Clinical trial NCT05447663
Conditions: Acute Myeloid Leukemia Allogeneic Stem Cell Transplantation
Keywords: Acute Myeloid Leukemia Acute myeloid leukemia post allogeneic stem cell transplantation AML allogeneic stem cell transplantation HDM201 siremadlin donor lymphocyte infusion DLI MDM2 p53 allo-SCT
Sponsor: Novartis Pharmaceuticals
Start date: 2023-02-23; Completion date: 2023-10-26
Enrollment: 8 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The purpose of this study was to confirm a safe dose and schedule as well as the preliminary efficacy of siremadlin alone, and in combination with donor lymphocyte infusion (DLI), in adult participants with Acute Myeloid Leukemia (AML) who were in remission following allogeneic stem cell transplantation (allo-SCT) but were at high risk for relapse based on the presence of pre-transplant risk factors.

Detailed description:
This is a Phase Ib/II, single arm, open label, multi-center study of siremadlin as monotherapy and in combination with DLI, in adult participants with AML.

The primary purpose of the study was to confirm the safe dose and schedule of siremadlin monotherapy and in combination with DLI. The study is also designed to assess the preliminary efficacy in preventing hematologic relapse.

The study was initially planned to enroll approximately 38 participants starting with a dose confirmation of siremadlin monotherapy (part 1) to determine the siremadlin recommended dose, followed by a treatment strategy of siremadlin/DLI (Part 2).

After enrolling 8 participants (at the starting dose 30 mg/day on days 1-5 of a 28-day treatment cycle) in part 1, Novartis took the decision to put the enrollment in permanent halt and terminate the siremadlin program. For that reason, the enrollment in part 2 will not be open. The Novartis decision was not driven by any safety concerns.

In part 1 approximately 12 participants were planned to be enrolled in 2 cohorts (starting dose 30 mg/day on days 1-5 of a 28-day treatment cycle, dose level +1 at 40 mg/day and dose level -1 at 20 mg/day) and participants were planned to be treated for a maximum of 24 cycles.

In part 2, participants were planned to follow a treatment strategy, which contains three consecutive phases for a maximum of 24 cycles in total:

* A priming phase with siremadlin monotherapy at the recommended dose determined in Part 1 (for at least 2 cycles). Participants who were not eligible for the combination phase of siremadlin/DLI could continue priming phase with siremadlin monotherapy.
* A combination phase of siremadlin in combination with DLI (siremadlin/DLI) for participants who were eligible to receive DLI (up to a total of 3 combination cycles).
* A maintenance phase with siremadlin monotherapy.

Arms: arm 1: Participants with AML post allogeneic stem cell transplantation (allo-SCT) received siremadlin monotherapy in part 1 and were to have received siremadlin monotherapy as well as in combination with donor lymphocyte infusion in part 2.
Interventions: intervention 1: Siremadlin
Intervention descriptions: intervention 1: Siremadlin was administered at a starting dose of 30 mg/day on days 1-5 of a 28-day treatment cycle (Part 1).

Protocol documents:
Prot_000.pdf: 
Official Title:  A Phase Ib/II, Open Label Study of Siremadlin Monotherapy and in Combination  
With Donor Lymphocyte Infusion as a Treatment for Patients With Acute 
Myeloid Leukemia Post-allogeneic Stem Cell Transplantation Who Are in 
Complete Remission But at High Risk for Relapse.
NCT Number: 
 NCT05447663 
Document Date: Protocol Amendment 2: 18-November-2022


 
 
 
 
 
Novartis Research and Development 
HDM201/Siremadlin 
Clinical Trial Protocol CHDM201K12201 
A phase Ib/II, open label study of siremadlin monotherapy 
and in combination with donor lymphocyte infusion as a 
treatment for patients with acute myeloid leukemia post-
allogeneic stem cell transplantation who are in complete 
remission but at high risk for relapse. 
Document type: 
Amended Protocol Version 
EUDRACT number: 
2021-003596-34 
Version number: 
02 (Clean) 
Clinical Trial Phase: 
I/II 
Release date: 
18-Nov-2022 (content final) 
Property of Novartis 
Confidential 
May not be used, divulged, published, or otherwise disclosed 
without the consent of Novartis 
 
Clinical Trial Protocol Template Version 4.0 dated 15-Feb-2021 


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Table of contents 
Table of contents ................................................................................................................. 2 
List of tables ........................................................................................................................ 6 
List of figures ...................................................................................................................... 8 
List of abbreviations ............................................................................................................ 9 
Glossary of terms ............................................................................................................... 13 
Amendment 2 (18-Nov-2022) ........................................................................................... 15 
Amendment 1 (06-Jul-2022) ............................................................................................. 18 
Protocol summary .............................................................................................................. 24 
1 
Introduction ....................................................................................................................... 29 
1.1 
Background ............................................................................................................ 29 
1.2 
Purpose .................................................................................................................. 34 
2 
Objectives, endpoints and estimands ................................................................................. 37 
2.1 
Primary estimands ................................................................................................. 40 
2.2 
Secondary estimands ............................................................................................. 42 
3 
Study design ...................................................................................................................... 42 
4 
Rationale ............................................................................................................................ 45 
4.1 
Rationale for study design ..................................................................................... 45 
4.2 
Rationale for dose/regimen and duration of treatment .......................................... 46 
4.3 
Rationale for choice of combination drugs (siremadlin with donor 
lymphocyte infusion) ............................................................................................. 49 
4.4 
Purpose and timing of interim analyses/design adaptations .................................. 51 
4.5 
Risks and benefits .................................................................................................. 51 
4.6 
Rationale for Public Health Emergency mitigation procedures ............................ 53 
 
 54 
5 
Study Population ............................................................................................................... 54 
5.1 
Inclusion criteria .................................................................................................... 55 
5.2 
Exclusion criteria ................................................................................................... 56 
6 
Treatment ........................................................................................................................... 58 
6.1 
Study treatment ...................................................................................................... 58 
6.1.1 
Investigational and control drugs .......................................................... 58 
6.1.2 
Treatment arms/group ........................................................................... 58 
6.1.3 
Guidelines for continuation of treatment .............................................. 59 
6.1.4 
Treatment duration ................................................................................ 60 
6.2 
Other treatment(s) .................................................................................................. 60 
6.2.1 
Donor Lymphocyte Infusion (DLI) ....................................................... 60 


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6.2.2 
Concomitant therapy ............................................................................. 60 
6.2.3 
Prohibited medications .......................................................................... 66 
6.2.4 
Supportive care measures ...................................................................... 67 
6.3 
Preparation and dispensation ................................................................................. 67 
6.3.1 
Handling of study treatment and other treatment .................................. 68 
6.3.2 
Instruction for prescribing and taking study treatment ......................... 69 
6.4 
Participant numbering, treatment assignment, randomization .............................. 70 
6.4.1 
Participant numbering ........................................................................... 70 
6.4.2 
Treatment assignment, randomization .................................................. 71 
6.5 
Treatment blinding ................................................................................................ 71 
6.6 
Dose escalation and dose modification.................................................................. 71 
6.6.1 
Dose escalation guidelines .................................................................... 72 
6.6.2 
Guidelines for dose escalation, determination of recommended 
dose for part 1 and maximum recommended dose for combination 
in part 2 ................................................................................................. 72 
6.6.3 
Definitions of dose limiting toxicities (DLTs) ...................................... 74 
6.6.4 
Dose modifications ................................................................................ 75 
6.6.5 
Follow-up for toxicities ......................................................................... 84 
6.7 
Additional treatment guidance ............................................................................... 87 
6.7.1 
Treatment compliance ........................................................................... 87 
6.7.2 
Emergency breaking of assigned treatment code .................................. 87 
7 
Informed consent procedures ............................................................................................ 88 
8 
Visit schedule and assessments ......................................................................................... 89 
8.1 
Screening ............................................................................................................. 121 
8.1.1 
Eligibility screening ............................................................................ 121 
8.1.2 
Information to be collected on screening failures ............................... 121 
8.2 
Participant demographics/other baseline characteristics ..................................... 121 
8.3 
Efficacy ................................................................................................................ 123 
8.3.1 
Efficacy - Disease status assessment ................................................... 123 
8.3.2 
Appropriateness of efficacy assessments ............................................ 125 
8.4 
Safety ................................................................................................................... 125 
8.4.1 
Laboratory evaluations ........................................................................ 126 
8.4.2 
Electrocardiogram (ECG) ................................................................... 127 
8.4.3 
Pregnancy and assessments of fertility ............................................... 129 
8.4.4 
Other safety evaluations ...................................................................... 130 
8.4.5 
Appropriateness of safety measurements ............................................ 131 
8.5 
Additional assessments ........................................................................................ 131 


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8.5.1 
Pharmacokinetics ................................................................................ 131 
 
 135 
9 
Discontinuation and completion ...................................................................................... 137 
9.1 
Discontinuation from study treatment and from study ........................................ 137 
9.1.1 
Discontinuation from study treatment ................................................. 137 
9.1.2 
Discontinuation from study ................................................................. 140 
9.1.3 
Lost to follow-up ................................................................................. 140 
9.2 
Withdrawal of informed consent and exercise of participants’ data privacy 
rights .................................................................................................................... 140 
9.3 
Study completion and post-study treatment ........................................................ 141 
9.4 
Early study termination by the sponsor ............................................................... 142 
10 Safety monitoring, reporting and committees ................................................................. 142 
10.1 
Definition of adverse events and reporting requirements .................................... 142 
10.1.1 
Adverse events .................................................................................... 142 
10.1.2 
Serious adverse events ........................................................................ 144 
10.1.3 
SAE reporting...................................................................................... 145 
10.1.4 
Pregnancy reporting ............................................................................ 146 
10.1.5 
Reporting of infection ......................................................................... 147 
10.1.6 
Reporting of study treatment errors including misuse/abuse .............. 147 
10.2 
Additional Safety Monitoring .............................................................................. 147 
10.3 
Committees .......................................................................................................... 147 
10.3.1 
Steering Committee ............................................................................. 147 
11 Data Collection and Database management .................................................................... 148 
11.1 
Data collection ..................................................................................................... 148 
11.2 
Database management and quality control .......................................................... 148 
11.3 
Site monitoring .................................................................................................... 149 
12 Data analysis and statistical methods .............................................................................. 149 
12.1 
Analysis sets ........................................................................................................ 150 
12.2 
Participant demographics and other baseline characteristics ............................... 151 
12.3 
Treatments ........................................................................................................... 151 
12.4 
Analysis supporting primary objectives .............................................................. 151 
12.4.1 
Definition of primary endpoint(s) ....................................................... 151 
12.4.2 
Statistical model, hypothesis, and method of analysis ........................ 152 
12.4.3 
Handling of intercurrent events of primary estimand ......................... 153 
12.4.4 
Handling of missing values not related to intercurrent event ............. 153 
12.4.5 
Sensitivity analyses ............................................................................. 153 


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12.4.6 
Supplementary analysis ....................................................................... 153 
12.5 
Analysis supporting secondary objectives ........................................................... 153 
12.5.1 
Efficacy and/or Pharmacodynamic endpoint(s) .................................. 153 
12.5.2 
Safety endpoints .................................................................................. 155 
12.5.3 
Pharmacokinetics ................................................................................ 157 
 158 
 
 158 
 
 159 
 
 160 
12.7 
Interim analyses ................................................................................................... 160 
12.8 
Sample size calculation........................................................................................ 160 
12.8.1 
Primary endpoint(s) ............................................................................. 160 
13 Ethical considerations and administrative procedures .................................................... 161 
13.1 
Regulatory and ethical considerations ................................................................. 161 
13.2 
Responsibilities of the investigator and IRB/IEC ................................................ 162 
13.3 
Publication of study protocol and results............................................................. 163 
13.4 
Quality Control and Quality Assurance ............................................................... 163 
13.5 
Participant Engagement ....................................................................................... 163 
14 Protocol adherence .......................................................................................................... 164 
14.1 
Protocol amendments........................................................................................... 164 
15 References ....................................................................................................................... 165 
16 Appendices ...................................................................................................................... 171 
16.1 
Appendix 1: Acute GvHD Staging Criteria (Harris et al 2016) .......................... 171 
16.2 
Appendix 2: Grading of Chronic GvHD (NIH Consensus Criteria) ................... 172 
16.3 
Appendix 3: Infection Severity Grading.............................................................. 176 
16.4 
Appendix 4: Prohibited medications and Concomitant medications to be used 
with caution and/or requiring actions during study drug treatment ..................... 179 
16.5 
Appendix 5: Patient Past History and Disease Characteristics ............................ 181 
16.6 
Appendix 6: Statistical details on the Bayesian Logistic Regression Model 
(BLRM) ............................................................................................................... 183 
16.6.1 
Statistical model for single agent ........................................................ 183 
16.6.2 
Prior specifications .............................................................................. 183 
16.6.3 
Operating characteristics ..................................................................... 186 
16.7 
Appendix 7: Statistical details on the Bayesian Time-to-DLT Model ................ 188 
16.7.1 
Statistical model .................................................................................. 188 
16.7.2 
Prior specifications .............................................................................. 189 
16.7.3 
Operating characteristics ..................................................................... 191 


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List of tables 
Table 2-1 
Objectives and related endpoints .......................................................... 37 
Table 6-1 
Study Treatment .................................................................................... 58 
Table 6-2 
Management of potential interactions of strong CYP3A inhibitors 
with siremadlin - Reduction level 1 (to 20% of the planned dose)* ..... 62 
Table 6-3 
Management of potential interactions of strong CYP3A inhibitors 
with siremadlin - Reduction level 2 (to 30% of the planned dose)* ..... 62 
Table 6-4 
Management of potential interactions of moderate CYP3A 
inhibitors with siremadlin ..................................................................... 63 
Table 6-5 
Timepoints for IST drug level measurements to be recorded by 
investigators .......................................................................................... 64 
Table 6-6 
Dose and treatment schedule ................................................................. 69 
Table 6-7 
Provisional siremadlin dose levels ........................................................ 72 
Table 6-8 
Criteria for defining dose limiting toxicities ......................................... 75 
Table 6-9 
Criteria for dose reduction / interruption and re-initiation of 
siremadlin treatment for adverse drug reactions. .................................. 78 
Table 6-10 
Follow-up evaluations for selected toxicities ........................................ 84 
Table 6-11 
Follow-up of abnormal liver chemistry results (not attributed to 
liver GvHD) .......................................................................................... 85 
Table 6-12 
Action required for isolated total bilirubin elevation ............................ 86 
Table 8-1 
Assessment Schedule, Dose confirmation siremadlin monotherapy 
(Part 1) ................................................................................................... 91 
Table 8-2 
Assessment Schedule, Overview (Part 2) ........................................... 109 
Table 8-3 
Assessment Schedule, Priming (Part 2) .............................................. 114 
Table 8-4 
Assessment Schedule, Combination and Maintenance (Part 2) .......... 117 
Table 8-5 
Response classification in AML at a given evaluation time (based 
on IWG Cheson et al 2003, ELN 2017 Döhner et al 2017) ................ 125 
Table 8-6 
Assessments and Specifications .......................................................... 126 
Table 8-7 
ECOG performance status ................................................................... 126 
Table 8-8 
Local clinical laboratory parameters collection plan .......................... 127 
Table 8-9 
Central clinical laboratory parameters collection plan ........................ 127 
Table 8-10 
Central ECG collection plan in Part 1 ................................................. 128 
Table 8-11 
Central ECG collection plan in Part 2 ................................................. 128 
Table 8-12 
Pharmacokinetic blood collection log for siremadlin (Part 1) ............ 132 
Table 8-13 
Pharmacokinetic blood collection log for siremadlin (Part 2) ............ 133 
 
 
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 136 
 
 136 
 
 137 
Table 10-1 
Guidance for capturing the study treatment errors including 
misuse/abuse ....................................................................................... 147 
Table 12-1 
Non-compartmental pharmacokinetic parameters* ............................ 157 
Table 12-2 
Data scenarios, inferential results and decisions (n=26) ..................... 161 
Table 12-3 
Operating characteristics for true CR/CRi rate (n=26) ....................... 161 
Table 16-1 
Acute GvHD Staging Criteria ............................................................. 171 
Table 16-2 
NIH global severity of chronic GvHD ................................................ 174 
Table 16-3 
Severity grading table and recurrence interval definitions ................. 176 
Table 16-4 
List of prohibited medications during study treatment ....................... 179 
Table 16-5 
List of medications to be used with caution and/or requiring actions 
during study treatment......................................................................... 179 
Table 16-6 
2016 WHO AML classification .......................................................... 181 
Table 16-7 
2017 ELN risk stratification by genetics ............................................. 181 
Table 16-8 
Prior distributions for single-agent parameters ................................... 184 
Table 16-9 
Historical data from [CHDM201X2101] for siremadlin single 
agent .................................................................................................... 184 
Table 16-10 
Historical data from [CHDM201H12101C] for siremadlin and 
sabatolimab combination .................................................................... 185 
Table 16-11 
Summary of prior distributions ........................................................... 185 
Table 16-12 
Probability of excessive toxicity estimated by the Bayesian model 
after each cohort .................................................................................. 186 
Table 16-13 
 Hypothetical true probabilities of DLT for different scenarios ......... 186 
Table 16-14 
Operating characteristics for different true values of DLT rate * ....... 187 
Table 16-15 
Time point for the safety analysis in the combination Phase* ............ 188 
Table 16-16 
Prior distributions for single-agent and interaction parameters .......... 189 
Table 16-17 
Historical data from [Guillaume et al (2019)] for DLI ....................... 190 
Table 16-18 
Summary of prior distributions ........................................................... 190 
Table 16-19 
Predicted DLT rate estimated by the Bayesian model after each 
cohort................................................................................................... 190 
Table 16-20 
Hypothetical true probabilities of DLT for different scenarios .......... 191 
Table 16-21 
Operating characteristics for different true values of DLT rate for 
n=9 patients * ...................................................................................... 192 
Table 16-22 
Operating characteristics for different true values of DLT rate 
based on n=18 patients* ...................................................................... 192 


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List of figures 
Figure 3-1 
Study design .......................................................................................... 44 
Figure 3-2 
Study Flow ............................................................................................ 45 
Figure 8-1 
Timing of study procedures ................................................................ 127 
Figure 9-1 
Post Treatment and Survival Follow up Design ................................. 139 
 


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List of abbreviations 
ADL 
Activities of Daily Living 
AE 
Adverse Event 
aGvHD 
Acute Graft Versus Host Disease 
ALLO-SCT 
Allogeneic Stem Cell Transplantation 
ALP 
Alkaline Phosphatase 
ALT 
Alanine Aminotransferase 
AML 
Acute Myeloid Leukemia  
ANC 
Absolute Neutrophil Count 
APTT 
Activated Partial Thromboplastin Time 
AST 
Aspartate Aminotransferase 
ATC 
Anatomical Therapeutic Chemical  
ATG 
Anti-Thymocyte Globulin 
AUC 
Area Under the Curve 
AV 
Atrioventricular 
BAT 
Best Available Treatment 
BLRM 
Bayesian Logistic Regression Model 
BMA 
Bone Marrow Aspirate 
BMB 
Bone Marrow Biopsy 
21 CFR 
Code of Federal Regulations 
CABG 
Coronary Artery Bypass Graft 
cGvHD 
Chronic Graft Versus Host Disease  
CI 
Confidence Interval 
CIBMTR 
Center for International Blood and Marrow Transplant Research  
CIOMS 
Council for International Organizations of Medical Sciences 
CK 
Creatine Kinase 
CMO&PS 
Chief Medical Office and Patient Safety  
CMV 
Cytomegalovirus 
CNS 
Central Nervous System 
COMB 
Combination phase 
CONF 
Confirmation phase 
COVID-19 
Coronavirus disease 2019 
CR 
Complete Remission 
CRF 
Case Report/Record Form (paper or electronic) 
CRi 
Complete Remission with incomplete hematological recovery 
CRO 
Contract Research Organization 
CSR 
Clinical study report 
CT 
Computed Tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
CTT 
Clinical Trial Team 
CV 
coefficient of variation 
DDI 
Drug-Drug Interactions 
DDS 
Dose Determining Set 
DILI 
Drug-Induced Liver Injury 
DLI 
Donor Lymphocyte Infusion 


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DLT 
Dose Limiting Toxicity 
DMSO 
Dimethyl sulfoxide 
DNA 
Deoxyribonucleic acid 
EBMT 
European Group for Blood and Marrow Transplantation 
EBV 
Epstein-Barr Virus 
EC 
Ethics Committtee 
ECG 
Electrocardiogram 
ECOG PS 
Eastern Cooperative Oncology Group Performance Status 
eCRF 
Electronic Case Report Form  
EDC 
Electronic Data Capture 
EFS 
Event Free Survival 
eGFR 
Estimated Glomerular Filtration Rate 
ELN 
European Leukemia Net 
EOS 
End of Study 
EOT 
End Of Treatment 
EWOC 
Escalation With Overdose Control  
FAS 
Full Analysis Set 
FDA 
Food and Drug Administration 
FLT3-ITD 
FMS Like Tyrosine Kinase 3- Internal Tandem Duplication 
FSH 
Follicle Stimulating Hormone 
G-CSF 
Granulocyte-Colony Stimulating Factor 
GCP 
Good Clinical Practice 
 
 
GGT 
Gamma-glutamyl transferase 
GI 
Gastrointestinal 
GLDH 
Glutamate Dehydrogenase 
GRFS 
Graft-versus-Host Disease/relapse-free survival 
GvHD 
Graft versus Host Disease 
GvL 
Graft-versus-leukaemia 
h 
Hour 
HBcAb 
Hepatitis B core antibody 
HBsAg 
Hepatitis B virus surface antigen 
HBV 
Hepatitis B Virus 
HCG 
Human Chorionic Gonadotropin 
HCV 
Hepatitis C Virus 
HDAC 
Histone deacetylase 
hERG 
Human ether-a-go-go-related gene 
HHV-6 
Human Herpes Virus 6 
HIV 
Human immunodeficiency virus 
HLA 
Human Leukocyte Antigen 
HMA 
Hypomethylating agent 
HR 
Hazard Ratio 
HSV 
Herpes Simplex Virus 
i.v. 
intravenous 
IB 
Investigator's Brochure 


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ICF 
Informed Consent Form 
ICH 
International Council for Harmonization of Technical Requirements for 
Pharmaceuticals for Human Use 
IDFU 
Investigational directions for use 
IEC 
Independent Ethics Committee 
IFN 
Interferon-gamma 
IL 
Interleukin 
IN 
Investigator Notification 
INR 
International Normalized Ratio 
IRB 
Institutional Review Board 
IRT 
Interactive Response Technology 
IST 
Immunosuppressive Therapy  
IUD 
Intrauterine Device 
IUS 
Intrauterine System 
IWG 
International Working Group 
LFS 
Leukemia- free survival  
LFT 
Liver function test  
LLN 
lower limit of normal 
LLOQ 
lower limit of quantification 
LPLV 
Last Participant Last Visit 
LUC 
Large unstained cells 
MAINT 
Maintenance phase 
MDM2 
Murine Double Minute-2 
MDS 
Myelodysplastic Syndrome 
MEC 
Minimum Exposure Criteria 
MedDRA 
Medical dictionary for regulatory activities  
MFC 
Multiparametric Flow Cytometry 
MFD 
Matched sibling/family donor 
mg 
milligram(s) 
MHC 
Major Histocompatibility Complex  
MI 
Myocardial Infarction  
mL 
milliliter(s) 
MPAL 
Mixed phenotype acute leukaemia 
MPN 
Myeloproliferative Neoplasm 
MRA 
Magnetic Resonance Angiography  
MRD 
Measurable Residual Disease 
MRI 
Magnetic Resonance Imaging 
MUD 
Matched Unrelated Donor  
MUGA 
Multiple gated acquisition 
N/A 
Not Applicable 
N/V 
Nausea and/or Vomiting 
NGS 
Next Generation Sequencing 
NIH 
National Institutes Health 
NOS 
Not Otherwise Specified  
NTI 
Narrow Therapeutic Index  


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NYHA 
New York Heart Association  
OS 
Overall Survival 
p.o. 
oral(ly) 
PB 
Peripheral Blood 
PBPK 
Physiological based pharmacokinetic modelling 
PCR 
Polymerase Chain Reaction  
PD 
Pharmacodynamic(s) 
PD-1 
Programmed cell death protein 1 
PK 
Pharmacokinetic(s) 
PLT 
Platelets 
PoC 
Proof of Concept 
PT 
prothrombin time 
PTFU 
Post -Treatment Follow-Up 
PRIM 
Priming phase 
QD 
Once a day 
QTcF 
QT interval corrected by Fridericia’s formula 
R Value 
ALT/ALP x ULN 
R/R 
Relapsed Refractory 
RD 
Recommended Dose 
RFS 
Relapse Free Survival 
RNA 
Ribonucleic acid 
SAE 
Serious Adverse Event 
sAML 
secondary Acute Myeloid Leukemia 
SAP 
Statistical Analysis Plan 
SARS-CoV-2 
Severe Acute Respiratory Syndrome coronavirus 2 
SD 
standard deviation 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
t-AML 
Therapy-related AML 
T3 
Triiodothyronine 
T4 
Thyroxine 
TAM 
Transient Abnormal Myelopoiesis  
TBIL 
Total bilirubin 
Tim-3 
T cell immunoglobulin and mucin domain 3  
TNF 
Tumor Necrosis Factor 
TRAIL-R 
TNF-related apoptosis-inducing ligand receptor 
TSH 
Thyroid Stimulating Hormone  
ULN 
Upper limit of normal 
WHO 
World Health Organization  
WoC 
Withdrawal of Consent 
WOCBP 
Women of Child Bearing Potential 


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Glossary of terms 
Additional treatment 
Medicinal products that may be used during the clinical trial as described in the 
protocol, but not as an investigational medicinal product (e.g. any background 
therapy). 
Assessment 
A procedure used to generate data required by the study 
Biologic Samples 
A biological specimen including, for example, blood (plasma, serum), saliva, tissue, 
urine, stool, etc. taken from a study participant. 
Clinical Trial Team 
A group of people responsible for the planning, execution and reporting of all clinical 
trial activities. Examples of team members include the Study Lead, Medical Monitor, 
Trial Statistician etc. 
Cohort 
A group of individuals who share a common exposure, experience or characteristic, 
or a group of individuals followed-up or traced over time. 
Cycles 
Number and timing or recommended repetitions of therapy are usually expressed as 
number of days (e.g., q28 days). 
Discontinuation from 
study 
Point/time when the participant permanently stops receiving the study treatment and 
further protocol required assessments or follow-up, for any reason. No specific 
request is made to stop the use of their samples or data. 
Discontinuation from 
study treatment 
Point/time when the participant permanently stops receiving the study treatment for 
any reason (prior to the planned completion of study drug administration, if any). 
Participant agrees to the other protocol required assessments including follow-up. No 
specific request is made to stop the use of their samples or data. 
Dosage 
Dose of the study treatment given to the participant in a time unit (e.g. 100 mg once 
a day, 75 mg twice a day). 
Electronic Data 
Capture (EDC) 
Electronic data capture (EDC) is the electronic acquisition of clinical study data using 
data collection systems, such as Web-based applications, interactive voice response 
systems and clinical laboratory interfaces. EDC includes the use of Electronic Case 
Report Forms (eCRFs) which are used to capture data transcribed from source 
data/documents used at the point of care. 
End of the clinical trial 
The end of the clinical trial is defined as the last visit of the last participant or at a 
later point in time as defined by the protocol. 
Enrollment 
Point/time of participant start the study treatment for the first time in the study. The 
action of enrolling one or more participants. 
Estimand  
As defined in the ICH E9(R1) addendum, estimand is a precise description of the 
treatment effect reflecting the clinical question posed by the trial objective. It 
summarizes at a population-level what the outcomes would be in the same 
participants under different treatment conditions being compared. Attributes of an 
estimand include the population, variable (or endpoint) and treatment of interest, as 
well as the specification of how the remaining intercurrent events are addressed and 
a population-level summary for the variable. 
Healthy volunteer 
A person with no known significant health problems who volunteers to be a study 
participant. 
Intercurrent events 
Events occurring after treatment initiation that affect either the interpretation or the 
existence of the measurements associated with the clinical question of interest. 
Investigational drug/ 
treatment 
The drug whose properties are being tested in the study. 
Medication number 
A unique identifier on the label of medication kits. 
Other treatment 
Treatment that may be needed/allowed during the conduct of the study (i.e. 
concomitant or rescue therapy) 
Part  
A sub-division of a study used to evaluate specific objectives or contain different 
populations. For example, one study could contain a single dose part and a multiple 
dose part, or a part in participants with established disease and in those with newly-
diagnosed disease. 
Participant 
A trial participant (can be a healthy volunteer or a patient). 


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Participant number 
A unique number assigned to each participant upon signing the informed consent. 
This number is the definitive, unique identifier for the participant and should be used 
to identify the participant throughout the study for all data collected, sample labels, 
etc. 
Period 
The subdivisions of the trial design (e.g., Screening, Treatment, Follow-up) which are 
described in the Protocol. Periods define the study phases and will be used in clinical 
trial database setup and eventually in analysis. 
Personal data 
Participant information collected by the Investigator that is coded and transferred to 
Novartis for the purpose of the clinical trial. This data includes participant identifier 
information, study information and biological samples. 
Premature participant 
withdrawal 
Point/time when the participant exits from the study prior to the planned completion 
of all study drug administration and/or assessments; at this time all study drug 
administration is discontinued and no further assessments are planned. 
Re-screening 
If a participant fails the initial screening and is considered as a Screen Failure, 
he/she can be invited once for a new Screening visit after medical judgment and as 
specified by the protocol. 
Remote 
Describes any trial activities performed at a location that is not the investigative site 
where the investigator will conduct the trial, but is for example a home or another 
appropriate location 
Screen Failure 
A participant who did not meet one or more criteria that were required for 
participation in the study 
Source 
Data/Document 
Source data refers to the initial record, document, or primary location from where 
data comes. The data source can be a database, a dataset, a spreadsheet or even 
hard-coded data, such as paper or eSource. 
Start of the clinical trial 
The start of the clinical trial is defined as the signature of the informed consent by the 
first participant. 
Study treatment 
Any drug or combination of drugs or intervention administered to the study 
participants as part of the required study procedures; includes investigational drug(s), 
control(s) or background therapy 
Study treatment 
discontinuation 
When the participant permanently stops taking any of the study drug(s) prior to the 
defined study treatment completion date (if any) for any reason; may or may not also 
be the point/time of study discontinuation. 
Treatment arm/group  
A treatment arm/group defines the dose and regimen or the combination, and may 
consist of 1 or more cohorts. 
Treatment of interest 
The treatment of interest and, as appropriate, the alternative treatment to which 
comparison will be made. These might be individual interventions, combinations of 
interventions administered concurrently, e.g., as add-on to standard of care, or might 
consist of an overall regimen involving a complex sequence of interventions. This is 
the treatment of interest used in describing the related clinical question of interest, 
which might or might not be the same as the study treatment. 
Variable (or endpoint) 
The variable (or endpoint) to be obtained for each participant that is required to 
address the clinical question. The specification of the variable might include whether 
the participant experiences an intercurrent event. 
Withdrawal of consent 
(WoC) /  
Withdrawal of consent from the study occurs when the participant explicitly requests 
to stop use of their data and/or biological samples AND no longer wishes to receive 
study treatment AND does not agree to further protocol required assessments. This 
request should be in writing (depending on local regulations) and recorded in the 
source documentation. 
This request should be distinguished from a request to discontinue the study. Other 
study participant’s rights are described in the corresponding informed consent form. 


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Amendment 2 (18-Nov-2022) 
Amendment rationale 
At the time of release of this amendment, no sites have been initiated, and no subject has been 
screened or received study treatment in this trial. 
The main purpose of this amendment is to restrict the participation of the German sites to Part 
1 of the study. The protocol will specify that the participating sites in Germany will enroll 
patients only in Part 1 with siremadlin monotherapy. The German sites are not permitted to 
enroll patients in Part 2, which includes Donor Lymphocyte Infusion (DLI) in combination with 
siremadlin.  
Changes to the protocol:  
Changes to specific sections of the protocol are shown in the track changes version of the 
protocol using strikethrough red font for deletions and red underline for insertions.  
 Protocol summary: Updated to clarify that Germany will not participate in Part 2 in the 
study design section.  
 Section 2.1 - Primary safety estimand for dose confirmation siremadlin monotherapy: 
Handling of remaining intercurrent events updated to withdrawal before completion of cycle 
1 with no DLT prior to completing sufficient scheduled safety assessments: such 
participants will be considered non-evaluable. 
 Section 2.1 - Primary safety estimand for combination phase: Handling of remaining 
intercurrent events updated to remove relapse and start of a new antineoplastic therapy 
following while-on-treatment estimand to evaluate safety regardless of relapse or start of 
new antineoplastic. 
 Section 2.1 - Primary safety estimand for combination phase: Handling of remaining 
intercurrent events updated to remove end of combination phase without experiencing DLT: 
participants will be censored at the last safety assessment in the combination phase 
 Section 2.1 - Primary efficacy estimand: Updated to remove “mainly DLI” in the Best 
Available Therapy (BAT) 
 Section 3- Study design: Updated to clarify that enrollment in Part 2 will not be applicable 
to the participating sites in Germany. 
 Section 5.2: Exclusion criteria 20 updated to clarify that QTcF should be collected prior to 
start of study treatment.  
 Section 6.2.2 – Concomitant therapy: Updated to provide a window of when concomitant 
medications data should be collected.  
 Section 6.2.2.1- Permitted concomitant therapy: Updated to clarify that concomitant use of 
systemic corticosteroids at higher than specified permitted doses is allowed in life-
threatening emergencies. 
 Section 6.6.2- Guidelines for dose escalation: Updated to clarify that enrollment in Part 2 
will not be applicable to the participating sites in Germany. 


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 
Table 6-3- Management of potential interactions of strong CYP3A inhibitors with 
siremadlin: Updated for consistency to start for with the lowest dose of 10 mg first and 
end up with the highest dose (eg. 20 mg) to make up total dose per cycle. 

 
 
 
 Table 8-1- Assessment Schedule, Dose confirmation siremadlin monotherapy (Part 1): 
Updated the footnote# 26 to add the Section 9.1.1.3 to get more details on the collection of 
disease response status during the survival follow-up visits for more clarity. 
 Table 8-2- Assessment Schedule, Overview (Part 2): Updated the footnote# 20 to add the 
Section 9.1.1.3 to get more details on the collection of disease response status during the 
survival follow-up visits for more clarity. 
 Section 8.3.1- Efficacy -Disease status assessments: Updated to clarify that hematology 
assessments will be also collected at the dose confirmation phase.  
 Table 8-12 - Extended windows (±2hr) for PK collections at 24 hr postdose for more 
flexibility. 
 Table 8-13 - Extended windows (±2hr) for PK collections at 24 hr postdose for more 
flexibility. 
 
 
 Section 9.1.1 Discontinuation from study treatment: Corrected the linked Section to 6.2.3 
(Prohibited medications). 
 Section 12.4.2: Statistical Model- Updated to add “off time to DLT for the participants in 
the DDS2” for better clarity.  
 Section 12.5.2 - Safety endpoints: Removed “treatment-emergent ≥ grade 3 immune-
related adverse events not attributed to GvHD” from the list of separate summaries of 
adverse events to be provided. 
 Section 12.5.3- Pharmacokinetics analyses: the first paragraph has been removed as the 
details on the pharmacokinetic analyses will be provided in a separate population 
pharmacokinetic report. 
 
 
 
 
 
 
 
 
 Additional minor changes have been made to correct typographical errors. 


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IRBs/IECs 
A copy of this amended protocol will be sent to the Institutional Review Board 
(IRBs)/Independent Ethics Committee (IECs) and Health Authorities. 
The changes described in this amended protocol require IRB/IEC approval prior to 
implementation. 


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Amendment 1 (06-Jul-2022) 
Amendment rationale 
As the release of this amendment, no sites have been initiated, and no subject has been screened 
or has received study treatment in this trial. 
The main purpose of this amendment is to comply with health authority’s request to modify the 
protocol as follows:  
 To modify the study design by adding a siremadlin monotherapy dose confirmation part 
(Part 1) with at least 6 evaluable participants to evaluate the safety and tolerability of 
siremadlin monotherapy and determine the recommended dose before commencing the 
treatment strategy part (Part 2), which includes siremadlin/donor lymphocyte infusion (DLI) 
combination as well as priming and maintenance with siremadlin monotherapy. 
 To specify that after the recommended siremadlin dose is determined in Part 1, enrollment 
in Part 2 will start after obtaining Health Authority’s approval as applicable. Enrollment in 
Part 2 will not be applicable to the participating sites in the United States. 
 To implement a larger dose reduction to 20% of siremadlin (instead of 30%) of the total 
planned dose when administered concomitantly with strong CYP3A inhibitors in the initial 
treatment cohort(s). Following the first safety review meeting and based on safety and 
siremadlin total exposure data, this may be changed to a dose reduction to 30% of the 
planned siremadlin dose with concomitant use of strong CYP3A inhibitors. 
 
 
 
 
 
 To clarify that the decision about DLI administration in eligible participants in Part 2 will 
be at the discretion of the treating investigator per the standard of practice.  
In addition, the following notable changes were made:  

 
 
 
 To remove the donor lymphocyte infusion (DLI) from the study treatment tables as it is not 
considered as Investigational Medicinal Product or Advanced Therapy Medicinal Products 
(ATMPs). 
 To clarify that a drug diary may be provided to the participants to enhance treatment 
compliance. 
Changes to the protocol:  
Changes to specific sections of the protocol are shown in the track changes version of the 
protocol using strikethrough red font for deletions and red underline for insertions.  
 Protocol summary: Updated to clarify the requirements to be fulfilled before starting Part 2 
and combination phase, and changes implement in the body content such as updates from 
new protocol template where applicable. 


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 Table 2-1: Secondary 
 objectives: the assessment of the effect of study 
treatment on MRD status after 6 months of study treatment and the exploration of the 
immunomodulatory effects of siremadlin have been removed. Clarified the objectives and 
the Part of the study where each objective will be assessed. 
 Section 3: Study design modified to add the dose confirmation siremadlin monotherapy 
(Part 1) and the Part 2 including the 3-part treatment strategy once the siremadlin 
monotherapy recommended dose is declared. Total number of participants has been updated 
from 32 to 38. Updated to clarify the requirements to be fulfilled before entering in Part 2 
and combination phase where applicable and that enrollment in Part 2 will not be applicable 
to the participating sites in the United States. 
 Figure 3-1: updated with the new study design. Footnotes have been updated to clarify the 
requirements to be fulfilled before starting Part 2 and combination phase where applicable. 
 Section 4.1: Updated to include the Part 2 wording. 
 Section 4.2: Updated to further explain the starting dose level at 30 mg/day with siremadlin 
and the cycle lenght of 42 days in the combination phase versus 28 days in siremadlin 
monotherapy phase. 
 Section 4.3: Updated to clarify that the administration of DLI in combination with 
siremadlin will be at the discretion of the treating investigator per standard of practice. 
 Section 4.5 Risk and benefits: Added the most frequent toxicities with siremadlin and that 
no potential clinical risk of QT prolongation was identified so far in preclinical studies. 
 
 
  
 Section 5.1: Inclusion criteria 3 updated to remove the sentence related to the patient 
receiving cyclophosphamide since participants are not required to have started or completed 
IST taper prior to start the study treatment. 
 Section 5.1: Inclusion criteria 4 updated to remove the pre-allo-SCT participant with AML 
in morphologic complete remission at time of transplant but with evidence of residual 
leukemia.  
 Section 5.1: Inclusion criteria 6 updated to clarify that DLI will only be applicable for the 
participants enrolled in Part 2. 
 Section 5.1: Inclusion criteria 8 removed the systemic GvHD prophylaxis or treatment IST 
taper to be started prior to start of study treatment or has been completed.  
 
 
 
  
 Section 5.2: Exclusion criteria 4 updated to add that a history of lower grades of GvHD is 
permitted if GvHD resolved to grade 0 for at least 4 weeks prior to start of study treatment. 


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 Section 5.2: Exclusion criteria 10 updated to add that prior systemic cancer-directed 
treatments or investigational modalities ≤ 5 half-lives or 4 weeks prior to starting study, 
whichever is longer.  
 Section 5.2: Exclusion criteria 12 updated to add the cancers treated with hormonal therapy. 
 Section 5.2: Exclusion criteria 17 updated to add the new language as per the protocol 
template version 5. 
 Section 5.2: Exclusion criteria number 18 has been added as it was missed in the previous 
protocol version. 
 Section 6.1; Table 6-1; Table 6-6: Removed the Donor Lymphocyte Infusion from the study 
treatment and Dose and treatment schedule and added in the Additional treatment 
paragraph. 
 Table 6-1: Study treatment table updated to add siremadlin 30 mg as an additional strength. 
 Section 6.1.2: Additional study treatment section removed as the supportive care measures 
have been moved in the Section 6.2 Other treatments. The subsequent subsections have been 
renumbered (for numbering continuity) due to deletion of Section 6.1.2 Additional study 
treatments. 
 Section 6.1.2 Treatment arms/group: Updated to add the Part 2 study design. 
 Section 6.1.3: 
 updated the eligibility criteria for DLI administration in combination with siremadlin to 
clarify that the participant should not have had Grade II-IV aGvHD  
(per Harris et al 2016) during priming phase.  
 Clarified the requirements to be fulfilled to enter the combination phase where 
applicable. 
 Updated the eligibility criteria to clarify that a participant can proceed to maintenance 
phase if he has no active aGvHD (per Harris et al 2016) 
 Section 6.1.4: Treatment duration- Updated to add the dose confirmation siremadlin 
monotherapy 
 Section 6.2.1: Updated to include the DLI text moved from Section 6.1.1. 
 Section 6.2.2: Updated to clarify the IST taper schedule and handling. 
 Section 6.2.2.1: Strong CYP3A inhibitors: Addition of the dose reduction of siremadlin to 
20% of the total planned dose per cycle (reduction level 1) in Table 6-2 and updated the 
dose reduction of siremadlin to 30% of the planned dose per cycle (reduction level 2) in 
Table 6-3 when given concomitantly with strong CYP3A inhibitors. 
 Section 6.2.3: Updated to add that DLI will not be permitted in study Part 1. 
 Section 6.3.1.1: Sentence added to inform that investigators may provide participants with 
drug diary to facilitate treatment compliance for treatments taken at home. 
 Section 6.3.1.2: Moved the donor lymphocyte infusion handling information from  
Section 6.3.2 to Section 6.3.1.2 [Handling of other treatment].  
 Table 6-5: Updated the title to “Timepoints for IST drug level measurements to be recorded 
by the investigators”.  


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 Section 6.6.1: Dose escalation guidelines – Updated to add the dose confirmation siremadlin 
therapy  
 Section 6.6.2: Guidelines for dose escalation and determining the recommended dose have 
been updated to clarify the requirements to be fulfilled before starting Part 2. 
 Section 6.6.3: DLT definition updated to add the minimum dose criteria and clarified the 
adverse events to be notified by the investigator to the Sponsor. 
 Section 6.6.4: Updated to clarify the guidelines for dose modifications decision for toxicities 
(other than GvHD) in Part 1 and Part 2. 
 Section 6.7.1: Treatment compliance- Updated to clarify the study treatment to be recorded 
on the study dispensation form. 
 Table 6-8: Criteria for defining dose limiting toxicities- updated to add any adverse event 
that leads to study treatment discontinuation if not clearly resulting from the underlying 
leukemia, inter-current illness, or concomitant medications. 
 Table 6-9: Dose modification of siremadlin for grade 4 neutropenia and for grade 4 
thrombocytopenia was revised. The revision conveys that siremadlin dose reduction by one 
dose level will occur after the first occurrence of grade 4 neutropenia and/or grade 4 
thrombocytopenia. Dose modification of siremadlin for asymptomatic amylase and/or 
lipase elevation and pancreatitis was clarified. 
 Section 7: Updated to include the new wording for the Informed Consent procedures section 
as per protocol template version 5. 
 Section 8: Updated as per protocol template version 5 language. 
 Table 8-1: Updated to add for the dose confirmation siremadlin monotherapy visit schedule 
assessment (Part 1), End of treatment visit, Post-treatment follow-up visit and Survival 
follow-up visits assessments 
 Table 8-2, Table 8-3 and Table 8-4:  

 
 
  
 
 
 
 
 
 Added additional checks for hematology and chemistry blood collection, and updated 
to Day 1, 8 and 15 of the first 2 cycles, then Day 1 and 15 of cycle 3 to cycle 6 during 
the priming phase and on Day 1 and 15 of each combination cycle during the 
combination phase. Clarified the hematology and chemistry collection during the Post 
treatment follow-up phase. 
 Updated the IST level measurement collection time and replaced “taper” with “level”.  
 Updated the acute GvHD and chronic GvHD collection time during the maintenance 
phase (Part 2) and during Post-treatment follow-up phase. 


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
 
  
 Section 8.2: Participant demographics section: 
 updated to add the data collection of prior antineoplastic therapy and allo-SCT 
characteristics at the screening visit. 
 
 
 
 Section 8.4.1: Updated to include the new wording from the protocol template version 5. 
 Section 8.4.3: Pregnancy and assessment of fertility updated as per protocol version 5. 
 Section 8.4.4: Other safety evaluation- Updated to add the dose confirmation siremadlin 
therapy part 1. 
 
 
 Table 8-10, Table 8-12; Table 8-14 and Table 8-16: Added for the dose confirmation 
siremadlin monotherapy assessments (Part 1). 
 
 
 
 Section 9.1.1.2: Post-treatment Follow-Up- Updated the wording for the withdrawal of 
consent as per protocol template version 5. 
 Section 9.1.1.3: Survival follow-up- Clarified the disease status collection during the 
survival follow-up period. 
 Section 9.2: Clarified the withdrawal of consent language as per protocol template version 
5. 
 Section 10.1.3: Safety reporting- Updated to include new guidances for the safety reporting 
timeframes and conditions. 
 Section 12.1, Section 12.2 and Section 12.3:  
 Updated to clarify the study treatment phases Part 1 and Part 2 wording.  
 Wording aligned with the objectives in Table 2-1. 
 Section 12.4: Analysis supporting primary objectives. – Updated to change the primary 
efficacy objective only applicable for part 2. 
 Section 12.5: Analysis supporting secondary objectives. Updated to add a secondary 
efficacy objective and endpoint applicable for part 1 
. 
 
  
 Section 12.8: Updated to include Part 1 and Part 2 study phases. 
 Section 13, Section 13.1 Regulatory and ethical considerations, 13.3 Publication of study 
protocol and results, Section 13.4 Quality Control and Quality Assurance, Section 13.5 
Participant Engagement: Updated to include the language/instructions for Clinical 
disclosure needs as per protocol version 5 
 Section 15: Updated the reference for Stein et al (2022) which was published in March 2022. 
. 
Removed the reference Schuurhuis et al (2018). 
 Additional minor changes have been made to correct typographical errors. 


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IRBs/IECs 
A copy of this amended protocol will be sent to the Institutional Review Board 
(IRBs)/Independent Ethics Committee (IECs) and Health Authorities. 
The changes described in this amended protocol require IRB/IEC approval prior to 
implementation.  
The changes herein affect the Informed Consent. Sites are required to update and submit for 
approval a revised Informed Consent that takes into account the changes described in this 
protocol amendment. 


