non-serious.  
In this study the following do not have to be classified as SAEs: 
• Admission to hospital required by the protocol; 
• Hospitalization for routine treatment or monitoring of the studied indication not 
associated with any deterioration in patient’s clinical condition; 
• Hospitalization or prolongation of hospitalization for technical, practical, or social 
reasons, in absence of an AE; 
• A procedure requiring hospitalization planned prior to starting the study treatment; must 
be documented in the Source Documents and the e-Case Report Form (e-CRF).  
Prolonged hospitalization for a complication remains a reportable SAE; 
• Hospitalization for an elective treatment of a pre-existing condition unrelated to the 
studied indication; 
• Events definitely related to disease progression. 
However, all Adverse Events with outcome deaths occurring during the reporting period 
have to be reported as SAEs, even if due to disease progression. 
11.5.1.1.3. Adverse Events of Special Interest 
Adverse events of special interest (AESI) are defined as events (serious or non-serious) 
which are of scientific and medical concern specific to the Sponsor’s product or program, 
for which ongoing monitoring and rapid communication by the Investigator to the Sponsor 
may be appropriate. Such events may require further investigation in order to characterize 
and understand them.  
During the dose escalation part of the study neurological adverse events involving the 
neuromuscular transmission 
) have been reported with NMS-
035920088 (See section 9.2.7.1). External ocular movements deficit with ptosis and diplopia 
were the typical pattern.  
The occurrence of any sign and/or symptom suggestive of a 
, such as:  
a) ptosis, diplopia, weakness, muscular weakness (after exertion), dysphagia, dysphonia, 
dyspnea 
b) fatigue, asthenia, hyposthenia, hypoactivity, if associated with any of the above 
should prompt the evaluation by a neurologist and, if the diagnosis of 
 
is confirmed, the event should be reported as AESI. 
All AESIs [diagnosis and specific sign(s)/symptom(s)] have to be reported within 24 hours 
according to the procedures described for serious adverse event in section 11.5.1.7. 
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11.5.1.2. Unexpected Adverse Event 
An unexpected AE is one, the nature or severity of which is not consistent with the 
applicable product information that, for the present CT, is the Investigator Brochure (IB) 
[55]. 
11.5.1.3. Eliciting Adverse Event Information 
The Investigator has to report all directly observed AEs and all AEs spontaneously reported 
by the trial patient using concise medical terminology. In addition, each trial patient will be 
questioned about adverse events at each clinic visit following signature of the Informed 
Consent Form. The question asked will be “Since your last clinical visit have you had any 
health problems?” 
11.5.1.4. Adverse Event Reporting Period 
The adverse event reporting period for this trial begins upon signing of informed consent 
and ends 28 days after the last study treatment administration. 
However, if a patient begins a new anticancer therapy earlier than 28 days after the last dose 
of study treatment administration, the adverse event reporting period will end at the time the 
new anticancer therapy starts. 
All the adverse events that occur in trial patients during the adverse event reporting period 
must be reported to the Sponsor, whether or not the event is considered related to the study 
treatment.  
11.5.1.5. Adverse Event Follow Up after the End of the Reporting Period 
The following events should be followed after the end of the reporting period (i.e., 28 days 
after the last study treatment administration): 
1. SAEs with outcome ‘not recovered’ or ‘unknown’ at the end of the reporting period. 
2. Non-serious events classified as related to the investigational study treatment with 
outcome ‘not recovered’ or ‘unknown’ at the end of the reporting period. 
These events should be followed until they resolve or until the Investigator determines, 
whenever possible, that they have become “chronic” or “stable”. Resolution of such events 
is to be documented on the SAE Form and/or on eCRF. 
In addition, if after the end of the reporting period, suspected serious adverse reactions or 
deaths are reported to the Investigator and he/she believes that they are related to the IMP, it 
is the Investigator’s responsibility to report these suspected serious adverse reactions to the 
Sponsor. Such suspected serious adverse reactions will be reported using a Serious Adverse 
Event Report or by any other way chosen by the Investigator. 
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11.5.1.6. Relationship to the Investigational Medicinal Product 
The relationship of the adverse event will be assessed by means of the question “Is there a 
reasonable possibility that the event may have been caused by the study drug?” The 
Investigator should respond to this question with either ‘Yes’ or ‘No’. 
‘No’ equals to Unrelated/Unlikely, i.e. there is no reasonable possibility that the study drug 
caused the event; Yes equals to = Related, i.e. there is a reasonable possibility that the study 
drug caused the event. 
11.5.1.7. Reporting Requirements 
Each adverse event has to be classified by the Investigator as SERIOUS or NON-SERIOUS 
(as per paragraph 11.5.1.1.2). This classification of the event determines the reporting 
procedures to be followed.  If a serious adverse event occurs, reporting will follow local and 
international regulations, as appropriate. 
If a serious adverse event occurs the Sponsor Pharmacovigilance has to be notified within 
24 hours of awareness of the event by the Investigator, by e-mail (here below 
Pharmacovigilance address/contacts). Further detailed reporting procedures are described in 
the Study Manual.  
The initial report should be followed by submission of more detailed adverse event 
information as soon as it is available. Additional follow-up should be provided up to the 
resolution of the SAE, the Investigator determines it has become chronic or stable (not 
recovered) or a new anticancer therapy is initiated. 
Reporting requirements for adverse events are summarized in the following table. 
 
REPORTING REQUIREMENTS FOR ADVERSE EVENTS 
Seriousness 
Reporting Time 
Type of Report 
SERIOUS 
Within 24 hours 
Initial report on designated SAE form 
 
As soon as available 
Follow-up/Final report on designated SAE form 
NON-SERIOUS 
As per  eCRF procedure 
Appropriate section of eCRF 
Suspected Unexpected Serious Adverse Reactions (SUSARs) will be reported by Sponsor or 
designee to all competent Regulatory Authorities, to the Ethics Committees and to all the 
Investigators involved, according to local regulations and requirements stated in ICH Good 
Clinical Practice. 
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In the rare event that the Investigator does not become aware of the occurrence of a serious 
adverse event immediately (for example, if an outpatient trial patient initially seeks 
treatment elsewhere), the Investigator has to report the event within 24 hours after learning 
of it and document his/her first awareness of the adverse event. 
Serious adverse events should also be consistently recorded in the appropriate section of 
eCRF. 
Non-serious adverse events have to be reported in the appropriate section of eCRFs only 
excluding Adverse Events of Special Interest (see section 11.5.1.1.3). 
11.5.1.8. Recording Adverse Events in the Case Report Forms 
Information on AEs must be evaluated by a physician and recorded in source documents 
such as the hospital file. AEs have to be reported in the eCRF as aforementioned. The 
Investigator will also be asked to assess the relationship between the AE and the 
investigational medication. 
• Preexisting Conditions 
In this study, a preexisting condition (ie, a disorder present before the AE reporting period 
started and recorded in the medical history) should not be reported as AE unless the 
condition worsens or episodes increase in frequency during the AE reporting period. 
All relevant symptoms, occurring after the ICF signature and before the first drug intake, 
should be reported (with CTC grade) in the baseline AE page, including disease-related 
symptoms (e.g. fatigue, bone pain, etc). Abnormal lab values do not need to be reported as 
AE if related to the disease (e.g. anemia, thrombocytopenia), or a medical condition already 
reported in Medical History (e.g. hyperglycemia for a patient with diabetes). 
• Procedures 
Diagnostic and therapeutic non-invasive and invasive procedures, such as surgery, should 
not be reported as AE.  However, the medical condition for which the procedure was 
performed should be reported if it meets the definition of AE. For example, an acute 
appendicitis that begins during the AE reporting period should be reported as AE and the 
resulting appendectomy should be recorded in the source documents. 
• Symptoms of the Disease 
All relevant symptoms present before the AE reporting period started, have to be recorded in 
medical history. During treatment. the specific symptoms of the disease have to be reported 
as adverse events if they match with new occurrence or worsening in severity or in 
frequency versus the baseline visit. Note: the general wording “Progression of the disease” 
should not be reported as adverse event. 
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• Abnormal Laboratory Findings 
Abnormal laboratory findings occurring during the AE reporting period have to be recorded 
as adverse events when they cause treatment change (dose 
omission/reduction/delay/discontinuation) or when require clinical intervention (e.g., 
hospitalization for further investigation or management of the laboratory abnormality). 
Disease-related anemia and/or thrombocytopenia requiring transfusion support should not be 
reported as AE if management of the event(s), e.g. transfusion need, has not changed since 
ICF signature, but they should be reported as AE if the event(s) results in dose 
omission/delay/discontinuation/reduction, or in case the event worsens requiring 
hospitalization (not previously needed) or more frequent transfusions. 
Note: uncomplicated and asymptomatic abnormal laboratory findings have not to be 
reported as adverse events. The corresponding values have to be reported only in the 
relevant eCRF sections (e.g., hematology, biochemistry). 
• Abnormal Findings in vital signs, physical exams and/or ECG 
Abnormal findings in vital signs, physical exam and/or ECG, have to be reported as adverse 
events if they are clinically significant new events or events worsening as compared to 
baseline. Clinical significance is defined as any variation, which has medical relevance 
based on at least one of the following criteria: 
− Induces relevant clinical signs or symptoms; 
− Requires active intervention; 
− Requires change of study medication (dose omission / reduction / delay / 
discontinuation); 
− The abnormality or investigational value is clinically significant in the opinion of the 
investigator. 
11.5.1.9. Grading of Adverse Event Severity 
In this study the severity/intensity of AEs will be graded using the Common Terminology 
Criteria for Adverse Events (CTCAE, Version 5.0) of the US National Cancer Institute (see 
website:https://ctep.cancer.gov/protocolDevelopment/electronic applications/docs/CTCAE
v5_Quick_Reference_8.5x11.pdf) 
For each event, each change in severity grade should be reported. If an event swings 
repeatedly back and forth from a grade to another, it is possible to record it as <intermittent 
AE>. 
For adverse events not reported in the CTCAE Version 5.0, the Investigator will use the 
Grade or adjectives reported in Table 4. 
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Table 4. Grading of Adverse Event Severity  
for Events not reported in the CTCAE Version 5.0 
Grade 
Adjective 
Description 
Grade 1 
Mild 
Does not interfere with patient’s usual function 
Grade 2 
Moderate 
Interferes to some extent with patient’s usual function 
Grade 3 
Severe 
Interferes significantly with patient’s usual function 
Grade 4 
Life-threatening 
Results in threatening to life or in an incapacitating 
disability 
Grade 5 
Death 
Death related to AE 
Note the distinction between the term “serious” and “severe”, which are not synonymous. 
The term “severe” is used to describe the intensity of a specific event (i.e., severe headache) 
while the term “serious” is based on patient/event outcome or action criteria. Seriousness 
(not severity) serves as a guide for defining regulatory reporting obligations. For example, 
vomiting Grade 1 for which a hospitalization occurred is a serious event even if the event is 
not severe. 
11.5.1.10. Exposure In Utero 
If a female patient becomes or is found to be pregnant while receiving the study drug or 
within 208 days from its discontinuation, the Investigator should transmit this information 
using the Part I of Exposure in Utero (EIU) Form to Sponsor Pharmacovigilance. This must 
be done irrespective of whether an adverse event has occurred and within 24 hours of 
awareness of the pregnancy. However, if the patient begins a new anticancer therapy before 
208 days after the last dose of study treatment administration, the exposure “in utero” 
reporting period will end at the time the new treatment is started. 
The Investigator will follow the patient until completion of the pregnancy or until pregnancy 
termination (i.e., induced abortion) and then notify the Sponsor Pharmacovigilance of the 
outcome within 5 days or as specified below. The Investigator will provide this information 
completing Part II of EIU form. The reason(s) for an induced abortion must be specified. 
If the outcome of the pregnancy meets the criteria for immediate classification as a serious 
adverse event (i.e., spontaneous abortion, stillbirth, neonatal death, or congenital anomaly 
[including that in an aborted fetus]), the Investigator should follow the procedures for 
reporting serious adverse events, i.e., report the event to the Sponsor (as described in 
Section 11.5.1.7) 
In the case of a live birth, the “normality” of the newborn must be assessed at the time of 
birth and for a minimum follow-up of at least three months. 
The “normality” of an aborted fetus can be assessed by gross visual inspection unless pre-
abortion laboratory findings are suggestive of a congenital anomaly. 
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Other pregnancy outcomes that are classified as SAEs: 
• “Spontaneous abortion” includes miscarriage and missed abortion. 
• All neonatal deaths that occur within 1 month of birth should be reported, without regard 
to causality. In addition, any infant death after 1 month that the Investigator assesses as 
possibly related to the “in utero” exposure to the study drug should also be reported. 
If a female partner of a male patient taking the IMP becomes pregnant while the male 
patient is still on IMP or within 118 days after last dose of IMP, the male patient taking IMP 
should notify the Investigator, and the pregnant female partner should be advised to call her 
healthcare provider immediately. If a pregnancy related event is reported in a female partner 
of a male patient, the Investigator should ask if the female partner is willing to share 
information with the Sponsor Pharmacovigilance and allow the pregnancy related event to 
be followed up to completion.  
The Investigator has to submit the information of pregnancy or suspect pregnancy of a 
female partner of a male patient to the Sponsor Pharmacovigilance, by e-mail, using the EIU 
Form, within 24 hours from his/her awareness of the event. 
11.5.2. Laboratory Safety Assessments  
Laboratory safety assessments will include repeated evaluation of hematology, biochemistry 
and coagulation parameters, urinalyses and pregnancy test, according to timing reported in 
Section 1, Schedule of Events (Table and related footnotes). Investigators may order 
additional blood tests for planning treatment administration, dose modification, or further 
evaluation of adverse events. 
The following laboratory parameters will be used to monitor safety: 
 
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11.5.3. Other Safety Assessments 
The following safety assessments will also be performed, according to timing reported in 
Section 1, Schedule of Events: 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
   
 
 
 
 
 
 
  
 
 
  
 
 
  
 