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Protocol summary 
Protocol number 
CHDM201K12201 
Full Title 
A phase Ib/II, open label study of siremadlin monotherapy and in combination with donor 
lymphocyte infusion as a treatment for patients with acute myeloid leukemia post-
allogeneic stem cell transplantation who are in complete remission but at high risk for 
relapse. 
Brief title 
A study of efficacy and safety of siremadlin alone and in combination with donor 
lymphocyte infusion (DLI) in adults with acute myeloid leukemia (AML) who have received 
allogeneic stem cell transplant (allo-SCT) but are at high risk for relapse. 
Sponsor and 
Clinical Phase 
Novartis 
Phase Ib/II 
Investigation 
type 
Drug 
Study type 
Interventional 
Purpose 
The primary purpose of this study is to confirm the safe dose and schedule of siremadlin 
monotherapy and in combination with DLI according to a treatment strategy that consists 
of three consecutive phases: priming phase with siremadlin monotherapy, followed by 
combination phase of siremadlin plus DLI in participants eligible to receive DLI, followed 
by maintenance phase with siremadlin monotherapy. 
The study is also designed to assess the preliminary efficacy in preventing hematologic 
relapse in patients with AML who achieved complete remission (CR) or CR with 
incomplete count recovery (CRi) following allo-SCT but are at high risk for relapse based 
on the presence of pre-transplant risk factors. 
Primary 
Objective(s)  
Safety Primary Objectives:  
 To determine the dose and schedule of siremadlin monotherapy that is tolerable 
without unacceptable toxicities (recommended dose for the treatment strategy Part 2), 
measured by incidence of dose-limiting toxicities (DLTs) in Part 1. 
The primary clinical question of interest is: Can siremadlin be safely administered as 
monotherapy on Days 1-5 of a 28-day cycle (at the starting dose level of 30 mg QD) to 
adult participants with AML who are in CR or CRi starting no earlier than ≥ Day 60 
after allo-SCT? 
 To determine the dose and schedule of siremadlin in combination with DLI that is 
tolerable without unacceptable toxicities (recommended dose for combination), 
measured by time to DLT- in Part 2. 
The primary clinical question of interest is: Following the priming phase with at least 2 
cycles of siremadlin monotherapy at the Recommended Dose (RD) for Part 2, can 
siremadlin be safely administered to adult participants with AML at the tolerated dose 
from the last priming cycle in combination with DLI? 
Efficacy Primary Objectives: 
 To evaluate the preliminary efficacy of study treatment strategy (siremadlin 
monotherapy as priming monotherapy and/or maintenance, with or without siremadlin 
in combination with DLI on prevention of hematologic relapse, measured by the 
proportion of participants who are alive and maintained CR or CRi with no evidence of 
hematologic relapse over at least 6 months after start of study treatment strategy (Part 
2). 
The primary clinical question of interest is: Does siremadlin given in a treatment 
strategy consisting of priming with or without combination and maintenance therapy 
have activity in preventing hematologic relapse or death (i.e., maintenance of CR/CRi) 
in adult participants with AML who are in CR/CRi after allo-SCT irrespective of 
treatment discontinuation? 
Secondary 
Objectives 
 To evaluate the preliminary efficacy of siremadlin monotherapy on prevention of 
hematologic relapse (Part 1- siremadlin monotherapy at the recommended dose for 
Part 2) 
 
To assess relapse free survival (RFS) (Part 2). 


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 
To assess cumulative incidence of relapse at 1 year and at 2 years after start of study 
treatment (Part 1 and Part 2). 
 
To assess overall survival (OS) (Part 2). 
 
To assess safety and tolerability of siremadlin monotherapy (during dose confirmation, 
priming and maintenance) and in combination with DLI (Part 1 and Part 2). 
 
To assess the proportion of participants stopping study treatment due to GvHD or 
other adverse events (Part 1 and Part 2). 
 
To assess the incidence of grade III and IV acute graft vs host disease (GvHD), 
moderate and severe chronic GvHD (Part 1 and Part 2). 
 
To assess GvHD-free/relapse-free survival (GRFS) (Part 1 and Part 2). 
 
To characterize the pharmacokinetics of siremadlin in monotherapy and in 
combination with DLI (Part 1 and Part 2). 
Study design 
This is a Phase Ib/II, single arm, open label, multi-center study of siremadlin as 
monotherapy and in combination with DLI, in adult participants with AML who are in CR or 
CRi post allo-SCT but are at high risk for relapse based on the presence of pre-transplant 
risk factors. 
The study will enroll approximately 38 participants.  
This will start with a dose confirmation of siremadlin monotherapy (Part 1) to explore a 
maximal of 3 dose levels (starting dose 30 mg/day on days 1-5 of a 28-day treatment 
cycle, with a dose level +1 at 40 mg/day and dose level -1 at 20 mg/day). It is assumed 
that approximately 12 participants will be enrolled in 2 cohorts to obtain at least 3 
evaluable patients in each cohort for a maximum of 24 cycles in total. 
Once the recommended siremadlin dose is determined in Part 1, enrollment in Part 2 of 
approximately 26 new participants will start after obtaining Health Authority’s approval as 
applicable. Enrollment in Part 2 will not be applicable to the participating sites in the 
United States and Germany. 
Participants enrolled in Part 2 will follow a treatment strategy, which contains siremadlin 
monotherapy (priming phase), potentially followed by siremadlin in combination with DLI 
(at the discretion of the treating investigator per standard of practice for participants who 
are eligible to receive DLI) then maintenance with siremadlin monotherapy for a 
maximum of 24 cycles in total: 
 
A priming phase with siremadlin monotherapy (for at least 2 cycles). Participants who 
are not eligible for the combination phase of siremadlin/DLI may continue priming 
phase with siremadlin monotherapy. 
 
A combination phase of siremadlin in combination with DLI (siremadlin/DLI) for 
participants who are eligible to receive DLI (up to a total of 3 combination cycles). 
 
A maintenance phase with siremadlin monotherapy. 
Rationale 
Although allo-SCT continues to be the most potent anti-leukemia treatment for AML, 
relapse after allo-SCT remains unacceptably high and is the main cause of treatment 
failure (~40%) and death in adults with AML following allo-SCT. Up to 40% of all relapses 
will occur within the first 6 months post-allo-SCT. 
There is currently no approved effective treatment available for AML patients with 
relapsing disease after transplant, and treatment options are very limited with poor 
outcomes. Therefore, exploring innovative treatment strategies for prevention of early 
relapse after allo-SCT remains a continuing area of unmet need. Post-transplant 
maintenance or preemptive strategies to enhance the graft-versus-leukemia (GvL) effect 
or to eradicate persistent residual disease may offer the chance for AML patients at high 
risk for relapsing disease for an improved outcome of allo-SCT as a potentially curable 
treatment. 
Siremadlin is a novel investigational MDM2 inhibitor with single-agent anti-AML activity as 
well as potential immunomodulatory effects, which may enhance GvL, reverse immune 
escape and delay/prevent AML relapse post-allo-SCT. Furthermore, the combination of 
siremadlin with DLI (strongly supported by preclinical data) may provide synergistic 
antitumor effects, further enhance the GvL response, and contribute to improving 
outcomes and successfully prevent relapse after allo-SCT. 


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Study population 
Study population includes adult patients with AML who underwent an allo-SCT and 
achieved CR or CRi but remain at high risk for relapse post-allo-SCT based on the 
presence of pretransplant risk factors as detailed in the inclusion criteria. 
Approximately 38 participants are planned to be enrolled and treated. 
Key Inclusion 
criteria 
Signed informed consent must be obtained prior to participation in the study. 
 
Adults ≥ 18 years of age 
 
Participants with AML diagnosis, who underwent one allo-SCT to treat AML and are 
currently at ≥ Day 60 but no later than Day 120 (≤ Day 120) post allo-SCT.  
 
Pre-allo-SCT - Participants must have any of the following risk factors that put them 
at high risk for relapse:  
● 
AML in first CR (CR1) prior to allo-SCT with one of the following: 
● 
Adverse risk genetic abnormalities per 2017 ELN risk stratification. 
● 
Patients with TP53 mutant AML at diagnosis are eligible if they meet eligibility 
criteria.  
● 
Therapy-related AML (t-AML). 
● 
Secondary AML (sAML) [AML secondary to antecedent myelodysplastic 
syndrome (MDS) or AML secondary to myeloproliferative neoplasm (MPN)]. 
● 
AML in second or greater CR (≥CR2) prior to allo-SCT. 
 
 
 
Allo-SCT must have the following characteristics: 
● Unmanipulated/T cell-replete bone marrow or peripheral blood stem cells as a 
graft source. 
● Matched related (family) donor (MFD) or matched unrelated donor (MUD): Human 
Leukocyte Antigen (HLA) matching of donor and recipient should be at a minimum of 
8/8 antigen or allele matched at HLA-A, -B, -C, -DRB1 loci. 
● Any conditioning regimen intensity is permitted, the use of anti-thymocyte globulin 
(ATG) or alemtuzumab or post-transplant cyclophosphamide as a part of conditioning 
is allowed 
● Donor lymphocytes are collected, cryopreserved and available for infusion (DLI), 
or obtaining donor lymphocytes for DLI is feasible (Part 2 only). 
 
Post-allo-SCT, participants must have achieved complete remission (CR) or CR with 
incomplete count recovery (CRi) with no current evidence of hematologic relapse 
(bone marrow blasts < 5%; no circulating blasts in the blood; no evidence of 
extramedullary disease) 
 
Adequate liver function tests (Aspartate Aminotransferase (AST) and Alanine 
Aminotransferase (ALT) ≤ 3 × upper limit of normal (ULN), total bilirubin ≤ 1.5 × ULN) 
and renal function (estimated Glomerular Filtration Rate (eGFR) ≥ 45 mL/min/1.73 
m2) (within 14 days prior to start of study treatment). 
 
Evidence of adequate engraftment post allo-SCT: Absolute neutrophil count (ANC) ≥ 
1.0x109/L, platelet count ≥ 75x109/L, hemoglobin ≥ 8 g/dL (within 14 days prior to 
start of study treatment). 
Key Exclusion 
criteria 
 
Prior exposure to Murine Double Minute (MDM)-inhibitor 
 
Active acute GvHD of any grade (per Harris et al 2016) requiring systemic therapy at 
time of study treatment initiation  
 
Active chronic GvHD of any grade (per National Institutes of Health (NIH) criteria and 
Jagasia et al 2015) requiring systemic therapy at time of study treatment initiation  
 
Past history of grade III or IV acute GvHD (per Harris et al 2016) and/or past history 
of moderate or severe chronic GvHD (per NIH criteria and Jagasia et al 2015). 
History of lower grades of GvHD is permitted if GvHD resolved to grade 0 for at least 
4 weeks prior to start of study treatment. 
 
Recipient of allo-SCT from a matched unrelated donor (MUD) with one or more 
antigen or allele mismatch at HLA-A, -B, -C, -DRB1 locus (HLA matching less than 
8/8 antigens)  
 
Recipient of allo-SCT from a haploidentical family donor  
 
Recipients of cord blood transplant as a graft source  


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 
Prior systemic cancer-directed treatments or investigational modalities ≤ 5 half-lives 
or 4 weeks prior to starting study, whichever is longer. 
 
Prior systemic AML-directed treatments given at any time after allo-SCT (including 
DLI)  
 
History of another primary malignancy that is currently clinically significant or 
currently requires active intervention. Participants who are receiving adjuvant 
hormonal therapy for breast, prostate or other cancers are eligible  
 
Participants who require treatment with moderate or strong CYP3A inducers within 
14 days prior to starting study treatment, or are expected to receive moderate or 
strong CYP3A4 inducers during the entire study  
 
GI disorders that may prevent the intake and absorption of oral siremadlin (eg, 
diarrhea, uncontrolled nausea and/or vomiting, Gastrointestinal (GI) bleeding, etc)  
 
Any concurrent severe and/or active uncontrolled bacterial, viral or fungal infection 
requiring parenteral antibacterial, antiviral or antifungal therapy. Prophylactic 
antimicrobial use (oral or parenteral) is allowed  
 
Cardiac or cardiac repolarization abnormality, including but not limited to any of the 
following:  
● 
History of myocardial infarction (MI), angina pectoris, or coronary artery bypass 
graft (CABG) within 6 months prior to starting study treatment. 
● 
Clinically significant cardiac arrhythmias (e.g., ventricular tachycardia), complete 
left bundle branch block, high-grade AV block (e.g., bifascicular block, Mobitz type II 
and third degree AV block). 
● 
Baseline QTcF interval > 470 ms. 
● 
Clinically significant and/or uncontrolled heart disease such as congestive heart 
failure requiring treatment (New York Heart Association (NYHA) Grade III/IV)  
 
Other concurrent severe and/or uncontrolled medical conditions or serious organ 
dysfunction or other co-morbidity that, in the opinion of the investigator, predisposes 
the participant to high risk of noncompliance with the protocol. 
Study treatment 
 
Siremadlin: Daily on Days 1-5 of every cycle. Starting dose level, 30 mg/day (Part 1); 
dose level +1, 40 mg/day; dose level -1, 20 mg/day. 
 
28-day cycle as monotherapy [Part 1, Part 2] 
 
42-day (6-week) cycle during combination phase of siremadlin with donor lymphocyte 
infusion (DLI) [Part 2] 
Treatment of 
interest 
Siremadlin 
Efficacy 
assessments 
Disease response assessment will be performed locally by the Investigator according to 
the European LeukemiaNet (ELN) AML recommendations and International Working 
Group (IWG) AML response criteria. 
The efficacy assessments will be done at screening, at regular intervals during treatment 
and during the follow-up phase for assessment of disease by collecting the below: 
 
Bone marrow aspirate (BMA) 
 
Bone marrow biopsies (BMB) 
 
Hematology 
 Extramedullary disease assessment [primarily via physical examination, additional 
evaluation if clinically indicated (imaging, lumbar puncture, tissue biopsy)]. 
Pharmacokinetic 
assessments  
Pharmacokinetic (PK) samples will be obtained and evaluated in all participants at all 
dose levels. 
Key safety 
assessments 
 
Acute GvHD 
 
Chronic GvHD 
 
Adverse events and serious adverse events 
 
Vital signs 
 
Monitoring of laboratory values 


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 
Eastern Cooperative Oncology Group Performance (ECOG) performance status 
 
12-lead -electrocardiograms (ECGs) 
Other 
assessments  
Data analysis 
Primary safety analysis:  
For participants in the Cycle 1 of Part 1 and the entire combination phase, assessing 
whether siremadlin at the tested dose levels does not lead to an unacceptable level of 
toxicity (DLTs) when administered alone or in combination with DLI will be based on the 
estimation of the probability of DLT for participants in the dose determining set for Part 1 
(DDS1) and DDS2 for combination phase in Part 2. 
Dose confirmation of siremadlin as monotherapy (Part 1) will be based on the incidence 
of DLTs and will be guided by a Bayesian logistic regression model with the standard 
EWOC. Dose confirmation of siremadlin in combination with DLI (siremadlin/DLI 
combination phase) in Part 2 will be based on time-to-DLT using Bayesian time to first 
DLT model with the standard EWOC considering all available information for up to 3 
cycles. 
Primary efficacy analysis:  
The efficacy of study treatment will be based on the proportion of participants remaining 
in CR/CRi as per investigator assessment for at least 6 months after the start of study 
treatment, among participants who initiated priming phase at the siremadlin RD for 
priming with/without DLI (Part 2). 
Decision criteria for trial success (dual-criterion) are based on proportion of participants 
who remain in CR/CRi by investigator assessment and are alive at least 6 months after 
the start of study treatment): Bayesian statistical significance: probability (CR/CRi rate > 
40% | data) ≥ 0.975 (the one-sided p-value must be less than 2.5%) (null value), and 
Clinical relevance: posterior median of CR/CRi rate ≥ 60% (decision value). 
Key words 
Phase Ib/II, siremadlin, donor lymphocyte infusion (DLI), MDM2, p53, Acute Myeloid 
Leukemia (AML). 


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1 
Introduction 
1.1 
Background 
Allogeneic stem cell transplantation (allo-SCT) for AML and relapse post-allo-
SCT 
Allo-SCT continues to be the most potent anti-leukemia treatment for adult patients with high-
risk AML. However, AML relapse after allo-SCT remains unacceptably high and is the main 
cause of treatment failure (~40%) and death in adults with AML following allo-SCT 
(Thekkudan et al 2020). 
According to a recent publication by D'Souza et al 2020, among allo-SCT recipients who died 
within 100 days, AML relapse was the most common cause of death (27%), followed by organ 
failure (25%), infection (20%), Graft Versus Host Disease (GVHD) (10%), hemorrhage (5%), 
graft rejection (2%), and other causes (9%). After day 100, the most common cause of death 
was relapse (61%), followed by infection (11%), organ failure (10%), GVHD (9%), hemorrhage 
(1%), graft failure (1%), second malignancy (1%), and other causes (6%).  
Most AML relapses after allo-SCT occur early within the first 6 months post-transplant, and 
survival after early relapse post-allo-SCT is dismal. 
Additionally, outcome data reported to the Center for International Blood and Marrow 
Transplant Research (CIBMTR) from 1788 patients with AML who relapsed after allo-SCT 
showed that median time to post-allo-SCT relapse was 7 months (range, 1 to 177) with 43% of 
relapses within <6 months, 39% between 6 months-2 years, 8% between 2-3 years, and 10% 
within ≥ 3 years. Treatment of relapse included chemotherapy alone, donor lymphocyte infusion 
(DLI) +/- chemotherapy, or second allo-SCT +/- chemotherapy +/- DLI, with subsequent CR 
rates of 29%. Survival for all patients was 23% at 1 year after relapse; however, 3-year Overall 
Survival (OS) correlated with time from allo-SCT to relapse with dismal survival with early 
disease relapse post-allo-SCT (OS 4% for relapses within the 1- to 6-month, 12% for the 6-
month to 2-year, 26% for the 2- to 3-year, and 38% for ≥3-year period (Bejanyan et al 2015). 
Another retrospective registry study of 263 patients with relapsed AML after allo-SCT with 
reduced intensity conditioning (RIC) by the Acute Leukemia Working Party of the European 
Society for Blood and Marrow Transplantation (EBMT), showed an estimated 2-year OS from 
post-allo-SCT relapse was 14%. Overall, 32% of patients achieved complete remission after 
their primary intervention for relapse, and longer interval between allo-SCT and relapse was 
the only factor predicting for response (P = 0.003, Hazard Ratio (HR) = 4.86, 95% Confidence 
interval (CI), 1.70-13.90). In a multivariate model, an interval from allo-SCT to relapse more 
than 5 months (HR = 0.50, 95% CI, 0.37-0.67, P <0.001), was associated with longer OS. Two-
year OS in patients who relapsed at a median of <5 months post-allo-SCT was 7.5%, vs 20.6% 
in those who relapsed >5 months post-allo-SCT, P <0.001 (Schmid et al 2012). 
Prevention of early relapse after transplant remains a continuing area of unmet need, and post-
transplant early cellular or pharmacologic maintenance or preemptive strategies to enhance the 
GvL effect or to eradicate persistent residual disease have been of renewed interest.  


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Therefore, it is important to identify patients who have a higher risk of relapse after allo-SCT 
to tailor transplant and post-transplant management strategies with an aim to reduce the relapse 
incidence, and to offer therapies to patients who would benefit most (Oran et al 2017). 
Pre-transplant risk factors and risk of relapse post-allo-SCT  
The presence of certain pre-transplant risk factors may identify a patient population with a 
particularly high risk for relapse rather early after allo-SCT, resulting in poor overall prognosis. 
These pre-transplant risk factors include but not limited to: (1) AML in first CR (CR1) prior 
to allo-SCT with either adverse risk (unfavorable) genetic abnormalities per 2017 ELN risk 
stratification, or therapy-related AML (t-AML), or secondary AML (sAML) [AML secondary 
to antecedent myelodysplastic syndrome or AML secondary to myeloproliferative 
neoplasm]; (2) AML in second CR (CR2) or greater prior to allo-SCT; (3) AML in 
morphologic 
CR 
(<5% 
leukemic 
blasts) 
at 
time 
of allo-SCT (prior 
to starting conditioning regimen) but with evidence of residual leukemia (Araki et al 2016, 
Ganapule et al 2017, 
Craddock et al 2018, 
Schmaelter et al 2020, 
Gilleece et al 2020, 
Hansen et al 2021 ). 
Allo-SCT for AML in CR1 with adverse risk genetic abnormalities per 2017 ELN risk 
stratification 
A retrospective analysis of 2028 patients who received an allo-SCT between 2000 and 2015 for 
de novo AML in CR1 showed that adverse risk cytogenetics at diagnosis was one of the overall 
factors predicting relapse (p < 0.001), and was associated with increased risk of relapse 
following transplant between 3 to 6 months (p < 0.001, HR 2.47, 95% CI [1.73–3.51]), 6 to 12 
months (p = 0.003, HR 1.97, 95% CI [1.26–3.07]), and later relapse > 12 months post-allo-SCT 
(p = 0.002, HR 1.94, 95% CI [1.27–2.97]) (Craddock et al 2018). 
Another recent report examined the effect of 2017 European LeukemiaNet (ELN) genetic risk 
stratification on allo-SCT outcomes of AML in 500 adult patients, in CR1 (n = 370) or CR2 
(n = 130), from 2005 to 2016. Patients were classified into favorable (12%), intermediate 
(57%), and adverse (32%) 2017 ELN risk groups. Patients in the adverse risk group had the 
highest risk of relapse and worst survival. OS at 2 years was 72%, 60%, and 45%, in the 
favorable, intermediate and adverse risk group, respectively (p <0.001). In multivariable 
analyses, the 2017 ELN classifier was an independent predictor of OS after allo-SCT with 
significantly higher overall mortality in the intermediate (HR = 1.68, 95% CI, 1.06-2.68; 
p = 0.03) and adverse (HR = 2.50, 95% CI [1.54-4.06]; p < 0.001) risk groups compared to the 
favorable risk group. Leukemia- free survival (LFS) was worse in the intermediate (HR = 1.63, 
95% CI [1.06-2.53]; p = 0.03) and adverse (HR 2.23, 95% CI [1.41-3.54]; p < 0.001) risk 
groups, while relapse was higher in the adverse risk group (HR = 2.36, 95% CI [1.28-4.35]; 
p = 0.006) as compared to the favorable risk group (Hansen et al 2021). The risk of relapse in 
patients with adverse risk genetics by ELN 2017 risk stratification following allo-SCT in CR1 
was estimated to be 45-55% (Loke et al 2020). 
Allo-SCT for AML in CR1 secondary to antecedent myelodysplastic syndrome or 
myeloproliferative neoplasm (sAML) or therapy-related AML (t-AML)  
A recent retrospective, EBMT registry-based, analysis of the outcomes of allo-SCT for sAML 
[AML that evolved from previous myeloid malignancy or therapy-related AML (t-AML)]  


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[n= 1325, including 825 evolved from previous MDS, MPN, MDS/MPN overlap, others; and 
500 t-AML following chemotherapy or radiation for other types of cancer], in comparison to 
de novo AML (11,439 patients), reported that among transplants in CR1 (n= 8,600), the 3-year 
cumulative incidence of relapse (RI) was 28.5% for de novo, and 35% for sAML. Three-year 
overall survival (OS), leukemia-free survival (LFS) and Graft-versus-Host Disease/relapse-free 
survival (GRFS) was 60.8%, 55.1%, and 38.6% for de novo, and 46.7%, 41.6%, and 28.4% for 
sAML, respectively. In multivariate analysis, sAML was associated with a lower OS (HR = 
1.33 ,95% CI [1.21–1.48]; p < 10−5), LFS (HR = 1.32, [95% CI: 1.19–1.45]; p < 10−5) and GRFS 
(HR = 1.2 [95% CI = 1.1–1.31]; p < 10−4); and higher RI (HR = 1.27 [95% CI = 1.12–1.44]; p 
< 10−3). Therefore, sAML is identified as an independent risk factor for outcome after allo-SCT 
in CR1 (Schmaelter et al 2020). 
AML in second CR (CR2) or greater prior to allo-SCT 
Remission status of CR2 at time of transplant is another significant independent variable for a 
significantly worse overall survival (HR = 1.49 for CR2 compared with CR1, P = 0.005) 
(Michelis et al 2015), particularly in patients with shorter duration of CR1 (Gilleece et al 2020). 
Beyond CR2 at time of allo-SCT, outcomes are poorer. For CR2 and CR3 status at time of allo-
SCT, the 5-year Event Free Survival (EFS) estimate was 49.7% and 33.3%, respectively; and 
the 5 year OS estimate was 48.2% and 31.2%, respectively (Ganapule et al 2017). 
MDM2 inhibitors and immunomodulatory effects  
Strong immunomodulatory effects of upregulated, functional p53 have been recently described 
in murine syngeneic solid cancer (Fang et al 2019, Wang et al 2021) and AML models treated 
with MDM2 inhibitors including siremadlin. Such immunomodulatory effects of siremadlin 
could be implemented in order to prevent relapses in AML patients who underwent allo-SCT. 
In this clinical setting, immune escape mechanisms, such as downregulation of the major 
histocompatibility complex (MHC)-II as well as pro-apoptotic receptors including Tumor 
Necrosis Factor (TNF)-related apoptosis-inducing ligand receptor (TRAIL-R-1 and TRAIL-R-
2, may promote relapse via evasion from the attack of alloreactive donor T cells post- allo-SCT 
(Christopher et al 2018, Zeng et al 2014). Preclinical murine data of AML models showed that 
MDM2 inhibition upregulates the expression of MHC-II and TRAIL-R1/2 in a p53-dependent 
manner, which consequently may enhance the anti-leukemia immunity post-allo-SCT and 
reverse immune escape. Furthermore, MDM2 inhibition synergized with the allogeneic immune 
response and increased the vulnerability of AML cells to allogeneic donor T-cells with 
improved long-term survival of leukemia-bearing mice when T-cells were combined with 
MDM2 inhibition. In addition, MDM2 inhibition promoted the cytotoxicity and longevity of 
the allogeneic donor CD8+ T cells as demonstrated by increased expression of the anti-tumor 
cytotoxicity markers (perforin, CD107a, IFN-γ, TNF and CD69), which resulted in long-term 
control of leukemia in murine models (Nguyen Huong Giang Ho et al, in preparation, 
confidential data on file). These findings suggest that MDM2 inhibition in combination with 
DLI may provide a therapeutic synergism and enhance graft-versus-leukemia (GvL) effects by 
augmenting allo-reactive immunity against leukemic blasts after allo-SCT. 


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Graft-versus-leukemia (GvL) 
The aim of allo-SCT is to impose a graft-versus-leukemia (GvL) response of sufficient breadth 
and depth to eliminate all remaining malignant cells. However, early progression or relapse may 
occur because GvL responses are nonexistent or insufficient in extent to arrest rapid growth 
kinetics of malignant cells. This unfortunate phenomenon might be a consequence of T cell 
depletion as GvHD prophylaxis or intrinsic defects in T or NK cell function or survival (eg, 
through exhaustion or apoptosis) (O'Neill and Chakraverty 2021). In addition, relapse may 
occur via immune escape mechanisms, such as downregulation of MHC-II and pro-apoptotic 
receptors including TRAIL-R1 and TRAIL-R2, which promote AML relapse via evasion of the 
allogeneic T cells. 
Maintenance treatments may be an effective strategy to provide early leukemia control and 
immunomodulatory support for the GvL effect provided by allogeneic immune responses in 
patients with high-risk AML. While some strategies focus on the enhancement of GvL, others 
aim to suppress early tumor progression before GvL is established or are designed to promote 
antitumor immunity (Burchert et al 2020). 
The hypothesis that pharmacological intervention, such as with siremadlin, in the early post-
transplant period can modulate the kinetics of disease relapse by providing early leukemia 
control and suppressing early progression before GvL is well established. 
Additionally, such intervention may provide an immunomodulatory support for the GvL effect 
and enhancement of the effect provided by allogeneic immune responses. 
Conceptually, there are a number of mechanisms by which adjunctive post-transplant therapies 
might reduce the risk of disease recurrence. Firstly, drugs with inherent anti-leukemic activity 
may simply augment the anti-tumor activity of the transplant. 
Secondly, the modulation of the kinetics of disease relapse may give the emerging allo-immune 
effect a competitive advantage, buying time for the establishment of a clinically significant GvL 
effect, prior to disease relapse. Thirdly, postponement of disease relapse can in principle permit 
delaying the administration of DLI until such time that the risk of severe GvHD is reduced. 
Finally, post-transplant pharmacological therapies may directly modify the allo-reactive 
response, potentially through up-regulation of tumor antigens or acceleration of T cell 
reconstitution (Loke et al 2020). 
SORMAIN, a placebo-controlled study of FM-like tyrosine kinase 3- internal tandem 
duplication (FLT3-ITD-targeted maintenance therapy with sorafenib with more than 4.5 years 
of median follow-up provided evidence that post-allo-SCT maintenance therapy can reduce the 
risk of relapse and death [HR for relapse or death in the sorafenib group vs placebo group was 
0.39 (95% CI, 0.18 to 0.85; log-rank P = 0.013). Of note, 63% of the patients in the sorafenib 
group were either not in hematologic CR or were not in molecular remission at the time of allo-
SCT, which is strongly predictive of poor survival. However, the relapse rate was only 15% 
after 2 years in the sorafenib arm, which appeared to be a clinically meaningful improvement 
(Burchert et al 2020). 
With Murine Double Minute-2 (MDM2) inhibition, preclinical murine data showed 
upregulation of MHC-II and the pro-apoptotic receptors TRAIL-R1/2 expression, which may 
reverse immune escape and enhance the anti-leukemia immunity post-allo-SCT 


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(Nguyen Huong Giang Ho et al, in preparation, confidential data on file) (see background 
section). 
Donor lymphocyte infusion (DLI) post-allo-SCT  
While DLI has more limited efficacy in treating relapsed post-transplant AML, prophylactic 
DLI may contribute to improving outcomes in high risk AML and may successfully prevent 
relapse after allo-SCT. DLI has been found to increase anti-leukemic T cells, but also reverses 
T cell exhaustion through increased IFN-γ production and reduced T cell inhibitory receptors, 
such as programmed cell death protein 1 (PD-1) and T cell immunoglobulin and mucin domain 
3 (Tim-3) (Liu et al 2018, Sterling and Webster 2020). 
A registry-based matched-pair analysis in adults receiving DLI in CR vs pair-matched controls 
for age, diagnosis, cytogenetics, stage, donor, gender, conditioning and T-cell depletion, 
demonstrated that among patients with high-risk AML (unfavorable cytogenetics and/or 
transplanted beyond first CR), prophylactic DLI recipients had a significantly improved 5-year 
OS [69.8% vs. 40.2% among controls; P = 0.027, HR = 0.387, 95% CI (0.116–0.898)] 
(Schmid et al 2019). 
Another retrospective analysis reported the outcomes of DLI after allo-SCT in a cohort of 46 
patients for high-risk AML (as defined by cytogenetic aberrations according to the ELN criteria 
and/or stage of the disease at transplant), compared to a matching control cohort of 34 patients 
with similar disease characteristics, selection criteria and treatment characteristics (without 
DLI). The estimated OS from transplantation among DLI recipients at 4 and 7 years were 78% 
and 67%, as compared with 34% and 31% in the control group (P <0.001). Ten patients (22%) 
have relapsed despite DLI, as compared with 53% in the control group (P = 0.004). The 6-year 
LFS was 68% after first DLI as compared with 38% in the control group (P = 0.011) 
(Jedlickova et al 2016). 
Synergism of DLI in combination with pharmacologic approaches  
The combination of DLI with novel agents is based on the assumption of synergistic antitumor 
effects without adding toxicity. Several phase II trials have demonstrated that targeted agents 
are compatible with immunosuppressive therapy, such as calcineurin inhibitors, which typically 
precludes simultaneous use of DLI. This opens a window of opportunity during the 4-6 weeks 
after allo-SCT for the administration of agents that are expected to delay leukemic cell 
outgrowth at a time when GvL effects are likely to be marginal. Furthermore, although most of 
these agents are not perfectly tolerated after allo-SCT, maintaining a therapeutically relevant 
dosage is usually possible, and toxicities are rapidly reversible on interruption 
(Schmid et al 2021). 
The combination of DLI with pharmacologic agents with immunomodulatory effects may 
enhance antitumor effects of DLI and/or reduce GvHD. Examples are hypomethylating agent 
(HMA) and histone deacetylases (HDAC) inhibitors, which increase T cell response by 
upregulated expression of epigenetically silenced tumor antigens, minor histocompatibility 
antigen, or HLA antigens on malignant cells (render malignant cells more visible for cytotoxic 
T cells). 


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Convincing data supporting the combination of DLI with a novel agent came from a 
retrospective study evaluating salvage therapy with the multikinase inhibitor sorafenib for post-
transplantation relapse of FLT3-ITD mutant AML. The subgroup of patients who received DLI 
in addition to sorafenib benefitted most and achieved a 3-year OS of 40%. Mechanistic analyses 
showed that sorafenib stimulatedInterleukin-15 (IL-15) production in the FLT3-ITD leukemic 
cells in responding patients, resulting in metabolic reprogramming and activation of leukemia-
reactive CD8 donor αꞵ T cells (Mathew et al 2018), (Burchert et al 2020). 
Furthermore, preclinical data from murine AML models showed that MDM2 inhibition 
synergized with the allogeneic immune response and increased the vulnerability of mouse and 
human AML cells to allogeneic T-cells. In leukemia-bearing mice treated with allo-SCT using 
bone marrow (BM) alone or in combination with T-cells, the addition of T-cells to the 
allogeneic BM graft improved survival. Treatment with MDM2-inhibitor in the absence of 
donor T-cells improved survival,but did not lead to long term protection. Only when T-cells 
were combined with MDM2-inhibition, > 80% of mice were protected long-term. The T-
cell/MDM2-inhibitor combination did not increase acute GVHD severity compared to T-
cells/vehicle. In addition, MDM2 inhibition promoted the cytotoxicity and longevity of the 
allogeneic donor CD8+ T cells as demonstrated by increased expression of the anti-tumor 
cytotoxicity markers (perforin, CD107a, Interferon Gamma (IFN-γ), TNF and CD69), which 
resulted in long-term control of leukemia in murine models. (Nguyen Huong Giang Ho et al, in 
preparation, confidential data on file). 
1.2 
Purpose 
This phase Ib/II study is designed to confirm a safe dose and schedule of siremadlin 
monotherapy and in combination with donor lymphocyte infusion (DLI) [according to a 
treatment strategy that consists of three consecutive phases: priming phase with siremadlin 
monotherapy, followed by combination phase of siremadlin plus DLI in participants eligible to 
receive DLI, followed by maintenance phase with siremadlin monotherapy] (for details, see 
Section 3). 
The study is also designed to assess the preliminary efficacy in preventing hematologic relapse 
in patients with AML who achieved complete remission (CR) or CR with incomplete count 
recovery (CRi) following allogeneic stem cell transplantation (allo-SCT) but are at high risk for 
relapse based on the presence of pre-transplant risk factors.  
In adults with AML who have received allo-SCT, the risk of relapse remains unacceptably high 
and is the main cause of treatment failure (~40%) and death (Thekkudan et al 2020). 
There is currently no approved effective treatment available for AML patients with relapsing 
disease after transplant, and treatment options are very limited and include best supportive care 
or palliative options, rapid withdrawal of immunosuppression, low or high-intensity 
chemotherapy followed by cellular immunotherapy, such as a second allo-SCT in selected cases 
or donor lymphocyte infusion (DLI). However, outcomes following these salvage treatments 
are generally poor and the majority of these patients eventually succumb to their disease. 
Therefore, exploring innovative treatment strategies early post allo-SCT may offer the chance 
for AML patients at high risk for relapsing disease for an improved outcome of allo-SCT as a 
potentially curable treatment. Of note, as more than 40% of relapses occur within the first 6 


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months post-allo-SCT, initiating therapy as early as possible after allo-SCT may be most 
effective (Bejanyan et al 2015). 
Thus far, there are no approved maintenance or preemptive therapies available for AML patients 
after allo-SCT, and few drugs are being used off-label and per local clinical practice guidelines 
in 
this 
setting 
in 
some 
regions 
(Heuser et al 2020, 
National Comprehensive Cancer Network (2021)). 
Patients with pre-transplant risk factors that increase the risk of AML relapse following allo-
SCT [such as adverse risk genetics at diagnosis, secondary or therapy-related AML, remission 
status of CR2 or greater at time of transplant, presence of residual leukemia prior to transplant 
(further details in Section 1.1)] represent the target population that would benefit most from 
post-transplant interventional strategies. Although the precise risk of relapsing AML post allo-
SCT is difficult to assess in this high-risk AML population, it might very well exceed 60% 
according to most recent interactions with external medical experts.  
Among AML patients with high-risk cytogenetic abnormalities treated with allo-SCT, TP53-
mutation status has a negative impact on outcomes with significantly inferior overall survival 
and event-free survival (Middeke et al 2016). 
Published reports indicate that prophylactic DLI may reduce or delay relapse in TP53 mutant 
AML patients (Gao et al 2019, Zhang et al 2021). 
In study CHDM201K12201, the eligibility will be independent of the TP53 mutational disease 
status prior to transplant. This is based on the hypothesis that siremadlin will have direct 
immunmodulatory effects on leukemic blasts (e.g., upregulation of MHC class II molecules) 
but also on lymphocyte subsets of the immune microenvironment of leukemic blasts. The TP53 
activation mediated by MDM2 inhibition promotes antitumor immunity in the tumor 
microenvironment regardless of the TP53 status of the tumor. This effect may be related to P53 
activation in TP53-non-mutated immune cells in the tumor microenvironment, even in case the 
infiltrating cancer cells harbor TP53 gene mutations (Fang et al 2019). 
Combining DLI with siremadlin may elicit immunomodulatory, potentially curative graft-
versus-leukemia (GvL) effects even against AML blasts with non-functional p53 via facilitating 
GvL-supportive immunologic reactions (activation of GvL-specific allo-reactive donor T cells 
including DLIs, or other immune cell subsets e.g., via cytokine (IL-15) release to the tumor 
microenvironment).  
Furthermore, as AML is a polyclonal disease, even in patients who had previously been 
diagnosed with TP53 gene-mutated AML clones, it remains unclear at time of transplant and 
with the clinical status of CR, whether relapsing AML would exclusively harbor TP53 gene 
mutations or, more likely, whether at least some of the relapsing clones would actually feature 
non-mutated TP53 genes and additional genetic features via clonal evolution. In such 
scenario, the proposed siremadlin/DLI treatment could possibly elicit a strong GvL response 
against TP53 gene non-mutated leukemic blasts that could be associated with a cross-over GvL 
effect even against TP53 gene-mutated leukemic blasts.  


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Taken together, this patient population at high risk to develop relapsing AML after allo-SCT, 
based on the aforementioned pre-transplant risk factors, is suitable to participate in this study 
to explore an innovative treatment strategy including early initiation of siremadlin therapy after 
transplant to prevent relapsing AML. 


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2 
Objectives, endpoints and estimands 
Table 2-1 
Objectives and related endpoints 
Objective(s) 
Endpoint(s) 
Primary objective(s) 
Endpoint(s) for primary objective(s) 
● Safety:  
 
● To determine the dose and schedule of siremadlin monotherapy that are 
tolerable without unacceptable toxicities (recommended dose for Part 2) [Part 1 - 
siremadlin monotherapy]. 
 
● To determine the dose and schedule of siremadlin in combination with DLI that 
are tolerable without unacceptable toxicities (recommended dose for combination) 
[Part 2 - siremadlin/DLI treatment strategy]. 
● Incidence of DLTs with siremadlin monotherapy in dose confirmation [Part 1] 
● Time to DLT with siremadlin/DLI in combination phase [Part 2] 
● Efficacy: 
 
● To evaluate the preliminary efficacy of study treatment strategy (siremadlin 
monotherapy, as priming and/or maintenance, with or without siremadlin in 
combination with DLI)) on prevention of hematologic relapse [Part 2 – siremadlin/DLI 
treatment strategy]. 
● Proportion of participants who are alive and maintained CR or CRi with no 
evidence of hematologic relapse over at least 6 months after start of study 
treatment strategy (siremadlin monotherapy, as priming and/or maintenance, 
with or without siremadlin in combination with DLI) [Part 2].  
Secondary objective(s) 
 To evaluate the preliminary efficacy of siremadlin monotherapy on prevention of 
hematologic relapse [Part 1 - siremadlin monotherapy at the recommended dose 
for Part 2]. 
Endpoint(s) for secondary objective(s) 
 Participants who are alive and maintained CR or CRi with no evidence of 
hematologic relapse over at least 6 months after start of siremadlin 
monotherapy [Part 1 - siremadlin monotherapy at the recommended dose 
for Part 2]. 
● To assess relapse free survival (RFS) [Part 2]. 
● Time from start of study treatment to the date of first documented 
hematologic relapse or death due to any cause, whichever occurs first 
● To assess cumulative incidence of relapse at 1 year and at 2 years after start of 
study treatment [Part 1, Part 2]. 
● Cumulative incidence of AML relapse at 1 year and at 2 years after start of 
study treatment  
● To assess overall survival (OS) [Part 2]. 
● Time from start of study treatment to the date of death from any cause.  
● To assess safety and tolerability of siremadlin monotherapy (during dose 
confirmation; priming and maintenance) and in combination with DLI [Part 1, Part 2]. 
● Incidence and severity of AEs and SAEs, changes in laboratory values and 
vital signs. 
● To assess the proportion of participants stopping study treatment due to GvHD or 
other adverse events [Part 1, Part 2]. 
● Proportion of participants with permanent discontinuation of study treatment 
due to GvHD or other adverse events. 


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Objective(s) 
Endpoint(s) 
● To assess the incidence of grade III and IV aGvHD, moderate and severe cGvHD 
[Part 1, Part 2]. 
● Incidence of treatment emergent grade III or grade IV aGvHD. 
Incidence of treatment emergent moderate to severe cGvHD. 
● To assess GvHD-free/relapse-free survival (GRFS) [Part 1, Part 2]. 
● Time from start of study treatment to the date of first documented occurrence 
or worsening of treatment emergent grade III or IV aGvHD, cGvHD requiring 
initiation of systemic immunosuppressive treatment, occurrence of disease 
relapse, or death due to any cause, whichever occurs first. 
● To characterize the PK of siremadlin in monotherapy and in combination with DLI 
[Part 1, Part 2]. 
● Pharmacokinetic parameters (e.g., AUC, Cmax, Tmax) and concentration vs 
time profiles of siremadlin in monotherapy and in combination with DLI. 


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2.1 
Primary estimands 
The estimand is the precise description of the treatment effect and reflects strategies to address 
events occurring during trial conduct which could impact the interpretation of the trial results 
(e.g premature discontinuation of treatment). 
Primary safety estimands: 
Dose confirmation siremadlin monotherapy (Part 1): 
The primary clinical question of interest is: Can siremadlin be safely administered as 
monotherapy on Days 1-5 of a 28-day cycle (at the starting dose level of 30 mg QD) to adult 
participants with AML who are in CR or CRi starting no earlier than ≥ Day 60 after allo-SCT? 
The justification for the primary safety estimand is that we wish to determine whether 
siremadlin leads to unacceptable level of toxicity [Dose Limiting Toxicity (DLT)] when 
administered as monotherapy in Part 1 and determine the siremadlin recommended dose (RD) 
for Part 2 as monotherapy. 
The primary estimand of safety for dose confirmation is described by the following attributes: 
1. Population: Adult participants with AML who are in CR/CRi after allo-SCT and meet 
eligibility as defined by the inclusion/exclusion criteria. 
2. Primary variable: DLT between first dose of siremadlin until end of Cycle 1. Any DLT from 
participants who initiated siremadlin during Cycle 1 will be considered. 
3. Treatment of interest: Siremadlin monotherapy. 
4. Handling of remaining intercurrent events: 
 Dose modifications, dose interruptions or discontinuations due to reasons other than 
DLT leading to less than minimum exposure: such participants will be considered non-
evaluable. (Section 6.6 and Section 12.1) 
 Withdrawal from study before completion of cycle 1 with no DLT prior to completing 
sufficient scheduled safety assessments: such participants will be considered non-
evaluable. 
5. The summary measure: incidence of DLTs. 
Combination phase: 
The primary clinical question of interest is: Following the priming phase with at least 2 cycles 
of siremadlin monotherapy at the RD for Part 2, can siremadlin be safely administered to adult 
participants with AML at the tolerated dose from the last priming cycle in combination with 
DLI? 
The justification for the primary safety estimand of combination phase is that we wish to 
determine whether siremadlin in combination with DLI leads to an unacceptable level of 
toxicity (DLT) when administered after priming phase and determine the siremadlin maximum 
recommended dose (RD) for combination considering the time to first DLT, dose and schedule. 
The primary estimand of safety for combination phase is described by the following attributes: 


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1. Population: Adult participants with AML who completed at least 2 cycles of priming phase 
and meet combination phase eligibility to receive DLI as defined in Section 6.1.4. 
2. Primary variable: 
Time-to-DLT, defined as time from start of combination phase to first DLT observed during 
the entire combination phase. 
3. Treatment of interest: Siremadlin, at the dose tolerated in the last cycle of priming phase, in 
combination with DLI (Section 6.1, Section 6.3.2). 
4. Handling of remaining intercurrent events: 
 Dose modifications, dose interruptions or discontinuations due to reasons other than 
DLT leading to less than minimum exposure (details in Section 6.6):  
 Participants who do not satisfy at least one cycle of minimum exposure and do not 
experience a DLT will be considered non-evaluable. 
 Participants who satisfy at least one cycle of minimum exposure will be censored 
at the last safety assessment at the end of the last cycle where minimum exposure 
to study treatment was satisfied. E.g., for a participant who received 2 cycles of 
combination therapy without any DLT and only met the minimum exposure for the 
first cycle, this participant will be censored at the end of the first cycle. 
 Death (not caused by study treatment) or withdrawal from study without experiencing 
DLT: participants will be censored at the last safety assessment at the end of the last 
cycle preceding death or withdrawal from study (while-on-treatment). 
5. The summary measure: probability of DLT 
Based on safety/tolerability outcomes of siremadlin/DLI combination, the study may identify a 
siremadlin maximum RD for combination. 
Primary efficacy estimand: 
The primary clinical question of interest is: Does siremadlin given in a treatment strategy 
consisting of priming, combination and maintenance therapy have activity in preventing 
hematologic relapse or death (i.e., maintenance of CR/CRi) in adult participants with AML who 
are in CR/CRi after allo-SCT irrespective of treatment discontinuation? 
The justification for the primary efficacy estimand is that we wish to estimate the effect of the 
study treatment and to assess it in the context of published data (included in the dual-criterion 
for efficacy assessment; more details in Section 12.8.1) of the same patient population treated 
with Best Available Therapy (BAT), in preventing early relapse of AML post-allo-SCT. The 
activity of siremadlin is assessed based on the absence of hematologic relapse (maintenance of 
CR/CRi), which is the most clinically meaningful endpoint in this post-transplant setting (CRi 
is also acceptable as complete hematologic recovery may be delayed early post-transplant 
(Dominietto et al 2001)). Patients requiring new antineoplastic therapy (including a second 
allo-SCT) before completing 6 months after start of study treatment are considered as failure to 
study treatment. Similarly, withdrawing consent before completing 6 months after start of study 
treatment could also be attributed to effects of the study treatment and are considered as failure. 
Discontinuation of study treatment due to other criteria or dose modification might not preclude 
maintenance of CR/CRi. Medical care of this life-threatening condition is provided also in the 


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context of a pandemic. The primary estimand will therefore assess the treatment effect 
regardless of any impact by a pandemic. 
The primary estimand of efficacy is described by the following attributes: 
1. Population: Adult participants with AML who are in CR/CRi after allo-SCT and meet 
priming phase eligibility as described in the inclusion/exclusion criteria who initiated 
priming phase at siremadlin RD for Part 2. 
2. Primary variable: CR/CRi per investigator assessment after completing 6 months from start 
of study treatment. Participants who die, relapse, start new antineoplastic therapy or 
withdrawal of consent prior to completing 6 months after start of study treatment will be 
considered as non-responders. (Döhner et al 2017,Cheson et al 2003). 
3. Treatment of interest: Siremadlin starting as priming monotherapy for at least 2 cycles, 
followed by combination of siremadlin with DLI for eligible participants, and then 
siremadlin monotherapy for maintenance. 
4. Handling of remaining intercurrent events: 
 Dose modification or treatment discontinuation due to any reason: All assessments will be 
taken into account regardless of any treatment interruption, dose adjustment or permanent 
discontinuation (treatment policy strategy). 
 Any Public Health emergency as declared by Local or Regional authorities i.e., pandemic, 
epidemic or natural disaster: All assessments will be taken into account regardless of any 
disruptions resulting from public health emergencies (refer to Section 4.6) (treatment policy 
strategy) 
5. The summary measure: Proportion of participants who maintained CR or CRi after at least 
6 months from start of study treatment and its 95% confidence interval. 
2.2 
Secondary estimands 
Not applicable. 
3 
Study design 
This is a Phase Ib/II, single arm, open label, multi-center study of siremadlin as monotherapy 
and in combination with Donor Lymphocytes Infusion (DLI), in adult participants with AML 
who are in complete remission (CR) or CR with incomplete count recovery (CRi) post allo-
SCT but are at high risk for relapse based on the presence of pre-transplant risk factors (as 
specified in Inclusion Criteria Section 5.1). 
The study will enroll approximately 38 participants and will start with the dose confirmation of 
siremadlin monotherapy (Part 1) followed by a treatment strategy with siremadlin/DLI (Part 2) 
(Figure 3-1): 
 Part 1- Dose confirmation siremadlin monotherapy: using siremadlin as a single agent, 
to explore a maximal of 3 dose levels (starting dose 30 mg/day on days 1-5 of a 28-day 
treatment cycle, dose level +1 at 40 mg/day and dose level -1 at 20 mg/day). It is assumed 
that approximately 12 participants will be enrolled in 2 cohorts to obtain at least 3 evaluable 
participants in each cohort. Based on the observed DLT rate, overall safety, tolerability, 
available PK (and preliminary efficacy) data generated, the participating investigators and 


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Novartis Team will make decisions regarding the siremadlin dose to be given to participants 
in the next cohort(s), as guided by a Bayesian Logistic Regression model (BLRM). A 
minimum of 6 evaluable participants are required to confirm the siremadlin monotherapy 
dose level that will be declared as the recommended dose for Part 2.  
 For each dose level, once the required number of evaluable participants has been confirmed, 
enrollment will be held until participants have completed the DLT observation period of 
one treatment cycle. Nevertheless, each participant will continue treatment at his/her 
tolerated siremadlin dose. 
 DLI in combination with siremadlin will not be permitted on study for participants in dose 
confirmation Part 1. Each participant treated in these dose confirmation cohorts (Part 1) will 
continue with siremadlin monotherapy for the entire duration of treatment (up to a 
maximum of 24 cycles).  
Once the recommended siremadlin dose is determined in Part 1, enrollment in Part 2 will start 
after obtaining Health Authority’s approval as applicable. Enrollment in Part 2 will not be 
applicable to the participating sites in the United States and Germany. 
 Part 2 - Treatment strategy (siremadlin/DLI): will enroll approximately 26 participants and 
will not start until the recommended dose for Part 2 is confirmed. Participants enrolled in 
Part 2 will follow a treatment strategy, which contains siremadlin monotherapy (priming 
phase), potentially followed by siremadlin in combination with DLI then maintenance with 
siremadlin monotherapy (as shown in Figure 3-1): 
 A priming phase with siremadlin monotherapy. Participants will be administered 
siremadlin orally on Days 1-5 of a 28-day cycle (for at least 2 cycles). Participants who 
are not eligible for the combination phase of siremadlin/DLI may continue priming 
phase with siremadlin monotherapy for up to a maximum of 24 cycles. 
 A combination phase of siremadlin in combination with DLI (siremadlin/DLI) for 
participants who are eligible to receive DLI (up to a total of 3 combination cycles). 
Criteria to start DLI/siremadlin combination phase are detailed in Section 6.1.4. 
Participants will be administered siremadlin orally on Days 1-5, at the dose that was 
received and tolerated in the last cycle of priming phase, in combination with DLI on 
Day 3 of every 42-day (6-week) cycle (see Section 6.3.2 for details of DLI starting dose 
and ramp-up dosing instructions). 
 A maintenance phase with siremadlin monotherapy. After completion of 
siremadlin/DLI combination phase, participants may enter maintenance phase with 
siremadlin monotherapy orally on Days 1-5 of a 28-day cycle starting at the dose that 
was tolerated in the last cycle in combination phase (refer to Section 6.1.4 for eligibility 
for maintenance phase). 
Intraparticipant dose escalation is not allowed in the trial: each participant will keep his/her 
allocated siremadlin dose throughout the treatment phases, provided it is well tolerated by the 
participant (dose modifications are allowed in case of toxicity, see Section 6.6.4).  
Study treatment will be administered for up to a maximum of 24 cycles in Part 2 (including 
priming phase, with or without combination phase, and maintenance phase) or until a participant 
experiences hematologic relapse, unacceptable toxicity, or withdrawal of consent, whichever is 
earlier. 