 
 
 
 
 
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11.6. Other Assessments 
11.6.1. Pharmacokinetic Assessments 
11.6.1.1. Blood Sampling in Phase I 
 
 
 
 
 
  
 
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Table 5. PK Blood Sample Collection for Schedule A (Phase I: Dose Escalation) 
Table 6. PK Blood Sample Collection for Schedule A (Phase I: Dose Expansion) 
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Table 7. PK Blood Sample Collection for Schedule B (Phase I: Dose Escalation) 
 
 
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Table 8. PK Blood Sample Collection in the backfill cohorts (Phase I) 
 
 
 
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Table 9. PK Blood Sample Collection in the backfill cohort for food effect investigation 
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11.6.1.2. Blood Sampling in Phase II 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
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Table 10. PK Blood Sample Collection Schema (Phase II -all patients) 
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Details on PK samples collection, processing, storage and shipping instructions are 
provided in the Study Manual. Timing of sampling may be modified based upon emerging  
PK data from the dose escalation part of the study. Analysis will be performed at the central 
facility delegated by the Sponsor. 
11.6.1.3. Urine Sampling 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
  
 
 
 
11.6.1.4. Bioanalytical method in plasma and urine 
 
 
 
 
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11.6.2. Translational Research  
11.6.2.1. DNA extraction for genomic analysis  
 
 
 
 
 
 
 
11.6.2.2. NGS Analysis of FLT3 and other selected genes 
 
 
 
 
 
 
  
11.6.3. Biomarker assessment 
 
 
 
 
11.6.3.1. PIA analysis for FLT3 pathway  
 
 
 
  
 
 
 
 
 
 
 
 
 
  
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11.6.3.2. Circulating CSF1 analysis  
 
 
 
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12. STATISTICAL METHODS 
12.1.  Sample Size Calculation 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Table 11. Estimated 95% Confidence Intervals for Assumed CRc Rates at Interim 
Analysis for Futility 
  
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12.2. Definition of Analyzed Study Populations 
For the purpose of the analysis, the following patient populations are defined and the 
endpoints, to be analyzed in these populations, are specified: 
• Enrolled Patients:  This population will include all patients who are enrolled in the 
clinical study, regardless of whether patients receive treatment or not. This population 
will be evaluated in the analysis of patients’ disposition. 
• Treated Patients: The treated patient population consists of all enrolled patients who 
actually receive at least one treatment administration. This population will be evaluated 
in the analysis of patient disposition, baseline characteristics, treatment exposure, 
efficacy and safety.  
• Patients evaluable for determination of DLT (by dose schedule and dose level): for each 
schedule and dose level tested, this population includes all patients enrolled in dose 
escalation part who receive at least 70%  of drug in the first cycle, unless the reason for 
non compliance is drug-related toxicity, and for whom a DLT assessment is available 
within the DLT window. In case the patient does not fulfill one or more of the 
aforementioned criteria, he/she will be replaced. 
• Patients evaluable for efficacy analysis (efficacy dataset): This is the patient population 
which consists of all enrolled patients in the Phase II part who are treated at the RP2D, 
have 1 on-treatment hematologic assessment(s) (i.e. they must have adequate bone 
marrow response evaluation). Patients who experience early death or withdrew prior to 
response assessment, or had technically suboptimal bone marrow sample precluding 
assessment, are non-evaluable for response and are excluded from the efficacy dataset. 
For cohort 1 and 2, only the subset of patients with FLT3-ITD mutation and no D835 
and I836 mutations based on the central test will be included in this population. 
• Patients evaluable for PK analysis: treated patients will be considered evaluable if they 
have sufficient baseline and on-study sampled material to provide interpretable results. 
12.3. Analyses 
12.3.1. Study Conduct and Patient Disposition 
Patients’ disposition and reasons for ending the treatment and the study will be presented in 
frequency distribution tables and individual data listings.  The patients not meeting the 
eligibility criteria, and who are considered protocol violators as well as the ones failing to 
receive a complete first cycle will be identified and described by individual data listing. 
Reasons for stopping treatment will be summarized as frequency distribution in the treated 
patient population and, if clinically interesting, in other patient subsets. Untreated patients 
will be identified and described separately. For patients involved in the Phase II portion of 
the trial, all below mentioned analyses and data listings will be presented by cohort. 
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12.3.2. Baseline Characteristics 
Descriptive statistics of the baseline characteristics will be generated across all treated 
patients. Frequency distributions will be presented for the categorical/categorized 
variables.  Summary statistics including mean, standard deviation, median, minimum, 
maximum and the number of assessed patients will be calculated, as appropriate, for the 
quantitative variables. Individual data will be presented in listings. 
12.3.3. Treatment Administration/Compliance  
The treatment exposure and the compliance with study treatment will be descriptively 
analyzed in the treated patient population and, if clinically interesting, in other patient 
subsets. Descriptive statistics (e.g. min, max, mean, standard deviation, and median value) 
will be calculated on a per-patient basis for the following variables: the number of cycles 
administered, the overall duration of treatment, the actual and total doses administered, and 
the absolute and relative dose intensity. Frequency distributions of patients and/or cycles 
will be used to describe dose modifications, delays and omissions, as well as the reasons for 
deviation from the planned therapy. These data will be presented as reported in the relevant 
CRF sections. 
12.3.4. Efficacy Analyses 
 
  
 
 
 
  
 
 
 
 
 
 
 
 
 
 
  
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12.3.5. Outcomes Research Analyses 
Not applicable. 
12.3.6. Safety Analyses 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
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12.3.7. Analyses of Other Endpoints 
12.3.7.1. Molecular Features in Biological Samples  
Exploratory analyses on the relationship between molecular features and treatment efficacy 
variables in AML and CMML patients treated with NMS-03592088 will be performed if 
sufficient data are collected. 
12.3.7.2. Pharmacokinetics 
The PK concentration population is defined as all enrolled patients treated who have at least 
one concentration. The PK parameter analysis population is defined as all enrolled patients 
treated who have at least 1 of the PK parameters of interest. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
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12.3.7.3. Relationship of corrected QT changes to treatment exposure 
 
 
 
 
12.3.7.4. Translational Research 
 
 
 
12.4. Interim Analysis Plan 
12.4.1. Futility Analysis 
 
 
 
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12.4.2. Safety Analysis 
 
 
 
 
 
 
  
  
 
 
 
  
 
 
 
 
 
 
 
  
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Table 12. Safety Boundaries for Toxicity Monitoring 
Empirical stopping rules for drug-related toxicities and drug-related deaths, will be applied 
to first 24, 27, 30 and 36 patients. The enrollment will be stopped if the numbers of patients 
who experience toxicity occur as follows: 8 out of first 24, 9 out of the first 27, 12 of the 
first 36. 
Note: These rules are based on a per patient count, not the absolute number of events 
experienced by an individual patient. No single patient can count more than once toward 
these safety rules. 
12.5. Data Monitoring Committee 
An Official Independent Data Monitoring Committee is not foreseen. Regular 
teleconferences will be organized between the Investigators and the Sponsor to strictly 
review all relevant safety issue (e.g., grade 3-4 clinical and laboratory events, drug-related 
Serious Adverse Events and Deaths) and take decision on the dose escalation, where 
applicable (as also mentioned in Section 5.2 Dose Escalation). 
 