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Figure 3-1 
Study design 
 
* Criteria to proceed with siremadlin dose increase or decrease or Go/No Go for the next Cohort (s): 
based on incidence of DLTs during the first cycle of study treatment in Cohort 1.  
** Go criteria to start treatment in Part 2 at the recommended dose (RD) for Part 2 determined based 
on incidence of DLTs during the first cycle of study treatment in Cohort 2, after obtaining Health 
Authority’s approval as applicable. Enrollment in Part 2 will not be applicable to the participating sites 
in the United States and Germany. 
*** The decision of DLI administration will be at the discretion of the treating investigator per standard 
of practice/institutional guidelines; however, participant must fulfill the combination phase eligibility 
criteria after completion of at least 2 cycles of priming.Safety, tolerability, available PK (if applicable) 
outcomes of siremadlin in combination with DLI will be analyzed in all participants (refer to 
Section 6.6.2 for evaluability criteria) when they complete at least the first cycle in combination phase. 
A Time-to-(first) DLT approach will be used to continuously assess the safety of the combination in 
individual participants and decide the maximum dose of siremadlin for combination phase. Afterwards 
participant entering the combination phase must be treated at a siremadlin dose not exceeding the 
maximum dose for combination. The maximum recommended dose for siremadlin/DLI combination will 
be declared after all evaluable participants have completed combination phase, and requires a 
minimum of 9 evaluable participants. Enrollment will not be held for safety assessment of the 
combination phase. 
Safety and tolerability data from all participants in combination phase will continue to be 
monitored on an ongoing basis following the same approach. (refer to Section 6.6.2 for details) 
Study Flow 
The study flow consists of 3 periods (see Figure 3-2): Pre-treatment (Screening), treatment and 
follow-up. 
Participants will undergo assessments during screening and periodically during treatment and 
follow-up as outlined in Table 8-1 and Table 8-2. 


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An end of treatment (EOT) visit will be performed when participants permanently discontinue 
study treatment. Participants will then enter safety/post-treatment follow-up (PTFU) as shown 
in Figure 3-2 (also see Section 9.1.1.1 and Section 9.1.1.2). 
All participants will be followed for survival as per Section 9.1.1.3. 
Figure 3-2 
Study Flow 
 
4 
Rationale 
4.1 
Rationale for study design 
Rationale for the proposed treatment strategy 
The curative effect of allo-SCT is dependent on the development of a robust GvL response of 
sufficient breadth and depth to eliminate all remaining malignant cells. However, the GvL 
response develops relatively slowly due to time necessary for engraftment and immune 
reconstitution post-transplant. In addition, mandatory, transient administration of IST required 
to suppress GvHD, also reduces the GvL effect. 
Unfortunately, up to 40% of all relapses will occur within the first 6 months post-allo-SCT 
(Bejanyan et al 2015). Therefore, early treatments that support establishing GvL effects 
potentially through up-regulation of tumor antigens or acceleration of T cell reconstitution may 
be especially beneficial to post allo SCT patients (Loke et al 2020). 
SORMAIN, a placebo-controlled study of FLT3-ITD-targeted therapy with sorafenib (N = 83) 
provided evidence that post-allo-SCT maintenance therapy can reduce the risk of relapse and 
death [HR for relapse or death in the sorafenib group vs placebo group was 0.39 (95% CI, 0.18 
to 0.85; log-rank p = 0.013). Of note, 63% of the patients in the sorafenib group were either not 
in hematologic CR or not in molecular remission at time of allo-SCT, which was strongly 
predictive of poor survival. However, the relapse rate was only 15% after 2 years in the 
sorafenib arm, which appeared to be a clinically meaningful improvement (Burchert et al 2020). 
With MDM2 inhibition, preclinical murine and human data showed upregulation of p53 
expression in which is associated with upregulation in TP53 non-mutated leukemic cells of 
MHC-II and the pro-apoptotic receptors TRAIL-R1/2, which may reverse immune escape and 
enhance the anti-leukemia immunity post-allo-SCT (Nguyen Huong Giang Ho et al, in 


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preparation, confidential data on file). Therefore, these findings strongly support the use of 
siremadlin post-allo-SCT. 
DLI is a treatment option with potential to enhance the GvL response and may contribute to 
improving outcomes and successfully prevent relapse after allo-SCT. However, DLI cannot be 
administered until 4-6 months post-allo-SCT due to the requirement to discontinue IST at least 
4 weeks prior and to have any GvHD resolved. Therefore, preventing early disease relapse with 
the early use of siremadlin monotherapy priming can, in principle, allows a larger proportion of 
patients to receive subsequent siremadlin/DLI combination therapy. 
Further, studies of DLI in AML have suggested that optimal use may require combination 
therapy that would further enhance the GvL effect, based on the assumption of synergistic 
antitumor effects without adding toxicity. Convincing data supporting the combination of DLI 
with a novel agent came from a retrospective study evaluating salvage therapy with the 
multikinase inhibitor sorafenib for post-transplant relapse of FLT3-ITD mutant AML. The 
subgroup of patients who received DLI in addition to sorafenib benefitted most and achieved a 
3-year OS of 40%. Mechanistic analyses showed that sorafenib stimulated IL-15 production in 
the FLT3-ITD leukemic cells in responding patients, resulting in metabolic reprogramming and 
activation of leukemia-reactive CD8 donor αꞵ T cells (Mathew et al 2018). 
The combination treatment of siremadlin plus DLI is strongly supported by preclinical data 
showing that MDM2 inhibition synergizes with the allogeneic immune response and increases 
the vulnerability of mouse and human AML cells to allogeneic T-cells (See further details in 
Section 4.3) (Nguyen Huong Giang Ho et al, in preparation, confidential data on file). 
DLI are routinely administered over multiple cycles scheduled at 4 to 8 week intervals, guided 
by the occurrence of GvHD as limiting toxicity. Repetitive DLI might increase the chance to 
reverse T-cell exhaustion, hence justifying multiple DLI administrations in the setting of 
complete remission (Schmid et al 2021). In the prophylactic setting, due to increasing risk of 
GvHD with each DLI infusion, treatment is often limited to 3 or 4 cycles. However, AML may 
relapse up to 4 years post-allo-SCT, with the majority of relapses occurring during the first 2 
years. These findings suggest that a treatment post-DLI might be necessary to ensure 
maintenance of the augmented GvL effect and subsequent suppression or clearance of residual 
leukemic cells for a prolonged period to prevent late-onset relapsing disease. 
Taken together, a 3-part treatment strategy in study CHDM201K12201 in Part 2 is proposed, 
consisting of an early upfront priming with siremadlin monotherapy (at least 2 cycles), followed 
by a siremadlin combination with DLI (up to 3 cycles), followed by siremadlin maintenance 
monotherapy (for up to 24 cycles, all siremadlin treatment cycles included) in order to allow 
for an optimal and lasting treatment success in preventing early relapses and enhancing GvL 
post-allo-SCT in high-risk AML patients. 
4.2 
Rationale for dose/regimen and duration of treatment 
Rationale for dose/regimen of siremadlin 
The starting dose level for siremadlin for participants enrolled in this trial is set at 30 mg p.o. 
administered once daily on Days 1-5 of each cycle (one cycle = 28 days for siremadlin 
monotherapy, one cycle = 42 days for siremadlin/DLI combination). The selection of the 


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starting dose level and the treatment regimen for siremadlin monotherapy in the dose 
confirmation (Part 1) is based on currently available preclinical and clinical safety, efficacy, PK 
and PKPD modeling information from the single agent first-in-human clinical trial 
[CHDM201X2101].  
In Study CHDM201K12201, the proposed mechanism of action is primarily dependent on 
immunomodulation and enhancement of the graft-versus-leukemia (GvL) effect. These 
immunomodulatory effects are hypothesized to occur at a lower dose of siremadlin as compared 
to the recommended dose for treatment of R/R (Relapsed Refractory) AML. Therefore, the 
proposed siremadlin dose levels in Study CHDM201K12201 (30 mg as a starting dose daily on 
days 1-5 of a 28-day cycle, dose level -1 at 20 mg daily, and dose level +1 at 40 mg daily) are 
lower, in terms of cumulative dose and maximum concentration, than the recommended dose 
for expansion established in patients with R/R AML in the first-in-human Study 
CHDM201X2101 (i.e., low-dose 2C at 45 mg daily on days 1-7). 
The starting dose level of siremadlin of 30 mg in Part 1 is considered safe by a BLRM utilizing 
historical data from prior studies on siremadlin (refer to Section 16.6 for details). 
In regards to the combination phase, siremadlin will be administered at 42-day interval between 
combination cycles (as opposed to 28-day interval between monotherapy cycles). The longer 
interval between DLIs is to evaluate for development of GvHD before the subsequent 
administration of DLI. Furthermore, the DLI starting dose, ramp up dosing and total number of 
DLI doses are strategies designed to minimize/prevent the risk of GvHD. 
Study CHDM201X2101: Stein et al 2021 (ASH abstract) Subset analysis of 19 patients 
treated with siremadlin monotherapy for relapsed refractory AML after prior allo-SCT. 
Among 91 patients with relapsed refractory (R/R) AML treated with siremadlin monotherapy 
in this first-in-human Study CHDM201X2101 (X2101) (NCT02143635), an exploratory post-
hoc analysis of safety and preliminary efficacy was conducted on a subset of patients (n=19) 
who had undergone allo-SCT before study entry, and who have relapsed AML after allo-SCT 
and were subsequently treated with siremadlin monotherapy. 
Eligible patients were ≥ 18 years with wild-type TP53 AML that have failed prior 
therapies. Siremadlin was administered to the 19 patients PO according to 4 different treatment 
regimens:  
 1A, 250 mg or 350 mg or 400 mg on day 1 of a 3-week cycle (n= 6)  
 1B, 120 mg or 150 mg on days 1 and 8 of a 4-week cycle (n= 4)  
 2A, 20 mg or 30 mg daily for the first 2 weeks of a 4-week cycle (n= 2)  
 2C, 45 mg daily for the first week of a 4-week cycle (n= 7) 
Grading of adverse events was per Common Terminology Criteria for Adverse Events 
(CTCAE) version 4.03. Response evaluation was per investigator’s assessment based on the 
International Working Group for AML (Cheson et al 2003).  
Demographics and baseline characteristics are summarized as follows: 19 patients with R/R 
AML after ≥1 allo-SCT had received siremadlin as salvage therapy for active disease 
[median leukemic blast at baseline from 18 out of 19 patients was 32% (range, 5%-94%)]. 
There were 10 (52.6%) male and 9 (47.4%) female patients. The median age was 64 years 


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(range: 30-72), 10 (52.6%) patients were <65 years and 9 (47.4%) patients were ≥65 years. The 
majority of patients was Caucasian (94.7%). Sixteen (84.2%) patients had an Eastern 
Cooperative Oncology Group (ECOG) performance status 0-1, and 3 (15.8%) patients had 
ECOG 2. Thirteen (68.4%) patients had received 1 prior allo-SCT, 5 (26.3%) had received 2 
prior allo-SCTs, and 1 (5.3%) had received 3 prior allo-SCTs. The median interval from most 
recent allo-SCT to start of siremadlin was 308 days (range, 119-1105); with 3 (15.8%) patients 
within ≤180 days, 7 (36.8%) >180 to ≤ 365 days, and 9 (47.4%) >365 days post last allo-SCT. 
The median number of prior lines of antineoplastic therapy between most recent allo-SCT and 
study entry was 1 (range, 0-3), consisting of 4 (21%) patients who received no prior lines of 
therapy and 15 (79%) who received hypomethylating agent (azacitidine or decitabine) +/- 
chemotherapy and +/- donor lymphocyte infusion in 3 participants. 
The median duration of exposure to siremadlin was 60 days (range, 21-203). The median dose 
intensity was 52.5 mg/day (range, 13.4-200) and the median cumulative dose was 630 mg 
(range, 250-1710). 
In regards to safety, 16 (84.2%) and 14 (73.7%) patients experienced grade ≥3 AEs and 
treatment-related AEs, respectively; 14 (73.7%) and 12 (63.2%) patients experienced serious 
AEs (SAEs) and treatment-related SAEs, respectively. Nine patients had AEs leading 
to siremadlin dose adjustment or interruption, and 1 patient had an AE leading to treatment 
discontinuation (fungal sinusitis, grade 3, SAE, occurred on Study Day 155 and resolved on 
Study Day 189 (duration 35 days), was not suspected to be related to siremadlin). The most 
common grade 3/4 non-hematological AEs were febrile neutropenia (n=11, 57.9%), 
hypokalemia (n=5, 26.3%), and tumor lysis syndrome (n=3, 15.8%). Of these, n=5 (26.3%) 
febrile neutropenia, and n=3 (15.8%) tumor lysis syndrome were suspected to be related to 
treatment. The most common grade 3/4 hematological AEs were anemia (n=8, 57.9%), 
thrombocytopenia (n=7, 36.8%), neutropenia (n=6, 31.6%) and leukopenia (n=4, 21.1%). Of 
these, n=6 (31.6%) thrombocytopenia; n=6 (31.6%) neutropenia; n=5 (26.3%) anemia; and n=4 
(21.1%) leukopenia, were suspected to be related to treatment. 
Graft vs host disease (GvHD) was observed in 4 participants (21.1%): grade 3, n=2 (10.5%); 
grade 2 and grade 1, each n=1 (5.3%). The shortest time interval from most recent allo-SCT to 
study treatment in these 4 patients was 302 days (grade 3 GvHD was reported in this patient). 
Three of these 4 participants had a history of GvHD prior to commencement of siremadlin. 
Siremadlin was continued safely at full dose (n=3) or dose-reduced (n=1) in all four 
participants. For 1 participant treated with 400 mg in Reg 1A, chronic GvHD was declared a 
dose-limiting toxicity. Of note, some of these GvHD were reported as “suspected” or “possible” 
reactivation per the investigator's verbatim terms without confirmation of GvHD diagnosis. 
Eleven patients were included in the dose determining set, and 3 (27.3%) patients had at least 
one event that was a dose limiting toxicity, including the aforementioned chronic GvHD. On-
treatment deaths (occurring up to 30 days after end of treatment) were reported in 4 patients (2 
AML-related, 1 euthanasia and 1 due to neutropenic infection). Overall, the safety profile was 
consistent with what was observed in the overall X2101 study population of hematologic 
malignancies (n=93) including n=91 R/R AML patients.  
In regards to efficacy, among 19 evaluable patients, 3 achieved a clinical response: 2 achieved 
complete remission (CR) and 1 CR with incomplete hematologic recovery (CRi), lasting 171, 


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41, and 134 days, respectively. The overall response rate (CR or CRi or partial response) was 
3/19 (15.8%) (95% confidence interval [3.4; 39.6]). 
In conclusion, the safety of siremadlin monotherapy in patients with relapsed AML following 
prior allo-SCT(s) appears to be consistent with that previously defined in R/R AML  
(Stein et al 2022). No excessive GvHD was reported and siremadlin could be continued safely 
at full or reduced dose. Preliminary efficacy data indicate anti-leukemic activity of single-agent 
siremadlin. Despite the limitation of this post-hoc analysis, these results support further 
exploration 
of siremadlin immuno-modulatory 
effects 
post-allo-SCT 
as 
a 
potential 
maintenance or preemptive treatment in AML patients with high risk of relapse to enhance the 
allogeneic graft vs leukemia, an important and potent therapy against AML relapse.  
Rationale for duration of study treatment 
Although the optimal duration of maintenance therapy post-allo-SCT remains to be determined, 
it should theoretically ensure maintenance of augmented GvL (derived from the allo-grafted 
donor immune cells as well as from the administered DLI) and suppression of residual leukemic 
cell growth for a prolonged period during the time post-allo-SCT with the highest risk for 
relapse. 
The proposed duration of 24 cycles (in total including siremadlin monotherapy and 
siremadlin/DLI combination) is supported by the reported time to relapse post-allo-SCT with 
the majority occurring within the first 2 years (in 1788 patients with AML who relapsed post-
allo-SCT: median time to relapse was 7 months with 43% occurring within <6 months, 39% 
between 6 months-2 years, and 18% beyond 2 years post-allo-SCT) (Bejanyan et al 2015). 
4.3 
Rationale for choice of combination drugs (siremadlin with donor 
lymphocyte infusion) 
While DLI has limited efficacy in treating relapsed AML post-allo-SCT, prophylactic DLI may 
contribute to improving outcomes in high risk AML and may successfully prevent relapse after 
allo-SCT. DLI has been found to increase anti-leukemic T cells, but also reverses T cell 
exhaustion through increased IFN-γ production and reduced T cell inhibitory receptors, such as 
programmed cell death protein 1 (PD-1) and T cell immunoglobulin and mucin domain 3  
(Tim-3) (Sterling and Webster 2020, Liu et al 2018). 
Further, prophylactic DLI recipients had a significantly improved 5-year OS [69.8% vs. 40.2% 
among controls; P = 0.027, HR = 0.387, 95% CI (0.116–0.898)] (Schmid et al 2019). 
DLI is almost exclusively considered after discontinuation of immunosuppression for > 30 days 
and is not recommended with active GvHD and infections. GvHD is the main complication of 
DLI. The reported median interval from allo-SCT to first DLI was 4-6 months. In dose-
escalating DLI administration protocols, 0.5-1 log increase and 4-6 week intervals are regarded 
as safe. Frequencies of DLI are typically guided by the occurrence of GvHD as limiting toxicity. 
In the prophylactic setting, and in the absence of GvHD, repeated DLI up to a total of 3 or 4 
applications have been given. Repetitive DLI might increase the chance to reverse T-cell 
exhaustion, hence justifying multiple DLI administrations of DLI in the setting of complete 
remission of disease (Schmid et al 2021). 


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Based on published data/reports in prophylactic/maintenance setting post-allo-SCT, the low 
DLI starting dose [starting DLI dose ranging between 1 x 105 and 5 x 106 CD3+ T cells/kg 
depending on the donor type], ramp-up dosing, frequency and total number of DLIs [repeated 
infusions every 4-8 weeks with increase in CD3+ dose by 0.5-1 log at each infusion, up to a 
total of 3-4 applications] are strategies to minimize the risk of GvHD associated with DLI 
(Schmid et al 2021, 
Craddock et al 2021, 
Guillaume et al 2019, 
Caldemeyer et al 2017, 
Horn et al 2015).  
For this study, the decision about DLI administration in eligible participants (Part 2) will be at 
the discretion of the treating investigator per the standard of practice/institutional 
guidelines.Based on the aforementioned rationale and published reports, the recommended 
starting DLI dose, for participants enrolled in this trial, is set at 2 × 105 CD3+ cells/kg for 
matched sibling/family donor (MFD), and at 1 × 105 CD3+ cells/kg 8/8 HLA-matched 
unrelated donor (MUD) to be administered on Day 3 of siremadlin. For subsequent DLI 
administrations, the CD3+ cell dose will be increased by 0.5 log increment with each infusion 
as compared to the prior DLI. The frequency of DLI infusion is recommended every 42 days, 
up to a total of 3 DLIs. 
Rationale for combination of DLI with siremadlin  
Refer to Background (Section 1.1) "Synergism of DLI in combination with pharmacologic 
approaches" for further details. 
The combination of DLI with pharmacologic agents with immunomodulatory effects may 
enhance antitumor effects of DLI (GvL effect). Several phase I/II single-arm trials and 
retrospective studies have shown the feasibility of combining DLI and pharmacologic therapies, 
providing circumstantial evidence for DLI-based combinations (Schmid et al 2021). 
Preclinical data from murine AML models showed that MDM2 inhibition synergized with the 
allogeneic immune response and increased the vulnerability of mouse and human AML cells to 
allogeneic T-cells. In leukemia-bearing mice treated with allo-SCT using bone marrow (BM) 
alone or in combination with T-cells, the addition of T-cells to the allogeneic BM graft 
improved survival. Treatment with MDM2-inhibitor in the absence of donor T-cells improved 
survival, but did not lead to long term protection. Only when T-cells were combined with 
MDM2-inhibition, > 80% of mice were protected long-term. The T-cell/MDM2-inhibitor 
combination did not increase acute GVHD severity compared to T-cells/vehicle. In addition, 
MDM2 inhibition promoted the cytotoxicity and longevity of the allogeneic donor CD8+ T 
cells as demonstrated by increased expression of the anti-tumor cytotoxicity markers (perforin, 
CD107a, IFN-γ, TNF and CD69), which resulted in long-term control of leukemia in murine 
models (Nguyen Huong Giang Ho et al, in preparation, confidential data on file). 
In this study, the potential risks of siremadlin in combination with DLI, GvHD in particular, 
will be minimized by the stated criteria (see Section 6.1.4 ) that must be met before 
siremadlin/DLI combination therapy can be initiated. Among these criteria, tolerability of 
siremadlin, defined as the absence of any toxicity requiring siremadlin dose modification in the 
last cycle of priming therapy, is required. In the combination phase, siremadlin will be 
administered at the dose that was received and tolerated in the last cycle of priming phase (i.e., 
equivalent to the siremadlin starting dose level for priming or lower as per individual 


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adjustment) at 42-day interval between combination cycles (as opposed to 28-day interval 
between priming/monotherapy cycles). Hence, exposure to siremadlin is lower in the 
combination phase with DLI as compared to the priming phase due to the expanded cycle 
length. 
The decision about DLI administration in eligible participants will be at the discretion of the 
treating investigator per the standard of practice. Recommendations for DLI starting dose, ramp 
up dosing and total number of DLI doses are specified in Section 6.3.1. For subsequent 
siremadlin/DLI cycle(s), absence of GvHD after the first siremadlin/ DLI combination cycle is 
required, as well as tolerability of siremadlin during the prior cycle (see Section 6.3.1 for 
details). 
Taken together, the outlined dose and schedule for the siremadlin/DLI combination treatment 
as well as the defined criteria are appropriate measures for mitigation and minimization of the 
GvHD risk that is potentially associated with this combination treatment.  
4.4 
Purpose and timing of interim analyses/design adaptations 
Not applicable. 
4.5 
Risks and benefits 
The most common reported toxicities of siremadlin are hematological (neutropenia, 
thrombocytopenia, anemia) and gastrointestinal (nausea, vomiting, diarrhea).  
Preclinical hERG study results suggest no potential clinical risk of QT prolongation; 
nevertheless, in context of limited clinical data, ECG monitoring is implemented in this study. 
The risk to participants in this trial may be minimized by compliance with the eligibility criteria 
(e.g., well-defined thresholds of blood counts at study entry), and study procedures, as well as 
close clinical monitoring. Further, specific dose-limiting toxicity definitions, specific dose 
modification/interruption/discontinuation rules, prophylactic or supportive management of 
study-drug induced adverse events are included and must be applied as outlined in the protocol 
based on clinical and/or laboratory findings (Section 6.6). 
Potential risk of GvHD exacerbation:  
Immunomodulatory agents may represent effective maintenance or preemptive interventions 
aiming at enhancing GvL effect of the allogeneic graft, and potentially restoring/improving 
immune surveillance and destruction of malignant cells by allo-reactive donor T cells, hence 
preventing or delaying hematological relapse post-allo-SCT. However, enhancing GvL effect 
of the allogeneic graft may be associated with increased risk or worsening of GvHD, an 
immune-mediated toxicity and a major cause of non-relapse mortality after allo-SCT. 
Therefore, siremadlin-mediated enhancement of GvL could potentially exacerbate acute and/or 
chronic GvHD. In addition, GvHD is the main limiting toxicity associated with DLI with 
increasing risk with each DLI infusion. 
Clinically significant acute and chronic GvHD following allo-SCT, contributing to post-allo-
SCT morbidity and mortality, occur with reported incidence rates range from 9% to 50% for 
acute GvHD and from 30% to 70% for chronic GvHD (Flowers et al 2002, 


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Lee and Flowers 2008, 
Flowers et al 2011, 
Jagasia et al 2012, 
Flowers and Martin 2015, 
Vaughn et al 2015). 
The incidence of GvHD varies based on several factors, including but not limited to degree of 
human leukocyte antigen (HLA) matching between the donor and recipient, graft source, 
conditioning regimen, and GvHD prophylaxis. 
Although GvHD remains a serious and common complication of allo-SCT, a shift in maximal 
grade of acute GvHD and a decrease in the proportion of grade III-IV disease over time have 
been reported in a retrospective analysis of data from the CIBMTR registry on 2905 participants 
who developed grade II-IV acute GvHD following allo-SCT for hematological malignancies 
(56% AML) between 1999 and 2012 [grade III-IV GvHD 56%, 47%, and 37% for 1999-2001, 
2002-2005, and 2006-2012, respectively]. The analysis also demonstrated a significant 
improvement in overall survival and treatment-related mortality overtime with a decline in 
deaths from organ failure and infection (Khoury et al 2017). 
Notably, analysis of the impact of chronic GvHD and its severity indicates a close relationship 
between chronic GvHD and the immune-mediated GvL effect; as demonstrated with a lower 
risk of relapse translating into improved DFS with mild or moderate chronic GvHD compared 
to no chronic GvHD ( Mo et al 2015). 
As the safety of siremadlin has not been assessed previously in the post-allo-SCT setting, the 
protocol stipulates starting with 3-6 participants to obtain 3 evaluable participants for DLT 
assessment of siremadlin monotherapy with observation for at least one treatment cycle 
followed by a Safety Review Meeting, before opening enrollment to further participants. 
Further, participants will be evaluated for DLT during the siremadlin/DLI combination phase, 
as well as assessment of adverse events and further safety information during the maintenance 
phase with siremadlin monotherapy, as a part of standard safety monitoring. 
Furthermore, the potential risks associated with siremadlin monotherapy and/or siremadlin/DLI 
combination, GvHD in particular, will be minimized by establishing criteria that must be met 
before start of priming phase, before combination therapy can be initiated, and before entering 
maintenance phase, as well as specifying the DLI starting dose, ramp up dosing, frequency and 
total number of DLI doses. 
In addition, detailed guidance for study treatment modification (dose interruption, resumption 
and discontinuation) due to GvHD is included (Section 6.6). 
Risk to the fetus:  
Women of child-bearing potential and sexually active males must be informed that taking the 
study treatment may involve unknown risks to the fetus if pregnancy were to occur during the 
study, and agree that in order to participate in the study they must adhere to the contraception 
requirements outlined in the exclusion criteria. If there is any question that the participant will 
not reliably comply, they should not be entered or continue in the study. 
SARS-CoV-2 and COVID-19 pandemic:  
No substantial additional risk for participants' safety due to the severe acute respiratory 
syndrome coronavirus 2 (SARS-CoV-2) virus and the coronavirus disease 19 (COVID-19) 


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pandemic is anticipated and the benefit- risk remains unchanged. In case of active COVID-19 
infection, a careful benefit-risk evaluation to be performed to determine whether participants 
can remain on study medication or not. 
Unmet medical need:  
Allo-SCT is a potentially curative treatment for AML, and the number of patients with AML 
eligible for allo-SCT has been increasing due to increased availability of donors (ie, 
haploidentical), development of less toxic (reduced intensity) conditioning regimens, and better 
management of GvHD, the principal toxicity associated with allo-SCT. 
Unfortunately, up to 40% of patients with AML ultimately experience leukemic relapse, which 
is the main cause of treatment failure following transplantation (Thekkudan et al 2020) and the 
most common cause of death post-allo-SCT within the first 100 days (27%) and after day 100 
(61%) (D'Souza et al 2020). 
Furthermore, up to 40% of all relapses will occur within the first 6 months post-allo-SCT, likely 
due to a relatively slow development of a robust GvL response required to control the growth 
of residual leukemic cells. Such relapses are concentrated in a subpopulation of patients with 
high-risk features present pre-transplant. Thus, a treatment strategy that prevents early relapse 
post-allo-SCT in patients with high-risk features pre-transplant, and allows for the development 
of a robust GvL response would be a significant benefit for AML patients and represents a high 
unmet medical need. 
ClinicalTrials.gov (as of 08-Jun-2020) lists more than 100 phase I-III interventional trials 
focusing on the prevention or treatment of relapse following allo-SCT, indicating that 
addressing 
this 
issue 
represents 
a 
major 
priority 
within 
the 
field 
(O'Neill and Chakraverty 2021). 
Evidence of preliminary activity of siremadlin in AML, and the proposed mechanism of action 
including immunomodulation-mediated GvL enhancement, as well as the synergy with DLI-
mediated anti-leukemia activity suggest that this treatment strategy (priming phase with 
siremadlin monotherapy, siremadlin/DLI combination, maintenance phase with siremadlin 
monotherapy) may be effective in prevention of AML relapse in the post-allo-SCT setting. 
Although a potential risk associated with this treatment strategy, mild to moderate stimulation 
of GvHD may enhance GvL and translate into better overall outcome of patients. 
Taking into consideration the risks associated with allo-SCT, the incremental risk of study 
treatment to the overall risk to patients in this trial is expected to be low. 
In conclusion, the overall benefit/risk assessment is supportive of the conduct of this study in 
these AML patients at increased relapse risk post-allo-SCT based on the presence of high risk 
features pre-transplant, who represent a patient population with substantial unmet need with 
limited therapeutic options and dismal clinical outcomes. 
4.6 
Rationale for Public Health Emergency mitigation procedures 
In the event of public health emergency as declared bylLocal or regional authorities i.e. 
pandemic, epidemic or natural disaster, mitigation procedures to ensure participant safety and 


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trial integrity are listed in relevant sections of the study protocol. Notification of the public 
health emergency should be discussed with Novartis prior to implementation of mitigation 
procedures, and permitted/approved by local or regional health authorities and ethics 
committees as appropriate. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
5 
Study Population 
Study population includes adult patients with AML who underwent an allo-SCT and achieved 
remission but at high risk for relapse post-allo-SCT based on the presence of pretransplant risk 
factors as detailed in the inclusion criteria. 
Approximately 38 participants are planned to be enrolled and treated. 


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The investigator or designee must ensure that only participants who meet all the following 
inclusion and none of the exclusion criteria are offered treatment in the study. 
5.1 
Inclusion criteria 
Participants eligible for inclusion in this study must meet all of the following criteria: 
1. Signed informed consent must be obtained prior to participation in the study. 
2. At the time of signing the informed consent form (ICF), participants must be adults ≥ 18 
years of age. 
3. Participants with AML diagnosis, who underwent one allo-SCT to treat AML and are 
currently at ≥ Day 60 but no later than Day 120 (≤ Day 120) post allo-SCT.  
4. Pre-allo-SCT - Participants must have any of the following risk factors that put them at 
high risk for relapse: 
 AML in first CR (CR1) prior to allo-SCT with one of the following:  
 Adverse risk genetic abnormalities per 2017 ELN risk stratification. Patients with 
TP53 mutant AML at diagnosis are eligible if they meet eligibility criteria. 
 Therapy-related AML (t-AML). 
 Secondary AML (sAML) [AML secondary to antecedent myelodysplastic 
syndrome (MDS) or AML secondary to myeloproliferative neoplasm (MPN)]. 
 AML in second or greater CR (≥CR2) prior to allo-SCT. 
5. Allo-SCT must have the following characteristics: 
 Unmanipulated/T cell-replete bone marrow or peripheral blood stem cells as a graft 
source. 
 Matched related (family) donor (MFD) or matched unrelated donor (MUD): Human 
Leukocyte Antigen (HLA) matching of donor and recipient should be at a minimum of 
8/8 antigen or allele matched at HLA-A, -B, -C, -DRB1 loci. 
 Any conditioning regimen intensity is permitted, the use of anti-thymocyte globulin 
(ATG) or alemtuzumab or post-transplant cyclophosphamide as a part of conditioning 
is allowed. 
6. Donor lymphocytes are collected, cryopreserved and available for infusion (DLI), or 
obtaining donor lymphocytes for DLI is feasible (applicable only for the Part 2). 
7. Post-allo-SCT, participants must have achieved complete remission (CR) or CR with 
incomplete count recovery (CRi) with no current evidence of hematologic relapse (bone 
marrow blasts <5%; no circulating blasts in the blood; no evidence of extramedullary 
disease). 
10. Eastern Cooperative Oncology Group (ECOG) performance status 0, 1 or 2.  
11. Laboratory test results maximum 14 days prior to start of study treatment within the 
following ranges: 
 AST and ALT ≤ 3 × upper limit of normal (ULN). 
 Total bilirubin ≤ 1.5 × ULN (except in the setting of isolated Gilbert syndrome, in which 
case higher total bilirubin is allowed provided that conjugated bilirubin is ≤ 1.5 x ULN). 


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 Estimated Glomerular Filtration Rate (eGFR) ≥ 45 mL/min/1.73 m2 (calculated, based 
on local laboratory, using the Modification of Diet in Renal Disease (MDRD) formula 
in adults). 
12. Evidence of adequate engraftment post allo-SCT: ANC ≥ 1.0x109/L, platelet count ≥ 
75x109/L, hemoglobin ≥ 8 g/dL (within 14 days prior to start of study treatment). 
5.2 
Exclusion criteria 
Participants meeting any of the following criteria are not eligible for inclusion in this study. 
1. Prior exposure to MDM-inhibitor. 
2. Active acute GvHD of any grade (per Harris et al 2016) requiring systemic therapy at time 
of study treatment initiation. 
3. Active chronic GvHD of any grade (per NIH criteria Jagasia et al 2015) requiring systemic 
therapy at time of study treatment initiation. 
4. Past history of grade III or IV acute GvHD (per Harris et al 2016) and/or past history of 
moderate or severe chronic GvHD (per NIH criteria (Jagasia et al 2015)). History of lower 
grades of GvHD is permitted if GvHD resolved to grade 0 for at least 4 weeks prior to start 
of study treatment. 
5.  Recipient of allo-SCT from a matched unrelated donor (MUD) with one or more antigen 
or allele mismatch at HLA-A, -B, -C, -DRB1 locus (HLA matching less than 8/8 antigens). 
6. Recipient of allo-SCT from a haploidentical family donor. 
7. Recipients of cord blood transplant as a graft source. 
8. Human immunodeficiency virus (HIV) infection not controlled by standard therapy and/or 
with known history of opportunistic infection. 
For countries where HIV status is mandatory: HIV status will be tested during screening 
using a local test. 
9. Active Hepatitis B (HBV) or Hepatitis C (HCV) infection. Participants whose disease is 
controlled under antiviral therapy should not be excluded. 
10. Prior systemic cancer-directed treatments or investigational modalities ≤ 5 half-lives or 4 
weeks prior to starting study, whichever is longer. 
11. Prior systemic AML-directed treatments given at any time after allo-SCT (including DLI). 
12. History of another primary malignancy that is currently clinically significant or currently 
requires active intervention. Participants who are receiving adjuvant hormonal therapy for 
breast, prostate or other cancers are eligible. 
13. Participants who require the use of herbal preparations/medications St. John’s wort 
(Hypericum perforatum) within 7 days prior to first dose of study treatment or are expected 
to use such products during the entire study. 
14. Participants who have consumed grapefruit, grapefruit products, Seville oranges (including 
marmalade containing Seville oranges) or Starfruit within 3 days prior to the initiation of 
study treatment. 
15. Participants who require treatment with moderate or strong CYP3A inducers within 14 days 
prior to starting study treatment, or are expected to receive moderate or strong CYP3A4 
inducers during the entire study. 


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16. Use of live vaccines within 30 days prior to first dose of siremadlin. 
17. Female participants who are pregnant or breastfeeding. 
 Women of child-bearing potential (WOCBP), defined as all women physiologically 
capable of becoming pregnant, unless they are using highly effective methods of 
contraception during the study until 2 weeks after the last dose of siremadlin. Highly 
effective contraception methods include:  
 Total abstinence (when this is in line with the preferred and usual lifestyle of the 
participant). Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-
ovulation methods) and withdrawal are not acceptable methods of contraception. 
 Female bilateral tubal ligation, female sterilization (have had surgical bilateral 
oophorectomy with or without hysterectomy) or total hysterectomy at least six 
weeks before taking study treatment. 
 Male sterilization (at least 6 months prior to screening/baseline). For female 
participants on the study the vasectomized male partner should be the sole partner. 
 Use of an intrauterine device (IUD) or intrauterine system (IUS). The use of 
hormonal IUDs is allowed as their effect is local. 
Any form of systemic hormonal contraception for example oral, injectable, implanted, 
transdermal hormonal patch or hormonal vaginal ring are excluded from use. Hormonal 
systemic contraception is excluded as no appropriate clinical DDI studies have been 
conducted and there is a potential for siremadlin to reduce the effectiveness of hormonal 
contraceptive methods via CYP3A4 induction. 
 Women are considered post-menopausal if they have had 12 months of natural 
(spontaneous) amenorrhea with an appropriate clinical profile (e.g. age-appropriate 
history of vasomotor symptoms). Women are considered not of child-bearing potential 
if they are post-menopausal or have had surgical bilateral oophorectomy (with or 
without hysterectomy), total hysterectomy or bilateral tubal ligation at least six weeks 
prior to enrollment on study. In the case of oophorectomy alone, only when the 
reproductive status of the woman has been confirmed by follow-up hormone level 
assessment is she considered to be not of child-bearing potential. 
 For male participants: A condom is required for all sexually active male participants to 
prevent them from fathering a child AND to prevent delivery of study treatment via 
seminal fluid to their partner during the study until 2 weeks after the last dose 
of siremadlin. In addition, male participants should not donate sperm for the time period 
specified above. 
If local regulations are more stringent than the contraception methods listed above to 
prevent pregnancy, local regulations apply and will be described in the ICF. 
18. GI disorders that may prevent the intake and absorption of oral siremadlin (e.g., diarrhea, 
uncontrolled nausea and/or vomiting, GI bleeding, etc). 
19. Any concurrent severe and/or active uncontrolled bacterial, viral or fungal infection 
requiring 
parenteral 
antibacterial, 
antiviral 
or 
antifungal 
therapy. Prophylactic 
antimicrobial use (oral or parenteral) is allowed. 
20a. 
Cardiac or cardiac repolarization abnormality, including but not limited to any of the 
following: 


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 History of myocardial infarction (MI), angina pectoris, or coronary artery bypass graft 
(CABG) within 6 months prior to starting study treatment. 
 Clinically significant cardiac arrhythmias (e.g., ventricular tachycardia), complete left 
bundle branch block, high-grade Atrioventricular (AV) block (e.g., bifascicular block, 
Mobitz type II and third degree AV block). 
 QT interval corrected by Fridericia's formula (QTcF) interval > 470 ms. 
Clinically significant and/or uncontrolled heart disease such as congestive heart failure 
requiring treatment (NYHA Grade III/IV). 
21. 
Other concurrent severe and/or uncontrolled medical conditions or serious organ 
dysfunction or other co-morbidity that, in the opinion of the investigator, predisposes the 
participant to high risk of noncompliance with the protocol. 
6 
Treatment 
6.1 
Study treatment 
In this study, the terms “investigational drug” and “study treatment” refer to the Novartis study 
drug, siremadlin.  
All dosages prescribed, dispensed to the participant and all dose changes during the study 
including the reason for any treatment must be recorded on the appropriate electronic case report 
form (eCRF) page. 
6.1.1 
Investigational and control drugs 
Table 6-1 
Study Treatment 
Study Drugs  
(Name and 
Strength) 
Pharmaceutical 
Dosage Form 
Route of 
Administration 
Presentation 
Sponsor 
(global or 
local) 
Siremadlin 
(HDM201) 10 mg, 
20 mg and 30 mg* 
Capsule 
Oral use (PO) 
Open label, bottles 
Global 
*During the study,siremadlin (HDM201) 30 mg capsule may be included as additional strength which will be 
globally supplied 
Refer to Section 6.3.2 for instruction for prescribing and taking study treatment 
6.1.2 
Treatment arms/group 
In this Proof of Concept (PoC) study, the following treatments will be assessed:  
Part 1: There will be one treatment arm that consists of siremadlin monotherapy. Refer to 
Section 6.3.1 for information on the regimen. 
Part 2: There will be one treatment arm that consists of up to 3 consecutive phases: priming 
phase with siremadlin monotherapy; potentially followed by siremadlin/DLI combination 
phase; and then maintenance phase siremadlin monotherapy. Participants who will not be 
eligible for the combination phase will continue with siremadlin monotherapy only. Refer to 
Section 6.3.1 for information on the regimen.  


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6.1.3 
Guidelines for continuation of treatment 
Eligibility for combination phase of siremadlin with donor lymphocyte infusion 
(DLI):  
The decision about DLI administration in eligible participants will be at the discretion of the 
treating investigator per the standard of practice/institutional guidelines. Participants who 
receive siremadlin in combination phase should be followed for safety and DLT evaluation as 
per Table 8-4. 
Eligible participant must meet all of the following to start combination phase: 
 Immunosuppressive therapy (IST) taper has been completed for at least 4 weeks.  
 Continue to be in CR or CRi without evidence of hematologic relapse. 
 No active aGvHD (per Harris et al 2016). 
 No Grade III-IV aGvHD (per Harris et al 2016) during priming phase. 
 No active cGvHD (per NIH criteria Jagasia et al 2015) during priming phase. 
 Have received at least 2 cycles of siremadlin monotherapy (priming). 
 Siremadlin has been tolerated (no siremadlin dose modification required for toxicity) during 
the cycle immediately preceding DLI. 
In the absence of GvHD after first DLI dose, subsequent DLI can be administered. 
Eligibility for siremadlin monotherapy in maintenance phase:  
For participants who completed or discontinued of the combination phase with siremadlin/DLI, 
the following should be met for participants to proceed to maintenance phase with siremadlin 
monotherapy: 
 Continue to be in CR or CRi without evidence of hematologic relapse. 
 No active Grade II-IV aGvHD (per Harris et al 2016). 
 No active moderate or severe cGvHD (per NIH criteria Jagasia et al 2015). 
 For participants who developed GvHD during the combination phase requiring systemic 
GvHD treatment, starting maintenance phase with siremadlin monotherapy is permitted if 
GvHD has improved to ≤ Grade I for acute and/or to ≤ mild for chronic, with persistence of 
improvement for at least 2 weeks. Continuation of systemic GvHD treatment during 
maintenance phase is permitted and does not preclude initiation of siremadlin monotherapy 
(see Section 6.2.2.1 for drug-drug interactions). 
 Adverse events / toxicities have resolved to ≤ CTCAE Grade 1 or to the participant’s 
baseline value, per the investigator assessment. 
In maintenance phase, siremadlin monotherapy will be administered starting at the dose that 
was tolerated in the last cycle of combination phase, orally on Days 1-5 of each 28-day 
treatment cycle. See Section 6.6.4 for further details of dose modifications.  


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6.1.4 
Treatment duration 
The planned duration of treatment is up to 24 cycles of siremadlin-containing cycles (including 
up to 3 cycles of siremadlin/DLI combination (Part 2) and for each cohort for the dose 
confirmation siremadlin monotherapy (Part 1). Participants may be discontinued from study 
treatment earlier due to:  
 Disease relapse  
 Unacceptable toxicity or intolerance 
 Initiation of a new antineoplastic therapy (including allo-SCT).  
 Other reasons as defined in Section 9.1.1 and Section 9.3.  
For participants who discontinued study treatment due to development of GvHD following DLI 
and requiring systemic therapy, the treating investigator may consider resuming siremadlin as 
monotherapy without additional DLIs, considering the participant's benefit/risk balance of 
continuing siremadlin as per investigator's judgement (see Section 6.6.4 for details). In this case, 
the participants should continue to conduct the assessments outlined in Table 8-3 . 
6.1.4.1 
Treatment beyond disease progression 
Treatment beyond disease progression is not permitted. 
6.2 
Other treatment(s) 
6.2.1 
Donor Lymphocyte Infusion (DLI)  
DLI administration in eligible participants in Part 2 will be at the discretion of the treating 
investigator and it should be administered according to standard local clinical practice or 
institutional guidelines.  
The starting dose, ramp-up dosing and frequency described must be followed as described in 
Section 6.3.1.2 
All dosages prescribed, administered to the participant and all dose changes during the study 
including the reason for any treatment must be recorded on the appropriate electronic case report 
form (eCRF) page. 
6.2.2 
Concomitant therapy 
All medications, procedures, and significant non-drug therapies (including physical therapy and 
blood transfusions) administered within 28 days of starting study treatment until 30 days after 
the last dose of siremadlin must be recorded on the appropriate Case Report Forms. 
Each concomitant drug must be individually assessed against all exclusion criteria/prohibited 
medication. If in doubt, the investigator should contact the Novartis medical monitor before 
enrolling a participant or allowing a new medication to be started. If the participant is already 
enrolled, contact Novartis to determine if the participant should continue participation in the 
study. 


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6.2.2.1 
Permitted concomitant therapy requiring caution and/or action 
Medications to be used with caution during study treatment in this study are listed below. For 
detailed guidance, please refer to appendix 4 (Section 16.4). 
Systemic corticosteroids:  
 For conditions other than GvHD or life-threatening emergencies, the use of systemic 
steroids and/or other immunosuppressive drugs should be limited and may only be 
administered for a limited duration, providing this is ≤ 10 mg/day prednisone or equivalent 
corticosteroid dose, in the following conditions: 
 For prophylaxis against imaging contrast dye allergy (higher doses for limited duration 
are permitted for local institutional practice). 
 For the management of transient exacerbation of other underlying diseases such as 
chronic obstructive pulmonary disease requiring treatment for ≤ 3 weeks. 
 For the management of infusion-related reactions (eg, Dimethyl sulfoxide (DMSO) 
with DLI infusion). 
 Replacement dose corticosteroids in the setting of adrenal insufficiency are allowed. 
 Non-systemic steroids (topical, inhaled, non-absorbable, nasal and ophthalmic steroids) are 
allowed. 
Vaccines: 
Inactivated vaccines, subunit, recombinant, polysaccharide and conjugate vaccines and toxoid 
vaccines are allowed. 
Strong CYP3A inhibitors:  
If such therapy is necessary, it can be introduced under the provision that the dose of siremadlin 
is reduced. Recommendation for the siremadlin dose, when given in combination with strong 
CYP3A inhibitors (e.g., posaconazole, ketoconazole, clarithromycin, indinavir, itraconazole, 
telaprevir, and voriconazole), are provided below: 
1. Reduction level 1 is a dose reduction to 20% of the planned dose per cycle (as provided in 
Table 6-2 below). The basis for this dose reduction is to mitigate potential safety concern 
given the 6-fold increase in siremadlin AUC observed with co-administration of 
itraconazole. 
2. Reduction level 2 is a dose reduction to 30% of the planned dose per cycle (as provided in 
Table 6-3 below). Application of dose reduction level 2 must not proceed until the 
investigators receive written confirmation from Novartis. The decision to adjust siremadlin 
dose reduction to level 2 may be taken upon review and evaluation of safety and siremadlin 
PK exposure data by the participating Investigators and Novartis study personnel. Safety 
data must be satisfactory and PK exposure not notably elevated and compatible with less 
significant dose reduction.  
The 
basis 
of 
this 
siremadlin dose 
reduction 
is 
supported 
by 
physiologically 
based pharmacokinetic (PBPK) modeling in SimCyp and guided by the predicted fold-change 
of cumulative area under the curve (AUC) and Day 5 AUC. 


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Given that the lower dose strength of siremadlin capsules is 10 mg, approximations are made 
to round the reduced doses. The intermittent dosing in reduced doses of the 20 and 30 mg QD 
planned doses allows more time to clear the drug and thereby reduce the accumulation 
(applicable to both Table 6-2, Table 6-3 and Table 6-4). 
Table 6-2 
Management of potential interactions of strong CYP3A inhibitors with 
siremadlin - Reduction level 1 (to 20% of the planned dose)* 
Dose Level of siremadlin 
Dose without strong CYP3A 
inhibitor 
Dose adjustment with strong 
CYP3A inhibitor 
40 mg 
Total dose/cycle 200 mg 
Day 1 – 40 mg 
Day 2 – 40 mg 
Day 3 – 40 mg 
Day 4 – 40 mg 
Day 5 – 40 mg 
Day 1 – 10 mg 
Day 2 – 10 mg 
Day 3 – 0 (No dose) 
Day 4 – 10 mg 
Day 5 – 10 mg 
30 mg 
Total dose/cycle 150 mg 
Day 1 – 30 mg 
Day 2 – 30 mg 
Day 3 – 30 mg 
Day 4 – 30 mg 
Day 5 – 30 mg 
Day 1 – 10 mg 
Day 2 – 0 (No dose) 
Day 3 – 10 mg 
Day 4 – 0 (No dose) 
Day 5 – 10 mg 
20 mg 
Total dose/cycle 100 mg 
Day 1 – 20 mg 
Day 2 – 20 mg 
Day 3 – 20 mg 
Day 4 – 20 mg 
Day 5 – 20 mg 
Day 1 – 10 mg 
Day 2 – 0 (No dose) 
Day 3 – 0 (No dose) 
Day 4 – 0 (No dose) 
Day 5 – 10 mg 
* Application of dose reduction level 2 must not proceed until the investigators receive written confirmation from 
Novartis 
Table 6-3 
Management of potential interactions of strong CYP3A inhibitors with 
siremadlin - Reduction level 2 (to 30% of the planned dose)* 
Dose Level of siremadlin 
Dose without strong CYP3A 
inhibitor 
Dose adjustment with strong 
CYP3A inhibitor 
40 mg 
Total dose/cycle 200 mg 
Day 1 – 40 mg 
Day 2 – 40 mg 
Day 3 – 40 mg 
Day 4 – 40 mg 
Day 5 – 40 mg 
Day 1 –10 mg 
Day 2 – 10 mg 
Day 3 – 10 mg 
Day 4 – 10 mg 
Day 5 – 20 mg 
30 mg 
Total dose/cycle 150 mg 
Day 1 – 30 mg 
Day 2 – 30 mg 
Day 3 – 30 mg 
Day 4 – 30 mg 
Day 5 – 30 mg 
Day 1 – 10 mg 
Day 2 – 10 mg 
Day 3 – 10 mg 
Day 4 – 10 mg 
Day 5 – 10 mg 
20 mg 
Total dose/cycle 100 mg 
Day 1 – 20 mg 
Day 2 – 20 mg 
Day 3 – 20 mg 
Day 4 – 20 mg 
Day 5 – 20 mg 
Day 1 – 10 mg 
Day 2 – 0 (No dose) 
Day 3 – 10 mg 
Day 4 – 0 (No dose) 
Day 5 – 10 mg 
* Application of dose reduction level 2 must not proceed until the investigators receive written confirmation from 
Novartis 


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Moderate CYP3A inhibitors:  
If such therapy is necessary, it can be introduced under the provision that the dose of siremadlin 
is reduced. Recommendation for siremadlin dose, when given in combination with moderate 
CYP3A inhibitors (such as erythromycin, fluconazole, ciprofloxacin, isavuconazole), are 
provided in Table 6-4 below. 
The basis adjustment of the siremadlin dose to 40% of the planned dose per cycle in case of 
concomitant administration of moderate CYP3A inhibitor is supported by physiologically 
based pharmacokinetic (PBPK) modeling in SimCyp and guided by the predicted fold-change 
of cumulative AUC and Day 5 AUC. 
Table 6-4 
Management of potential interactions of moderate CYP3A inhibitors 
with siremadlin 
Dose Level of siremadlin 
Dose without moderate CYP3A 
inhibitor 
Dose adjustment with moderate 
CYP3A inhibitor 
40 mg 
Total dose/cycle 200 mg 
Day 1 – 40 mg 
Day 2 – 40 mg 
Day 3 – 40 mg 
Day 4 – 40 mg 
Day 5 – 40 mg 
Day 1 – 10 mg 
Day 2 – 10 mg 
Day 3 – 20 mg 
Day 4 – 20 mg 
Day 5 – 20 mg 
30 mg 
Total dose/cycle 150 mg 
Day 1 – 30 mg 
Day 2 – 30 mg 
Day 3 – 30 mg 
Day 4 – 30 mg 
Day 5 – 30 mg 
Day 1 – 10 mg 
Day 2 – 10 mg 
Day 3 – 10 mg 
Day 4 – 10 mg 
Day 5 – 20 mg 
20 mg 
Total dose/cycle 100 mg 
Day 1 – 20 mg 
Day 2 – 20 mg 
Day 3 – 20 mg 
Day 4 – 20 mg 
Day 5 – 20 mg 
Day 1 – 10 mg 
Day 2 – 10 mg 
Day 3 – 0 (No dose) 
Day 4 – 10 mg 
Day 5 – 10 mg 
Antifungal therapy with azole agents is an important standard of care in AML patients. 
However, all azole antifungal agents carry drug-drug interaction liabilities because of their 
moderate to strong inhibitory effects on cytochrome CYP3A enzyme. Siremadlin, as a substrate 
for CYP3A, has a potential for increased exposure in participants concomitantly treated with 
azole agents, which might have an impact on safety and tolerability. 
Indeed, in a drug interaction study in healthy volunteers ([CHDM201X1102]) that investigated 
the effect of itraconazole (strong CYP3A inhibitor) on the pharmacokinetic properties of 
siremadlin, itraconazole administered with a single dose of siremadlin increased mean Cmax 
and AUCinf of siremadlin by 1.42- and 6.13-fold, respectively, compared with siremadlin 
alone. Since siremadlin will be used in a patient population that frequently requires concomitant 
medications with azole antifungals (eg, especially posaconazole) or antibiotics, guidelines on 
dose adjustment of siremadlin would be required when co-administered with strong or moderate 
CYP3A inhibitors. Information gained from this trial would allow for the confirmation of the 
proposed dose adjustment in the patient population or alternatively may be used to inform on 
instructions for different or refined dose adjustment requirements. This will be based on the 
comparison of PK systemic exposure of siremadlin in participants not requiring and then 
requiring concomitant administration of strong or moderate CYP3A inhibitors and conversely 
if possible (depending upon the observed data), and also from the PK exposure data with and 


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without strong and moderate CYP3A inhibitors of this trial (and other trial(s) with similar 
approach if applicable). This will be further supported by PBPK modeling based on the 
available data. 
Anti-GvHD medications with narrow therapeutic index substrates of CYP3A 
(e.g. tacrolimus, cyclosporine, sirolimus) 
If systemic GvHD prophylaxis or treatment [immunosuppressive therapy (IST)] taper has not 
been started or completed at study entry, IST taper schedule and duration will be per 
institutional guidelines and at the discretion of the treating investigator. 
Tacrolimus, cyclosporine, sirolimus are IST agents and are all sensitive CYP3A substrates. 
In vitro siremadlin was identified as a reversible and time-dependent inhibitor and as an inducer 
of CYP3A. Drug-drug interactions (DDI) of siremadlin with IST agents cannot be predicted 
based on in vitro data. 
Therefore increased systemic exposure of tacrolimus, cyclosporine, or sirolimus in presence of 
siremadlin cannot be excluded. 
Owing to the narrow therapeutic index of these IST agents, drug levels of cyclosporine, 
tacrolimus, and/or sirolimus will be measured by local laboratories before (within 
approximately a week) and during siremadlin administration, monitored and reported (see 
Table 6-5). 
The desired IST target range during IST taper will be per the local institutional standard of 
practice and at the discretion of the treating investigator. 
For IST blood levels measured before siremadlin administration (approximately a week): 
 If IST blood levels are within the desired range, no IST dose change reduction is needed. 
 If IST blood levels are notably higher or lower, the IST dose will be adapted as needed as 
per the local institutional standard of practice and at the discretion of the treating 
investigator. 
Table 6-5 
Timepoints for IST drug level measurements to be recorded by 
investigators  
Time relative 
to siremadlin 
administration 
(D1-5) of a 
given cycle 
Cyclosporine 
Trough(2)  
ng/mL 
Cyclosporine 
2-hour 
concentration 
(C2)(2) 
ng/mL 
Tacrolimus 
Trough 
ng/mL 
Sirolimus 
Trough 
ng/mL 
Action taken 
by 
investigator 
for IST dose 
adjustment (if 
applicable)  
Selected 
Clinical 
measures 
(3) 
Within 
approximately 
1 week 
before(1) 
  
  
  
  
  
  
D1 of 
siremadlin 
  
  
  
  
  
  
D5 of 
siremadlin 
  
  
  
  
  
  
(1) Report the last IST level measurements within the week before starting siremadlin. If not possible, IST 
levels from up to 8-9 days before are acceptable 


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Time relative 
to siremadlin 
administration 
(D1-5) of a 
given cycle 
Cyclosporine 
Trough(2)  
ng/mL 
Cyclosporine 
2-hour 
concentration 
(C2)(2) 
ng/mL 
Tacrolimus 
Trough 
ng/mL 
Sirolimus 
Trough 
ng/mL 
Action taken 
by 
investigator 
for IST dose 
adjustment (if 
applicable)  
Selected 
Clinical 
measures 
(3) 
(2) Either cyclosporine trough level or cyclosporine 2-hour concentration (C2) level can be measured per the 
local institutional standard of practice. 
(3) Selected clinical measures include signs and symptoms not already recorded under safety assessments 
that indicate high or low IST levels, such as GvHD exacerbation, nephrotoxicity, hepatotoxicity, and other 
toxicities. 
Participants who are receiving azole antifungals (strong or moderate inhibitors of CYP3A) 
simultaneously with siremadlin and IST agent(s) (cyclosporine, tacrolimus, and/or sirolimus), 
the recommendation for siremadlin dose adjustment when combined with azoles must be 
followed as outlined inTable 6-2, Table 6-3 and Table 6-4 for strong and moderate inhibitors of 
CYP3A, respectively. Monitoring will be followed as per the local institutional standard of 
practice and local labels.  
For additional information on the PK properties and interaction, please refer to local labels of 
tacrolimus, cyclosporine, sirolimus, and to [Siremadlin (HDM201) Investigator’s Brochure]. 
Additional therapeutic monitoring references are made to (Clinical Guidelines for Transplant 
Medications. BC Transplant. 2019 and McCune and Bemer 2016). 
Some PK properties and therapeutic monitoring indications are summarized below: 
 Cyclosporine is an inhibitor of CYP3A4 and the multidrug efflux transporter P-
glycoprotein. Cyclosporine is extensively metabolised to approximately 15 metabolites. 
Metabolism mainly takes place in the liver via cytochrome P450 3A4 (CYP3A4). Mutual 
interaction of cyclosporine and siremadlin cannot be excluded. There is a high variability in 
the data reported on the terminal half-life (T1/2) of ciclosporin depending on the assay 
applied and on the target population. T1/2 ranged from 6.3 hours in healthy volunteers to 
20.4 hours in patients with severe liver disease. T1/2 in kidney-transplanted patients was 
approximately 11 hours, with a range between 4 and 25 hours. Evidence shows that the 
monitoring of cyclosporine at the 2 hour concentration point (C2) is the most accurate single 
time point for assessment of cyclosporine absorption and immunosuppressive effect. By 
monitoring C2 target concentrations in renal and liver transplant recipients one can more 
accurately adjust the patients’ cyclosporine dose to minimize toxicity and rejection rates. 
However, C2 measurements are not done in all patients and some stem cell transplant 
institutions 
use 
cyclosporine trough 
concentration for 
drug 
level 
monitoring 
(Clinical Guidelines for Transplant Medications. BC Transplant. 2019, 
McCune and Bemer 2016). 
 Sirolimus is extensively metabolised by the CYP3A4 isozyme in the intestinal wall and 
liver. Sirolimus is also a substrate for the multidrug efflux pump, P-glycoprotein (P-gp) 
located in the small intestine. Therefore, absorption and the subsequent elimination of 
sirolimus may be influenced by substances that affect these proteins. Following the 
administration of sirolimus oral solution, sirolimus is rapidly absorbed, with a time to peak 
concentration of 1 hour in healthy volunteers receiving single doses and 2 hours in patients 
with stable renal allografts receiving multiple doses. The terminal half-life in stable renal 
transplant patients after multiple oral doses was 62 ±16h. The effective half-life, however, 


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is shorter and mean steady-state concentrations were achieved after 5 to 7 days. Whole 
blood trough levels of sirolimus should be closely monitored in the following populations 
when inducers or inhibitors of CYP3A4 are concurrently administered and after their 
discontinuation. 
 Systemically available tacrolimus is metabolised by hepatic CYP3A4. There is also 
evidence of gastrointestinal metabolism by CYP3A4 in the intestinal wall. Concomitant use 
of substances known to inhibit or induce CYP3A4 may affect the metabolism of tacrolimus 
and thereby increase or decrease tacrolimus blood levels. Tacrolimus is a known (weak) 
CYP3A4 inhibitor; thus concomitant use of tacrolimus with medicinal products known to 
be metabolised by CYP3A4 may affect the metabolism of such medicinal products. The 
half-life of tacrolimus is long and variable. In healthy volunteers, the mean half-life in whole 
blood is approximately 43 hours. Further, (McCune and Bemer 2016) reported that 
tacrolimus has a volume of distribution of 1.67 L/kg, oral bioavailability of 31–49% and a 
half-life of 18.2 hours. A strong correlation exists between AUC and whole blood trough 
levels at steady-state for tacrolimus. Therefore, monitoring of whole blood trough levels of 
tacrolimus provides a good estimate of systemic exposure. As tacrolimus is a substance 
with low clearance, adjustments to the tacrolimus dose regimen may take several days 
before steady state is achieved. 
There is a low potential of interaction related to impact of IST agents on siremadlin, which will 
be investigated by PK concentration collected for siremadlin. 
6.2.2.2 
Use of bisphosphonates 
Bisphosphonates may be given according to their local product license and routine clinical 
practice, at the investigator’s discretion. 
No drug-drug interaction is expected between siremadlin and bisphosphonates. 
Bisphosphonates are not inhibitors of human CYP450 enzymes and do not undergo metabolism 
in vivo. 
6.2.3 
Prohibited medications 
 During course of the study, no additional investigational drugs, devices, chemotherapy, 
immunotherapy or any other therapies that may be active against cancer or modulate the 
immune response would be allowed. DLI will not be permitted on study during Part 1. 
 The use of live vaccines is not allowed through the duration of the study treatment and at 
least 30 days after the last dose of siremadlin or longer as applicable per vaccination 
guidelines post-allo-SCT. 
 Prior to starting DLI in combination with siremadlin, IST taper must have been completed 
for at least 4 weeks. The use of systemic corticosteroids and/or immunosuppressive 
treatment is not allowed during DLI cycles in combination with siremadlin unless given for 
the conditions listed in the concomitant medications in Section 6.2.2.1 
 Strong or moderate CYP3A inducers: Concomitant use of strong CYP3A inducers (e.g., 
carbamazepine, phenytoin, rifampin) or moderate CYP3A inducers (e.g., bosentan, 
efavirenz, etravirine, modafinil, nafcillin) are prohibited within 14 days prior to start and 


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during the study treatment period as siremadlin is primarily metabolized by CYP3A4. 
Alternative treatments with less CYP3A induction should be considered. 
 Use of the herbal preparations/medications with St. John’s wort are prohibited during study 
treatment period due to potential drug-drug interaction. Participants should stop using these 
herbal medications 7 days prior to first dose of study drug. 
 Use of CYP3A substrates with a narrow therapeutic index (NTI) are prohibited 24 hours 
before and 48 hours after siremadlin administration as in vitro experiments have shown 
siremadlin to be both a time-dependent and reversible inhibitor of CYP3A4/5. For anti-
GvHD medications with narrow therapeutic index substrates of CYP3A see under 
Section 6.2.1. 
Refer to Table 16-4 in appendix 4 (Section 16.4) for a detailed list of prohibited concomitant 
medications. 
6.2.4 
Supportive care measures 
Participants should receive appropriate supportive care measures (including blood product 
support, anti-emetics, anti-diarrheal treatment, prophylactic or therapeutic anti-microbials, pre-
medication prior to DLI administration, etc.) at the discretion of the treating Investigator and 
per the local standard of practice (refer to Section 6.3.2). However, each additional medication 
must be individually assessed against all exclusion criteria/prohibited medications and for 
potential drug-drug interactions (refer to concomitant/prohibited medications, appendix 4 
Section 16.4).  
6.3 
Preparation and dispensation 
Each study site will be supplied with siremadlin in packaging as described under investigational 
and control drugs section (Section 6.1.1). 
A unique medication number is printed on the study medication label. 
Investigator staff will identify the study medication kits to dispense to the participant by 
contacting the IRT and obtaining the medication number(s). The study medication has a 2-part 
label (base plus tear-off label), immediately before dispensing the medication kit to the 
participant, site personnel will detach the outer part of the label from the packaging and affix it 
to the source document. 
DLI may be administered as fresh product or cryopreserved product after thawing. Procedures 
for DLI processing, cryopreservation, thawing and administration will be according to the local 
institutional practice. For further details please refer to Section 6.3.1.2  
As per Section 4.6, during a Public Health emergency as declared by Local or Regional 
authorities i.e. pandemic, epidemic or natural disaster, that limits or prevents on-site study visits, 
delivery of siremadlin directly to a participant's home may be permitted (if allowed by Local or 
Regional Health Authorities and Ethics Committees as appropriate) in the event the Investigator 
has decided that an on-site visit by the participant is no longer appropriate or possible, and that 
it is in the interest of the participant's health to administer the study treatment even without 
performing an on-site visit. The dispatch of siremadlin from the site to the participant’s home 
remains under the accountability of the Investigator. 


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Each shipment/provisioning will be for a maximum of 2-months supply. In this case, regular 
phone calls or virtual contacts (every 4-weeks or more frequently if needed) will occur between 
the site and the participant for instructional purposes, safety monitoring, investigation of any 
adverse events, ensuring participants continue to benefit from treatment, and discussion of the 
participant's health status until the participants can resume visits at the study site. 
6.3.1 
Handling of study treatment and other treatment 
6.3.1.1 
Handling of study treatment 
Study treatment must be received by a designated person at the study site, handled and stored 
safely and properly and kept in a secured location to which only the investigator and designated 
site personnel have access. Upon receipt, all study treatment must be stored according to the 
instructions specified on the labels and in the Investigator's Brochure. 
Clinical supplies are to be dispensed only in accordance with the protocol. Technical complaints 
are to be reported to the respective Novartis CO Quality Assurance. 
Medication labels will be in the local language and comply with the legal requirements of each 
country. They will include storage conditions for the study treatment but no information about 
the participant except for the medication number. 
The investigator must maintain an accurate record of the shipment and dispensing of study 
treatment in a drug accountability log. Monitoring of drug accountability will be performed by 
field monitors during site or remote monitoring visits, and at the completion of the trial. 
For study drugs administered at home, participants will be asked to return all unused study 
drugs and packaging to the site at the next visit and at the end of the study or at the time of 
discontinuation of study treatment. The investigator may provide a drug diary with detailed 
instructions to the participant to facilitate treatment compliance. 
The site may destroy and document destruction of unused study treatment, drug labels and 
packaging as appropriate in compliance with site processes, monitoring processes, and per local 
regulation/guidelines. Otherwise, the investigator will return all unused study treatment, 
packaging, drug labels, and a copy of the completed drug accountability log to the Novartis 
monitor or to the Novartis address provided in the investigator folder at each site. 
6.3.1.2 
Handling of other treatment 
Donor Lymphocyte Infusion (DLI): For eligibility requirements that must be met before 
starting siremadlin/DLI combination phase, please refer to Section 6.1.3.  
DLI is a cellular therapy, which is used in the population enrolled in this study. The decision 
about DLI administration in eligible participants will be at the discretion of the treating 
investigator and it should be administered according to standard local clinical practice or 
institutional guidelines. However, the starting dose, ramp-up dosing and frequency described 
below must be followed. 
Pre-medication prior to DLI administration: Per local standard of practice. However, 
participants should not receive systemic corticosteroids prophylactically as a pre-medication to 


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prevent infusion-related reaction (ie, to DMSO) unless a participant experienced a prior 
clinically significant infusion-related reaction (eg, anaphylactic/anaphylactoid reactions). 
Immunosuppressive therapy (IST)/GvHD prophylaxis/treatment: Participants who have 
not completed IST taper prior to start of study treatment will continue to receive IST and 
tapering according to local standard of practice and as clinically appropriate. However, 
instructions for level monitoring and dose adjustments pre-, during, and post-siremadlin 
administration must be followed as in Section 6.2.2.1 and Table 6-5 for anti-GvHD medications 
with narrow therapeutic index substrates of CYP3A. 
Starting DLI dose: DLI should be administered, after siremadlin, on day 3 of a 42-day (6-
week) combination cycle, starting at a low dose based on donor type as follows: 
 Matched sibling/family donor (MFD): 2 × 105 CD3+ cells/kg 
 8/8 HLA-matched unrelated donor (MUD): 1 × 105 CD3+ cells/kg 
Subsequent DLI administration:  
 In the absence of GvHD exacerbation after first DLI dose, DLI can be repeated (DLI ramp-
up dosing) with the next combination cycle within 42 days in combination with siremadlin. 
 DLI should be administered, after siremadlin, on day 3 of a 42-day (6-week) 
combination cycle. 
 DLI ramp-up dosing: increase CD3+ cell dose by 0.5 log increment with each 
subsequent infusion as compared to the prior DLI dose, for up to a total of 3 DLIs. 
 In the absence of clinically significant GvHD and the absence of hematologic overt relapse, 
continue with DLI in combination with siremadlin for up to a total of 3 cycles with 
DLI/siremadlin combination. 
In case of development of or exacerbation of GvHD of any severity following DLI 
administration, please refer to Section 6.6.4. 
6.3.2 
Instruction for prescribing and taking study treatment 
Table 6-6 
Dose and treatment schedule 
Study Drugs 
Dose 
Frequency  
Regimen 
Siremadlin 
As assigned 
Starting dose level: 30 mg 
Daily on days 1 to 5 of every cycle: 
● 28-day cycle during Part 1, priming 
and maintenance phases 
(monotherapy) 
● 42-day (6-week) cycle during 
combination phase with DLI 
(siremadlin/DLI combination) 
QD fasted 
All kits of study treatment assigned by the IRT will be recorded in the IRT system. 
Siremadlin 
Participants should take siremadlin on an empty stomach (i.e. fast from food and drink, except 
water) at least 1 hour before or 2 hours after a meal. The participant should take the capsules in 
the morning, at approximately the same time each day of dosing, with a glass of water and 
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If the participant is assigned to a dose level where multiple capsules are to be taken, the capsules 
should be taken consecutively, within as short an interval as possible. On the visit days, the 
participant will take siremadlin at the clinic under the supervision of the investigator or designee 
and on other days at home. 
If a participant misses doses of siremadlin within 8 hours of the time it is usually taken, the 
participant should take the missed dose as soon as possible on the same day. If the participant 
misses a dose by more than 8 hours, the participant should not take the missed dose and should 
resume the usual dosing schedule at the usual time the following day. Any missed dose should 
be reported to the Investigator at the next study visit. If a participant vomits after taking 
siremadlin, the dose should not be re-administered and the participant should take their next 
dose at the usual time the following day. 
On days that PK samples are obtained, the participant will be instructed to bring his/her 
siremadlin capsules to the clinic and take siremadlin during the clinic visit after the pre-dose 
PK sampling and prior to post-dose PK sampling, under the supervision and when instructed 
by the study staff. The exact time for dose administration and breakfast intake must be recorded 
in the source documents and eCRF. In addition, on the days of full PK sampling, if a participant 
vomits within the first 4 hours after dose administration, the exact time of the first episode of 
vomiting should be recorded on the CRF and the dose should not be re-administered. 
A reduced dose of siremadlin per day with concomitant use with either strong or moderate 
CYP3A inhibitors is necessary (see Section 6.2.2.1).  
6.4 
Participant numbering, treatment assignment, randomization 
6.4.1 
Participant numbering 
Each participant is identified in the study by a Participant Number (Participant No.), that is 
assigned when the participant is enrolled for screening and is retained as a primary identifier 
for the participant throughout his/her participation in the trial. 
The Participant No. consists of the Center Number (Center No.) (as assigned by Novartis to the 
investigative site) with a sequential participant number suffixed to it, so that each participant’s 
participation is numbered uniquely across the entire database. 
Upon signing the informed consent form, the site will use the electronic data capture system 
(eCRF) to assign the participant to the next sequential Participant No. available. 
The investigator or designated staff will then contact the Interactive Response Technology 
(IRT) and provide the requested identifying information (including the assigned Participant 
No.) to enroll the participant. Once assigned, the participant No. must not be reused for any 
other participant and the participant No. for that individual must not be changed, unless the 
participant is re-screened. 
If the participant fails to start treatment for any reason, the reason will be entered into the 
appropriate eCRF page and IRT should be notified as soon as possible. Re-screening is allowed 
once for participants that were initially screen failures for any reason. A new ICF will need to 
be signed and all eligibility criteria must be re-checked and met prior to enrollment of the 


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participant into the study. A new participant No. should be assigned for all re-screened 
participants. 
A new ICF will need to be signed if the investigator chooses to re-screen the participant after a 
participant has screen failed, and the participant will be assigned a new Participant No. 
6.4.2 
Treatment assignment, randomization 
No randomization will be performed in the study. 
The assignment of a participant to a particular dose cohort will be using the IRT system and 
will be coordinated by Novartis. 
Following screening and prior to dosing at C1D1, the investigator (or delegate) will call or log 
on to the IRT and confirm that the participant fulfills all the inclusion/exclusion criteria by 
completing the eligibility criteria checklist embedded in the system. The IRT will assign a 
unique medication number for the investigational drug: siremadlin. 
6.4.2.1 
Replacement policy 
Dose confirmation part 
Participants will not be replaced on study. However, if a participant is considered as non-
evaluable for the escalation decisions, enrollment of a new participant to the current cohort will 
be considered if there is less than the required number of evaluable participants. Enrollment of 
new participants may be considered until at least the minimum number of evaluable participants 
is achieved within the cohort (refer to Section 12.8.1). Minimum and maximum numbers of 
evaluable participants per cohort are defined in the guidelines for dose escalation and 
determination section. 
6.5 
Treatment blinding 
Not applicable. 
6.6 
Dose escalation and dose modification 
Up to three dose levels of siremadlin may be evaluated during Part 1, if applicable. The 
assessment of the tested dose levels of siremadlin as monotherapy will be guided by a BLRM 
with overdose control criteria (EWOC) based on the DLT incidence reported during the first 
cycle as well as an overall safety overview for participants included in the DDS1. Based on the 
safety assessment, the decision on the siremadlin RD for priming in subsequent cohort will be 
made. 
For the combination phase, the assessment of participants' siremadlin dose levels for 
combination phase will be guided by a Bayesian time-to-DLT model with overdose control 
criteria (EWOC) based on the DLT incidence reported in each cycle of combination phase for 
participants in DDS2. The siremadlin recommended dose for combination will be determined 
based on the safety assessment. 
Intra-participant dose escalation is not permitted for any of the treatment phases. Guidance for 
dose modifications is provided in Section 6.6.4. 


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6.6.1 
Dose escalation guidelines 
6.6.1.1 
Starting dose 
The starting dose level of siremadlin monotherapy in Part 1 is 30 mg p.o. administered once 
daily on Days 1-5 of each cycle [one cycle = 28 days] (see Section 4.2 for dose selection 
rationale). 
6.6.1.2 
Provisional dose levels 
Table 6-7 describes the starting dose level in Part 1 and the dose levels that may be evaluated 
during this part. Refer to Section 4.2 for siremadlin dosing rationale. 
Table 6-7 
Provisional siremadlin dose levels 
Dose level 
Proposed daily dose 
Increment from previous dose 
-1** 
20 mg 
-33% 
1 
30 mg 
Starting dose 
+1 
40 mg 
+33% 
**Dose level -1 represents treatment dose for participants requiring a dose reduction from the starting dose 
level. No dose reduction below dose level -1 (20 mg) is permitted for this study. 
6.6.2 
Guidelines for dose escalation, determination of recommended dose 
for part 1 and maximum recommended dose for combination in part 2 
Dose confirmation siremadlin monotherapy phase (Part 1) 
For the purposes of assessing the risk of overdosing (as defined by EWOC criterion, see details 
below) of siremadlin monotherapy, participants must be in the dose-determining set of the Part 
1 (DDS1) (details in Section 12.1). 
If one or more participants fail to meet the evaluability criteria, the replacement policy (see 
Section 6.4.1) may be used to enroll additional participants to the same cohort, in order to 
support the benefit-risk assessment. 
Dose de-escalation decisions will occur after the required number of evaluable participants have 
completed Cycle 1. The first cohort of at least 3 evaluable participants will be treated at the 
starting dose level of siremadlin (DL1) 30 mg QD Days 1-5 of a 28-day cycle. 
If the EWOC criterion is satisfied (probability of excessive toxicity is lower than 25%), the 
Bayesian model will recommend to open a second cohort of at least 6 evaluable participants at 
the next dose level (DL+1) at 40 mg. If the decision is to de-escalate to 20 mg (DL-1), a second 
cohort will enroll at least 6 evaluable participants. If the decision is to maintain 30 mg, a second 
cohort will enroll at least 3 evaluable participants. 
A dose level to be declared as RD must be tested with at least 6 evaluable participants. The 
siremadlin RD for priming will be selected among 20 mg, 30 mg and 40 mg, considering 
additional safety information beyond the first cycle (DLT observation period) and available 
clinical pharmacology data, tolerability data, and recommendations from participating 
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To reduce the risk of exposing participants to an overly toxic dose in Part 1, when 2 participants 
experience a DLT in a new cohort, the BLRM will be updated with the most up-to-date new 
information from all cohorts, without waiting for all participants from the current cohort to 
complete the evaluation period. If the two DLTs occur in a de-escalation cohort, enrollment to 
that cohort will stop. 
Dose de-escalation decisions will be made by participating Investigators and Novartis study 
personnel. Decisions will be based on a synthesis of all relevant data available from all dose 
levels evaluated in the ongoing study including safety information, DLTs, all CTCAE Grade ≥ 
2 toxicity data during DLT observation period, if possible PK, and PD (optional) data from 
evaluable participants. The recommended dose for the next cohort of participants will be guided 
by the statistical models with EWOC principle. 
Once the recommended siremadlin dose is determined in Part 1, enrollment in Part 2 will 
start after having obtained Health Authority’s approval as applicable. Enrollment in Part 
2 will not be applicable to participating sites in the United States and Germany. 
Combination phase (in Part 2) 
DLT evaluation will be performed for all participants over the entire siremadlin/DLI 
combination phase. Safety assessments will be conducted after each cohort of 3 participants 
completed the first siremadlin/DLI treatment cycle or experienced a DLT event. After the first 
assessment, a maximum dose for siremadlin will be provided by a Bayesian time-to-(first) DLT 
model and used as an upper limit for participants to enter combination phase The maximum 
dose will be updated continuously following safety assessments taking into consideration all 
available information, also from cycles after Cycle 1. The final safety assessment will take place 
after all participants in dose-determining set 2 (DDS2) (see DDS2 of the combination phase in 
Section 12.1) complete combination phase. Determination of the siremadlin maximum RD for 
combination requires a minimum of 9 evaluable participants and satisfies EWOC principle for 
each of the three cycles of combination phase. A dose level to be declared as maximum RD for 
combination must be tested with at least 3 evaluable participants treated at or above that dose 
level. 
6.6.2.1 
Implementation of dose escalation decisions 
To implement dose escalation decisions for Part 1, the available toxicity information (including 
adverse events and laboratory abnormalities that are not DLTs), the recommendations from the 
BLRM, if possible available PK and PD (optional) information will all be evaluated by the 
Investigators and Novartis study personnel (including the study physician and statistician) 
during a dose decision meeting by teleconference. Similarly, decisions to reduce participants' 
dose levels for the combination phase (Part 2) will be made on basis of all available toxicity 
information, the recommendations of the time-to-DLT model, and other relevant information 
by the Investigators and Novartis study personnel. 
Drug administration at the next larger dose level may not proceed until the investigator receives 
written confirmation from Novartis indicating that the results of the previous dose level were 
evaluated and that it is permissible to proceed to a larger dose level. 


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6.6.2.2 
Intra-Participant dose escalation 
Intra-participant dose escalation is not permitted. 
6.6.3 
Definitions of dose limiting toxicities (DLTs) 
A dose-limiting toxicity (DLT) is defined as an adverse event or abnormal laboratory value 
assessed, by the Investigator, to be at least possibly related to study treatment (siremadlin 
monotherapy and/or siremadlin in combination with DLI), and as unrelated to disease, disease 
progression, inter-current illness, or concomitant medications, that occurs during the DLT 
observation period and meets any of the criteria included in Table 6-8. These DLT criteria apply 
for both Part 1 and Part 2. 
The DLT observation period will be within the first treatment cycle with siremadlin 
monotherapy in Part 1, and within the complete Part 2 (starting at day of first DLI and ending 
at end of the last siremadlin/DLI cycle). 
A participant meets the minimum dose criteria if he/she received during the first cycle at least 
75% of the total planned doses for siremadlin (e.g., ≥ 4 out of 5 daily doses of siremadlin (Part 
1 and Part 2).  
Participant meets the minimum dose criteria if he/she received the planned dose of DLI and at 
least 75% of the total planned doses for siremadlin as defined in the dose and treatment schedule 
(see Section 6.3.2) for a given cycle (Part 2).  
The National Cancer Institute Common Terminology Criteria for Adverse events (NCI 
CTCAE) version 5.0 will be used for all grading except for GvHD; (Harris et al 2016) will be 
used for acute GvHD, and NIH consensus criteria will be used for chronic GvHD 
(Jagasia et al 2015). 
For the purpose of dose-escalation decisions, DLTs will be considered and included in the 
BLRM (Part 1). 
The investigator must notify the sponsor immediately of any unexpected CTCAE grade ≥ 3 
adverse events or laboratory abnormalities that are not consistent with the observed safety 
profile of siremadlin or any adverse events meeting DLT criteria. Prior to enrolling participants 
into a larger dose level, CTCAE grade ≥ 2 adverse events will be reviewed for all participants 
at the current dose level. 
If a participant experiences a DLT (during the DLT observation period) then study treatment 
must be interrupted and may be permanently discontinued depending on the severity of and 
recovery from the DLT (refer to Table 6-9 and Section 6.6.4). If the DLT (other than GvHD) 
resolves to CTCAE grade 1 or baseline value, the participant may continue to receive study 
treatment following consultation with the Novartis medical monitor. 
For acute GvHD and/or chronic GvHD that meet DLT criteria, refer to Section 6.6.4 for study 
treatment interruption, re-initiation and/or discontinuation. 


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Table 6-8 
Criteria for defining dose limiting toxicities 
Toxicity 
DLT criteria 
DLTs considered related to graft vs host disease (GvHD) by the Investigator assessment 
GvHD 
Grade 3 - 4 acute GvHD [per Harris et al 2016 
Moderate chronic GvHD [per NIH criteria] 
Severe chronic GvHD [per NIH criteria] 
Other DLTs excluding acute or chronic GvHD by the investigator assessment 
Hematology 
(in the absence of leukemic 
infiltration in the bone 
marrow) 
Grade 4 neutropenia and/or thrombocytopenia, that do not respond to growth 
factor or transfusion support within 14 days 
Grade ≥ 3 febrile neutropenia 
Grade ≥ 3 thrombocytopenia with clinically significant bleeding 
GI 
(not considered related to 
GvHD) 
Grade 3 nausea and vomiting, that do not resolve to ≤ Grade 1 within 48 hours 
of starting anti-emetic therapy 
Grade 4 nausea and vomiting (regardless of duration)  
Grade 3 diarrhea, that do not resolve to ≤ Grade 1 within 48 hours of starting 
anti-diarrhea treatment 
Grade 4 diarrhea (regardless of duration)  
Liver 
(not considered related to 
GvHD) 
Blood bilirubin increase ≥ Grade 2 (caused by increased direct bilirubin) with 
ALT and/or AST ≥ Grade 2, without evidence of cholestasis and with absence 
of any alternative cause likely explaining the combination of increased 
ALT or AST and blood bilirubin 
Others 
Any other unacceptable non-hematological toxicity encountered by a 
participant as determined by the Investigators and Novartis 
Grade 3-5 non-hematological toxicity not clearly resulting from the underlying 
leukemia, inter-current illness, or concomitant medications 
Any AE that leads to study treatment discontinuation if not clearly resulting 
from the underlying leukemia, inter-current illness, or concomitant medications 
Any treatment-related (non-relapse) death 
Exceptions for DLT criteria 
● Grade 3 fatigue, asthenia, fever, or constipation 
● Grade 3 anorexia, nausea, vomiting, diarrhea not requiring hospitalization, tube feeding or use of total 
parenteral nutrition (TPN) 
● Grade 3 or 4 isolated laboratory abnormalities that last ≤3 days 
6.6.4 
Dose modifications 
For participants who do not tolerate the protocol-specified dosing schedule, dose interruptions, 
and/or reductions are required in order to allow participants to continue the study treatment. 
These dose modifications are summarized in Table 6-9 . Deviations to mandatory dose 
interruptions and/or reductions are not allowed. Permanent discontinuation from study 
treatment is mandatory for specific events indicated as such in Table 6-9 or listed in 
Section 6.6.4. 
These dose changes must be recorded on the appropriate CRF. 
Any final decisions concerning dose modifications or permanently discontinuing the participant 
from study drug due to study drug related toxicities will occur following a documented 
discussion with Novartis. 


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Participants who discontinue the study due to an adverse event or an abnormal laboratory value 
must be followed as described in Section 9.1.1. 
The following general guidelines apply for dose modification (interruption, 
reduction and/or permanent discontinuation) decision for toxicities (other than 
GvHD): 
 If a participant requires a dose interruption or delay in initiation of a treatment cycle due 
to toxicities [other than GvHD] for more than 28 consecutive days with siremadlin 
monotherapy (measured from the intended start date of the new cycle, i.e., from Day 29 of 
the previous cycle), or more than 42 days for siremadlin/DLI combination cycles 
(measured from Week 7/Day 43 of the previous cycle), then the participant should be 
discontinued from the study treatment. 
 If a participant experiences an adverse event (AE) meeting the criteria for DLT as outlined 
in Section 6.6.3 study treatment must be withheld. 
 Following resolution of the toxicity to ≤ Grade 1 or to the participant’s baseline value 
prior to worsening of AE, the participant may resume study treatment at the same or a 
lower dose level (Table 6-9) assessed to be safe, if there is no evidence of hematologic 
relapse, at the discretion of the treating Investigator. 
 If after siremadlin is resumed at a lower dose level, toxicity recurs with the same or worse 
severity, study treatment (siremadlin) must be discontinued permanently. 
 Criteria for dose modification for adverse drug reactions are summarized in Table 6-9. 
Graft-versus-host disease (GvHD) and study treatment dose modification  
GvHD following treatment with siremadlin monotherapy (dose confirmation 
monotherapy in Part 1, priming and/or maintenance phase in Part 2):  
 For GvHD [acute (per Harris et al 2016) and/or chronic (per NIH criteria)] meeting DLT 
definition and/or GvHD requiring systemic anti-GvHD therapy: Interrupt siremadlin. 
 Assessment and treatment of GvHD will be at the discretion of the treating physician and 
per the local standard of practice (see Section 8.4.4.1 and Section 8.4.4.2 for details). 
 For acute GvHD ≤ Grade II and/or mild chronic GvHD and/or moderate chronic GvHD 
excluding lung: 
 If systemic anti-GvHD therapy is not required, maintain siremadlin at the same dose 
level. 
 If systemic anti-GvHD therapy is required, interrupt siremadlin. Upon improvement 
of GvHD to ≤ Grade I for acute and/or to ≤ mild for chronic, and persistence of 
improvement for at least 2 weeks, resuming siremadlin is permitted as monotherapy, 
at the discretion of the treating investigator at the same dose level. 
 If GvHD symptoms reoccur or worsen following re-initiation of siremadlin requiring 
systemic anti-GvHD therapy:  
 Interrupt siremadlin. 
 GvHD treatment per the local standard of practice. 