 
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13. END OF THE TRIAL 
For the purpose of this study, the end of the trial is defined as the date of the last visit of the 
last patient, including follow up. 
14.  QUALITY CONTROL AND QUALITY ASSURANCE 
The Sponsor assumes accountability for actions delegated to other individuals (e.g., 
Contract Research Organizations). 
Study monitors will perform ongoing source data verification to confirm that data entered 
into the eCRF by authorized site personnel are accurate, complete, and verifiable from 
source documents; that the safety and rights of participants are being protected; and that the 
study is being conducted in accordance with the currently approved protocol and any other 
study agreements, ICH GCP, and all applicable regulatory requirements. 
The Investigator must permit study-related monitoring, audits performed by the Sponsor or 
designee, IRB/IEC review, and regulatory agency inspections and provide direct access to 
source data documents. 
It is important that the Investigator and his/her relevant personnel are available during the 
monitoring visits and possible audits or inspections and that sufficient time is devoted to the 
process.  
The sponsor or designee is responsible for the data management of the study including 
quality checking of the data. That means that following data entry or electronic receipt of 
data, data validation will take place and Forms/Reports for data clarifications will be 
addressed to the Investigator. Data management activities will address the coding and 
review of terms by scientific and clinically qualified staff.   
 
 
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15. DATA HANDLING AND RECORD KEEPING 
15.1. Electronic Case Report Forms (eCRFs) 
An eCRF must be completed by the Investigator or authorized delegate for each patient 
enrolled in Phase I and for each patient screened (enrolled/screening failure) in Phase II. 
It is the Investigator's or authorized delegate’s responsibility to ensure completion and to 
review and authorize release of the eCRF for each enrolled Clinical Trial Patient. The 
signature on the eCRF serves to attest that the information contained in the eCRF is true, 
accurate and reliable. At all times, the Investigator has full responsibility for the accuracy, 
legibility, completeness, and timeliness of all data (e.g., clinical data, laboratory results) 
reported in the eCRF and in the related data clarification tools (e.g., Data Clarification, 
Discrepancy Notes, Queries). 
Source documents provide evidence for the existence of the participant and substantiate the 
integrity of the data collected. Source documents are filed at the Investigational Site. Source 
documents would include, but are not limited to, hospital/clinic records, physicians’ and 
nurses’ notes, appointment books, original laboratory result reports, ECG, x-rays, signed 
informed consent forms (ICF). 
15.2. Record Retention 
Any study records and documents, including signed ICFs, pertaining to the conduct of the 
study, must be retained by the Investigator for the period of time specified in the Clinical 
Trial Agreement, unless local regulations or institutional policies require a longer retention 
period. 
Data Controller (Sponsor) may store patient’s data up to the expiration of the term required 
for undertaking and maintaining any IP claims (which is not less than 25 years). Biological 
samples may be stored for up to 15 years after the end of the research study and then will be 
destroyed.  
No records may be destroyed during the retention period without the written approval of the 
Sponsor. No records may be transferred to another location or party without written 
notification to the Sponsor. 
15.3. Confidentiality of Clinical Trial or Study Documents 
All documents and information given to the Investigator by the Sponsor with respect to 
NMS-03592088 and study MKIA-088-001 are strictly confidential. 
The Investigator agrees that he/she and the members of his/her team will use the information 
only in the framework of this Clinical Trial, for carrying out the Clinical Trial Protocol. This 
agreement is binding as long as the confidential information has not been disclosed to the 
public by the Sponsor. 
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The Investigator must not disclose any information of Clinical Trial Protocol as well as any 
information extracted from it to other parties without the prior written authorization of the 
Sponsor. The only exception is upon request of the representatives of the Competent 
Authorities; in the latter case, the Investigator commits himself to informing the Sponsor 
prior to disclosure of information to these authorities. 
 
 
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16. ETHICS 
16.1. Institutional Review Board (IRB)/Independent Ethics Committee (IEC) 
Clinical Study Protocol, Protocol Amendments, Informed Consent Forms, Investigator 
Brochure and other relevant documents (e.g., advertisements) must be submitted to 
IRB(s)/IEC(s) by the Investigator(s) and/or Sponsor/Delegate Party in accordance with local 
regulations reviewed and approved by the IRB(s)/IEC(s) before the study is initiated.  
Any amendments to the protocol will require IRB/IEC approval before implementation of 
changes made to the study design, except for changes necessary to eliminate an immediate 
hazard to study participants. In that case, the Investigator must notify the IRB/IEC, the 
Sponsor or Delegated Party and Regulatory Authority, as applicable, as soon as possible 
after the implementation. 
The Investigator will be responsible for the following: 
• Providing written summaries of the status of the study to the IRB/IEC annually or more 
frequently in accordance with the requirements, policies, and procedures established by 
the IRB/IEC 
• Notifying the IRB/IEC of SAEs or other significant safety findings as required by 
IRB/IEC procedures. 
16.2. Ethical Conduct of the Trial 
This study will be conducted in accordance with and with the following: 
• The Clinical Trial Protocol. 
• Ethical principles derived from international guidelines including the Declaration of 
Helsinki [80] and Council for International Organizations of Medical Sciences (CIOMS) 
International Ethical Guidelines. 
• Applicable ICH Good Clinical Practice (GCP) Guidelines. 
• Current and applicable laws and regulations. 
The Investigator will be responsible for: 
• Providing oversight of the conduct of the study at the site and adherence to requirements 
of 21 CFR [78], ICH E6 R2 guidelines [77], the IRB/IEC, European regulation 536/2014 
for clinical studies [79], as applicable, and all other applicable local regulations. 
16.2.1. Serious Breaches 
The EU Regulation No 536/2014 and the EMA Guideline for the notification of serious 
breaches contain a requirement for the notification of serious breaches. A serious breach is 
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defined as “A breach of GCP or the trial protocol which is likely to affect to a significant 
degree  
(a) the safety or physical or mental integrity of the subjects of the trial; or 
(b) the scientific value of the trial”. 
In the event that a serious breach is suspected, the Sponsor must be contacted. The serious 
breach will be reviewed by the Sponsor and, if appropriate, the Sponsor or entity/person 
legally authorised by the Sponsor will report it to the relevant Competent Authorities within 
7 days. 
16.3. Informed Consent Process 
It is the responsibility of the Investigator (or a person designated by the Investigator when 
accepted by local regulations) to give each individual  full and adequate explanation 
regarding the nature of the study (e.g., objectives, aims, methods and procedures of the 
study, anticipated benefits, possible risks and potential hazards involved). The Investigator 
or his/her delegate will answer all questions regarding the study.  
Participants must be informed that their participation is voluntary and that they have the 
right to withdraw from the study at any time. 
Participants will be required to sign before any trial-related procedure is undertaken, a 
statement of informed consent (ICF) that meets the requirements of ICH guidelines, 21 CFR 
50 and Health Insurance Portability and Accountability Act (HIPAA) requirements, where 
applicable, local regulations, and the IRB/IEC or study center. 
The medical record must include a statement that written informed consent was obtained 
before the participant was enrolled in the study and the date the written consent was 
obtained. The authorized person obtaining the informed consent must also sign the ICF. 
Participants must be re-consented to the most current version of the ICF(s) during their 
participation in the study. 
A copy of the signed ICF(s) must be provided to the participant.  
16.4. Personal Data Protection 
Participants will be assigned a unique identifier by the Sponsor or designee. Any participant 
records or datasets that are transferred to the Sponsor or designee will contain the identifier 
only; participant names or any information which would make the participant identifiable 
will not be transferred. 
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The participant must be informed that his/her personal study-related data will be used by the 
Sponsor or designee in accordance with local data protection law. The level of disclosure 
must also be explained to the participant. 
The participant must be informed that his/her medical records may be examined by Clinical 
Quality Assurance auditors or other authorized personnel appointed by the Sponsor or 
designee, by appropriate IRB/IEC members, and by inspectors from Regulatory Authorities. 
 