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 Upon improvement of GvHD to ≤ Grade I for acute and/or to ≤ mild for chronic, 
and persistence of improvement for at least 2 weeks, resuming siremadlin is 
permitted as monotherapy, with a dose modification (decrease by one dose level). 
 If GvHD symptoms reoccur or worsen following re-initiation of siremadlin 
requiring systemic anti-GvHD therapy: Discontinue siremadlin permanently. 
 For acute GvHD Grade III: 
 Interrupt siremadlin. 
 GvHD treatment per the local standard of practice. 
 Upon improvement of acute GvHD to ≤ Grade I, and persistence of improvement for 
at least 2 weeks, resuming siremadlin is permitted as monotherapy, with a dose 
modification (decrease by one dose level). 
 If GvHD symptoms reoccur or worsen following re-initiation of siremadlin requiring 
systemic GvHD therapy: Discontinue siremadlin permanently. 
 For acute GvHD Grade IV and/or moderate chronic lung GvHD and/or severe chronic 
GvHD: Discontinue siremadlin permanently. 
 Continuation of systemic anti-GvHD treatment is allowed when resuming siremadlin. 
Note: Caution with drug-drug interaction between siremadlin and anti-GvHD medications 
with narrow therapeutic index substrates of CYP3A (e.g. tacrolimus, cyclosporine, 
sirolimus), and drug level monitoring and dose adjustment must be followed as outlined in 
Section 6.2.2.1. 
 If GvHD occurs following siremadlin monotherapy during priming phase (Part 2):  
 For acute GvHD Grade I and/or mild chronic GvHD, participant may proceed to 
DLI/siremadlin combination phase when all eligibility criteria to receive DLI are met 
without delay. 
 For acute GvHD Grade II GvHD, DLI/siremadlin combination phase should be 
delayed and the participant should receive an additional cycle of siremadlin 
monotherapy before proceeding to DLI/siremadlin combination. 
 In case of development of Grade III/IV acute GvHD and/or moderate/severe chronic 
GvHD during priming phase, the participant will not be eligible to receive any DLI in 
combination with siremadlin. 
GvHD following treatment with siremadlin/DLI in combination phase (Part 2): 
In case of development of GvHD [new onset GvHD of any severity, or worsening of preexisting 
GvHD from priming phase] during siremadlin/DLI combination phase: 
 No additional DLI dose(s) should be administered (permanent discontinuation of 
subsequent DLI). 
 Treatment of GvHD will be at the discretion of the treating physician and per the local 
standard of practice. 
 For GvHD (acute or chronic) requiring systemic anti-GvHD therapy: Interrupt siremadlin. 
 Following permanent discontinuation of DLI due to development of GvHD, proceeding to 
maintenance phase with siremadlin monotherapy is permitted, if GvHD has improved to ≤ 


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Grade I for acute and/or to ≤ mild for chronic, and persistence of improvement for at least 
2 weeks.  
 For acute GvHD ≤ Grade II and/or mild chronic GvHD and/or moderate chronic GvHD 
excluding lung: 
 Upon improvement of GvHD to ≤ Grade I for acute and/or to ≤ mild for chronic, and 
persistence of improvement for at least 2 weeks: Proceed to maintenance phase with 
siremadlin monotherapy at the same dose level. 
 If GvHD symptoms reoccur or worsen following re-initiation of siremadlin requiring 
systemic anti-GvHD therapy: 
 Interrupt siremadlin. 
 Continue GvHD treatment per the local standard of practice. 
 Upon improvement of GvHD to ≤ Grade I for acute and/or to ≤ mild for chronic, 
and persistence of improvement for at least 2 weeks, resuming siremadlin is 
permitted as monotherapy, with a dose modification (decrease by one dose level). 
 If GvHD symptoms reoccur or worsen following re-initiation of siremadlin 
requiring systemic anti-GvHD therapy: Discontinue siremadlin permanently. 
 For acute GvHD Grade III-IV and/or moderate chronic lung GvHD and/or severe chronic 
GvHD: 
 Upon improvement of GvHD to ≤ Grade I for acute and/or to ≤ mild for chronic, and 
persistence of improvement for at least 2 weeks: Proceed to maintenance phase 
with siremadlin monotherapy with a dose modification (decrease by one dose level). 
 If GvHD symptoms reoccur or worsen following re-initiation of siremadlin requiring 
systemic anti-GvHD therapy: Discontinue siremadlin permanently. 
 Continuation of systemic GvHD treatment is allowed when resuming siremadlin. Note: 
Caution with drug-drug interaction between siremadlin and anti-GvHD medications with 
narrow therapeutic index substrates of CYP3A (e.g. tacrolimus, cyclosporine, sirolimus), 
and drug level monitoring and dose adjustment must be followed as outlined in 
Section 6.2.2.1 . 
 Participants who tolerate siremadlin monotherapy re-initiation as the maintenance phase 
of treatment may continue as planned. 
Table 6-9 
Criteria for dose reduction / interruption and re-initiation of siremadlin 
treatment for adverse drug reactions. 
Dose modifications for siremadlin  
Worst toxicity CTCAE v5.0 Gradea 
Recommended dose modification 
Hematology 
Neutropenia (ANC) 
Grade 1 (ANC < LLN - 1500/mm3) and 
Grade 2 (ANC < 1500 - 1000/mm3) 
Maintain siremadlin dose level without interruption 
Grade 3 (ANC <1000 - 500/mm3) 
● Interrupt siremadlin and monitor blood count twice weekly 
● When neutropenia is resolved to ≤ Grade 2, resume siremadlin at 
the same dose level 
● Granulocyte-Colony Stimulating Factor (G-CSF)/myeloid growth 


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factors may be administered at the discretion of the treating 
Investigator, in accordance with local standard of practice 
Grade 4 (ANC <500/mm3) 
Interrupt siremadlin and monitor blood count twice weekly 
When neutropenia is resolved to ≤ Grade 2, resume siremadlin with 
a dose modification (decrease by one dose level) 
● G-CSF/myeloid growth factors may be administered at the 
discretion of the treating Investigator, in accordance with local 
standard of practice 
Grade ≥ 3 febrile neutropenia 
● Interrupt siremadlin and monitor blood count twice weekly 
● Treatment of febrile neutropenia per local standard of practice 
● When neutropenia is resolved to ≤ Grade 2, resume siremadlin 
with a dose modification (decrease by one dose level) 
● G-CSF/myeloid growth factors may be administered at the 
discretion of the treating Investigator, in accordance with local 
standard of practice 
Thrombocytopenia 
Grade 1 (PLT < LLN - 75,000/mm3) and 
Grade 2 (PLT < 75,000 - 50,000/mm3) 
Maintain siremadlin dose level without interruption 
Grade 3 (PLT < 50,000 - 25,000/mm3) 
without clinically significant bleeding 
● Interrupt siremadlin and monitor blood count twice weekly 
● When thrombocytopenia is resolved to ≤ Grade 2, resume 
siremadlin at the same dose level 
● Platelet (PLT) transfusion, supportive care and management of 
bleeding may be administered at the discretion of the treating 
Investigator, in accordance with local standard of practice 
Grade ≥ 3 thrombocytopenia with 
clinically significant bleeding 
● Interrupt siremadlin and monitor blood count twice weekly 
● When thrombocytopenia is resolved to ≤ Grade 2, resume 
siremadlin with a dose modification (decrease by one dose level) 
● Management of bleeding, platelet transfusion and supportive care 
in accordance with local standard of practice 
Grade 4 (PLT < 25,000/mm3) 
Interrupt siremadlin and monitor blood count twice weekly 
When thrombocytopenia is resolved to ≤ Grade 2, resume 
siremadlin with a dose modification (decrease by one dose level) 
● Platelet transfusion, supportive care and management of bleeding 
may be administered at the discretion of the treating Investigator, in 
accordance with local standard of practice 
Renal: serum creatinine  
Grade 1 (> ULN - 1.5 x ULN) 
Maintain siremadlin dose level without interruption 
Grade 2 (> 1.5 - 3.0 x baseline; > 1.5 – 
3.0 x ULN) 
● Interrupt siremadlin 
● Assess potential etiologies for elevated creatinine in the post-allo-
SCT setting. 
● Upon resolution to ≤ Grade 1 or baseline value prior to worsening 
of AE, resume siremadlin at the same dose level 
● If serum creatinine elevation reoccurs as ≥ Grade 2 after resuming 
siremadlin: 
● Interrupt siremadlin 
● Upon resolution to ≤ Grade 1 or baseline value prior to worsening 
of AE, may resume siremadlin with a dose modification 
(decrease by one dose level) 
Grade 3 (> 3.0 x baseline; >3.0 - 6.0 x 
ULN) 
Interrupt siremadlin until resolution to ≤ Grade 1 or baseline 
value prior to worsening of AE, then resume siremadlin with a dose 
modification (decrease by one dose level) 
Grade 4 (> 6.0 x ULN) 
Discontinue siremadlin 


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Hepatic (not attributed to liver GvHD): Also refer to Table 6-11 and Table 6-12 for follow up of abnormal 
liver chemistry results.  
Isolated total bilirubin elevation 
Grade 1 (> ULN - 1.5 x ULN if baseline 
was normal; > 1.0 - 1.5 x baseline if 
baseline was abnormal) 
Maintain siremadlin dose level without interruption 
Grade 2 (> 1.5 - 3.0 x ULN if baseline 
was normal; > 1.5 - 3.0 x baseline if 
baseline was abnormal)  
● Interrupt siremadlin 
● Repeat liver function tests (LFTs)b at least weekly, or more 
frequently if clinically indicated, until resolved to ≤ 1.5 x ULN or to 
baseline. 
● Upon resolution to ≤ Grade 1 or baseline value prior to worsening 
of AE, resume siremadlin at the same dose level 
● If total bilirubin elevation reoccurs as ≥ Grade 2 after resuming 
siremadlin: 
 
● Interrupt siremadlin 
 
● Upon resolution to ≤ Grade 1 or baseline value prior to 
worsening of AE, may resume siremadlin with a dose modification 
(decrease by one dose level) 
Grade 3 (> 3.0 - 10.0 x ULN if baseline 
was normal; > 3.0 - 10.0 x baseline if 
baseline was abnormal) 
● Interrupt siremadlin 
● Repeat LFTsb within 48-72 hours from awareness of the abnormal 
results, then monitor LFTs weekly, or more frequently if clinically 
indicated, until resolved to ≤ Grade 1 or to baseline value prior to 
worsening of AE 
● If total bilirubin > 3.0 x ULN is due to the indirect (non-conjugated) 
component only, assess for hemolysis as the etiology per 
institutional guidelines (e.g. review of peripheral blood smear and 
haptoglobin determination) 
● Upon resolution to ≤ Grade 1 or baseline value prior to worsening 
of AE, may consider resuming siremadlin with a dose modification 
after discussion with the Novartis Medical Monitor 
Grade 4 (> 10.0 x ULN if baseline was 
normal; > 10.0 x baseline if baseline 
was abnormal)* 
● Discontinue siremadlin 
● Repeat LFTsb as soon as possible, preferably within 48-72 hours 
from awareness of the abnormal results; then monitor weekly, or as 
clinically indicated, until resolved to baseline or stabilization over 4 
weeks 
Isolated AST or ALT elevation  
Grade 1 (> ULN - 3.0 x ULN if baseline 
was normal; 1.5 - 3.0 x baseline if 
baseline was abnormal) 
Maintain siremadlin dose level without interruption 
Grade 2 (> 3.0 - 5.0 x ULN if baseline 
was normal; > 3.0 - 5.0 x baseline if 
baseline was abnormal) 
● Interrupt siremadlin 
● Repeat LFTsb at least weekly, or more frequently if clinically 
indicated, until resolved to ≤ Grade 1 or to baseline 
● Upon resolution to ≤ Grade 1 or baseline value prior to worsening 
of AE, resume siremadlin at the same dose level 
● If AST or ALT elevation reoccurs as ≥ Grade 2 after resuming 
siremadlin: 
 
● Interrupt siremadlin 
 
● Upon resolution to ≤ Grade 1 or baseline value prior to 
worsening of AE, may resume siremadlin with a dose modification 
(decrease by one dose level) 
Grade 3 (> 5.0 - 20.0 x ULN if baseline 
was normal; > 5.0 - 20.0 x baseline if 
baseline was abnormal) 
● Interrupt siremadlin 
● Repeat LFTsb within 48-72 hours from awareness of the abnormal 
results, then monitor LFTs weekly, or more frequently if clinically 
indicated, until resolved to ≤ Grade 1 or to baseline  
● Upon resolution to ≤ Grade 1 or baseline value prior to worsening 
of AE, may consider resuming siremadlin with a dose modification 
after discussion with the Novartis Medical Monitor 


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Grade 4 (> 20.0 x ULN if baseline was 
normal; > 20.0 x baseline if baseline 
was abnormal) 
● Discontinue the treatment 
● Repeat LFTsb as soon as possible, preferably within 48-72 hours 
from awareness of the abnormal results; then monitor LFTsb weekly, 
or more frequently if clinically indicated, until resolved to baseline or 
stabilization over 4 weeks 
Combined c elevations of AST or ALT and total bilirubin 
● For participants with normal baseline 
ALT and AST and total bilirubin value:  
 
● AST or ALT > 3.0 x ULN 
combined with total bilirubin > 2.0 x 
ULN without evidence of cholestasisd 
OR 
● For participants with elevated 
baseline AST or ALT or total bilirubin 
value:  
 
● AST or ALT > 2 x baseline OR > 
300 U/L (whichever occurs first) and 
Total bilirubin > 2 x ULN 
OR 
● AST or ALT > 2 x baseline OR > 300 
U/L (whichever occurs first) and Total 
bilirubin normal or elevated with liver 
symptoms. 
**Note: For participants with Gilbert’s 
syndrome, at least 2-fold increase in 
direct bilirubin. 
● Interrupt treatment and assess for potential DILI as a causality 
● Repeat as soon as possible, preferably within 48 hours from 
awareness of the abnormal results, then with weekly monitoring of 
LFTsb, or as clinically indicated, until AST, ALT, or total bilirubin 
have resolved ≤ Grade 1 or to baseline. 
(Refer to the Section 6.6.5.1 for additional follow-up evaluations as 
applicable.) 
● If DILI (causality indicates drug-related): Permanently discontinue 
siremadlin 
● If not DILI (causality is not related): Treat the identified cause 
according to institutional guidelines. Once resolved, may resume 
siremadlin at the same dose level. 
Asymptomatic amylase and/or lipase elevation 
Grade 1 (> ULN - 1.5 x ULN) 
without symptoms or clinical 
manifestations of pancreatitis 
Maintain siremadlin dose level without interruption 
Grade 2 (> 1.5 - 2.0 x ULN; > 2.0 - 5.0 
x ULN without symptoms or clinical 
manifestations of pancreatitis) 
● Interrupt siremadlin 
● Upon resolution to ≤ Grade 1 or baseline value prior to worsening 
of AE, may resume siremadlin at the same dose level 
Grade 3 (> 5.0 x ULN without 
symptoms or clinical manifestations of 
pancreatitis) 
● Interrupt siremadlin. 
● A Computed Tomography (CT) scan or other imaging study to 
assess the pancreas, liver, and gallbladder must be performed 
within one week of the first occurrence. 
● Upon resolution to ≤ Grade 1 or baseline value prior to worsening 
of AE, may resume siremadlin at the same dose level 
● If amylase and/or lipase elevation reoccur as ≥ Grade 2 after 
resuming siremadlin: 
 
● Interrupt siremadlin 
 
● Upon resolution to ≤ Grade 1 or baseline value prior to 
worsening of AE, may resume siremadlin with a dose modification 
(decrease by one dose level) 
Gastrointestinal 
Pancreatitis 
Grade 2 
● Interrupt siremadlin 
● Manage per institutional practice 
● Upon resolution, may resume siremadlin at the same dose level, if 
no clinical evidence of pancreatitis and after discussion with the 
Novartis Medical Monitor 
Grade ≥ 3 
● Interrupt siremadlin 
● A CT scan or other imaging study to assess the pancreas, liver, 
and gallbladder must be performed within one week of the first 
occurrence of Grade ≥ 3 


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● If pancreatic pathology or other etiologies have been identified, 
may consider resuming siremadlin upon resolution, after discussion 
with the Novartis Medical Monitor 
Diarrhea*** (not attributed to GI GvHD) 
Grade 1 
● Maintain siremadlin dose level without interruption 
● Apply/ modify anti-diarrheal treatment 
Grade 2 
● Interrupt siremadlin 
● Apply/ modify anti-diarrheal treatment per institutional guidelines 
● Upon resolution to ≤ Grade 1 or baseline value prior to worsening 
of AE, resume siremadlin at the same dose level. 
● If diarrhea reoccurs as ≥ Grade 2: 
 
● Interrupt siremadlin 
 
● Upon resolution to ≤ Grade 1 or baseline value prior to 
worsening of AE, may resume siremadlin with a dose 
modification(decrease by one dose level) 
Grade 3 
● Interrupt siremadlin 
● Apply/ modify anti-diarrheal treatment per institutional guidelines 
● Upon resolution to ≤ Grade 1 or baseline value prior to worsening 
of AE: 
 
● If resolved within < 3 days of starting anti-diarrhea treatment, 
resume siremadlin at the same dose level 
 
● If resolved within ≥ 3 days of starting anti-diarrhea treatment, 
may resume siremadlin with a dose modification (decrease by one 
dose level) 
Grade 4 
Discontinue siremadlin 
Nausea and/or Vomiting (n/v) (not attributed to GI GvHD) 
Grade 1 
● Maintain siremadlin dose level without interruption 
● Apply/ modify anti-emetic treatments 
Grade 2 
● Interrupt siremadlin  
● Apply/ modify anti-emetic treatments per institutional guidelines 
● Upon resolution of n/v to ≤ Grade 1 or baseline value prior to 
worsening of AE, resume siremadlin at the same dose level 
● If n/v reoccurs as ≥ Grade 2: 
 
● Interrupt siremadlin 
 
● Upon resolution to ≤ Grade 1 or baseline value prior to 
worsening of AE, may resume siremadlin with a dose modification 
(decrease by one dose level) 
Grade 3 
● If n/v cannot be controlled with anti-emetic treatments, interrupt 
siremadlin. 
● Upon resolution of n/v to Grade ≤ 1 or baseline value prior to 
worsening of AE: 
 
● If n/v resolved in < 48 hours, resume siremadlin at the same 
dose level 
 
● If n/v resolved in ≥ 48 hours, consider resuming 
siremadlin with a dose modification (decrease by one dose level) 
Grade 4 
Discontinue siremadlin 
Cardiovascular  
ECG QTc-Interval prolonged 
Grade 3 (Average QTc ≥ 501 ms; or > 
60 ms change from baseline) 
● Interrupt siremadlin  
● See Section 6.6.5.2 for evaluation and follow up. 
● Upon resolution to ≤ Grade 1 or baseline value prior to worsening 
of AE, may consider resuming siremadlin after discussion with the 
Novartis Medical Monitor 
Grade 4 
Discontinue siremadlin 


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Skin and subcutaneous tissue disorders 
Rash/photosensitivity (excluding acute or chronic skin GvHD by the investigator assessment) 
Grade 1 
● Maintain siremadlin dose level without interruption 
● Consider initiating appropriate skin toxicity therapy (such as 
antihistamines, topical corticosteroids) 
Grade 2 
● Continue siremadlin without dose modification 
● Initiate/intensify appropriate skin toxicity therapy (such as 
antihistamines, topical corticosteroids) 
Grade 3, despite skin toxicity therapy 
● Interrupt siremadlin until resolution to ≤ Grade 1 or 
baseline value prior to worsening of AE  
● Consider Dermatology consultation and skin biopsy to exclude 
GvHD or other etiologies as clinically appropriate 
● Upon resolution to ≤ Grade 1 or baseline value prior to worsening 
of AE: 
 
● If resolved in ≤ 14 days, resume siremadlin with a dose 
modification (decrease by one dose level) 
 
● If resolved in > 14 days (despite appropriate skin toxicity 
therapy): discontinue siremadlin 
Grade 4, despite skin toxicity therapy 
Discontinue siremadlin 
Other adverse events 
Grade 1 
Maintain siremadlin dose level without interruption 
Grade 2 
● Siremadlin interruption may be considered, at Investigator 
discretion, and if the events are non-manageable by symptomatic 
therapy 
● Upon resolution to ≤ Grade 1 or baseline value prior to worsening 
of AE, resume siremadlin at the same dose level 
Grade 3 
● Interrupt siremadlin 
● Upon resolution to ≤ Grade 1 or baseline value prior to worsening 
of AE, resuming siremadlin must be discussed with the Novartis 
Medical Monitor 
Grade 4 
● Discontinue siremadlin 
● If resuming siremadlin is being considered (based on the adverse 
event, identified etiology, and upon resolution to ≤ Grade 1), it must 
be discussed with the Novartis Medical Monitor 
a Common Toxicity Criteria for Adverse Events (CTCAE Version 5.0) 
b Core LFTs consist of ALT, AST, GGT, total bilirubin (fractionated [direct and indirect], if total bilirubin > 2.0 x 
ULN), and alkaline phosphatase (ALP) (fractionated [quantification of isoforms], if ALP > 2.0 x ULN). 
c “Combined” defined as total bilirubin increase to the defined threshold concurrently with ALT/AST increase to 
the defined threshold.  
d “Cholestasis” defined as ALP elevation (> 2.0 xULN and R value <2) in participants without bone pathology or 
elevation of ALP liver fraction in participants with bone pathology. 
*Note: The R value is calculated by dividing the ALT by the ALP, using multiples of the ULN for both values. It 
denotes whether the relative pattern of ALT and/or ALP elevation is due to cholestatic (R ≤ 2), hepatocellular 
(R ≥ 5), or mixed (R > 2 and < 5) liver injury. 
**Note: Bilirubin can be elevated either as part of a “Hy’s law” constellation with a preceding elevation of 
ALT/AST, or as part of a cholestatic reaction with simultaneous elevation of other cholestatic parameters (ALP, 
Gamma-glutamyl transferase (GGT)). Isolated bilirubin can be seen in conjunction with treatments that inhibit 
bilirubin conjugation or excretion. Alternative causes of bilirubin elevation should be ruled out. If combined 
elevations of AST or ALT and total bilirubin do not meet the defined thresholds, please follow the instructions 
for isolated elevation of total bilirubin and isolated elevation of AST/ALT, and take a conservative action based 
on the degree of the elevations (e.g. discontinue treatment at the situation when omit dose is needed for one 
parameter and discontinue treatment is required for another parameter). After all elevations resolve to the 
defined thresholds that allow treatment re-initiation, re-start the treatment either at the same dose or at one 
dose lower if meeting a criterion for dose reduction. 
*** Note: Anti-diarrheal medication is recommended at the first sign of abdominal cramping, loose stools, or 
overt diarrhea. 


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6.6.5 
Follow-up for toxicities 
Participants whose treatment is interrupted or permanently discontinued due to an adverse event 
or clinically significant laboratory value, must be followed up at least once a week (or more 
frequently if required by institutional practices, or if clinically indicated) for 4 weeks, and 
subsequently at approximately 4-week intervals, until resolution or stabilization of the event, 
whichever comes first. 
Appropriate clinical specialists for specific toxicities, such as cardiologist, gastroenterologist, 
etc., should be consulted as deemed necessary. All participants must be followed up for adverse 
events and serious adverse events for 30 days following the last doses of siremadlin. 
Table 6-10 outlines the follow-up evaluation recommended for toxicities of specific types and 
CTCAE grades. 
Table 6-10 
Follow-up evaluations for selected toxicities  
TOXICITY 
FOLLOW-UP EVALUATION 
Hematologic: 
Neutropenia ≥ CTCAE grade 3 
Thrombocytopenia ≥ CTCAE grade 3 
Test twice weekly until ≤ CTCAE grade 2 
Continue to test weekly until resolution to baseline or stabilization. 
Monitor for bleeding and infections. 
Pancreatic 
Amylase or lipase ≥ CTCAE grade 3 
Test twice weekly until ≤ CTCAE grade 2. 
Continue to test weekly until resolution to ≤ CTCAE grade 1 or 
stabilization. 
A CT scan or equivalent imaging procedure to assess the pancreas, 
liver, and gallbladder is recommended within 7 days of the first 
occurrence of any ≥ CTCAE grade 3 result. 
In participants with serum triglycerides ≥ 500 mg/dL, urine amylase 
also needs to be tested. 
Cardiac disorders 
QT and ECG 
ECG changes indicative of ischemic 
event 
Twice weekly ECGs until normalization or stabilization of ECG 
findings. 
6.6.5.1 
Follow up on potential drug-induced liver injury (DILI) cases 
Increased transaminases (AST/ALT) combined with increased total bilirubin (TBIL) may be 
indicative of potentially severe DILI, and should be considered as clinically important events 
and assessed appropriately to establish the diagnosis.  
The threshold for potential DILI may depend on the participant’s baseline AST/ALT and TBIL 
value, as outlined in Table 6-11 and Table 6-12. 
As DILI is essentially a diagnosis of exclusion, other causes of abnormal liver tests should be 
considered and their role clarified before DILI is assumed as the cause of liver injury, as 
follows: 
1. A detailed assessment of potential treatment-emergent GvHD of liver (acute or chronic) 
should be performed by the Investigator. 
2. A detailed history, including relevant information, such as cardiac disease, history of any 
pre-existing liver conditions or risk factors, blood transfusions, IV drug abuse, travel, 
work, alcohol intake, and full clinical examination for evidence of acute or chronic liver 
disease, cardiac disease and infection etc. should be performed. 


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3. Review of concomitant medications, including nonprescription medications and herbal 
and dietary supplement preparations, alcohol use, recreational drug use, special diets, and 
chemicals exposed to within one month of the onset of the liver injury. 
4. Further testing for acute hepatitis A, B, C or E infection, other hepatotropic viral infection 
(eg, EBV, CMV, HSV, HHV-6, adenovirus, etc.), and autoimmune hepatitis may be 
warranted as clinically indicated and per standard of practice post-allo-SCT.  
5. Relevant Liver imaging (eg, biliary tract) and liver biopsy may be considered as clinically 
indicated or after consultation with specialist/hepatologist.  
6. Other causes should also be considered based upon participants’ medical history (eg, 
hyperthyroidism / thyrotoxic hepatitis – T3, T4, TSH; cardiovascular disease / ischemic 
hepatitis – ECG, echocardiogram, prior hypotensive episodes; Type 1 diabetes / 
glycogenic hepatitis). 
7. Obtain an unscheduled PK sample, as close as possible to last dose of study treatment, to 
determine exposure to study treatment and metabolites. 
If abnormalities are confirmed, close observation and follow-up are required. Guidelines for 
follow-up on potential DILI cases are described in Table 6-11 and Table 6-12. 
Following appropriate causality assessments, the causality of the treatment is estimated as 
“probable” ie, >50% likely, if it appears greater than all other possible causes of liver injury 
combined. The term “treatment-induced” indicates probably caused by the treatment, not by 
something else, and only such a case can be considered a DILI case and should be reported as 
an SAE. 
All cases confirmed on repeat testing meeting the laboratory criteria in Table 6-11 and 
Table 6-12, with no other alternative cause including liver GvHD for LFT abnormalities 
identified, should be considered as “medically significant,” and thus, meet the definition of SAE 
and should be reported as SAE using the term “potential treatment-induced liver injury.” All 
events should be followed up with the outcome clearly documented. 
Criteria for siremadlin dose modification (interruption, re-initiation, dose reduction or 
permanent discontinuation) for adverse drug reactions are listed in Table 6-9. 
Table 6-11 
Follow-up of abnormal liver chemistry results (not attributed to liver 
GvHD) 
ALT 
TBIL 
Liver symptoms 
Action 
ALT increase without bilirubin increase 
● If normal at baseline: 
ALT > 3 x ULN 
Normal. 
For participants with 
Gilbert’s syndrome: No 
change in baseline TBIL 
None 
● Measure liver function tests 
(LFTs) [alanine 
aminotransferase (ALT), 
aspartate aminotransferase 
(AST), alkaline phosphatase 
(ALP), gamma-glutamyl 
transferase (GGT), TBIL, direct 
and indirect bilirubin, albumin], 
prothrombin time 
(PT)/International Normalized 
Ratio (INR), lactate 
dehydrogenase (LDH), creatine 
kinase (CK), and glutamate 
● If elevated at baseline: 
ALT > 2 x baseline or > 
200 U/L (whichever 
occurs first) 


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ALT 
TBIL 
Liver symptoms 
Action 
dehydrogenase (GLDH) at least 
weekly or more frequently if 
clinically indicated, until resolved 
to ≤ Grade 1 or to baseline.  
● Follow-up for symptoms. 
● If normal at baseline: 
ALT > 5 x ULN for more 
than two weeks 
Normal. 
For participants with 
Gilbert’s syndrome: No 
change in baseline TBIL 
None 
● Measure LFTs [ALT, AST, 
ALP, GGT, TBIL, direct and 
indirect bilirubin, albumin], 
PT/INR, LDH, CK, and GLDH 
within 48-72 hours from 
awareness of the abnormal 
results, then monitor weekly or 
more frequently if clinically 
indicated, until resolved to ≤ 
Grade 1 or to baseline or 
stabilization over 4 weeks.  
● Follow-up for symptoms. 
● Initiate close monitoring and 
workup for competing etiologies. 
● If elevated at 
baseline: ALT > 3 x 
baseline or > 300 U/L 
(whichever occurs first) 
for more than two weeks 
● If normal at baseline: 
ALT > 8 x ULN 
Normal. 
For participants with 
Gilbert’s syndrome: No 
change in baseline TBIL 
None 
ALT increase with bilirubin increase 
● If normal at baseline: 
ALT > 3 x ULN 
TBIL > 2 x ULN (or INR > 
1.5) 
For participants with 
Gilbert’s syndrome: 
Doubling of direct 
bilirubin 
None 
● If elevated at baseline: 
ALT > 2 x baseline or > 
200 U/L (whichever 
occurs first) 
● If normal at baseline: 
ALT > 3 x ULN 
Normal or elevated 
Severe fatigue, 
nausea, vomiting, 
right upper 
quadrant pain 
● If elevated at baseline: 
ALT > 2 x baseline or > 
200 U/L (whichever 
occurs first) 
Table 6-12 
Action required for isolated total bilirubin elevation 
Abnormality 
Action required 
Any elevation > ULN 
Fractionate bilirubin, evaluate for cholestatic liver injury (ALP) or 
alternative causes of bilirubin elevation. Treat alternative causes 
according to local institutional guidelines. 
Grade 2 (>1.5 - 3.0 x ULN if baseline was 
normal; >1.5 - 3.0 x baseline if baseline 
was abnormal) 
Repeat LFTs at least weekly or more frequently if clinically 
indicated, until resolution to ≤ Grade 1 or to baseline. 
Grade 3 (>3.0 - 10.0 x ULN if baseline 
was normal; >3.0 - 10.0 x baseline if 
baseline was abnormal) 
Repeat LFTs within 48-72 hours from awareness of the abnormal 
results, then monitor LFTs weekly or more frequently if clinically 
indicated, until resolved to ≤ Grade 1 or to baseline. 
Grade 4 (>10.0 x ULN if baseline was 
normal; >10.0 x baseline if baseline was 
abnormal) 
Repeat LFTs as soon as possible, preferably within 48-72 hours 
from awareness of the abnormal results; then monitor 
LFTs weekly, or more frequently if clinically indicated, until 
resolved to baseline or stabilization over 4 weeks. 
The participant should be monitored clinically at least weekly or as 
clinically indicated, until stabilization of bilirubin. 
Note: Bilirubin can be elevated either as part of a “Hy’s law” constellation with a preceding elevation of 
ALT/AST, or as part of a cholestatic reaction with simultaneous elevation of other cholestatic parameters (ALP, 
GGT). Isolated bilirubin can be seen in conjunction with treatments that inhibit bilirubin conjugation or excretion. 
Alternative causes of bilirubin elevation should be ruled out. 


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6.6.5.2 
Follow up for QTcF Prolongation 
In case QTcF > 500 ms (or QTcF prolongation >60 ms from baseline): 
 Assess the quality of the ECG recording. Collect two additional ECGs as soon as possible 
and submit the triplicate for central review. 
 A time-matched PK sample for siremadlin should be collected just after the triplicate ECGs 
are performed due to prolonged QTc, and to record the time and date of the last siremadlin 
intake to determine the drug exposure. 
 Determine the serum electrolyte levels (in particular hypokalemia, hypomagnesemia, 
hypocalcemia). If abnormal, correct abnormalities. 
 Review concomitant medication use for possible causes for QT prolongation (refer to 
crediblemedicines.org). Record all concomitant medications in the appropriate eCRF page. 
 Monitor ECG per the institutional standards (e.g. twice weekly ECGs until normalization 
or stabilization of ECG findings).  
 If resuming siremadlin is considered upon resolution to ≤ Grade 1 or baseline, monitor 
ECGs closely pre- and post-dose (Table 8-11) with a time-matched PK samples at the same 
time point as ECG taken immediately after ECG (Table 8-12 ).  
6.7 
Additional treatment guidance 
6.7.1 
Treatment compliance 
Every time study drug siremadlin is to be administered, IRT must be contacted to register the 
drug dispensed and/or assign a medication (kit) number. 
For study drug taken at home (e.g. for capsules of siremadlin on dosing days participants do not 
go to the clinic), the investigator must promote compliance by instructing the participant to take 
the study drugs exactly as prescribed and by stating that compliance is necessary for the 
participant’s safety and the validity of the study. The participant must also be instructed to 
contact the investigator if he/she is unable for any reason to take the study drug as prescribed. 
Compliance will be assessed by the investigator and/or study personnel at each visit using pill 
counts and information provided by the participant. This information should be captured in the 
source document at each visit. 
DLI will be administered in the clinic or as per local institutional practice. 
The date and time of the study treatment administration (siremadlin) and DLI during the study 
and any deviations from the protocol treatment schedule will be captured by the investigator 
staff on the appropriate study drug dispensing form. Compliance with the study treatment and 
any protocol deviations will be assessed by the field monitor on an ongoing basis. All study 
drug dispensed and returned (if applicable) must be recorded in the Drug Accountability Log. 
Pharmacokinetic parameters (measures of siremadlin) will be determined in all participants 
treated with Siremadlin, as detailed in pharmacokinetics section. 
6.7.2 
Emergency breaking of assigned treatment code 
Not applicable 


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7 
Informed consent procedures 
The Investigator or his/her representative will explain the nature of the study, including the risks 
and benefits, to the participant or their legally authorized representative (defined as [X]) and 
answer all questions regarding the study. 
Participants must be informed that their participation is voluntary. Participants or their legally 
authorized representatives will be required to sign a statement of informed consent that meets 
the requirements of 21 CFR 50, local regulations, ICH guidelines, privacy and data protection 
requirements, where applicable, 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. 
Eligible participants may only be included in the study after providing (witnessed, where 
required by law or regulation), IRB/IEC-approved informed consent. 
If applicable, in cases where the participant's representative(s) gives consent (if allowed 
according to local requirements), the participant must be informed about the study to the extent 
possible given his/her level of understanding. If the participant is capable of doing so, he/she 
must indicate agreement by personally signing and dating the written informed consent 
document. 
Informed consent must be obtained before conducting any study-specific procedures (e.g. all of 
the procedures described in the protocol). The process of obtaining informed consent must be 
documented in the participant source documents. 
Novartis will provide to investigators in a separate document a proposed informed consent form 
that complies with the ICH E6 GCP guidelines and regulatory requirements and is considered 
appropriate for this study. Any changes to the proposed consent form suggested by the 
investigator must be agreed by Novartis before submission to the IRB/IEC. 
Information about common side effects already known about the investigational treatment can 
be found in the Investigator's Brochure (IB) . This information will be included in the participant 
informed consent and should be discussed with the participant during the study as needed. Any 
new information regarding the safety profile of the investigational drug that is identified 
between IB updates will be communicated as appropriate, for example, via an investigator 
notification or an aggregate safety finding. New information might require an update to the 
informed consent and then must be discussed with the participant. 
The following informed consents are included in this study: 
 Main study consent, which also included:  
 A subsection that requires a separate signature for the ‘Optional Consent for Additional 
Research’ to allow future research on data/samples collected during this study. 
 As applicable, Pregnancy Outcomes Reporting Consent for female participants or the 
female partners of any male participants who took study treatment. 
 Patient information sheet for female partners of any male participants who took study 
treatment. 


Novartis 
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Amended Protocol Version 02 (Clean) 
 
Protocol No. CHDM201K12201 
 
 
Women of child-bearing potential must be informed that taking the study treatment may involve 
unknown risks to the fetus if pregnancy were to occur during the study and agree that in order 
to participate in the study they must adhere to the contraception requirements. 
Male participants must be informed that if a female partner becomes pregnant while he is 
enrolled in the study, contact with the female partner will be attempted to request her consent 
to collect pregnancy outcome information. 
A copy of the approved version of all consent forms must be provided to Novartis after IRB/IEC 
approval. 
As per Section 4.6, during a public health emergency as declared by local or regional authorities 
i.e. pandemic, epidemic or natural disaster, that may challenge the ability to obtain a standard 
written informed consent due to limits that prevent an on-site visit, Investigator may conduct 
the informed consent discussion remotely (e.g. telephone, videoconference) if allowable by a 
local health authority. 
Guidance issued by local regulatory bodies on this aspect prevail and must be implemented and 
appropriately documented (e.g. the presence of an impartial witness, sign/dating separate ICFs 
by trial participant and person obtaining informed consent, etc.). 
8 
Visit schedule and assessments 
The Assessment Schedule Table 8-1, Table 8-2, Table 8-3, and Table 8-4 lists all of the 
assessments when they are performed. All data obtained from these assessments must be 
supported in the participant’s source documentation. 
Participants should be seen (or contacted during safety and survival follow-up) for all 
visits/assessments as outlined in the assessment schedule Table 8-1, Table 8-2, Table 8-3, and 
Table 8-4 or as close to the designated day/time as possible. Missed or rescheduled visits should 
not lead to automatic discontinuation. 
The “X” in the table denotes the assessments to be recorded in the clinical database or received 
electronically from a vendor. The “S” in the table denotes the assessments that are only in the 
participant’s source documentation and do not need to be recorded in the clinical database. 
Each treatment cycle in dose confirmation siremadlin monotherapy (Part 1), priming and 
maintenance phase (Part 2) is 28 days. Each treatment cycle in combination phase (Part 2) is 42 
days. Screening evaluations should be performed within ≤ 28 days of C1D1 (except for the 
pregnancy test which has to be performed within 72 hours before the first dose). 
During the course of the study, visits, test and/or procedures should occur on schedule whenever 
possible. A visit window of +/- 3 days is allowed for study procedures (including treatment 
administration). See Section 6.1 for details on study treatment. A window of - 7 days from the 
planned visit date is allowed for bone marrow aspirate (BMA) procedures before starting 
siremadlin day 1 of the planned visit. Further, a maximum of +/- 7 days is allowed between 
BMA efficacy, extramedullary disease assessment (if applicable) and hematology assessments 
of the same visit except at assessments directly prior to DLI administration (combination phase) 
which have a maximum window of - 14 days. 


Novartis 
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Amended Protocol Version 02 (Clean) 
 
Protocol No. CHDM201K12201 
 
 
Note: If a treatment cycle is delayed at any time during the study, all study visits and safety and 
efficacy assessments should continue according to the appropriate number of calendar days 
measured from Day 1 of the previous cycle, or more often if clinically indicated. When 
treatment is resumed, the first day of study treatment administration will be considered as Day 
1 of the new treatment cycle and visit schedule will be shifted accordingly. 
On PK collection days the windows are provided in Section 8.5.1 . 
Participants who discontinue the study treatment for any reason should be scheduled for an end 
of treatment (EOT) visit as soon as possible and within 14 days from the decision to 
permanently discontinue study treatment, at which time all of the assessments listed for the 
EOT visit will be performed. After discontinuation of study treatment, participants will be 
followed for post-treatment assessments and survival. During the survival follow-up and post 
treatment follow-up, a visit window of +/- 14 days is allowed.  
For information on post-treatment and survival follow-ups, please refer toSection 9.1.1. 
As per Section 4.6, during a public health emergency as declared by local or regional authorities 
i.e. pandemic, epidemic or natural disaster that limits or prevents on-site study visits, alternative 
methods of providing continuing care may be implemented by the investigator as the situation 
dictates. If allowable by a local health authority, national and local regulations and depending 
on operational capabilities, phone calls, virtual contacts (e.g. tele consult) or visits by site staff/ 
off-site healthcare professional(s) staff to the participant´s home, can replace certain protocol 
assessments, for the duration of the disruption until it is safe for the participant to visit the site 
again. If the Investigator delegates tasks to an off-site healthcare professional, the Investigator 
must ensure the individual(s) is/are qualified and appropriately trained to perform assigned 
duties. The Investigator must oversee their conduct and remain responsible for the evaluation 
of the data collected.  


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Amended Protocol Version 02 (Clean) 
 
 
Protocol No. CHDM201K12201 
 
 
Table 8-1 
Assessment Schedule, Dose confirmation siremadlin monotherapy (Part 1)  
Period 
Part 1: Siremadlin monotherapy - Cycles duration: 28 days 
End of Treatment of dose 
confirmation phase 
Safet
y 
Follo
w-up 
Post-
Treatme
nt 
Follow-
up 
Survival 
Follow-
up 
Cycle 
 
Cycle 1 
Cycle 2 
Cycle 3 (and subsequent cycles, 
if required) 
 
 
 
 
Visit Name SCREEN
ING 
CO
NF 
C1D
1 
CON
F 
C1D
5 
CON
F 
C1D
8 
CON
F 
C1D
15 
CO
NF 
C2D
1 
CO
NF 
C2D
8 
CON
F 
C2D
15 
CONF CxD1 
EOT CONF 
Safet
y 
Follo
w-up 
Post-
Treatme
nt 
Follow-
up 
Survival 
Follow-
up 
Days 
-28 to 
-1 
D1 
D5 
D8 
D15 
D1 
D8 
D15 
D1 
- 
30 
days 
after 
EOT 
Every 6 
mo until 
EOS 
(End of 
Study) 
every 3 
mo until 
EOS 
Informed 
Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
IRT 
Registration 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
Demograph
y 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/ 
Exclusion 
criteria 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Medical 
history/curr
ent medical 
conditions1 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Disease 
History2 
X 
 
 
 
 
 
 
 
 
 
 
 
 


Novartis 
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Amended Protocol Version 02 (Clean) 
 
 
Protocol No. CHDM201K12201 
 
 
Period 
Part 1: Siremadlin monotherapy - Cycles duration: 28 days 
End of Treatment of dose 
confirmation phase 
Safet
y 
Follo
w-up 
Post-
Treatme
nt 
Follow-
up 
Survival 
Follow-
up 
Cycle 
 
Cycle 1 
Cycle 2 
Cycle 3 (and subsequent cycles, 
if required) 
 
 
 
 
Visit Name SCREEN
ING 
CO
NF 
C1D
1 
CON
F 
C1D
5 
CON
F 
C1D
8 
CON
F 
C1D
15 
CO
NF 
C2D
1 
CO
NF 
C2D
8 
CON
F 
C2D
15 
CONF CxD1 
EOT CONF 
Safet
y 
Follo
w-up 
Post-
Treatme
nt 
Follow-
up 
Survival 
Follow-
up 
Days 
-28 to 
-1 
D1 
D5 
D8 
D15 
D1 
D8 
D15 
D1 
- 
30 
days 
after 
EOT 
Every 6 
mo until 
EOS 
(End of 
Study) 
every 3 
mo until 
EOS 
Prior 
antineoplast
ic therapies 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Prior 
concomitant 
medications
, surgery 
and medical 
procedures 
X 
Continuous 
X 
X 
X 
 
Adverse 
Events 
X 
Continuous 
X 
X3 
 
 
Physical 
Examinatio
n 
S 
S 
 
 
 
S 
 
 
S 
S 
 
S 
 
Vital Signs 
X 
X 
 
 
 
X 
 
 
X 
X 
 
X 
 
Body 
Weight 
X 
X 
 
 
 
X 
 
 
X 
X 
 
X 
 


Novartis 
Confidential 
Page 93 of 192 
Amended Protocol Version 02 (Clean) 
 
 
Protocol No. CHDM201K12201 
 
 
Period 
Part 1: Siremadlin monotherapy - Cycles duration: 28 days 
End of Treatment of dose 
confirmation phase 
Safet
y 
Follo
w-up 
Post-
Treatme
nt 
Follow-
up 
Survival 
Follow-
up 
Cycle 
 
Cycle 1 
Cycle 2 
Cycle 3 (and subsequent cycles, 
if required) 
 
 
 
 
Visit Name SCREEN
ING 
CO
NF 
C1D
1 
CON
F 
C1D
5 
CON
F 
C1D
8 
CON
F 
C1D
15 
CO
NF 
C2D
1 
CO
NF 
C2D
8 
CON
F 
C2D
15 
CONF CxD1 
EOT CONF 
Safet
y 
Follo
w-up 
Post-
Treatme
nt 
Follow-
up 
Survival 
Follow-
up 
Days 
-28 to 
-1 
D1 
D5 
D8 
D15 
D1 
D8 
D15 
D1 
- 
30 
days 
after 
EOT 
Every 6 
mo until 
EOS 
(End of 
Study) 
every 3 
mo until 
EOS 
Body 
Height 
X 
 
 
 
 
 
 
 
 
 
 
 
 
ECOG PS 
X 
X 
 
 
 
X 
 
 
X 
X 
 
 
 
Hematology 
X 
X 
 
X 
X 
X 
X 
X 
at days 1 & 15 at each cycle until 
CONF C6 and thereafter every 
cycle Day 1 and as clinically 
indicated 
X 
 
Every 3 
months 
(starting 
from last 
on 
treatmen
t efficacy 
assessm
ent) and 
if 
clinically 
indicated 
 
Chemistry 
X 
X 
 
X 
X 
X 
X 
X 
at days 1 & 15 at each cycle until 
CONF C6 and thereafter every 
cycle Day 1 and as clinically 
indicated 
X 
 
If 
clinically 
indicated 
 


Novartis 
Confidential 
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Amended Protocol Version 02 (Clean) 
 
 
Protocol No. CHDM201K12201 
 
 
Period 
Part 1: Siremadlin monotherapy - Cycles duration: 28 days 
End of Treatment of dose 
confirmation phase 
Safet
y 
Follo
w-up 
Post-
Treatme
nt 
Follow-
up 
Survival 
Follow-
up 
Cycle 
 
Cycle 1 
Cycle 2 
Cycle 3 (and subsequent cycles, 
if required) 
 
 
 
 
Visit Name SCREEN
ING 
CO
NF 
C1D
1 
CON
F 
C1D
5 
CON
F 
C1D
8 
CON
F 
C1D
15 
CO
NF 
C2D
1 
CO
NF 
C2D
8 
CON
F 
C2D
15 
CONF CxD1 
EOT CONF 
Safet
y 
Follo
w-up 
Post-
Treatme
nt 
Follow-
up 
Survival 
Follow-
up 
Days 
-28 to 
-1 
D1 
D5 
D8 
D15 
D1 
D8 
D15 
D1 
- 
30 
days 
after 
EOT 
Every 6 
mo until 
EOS 
(End of 
Study) 
every 3 
mo until 
EOS 
Coagulation 
X 
If clinically indicated 
 
 
 
Cytogenetic
s4 
X 
 
Virology 
hepatitis B 
and C 
S 
 
 
 
 
 
 
 
 
If clinically indicated 
 
 
 
HIV 
serology 
(only if 
required per 
local 
regulation) 
S 
 
 
 
 
 
 
 
 
 
 
 
 
GLDH 
X5 
 
 
 
 
 
 
 
 
If clinically indicated 
 
 
 
Acute 
GvHD 
assessment
6 
X6 
X 
 
 
 
 
X 
 
 
at each cycle until CONF C6D1 
and thereafter every 2 cycles and 
as clinically indicated 
X 
X 
Every 3 
months 
(starting 
from last 
on 
 


Novartis 
Confidential 
Page 95 of 192 
Amended Protocol Version 02 (Clean) 
 
 
Protocol No. CHDM201K12201 
 
 
Period 
Part 1: Siremadlin monotherapy - Cycles duration: 28 days 
End of Treatment of dose 
confirmation phase 
Safet
y 
Follo
w-up 
Post-
Treatme
nt 
Follow-
up 
Survival 
Follow-
up 
Cycle 
 
Cycle 1 
Cycle 2 
Cycle 3 (and subsequent cycles, 
if required) 
 
 
 
 
Visit Name SCREEN
ING 
CO
NF 
C1D
1 
CON
F 
C1D
5 
CON
F 
C1D
8 
CON
F 
C1D
15 
CO
NF 
C2D
1 
CO
NF 
C2D
8 
CON
F 
C2D
15 
CONF CxD1 
EOT CONF 
Safet
y 
Follo
w-up 
Post-
Treatme
nt 
Follow-
up 
Survival 
Follow-
up 
Days 
-28 to 
-1 
D1 
D5 
D8 
D15 
D1 
D8 
D15 
D1 
- 
30 
days 
after 
EOT 
Every 6 
mo until 
EOS 
(End of 
Study) 
every 3 
mo until 
EOS 
treatmen
t efficacy 
assessm
ent) and 
if 
clinically 
indicated 
Chronic 
GvHD 
assessment 
X6 
X 
 
 
 
X 
 
 
at each cycle until CONF C6D1 
and thereafter every 2 cycles and 
as clinically indicated 
X 
X 
Every 3 
months 
(starting 
from last 
on 
treatmen
t efficacy 
assessm
ent) and 
if 
clinically 
indicated 
7 
 


Novartis 
Confidential 
Page 96 of 192 
Amended Protocol Version 02 (Clean) 
 
 
Protocol No. CHDM201K12201 
 
 
Period 
Part 1: Siremadlin monotherapy - Cycles duration: 28 days 
End of Treatment of dose 
confirmation phase 
Safet
y 
Follo
w-up 
Post-
Treatme
nt 
Follow-
up 
Survival 
Follow-
up 
Cycle 
 
Cycle 1 
Cycle 2 
Cycle 3 (and subsequent cycles, 
if required) 
 
 
 
 
Visit Name SCREEN
ING 
CO
NF 
C1D
1 
CON
F 
C1D
5 
CON
F 
C1D
8 
CON
F 
C1D
15 
CO
NF 
C2D
1 
CO
NF 
C2D
8 
CON
F 
C2D
15 
CONF CxD1 
EOT CONF 
Safet
y 
Follo
w-up 
Post-
Treatme
nt 
Follow-
up 
Survival 
Follow-
up 
Days 
-28 to 
-1 
D1 
D5 
D8 
D15 
D1 
D8 
D15 
D1 
- 
30 
days 
after 
EOT 
Every 6 
mo until 
EOS 
(End of 
Study) 
every 3 
mo until 
EOS 
Urinalysis 
(dipstick) 
S 
If clinically indicated 
 
If clinically indicated 
 
 
 
Serum 
Pregnancy 
test 8 
 
S9 
 
 
S9 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urine 
Pregnancy 
Test OR 
Serum 
Pregnancy 
Test10 
 
 
 
 
 
 
S 
 
 
 
 
S 
 
 
 
12-Lead 
ECG 
(triplicates)1
1 
X 
X 
X 
 
 
If clinically 
indicated 
at CONF C4D1 and if clinically 
indicated 
X 
 
 
 
Echocardio
gram or 
MUGA 
X12 
If clinically indicated 
If clinically indicated 
 
 
 


Novartis 
Confidential 
Page 97 of 192 
Amended Protocol Version 02 (Clean) 
 
 
Protocol No. CHDM201K12201 
 
 
Period 
Part 1: Siremadlin monotherapy - Cycles duration: 28 days 
End of Treatment of dose 
confirmation phase 
Safet
y 
Follo
w-up 
Post-
Treatme
nt 
Follow-
up 
Survival 
Follow-
up 
Cycle 
 
Cycle 1 
Cycle 2 
Cycle 3 (and subsequent cycles, 
if required) 
 
 
 
 
Visit Name SCREEN
ING 
CO
NF 
C1D
1 
CON
F 
C1D
5 
CON
F 
C1D
8 
CON
F 
C1D
15 
CO
NF 
C2D
1 
CO
NF 
C2D
8 
CON
F 
C2D
15 
CONF CxD1 
EOT CONF 
Safet
y 
Follo
w-up 
Post-
Treatme
nt 
Follow-
up 
Survival 
Follow-
up 
Days 
-28 to 
-1 
D1 
D5 
D8 
D15 
D1 
D8 
D15 
D1 
- 
30 
days 
after 
EOT 
Every 6 
mo until 
EOS 
(End of 
Study) 
every 3 
mo until 
EOS 
IRT-Drug 
dispensatio
n for 
siremadlin 
 
 
X 
 
 
 
 
X 
 
 
X 
 
 
 
 
Siremadlin 
administrati
on13 
 
X 
 
 
 
X 
 
 
X 
 
 
 
 
Efficacy - 
Bone 
marrow 
aspirate 
and/or 
biopsy 
X 
D1 of every 3 cycles (starting from C3D1) until completion of 12 cycles of 
study treatment then every 6 cycles thereafter and as clinically indicated 
X14 
 
Every 6 
mo until 
relapse 
or start 
of new 
therapy 
and as 
clinically 
indicated
. Note: If 
participa
nt had 
end of 
 


Novartis 
Confidential 
Page 98 of 192 
Amended Protocol Version 02 (Clean) 
 
 
Protocol No. CHDM201K12201 
 
 
Period 
Part 1: Siremadlin monotherapy - Cycles duration: 28 days 
End of Treatment of dose 
confirmation phase 
Safet
y 
Follo
w-up 
Post-
Treatme
nt 
Follow-
up 
Survival 
Follow-
up 
Cycle 
 
Cycle 1 
Cycle 2 
Cycle 3 (and subsequent cycles, 
if required) 
 
 
 
 
Visit Name SCREEN
ING 
CO
NF 
C1D
1 
CON
F 
C1D
5 
CON
F 
C1D
8 
CON
F 
C1D
15 
CO
NF 
C2D
1 
CO
NF 
C2D
8 
CON
F 
C2D
15 
CONF CxD1 
EOT CONF 
Safet
y 
Follo
w-up 
Post-
Treatme
nt 
Follow-
up 
Survival 
Follow-
up 
Days 
-28 to 
-1 
D1 
D5 
D8 
D15 
D1 
D8 
D15 
D1 
- 
30 
days 
after 
EOT 
Every 6 
mo until 
EOS 
(End of 
Study) 
every 3 
mo until 
EOS 
treatmen
t visit 
less than 
6 months 
after 
enrollme
nt, an 
extra 
efficacy 
assessm
ent must 
be 
performe
d at 
month 3 
after 
EOT 


Novartis 
Confidential 
Page 99 of 192 
Amended Protocol Version 02 (Clean) 
 
 
Protocol No. CHDM201K12201 
 
 
Period 
Part 1: Siremadlin monotherapy - Cycles duration: 28 days 
End of Treatment of dose 
confirmation phase 
Safet
y 
Follo
w-up 
Post-
Treatme
nt 
Follow-
up 
Survival 
Follow-
up 
Cycle 
 
Cycle 1 
Cycle 2 
Cycle 3 (and subsequent cycles, 
if required) 
 
 
 
 
Visit Name SCREEN
ING 
CO
NF 
C1D
1 
CON
F 
C1D
5 
CON
F 
C1D
8 
CON
F 
C1D
15 
CO
NF 
C2D
1 
CO
NF 
C2D
8 
CON
F 
C2D
15 
CONF CxD1 
EOT CONF 
Safet
y 
Follo
w-up 
Post-
Treatme
nt 
Follow-
up 
Survival 
Follow-
up 
Days 
-28 to 
-1 
D1 
D5 
D8 
D15 
D1 
D8 
D15 
D1 
- 
30 
days 
after 
EOT 
Every 6 
mo until 
EOS 
(End of 
Study) 
every 3 
mo until 
EOS 
Efficacy – 
extramedull
ary disease 
assessment
15 
X 
D1 of every 3 cycles (starting from C3D1) until completion of 12 cycles of 
study treatment then every 6 cycles thereafter and as clinically indicated 
X14 
 
Every 6 
mo until 
relapse 
or start 
of new 
therapy 
and as 
clinically 
indicated
. Note: If 
participa
nt had 
end of 
treatmen
t visit 
less than 
6 months 
after 
enrollme
nt, an 
 


Novartis 
Confidential 
Page 100 of 192 
Amended Protocol Version 02 (Clean) 
 
 
Protocol No. CHDM201K12201 
 
 
Period 
Part 1: Siremadlin monotherapy - Cycles duration: 28 days 
End of Treatment of dose 
confirmation phase 
Safet
y 
Follo
w-up 
Post-
Treatme
nt 
Follow-
up 
Survival 
Follow-
up 
Cycle 
 
Cycle 1 
Cycle 2 
Cycle 3 (and subsequent cycles, 
if required) 
 
 
 
 
Visit Name SCREEN
ING 
CO
NF 
C1D
1 
CON
F 
C1D
5 
CON
F 
C1D
8 
CON
F 
C1D
15 
CO
NF 
C2D
1 
CO
NF 
C2D
8 
CON
F 
C2D
15 
CONF CxD1 
EOT CONF 
Safet
y 
Follo
w-up 
Post-
Treatme
nt 
Follow-
up 
Survival 
Follow-
up 
Days 
-28 to 
-1 
D1 
D5 
D8 
D15 
D1 
D8 
D15 
D1 
- 
30 
days 
after 
EOT 
Every 6 
mo until 
EOS 
(End of 
Study) 
every 3 
mo until 
EOS 
extra 
efficacy 
assessm
ent must 
be 
performe
d at 
month 3 
after 
EOT 
Efficacy - 
response 
assessment
16 
X17 
D1 of every 3 cycles (starting from C3D1) until completion of 12 cycles of 
study treatment then every 6 cycles thereafter and as clinically indicated 
X14 
 
Every 6 
mo until 
relapse 
or start 
of new 
therapy 
and as 
clinically 
indicated
. Note: If 
 


Novartis 
Confidential 
Page 101 of 192 
Amended Protocol Version 02 (Clean) 
 
 
Protocol No. CHDM201K12201 
 
 
Period 
Part 1: Siremadlin monotherapy - Cycles duration: 28 days 
End of Treatment of dose 
confirmation phase 
Safet
y 
Follo
w-up 
Post-
Treatme
nt 
Follow-
up 
Survival 
Follow-
up 
Cycle 
 
Cycle 1 
Cycle 2 
Cycle 3 (and subsequent cycles, 
if required) 
 
 
 
 
Visit Name SCREEN
ING 
CO
NF 
C1D
1 
CON
F 
C1D
5 
CON
F 
C1D
8 
CON
F 
C1D
15 
CO
NF 
C2D
1 
CO
NF 
C2D
8 
CON
F 
C2D
15 
CONF CxD1 
EOT CONF 
Safet
y 
Follo
w-up 
Post-
Treatme
nt 
Follow-
up 
Survival 
Follow-
up 
Days 
-28 to 
-1 
D1 
D5 
D8 
D15 
D1 
D8 
D15 
D1 
- 
30 
days 
after 
EOT 
Every 6 
mo until 
EOS 
(End of 
Study) 
every 3 
mo until 
EOS 
participa
nt had 
end of 
treatmen
t visit 
less than 
6 months 
after 
enrollme
nt, an 
extra 
efficacy 
assessm
ent must 
be 
performe
d at 
month 3 
after 
EOT 


Novartis 
Confidential 
Page 102 of 192 
Amended Protocol Version 02 (Clean) 
 
 
Protocol No. CHDM201K12201 
 
 
Period 
Part 1: Siremadlin monotherapy - Cycles duration: 28 days 
End of Treatment of dose 
confirmation phase 
Safet
y 
Follo
w-up 
Post-
Treatme
nt 
Follow-
up 
Survival 
Follow-
up 
Cycle 
 
Cycle 1 
Cycle 2 
Cycle 3 (and subsequent cycles, 
if required) 
 
 
 
 
Visit Name SCREEN
ING 
CO
NF 
C1D
1 
CON
F 
C1D
5 
CON
F 
C1D
8 
CON
F 
C1D
15 
CO
NF 
C2D
1 
CO
NF 
C2D
8 
CON
F 
C2D
15 
CONF CxD1 
EOT CONF 
Safet
y 
Follo
w-up 
Post-
Treatme
nt 
Follow-
up 
Survival 
Follow-
up 
Days 
-28 to 
-1 
D1 
D5 
D8 
D15 
D1 
D8 
D15 
D1 
- 
30 
days 
after 
EOT 
Every 6 
mo until 
EOS 
(End of 
Study) 
every 3 
mo until 
EOS 
IST levels 
X18 
X19 
X19 
 
 
 
 
 
 
 
 
 
 
PK sample 
for 
siremadlin20 
 
X21 
X22 
 
 
 
 
 
Predose (0h) and 3h postdose 
PK samples at CONF C4D1, 
C7D1, C10D1, C13D1, C19D1, 
and PK profile (see note (20) on 
C5D1 and C5D5 
 
 
 
 


Novartis 
Confidential 
Page 103 of 192 
Amended Protocol Version 02 (Clean) 
 
 
Protocol No. CHDM201K12201 
 
 
Period 
Part 1: Siremadlin monotherapy - Cycles duration: 28 days 
End of Treatment of dose 
confirmation phase 
Safet
y 
Follo
w-up 
Post-
Treatme
nt 
Follow-
up 
Survival 
Follow-
up 
Cycle 
 
Cycle 1 
Cycle 2 
Cycle 3 (and subsequent cycles, 
if required) 
 
 
 
 
Visit Name SCREEN
ING 
CO
NF 
C1D
1 
CON
F 
C1D
5 
CON
F 
C1D
8 
CON
F 
C1D
15 
CO
NF 
C2D
1 
CO
NF 
C2D
8 
CON
F 
C2D
15 
CONF CxD1 
EOT CONF 
Safet
y 
Follo
w-up 
Post-
Treatme
nt 
Follow-
up 
Survival 
Follow-
up 
Days 
-28 to 
-1 
D1 
D5 
D8 
D15 
D1 
D8 
D15 
D1 
- 
30 
days 
after 
EOT 
Every 6 
mo until 
EOS 
(End of 
Study) 
every 3 
mo until 
EOS 


Novartis 
Confidential 
Page 104 of 192 
Amended Protocol Version 02 (Clean) 
 
 
Protocol No. CHDM201K12201 
 
 
Period 
Part 1: Siremadlin monotherapy - Cycles duration: 28 days 
End of Treatment of dose 
confirmation phase 
Safet
y 
Follo
w-up 
Post-
Treatme
nt 
Follow-
up 
Survival 
Follow-
up 
Cycle 
 
Cycle 1 
Cycle 2 
Cycle 3 (and subsequent cycles, 
if required) 
 
 
 
 
Visit Name SCREEN
ING 
CO
NF 
C1D
1 
CON
F 
C1D
5 
CON
F 
C1D
8 
CON
F 
C1D
15 
CO
NF 
C2D
1 
CO
NF 
C2D
8 
CON
F 
C2D
15 
CONF CxD1 
EOT CONF 
Safet
y 
Follo
w-up 
Post-
Treatme
nt 
Follow-
up 
Survival 
Follow-
up 
Days 
-28 to 
-1 
D1 
D5 
D8 
D15 
D1 
D8 
D15 
D1 
- 
30 
days 
after 
EOT 
Every 6 
mo until 
EOS 
(End of 
Study) 
every 3 
mo until 
EOS 


Novartis 
Confidential 
Page 105 of 192 
Amended Protocol Version 02 (Clean) 
 
 
Protocol No. CHDM201K12201 
 
 
Period 
Part 1: Siremadlin monotherapy - Cycles duration: 28 days 
End of Treatment of dose 
confirmation phase 
Safet
y 
Follo
w-up 
Post-
Treatme
nt 
Follow-
up 
Survival 
Follow-
up 
Cycle 
 
Cycle 1 
Cycle 2 
Cycle 3 (and subsequent cycles, 
if required) 
 
 
 
 
Visit Name SCREEN
ING 
CO
NF 
C1D
1 
CON
F 
C1D
5 
CON
F 
C1D
8 
CON
F 
C1D
15 
CO
NF 
C2D
1 
CO
NF 
C2D
8 
CON
F 
C2D
15 
CONF CxD1 
EOT CONF 
Safet
y 
Follo
w-up 
Post-
Treatme
nt 
Follow-
up 
Survival 
Follow-
up 
Days 
-28 to 
-1 
D1 
D5 
D8 
D15 
D1 
D8 
D15 
D1 
- 
30 
days 
after 
EOT 
Every 6 
mo until 
EOS 
(End of 
Study) 
every 3 
mo until 
EOS 
Antineoplas
tic therapies 
since 
discontinuat
ion 
(including a 
second allo-
SCT) 
 
 
 
 
 
 
 
 
 
 
X 
X 
X 


Novartis 
Confidential 
Page 106 of 192 
Amended Protocol Version 02 (Clean) 
 
 
Protocol No. CHDM201K12201 
 
 
Period 
Part 1: Siremadlin monotherapy - Cycles duration: 28 days 
End of Treatment of dose 
confirmation phase 
Safet
y 
Follo
w-up 
Post-
Treatme
nt 
Follow-
up 
Survival 
Follow-
up 
Cycle 
 
Cycle 1 
Cycle 2 
Cycle 3 (and subsequent cycles, 
if required) 
 
 
 
 
Visit Name SCREEN
ING 
CO
NF 
C1D
1 
CON
F 
C1D
5 
CON
F 
C1D
8 
CON
F 
C1D
15 
CO
NF 
C2D
1 
CO
NF 
C2D
8 
CON
F 
C2D
15 
CONF CxD1 
EOT CONF 
Safet
y 
Follo
w-up 
Post-
Treatme
nt 
Follow-
up 
Survival 
Follow-
up 
Days 
-28 to 
-1 
D1 
D5 
D8 
D15 
D1 
D8 
D15 
D1 
- 
30 
days 
after 
EOT 
Every 6 
mo until 
EOS 
(End of 
Study) 
every 3 
mo until 
EOS 
Collection 
of disease 
response 
status 
 
 
 
 
 
 
 
 
 
 
 
 
For 
participan
t who 
received 
new 
antineopl
astic 
therapy 
while in 
CR/CRi26 
Survival 
Follow-up 
 
 
 
 
 
 
 
X 
Disposition 
X 
 
 
 
 
 
 
 
 
X 
 
X 
 
X Assessment to be recorded in the clinical database or received electronically from a vendor. 
S Assessment to be recorded in the source documentation only. 
1 Include allo-SCT and GvHD (acute and chronic) history. 
2 The last assessment of bone marrow and/or peripheral blood counts should be used within 28 days prior to enrollment. 


Novartis 
Confidential 
Page 107 of 192 
Amended Protocol Version 02 (Clean) 
 
 
Protocol No. CHDM201K12201 
 
 
Period 
Part 1: Siremadlin monotherapy - Cycles duration: 28 days 
End of Treatment of dose 
confirmation phase 
Safet
y 
Follo
w-up 
Post-
Treatme
nt 
Follow-
up 
Survival 
Follow-
up 
Cycle 
 
Cycle 1 
Cycle 2 
Cycle 3 (and subsequent cycles, 
if required) 
 
 
 
 
Visit Name SCREEN
ING 
CO
NF 
C1D
1 
CON
F 
C1D
5 
CON
F 
C1D
8 
CON
F 
C1D
15 
CO
NF 
C2D
1 
CO
NF 
C2D
8 
CON
F 
C2D
15 
CONF CxD1 
EOT CONF 
Safet
y 
Follo
w-up 
Post-
Treatme
nt 
Follow-
up 
Survival 
Follow-
up 
Days 
-28 to 
-1 
D1 
D5 
D8 
D15 
D1 
D8 
D15 
D1 
- 
30 
days 
after 
EOT 
Every 6 
mo until 
EOS 
(End of 
Study) 
every 3 
mo until 
EOS 
3 If the participant begins new antineoplastic medication before the end of the safety follow-up period, then only suspected AEs and suspected SAEs will continue to be 
collected. See Section 10.1. 
4 To be performed locally. Assessment to be recorded in the clinical database (eCRF). 
5 Refer to Section 6.6.5.1 for DILI follow-up. 
6 If it was performed as part of screening assessment within the previous 7 days, it is not needed to repeat it. 
7Aligned with the response assessment. 
8 This test will be performed only for women of child-bearing potential. 
9 To be taken at screening and confirmed within 72 hours prior to planned first dose. 
10 Urine or serum test may be performed, depending on local regulations, only for women of child-bearing potential. 
11 Refer to Section 8.4.2 for detailed guidance on timepoints. 
12 A pre-existing assessment may be used (if done within 6 months prior to enrollment). 
13 On days 1 to 5 of each cycle. 
14 This assessment will not be needed at EOT if done at C24D1. 
15 Extramedullary disease is to be assessed via physical examination. Additional evaluation [eg, imaging, procedures (tissue biopsy, lumbar puncture), etc.] will be 
performed as clinically indicated per the investigator's assessment. 
16 See Section 8.3.1 for details on response assessment. 
17 A pre-existing assessment done as part of standard of care can be used, if done within 28 days of start of study treatment for bone marrow and peripheral blood 
counts (within 14 days of start of study treatment. 


Novartis 
Confidential 
Page 108 of 192 
Amended Protocol Version 02 (Clean) 
 
 
Protocol No. CHDM201K12201 
 
 
Period 
Part 1: Siremadlin monotherapy - Cycles duration: 28 days 
End of Treatment of dose 
confirmation phase 
Safet
y 
Follo
w-up 
Post-
Treatme
nt 
Follow-
up 
Survival 
Follow-
up 
Cycle 
 
Cycle 1 
Cycle 2 
Cycle 3 (and subsequent cycles, 
if required) 
 
 
 
 
Visit Name SCREEN
ING 
CO
NF 
C1D
1 
CON
F 
C1D
5 
CON
F 
C1D
8 
CON
F 
C1D
15 
CO
NF 
C2D
1 
CO
NF 
C2D
8 
CON
F 
C2D
15 
CONF CxD1 
EOT CONF 
Safet
y 
Follo
w-up 
Post-
Treatme
nt 
Follow-
up 
Survival 
Follow-
up 
Days 
-28 to 
-1 
D1 
D5 
D8 
D15 
D1 
D8 
D15 
D1 
- 
30 
days 
after 
EOT 
Every 6 
mo until 
EOS 
(End of 
Study) 
every 3 
mo until 
EOS 
18 Report the last IST level measurements within 7 to 9 days before starting siremadlin. 
19 IST level to be measured prior to siremadlin administration 
20 Refer to appropriate table of Section 8.5.1.1 for detailed timepoints and collection schedule for siremadlin PK sampling. 
21 Sampling to be performed at pre-dose of siremadlin, and 0.5h, 1h, 2h, 3h, 6h, 8h, 10h, and 24h post-dose. 
22 Sampling to be performed at pre-dose of siremadlin, and 0.5h, 1h, 2h, 3h, 6h, and 8h post-dose. 
 
 
 
 
 
 
 
26 New anti-neoplastic therapy includes second allo-SCT see Section 9.1.1.3 for more details. The visit can either be via phone call or on-site (if participant happens to 
be visiting the site). 


Novartis 
Confidential 
Page 109 of 192 
Amended Protocol Version 02 (Clean) 
 
 
Protocol No. CHDM201K12201 
 
 
Table 8-2 
Assessment Schedule, Overview (Part 2) 
Period 
Pre-Treatment 
Treatment 
End of Treatment Safety Follow-up Post-Treatment Follow-up Survival Follow-up 
Visit Name 
Screening 
Priming 
Combination Maintenance End of Treatment Safety Follow-up Post-Treatment Follow-up Survival Follow-up 
Days 
-28 to -1 
Ref to  
Table 8-3  
Ref to  
Table 8-4 
Ref to  
Table 8-4 
EOT 
30 days after EOT 
Every 6 mo after EOT 
every 3 mo until EOS 
Informed consent 
X 
 
 
 
 
 
 
 
IRT Registration 
X 
 
 
 
X 
 
 
 
Demography 
X 
 
 
 
 
 
 
 
Inclusion / 
Exclusion criteria 
X 
 
 
 
 
 
 
 
Medical 
history/current 
medical 
conditions1 
X 
 
 
 
 
 
 
 
Disease History2 
X 
 
 
 
 
 
 
 
Prior 
antineoplastic 
therapies 
X 
 
 
 
 
 
 
 
Prior/concomitant 
medications, 
surgery and 
medical 
procedures 
X 
 
 
 
X 
X 
X 
 
Adverse Events 
X 
 
 
 
X 
X3 
 
 
Physical 
Examination 
S 
 
 
 
S 
 
S 
 
Vital Signs 
X 
 
 
 
X 
 
X 
 
Body Height 
X 
 
 
 
 
 
 
 
Body Weight 
X 
 
 
 
X 
 
X 
 
ECOG PS 
X 
 
 
 
X 
 
 
 
Acute GvHD 
assessment 
X 
 
 
 
X 
X 
Every 3 months (starting 
from last on treatment 
 


Novartis 
Confidential 
Page 110 of 192 
Amended Protocol Version 02 (Clean) 
 
 
Protocol No. CHDM201K12201 
 
 
Period 
Pre-Treatment 
Treatment 
End of Treatment Safety Follow-up Post-Treatment Follow-up Survival Follow-up 
Visit Name 
Screening 
Priming 
Combination Maintenance End of Treatment Safety Follow-up Post-Treatment Follow-up Survival Follow-up 
Days 
-28 to -1 
Ref to  
Table 8-3  
Ref to  
Table 8-4 
Ref to  
Table 8-4 
EOT 
30 days after EOT 
Every 6 mo after EOT 
every 3 mo until EOS 
efficacy assessment) and if 
clinically indicated 
4 
Chronic GvHD 
assessment 
X 
  
  
  
X 
X 
Every 3 months (starting 
from last on treatment 
efficacy assessment) and if 
clinically indicated 
4 
  
Hematology 
X 
  
  
  
X 
  
Every 3 months (starting 
from last on treatment 
efficacy assessment) and if 
clinically indicated 
  
Chemistry 
X 
  
  
  
X 
  
 If clinically indicated 
  
Coagulation 
X 
  
  
  
If clinically 
indicated 
  
  
  
Cytogenetics 5 
X 
  
  
  
  
  
  
  
Urinalysis 
(dipstick) 
S 
  
  
  
If clinically 
indicated 
  
  
  
Virology hepatitis 
B and C 
S 
  
  
  
If clinically 
indicated 
  
  
  
HIV serology 
(only if required 
per local 
regulation) 
S 
  
  
  
  
  
  
  
GLDH 
X6 
  
  
  
If clinically 
indicated 
  
  
  
Serum 
Pregnancy test 7 
S8 
  
  
  
S 
  
  
  


Novartis 
Confidential 
Page 111 of 192 
Amended Protocol Version 02 (Clean) 
 
 
Protocol No. CHDM201K12201 
 
 
Period 
Pre-Treatment 
Treatment 
End of Treatment Safety Follow-up Post-Treatment Follow-up Survival Follow-up 
Visit Name 
Screening 
Priming 
Combination Maintenance End of Treatment Safety Follow-up Post-Treatment Follow-up Survival Follow-up 
Days 
-28 to -1 
Ref to  
Table 8-3  
Ref to  
Table 8-4 
Ref to  
Table 8-4 
EOT 
30 days after EOT 
Every 6 mo after EOT 
every 3 mo until EOS 
Urine Pregnancy 
Test OR Serum 
Pregnancy Test9 
  
  
  
  
  
S 
  
  
12-Lead ECG 
(triplicates)10 
X 
  
  
  
X 
  
  
  
Echocardiogram 
or MUGA 
X11 
  
  
  
If clinically 
indicated 
  
  
  
Efficacy - Bone 
marrow aspirate 
and/or biopsy 
X 
D1 of every 3 cycles (starting from 
C3D1) until completion of 12 cycles of 
study treatment then every 6 cycles 
thereafter and as clinically indicated 
X12 
  
Every 6 mo until relapse or 
start of new therapy and as 
clinically indicated. Note: If 
participant had end of 
treatment visit less than 6 
months after enrollment, an 
extra efficacy assessment 
must be performed at 
month 3 after EOT 
  
Efficacy - 
extramedullary 
disease 
assessment13 
X 
D1 of every 3 cycles (starting from 
C3D1) until completion of 12 cycles of 
study treatment then every 6 cycles 
thereafter and as clinically indicated 
X12 
  
Every 6 mo until relapse or 
start of new therapy and as 
clinically indicated. Note: If 
participant had end of 
treatment visit less than 6 
months after enrollment, an 
extra efficacy assessment 
must be performed at 
month 3 after EOT 
  
Efficacy - 
response 
assessment14 
X15 
D1 of every 3 cycles (starting from 
C3D1) until completion of 12 cycles of 
study treatment then every 6 cycles 
thereafter and as clinically indicated 
X12 
  
Every 6 mo until relapse or 
start of new therapy and as 
clinically indicated. Note: If 
participant had end of 
treatment visit less than 6 
months after enrollment, an 
extra efficacy assessment 
  


Novartis 
Confidential 
Page 112 of 192 
Amended Protocol Version 02 (Clean) 
 
 
Protocol No. CHDM201K12201 
 
 
Period 
Pre-Treatment 
Treatment 
End of Treatment Safety Follow-up Post-Treatment Follow-up Survival Follow-up 
Visit Name 
Screening 
Priming 
Combination Maintenance End of Treatment Safety Follow-up Post-Treatment Follow-up Survival Follow-up 
Days 
-28 to -1 
Ref to  
Table 8-3  
Ref to  
Table 8-4 
Ref to  
Table 8-4 
EOT 
30 days after EOT 
Every 6 mo after EOT 
every 3 mo until EOS 
must be performed at 
month 3 after EOT 
IST level 
X16 
 X17 
  
  
  
  
  
  
Antineoplastic 
therapies since 
discontinuation 
(including a 
second allo-SCT) 
  
  
  
  
  
X 
X 
X 
Disposition 
X 
  
  
  
X 
  
X 
  
Collection of 
disease 
response status 
  
  
  
  
  
  
  
For participant who 
received new 


Novartis 
Confidential 
Page 113 of 192 
Amended Protocol Version 02 (Clean) 
 
 
Protocol No. CHDM201K12201 
 
 
Period 
Pre-Treatment 
Treatment 
End of Treatment Safety Follow-up Post-Treatment Follow-up Survival Follow-up 
Visit Name 
Screening 
Priming 
Combination Maintenance End of Treatment Safety Follow-up Post-Treatment Follow-up Survival Follow-up 
Days 
-28 to -1 
Ref to  
Table 8-3  
Ref to  
Table 8-4 
Ref to  
Table 8-4 
EOT 
30 days after EOT 
Every 6 mo after EOT 
every 3 mo until EOS 
antineoplastic therapy 
while in CR/CRi20 
Survival Follow-
up 
  
  
  
  
  
  
  
X 
X Assessment to be recorded in the clinical database or received electronically from a vendor 
S Assessment to be recorded in the source documentation only 
1 Include allo-SCT and GvHD (acute and chronic) history 
2 The last assessment of bone marrow and/or peripheral blood counts should be used within 28 days prior to enrollment 
3 If the participant begins new antineoplastic medication before the end of the safety follow-up period, then only suspected AEs and suspected SAEs will continue to be 
collected. See Section 10.1 
4 Aligned with the response assessment 
5 To be performed locally. Assessment to be recorded in the clinical database (eCRF) 
6 Refer to Section 6.6.5.1 for DILI follow-up. 
7 This test will be performed only for women of child-bearing potential.  
8 To be taken at screening and confirmed within 72 hours prior to planned first dose 
9 Urine or serum test may be performed, depending on local regulations, only for women of child-bearing potential 
10 Refer to Section 8.4.2 for detailed guidance on timepoints 
10 A pre-existing assessment may be used (if done within 6 months prior to enrollment) 
12 This assessment will not be needed at EOT if done at C24D1. 
13 Extramedullary disease is to be assessed via physical examination. Additional evaluation [eg, imaging, procedures (tissue biopsy, lumbar puncture), etc.] will be 
performed as clinically indicated per the investigator's assessment 
14 See Section 8.3.1 for details on response assessments 
15 A pre-existing assessment done as part of standard of care can be used, if done within 28 days of start of study treatment for bone marrow and peripheral blood 
counts (within 14 days of start of study treatment . 
16 Report the last IST level measurements within 7 to 9 days before starting siremadlin 
17 IST level to be measured prior to siremadlin administration 
 
 
20 New anti-neoplastic therapy includes second allo-SCT. The visit can either be via phone call or on-site (if participant happens to be visiting the site) 


Novartis 
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Page 114 of 192 
Amended Protocol Version 02 (Clean) 
 
 
Protocol No. CHDM201K12201 
 
 
Table 8-3 
Assessment Schedule, Priming (Part 2) 
Period 
Priming (PRIM) - Cycles duration: 28 days 
End of Priming phase disposition 
Cycle 
Cycle 1 
Cycle 2 
Cycle 3 (and subsequent cycles, if required) 
 
Visit Name 
PRIM 
C1D1 
 
PRIM 
C1D5 
PRIM 
C1D8 
PRIM 
C1D15 
PRIM 
C2D1 
 
PRIM 
C2D8 
PRIM 
C2D15 
PRIM CxD1 
EO PRIM Disposition 
Days 
D1 
 
D5 
D8 
D15 
D1 
 
D8 
D15 
D1 
- 
Comments 
 
 
 
 
 
 
 
 
 
 
For patients moving to combination 
therapy, see Table 8-4  
concomitant 
medications, 
surgery and 
medical 
procedures 
 
Continuous 
 
Adverse Events 
 
Continuous 
 
Physical 
Examination 
S 
 
 
 
 
S 
 
 
 
S 
 
Vital Signs 
X 
 
 
 
 
X 
 
 
 
X 
 
Body Weight 
X 
 
 
 
 
X 
 
 
 
X 
 
ECOG PS 
X 
 
 
 
 
X 
 
 
 
X 
 
Hematology 
X 
  
  
X 
X 
X 
  
X 
X 
at days 1 & 15 at each cycle until PRIM C6 and 
thereafter every cycle Day 1 and as clinically 
indicated  
  
Chemistry 
X 
  
  
X 
X 
X 
  
X 
X 
at days 1 & 15 at each cycle until PRIM C6 and 
thereafter every cycle Day 1and as clinically 
indicated 
  
Coagulation 
 
 
If clinically indicated 
  
Acute GvHD 
assessment 
X1 
  
  
 
 
X 
  
 
 
at each cycle until PRIM C6D1 and thereafter 
every 2 cycles and as clinically indicated 
  
Chronic GvHD 
assessment 
X1 
  
  
 
 
X 
  
 
 
at each cycle until PRIM C6D1 and thereafter 
every 2 cycles and as clinically indicated 
  
Urinalysis 
(dipstick) 
 
If clinically indicated 
  


Novartis 
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Page 115 of 192 
Amended Protocol Version 02 (Clean) 
 
 
Protocol No. CHDM201K12201 
 
 
Period 
Priming (PRIM) - Cycles duration: 28 days 
End of Priming phase disposition 
Cycle 
Cycle 1 
Cycle 2 
Cycle 3 (and subsequent cycles, if required) 
 
Visit Name 
PRIM 
C1D1 
 
PRIM 
C1D5 
PRIM 
C1D8 
PRIM 
C1D15 
PRIM 
C2D1 
 
PRIM 
C2D8 
PRIM 
C2D15 
PRIM CxD1 
EO PRIM Disposition 
Days 
D1 
 
D5 
D8 
D15 
D1 
 
D8 
D15 
D1 
- 
Serum Pregnancy 
test 2 
S3 
  
  
 
 
  
  
 
 
  
  
Urine Pregnancy 
Test OR Serum 
Pregnancy Test4 
  
  
  
 
 
S 
  
 
 
S 
  
12-Lead ECG 
(triplicates)5 
X 
  
X 
 
 
If clinically indicated 
at PRIM C4D1 and if clinically indicated 
  
Echocardiogram 
or MUGA 
If clinically indicated 
  
IST level 
X6 
 
X6 
 
 
 
 
 
 
 
 
IRT-Drug 
dispensation for 
siremadlin 
X 
  
  
 
 
X 
 
 
 
X 
  
Siremadlin 
administration7 
 X 
 
 
X 
 
 
X 
  
Efficacy 
assessments 
 
 
 
 
Refer to Table 8-2 for detailed assessments and 
schedule 
  
PK sample for 
siremadlin8 
X9 
  
X10 
 
 
  
 
 
 
Predose (0h) and 3h postdose PK samples at 
PRIM C4D1, C7D1, C10D1, C13D1, C19D1, 
and PK profile (see note 10) on C5D1 and 
C5D5 
  


Novartis 
Confidential 
Page 116 of 192 
Amended Protocol Version 02 (Clean) 
 
 
Protocol No. CHDM201K12201 
 
 
Period 
Priming (PRIM) - Cycles duration: 28 days 
End of Priming phase disposition 
Cycle 
Cycle 1 
Cycle 2 
Cycle 3 (and subsequent cycles, if required) 
 
Visit Name 
PRIM 
C1D1 
 
PRIM 
C1D5 
PRIM 
C1D8 
PRIM 
C1D15 
PRIM 
C2D1 
 
PRIM 
C2D8 
PRIM 
C2D15 
PRIM CxD1 
EO PRIM Disposition 
Days 
D1 
 
D5 
D8 
D15 
D1 
 
D8 
D15 
D1 
- 
Disposition 
  
  
  
 
 
  
  
 
 
  
Participants can go either to 
Combination phase or to End of 
Treatment 
X Assessment to be recorded in the clinical database or received electronically from a vendor 
S Assessment to be recorded in the source documentation only 
1 If it was performed as part of screening assessment within the previous 7 days, it is not needed to repeat it 
2 This test will be performed only for women of child-bearing potential 
3 To be performed only if it was not done in screening within 72 hours before first dose 
4 Urine or serum test may be performed, depending on local regulations, only for women of child-bearing potential 
5 Refer to Section 8.4.2 for detailed guidance on timepoints 
6 IST level to be measured prior to siremadlin administration 
7 On days 1 to 5 of each cycle 
8 Refer to appropriate table of Section 8.5.1.1 for detailed timepoints and collection schedule for siremadlin PK sampling. 
9 Sampling to be performed at pre-dose of siremadlin, and 0.5h, 1h, 2h, 3h, 6h, 8h, 10h, and 24h post-dose 
10 Sampling to be performed at pre-dose of siremadlin, and 0.5h, 1h, 2h, 3h, 6h, and 8h post-dose 
 
  


Novartis 
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Page 117 of 192 
Amended Protocol Version 02 (Clean) 
 
 
Protocol No. CHDM201K12201 
 
 
Table 8-4 
Assessment Schedule, Combination and Maintenance (Part 2) 
Period 
Combination (COMB) - Cycles duration: 42 days 
End of Combination phase 
disposition 
Maintenance (MAINT) - Cycles duration: 
28 days 
Cycle 
Cycle 1 
Cycle 2 
Cycle 3 
 
Cycle 1 
Cycle 2 (and subsequent 
cycles) 
Visit Name 
COM
B 
C1D
1 
COM
B 
C1D
3 
COM
B 
C1D
5 
COMBC1
D15 
COM
B 
C2D
1 
COM
B 
C2D
3 
COMBC2
D15 
COM
B 
C3D
1 
COM
B 
C3D
3 
COM
B 
C3D
5 
COM
B 
C3D
15 
EO COMB Disposition 
MAINT 
C1D1 
MAINT 
C1D5 
MAINT CxD1 
Days 
D1 
D3 
D5 
D15 
D1 
D3 
D15 
D1 
D3 
D5 
D15 
- 
D1 
D5 
D1 
concomitant 
medications, 
surgery and 
medical 
procedures 
Continuous 
Adverse 
Events 
Continuous 
Physical 
Examination 
S 
 
 
 
S 
 
 
S 
 
 
 
 
S 
 
S 
Vital Signs 
X 
 
 
 
X 
 
 
X 
 
 
 
 
X 
 
X 
Body Weight 
X 
 
 
 
X 
 
 
X 
 
 
 
 
X 
 
X 
ECOG PS 
X 
 
 
 
X 
 
 
X 
 
 
 
 
X 
 
X 
Hematology 
X 
 
 
 
X 
X 
 
 
X 
X 
 
 
 
X 
 
 
X 
 
X 
Chemistry 
X 
 
 
X 
X 
 
X 
X 
 
 
X 
 
X 
 
At MAINT C2D1, C3D1 and 
every 3 cycles thereafter 
Coagulation 
If clinically indicated 
Acute GvHD 
assessment 
X 
  
  
 
X 
  
 
X 
  
  
 
  
X 
  
At MAINT C2D1, C3D1 and 
every 3 cycles thereafter and 
as clinically indicated 


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Period 
Combination (COMB) - Cycles duration: 42 days 
End of Combination phase 
disposition 
Maintenance (MAINT) - Cycles duration: 
28 days 
Cycle 
Cycle 1 
Cycle 2 
Cycle 3 
 
Cycle 1 
Cycle 2 (and subsequent 
cycles) 
Visit Name 
COM
B 
C1D
1 
COM
B 
C1D
3 
COM
B 
C1D
5 
COMBC1
D15 
COM
B 
C2D
1 
COM
B 
C2D
3 
COMBC2
D15 
COM
B 
C3D
1 
COM
B 
C3D
3 
COM
B 
C3D
5 
COM
B 
C3D
15 
EO COMB Disposition 
MAINT 
C1D1 
MAINT 
C1D5 
MAINT CxD1 
Days 
D1 
D3 
D5 
D15 
D1 
D3 
D15 
D1 
D3 
D5 
D15 
- 
D1 
D5 
D1 
Chronic 
GvHD 
assessment 
X 
  
  
 
X 
  
 
X 
  
  
 
  
X 
  
At MAINT C2D1, C3D1 and 
every 3 cycles thereafter and 
as clinically indicated 
Urinalysis 
(dipstick) 
If clinically indicated 
Urine 
Pregnancy 
Test OR 
Serum 
Pregnancy 
Test1 
S 
  
  
 
S 
  
 
S 
  
  
 
  
S 
  
S 
12-Lead 
ECG 
(triplicates) 
X2 
  
  
 
  
  
 
  
  
  
 
  
  
  
  
Echocardiog
ram or 
MUGA 
If clinically indicated 
IRT-Drug 
dispensation 
for 
siremadlin 
X 
  
  
 
X 
  
 
X 
  
  
 
  
X 
  
X 
Siremadlin 
administratio
n3 
X 
 
X 
 
X 
 
  
X 
X 
X 


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Period 
Combination (COMB) - Cycles duration: 42 days 
End of Combination phase 
disposition 
Maintenance (MAINT) - Cycles duration: 
28 days 
Cycle 
Cycle 1 
Cycle 2 
Cycle 3 
 
Cycle 1 
Cycle 2 (and subsequent 
cycles) 
Visit Name 
COM
B 
C1D
1 
COM
B 
C1D
3 
COM
B 
C1D
5 
COMBC1
D15 
COM
B 
C2D
1 
COM
B 
C2D
3 
COMBC2
D15 
COM
B 
C3D
1 
COM
B 
C3D
3 
COM
B 
C3D
5 
COM
B 
C3D
15 
EO COMB Disposition 
MAINT 
C1D1 
MAINT 
C1D5 
MAINT CxD1 
Days 
D1 
D3 
D5 
D15 
D1 
D3 
D15 
D1 
D3 
D5 
D15 
- 
D1 
D5 
D1 
DLI 
administratio
n 
  
X 
  
 
  
X 
 
  
X 
  
 
  
  
  
  
Efficacy 
assessment
s 
Refer to Table 8-2 for details on assessments and schedule 
Efficacy - 
Bone 
marrow 
aspirate 
and/or 
biopsy4 
X5 
  
  
 
  
  
 
  
  
  
 
  
X6 
  
D1 of every 3 cycles (starting 
from Maint C3D1) until 
completion of 12 cycles of 
study treatment then every 6 
cycles thereafter and as 
clinically indicated 
Efficacy - 
extramedulla
ry disease 
assessment4
,7 
X5 
  
  
 
  
  
 
  
  
  
 
  
X6 
  
D1 of every 3 cycles (starting 
Maint C3D1) until completion 
of 12 cycles of study 
treatment then every 6 cycles 
thereafter and as clinically 
indicated 
Efficacy - 
response 
assessment4
,8 
X5 
  
  
 
  
  
 
  
  
  
 
  
X6 
  
D1 of every 3 cycles (starting 
from Maint C3D1) until 
completion of 12 cycles of 
study treatment then every 6 
cycles thereafter and as 
clinically indicated 
PK sample 
for 
siremadlin9 
X10 
  
X10 
 
  
  
 
X10 
  
X10 
 
  
X10 
X10 
At MAINT C4D1, C7D1, 
C10D1, C13D1, and C19D1 


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Period 
Combination (COMB) - Cycles duration: 42 days 
End of Combination phase 
disposition 
Maintenance (MAINT) - Cycles duration: 
28 days 
Cycle 
Cycle 1 
Cycle 2 
Cycle 3 
 
Cycle 1 
Cycle 2 (and subsequent 
cycles) 
Visit Name 
COM
B 
C1D
1 
COM
B 
C1D
3 
COM
B 
C1D
5 
COMBC1
D15 
COM
B 
C2D
1 
COM
B 
C2D
3 
COMBC2
D15 
COM
B 
C3D
1 
COM
B 
C3D
3 
COM
B 
C3D
5 
COM
B 
C3D
15 
EO COMB Disposition 
MAINT 
C1D1 
MAINT 
C1D5 
MAINT CxD1 
Days 
D1 
D3 
D5 
D15 
D1 
D3 
D15 
D1 
D3 
D5 
D15 
- 
D1 
D5 
D1 
Disposition 
  
  
  
 
  
  
 
  
  
  
 
X 
  
  
 
X Assessment to be recorded in the clinical database or received electronically from a vendor 
S Assessment to be recorded in the source documentation only 
1 Urine or serum test may be performed, depending on local regulations, only for women of child-bearing potential 
2 To be performed only if participant entered combination prior to completion of cycle 4 in Priming. Refer to Section 8.4.2 for detailed guidance on timepoints 
3 On days 1 to 5 of each cycle 
4 Assessment to be performed prior to DLI administration - protocol allows a 14 days window for efficacy assessments 
. 
5 If the bone marrow assessment was performed at last cycle (in priming phase), this assessment may be postponed to the third cycle of the combination phase (to 
maintain the frequency of BMA/BMB every 3 cycles). 
6 If the bone marrow assessment was performed at last cycle (in combination phase), this assessment may be postponed to the third cycle of the maintenance phase (to 
maintain the frequency of BMA/BMB every 3 cycles) 
7 Extramedullary disease is to be assessed via physical examination. Additional evaluation [eg, imaging, procedures (tissue biopsy, lumbar puncture), etc.] will be 
performed as clinically indicated per the investigator's assessment 
8 See Section 8.3.1 for details on response assessments 
9 Refer to appropriate table of Section 8.5.1.1 for detailed timepoints and collection schedule for siremadlin PK sampling. 
10 Sampling to be performed at pre-dose, 0.5h, 1h, 2h, 3h, 6h, and 8h post-dose at this specific time point. 
 


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8.1 
Screening 
All participants must provide signed ICFs prior to performing any study specific procedures. 
Participants will be evaluated against all study inclusion and exclusion criteria. 
After signing the ICFs, screening assessments should be completed within 28 days prior to the 
start of study treatment (C1D1), with the exception of the local serum pregnancy test (for 
women of child-bearing potential) which must be conducted and confirmed as negative within 
72 hrs prior to the start of study treatment. Laboratory parameters may be retested within the 
28-day screening period. If the repeat value remains outside of the specified ranges, the 
participant will be considered a screen failure. 
Re-screening should only occur after a participant has failed screening. An individual 
participant may only be re-screened once for the study. Participant will need to be re-consented 
and a new ICF will need to be signed if the investigator chooses to re-screen the participant. 
Any re-screened participant should receive a new participant No., and the original participant 
number must be noted on the Re-Screening CRF. All required screening activities must be 
performed when the participant is re-screened for participation in the study. 
8.1.1 
Eligibility screening 
Following registering in the IRT for screening, participant eligibility will be checked once all 
screening procedures are completed. The eligibility check will be embedded in the IRT system. 
Please refer and comply with detailed guidelines in the IRT manual. 
8.1.2 
Information to be collected on screening failures 
Participants who sign an informed consent form and subsequently found to be ineligible will be 
considered a screen failure. The reason for screen failure should be entered on the applicable 
CRF. The demographic information, informed consent, and Inclusion/Exclusion pages must 
also be completed for screen failure participants. No other data will be entered into the clinical 
database for participants who are screen failures, unless the participant experienced a serious 
adverse event during the screening phase (see SAE Section 10.1.3 for reporting details). 
Participants who sign an informed consent and are considered eligible but fail to be started on 
treatment for any reason will be considered an early terminator. The reason for early termination 
should be captured on the appropriate disposition Case Report Form. 
8.2 
Participant demographics/other baseline characteristics 
Demographics and other baseline characteristics data to be collected on all participants include: 
 Relevant medical history and current medical conditions 
 Disease (AML) history, including  
 Date of initial diagnosis and date of disease relapse(s). 
 2016 World Health Organization (WHO) AML classification (Arber et al 2016). 
 From initial diagnosis: ELN cytogenetic risk stratification (Döhner et al 2017), and any 
additional molecular markers (FLT3-TKD, isocitrate dehydrogenase 1 and 2 (IDH1/2), 


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DNMT3A, c-KIT, and others) (National Comprehensive Cancer Network (2021)). 
Refer to Appendix 5 Section 16.5 for details. 
 For participants who received allo-SCT in CR2 or greater: In addition to ELN 
cytogenetic risk stratification (Döhner et al 2017), and any additional molecular 
markers (FLT3-TKD, isocitrate dehydrogenase 1 and 2 (IDH1/2), DNMT3A, c-KIT, 
and others), collect data on the latest results of cytogenetics and molecular markers that 
were last performed prior to allo-SCT. Refer to Appendix 5 Section 16.5 for details. 
 Prior antineoplastic therapies [prior to and post-allo-SCT (before start of study treatment)].  
 Allo-SCT characteristics, conditioning regimen intensity, disease remission status at 
transplant (e.g., CR with undetectable MRD, CR with detectable MRD), timing of transplant 
(e.g., CR1, ≥CR2), prior and current history of acute GvHD or chronic GvHD, prior and 
current immunosuppressive therapy (systemic GvHD prophylaxis or treatment) and date of 
completion). 
 Race/ethnicity (in order to allow for signal detection and racial/ethnic sensitivity reports 
required for registration in multiple countries). 
 All prior and concomitant medications and medical procedure must be documented. All 
prescription medications, over-the-counter drugs and significant non-drug therapies prior to 
the start of the study must be documented. See the protocol Section 6.2.1 Concomitant 
Therapy for further details on what information must be recorded on the appropriate page 
of the eCRF. 
Participant race/ethnicity data are collected and analyzed to identify any differences in the 
safety and/or efficacy profile of the treatment due to these characteristics. In addition, we need 
to assess the diversity of the study population as required by Health Authorities. 
Investigators will have the discretion to record abnormal test findings on the medical history 
CRF whenever in their judgment, the test abnormality occurred prior to the informed consent 
signature. Significant new findings that begin or worsen after informed consent must be 
recorded on the AE page of the participant’s eCRF. 
Other assessments will be completed for the purpose of determining eligibility for inclusion in 
the study as reported in Section 5. 
Assessments to be performed at screening include: 
 Physical examination. 
 ECOG Performance Status, body height, weight, vital signs (blood pressure (supine position 
preferred when ECGs are collected) and pulse, and body temperature). 
 Laboratory: hematology, chemistry, coagulation, urinalysis, serum pregnancy test for 
women of child-bearing potential, virology hepatitis B and C, HIV serology (only if 
required per local regulation), GLDH. 
If multiple laboratory tests were performed during screening to confirm eligibility, the lab 
values closest to enrollment (C1D1 visit) should be used (last available values during 
screening). 
 Triplicate 12-lead central ECG. 


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 Echocardiogram (or MUGA- Multiple gated acquisition) unless it was performed within 6 
months of enrollment. 
 Cytogenetics. 
 Bone marrow biopsy / aspirate and peripheral blood to establish the diagnosis. If a bone 
marrow aspirate or biopsy was conducted during the regular work-up of the participant and 
falls within 28 days prior to the first dose of study treatment (C1D1 visit) (although prior to 
signing main study ICF), it may be considered as the baseline assessment for the study. Any 
deviation from this timelines needs to be confirmed with Novartis. 
 CT Scan/MRI if extramedullary disease is present or suspected. 

 
 
 
 
 
Blood samples for PK will be taken during screening in order to perform the required IST 
tapering (ref to Section 6.2.2.1 for details). 
8.3 
Efficacy 
Efficacy / disease response assessments will be performed locally, by the Investigator 
assessment, according to the schedule depicted in Table 8-1, Table 8-2, Table 8-3, and  
Table 8-4. 
8.3.1 
Efficacy - Disease status assessment 
The study primary efficacy endpoint is measured by the proportion of participants who are alive 
and maintained CR or CRi with no evidence of hematologic relapse (per investigator 
assessment) over at least 6 months after start of study treatment (siremadlin monotherapy, as 
priming and/or maintenance, with or without siremadlin in combination with DLI).  
Disease response assessment will be according to the European LeukemiaNet (ELN) AML 
recommendations (Döhner et al 2017) and International Working Group (IWG) AML response 
criteria (Cheson et al 2003). 
Disease status evaluation at baseline and efficacy assessment during study treatment consist of 
evaluation of bone marrow aspirate (BMA)/bone marrow biopsy (BMB), peripheral blood (PB), 
hematology assessments and extramedullary disease assessments. Disease status assessment 
will be either complete remission, complete remission with incomplete hematologic recovery, 
or hematologic relapse. 
Bone marrow assessments will be performed as outlined in Table 8-1 and in Table 8-2 at 
screening, and on D1 (pre-dose of study treatment) of every 3 cycles until completion of 12 
cycles of study treatment (since study entry) then every 6 cycles thereafter (+/- 14 days) and as 
clinically indicated. 