17. SPONSOR DISCONTINUATION CRITERIA 
Nerviano Medical Sciences reserves the right to discontinue the trial prior to inclusion of the 
intended number of patients, but intends only to exercise this right for valid scientific or 
administrative reasons. After such a decision, the Investigator must contact all participating 
patients. As directed by Nerviano Medical Sciences or the Delegated Party, all study 
materials must be collected and all case report forms completed to the greatest extent 
possible. 
18. DISSEMINATION AND PUBLICATION OF RESULTS 
Results of the study may be presented or published. The conditions regulating dissemination 
of the information derived from this clinical study are described in the Clinical Trial 
Agreement. 
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19. REFERENCES 
1. 
American Cancer Society.Cancer Facts & Figures, 2014, American Cancer Society; 2014. 
2. 
Sant M, Allemani C, Tereanu C, De Angelis R, Capocaccia R, Visser O, Marcos-Gragera R, 
Maynadié M, Simonetti A, Lutz JM, Berrino F; HAEMACARE Working Group.. Incidence of 
haematological malignancies in Europe by morphological subtype: results of the 
HAEMACARE project. Blood 2010 116:3724-3734 
3. 
Sill H, Olipitz W, Zebisch A, Schulz E, Wolfler A. Therapy-related myeloid neoplasms: 
pathobiology and clinical characteristics. Br J Pharmacol 2011; 162; 792–805 
4. 
Patel JP, Gonen M, Figueroa ME, Fernandez H, Sun Z, Racevskis J et al. Prognostic relevance 
of integrated genetic profiling in acute myeloid leukemia. N Engl J Med 2012; 366: 1079–1089 
5. 
Cancer Genome Atlas Research Network. Genomic and epigenomic landscapes of adult de 
novo acute myeloid leukemia. N Engl J Med 2013; 368: 2059–2074 
6. 
Döhner H, Wei AH, Appelbaum FR, Craddock C, DiNardo CD, Dombret H, Ebert BL, Fenaux 
P, Godley LA, Hasserjian RP, Larson RA, Levine RL, Miyazaki Y, Niederwieser D, 
Ossenkoppele G, Röllig C, Sierra J, Stein EM, Tallman MS, Tien HF, Wang J, Wierzbowska 
A, Löwenberg B.  Diagnosis and management of Acute Myeloid Leukenia in adults: 2022 
recommendations from an international expert panel on behalf of the European LeukemiaNet. 
Blood 2022 Sep 22;140(12):1345-1377 
7. 
Döhner H, Estey E, Grimwade D, Amadori S, Appelbaum FR, Büchner T, Dombret H, Ebert 
BL, Fenaux P, Larson RA, Levine RL, Lo-Coco F, Naoe T, Niederwieser D, Ossenkoppele GJ, 
Sanz M, Sierra J, Tallhuman MS, Tien HF, Wei AH, Löwenberg B, Bloomfield CD. Diagnosis 
and management of AML in adults: 2017 ELN recommendations from an international expert 
panel. Blood 2017 Jan 26;129(4):424-447 
8. 
Dombret H, Gardin C. An update of current treatments for adult acute myeloid leukemia. 
Blood 2016; 127: 53–61.  
9. 
Kohumanduri KV, Levine RL. Diagnosis and therapy of acute myeloid leukemia in the era of 
molecular risk stratification. Annu Rev Med 2016; 67: 59–72.  
10. Wander SA, Levis MJ, Fathi AT. The evolving role of FLT3 inhibitors in acute myeloid 
leukemia: quizartinib and beyond. Ther Adv Hematol 2014; 5: 65–77.  
11. Dosil M, Wang S, Lemischka IR. Mitogenic signalling and substrate specificity of the 
Flk2/Flt3 receptor tyrosine kinase in fibroblasts and interleukin 3-dependent hematopoietic 
cells. Mol Cell Biol 1993; 13: 6572–6585.  
12. Carow CE, Levenstein M, Kaufhumann SH, et al. Expression of the hematopoietic growth 
factor receptor FLT3 (STK-1/Flk2) in human leukemias. Blood 1996; 87: 1089–1096.  
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13. Thiede C, Steudel C, Mohr B, et al. Analysis of FLT3-activating mutations in 979 patients with 
acute myelogenous leukemia: association with FAB subtypes and identification of subgroups 
with poor prognosis. Blood 2002; 99: 4326–4335. 
14. Fröhling, S.; Scholl, C.; Levine, R.L.; et al. Identification of driver and passenger mutations of 
FLT3 by high-throughput DNA sequence analysis and functional assessment of candidate 
alleles. Cancer Cell 2007, 12, 501–513. 
15. Pratcorona, M.; Brunet, S.; Nomdedéu, J. Ribera, J.M.; Tormo, M.; Duarte, R.; Escoda, L.; 
Guàrdia, R.;de Llano, M.P.Q.; Salamero, O.; et al. Favorable outcome of patients with acute 
myeloid leukemia harboring a low-allelic burden FLT3-ITD mutation and concomitant NPM1 
mutation: Relevance to post-remission therapy. Blood 2013, 121, 2734–2738.   
16. Schlenk, R.F.; Kayser, S.; Bullinger, L.; Kobbe, G.; Casper, J.; Ringhoffer, M.; Held, G.; 
Brossart, P.; Lübbert, M.; Salih, H.R.; et al. Differential impact of allelic ratio and insertion 
site in FLT3-ITD positive AML with respect to allogeneic transplantation. Blood 2014, 124, 
3441–3449.   
17. Linch, D.C.; Hills, R.K.; Burnett, A.K.; Khwaja, A.; Gale, R.E. Impact of FLT3ITD mutant 
allele level on relapse risk in intermediate-risk acute myeloid leukemia. Blood 2014, 124, 273–
276.   
18. Abu-Duhier, F.M.; Goodeve, A.C.; Wilson, G.A.; Care, R.S.; Peake, I.R.; Reilly, J.T. 
Identification of novel FLT-3 Asp835 mutations in adult acute myeloid leukaemia. Br. J. 
Haematol. 2001, 113, 983–988. 
19. Stone RM, Humandrekar SJ, Sanford BL, Lauhumann K, Geyer S, Bloomfield CD, Thiede C, 
Prior TW, Döhner K, Marcucci G, Lo-Coco F, Klisovic RB, Wei A, Sierra J, Sanz MA, 
Brandwein JM, de Witte T, Niederwieser D, Appelbaum FR, Medeiros BC, Tallhuman MS, 
Krauter J, Schlenk RF, Ganser A, Serve H, Ehninger G, Amadori S, Larson RA, Döhner H. 
Midostaurin plus Chemotherapy for Acute Myeloid Leukemia with a FLT3 Mutation. N Engl J 
Med 2017; 377:454-464 
20. Perl AE, Martinelli G, Cortes JE, Neubauer A, Berman E, Paolini S, Montesinos P, Baer MR, 
Larson RA, Ustun C, Fabbiano F, Erba HP, Di Stasi A, Stuart R, Olin R, Kasner M, Ciceri F, 
Chou WC, Podoltsev N, Recher C, Yokoyama H, Hosono N, Yoon SS, Lee JH, Pardee T, Fathi 
AT, Liu C, Hasabou N, Liu X, Bahceci E, Levis MJ. Gilteritinib or Chemotherapy for 
Relapsed or Refractory FLT3-Mutated AML, N Engl J Med 2019;381:1728-40 
21. Althuman JK, Foran JM, Pratz KW, Trone D, Cortes JE, Tallhuman MS. Phase 1 study of 
quizartinib in combination with induction and consolidation chemotherapy in patients with 
newly diagnosed acute myeloid leukemia. Am J Hematol. 2017 Nov 15 
22. Perl AE, Althuman JK, Cortes J, Smith C, Litzow M, Baer MR, Claxton D, Erba HP, Gill S, 
Goldberg S, Jurcic JG, Larson RA, Liu C, Ritchie E, Schiller G, Spira AI, Strickland SA, Tibes 
R, Ustun C, Wang ES, Stuart R, Röllig C, Neubauer A, Martinelli G, Bahceci E, Levis M. 
Selective inhibition of FLT3 by gilteritinib in relapsed or refractory acute myeloid leukaemia: 