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After the EOT, bone marrow assessments will be performed every 6 months and as clinically 
indicated until relapse, start of a new anti-neoplastic treatment, death, lost to follow-up or 
withdrawal of consent. 
Additional (unscheduled) bone marrow assessments may be performed as clinically indicated. 
Bone marrow and peripheral blood pathology specimens (i.e. bone marrow aspirate slides, bone 
marrow biopsy block if applicable, peripheral blood smears) prepared locally for the disease 
response assessment should be sent to the Novartis designated central laboratory for storage. 
This includes specimens taken during the regular work-up of the participant and used as baseline 
assessment for the study as mentioned in Section 8.2. A copy of the corresponding pathology 
reports should be collected and sent to the Novartis designated central laboratory for storage. 
Central morphology review of the pathology specimens may be performed, if deemed 
necessary. 
Hematology assessments will be performed at screening, and pre-dose at D1 of each cycle (in 
dose confirmation, priming, combination and maintenance phase), at the end of treatment visit, 
at unscheduled visit as clinically indicated, and every 3 months for participants who enter post-
treatment follow-up. 
In case of missing data for the full assessment required to qualify for a given response, the 
overall assessment “unknown” will be assigned unless relapse was seen in at least one 
compartment (i.e. bone marrow or blood, or appearance of extramedullary disease). 
Disease status evaluation at baseline: the last assessment of bone marrow (within 28 days of 
start of study treatment) and peripheral blood counts as well as extramedullary disease 
assessment (within 14 days of start of study treatment) at the screening visit may be used. Any 
disease response assessments obtained after start of study treatment (C1D1 and beyond) cannot 
be considered baseline assessment.  
Extramedullary disease assessment: is performed primarily via physical examination. 
Additional evaluation for extramedullary disease [eg, imaging, procedures (tissue biopsy, 
lumbar puncture), etc.] will be performed as clinically indicated per the investigator's 
assessment. Cerebrospinal fluid assessment and relevant imaging techniques may be performed, 
as clinically appropriate at the investigator's discretion, in case of symptoms suggestive of 
meningeosis leukemia, and/or prior history of central nervous system involvement with AML. 
In case of appearance or reappearance of extramedullary disease during the study, the lesions 
should be considered for confirmation by imaging or biopsy if technically and/or clinically 
feasible. 
Assessment for the presence or absence of extramedullary disease will be performed at a similar 
schedule as the bone marrow assessment and should be performed prior to the first cycle of the 
siremadlin/DLI combination. 
The presence or absence and physical location of extramedullary disease are to be recorded on 
the CRFs. 
Participants can be assessed for disease response (bone marrow assessment, hematology, 
extramedullary disease assessment) at any time if clinically indicated, for example in case of 
suspicion of relapse. Therefore, more frequent efficacy assessments may be performed at the 


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investigator’s discretion, if medically indicated, and should be recorded on the Unscheduled 
Visit eCRFs. All scheduled and unscheduled assessments will be analyzed. 
Clinical suspicion of relapse at any time will require an evaluation promptly, rather than waiting 
for the next scheduled assessment. 
In case of an unscheduled or delayed disease evaluation of any reason, subsequent assessments 
should be performed according to the originally planned schedule. 
Table 8-5 
Response classification in AML at a given evaluation time (based on 
IWG Cheson et al 2003, ELN 2017 Döhner et al 2017) 
Response Category 
Definition1 
Complete remission 
(CR) 
● Bone marrow: blasts < 5% 
● Peripheral blood: No circulating blasts or blasts with Auer rods 
● No evidence of extramedullary disease (such as Central Nervous System (CNS) 
or soft tissue involvement) 
● Neutrophils ≥ 1.0x109/L 
● Platelets ≥ 100x109/L 
Complete remission 
with incomplete 
hematologic recovery 
(CRi) 
● Bone marrow: blasts < 5% 
● Peripheral blood: No circulating blasts or blasts with Auer rods 
● No evidence of extramedullary disease (such as CNS or soft tissue involvement) 
● Neutrophils < 1.0x109/L or platelets < 100x109/L 
Hematologic relapse 
(from CR or CRi) 
Only in participants with CR or CRi. Any of the following: 
● Reappearance of blasts in peripheral blood 
OR 
● Bone marrow blasts ≥ 5% 
OR 
● Development of extramedullary disease 
Unknown 
In case the response assessment was not done or the assessment was incomplete 
1 If not defined otherwise, all of these criteria apply. 
8.3.2 
Appropriateness of efficacy assessments 
The assessment of response to study treatment is based on standardized criteria as proposed by 
the European LeukemiaNet (ELN) and the International Working Group (IWG) 
(Cheson et al 2003, Döhner et al 2017) in Table 8-5. 
8.4 
Safety 
Safety assessments are specified below in Table 8-6 with the assessment schedule detailing 
when each assessment is to be performed. 
For details on AE collection and reporting, refer to AE section. 
As per Section 4.6, during a public health emergency as declared by local or regional authorities 
i.e. pandemic, epidemic or natural disaster, that limits or prevents on-site study visits, regular 
phone or virtual calls can occur (every 4 weeks or more frequently if needed) for safety 
monitoring and discussion of the participant´s health status until it is safe for the participant to 
visit the site again. 


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Table 8-6 
Assessments and Specifications 
Assessment 
Specification 
Physical 
examination 
A complete physical examination will include the examination of general appearance, 
skin, neck (including thyroid), eyes, ears, nose, throat, lungs, heart, abdomen, back, 
lymph nodes, extremities, vascular, and neurological. 
If indicated based on medical history and/or symptoms, rectal, external genitalia, breast, 
and pelvic exams will be performed. 
A complete physical examination is required at D1 of each cycle.Information for all 
physical examinations must be included in the source documentation at the study site. 
Clinically relevant findings that are present prior to signing informed consent must be 
recorded on the appropriate CRF that captures medical history. Significant findings 
made after signing informed consent, which meet the definition of an Adverse Event, must 
be recorded as an adverse event. 
Vital signs 
Vital signs include blood pressure (supine position preferred when ECG is collected), 
pulse measurement, and body temperature. 
Height and weight 
Height in centimeters (cm) will be measured at Screening. Body weight (to the nearest 0.1 
kilogram (kg) in indoor clothing, but without shoes) will be measured at screening and at 
subsequent timepoints as specified in Table 8-1; Table 8-2; Table 8-3; and Table 8-4 
Performance status: 
ECOG Performance status scale will be used as described in Table 8-7. 
Table 8-7 
ECOG performance status 
Grade 
ECOG Status 
0 
Fully active, able to carry on all pre-disease performance without restriction 
1 
Restricted in physically strenuous activity but ambulatory and able to carry out work of a light or 
sedentary nature (e.g., light house work, office work) 
2 
Ambulatory and capable of all self-care but unable to carry out any work activities. Up and about 
more than 50% of waking hours 
3 
Capable of only limited self-care, confined to bed or chair more than 50% of waking hours 
4 
Completely disabled. Cannot carry on any self-care. Totally confined to bed or chair 
5 
Death 
8.4.1 
Laboratory evaluations 
Local clinical laboratory parameters will be used for the analysis of scheduled hematology, 
chemistry and other blood specimens collected as part of safety monitoring (as detailed 
in Table 8-1; Table 8-2; Table 8-3; Table 8-4 and Table 8-8; Table 8-9) and the results will be 
collected in the eCRF. 
Unscheduled assessments of these parameters can be performed more often as clinically 
indicated. It is preferable to use the same laboratory for all the assessments performed, 
especially for the hematology assessments. 
A central laboratory will be used for the parameters listed in Table 8-9 and as per the schedule 
in Table 8-1; Table 8-2; Table 8-3, and Table 8-4. 
Laboratory values obtained during the Screening phase will be used to assess participant’s 
eligibility. 
Novartis must be provided with a copy of the certification and a tabulation of the normal ranges 
and units for all local laboratories used to the trial. 


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As per Section 4.6, during a public health emergency as declared by local or regional authorities' 
i.e. pandemic, epidemic or natural disaster, that limits or prevents on-site study visits, if 
participants cannot visit the site for protocol-specified safety lab assessments, an alternative lab 
(local) collection site may be used.  
Clinically significant abnormalities must be recorded as either medical history/current medical 
conditions or adverse events as appropriate. 
Table 8-8 
Local clinical laboratory parameters collection plan 
Test Category 
Test Name 
Hematology 
Hemoglobin (Hgb), Leucocytes, Platelets, Erythrocyte Cell Morphology, Differential 
(Basophils, Eosinophils, Lymphocytes, Monocytes, Neutrophils, Bands, metamyelocytes, 
myelocytes, promyelocytes, blasts, Other), (absolute value preferred, %s are acceptable), 
atypical cells (e.g. Large unstained cells (LUC), erythroblasts) 
Chemistry 
Albumin, Alkaline phosphatase, ALT, AST, Gamma-glutamyl-transferase (GGT), Lactate 
dehydrogenase (LDH), Bicarbonate, Calcium, Magnesium, Phosphate, Sodium, Potassium, 
Creatinine, Creatine kinase, (Direct Bilirubin, Indirect Bilirubin)*, eGFR, Total Bilirubin, Total 
Cholesterol, Total Protein, Blood Urea Nitrogen (BUN) or Urea, Uric Acid, Amylase, Lipase, 
Glucose (fasting) 
Virology** 
HBsAg, HBcAb, HBV DNA (in participants positive for HBcAb), HCV RNA (PCR- 
Polymerase Chain Reaction) HIV (Only if required by local regulation) 
Urinalysis** 
Dipstick examination includes specific gravity, pH, glucose, protein, blood, bilirubin, ketones 
and WBC as clinically indicated. If urinalysis dipstick shows abnormalities, the site should 
perform a more detailed urinalysis follow-up as clinically indicated and per local practice. 
Coagulation 
International normalized ratio (INR), Activated partial thromboplastin time (APTT) 
Pregnancy** 
Test 
Serum / Urine pregnancy test (refer to Section 8.4.3 'Pregnancy and assessments of 
fertility') 
* Indirect and direct bilirubin only required if total bilirubin is abnormal 
** Virology, urinalysis, and pregnancy test will only be reported in the source documentation 
Table 8-9 
Central clinical laboratory parameters collection plan 
Test Category 
Test Name 
Chemistry for DILI1 
Glutamate dehydrogenase (GLDH) 
1 at baseline and as clinically indicated for follow-up of DILI per Section 6.6.5.1 
8.4.2 
Electrocardiogram (ECG) 
Electrocardiograms (ECGs) must be recorded after 10 minutes rest in the supine position to 
ensure a stable baseline. The preferred sequence of cardiovascular data collection during study 
visits is ECG collection first, followed by vital signs, blood sampling, and any remaining 
assessments for that visit (refer to flow diagram below). 
Figure 8-1 
Timing of study procedures 
 
The ECG are to be collected with ECG machines supplied by the central ECG vendor at the 
timepoints indicated in the ECG collection plan (Table 8-10 and Table 8-11) and transmitted to 
the central ECG vendor to be centrally reviewed by an independent reviewer. Full details of all 


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procedures relating to the ECG collection and reporting will be contained in the technical 
manual, which is provided to the site by the ECG vendor. Any original ECG not transmitted 
electronically to the central ECG vendor should be forwarded for central review. Any identifier 
details must be redacted e.g. participant initials, date of birth as per local regulations. 
Triplicate 12 lead ECGs are to be recorded approximately 2 minutes apart. The mean QTcF 
value for each visit will be calculated from the triplicate ECGs for each participant. The 
Fridericia QT correction formula (QTcF) must be used for clinical decisions. The investigator 
must calculate QTcF if it is not auto-calculated by the ECG machine. 
Clinically significant abnormalities present at screening should be reported on the appropriate 
CRF. New or worsened significant findings occurring after informed consent must be recorded 
as adverse events. 
In case of QTcF prolongation, please refer to Section 6.6.5.2 "Follow up for QTcF 
prolongation" 
Additional, unscheduled, safety ECGs may be repeated at the discretion of the investigator at 
any time during the study as clinically indicated and transmitted electronically to the central 
ECG vendor as unscheduled timepoints. For any ECGs with participant safety concerns, two 
additional ECGs must be performed to confirm the safety finding. ECG safety monitoring, or a 
review process, should be in place for clinically significant ECG findings at baseline before 
administration of study treatment and during the study. 
Table 8-10 
Central ECG collection plan in Part 1 
Cycle 
Day 
Time point* 
Number of ECG 
Replicates 
Screening 
Day -28 to Day -1 
anytime 
12 Lead Triplicate 
CONF Cycle 1 
Day 1 
Pre-dose1 
Post-dose 3h2 
Post-dose 8h2 
12 Lead Triplicate 
Day 5 
Pre-dose1 
Post-dose2 3h 
Post-dose2 8h 
12 Lead Triplicate 
CONF Cycle 4 
Day 1 
Pre-dose1 
12 Lead Triplicate 
Post-dose2 3h 
12 Lead Triplicate 
EOT 
 
Anytime 
12 Lead triplicate 
Unscheduled or Unplanned sample 
Anytime as 
clinically indicated 
12 Lead triplicate 
* When PK is collected at the same time point as ECG, the PK sample should be taken immediately after ECG  
1ECG collection prior to any study drug dosing 
2 ECG collection after siremadlin intake 
Table 8-11 
Central ECG collection plan in Part 2 
Cycle 
Day 
Time point* 
Number of ECG 
Replicates 
Screening 
Day -28 to Day -1 
anytime 
12 Lead Triplicate 
PRIM Cycle 1 
Day 1 
Pre-dose1 
Post-dose 3h2 
Post-dose 8h2 
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Day 5 
Pre-dose1 
Post-dose2 3h 
Post-dose2 8h 
12 Lead Triplicate 
PRIM Cycle 4 - If participant entered 
combination prior to reaching cycle 4 in 
priming, perform ECG assessment at 
COMB Cycle 1 as indicated below 
Day 1 
Pre-dose1 
12 Lead Triplicate 
Post-dose2 3h 
12 Lead Triplicate 
COMB Cycle 1 - To be performed only 
if participant entered combination prior 
to completion of cycle 4 in Priming 
EOT 
Day 1 
 
N/A 
Pre-dose1 
12 Lead Triplicate 
Post-dose2 3h 
Anytime 
12 Lead Triplicate 
12 Lead Triplicate 
Unscheduled or Unplanned sample 
Anytime as 
clinically indicated 
12 Lead Triplicate 
* When PK is collected at the same time point as ECG, the PK sample should be taken immediately after 
ECG 1 
ECG collection prior to any study drug dosing 
2 ECG collection after siremadlin intake 
8.4.2.1 
Cardiac imaging - MRA (magnetic resonance angiography), MUGA 
(multiple gated acquisition) scan or echocardiogram 
The left ventricular cardiac function will be evaluated by echocardiogram or MUGA at baseline 
according to the visit schedule in Table 8-1; Table 8-2; Table 8-3; and Table 8-4 and if clinically 
indicated. 
8.4.2.2 
Cardiac enzymes 
Not applicable 
8.4.3 
Pregnancy and assessments of fertility 
A condom is required for all sexually active male participants to prevent them from fathering a 
child AND to prevent delivery of study treatment via seminal fluid to their partner during the 
study until 2 weeks after the last dose of siremadlin. In addition, male participants should not 
donate sperm for the time period specified above. 
All pre-menopausal women who are not surgically sterile will have pregnancy testing. 
Additional pregnancy testing might be performed if requested by local requirements. 
At screening, a serum pregnancy test (serum ß-HCG) must be performed within 72 hours before 
the first dose. 
During the study, a urine/serum pregnancy test should be performed at Day 1 of each cycle 
(except Cycle 1 if a pregnancy test had been performed within 72 hours of the first dose) and a 
serum pregnancy test at EOT visit. Pregnancy testing (urine/serum) should occur at Day 30 of 
the safety follow-up period. Refer to Table 8-1; Table 8-2; Table 8-3; and Table 8-4 for 
pregnancy testing schedule. 
Positive urine pregnancy needs to be confirmed with a serum test. Confirmed positive 
pregnancy test requires immediate discontinuation of study treatment and discontinuation from 
study. See Section 10.1.4 for pregnancy reporting. 
The pregnancy tests will be recorded only in the source documentation, not in the CRF.  


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Women of childbearing potential should employ the use of highly effective contraception 
during the study until 2 weeks after the last dose of siremadlin. Highly effective contraception 
methods are defined in Section 5.2. 
As per Section 4.6, during a public health emergency as declared by local or regional authorities' 
i.e. pandemic, epidemic or natural disaster, that limits or prevents on-site study visits, if 
participants cannot visit the site to have serum pregnancy tests, urine pregnancy test kits may 
be used. Relevant participants can perform the urine pregnancy test at home and report the result 
to the site. It is important that participants are instructed to perform the urine pregnancy test 
first and only if the test result is negative proceed with the administration of the study treatment. 
A communication process should be established with the participant so that the Site is informed 
and can verify the pregnancy test results (e.g., following country specific measures). 
Assessments of fertility 
A woman is considered of childbearing potential from menarche and until becoming post 
menopausal unless permanently sterile. Permanent sterilization methods include hysterectomy, 
bilateral salpingectomy and bilateral oophorectomy. Medical documentation of oophorectomy, 
hysterectomy, or tubal ligation must be retained as source documents. 
A postmenopausal state is defined as no menses for 12 months without an alternative medical 
cause and an appropriate clinical profile. 
In absence of the medical documentation confirming permanent sterilization, or if the post-
menopausal status is not clear, the investigator should use his medical judgment to appropriately 
evaluate the fertility state of the woman and document it in the source document. 
8.4.4 
Other safety evaluations 
8.4.4.1 
aGvHD assessment 
aGvHD staging and grading will be performed by the Investigator at baseline, at Day 1 visit of 
treatment cycles as outlined in the various treatment phases (Part 1 and Part 2)), at EOT visit, 
at the Safety Follow-up visit, every 3 months during post treatment Follow-up, and as clinically 
indicated as outlined in Table 8-1, Table 8-2, and Table 8-3, and Table 8-4. 
aGvHD grading and staging will be performed using standard criteria (Harris et al 2016): 
measures of body surface area aGvHD skin rash, stool volumes or frequency per 24h time 
period, and serum bilirubin levels, staging by organ (skin; liver; upper GI; lower GI) and overall 
grading at the time of the evaluation should be reported according to Appendix 1 Section 16.1. 
The data should be entered in the appropriate CRFs. 
In addition, Investigator should record and report any management action of aGvHD in 
appropriate CRF(s). 
Note: Additional aGvHD assessments (including biopsy of the organ involved) may be done as 
per institutional guidelines at investigator’s discretion. aGvHD assessments performed at 
unscheduled visit and leading to a change in patient's management after the last dose of study 
treatment should be recorded in the CRF. 


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8.4.4.2 
cGvHD assessment 
Occurrence of definitive and possible manifestations of cGvHD will be assessed by the 
Investigator at baseline, at Day 1 visit of treatment cycles as outlined in the various treatment 
phases (Part 1 and Part 2), at EOT visit, at the Safety Follow-up visit, every 3 months during 
post 
treatment 
Follow-up, 
and 
as 
clinically 
indicated 
as 
outlined 
in Table 8-1, Table 8-2, Table 8-3 and Table 8-4. 
Occurrence of cGvHD will be reported on appropriate specific CRF. 
Investigator will assess cGvHD as per NIH consensus guidelines for cGvHD (Appendix 2, 
Section 16.2): overall grading (mild, moderate, severe) at the time of cGvHD diagnosis which 
will be reported in corresponding CRF. 
Additional cGvHD assessments (including biopsy of the organ involved) may be done as per 
institutional guidelines at investigator’s discretion.  
In addition, Investigator should indicate if a systemic treatment is initiated for cGvHD in 
appropriate CRF(s).  
8.4.5 
Appropriateness of safety measurements 
The safety assessments selected are standard for this indication/participant population, 
including acute and chronic GvHD as potential complication of allo-SCT and DLI. 
8.5 
Additional assessments 
8.5.1 
Pharmacokinetics 
Pharmacokinetic (PK) samples will be obtained and evaluated in all participants at all 
siremadlin dose levels. The exact dates and clock times of study drugs administration and 
sample blood collection will be recorded on the appropriate CRF. Any sampling issues should 
be noted on the CRF and on appropriate source documentation. 
If participants experience an SAE or an AE leading to the discontinuation of the study treatment, 
an unscheduled PK blood sample should be obtained as close as possible to the event 
occurrence. The date and time of the last dose and the time of PK blood draw should be 
recorded. 
 
 
8.5.1.1 
Pharmacokinetic blood collection and handling 
 All sampling is relative to the administration of siremadlin. 
 Serial blood samples from all enrolled participants will be collected at specified time points 
as outlined in Table 8-12 and Table 8-13 to measure siremadlin PK. 
 On days of sample blood collection, participants should take their medication at the clinic 
immediately after the first blood sample (e.g., pre-dose/0 hr sample). The exact dates and 
clock times of study drugs administration and sample blood collection will be recorded on 


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the appropriate CRF. Any sampling issues should be noted on the CRF and on appropriate 
source documentation. 
 Blood samples of 2 mL per time point will be taken by either direct venipuncture or an 
indwelling cannula inserted in a forearm vein opposite to the arm used for infusion (when 
applicable). 
 When PK is collected at the same time point as ECG, the PK sample should be taken 
immediately after ECG. 
 If vomiting occurs within 4 hours following siremadlin administration on the day of a post 
dose PK blood sample collection, the clock time of vomiting should be recorded in the 
appropriate CRF page.  
 After permanent discontinuation of siremadlin, the samples scheduled for pre- and post-
siremadlin treatment (Table 8-12 and Table 8-13) should no longer be collected. 
Refer to the [CHDM201K12201 Laboratory Manual] for detailed instructions for the collection, 
handling, and shipment of PK samples.  
Table 8-12 
Pharmacokinetic blood collection log for siremadlin (Part 1)  
Cycle 
Day 
Scheduled Time Point (sampling 
window) 
Dose Confirmation (CONF) 
CONF Cycle 1  
1 
Pre-dose/0 h a, c 
0.5 h (±10 min) 
1 h (±10 min) 
2 h (±10 min) 
3 h (±15 min) c 
6 h (±15 min) 
8 h (±30 min) c 
10 (±30 min) 
24h (±2h) 
5 
Pre-dose/0 h c 
0.5 h (±10 min) 
1 h (±10 min) 
2 h (±10 min) 
3 h (±15 min) c 
6 h (±15 min) 
8 h (±30 min) c 
CONF Cycle 5 
1 
Pre-dose/0 h a 
0.5 h (±10 min) 
1 h (±10 min) 
2 h (±10 min) 
3 h (±15 min) 
6 h (±15 min) 
8 h (±30 min) 
5 
Pre-dose/0 h 
0.5 h (±10 min) 
1 h (±10 min) 


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Cycle 
Day 
Scheduled Time Point (sampling 
window) 
2 h (±10 min) 
3 h (±15 min) 
6 h (±15 min) 
8 h (±30 min) 
CONF Cycles 4, 7, 10, 13, and 19 
1 
Pre-dose/0 h a 
 3 h (±15 min) 
Unscheduled sample 
- 
Unscheduled Anytime b, c 
a Collect PK sample immediately prior to siremadlin administration 
b Unscheduled PK blood samples may be collected at any time for measurement of plasma drug 
concentrations if clinically indicated or at the Investigator’s discretion and will be uniquely identified. 
c When PK is collected at the same time point as ECG, the PK sample should be taken immediately after ECG. 
Table 8-13 
Pharmacokinetic blood collection log for siremadlin (Part 2) 
Cycle 
Day 
Scheduled Time Point (sampling 
window) 
PRIMING (PRIM) 
PRIM Cycle 1  
1 
Pre-dose/0 h a, c 
0.5 h (±10 min) 
1 h (±10 min) 
2 h (±10 min) 
3 h (±15 min) c 
6 h (±15 min) 
8 h (±30 min) c 
10 (±30 min) 
24h (±2h) 
5 
Pre-dose/0 h c 
0.5 h (±10 min) 
1 h (±10 min) 
2 h (±10 min) 
3 h (±15 min) c 
6 h (±15 min) 
8 h (±30 min) c 
PRIM Cycle 5 
Applicable to participants who did 
not enter combination phase. For 
participants who proceed to 
siremadlin/DLI, follow the schedule 
for combination phase, then 
proceed to maintenance phase 
assessment schedule. 
1 
Pre-dose/0 h a 
0.5 h (±10 min) 
1 h (±10 min) 
2 h (±10 min) 
3 h (±15 min) 
6 h (±15 min) 
8 h (±30 min) 
5 
Pre-dose/0 h 
0.5 h (±10 min) 
1 h (±10 min) 
2 h (±10 min) 
3 h (±15 min) 
6 h (±15 min) 
8 h (±30 min) 


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Cycle 
Day 
Scheduled Time Point (sampling 
window) 
PRIM Cycles 4, 7, 10, 13, and 19 
1 
Pre-dose/0 h a 
 3 h (±15 min) 
COMBINATION (COMB) 
COMB Cycle 1 
and 
COMB Cycle 3 
1 
Pre-dose/0 h a,c 
0.5 h (±10 min) 
1 h (±10 min) 
2 h (±10 min) 
3 h (±15 min)c 
6 h (±15 min) 
8 h (±30 min) 
5 
Pre-dose/0 h a,c 
0.5 h (±10 min) 
1 h (±10 min) 
2 h (±10 min) 
3 h (±15 min)c 
6 h (±15 min) 
8 h (±30 min) 
MAINTENANCE (MAINT) 
MAINT Cycle 1 
Applicable to participants who 
received the combination phase 
(siremadlin/DLI). Otherwise, for 
participants who did not receive the 
combination phase; follow the 
assessment schedule for priming 
phase. 
1 
Pre-dose/0 h a 
0.5 h (±10 min) 
1 h (±10 min) 
2 h (±10 min) 
3 h (±15 min) 
6 h (±15 min) 
8 h (±30 min) 
5 
Pre-dose/0 h a 
0.5 h (±10 min) 
1 h (±10 min) 
2 h (±10 min) 
3 h (±15 min) 
6 h (±15 min) 
8 h (±30 min) 
MAINT Cycles 4, 7, 10, 13, and 19 
1 
Pre-dose/0 h a 
3 h (±15 min) 
Unscheduled sample 
- 
Unscheduled Anytime b, c 
a Collect PK sample immediately prior to siremadlin administration 
b Unscheduled PK blood samples may be collected at any time for measurement of plasma drug 
concentrations if clinically indicated or at the Investigator’s discretion and will be uniquely identified 
c When PK is collected at the same time point as ECG, the PK sample should be taken immediately after ECG  
8.5.1.2 
Analytical method 
Plasma concentrations of siremadlin will be determined using a validated LC-MS assay, with a 
current lower limit of quantification (LLOQ) of 1 ng/mL. The details of the assay will be 
documented in the [CHDM201K12201 Laboratory Manual]. 


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Concentrations will be expressed in mass per volume units. Concentrations below the LLOQ 
will be reported as “zero” and missing data will be labeled as such in the Bioanalytical Data 
Report. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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9 
Discontinuation and completion 
9.1 
Discontinuation from study treatment and from study 
9.1.1 
Discontinuation from study treatment 
Discontinuation of study treatment for a participant occurs when the treatments (siremadlin 
monotherapy or siremadlin in combination with DLI) is permanently stopped for any reason 
(prior to the planned completion of study drug administration, if any) and can be initiated by 
either the participant or the investigator. Discontinuation of DLI only while continuing 
siremadlin monotherapy is NOT considered a study treatment discontinuation. 
The investigator must discontinue study treatment for a given participant if, he/she believes that 
continuation would negatively impact the participant's well-being. 
Discontinuation from study treatment is required under the following circumstances: 


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 Participant/guardian decision 
 Pregnancy 
 Use of prohibited treatment as per recommendations Section 6.2.3. 
 Any situation in which continued study participation might result in a safety risk to the 
participant  
 Any adverse event or laboratory abnormalities that in the judgment of the investigator, 
taking into consideration the participant’s overall status, prevents the participant from 
continuing participation in the study. 
 Protocol defined reasons for discontinuation (see Section 6.1.4) 
 Termination of the study by Novartis 
If discontinuation from study treatment occurs, the investigator should make a reasonable effort 
to understand the primary reason for the participant’s discontinuation from study treatment and 
record this information. 
Participants who discontinue from study treatment agree to return for the end of treatment and 
follow-up visits indicated in the Assessment Schedule (refer to Section 8 and below). 
If the participant cannot or is unwilling to attend any visit(s), the site staff should maintain 
regular telephone contact with the participant, or with a person pre-designated by the 
participant. This telephone contact should preferably be done according to the study visit 
schedule. 
After discontinuation from study treatment, at a minimum, in abbreviated visits, the following 
data should be collected at clinic visits or via telephone/email contact: 
 New / concomitant treatments 
 Adverse Events / Serious Adverse Events 
The investigator must also contact the IRT to register the participant’s discontinuation from 
study treatment. 
9.1.1.1 
Safety Follow-up 
All participants who discontinue from study treatment must be followed for safety for 30 days 
after the last dose of siremadlin. All safety assessments should be completed as per Table 8-1 
and Table 8-2. However, if the participant begins new anti-neoplastic therapy before the end of 
the safety follow-up period, the collection of new SAEs and AEs unrelated to study medication 
will stop, and thereafter only AEs and SAEs suspected to be related to study treatment will 
continue to be collected up to the end of the safety follow-up period. Suspected SAEs will 
continue to be collected beyond the 30-Day safety visit (in Post-Treatment follow-up). For 
female participants of childbearing potential, a pregnancy test will be performed at the 
timepoints listed in Table 8-1 and Table 8-2. 
9.1.1.2 
Post-Treatment Follow-up 
For participants who completed the planned study treatment (24 cycles) or discontinued 
treatment earlier for reasons other than documented disease relapse, death, lost to follow-up, or 
withdrawal of consent/opposition to use data/biological samples, efficacy assessments will 


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continue to be performed as per Table 8-1 and Table 8-2 with hematological assessments and 
bone marrow assessments or as clinically indicated until documented disease relapse, start of a 
new anti-neoplastic treatment (including second allo-SCT), death, lost to follow-up, or 
withdrawal of consent/exercice of participants’ data privacy rights. 
Figure 9-1 
Post Treatment and Survival Follow up Design 
  
* Via phone call or on site visit if participant happens to be visiting the site 
9.1.1.3 
Survival Follow-up 
Participants will enter the survival follow-up period once they complete the safety follow-up 
period or for those who had entered the post-treatment follow-up phase, once they have disease 
relapse or started a new anti-neoplastic therapy (including second allo-SCT) (whichever is 


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later). Participants will then be contacted by telephone every 12 weeks or if they happen to be 
visiting the site to follow-up on their survival status. Any new anti-neoplastic therapy that has 
been started since the last contact date (including second allo-SCT) and any SAEs related to 
study treatment will also be collected during these phone calls. Additionally, for participants 
who start a new anti-neoplastic therapy (including second allo-SCT) but remained in CR/CRi, 
disease response status per the investigator’s local assessments (if available) will be collected 
every 12 weeks (if participant happens to be visiting the site) until documented disease relapse 
(Figure 9-1). 
9.1.2 
Discontinuation from study 
Discontinuation from study is when the participant permanently stops receiving the study 
treatment, and further protocol-required assessments or follow-up, for any reason. 
If the participant agrees, a final evaluation at the time of the participant’s study discontinuation 
should be made as detailed in the assessment table (refer to Section 8). 
9.1.3 
Lost to follow-up 
For participants whose status is unclear because they fail to appear for study visits without 
stating an intention to discontinue from study treatment or discontinue from study or withdraw 
consent/exercice of participants’ data privacy rights, the investigator must show "due diligence" 
by documenting in the source documents steps taken to contact the participant, e.g. dates of 
telephone calls, registered letters, etc. A participant should not be considered as lost to follow-
up until due diligence has been completed or until the end of the study. 
9.2 
Withdrawal of informed consent and exercise of participants’ 
data privacy rights  
Participants may voluntarily withdraw consent to participate in the study for any reason at any 
time. 
Withdrawal of consent/opposition to use of data and/ or biological samples occurs in countries 
where the legal justification to collect and process the data is consent and when a participant: 
 Explicitly requests to stop use of their data 
and 
 No longer wishes to receive study treatment 
and 
 Does not want any further visits or assessments (including further study-related contacts) 
This request should be as per local regulations(e.g. in writing) and recorded in the source 
documentation. 
Withdrawal of consent impacts ability to further contact the participant collect follow-up data 
(e.g. to respond to data queries) and potentially other country-specific restrictions. It is therefore 
very important to ensure accurate recording of withdrawal vs discontinuation based on the 
protocol definitions of these terms. 


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In this situation, the Investigator should make a reasonable effort (e.g. telephone, e-mail, letter) 
to understand the primary reason for the participant’s decision to withdraw their consent/ 
exercice data privacy rights and record this information. The Investigator shall clearly document 
if the participant has witdrawn his/her consent for the use of data in addition to a study 
discontinuation. 
Study treatment must be discontinued and no further assessments conducted, and the data that 
would have been collected at subsequent visits will be considered missing. 
Further attempts to contact the participant are not allowed unless safety findings require 
communicating or follow-up. 
If the participant agrees, a final evaluation at the time of the participant’s withdrawal of consent/ 
exercice dataprivacy rights should be made as detailed in Section 8. 
Further details on withdrawal of consent or the exercise of participants' data privacy rights are 
included in the corresponding informed consent form. 
9.3 
Study completion and post-study treatment 
Study completion is defined as when the last participant finishes their Study Completion visit 
and any repeat assessments associated with this visit have been documented and followed-up 
appropriately by the Investigator or, in the event of an early study termination decision, the date 
of that decision. 
Following completion of the safety follow-up period and/or post-treatment follow-up period, 
all participants will be followed for survival (see Section 9.1.1.3). 
The information collected is kept as source documentation. All SAEs reported during this time 
period must be reported as described in Section 10.1.3. Documentation of attempts to contact 
the participant should be recorded in the source documentation. 
The primary CR rate analysis will be conducted after the last participant enrolled and treated 
has completed 6 months from start of study treatment. Following the cut-off date for the 
analysis reported in the primary Clinical Study Report (CSR), the study will remain open and 
ongoing participants will continue to receive study treatment and be followed per the schedule 
of assessments until discontinuation criteria is met per Section 9.1.1. 
The end of study (EOS) is defined as the earliest occurrence of one of the following: 
 All participants have been followed for at least 3 years since start of study treatment or have 
died, been lost to follow-up or have withdrawn consent to further participation in the study. 
At the end of the study, in alignment with local regulations, treatment continuity will be offered 
outside this study through an alternative setting to participants who are receiving treatment with 
siremadlin and in the opinion of investigator are still deriving clinical benefit. Safety will be 
monitored and reported to Health Authorities as per regulatory requirements. 
The final analysis will occur at the end of the study. All available data from all participants up 
to this cut-off date will be analyzed and summarized in a final CSR. 


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9.4 
Early study termination by the sponsor 
The study can be terminated by Novartis at any time. 
Reasons for early termination: 
 Unexpected, significant, or unacceptable safety risk to participants enrolled in the study 
 Decision based on recommendations from applicable board(s) after review of safety and 
efficacy data 
 Discontinuation of study drug development 
 Practical reasons (including slow enrollment), 
 Regulatory reasons 
 Medical reasons 
In taking the decision to terminate, Novartis will always consider participant welfare and safety. 
Should early termination be necessary, participants must be seen as soon as possible to perform 
their End of Treatment (EOT) Visit and the assessments for EOT as described in Section 8 and 
will be treated as a participant who discontinued from study treatment. The investigator may be 
informed of additional procedures to be followed in order to ensure that adequate consideration 
is given to the protection of the participant’s interests. The investigator or sponsor depending 
on local regulation will be responsible for informing IRBs/IECs of the early termination of the 
trial. 
In the event that the study is terminated prematurely, e.g., due investigator recommendation at 
the safety review meeting or Novartis decision, participants still receiving study treatment and 
who, according to investigator assessment, continue to benefit from the treatment, will be 
offered to continue study treatment as per protocol or through an alternative setting (see 
Section 9.3). 
10 
Safety monitoring, reporting and committees 
10.1 
Definition of adverse events and reporting requirements 
10.1.1 
Adverse events 
An adverse event (AE) is any untoward medical occurrence (e.g., any unfavorable and 
unintended sign [including abnormal laboratory findings], symptom or disease) in a clinical 
investigation participant after providing written informed consent for participation in the study. 
Therefore, an AE may or may not be temporally or causally associated with the use of a 
medicinal (investigational) product. 
The investigator has the responsibility for managing the safety of individual participant and 
identifying adverse events. 
Novartis qualified medical personnel will be readily available to advise on trial related medical 
questions or problems. 
The occurrence of adverse events must be sought by non-directive questioning of the participant 
at each visit during the study. Adverse events also may be detected when they are volunteered 


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by the participant during or between visits or through physical examination findings, laboratory 
test findings, or other assessments. 
Adverse events must be recorded under the signs, symptoms, or diagnosis associated with them, 
accompanied by the following information (as far as possible) (if the event is serious refer to 
Section 10.1.2): 
1. The Common Toxicity Criteria (CTC) AE grade (CTCAE version 5.0 or higher) will be 
used for grading of all adverse events except for GvHD (Harris et al 2016 for aGvHD and 
NIH consensus criteria for cGvHD (Jagasia et al 2015)). 
2. Its relationship to the study treatment. If the event is due to lack of efficacy or progression 
of underlying illness (i.e. progression of the study indication) the assessment of causality 
will usually be ‘Not suspected.’ The rationale for this guidance is that the symptoms of a 
lack of efficacy or progression of underlying illness are not caused by the trial drug, they 
happen in spite of its administration and/or both lack of efficacy and progression of 
underlying disease can only be evaluated meaningfully by an analysis of cohorts, not on a 
single participant 
3. Its duration (start and end dates or ongoing) and the outcome must be reported. 
4. Whether it constitutes a SAE (see Section 10.1.2 for definition of SAE) and which 
seriousness criteria have been met. 
5. Action taken regarding with study treatment. 
All adverse events must be treated appropriately. Treatment may include one or more of 
the following: 
 Dose not changed 
 Dose reduced/increased 
 Drug interrupted/permanently discontinued 
6. Its outcome (i.e., recovery status or whether it was fatal). 
If the event worsens the event should be reported a second time in the CRF noting the start date 
when the event worsens in toxicity. For grade 3 and 4 adverse events only, if improvement to a 
lower grade is determined a new entry for this event should be reported in the CRF noting the 
start date when the event improved from having been Grade 3 or Grade 4. 
Conditions that were already present at the time of informed consent should be recorded in 
medical history of the participant. 
Adverse events (including lab abnormalities that constitute AEs) should be described using a 
diagnosis whenever possible, rather than individual underlying signs and symptoms. 
Adverse event monitoring should be continued for at least 30 days following the last dose of 
study treatment OR until the start of a new antineoplastic medication if sooner than 30 days 
after last dose of the study treatment. 
Once an adverse event is detected, it must be followed until its resolution or until it is judged to 
be permanent (e.g., continuing at the end of the study), and assessment must be made at each 
visit (or more frequently, if necessary) of any changes in severity, the suspected relationship to 
the interventions required to treat it, and the outcome. 


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Disease progression (including fatal outcomes), if documented by use of appropriate method, 
should not be reported as a serious adverse event, except if the investigator considers that 
progression of malignancy is related to study treatment. 
Adverse events separate from the progression of malignancy (for example deep vein thrombosis 
at the time of progression or hemoptysis concurrent with finding of disease progression) will 
be reported as per usual guidelines used for such events with proper attribution regarding 
relatedness to the drug. 
Information about adverse drug reactions for the investigational drug can be found in the 
Investigator's Brochure (IB). 
Abnormal laboratory values or test results constitute adverse events only if they fulfill at least 
one of the following criteria: 
 they induce clinical signs or symptoms 
 they are considered clinically significant 
 they require therapy 
Clinically significant abnormal laboratory values or test results must be identified through a 
review of values outside of normal ranges/clinically notable ranges, significant changes from 
baseline or the previous visit, or values which are considered to be non-typical in participant 
with the underlying disease. 
10.1.2 
Serious adverse events 
An SAE is defined as any adverse event [appearance of (or worsening of any pre-existing)] 
undesirable sign(s), symptom(s), or medical conditions(s) which meets any one of the following 
criteria: 
 fatal 
 life-threatening 
Life-threatening in the context of a SAE refers to a reaction in which the participant was at risk 
of death at the time of the reaction; it does not refer to a reaction that hypothetically might have 
caused death if it were more severe (please refer to the ICH-E2D Guidelines). 
 results in persistent or significant disability/incapacity. 
 constitutes a congenital anomaly/birth defect 
 requires inpatient hospitalization or prolongation of existing hospitalization, unless 
hospitalization is for:  
 routine treatment or monitoring of the studied indication, not associated with any 
deterioration in condition. 
 elective or pre-planned treatment for a pre-existing condition that is unrelated to the 
indication under study and has not worsened since signing the informed consent. 
 social reasons and respite care in the absence of any deterioration in the participant’s 
general condition. 
 treatment on an emergency outpatient basis for an event not fulfilling any of the 
definitions of a SAE given above and not resulting in hospital admission. 


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 is medically significant, e.g., defined as an event that jeopardizes the participant or may 
require medical or surgical intervention to prevent one of the outcomes listed above. 
Medical and scientific judgment should be exercised in deciding whether other situations should 
be considered serious reactions, such as important medical events that might not be immediately 
life threatening or result in death or hospitalization but might jeopardize the participant or might 
require intervention to prevent one of the other outcomes listed above. Such events should be 
considered as “medically significant.” Examples of such events are intensive treatment in an 
emergency room or at home for allergic bronchospasm, blood dyscrasias, or convulsions that 
do not result in hospitalization or development of dependency or abuse (please refer to the ICH-
E2D Guidelines). 
All new malignant neoplasms will be assessed as serious under “medically significant” if other 
seriousness criteria are not met and the malignant neoplasm is not a disease progression of the 
study indication. 
Any suspected transmission via a medicinal product of an infectious agent is also considered a 
serious adverse reaction. 
All reports of intentional misuse and abuse of the product are also considered serious adverse 
event irrespective if a clinical event has occurred. 
10.1.3 
SAE reporting 
To ensure participant safety, every SAE, regardless of causality, occurring after the participant 
has provided informed consent and until the end of the safety follow-up period (Section 9.1.1) 
must be reported to Novartis safety immediately, without undue delay, but under no 
circumstances later than within 24 hours of obtaining knowledge of the events (Note: If more 
stringent, local regulations regarding reporting timelines prevail). Detailed instructions 
regarding the submission process and requirements are to be found in the investigator folder 
provided to each site. Information about all SAEs is collected and recorded on the Serious 
Adverse Event Report Form in the eCRF; all applicable sections of the form must be completed 
in order to provide a clinically thorough report. 
SAE reporting timeframes and conditions: 
1. Treated participants: ALL SAEs that occurred between the time participant has provided 
informed consent until 30 days after the participant has discontinued or stopped study 
treatment must be reported to the Novartis Chief Medical Office and Patient Safety (CMO 
& PS) irrespective of the investigator’s assessment of causality 
2. Participants who are screened but have not received any study treatment: ALL SAEs that 
occurred after the participant has provided informed consent and through the time the 
participant is deemed a Screen Failure and/ or dropped-out the study due any reason without 
receiving the study medication must be reported to the Novartis CMO & PS irrespective of 
the investigator’s assessment of causality 
3. Any SAEs that occurred after the 30-day period past the last dose of study treatment should 
only be reported to the Novartis CMO & PS if the investigator suspects a causal relationship 
with the study treatment, unless otherwise specified by local law/regulations. 


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All follow-up information for the SAE including information on complications, progression of 
the initial SAE and recurrent episodes must be reported as follow-up to the original episode 
immediately, without undue delay, but under no circumstances later than within 24 hours of the 
investigator receiving the follow-up information (Note: If more stringent, local regulations 
regarding reporting timelines prevail). An SAE occurring at a different time interval or 
otherwise considered completely unrelated to a previously reported one must be reported 
separately as a new event. 
If the SAE is not previously documented in the Investigator’s Brochure or Package Insert (new 
occurrence) and is thought to be related to the study treatment, a Novartis CMO & PS 
Department associate may urgently require further information from the investigator for health 
authority reporting. Novartis may need to issue an Investigator Notification (IN) to inform all 
investigators involved in any study with the same study treatment that this SAE has been 
reported. 
Suspected Unexpected Serious Adverse Reactions (SUSARs) will be collected and reported to 
the competent authorities and relevant ethics committees in accordance with EU Guidance 
2011/C 172/01 or as per national regulatory requirements in participating countries. 
10.1.4 
Pregnancy reporting 
Pregnancies 
If a female trial participant becomes pregnant, the study treatment should be stopped, and the 
pregnancy consent form should be presented to the trial participant. The participant must be 
given adequate time to read, review and sign the pregnancy consent form. This consent form is 
necessary to allow the investigator to collect and report information regarding the pregnancy. 
To ensure participant safety, each pregnancy occurring after signing the informed consent must 
be reported to Novartis within 24 hours of learning of its occurrence. The pregnancy should be 
followed up to determine outcome, including spontaneous or voluntary termination, details of 
the birth, and the presence or absence of any birth defects, congenital abnormalities, or maternal 
and/or newborn complications. 
Pregnancy should be recorded and reported by the investigator to the Novartis Chief Medical 
Office and Patient Safety (CMO&PS). Pregnancy follow-up should be recorded on the same 
form and should include an assessment of the possible relationship to the study treatment and 
pregnancy outcome. Any SAE experienced during pregnancy must be reported. 
If a female partner of a male trial participant who took study treatment in this study becomes 
pregnant, pregnancy outcomes should be collected. Consent to report information regarding 
these pregnancy outcomes should be obtained from the mother. 
After consent is provided, the pregnancy reporting will occur up to one year after the estimated 
date of delivery. 
For all pregnancies with live birth and/or unknown outcome the newborn has to be followed up 
to obtain infant health status and development up to twelve months after delivery. 


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10.1.5 
Reporting of infection 
Infections will be reported as adverse events and the AE severity grade will be assessed 
according to CTCAE grading as defined in Section 10.1.1 . 
In addition, Investigators will detail the type of infection as well as the method of diagnosis and 
assess the event according to the Infection Severity grading (BMT CTN 2013, Section 16.3 
Appendix 3). 
10.1.6 
Reporting of study treatment errors including misuse/abuse 
Medication errors are unintentional errors in the prescribing, dispensing, administration or 
monitoring of a medicine while under the control of a healthcare professional, participant or 
consumer (EMA definition). 
Misuse refers to situations where the medicinal product is intentionally and inappropriately used 
not in accordance with the protocol. 
Abuse corresponds to the persistent or sporadic, intentional excessive use of a medicinal 
product, which is accompanied by harmful physical or psychological effects. 
Study treatment errors and uses outside of what is foreseen in the protocol will be recorded on 
the appropriate CRF irrespective of whether or not associated with an AE/SAE and reported to 
Safety only if associated with an SAE. Misuse or abuse will be collected and reported in the 
safety database irrespective of it being associated with an AE/SAE within 24 hours of 
Investigator’s awareness. 
Table 10-1 
Guidance for capturing the study treatment errors including 
misuse/abuse 
Treatment error type 
Document in Dosing 
CRF (Yes/No) 
Document in AE eCRF 
Complete SAE form 
Unintentional study 
treatment error 
Yes 
Only if associated with an 
AE 
Only if associated with an 
SAE 
Misuse/Abuse 
Yes 
Yes 
Yes, even if not 
associated with a SAE 
For more information on AE and SAE definition and reporting requirements, please see the 
respective sections. 
10.2 
Additional Safety Monitoring 
Not applicable. 
10.3 
Committees 
10.3.1 
Steering Committee 
The Steering Committee (SC) will be established comprising investigators participating in the 
trial, i.e., not being Novartis representatives from the Clinical Trial Team (CTT). 
The SC will ensure transparent management of the study according to the protocol through 
recommending and approving modifications as circumstances require. The SC will periodically 


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review the study data and will make recommendations on the study conduct (including study 
termination). The SC will review protocol amendments as appropriate. Together with the CTT, 
the SC will also develop recommendations for publications of study results including authorship 
rules. 
The details of the role of the steering committee will be defined in the Steering Committee 
charter. 
11 
Data Collection and Database management 
11.1 
Data collection 
Designated investigator staff will enter the data required by the protocol into the Electronic 
Case Report Forms (eCRF). The eCRFs have been built using fully validated secure web-
enabled software that conforms to 21 CFR Part 11 requirements, Investigator site staff will not 
be given access to the Electronic data capture (EDC) system until they have been trained. 
Automatic validation programs check for data discrepancies in the eCRFs, allow modification 
and/or verification of the entered data by the investigator staff. 
The investigator/designee is responsible for assuring that the data (recorded on CRFs) (entered 
into eCRF) is complete, accurate, and that entry and updates are performed in a timely manner. 
The Investigator must certify that the data entered are complete and accurate. 
In addition to data entered into the eCRF, requisition forms may also need to be completed for 
(e.g., PK, 
 etc.) sample collection. After final database lock, the investigator will 
receive copies of the participant data for archiving at the investigational site. 
All data should be recorded, handled, and stored in a way that allows its accurate reporting, 
interpretation, and verification. 
11.2 
Database management and quality control 
Novartis personnel (or designated Contract Research Organization (CRO)) will review the data 
entered by investigational staff for completeness and accuracy. Electronic data queries stating 
the nature of the problem and requesting clarification will be created for discrepancies and 
missing values and sent to the investigational site via the EDC system. Designated investigator 
site staff are required to respond promptly to queries and to make any necessary changes to the 
data. 
Concomitant treatments and prior medications entered into the database will be coded using the 
World Health Organization (WHO) Drug Reference List, which employs the Anatomical 
Therapeutic Chemical classification system. Medical history/current medical conditions and 
adverse events will be coded using the Medical Dictionary for Regulatory Activities (MedDRA) 
terminology. 
Dates of screenings, enrollment, and screen failures, as well as data about study drugs dispensed 
to the participant globally will be tracked using an Interactive Response Technology (IRT). The 
system will be supplied by a vendor, who will also manage the database. The data will be sent 
electronically to Novartis (or a designated CRO) at specific timelines. 