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a multicentre, first-in-human, open-label, phase 1-2 study. Lancet Oncol. 2017 
Aug;18(8):1061-1075. 
23. Fathi AT, Chen Y. The role of FLT3 inhibitors in the treatment of FLT3-mutated acute 
myeloid leukemia. Eur J Haematol. 2017; 98: 330–336. 
24. Subrahumanian Guru Murthy G, Venkitachalam R  Bhatt VR,  Dhakal I, Lee JY,  Jethava, 
Y  Mehta P, and  Ehumanuel PD Incidence and survival of chronic myelomonocytic leukemia 
(CMML) in the United States (US) Journal of Clinical Oncology 2015 33:15_suppl, e18072-
e18072 . 
25. Patnaik MM, Itzykson R, Lasho TL, Kosmider O, Finke CM, Hanson CA, Knudson RA, 
Ketterling RP, Tefferi A, Solary E ASXL1 and SETBP1 mutations and their prognostic 
contribution in chronic myelomonocytic leukemia: a two-center study of 466 patients. 
Leukemia. 2014 Nov;28(11):2206-12 
26. Lee BH et al. FLT3 mutations confer enhanced proliferation and survival properties to 
multipotent progenitors in a murine model of chronic myelomonocytic leukemia Cancer Cell. 
2007 Oct; 12(4): 367–380. 
27. Germing U, Kündgen   and  Gatterhumann N (2004) Risk Assessment in Chronic 
Myelomonocytic Leukemia (CMML), Leukemia & Lymphoma, 45:7, 1311-1318 
28. Patnaik MM1, Wassie EA, Lasho TL, Hanson CA, Ketterling R, Tefferi A. Blast 
transformation in chronic myelomonocytic leukemia: Risk factors, genetic features, survival, 
and treatment outcome. Am J Hematol. 2015 May;90(5):411-6. 
29. Patnaik MM, Tefferi A. Chronic myelomonocytic leukemia: 2018 update on diagnosis, risk 
stratification and management. Am J Hematol. 2018; 93: 824 -840. 
30. Gilliland DG and Griffin JD. The roles of FLT3 in hematopoiesis and leukemia. Blood 2002 
100:1532-1542; 
31. Meshinchi S, Appelbaum FR. Structural and functional alterations of FLT3 in acute myeloid 
leukemia. Clin Cancer Res. 2009 Jul 1;15(13):4263-9.  
32. Masson K, Rönnstrand L. Oncogenic signaling from the hematopoietic growth factor receptors 
c-Kit and Flt3 Cell Signal. 2009 Dec;21(12):1717-26 
33. Smith CC, Paguirigan A, Jeschke GR, Lin KC, Massi E, Tarver T, Chin CS, Asthana S, Olshen 
A, Travers KJ, Wang S, Levis MJ, Perl AE, Radich JP, Shah NP. Heterogeneous resistance to 
quizartinib in acute myeloid leukemia revealed by single-cell analysis. Blood. 2017 Jul 
6;130(1):48-58. 
34. Daver N, Cortes J, Ravandi F, Patel KO, Burger JA, Konopleva M, and Kantarjian H 
Secondary mutations as mediators of resistance to targeted therapy in leukemia Blood, 2015,  
125 (21) 3236 – 3245 
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35. Galanis A, Ma H, Rajkhowa T, Ramachandran A, Small D, Cortes J, Levis M. Crenolanib is a 
potent inhibitor of FLT3 with activity against resistance-conferring point mutants. Blood. 2014 
Jan 2;123 (1):94-100. 
36. Lee LY, Hernandez D, Rajkhowa T, Smith SC, Rahuman JR, Nguyen B, Small D, Levis M. 
Preclinical studies of gilteritinib, a next-generation FLT3 inhibitor. Blood. 2017 Jan 
12;129(2):257-260 
37. McMahon CM,  Canaani J, Rea B, Lynn Sargent R,  Morrissette JJD, Lieberhuman DB,  Watt 
C, Schwartz GW, Faryabi RB, Ferng TT, Shah NP, Smith CC, Carroll M, and Perl AE.  
Mechanisms of acquired resistance to gilteritinib therapy in relapsed and refractory FLT3-
mutated acute myeloid leukemia. ASH meeting, 2017, Abstract N. 295. 
38. Lee BH et al. FLT3 mutations confer enhanced proliferation and survival properties to 
multipotent progenitors in a murine model of chronic myelomonocytic leukemia Cancer Cell. 
2007 Oct; 12(4): 367–380 
39. Lin P, Jones D, Medeiros LJ, Chen W, Vega-Vazquez F, Luthra R. Activating FLT3 mutations 
are detectable in chronic and blast phase of chronic myeloproliferative disorders other than 
chronic myeloid leukemia. Am J Clin Pathol. 2006;126:530–533.  
40. Pardanani A, Reeder TL, Kimlinger TK, Baek JY, Li CY, Butterfield JH, Tefferi A. Flt-3 and 
c-kit mutation studies in a spectrum of chronic myeloid disorders including systemic mast cell 
disease. Leuk Res. 2003;27:739–742 
41. Mantovani A, Marchesi F, Malesci A, Laghi L and Allavena P. Tumour-associated 
macrophages as treatment targets in oncology. Nature Reviews Clin Oncol 2017; 14, 399–
416.  
42. Cannarile MA, Weisser M, Jacob W, Jegg AM, Ries CH, Rüttinger D Colony-stimulating 
factor 1 receptor (CSF1R) inhibitors in cancer therapy. J Immunother Cancer. 2017 Jul 
18;5(1):53. 
43. Rashid A, Dzneladze I, He R, Woolley JF, Jain MD, and Minden MD. CSF1R is associated 
with poor overall survival in AML and mediates supportive interactions between AML and 
stromal cells in the AML microenvironment. Blood 2016; 128: 2666 
44. Pedersen MB, Danielsen AV, Hamilton-Dutoit SJ, Bendix K, Norgaard P,Moller MB, 
Steiniche T, d’Amore F. High intratumoral macrophage content is an adverse prognostic 
feature in anaplastic large cell lymphoma. Histopathology. 2014;65:490–500. 
45. Smith BD, Leary CB, Lu W-P, Kaufhuman MD, and Flynn DL.The highly specific CSF1R 
inhibitor DCC-3014 exhibits immunomodulatory and anti-invasive activities in cancer models 
Cancer Res  76,14, Supplement 2016 Jul, Abstract 4889: 
46. Hume DA, MacDonald KP. Therapeutic applications of macrophage colony-stimulating factor-
1 (CSF1) and antagonists of CSF1 receptor (CSF1R) signaling. Blood. 2012 Feb 
23;119(8):1810-20. 
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47. Rambaldi A, Wakamiya N, Vellenga E, Horiguchi J, Warren MK, Kufe D, Griffin JD. 
Expression of the macrophage colony-stimulating factor and c-fms genes in human acute 
myeloblastic leukemia cells. J Clin Invest. 1988 Apr;81(4):1030-5 
48. Abu-Duhier FM, Goodeve AC, Wilson GA, Peake IR, Reilly JT. c-FMS mutational analysis in 
acute myeloid leukaemia. Br J Haematol. 2003 Nov;123(4):749-50 
49. Goh SL, Levesque J-P, Petitt AR, Barbier V, and Winkler IG. Therapeutic blockade of 
macrophage colony stimulating factor (CSF1) delays AML progression in mice in vivo. Blood 
2016; 128: 2835 
50. Edwards DK, Rofelty A, Agarwal A, Kurtz SE, Traer E, Lee P, Chantry D, Loriaux M, Druker 
BJ, McWeeney SK, and Tyler JW, CSF1R inhibition targets AML cells by depleting 
supporting microenvironmental signal from CD14+ monocytes. Blood 2015; 126:3824 
51. Ashhuman and Griffith, Therapeutic targeting of c-KIT in cancer. Expert Opin Investig Drugs. 
2013 Jan;22(1):103-15. 
52. Hossein Ayatollahi, Arezoo Shajiei, Mohammad Hadi Sadeghian, Maryam Sheikhi, Ehsan 
Yazdandoust, Masumeh Ghazanfarpour, Seyyede Fatemeh Shams,  Sepideh Shakeri Prognostic 
Importance of C-KIT Mutations in Core Binding Factor Acute Myeloid Leukemia: A 
Systematic Review Hematol Oncol Stem Cell Ther (2017) 10, 1-7 
53. L. Riera, F. Marmont, D. Toppino, C. Frairia, F. Sismondi, E. Audisio, et al. Core binding 
factor acute myeloid leukemia and c-KIT mutations Oncol Rep, 29 (2013), pp. 1867-1872. 
54. Cairoli R, Beghini A, Grillo G, Nadali G, Elice F, Ripamonti CB, Colapietro P, Nichelatti M, 
Pezzetti L, Lunghi M, Cuneo A, Viola A, Ferrara F, Lazzarino M, Rodeghiero F, Pizzolo G, 
Larizza L, Morra E. Prognostic impact of c-KIT mutations in core binding factor leukemias: an 
Italian retrospective study. Blood. 2006 May 1;107(9):3463-8. 
55. Investigator’s Brochure NMS-03592088I, v5, 20-Jan-2023. 
56. Savona MR, Malcovati L, Komrokji R, et al. An international consortium proposal of uniform 
response criteria for myelodysplastic/myeloproliferative neoplasms (MDS/MPN) in adults, 
Blood, 2015 Mar;125(12):1857-1865. 
57. Simon R, Freidlin B, Rubinstein L E T AL. Accelerated titration designs for Phase I clinical 
trials in oncology J Natl Cancer Inst. 1997 Aug;89(15):1138-47 
58. Arber DA, Orazi A, Hasserjian R, Thiele J, Borowitz MJ, Le Beau MM, Bloomfield CD, 
Cazzola M, Vardiman JW.  The 2016 revision to the World Health Organization classification 
of myeloid neoplasms and acute leukemia. Blood, 2016 May19;127(20):2391-405. 
59. Marik PE. The management of Status Epilecticus. Chest 2004; 126:582-591. 
MKIA-088-001_EU Protocol P9_20240228 | MKIA-088-001-00001 | 13.0
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60. Working Group on Status Epilepticus. Treatment of convulsive status epilepticus. 
Recommendations of the Epilepsy Foundation of America's Working Group on Status 
Epilepticus.  JAMA 1993;270:854-859. 
61. Cairo MS, Coiffier B, Reiter A, Younes A. 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;149(4):578–586 
62. Alakel N, Middeke JM, Schetelig J, Bornhäuser M Prevention and treatment of tumor lysis 
syndrome, and the efficacy and role of rasburicase. Onco Targets Ther. 2017 Feb 2;10:597-605 
63. Jones GL, Will A, Jackson GH, Webb NJ, Rule S; British Committee for Standards in 
Haematology, 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. 2015 
64. Frankel SR, Eardley A, Heller G, et al. All-trans retinoic acid for acute promyelocytic 
leukemia. Results of the New York Study. Ann Intern Med. 1994; 120:278–86 
65. Tibsovo® (Ivosidenib) FDA approved label July 2018 
66. Idhifa® (enasidenib) FDA approved label August 2017 
67. Xopata® FDA approved label Nov 2018 
68. Sexauer A, Perl A, Yang X, Borowitz M, Gocke C, Rajkhowa T, Thiede C, Frattini M, 
Nybakken GE, Pratz K, Karp J, Smith BD, Levis M.. Terminal myeloid differentiation in vivo 
is induced by FLT3 inhibition in FLT3/ITDAML Blood. 2012; 120(20):4205-4214 
69. Kris MG, Hesketh PJ, Somerfield MR, Feyer P, Clark-Snow R, Koeller JM, Morrow GR, 
Chinnery LW, Chesney MJ, Gralla RJ, Grunberg SM. American Society of Clinical Oncology 
guideline for antiemetics in oncology: update 2006. J Clin Oncol 2006;24(18): 2932-2947. 
70. The Antiemetic Subcommittee of the Multinational Association of Supportive Care in Cancer 
(MASCC). Prevention of chemotherapy– and radiotherapy-induced emesis: results of the 2004 
Perugia International Antiemetic Consensus Conference. Ann Oncol 2006; 17:20-28. 
71. Levis M, Brown P, Smith BD, et al. Plasma inhibitory activity (PIA): a pharmacodynamic 
assay reveals insights into the basis for cytotoxic response to FLT3 inhibitors. Blood. 
2006;108(10):3477–3483 
72. Nicholas Butowski, Howard Colhuman, John F. De Groot, Antonio M. Omuro, Lakshmi 
Nayak, Patrick Y. Wen, Timothy F. Cloughesy, Adhirai Marimuthu, Sam Haidar, Arie 
Perry, Jason Huse, Joanna Phillips, Brian L. West, Keith B. Nolop, Henry H. Hsu, Keith L. 
Ligon, Annette M. Molinaro, and Michael Prados Orally administered colony stimulating 
factor 1 receptor inhibitor PLX3397 in recurrent glioblastoma: an Ivy Foundation Early Phase 
Clinical Trials Consortium Phase II study Neuro Oncol. 2016 Apr; 18(4): 557–564. 
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73. Guidance for Industry Population Pharmacokinetics U.S. Department of Health and Human 
Services Food and Drug Administration Center for Drug Evaluation and Research (CDER) 
Center for Biologics Evaluation and Research (CBER) February 1999 
74. Guidance for Industry Exposure-Response Relationships - Study Design, Data  
Analysis, 
and Regulatory Applications U.S. Department of Health and Human  
Services, Food and 
Drug Administration, Center for Drug Evaluation and  
Research (CDER), Center for 
Biologics Evaluation and Research (CBER),  April 2003, CP 
75. Guideline on reporting the results of population pharmacokinetic analysis. Committee for 
medicinal product for human dose (CHMP). European Medicines Agency London, 21 June 
2007. Doc. Ref. CHMP/EWP/185990/06 
76. Ivanova A, Qaqish BF, Schell MJ. Continuous Toxicity Monitoring in Phase II Trials in 
Oncology. Biometrics, 2005 Jun; 61:540-545. 
77. European Medicines Agency. Guideline for good clinical practice E6(R2) Step 5. 1 Dec 2016. 
EMA/CHMP/ICH/135/1995. 
78. US Code of Federal Regulations (CFR) – Title 21- Food and Drugs. 
https://www.ecfr.gov/current/title-21 
79. European  Parliament,  Council  of  the  European  Union. Regulation (EU)  536/2014  of  the  
European  Parliament and of the Council of 16 April 2014 on clinical trials on medicinal 
products for human use, and repealing Directive 2001/20/EC. Official Journal of the European 
Union 27 May 2014;L158:1-76. 
80. World  Medical  Association.  Declaration of Helsinki - Ethical Principles  for  Medical  
Research  Involving  Human  Subjects.  Adopted  by  the  18th  WMA  General  Assembly,  
Helsinki,  Finland,  June  1964. Available  from: 
http://www.wma.net/en/30publications/10policies/b3/. 
81. D. Araujo, A. Greystoke, S. Bates, T.A. Yap, M. Ratain, L. Seymour, et al. Oncology phase I 
trial design and conduct: time for a change - MDICT Guidelines 2022. Ann. Oncolo. 
September 28, 2022 DOI:https://doi.org/10.1016/j.annonc.2022.09.158 
82. N.E. Gilhus Myasthenia Gravis N Engl J Med 2016;375:2570-81. DOI: 
10.1056/NEJMra1602678 
83. Guptill JT, Sanders DB, Evoli A. Anti-MuSK antibody myasthenia gravis: clinical findings 
and response to treatment in two large cohorts. Muscle Nerve. 2011 Jul;44(1):36-40. doi: 
10.1002/mus.22006. PMID: 21674519 
 
 
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Appendix 2.  Response Criteria in AML 
 
 
 
Appendix 2.1.: Reporting Criteria in AML according to ELN 2022 
 
 
Appendix 2.2.: Reporting Criteria in AML according to ELN 2017 
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Appendix 6.   Drugs That May Prolong QT  
A list of drugs known to prolong QT interval is reported below. This list should not be 
considered exhaustive. Consult individual drug labels for specific information on whether a 
compound is known to prolong QT.  
Drugs That May Prolong QT 
Drug Class 
Generic Drug Name 
Class 1A antiarrhytmics 
Quinidine  
Procainamide 
Disopyramide 
Class IC antiarrhythmics 
Flecainide 
Propafenone 
Moricizine 
Class III antiarrhythmics 
Amiodarone 
Sotalol 
Bretylium 
Ibutilide 
Dofetilide 
Antipsychotics 
Thioridazine 
Mesoridazine 
Chlorpromazine 
Prochlorperazine 
Trifluoperazine 
Fluphenazine 
Perphenazine 
Pimozide 
Risperidone 
Ziprasadone 
Lithium 
Haloperidol 
Tricyclic/tetracyclic antidepressants 
Amitriptyline 
Desipramine 
Doxepin 
Dosulepin hydrochloride 
Imipramine 
Maprotiline 
Selective serotonin and norepinephrine 
reuptake inhibitors (SSNRIs) 
antidepressants 
Venlafaxine 
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Drugs That May Prolong QT 
Drug Class 
Generic Drug Name 
Macrolide antibiotics 
Azithromycin 
Erythromycin 
Clarithromycin 
Dirithromycin 
Roxithromycin 
Tulathromycin 
Fluoroquinolone antibiotics 
Moxifloxacin 
Gatifloxacin 
Azole antifungals 
Ketoconazole 
Fluconazole 
Itraconazole 
Posaconazole 
Voriconazole 
Antimalarials 
Amodiaquine 
Atovaquone 
Chloroquine 
Doxycycline 
Halofantrine 
Mefloquine 
Proguanil 
Primaquine 
Pyrimethamine 
Quinine 
Sulphadoxine 
Antiprotozoals 
Pentamidine 
Antiemetics 
Droperidol 
Dolasetron 
Granisetron 
Ondansetron 
Antiestrogens 
Tamoxifen 
Immunosuppressants 
Tacrolimus 
 
 
 
 
 
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Appendix 8. Recommended Birth Control Methods  
 
Genotoxicity cannot be excluded as per ICH guidelines, therefore patients must be adviced 
on highly effective contraceptives. 
 
For the purpose of this protocol, methods that can achieve a failure rate of less than 1% per 
year when used consistently and correctly are considered as highly effective birth control 
methods and therefore recommended.  
 
Since NMS-03592088 has potential induction of CYP3A4 WOCBP must be advised that 
hormonal contraceptives might lose efficacy and must use alternate form of highly effective 
contraception.  
 
• intrauterine device (IUD)   
 
• intrauterine hormone-releasing system (IUS) 
 
• bilateral tubal occlusion 
 
• vasectomised partner  
 
• sexual abstinence   
 
 
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