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Once all the necessary actions have been completed and the database has been declared to be 
complete and accurate, it will be locked and made available for data analysis. Any changes to 
the database after that time can only be made after written agreement by Novartis development 
management. 
11.3 
Site monitoring 
Before study initiation, at a site initiation visit or at an investigator’s meeting, a Novartis 
representative will review the protocol and data capture requirements (i.e. eSource DDE or 
eCRFs) with the investigators and their staff. During the study, Novartis employs several 
methods of ensuring protocol and GCP compliance and the quality/integrity of the sites’ data. 
The field monitor will visit the site to check the completeness of participant records, the 
accuracy of data capture / data entry, the adherence to the protocol and to Good Clinical 
Practice, the progress of enrollment, and to ensure that study treatment is being stored, 
dispensed, and accounted for according to specifications. Key study personnel must be available 
to assist the field monitor during these visits. A central analytics organization may analyze data 
& identify risks & trends for site operational parameters and provide reports to Novartis clinical 
teams to assist with trial oversight. 
The investigator must maintain source documents for each participant in the study, consisting 
of case and visit notes (hospital or clinic medical records) containing demographic and medical 
information, laboratory data, electrocardiograms, and the results of any other tests or 
assessments. All information on CRFs must be traceable to these source documents in the 
participant's file. The investigator must also keep the original informed consent form signed by 
the participant (a signed copy is given to the participant). 
The investigator must give the monitor access to all relevant source documents to confirm their 
consistency with the data capture and/or data entry. Novartis monitoring standards require full 
verification for the presence of informed consent, adherence to the inclusion/exclusion criteria, 
documentation of SAEs, and of data that will be used for all primary variables. Additional 
checks of the consistency of the source data with the CRFs are performed according to the 
study-specific monitoring plan. No information in source documents about the identity of the 
participants will be disclosed. 
12 
Data analysis and statistical methods 
The primary safety analysis for Part 1 will be performed after participants at each dose level in 
dose-determining set of Part 1 have completed DLT observation period of one cycle.  
The primary safety analysis for Part 2 will be performed after each participant in dose-
determining set of Part 2 has completed at least one cycle of siremadlin/DLI combination. 
The primary efficacy analysis will be performed on all participant data at the time all 
participants will have completed at least 6 months or discontinued earlier. 
The final efficacy and safety analysis will be performed at the end of study as defined in 
Section 9.3. 


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Categorical data will be presented as frequencies and percentages. For continuous data, mean, 
standard deviation, median, minimum, and maximum will be presented. For selected 
parameters, 25th and 75th percentiles will also be presented when applicable. 
Any data analysis carried out independently by the investigator should be submitted to Novartis 
before publication or presentation. 
12.1 
Analysis sets 
The Full Analysis Set (FAS) comprises all participants that received any study drug (i.e. at least 
one dose of siremadlin with or without DLI). 
The Safety Set includes all participants from the FAS. 
The Dose-Determining Set (DDS) includes all participants during the dose determination phase 
of the study (DLT assessment) who met the minimum required number of treatment cycles(s), 
met the minimum exposure criteria (MEC), met the minimum follow up/observation after 
treatment and have sufficient safety evaluations, or have experienced a DLT during the 
observation period. 
There are two DDSs: DDS1 for Part 1 and DDS2 for Part 2: 
 DDS1 (Part 1): consists of participants who met the MEC1 and had sufficient safety 
evaluations or had a DLT during Cycle 1. A participant has met the MEC1 if they have 
received during the first cycle at least 75% of the total planned doses for siremadlin (e.g., ≥ 
4 out of 5 daily doses of siremadlin). Participants receiving a reduced dose of siremadlin 
due to co-administration of strong or moderate CYP3A4 inhibitors as described 
in Section 6.2.2.1, will be considered to have received the full planned dose. Participants 
who do not experience a DLT during Cycle 1 are considered to have sufficient safety 
evaluations if they have been observed at least from Day 1 to the end of Cycle 1 following 
the first dose of siremadlin, and are considered by both the sponsor and investigators to have 
enough safety data to conclude that a DLT did not occur. 
 DDS2 (combination phase in Part 2): consists of participants who met the MEC2 for at least 
Cycle 1 of combination and had sufficient safety evaluations or had a DLT during 
combination phase. A participant has met the MEC2 if they have received the planned dose 
of DLI and at least 75% of the total planned doses for siremadlin as defined in the dose and 
treatment schedule (see Section 6.3.2) for a given cycle. Participants receiving a reduced 
dose of siremadlin due to co-administration of strong or moderate CYP3A4 inhibitors as 
described in Section 6.2.2.1, will be considered to have received the full planned dose. 
Participants who do not experience a DLT during cycle(s) of DLI administration 
(combination phase) are considered to have sufficient safety evaluations if they have been 
observed at least from Day 1 to the end of their combination phase,and are considered by 
both the sponsor and investigators to have enough safety data to conclude that a DLT did 
not occur. Participants will be analyzed according to the study treatment received as defined 
for FAS.  
The Pharmacokinetic analysis set for all (PAS-all) includes all participants in the safety set who 
provide at least one evaluable PK concentration of siremadlin (see Section 8.5.1.1 and 
Section 12.5.3). 


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For a concentration to be evaluable: 
 Dosing information must be properly documented (data and time of administration) 
 Participant takes the dose of study treatments as described in Section 6.3.2 
 Participant did not vomit within 4 hours after the oral dosing of siremadlin 
 For pre-dose samples: the sample is collected before the next dose administration 
 For post-dose samples: the planned dose of siremadlin must be taken prior to sampling 
12.2 
Participant demographics and other baseline characteristics 
Demographic and other baseline data including disease characteristics will be summarized 
descriptively for all participants for the FAS separately for Part 1 and Part 2. 
Relevant medical histories and current medical conditions at baseline will be summarized 
separately by system organ class and preferred term. 
12.3 
Treatments 
The Safety set will be used for the analyses below. 
Exposure to siremadlin in Part 1 will be summarized by dose cohort. In Part 2 the duration of 
exposure to siremadlin by priming phase, combination phase, maintenance phase, and entire 
treatment period, and to DLI as well as the dose intensity (computed as the ratio of actual 
cumulative dose received and actual duration of exposure) and the relative dose intensity 
(computed as the ratio of dose intensity and planned dose intensity) will be summarized by 
descriptive statistics. 
Concomitant medications and significant non-drug therapies prior to and after the start of the 
study treatment will be summarized according to the Anatomical Therapeutic Chemical (ATC) 
classification system. 
The number of participants with dose adjustments and the reasons will be summarized by study 
part, siremadlin and DLI. All dosing data will be listed 
12.4 
Analysis supporting primary objectives 
The primary safety objective is to confirm the dose and schedule that are tolerable and safe 
without unacceptable toxicities (dose limiting toxicities [DLTs]) of siremadlin monotherapy in 
Part 1 and for siremadlin in combination with DLI in Part 2. 
The primary efficacy objective is to evaluate the preliminary efficacy of siremadlin study 
treatment strategy (siremadlin monotherapy, as priming and/or maintenance, with or without 
siremadlin in combination with DLI) in Part 2, on prevention of hematologic relapse. 
12.4.1 
Definition of primary endpoint(s) 
The primary safety endpoints are the incidence of DLTs in Part 1 and time-to-DLT in Part 2 
respectively during DLT evaluation period for participants included in the DDS. 
The primary efficacy endpoint of the study is the proportion of participants who are alive and 
remain in CR/Cri with no evidence of hematologic relapse over at least 6 months after the start 


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of study treatment (siremadlin monotherapy, as priming and/or maintenance, with or without 
siremadlin in combination with DLI in Part 2. (Cheson et al 2003, Döhner et al 2017 and 
Table 8-3). 
12.4.2 
Statistical model, hypothesis, and method of analysis 
Primary safety analysis (incidence of DLT and time-to-DLT) 
For participants in the Cycle 1 of Part 1 and the entire combination phase in Part 2, assessing 
whether siremadlin at the tested dose levels does not lead to an unacceptable level of toxicity 
(DLTs) when administered alone or in combination with DLI will be based on the estimation 
of the probability of DLT for participants in the DDS1 for Part 1 and of time to DLT for the 
participants in the DDS2 for combination phase in Part 2. Dose confirmation of siremadlin as 
monotherapy (Part 1) will be based on the incidence of DLTs and will be guided by a Bayesian 
logistic regression model with the EWOC principle that the risk of excessive toxicity (DLT rate 
≥ 33%) is less than 25% (EWOC principle, Babb et al 1998). The starting dose level of the 
priming phase is 30 mg siremadlin QD (Day 1 to 5, 28-day cycle). Dose confirmation of 
siremadlin in combination with DLI (siremadlin/DLI combination phase in Part 2) will be based 
on time-to-DLT using Bayesian time to first DLT model with the EWOC principle considering 
all available information for up to 3 cycles. A full assessment of the prior risk to participants 
and a summary of the operating characteristics of the models is given in Section 16.6 and 
Section 16.7. 
Primary efficacy analysis (proportion of participants who remain in CR/CRi 6 
months after the start of study treatment) 
The efficacy of study treatment will be based on the proportion of participants remaining in 
CR/CRi as per investigator assessment for at least 6 months after the start of study treatment 
among participants who initiated priming phase at the siremadlin RD for priming with/without 
DLI (Part 2). Assuming a minimally informative prior distribution (Beta(0.67,1) with mean 
40% based on the null value (details on null value in Section 1) in the statistical criterion, the 
distribution of the CR/CRi rate will be updated with all available data from participants who 
are in the FAS and have initiated siremadlin (at RD for priming or a tolerated siremadlin dose 
lower than RD for priming) as monotherapy with or without siremadlin/DLI combination. 
Decision criteria for trial success (dual-criterion) are based on proportion of participants who 
remain in CR/CRi by investigator assessment and are alive at least 6 months after the start of 
study treatment): 
 Bayesian statistical significance: probability (CR/CRi rate > 40% | data) ≥ 0.975 (the one-
sided p-value must be less than 2.5%) (null value), and 
 Clinical relevance: posterior median of CR/CRi rate ≥ 60% (decision value) 
The results will be also presented with a frequentist formulation. The CR/CRi rate and the exact 
95% confidence interval (CI) (Clopper and Pearson 1934), as well as the 1-sided p-value will 
be provided. The test will be performed using an overall one-sided 2.5% level of significance. 
Thus, the null hypothesis (H0:CR/CRi ≤ 40%) will be rejected if the lower bound of the two-
sided 95% exact CI is >40%. 


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The analysis will be performed using data up to the analysis data cut-off date, which will be at 
the time all participants who are in FAS and initiated priming phase at RD for priming 
with/without DLI will have completed at least 6 months or discontinued earlier. 
12.4.3 
Handling of intercurrent events of primary estimand 
Handling of intercurrent events of the primary efficacy and safety estimands is described in 
Section 2.1. 
12.4.4 
Handling of missing values not related to intercurrent event 
For the determination of CR/CRi, an adequate response assessment is considered any disease 
assessment indicating response status apart from “unknown” or “not done”. If no subsequent 
assessment or the subsequent assessment of an inadequate response does not show CR/CRi, the 
inadequate response will be regarded as no CR/CRi. 
12.4.5 
Sensitivity analyses 
Sensitivity analyses (if appropriate) will be described in the Statistical Analysis Plan (SAP). 
12.4.6 
Supplementary analysis 
Supplementary analyses (if appropriate) will be described in the SAP. 
12.5 
Analysis supporting secondary objectives 
The secondary objectives for Part 2 are to assess the effect of siremadlin with/without DLI on 
safety and tolerability, Relapse free survival (RFS), Cumulative incidence of relapse, Overall 
Survival (OS), proportion of participants stopping study treatment due to GvHD/AE, incidence 
of treatment-emergent GvHD, GvHD-free/relapse-free survival (GRFS), and PK. A separate 
objective for Part 1 siremadlin monotherapy is to evaluate the preliminary efficacy of siremadlin 
monotherapy on prevention of hematologic relapse at the recomended dose for Part 2.  
12.5.1 
Efficacy and/or Pharmacodynamic endpoint(s) 
Efficacy endpoints will be analyzed and summarized for the FAS and by dose level of 
siremadlin in priming phase unless otherwise specified. 
Time-to-event endpoints will be analyzed using Kaplan-Meier method for participants in the 
FAS who initiated priming phase at siremadlin RD for priming: the Kaplan-Meier curves, 
medians and 95% CI of the medians will be presented. 
No formal statistical tests will be performed for any of the secondary efficacy endpoints and 
hence no multiplicity adjustment will be applied.  
Relapse-Free Survival (RFS) 
RFS is defined as the time from start of study treatment to the date of first documented 
hematologic relapse or death due to any cause, whichever occurs first. RFS will be censored if 
no RFS event is observed before the first to occur between: (i) the analysis cut-off date, and (ii) 
the date when a new anti-neoplastic therapy is started. The censoring date will be the date of 


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the last adequate response assessment. The handling of intercurrent events will be the same as 
the primary estimand (Section 2.1). 
RFS will be analyzed in the FAS population who initiated priming phase at siremadlin RD for 
priming and the RFS distribution will be estimated using the Kaplan-Meier method. Kaplan-
Meier curve, median and 95% confidence interval of the median will be presented. The KM 
estimates at 1 year and 2 year will be presented with their 95% CI. 
Cumulative incidence of relapse 
Cumulative incidence of relapse (CIR) is defined as the time from start of study treatment to 
the date of first documented hematologic relapse. Participants will be censored if no relapse is 
observed before the first to occure between: (i) the analysis cut-off date, and (ii) the date when 
a new anti-neoplastic therapy is started. The censoring date will be the date of the last adequate 
response assessment. 
CIR will be analyzed in the FAS population who initiated priming phase at siremadlin RD in 
Part 2 and who are at the RD in Part 1 nd will be estimated using the Kaplan-Meier method. 
CIR curve will be presented as well as the CIR estimates at 1 year and 2 year with their 95% 
CI. 
Overall Survival (OS) 
OS is defined as the time from start date of treatment to date of death due to any cause. If a 
participant is not known to have died, then OS will be censored at the latest date the 
participant was known to be alive (on or before the cut-off date). All deaths will be taken into 
account whenever the death occurred, i.e. even after new anti-neoplastic therapy, allo-SCT, 
interruptions, or discontinuation of study treatment due to any reason. OS will be estimated 
by Kaplan-Meier method for participants who initiate priming phase at siremadlin RD for 
priming. The median OS and 95% CI will be presented. 
GvHD-free/relapse-free survival (GRFS) 
GRFS is defined as the time from start of treatment to the date of first documented occurrence 
or worsening of treatment emergent grade III or IV aGvHD or cGvHD requiring initiation of 
systemic immunosuppressive treatment, hematologic relapse, or death due to any cause, 
whichever occurs first. GRFS will be censored if no GRFS event is observed before the first to 
occur between: (i) the analysis cut-off date, and (ii) the date when a new anti-neoplastic therapy 
is started. The censoring date will be the date of the last adequate response assessment of GvHD 
assessment given confirmed remission in a subsequent efficacy assessment. 
GRFS will be analyzed in the FAS population and the GRFS distribution will be estimated 
using the Kaplan-Meier method. Kaplan-Meier curves, medians and 95% confidence intervals 
of the medians will be presented. 


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Participants remaining in CR/CRi (in Part 1) 
The participants who are alive and maintained CR/CRi with no eveidence of hematologic 
relapse over at least 6 months after start of siremadlin monotherapy [Part 1 - siremadlin 
monotherapy at the recommended dose for Part 2]. 
12.5.2 
Safety endpoints 
Safety analyses will be summarized for the safety set and by dose level of siremadlin by 
treatment phase and study part. 
Safety summaries (tables, figures) include only data from the on-treatment period with the 
exception of baseline data which will also be summarized where appropriate (e.g. change from 
baseline summaries). In addition, a separate summary for death including on treatment and post 
treatment deaths will be provided. In particular, summary tables for adverse events (AEs) will 
summarize only on-treatment events, with a start date during the on-treatment period 
(treatment-emergent AEs). 
The overall observation period will be divided into three mutually exclusive segments for the 
entire treatment period: 
1. Pre-treatment period: from day of participant’s informed consent to the day before first 
administration of siremadlin. 
2. On-treatment period: from date of first administration of siremadlin 30 days after date of 
last administration of siremadlin if monotherapy is used in last cycle, or 42 days after date 
of last administration of siremadlin if combination with DLI therapy is used in last cycle. 
3. Post-treatment period: any observation starting at Day 31 after last administration of 
siremadlin if monotherapy is used in last cycle, or at Day 43 after date of last administration 
of siremadlin if combination with DLI therapy is used in last cycle. 
The on-treatment period is further divided by treatment phase(s) for Part 2: 
Priming phase: from date of first administration of siremadlin to 30 days after date of last 
administration of siremadlin in priming phase, or until the first administration of siremadlin in 
combination phase. 
Combination phase: from date of first administration of siremadlin in first combination with 
DLI cycle to 42 days after date of last administration of siremadlin in combination phase, or 
until the first administration of siremadlin in maintenance phase. 
Maintenance phase: from date of first administration of siremadlin to 30 days after date of last 
administration of siremadlin in maintenance phase. 
Adverse events 
Summary tables for adverse events (AEs) will include only AEs that started or worsened during 
the on-treatment period. The number (and percentage) of participants with treatment emergent 
adverse events will be summarized by primary system organ class, preferred term and maximum 
severity. 


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Separate summaries will be provided for study medication related adverse events, death, serious 
adverse events, other significant adverse events leading to discontinuation, and adverse events 
leading to dose adjustment. 
Separate summaries will be provided for: 
 treatment emergent grade III or grade IV acute GvHD 
 treatment emergent moderate to severe chronic GvHD 
Serious adverse events and non-serious adverse events will be tabulated. All deaths (on-
treatment and post-treatment) will be summarized. 
In addition, all AEs and SAEs which started during the overall safety period will be 
summarized. All reported AEs will be listed and those that started during the pre-treatment, on-
treatment period and post-treatment period will be flagged. 
Vital signs 
All vital signs abnormalities will be summarized. 
12-lead ECG 
HR and QTcF will be obtained from 12-lead ECGs for each participant at screening and during 
the study. ECG data will be read and interpreted centrally. 
Categorical analysis of QTcF interval and HR data will be based on the summary of number of 
participants meeting or exceeding predefined limits. 
Clinical laboratory evaluations 
Grading of laboratory values will be assigned programmatically as per National Cancer Institute 
(NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. The 
calculation of CTCAE grades will be based on the observed laboratory values only, clinical 
assessments will not be taken into account. 
CTCAE Grade 0 will be assigned for all non-missing values not graded as 1 or higher. 
For laboratory tests where grades are not defined by CTCAE version 5.0, results will be 
categorized as low/normal/high based on laboratory normal ranges. 
For laboratory tests where grades are defined by CTCAE v5.0: 
 Shift tables using CTCAE v5.0 grades to compare baseline to the worst on-treatment value 
For laboratory tests where grades are not defined by CTCAE v5.0: 
 Shift tables using the low/normal/high/ (low and high) classification to compare baseline 
to the worst on-treatment value 
ECOG PS 
ECOG PS will be summarized at each time point during the study. 


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12.5.3 
Pharmacokinetics 
Siremadlin drug concentrations 
Pharmacokinetic parameters will be derived from the individual concentration versus time 
profile using a non-compartmental method as implemented in Phoenix WinNonlin (Version 8.0 
or higher; Pharsight, Mountain View, CA). The pharmacokinetic parameters described in 
Table 12-1 will be determined as deemed appropriate. Additional PK parameters may be 
estimated as needed. Pharmacokinetic parameters will be determined using the actual recorded 
sampling times and non-compartmental method(s) with Phoenix WinNonlin. 
Table 12-1 
Non-compartmental pharmacokinetic parameters* 
AUC0-t 
The area under the concentration vs. time Curve (AUC) from time zero to specified time 
point.Note: as the last sampling time of the PK profiles at PRIM Cycle 1 Day 1 is 24h postdose, 
AUC0-24h will be determined (when feasible) for siremadlin; for the PK profiles collected at Day 1 
and Day 5 of other cycles, AUC0-8h will be determined (when feasible) for siremadlin 
AUClast 
The AUC from time zero to the last quantifiable concentration point (Tlast) (mass x time x volume-1) 
Ctrough 
Concentration that is just prior to the beginning of, or at the end, of a dosing interval; 
corresponding to the pre-dose concentration (when feasible) 
Cmax 
The maximum (peak) observed plasma, blood, serum, or other body fluid drug concentration 
following drug administration (mass x volume-1) 
C3h 
Concentration at 3 hours post-dose (when feasible) 
Tlast 
Time at which the last measurable concentration was observed (time) 
Note: for the PK profiles of selected cycles 
Tmax 
The time to reach maximum (peak) plasma, blood, serum, or other body fluid drug concentration 
after drug administration (time) 
* Details of sampling time are included in Table 8-12 and Table 8-13. 
The respective PAS for siremadlin will be used in all pharmacokinetic data analyses. 
Siremadlin concentration data will be listed by participant, treatment phase, and visit/sampling 
time point (See Section 8.5.1 for details). Descriptive summary statistics for siremadlin 
concentrations will be provided by visit/sampling time point. Summary statistics will include 
mean (arithmetic and geometric), standard deviation (SD), coefficient of variation (CV) 
(arithmetic and geometric), median, minimum, and maximum, as well as the frequency (n, %) 
of concentrations below the lower limit of quantification (LLOQ) and reported as zero. Values 
below the LLOQ will be treated as missing for the calculation of the geometric means and 
geometric CV%. 
The PAS will be used for the PK data analysis and PK summary statistics. Descriptive statistics 
of all pharmacokinetic parameters (e.g. AUCs, Cmax) will include arithmetic and geometric 
mean, median, SD, and CV, geometric CV, minimum and maximum. Zero concentrations will 
not be included in the geometric mean calculation. Since Tmax is generally evaluated by a 
nonparametric method, median values and ranges will be given for this parameter. 
Missing values for any PK parameters or concentrations will not be imputed and will be treated 
as missing. 
All concentration vs. time profiles data for siremadlin will be displayed graphically. 


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Population pharmacokinetic analysis (Siremadlin) 
If there is sufficient data for analysis, the details of the population pharmacokinetic analyses 
may be provided in a separate reporting and analysis plan, and the results may be reported in a 
separate population pharmacokinetic report. 
Drug concentrations of IST agents (tacrolimus, cyclosporine, sirolimus) 
Blood concentration data of tacrolimus, cyclosporine, sirolimus collected by the 
investigator/per local institutional standard of practice will be listed by participant, and 
visit/sampling time point. Descriptive summary statistics for concentrations will be provided 
by visit/sampling time point. 
All concentration vs. time data will be displayed graphically 


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12.7 
Interim analyses 
No formal interim analysis is planned for this trial. 
12.8 
Sample size calculation 
12.8.1 
Primary endpoint(s) 
Primary safety endpoint 
No formal statistical power calculations to determine sample size were performed for this study. 
For Part 1, initially, 3-6 participants will be enrolled at the starting dose level (siremadlin 30 
mg QD D1-5) to have at least 3 evaluable participants. Upon observation of specific toxicities 
(see Section 6.6 for details), the participating Investigators and Novartis study personnel will 
decide to increase/decrease the dose or expand at 30 mg QD siremadlin. For a dose level to be 
considered for RD for Part 2, at least 6 evaluable participants are required. For combination 
phase in Part 2, the maximum RD for siremadlin/DLI combination will be decided with data 
from all evaluable participants (at least 9 evaluable participants are required) when they have 
completed siremadlin/DLI combination phase or experienced a DLT. For a dose level to be 
declared as maximum RD for combination it must be tested with at least 3 evaluable participants 
treated at or above that dose level. 
Primary efficacy endpoint 
The efficacy of study treatment will be based on the proportion of participants remaining in 
CR/CRi as per investigator assessment in Part 2. Decision criteria for trial success (dual 
criterion) are based on proportion of participants who remain in CR/CRi by investigator 
assessment and are alive at least 6 months after the start of study treatment): 
 Bayesian statistical significance: probability (CR/CRi rate > 40% | data) ≥ 0.975 (the one-
sided p-value must be less than 2.5%) (null value; details about rationale in Section 1), and 
 Clinical relevance: posterior median of CR/CRi rate ≥ 60% (decision value) 
With two criteria stated above the minimally required sample size (nmin) is 22, and the final 
sample size was set to 26 including participants who initiated priming phase at siremadlin RD 
for priming. For 26 participants (included for the primary efficacy analysis), the table below 


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shows data scenarios (number of participants remaining in CR/CRi) with respective inferential 
results and decisions.  
Based on simulations (Table 12-2), a total of 16 responders out of 26 participants (62%) is 
required for trial success, with estimates of 60% for the posterior median CR/CRi rate and 98% 
for the posterior probability for a positive effect (CR/CRi >40%). If the number of participants 
with CR/CRi is less than 16, both criteria are not met (NO-GO).  
Table 12-2 
Data scenarios, inferential results and decisions (n=26) 
Observed CR/CRi rate 
Posterior median 
CR/CRi 
Posterior probability for 
a positive effect 
(CR/CRi >40%) 
Decision for trial 
success 
10/26 (0.38) 
0.38 
0.43 
Failed 
11/26 (0.42) 
0.42 
0.58 
Failed 
12/26 (0.46) 
0.46 
0.73 
Failed 
13/26 (0.5) 
0.49 
0.84 
Failed 
14/26 (0.54) 
0.53 
0.92 
Failed 
15/26 (0.58) 
0.57 
0.96 
Failed 
16/26 (0.62) 
0.6 
0.98 
Successful 
17/26 (0.65) 
0.64 
0.99 
Successful 
A minimally informative prior distribution (Beta (0.67,1)) with mean 40% based on the null value in the statistical 
criteria has been used in these calculations. Operating characteristics for various true CR/CRi rates are 
presented in Table 12-3 below. The type-I error under the null value (CR/CRi rate = 40%) is 2% and power is 
52% assuming a true CR/CRi rate of 60%. 
Table 12-3 
Operating characteristics for true CR/CRi rate (n=26) 
True proportion of participants 
in CR/CRi 
Probability of success (Go) 
Probability of futility (No Go) 
0.30 
0.00 
1.00 
0.35 
0.01 
0.99 
0.40* 
0.02 
0.98 
0.45 
0.07 
0.93 
0.50 
0.16 
0.84 
0.55 
0.32 
0.68 
0.60** 
0.52 
0.48 
0.65 
0.72 
0.28 
0.70 
0.88 
0.12 
0.75 
0.96 
0.04 
0.80 
0.99 
0.01 
For a true CR/CRi rate of 40% (null value), the probability for a trial success is 2% (type-I error). **For a true 
CR/CRi rate of 60%, the probability for a trial success is 52% (power). These calculations were made using the 
software R (version 3.6.1) using the RBestT package. 
13 
Ethical considerations and administrative procedures 
13.1 
Regulatory and ethical considerations 
This study will be conducted in accordance with the protocol and with the following:  
 Consensus ethical principles derived from international guidelines including the 
Declaration of Helsinki and Council for International Organizations of Medical 
Sciences (CIOMS) international ethical guidelines.  


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 Applicable ICH Good Clinical Practice (GCP) guidelines  
 Applicable laws and regulations 
The protocol, protocol amendments, ICF, Investigator’s Brochure, [IDFU] Investigational 
directions for use, and other relevant documents (e.g. advertisements) must be submitted to an 
IRB/IEC by the Investigator and reviewed and approved by the IRB/IEC 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.  
Protocols and any substantial amendments/modifications to the protocol will require health 
authority approval prior to initiation except for changes necessary to eliminate an immediate 
hazard to study participants. 
The Investigator will be responsible for the following:  
 Signing a protocol signature page confirming his/her agreement to conduct the study in 
accordance with these documents and all of the instructions and procedures found in 
this protocol and to give access to all relevant data and records to Novartis monitors, 
auditors, Novartis Quality Assurance representatives, designated agents of Novartis, 
IRBs/IECs and regulatory authorities as required.  
 Providing written summaries of the status of the study to the IRB/IEC annually or more 
frequently in accordance with there requirements, policies, and procedures EC of SAEs 
or other significant safety findings as required by IRB/IEC procedures.  
 Notifying the IRB/IEC of SAEs or other significant safety findings as required by 
IRB/IEC procedures.  
 Providing oversight of the conduct of the study at the site and adherence to requirements 
of 21CFR, ICH guidelines, the IRB/IEC, European regulation 536/2014 for clinical 
studies (if applicable), and all other applicable local regulations.  
 Inform Novartis immediately if an inspection of the clinical site is requested by a 
regulatory authority. 
This clinical study was designed and shall be implemented, executed and reported in accordance 
with the ICH Harmonized Tripartite Guidelines for Good Clinical Practice, with applicable 
local regulations (including European Directive 2001/20/EC, or European Clinical Trial 
Regulation 536/2014, US CFR 21), and with the ethical principles laid down in the Declaration 
of Helsinki. 
13.2 
Responsibilities of the investigator and IRB/IEC 
Before initiating a trial, the investigator/institution must obtain approval/favorable opinion from 
the Institutional Review Board/Independent Ethics Committee (IRB/IEC) for the trial protocol, 
written informed consent form, consent form updates, participant recruitment procedures (e.g., 
advertisements) and any other written information to be provided to participants. Prior to study 
start, the investigator is required to sign a protocol signature page confirming his/her agreement 


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to conduct the study in accordance with these documents and all of the instructions and 
procedures found in this protocol and to give access to all relevant data and records to Novartis 
monitors, auditors, Novartis Quality Assurance representatives, designated agents of Novartis, 
IRBs/IECs, and regulatory authorities as required. If an inspection of the clinical site is 
requested by a regulatory authority, the investigator must inform Novartis immediately that this 
request has been made. 
13.3 
Publication of study protocol and results 
The protocol will be registered in a publicly accessible database such as clinicaltrials.gov and 
as required in EudraCT. In addition, after study completion (defined as last patient last visit) 
and finalization of the study report the results of this trial will be submitted for publication and 
posted in a publicly accessible database of clinical trial results, such as the Novartis clinical trial 
results website and all required health authority websites (e.g. Clinicaltrials.gov, EudraCT etc). 
For details on the Novartis publication policy including authorship criteria, please refer to the 
Novartis publication policy training materials that were provided to you at the trial investigator 
meetings. 
Any data analysis carried out independently by the Investigator should be submitted to Novartis 
before publication or presentation. 
Summary results of primary and secondary endpoints will be disclosed based upon the global 
Last Participant Last Visit (LPLV) date, since multinational studies are locked and reported 
based upon the global LPLV. 
13.4 
Quality Control and Quality Assurance 
Participants will be assigned a unique identifier by Novartis. Any participant records or datasets 
that are transferred to Novartis will contain the identifier only; participant names or any 
information which would make the participant identifiable will not be transferred.  
The participant must be informed that his/her personal study-related data will be used by 
Novartis in accordance with local data protection law. The level of disclosure must also be 
explained to the participant who will be required to give consent for their data to be used as 
described in the informed consent.  
The participant must be informed that his/her medical records may be examined by Clinical 
Quality Assurance auditors or other authorized personnel appointed by Novartis, by appropriate 
IRB/IEC members, and by inspectors from regulatory authorities.  
Novartis has appropriate processes and policies in place to handle personal data breaches 
according to applicable privacy laws. 
13.5 
Participant Engagement 
The following participant engagement initiatives are included in this study and will be provided, 
as available, for distribution to study participants at the timepoints indicated. If compliance is 
impacted by cultural norms or local laws and regulations, sites may discuss modifications to 
these requirements with Novartis. 


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 Thank You Letter 
 Plain language trial summary - after CSR publication 
 Individual study results - after CSR publication 
14 
Protocol adherence 
This protocol defines the study objectives, the study procedures and the data to be collected on 
study participants. Additional assessments required to ensure safety of participants should be 
administered as deemed necessary on a case by case basis. Under no circumstances including 
incidental collection is an Investigator allowed to collect additional data or conduct any 
additional procedures for any purpose involving any investigational drugs under the protocol, 
other than the purpose of the study. If despite this interdiction prohibition, data, information, 
observation would be incidentally collected, the investigator shall immediately disclose it to 
Novartis and not use it for any purpose other than the study, except for the appropriate 
monitoring on study participants. 
Investigators ascertain they will apply due diligence to avoid protocol deviations. If an 
Investigator feels a protocol deviation would improve the conduct of the study this must be 
considered a protocol amendment, and unless such an amendment is agreed upon by Novartis 
and approved by the IRB/IEC and Health Authorities, where required, it cannot be 
implemented. 
14.1 
Protocol amendments 
Any change or addition to the protocol can only be made in a written protocol amendment that 
must be approved by Novartis, health authorities where required, and the IRB/IEC prior to 
implementation. 
Only amendments that are required for participant safety may be implemented immediately 
provided the health authorities are subsequently notified by protocol amendment and the 
reviewing IRB/IEC is notified. 
Notwithstanding the need for approval of formal protocol amendments, the investigator is 
expected to take any immediate action required for the safety of any participant included in this 
study, even if this action represents a deviation from the protocol. In such cases, Novartis should 
be notified of this action and the IRB/IEC at the study site should be informed according to 
local regulations. 


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15 
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disease assessed by multiparameter flow cytometry on outcomes for adult AML patients 
receiving haploidentical allografts. Bone Marrow Transplant p. 567-577. 
Liu L, Chang YJ, Xu LP, et al (2018) Reversal of T Cell Exhaustion by the First Donor 
Lymphocyte Infusion Is Associated with the Persistently Effective Antileukemic Responses in 
Patients with Relapsed AML after Allo-HSCT. Biol Blood Marrow Transplant p. 1350-1359. 
Loke J, Malladi R, Moss P, et al (2020) The role of allogeneic stem cell transplantation in the 
management of acute myeloid leukaemia: a triumph of hope and experience. Br J Haematol p. 
129-146. 
Mathew NR, Baumgartner F, Braun L, et al (2018) Sorafenib promotes graft-versus-leukemia 
activity in mice and humans through IL-15 production in FLT3-ITD-mutant leukemia cells. 
Nat Med p. 282-291. 
McCune JS, Bemer MJ (2016) Pharmacokinetics, Pharmacodynamics and Pharmacogenomics 
of Immunosuppressants in Allogeneic Haematopoietic Cell Transplantation: Part I. Clin 
Pharmacokinet p. 525-50. 
Michelis FV, Messner HA, Atenafu EG, et al (2015) Patient age, remission status and HCT-
CI in a combined score are prognostic for patients with AML undergoing allogeneic 
hematopoietic cell transplantation in CR1 and CR2. Bone Marrow Transplant p. 1405-10. 
Middeke JM, Herold S, Rücker-Braun E, et al (2016) TP53 mutation in patients with high-risk 
acute myeloid leukaemia treated with allogeneic haematopoietic stem cell transplantation. Br 
J Haematol p. 914-22. 
Mo XD, Xu LP, Zhang XH, et al (2015) Chronic GVHD induced GVL effect after 
unmanipulated haploidentical hematopoietic SCT for AML and myelodysplastic syndrome. 
Bone Marrow Transplant p. 127-33. 
National Comprehensive Cancer Network (2021) Acute Myeloid Leukemia (Version 3.2021).  
Neuenschwander, B., Matano, et al (2014) A Bayesian Industry Approach to Phase I 
Combination Trials in Oncology. p. 95-136. 


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Neuenschwander, B., Roychoudhury, Schmidli, H., (2016) On the Use of Co-Data in Clinical 
Trials p. 345-354. 
Nguyen Huong Giang Ho et al in preparation. 
O'Neill AT, Chakraverty R (2021) Graft Versus Leukemia: Current Status and Future 
Perspectives. J Clin Oncol p. 361-372. 
Oran B, Jorgensen JL, Marin D, et al (2017) Pre-transplantation minimal residual disease with 
cytogenetic and molecular diagnostic features improves risk stratification in acute myeloid 
leukemia. Haematologica p. 110-117. 
Papaemmanuil E, Gerstung M, Bullinger L, et al (2016) Genomic Classification and 
Prognosis in Acute Myeloid Leukemia. N Engl J Med p. 2209-2221. 
Schmaelter AK, Labopin M, Socié G, et al (2020) Inferior outcome of allogeneic stem cell 
transplantation for secondary acute myeloid leukemia in first complete remission as compared 
to de novo acute myeloid leukemia. Blood Cancer J p. 26. 
Schmid C, Kuball J, Bug G (2021) Defining the Role of Donor Lymphocyte Infusion in High-
Risk Hematologic Malignancies. J Clin Oncol p. 397-418. 
Schmid C, Labopin M, Nagler A, et al (2012) Treatment, risk factors, and outcome of adults 
with relapsed AML after reduced intensity conditioning for allogeneic stem cell 
transplantation. Blood p. 1599-606. 
Schmid C, Labopin M, Schaap N, et al (2019) Prophylactic donor lymphocyte infusion after 
allogeneic stem cell transplantation in acute leukaemia - a matched pair analysis by the Acute 
Leukaemia Working Party of EBMT. Br J Haematol p. 782-787. 
Shah MV, Jorgensen JL, Saliba RM, et al (2018) Early Post-Transplant Minimal Residual 
Disease Assessment Improves Risk Stratification in Acute Myeloid Leukemia. Biol Blood 
Marrow Transplant p. 1514-1520. 
Spiegelhalter DJ, Abrams KR, Myles JP (2004) Bayesian Approaches to Clinical Trials and 
Health-Care Evaluation. 
Stein EM, DeAngelo DJ, Chromik J, et al (2022) Results from a First-in-Human Phase I 
Study of Siremadlin (HDM201) in Patients with Advanced Wild-Type TP53 Solid Tumors 
and Acute Leukemia. Clin Cancer Res p. 870-881. 
Stein et al. Siremadlin (HDM201) Is Well Tolerated and Demonstrates Clinical Activity in 
Patients with Acute Myeloid Leukemia Who Have Relapsed after Allogeneic Stem Cell 
Transplantation: A Subset Analysis of Safety and Preliminary Efficacy - Abstract #3417 
available online.  
Sterling C, Webster J (2020) Harnessing the immune system after allogeneic stem cell 
transplant in acute myeloid leukemia. Am J Hematol p. 529-547. 
Terwijn M, van Putten WL, Kelder A, et al (2013) High prognostic impact of flow cytometric 
minimal residual disease detection in acute myeloid leukemia: data from the HOVON/SAKK 
AML 42A study. J Clin Oncol p. 3889-97. 


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Thekkudan SF, de Lima M, Metheny L (2020) Prevention of relapse after allogeneic stem cell 
transplantation in acute myeloid leukemia: Updates and challenges p. e77. 
 
 
 
 
 
Tyner JW, Tognon CE, Bottomly D, et al (2018) Functional genomic landscape of acute 
myeloid leukaemia. Nature p. 526-531. 
Vaughn JE, Gooley T, Maziarz RT, et al (2015) Pre-transplant comorbidity burden and post-
transplant chronic graft-versus-host disease. Br J Haematol p. 411-6. 
Walter RB, Gooley TA, Wood BL, et al (2011) Impact of pretransplantation minimal residual 
disease, as detected by multiparametric flow cytometry, on outcome of myeloablative 
hematopoietic cell transplantation for acute myeloid leukemia. J Clin Oncol p. 1190-7. 
Wang HQ, Mulford IJ, Sharp F, et al (2021) Inhibition of MDM2 Promotes Antitumor 
Responses in p53 Wild-Type Cancer Cells through Their Interaction with the Immune and 
Stromal Microenvironment. Cancer Res p. 3079-3091. 
Zeng DF, Zhang J, Zhu LD, et al (2014) Analysis of drug resistance-associated proteins 
expressions of patients with the recurrent of acute leukemia via protein microarray 
technology. Eur Rev Med Pharmacol Sci p. 537-43. 
Zhang R, Wang L, Chen P, et al (2021) Haematologic malignancies with unfavourable gene 
mutations benefit from donor lymphocyte infusion with/without decitabine for prophylaxis of 
relapse after allogeneic HSCT: A pilot study. Cancer Med p. 3165-3176. 
Zhou Y, Othus M, Araki D, et al (2016) Pre-and post-transplant quantification of measurable 
('minimal') residual disease via multiparameter flow cytometry in adult acute myeloid 
leukemia. Leukemia p. 1456-64. 


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16 
Appendices 
16.1 
Appendix 1: Acute GvHD Staging Criteria (Harris et al 2016) 
Organ staging will be performed according to updated NIH criteria as described by 
(Harris et al 2016) in Table 16-1. 
Table 16-1 
Acute GvHD Staging Criteria 
Stage 
Skin 
(Active Erythema 
Only) 
Liver 
(Bilirubin) 
Upper GI 
Lower GI 
(stool output/day) 
Stage 0 
No active 
(Erythematous) 
GvHD rash 
< 2mg/dL 
No or intermittent 
nausea, vomiting 
or anorexia 
Adult: 
< 500mL/day or < 3 
episodes/day 
Child: 
< 10mL/kg/day or < 4 
episodes/day 
Stage 1 
Maculopapular rash < 
25% BSA 
2-3 mg/dL 
Persistent 
nausea, vomiting 
or anorexia 
Adult: 500-999mL/day or 3-4 
episodes/dayChild: 10-
19.9mL/kg/day or 4-6 
episodes/day 
Stage 2 
Maculopapular rash < 
25%-50% BSA 
3.1-6 mg/dL 
  
Adult: 1000-1500mL/day or 5-7 
episodes/dayChild: 20-
30mL/kg/day or 7-10 
episodes/day 
Stage 3 
Maculopapular rash > 
50% BSA 
6.1-15mg/dL 
  
Adult: > 1500mL/day or > 7 
episodes/dayChild: > 
30mL/kg/day or > 10 
episodes/day 
Stage 4 
Generalized 
erythroderma (> 50% 
BSA) plus bullous 
formation and 
desquamation > 
5%BSA 
> 15 mg/dL 
  
Severe abdominal pain with or 
without ileus or grossly bloody 
stool (regardless of stool 
volume) 
Overall clinical grade (based on most severe target organ involvement): 
Grade 0: No Stage 1-4 of any organ. 
Grade I: Stage 1-2 skin without liver, upper GI or lower GI involvement. 
Grade II: Stage 3 rash and/or stage 1 liver and/or Stage 1 upper GI and/or Stage 1 lower GI. 
Grade III: Stage 2-3 liver and/or Stage 2-3 lower GI with Stage 0-3 skin and/or Stage 0-1 upper GI. 
Grade IV: Stage 4 skin, liver or lower GI involvement, with Stage 0-1 upper GI 


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16.2 
Appendix 2: Grading of Chronic GvHD (NIH Consensus Criteria) 
Grading of chronic GvHD as described by (Jagasia et al 2015) should be performed as 
described below. 
 
Organ scoring of chronic GvHD. ECOG indicates Eastern Cooperative Oncology Group; KPS, 
Karnofsky Performance Status; LPS, Lansky Performance Status; BSA, body surface area; 
ADL, activities of daily living; LFTs, liver function tests; AP, alkaline phosphatase; ALT, 
alanine aminotransferase; ULN, normal upper limit. *Weight loss within 3 months. Skin scoring 
should use both percentage of BSA involved by disease signs and the cutaneous features scales. 
When a discrepancy exists between the percentage of total body surface (BSA) score and the 
skin feature score, OR if superficial sclerotic features are present (Score 2), but there is 


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impaired mobility or ulceration (Score 3), the higher level should be used for the final skin 
scoring. To be completed by specialist or trained medical providers. **Lung scoring should be 
performed using both the symptoms and FEV1 scores whenever possible. FEV1 should be used 
in the final lung scoring where there is discrepancy between symptoms and FEV1 scores 
 


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Table 16-2 
NIH global severity of chronic GvHD 
Mild 
1 or 2 organs involved with no more than score 1 plus Lung score 0 
● Mild oral symptoms, no decrease in oral intake 
● Mild dry eyes, lubricant eyedrops ≤ 3x/day 
Moderate 
3 or more organs involved with no more than score 1 
OR 
Lung score 1 (FEV1 60-79% or dyspnea with stairs) 
OR 
At least 1 organ (not lung) or site with score 2 
● 19-50% body surface area involved or superficial sclerosis 
● Moderate dry eyes, eyedrops ≥ 3x/days or punctal plugs 
Severe 
At least 1 organ or site with score 3 
● ≥ 50% body surface area involved 
● Deep sclerosis, impaired mobility or ulceration 
● Severe oral symptoms with major limitation in oral intake 


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● Severe dry eyes affecting ADL 
 OR 
Lung score 2 or 3(FEV1 40-59% or dyspnea walking on flat ground) 
(Jagasia et al 2015, Lee 2017) 
Key points: In skin: higher of the 2 scores to be used for calculating global severity. If the entire abnormality in 
an organ is noted to be unequivocally explained by a non-GvHD documented cause, that organ is not included 
for calculation of the global severity. If the abnormality in an organ is attributed to multifactorial causes (GvHD 
plus other causes) the scored organ will be used for calculation of the global severity regardless of the 
contributing causes (no downgrading of organ severity score). 


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16.3 
Appendix 3: Infection Severity Grading 
Infections will be categorized according to type (i.e. bacterial, viral and fungal) and Blood and 
Marrow Transplant Clinical Trials Network (BMT CTN) severity (i.e. grade III infection, yes 
vs. no) (BMT CTN 2013). 
Table 16-3 
Severity grading table and recurrence interval definitions 
Type of Infection/ 
Severity grade 
Grade 1 
Grade 2 
Grade 3 
Bacterial infections 
Bacterial focus NOS 
requiring no more than 14 
days of therapy for 
treatment (e.g. urinary 
tract infection) 
Bacteremia (except CoNS) 
without severe sepsis *** 
Bacteremia with deep 
organ involvement (e.g. 
with new or worsening 
pulmonary infiltrates; 
endocarditis) 
Coag Neg Staph (S. epi), 
Corynebacterium, or 
Propioniobacterium 
bacteremia 
Bacterial focus with 
persistent signs, 
symptoms or persistent 
positive cultures requiring 
greater than 14 days of 
therapy 
Severe sepsis with 
bacteremia 
Cellulitis responding to 
initial therapy within 14 
days 
Cellulitis requiring a 
change in therapy d/t 
progression 
Fasciitis requiring 
debridement 
  
Localized or diffuse 
infections requiring 
incision with or without 
drain placement 
  
  
Any pneumonia 
documented or presumed 
to be bacterial 
Pneumonia requiring 
intubation 
  
  
Brain abscess or 
meningitis without 
bacteremia 
C. Difficile toxin positive 
stool with diarrhea < 1L 
without abdominal pain 
(child < 20 mL/kg) 
C. Difficile toxin positive 
stool with diarrhea > 1L 
(child > 20 mL/kg) or with 
abdominal pain 
C. Difficile toxin positive 
stool with toxic dilatation 
or renal insufficiency 
with/without diarrhea 
Fungal infections 
Superficial candida 
infection (e.g. oral thrush, 
vaginal candidiasis) 
Candida esophagitis 
(biopsy proven) 
Fungemia including 
Candidemia 
Proven or probable fungal 
sinusitis confirmed 
radiologically without 
orbital, brain, or bone 
involvement 
Proven or probable 
invasive fungal infections 
(e.g. Aspergillus, Mucor, 
Fusarium, Scedosporium) 
  
Disseminated infections 
(defined as multifocal 
pneumonia, presence of 
urinary or blood antigen, 
and/or CNS involvement) 
with Histoplasmosis, 
Blastomycosis, 
Coccidiomycosis, or 
Cryptococcus 


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Type of Infection/ 
Severity grade 
Grade 1 
Grade 2 
Grade 3 
  
Pneumocystis jiroveci 
pneumonia (regardless of 
PaO2 level) 
Viral Infections 
Mucous HSV infection 
  
  
Dermatomal Zoster 
VZV infection with 3 or 
more dermatomes 
Severe ZVZ infection 
(coagulopathy or organ 
involvement) 
Asymptomatic CMV 
viremia untreated or a 
CMV viremia with viral 
load decline by at least 2/3 
of the baseline value after 
2 weeks of therapy 
Clinically active CMV 
infection (e.g. symptoms, 
cytopenias) or CMV 
viremia not decreasing by 
at least 2/3 of the baseline 
value after 2 weeks of 
therapy 
CMV end-organ 
involvement (pneumonitis, 
enteritis, retinitis) 
EBV reactivation not 
treated with rituximab 
EBV reactivation requiring 
institution of therapy with 
rituximab 
EBV PTLD 
Adenoviral conjunctivitis 
asymptomatic viruria, 
asymptomatic stool 
shedding and viremia not 
requiring treatment 
Adenoviral upper 
respiratory infection, 
viremia, or symptomatic 
viruria requiring treatment 
Adenovirus with end-organ 
involvement (except 
conjunctivitis and upper 
respiratory tract) 
Asymptomatic HHV-6 
viremia untreated or an 
HHV-6 viremia with a viral 
load decline by at least 0.5 
log after 2 weeks of 
therapy 
Clinically active HHV-6 
infection (e.g. symptoms, 
cytopenias) or HHV-6 
viremia without viral load 
decline 0.5 log after 2 
weeks of therapy 
  
BK viremia or viruria with 
cystitis not requiring 
intervention 
BK viremia or viruria with 
clinical consequence 
requiring prolonged 
therapy and/or surgical 
intervention 
  
  
Enterocolitis with enteric 
viruses 
  
  
Symptomatic upper tract 
respiratory virus 
Lower tract respiratory 
viruses 
Viremia (virus not 
otherwise specified) not 
requiring therapy 
Any viremia (virus not 
otherwise specified) 
requiring therapy 
  
  
  
Any viral encephalitis or 
meningitis 
Parasitic infections 
  
  
CNS or other organ 
toxoplasmosis 
Strongyloides 
hyperinfection 
Nonmicrobiologically 
defined infections 
Uncomplicated fever with 
negative cultures 
responding within 14 days 
  
  
Clinically documented 
infection not requiring 
inpatient management 
Pneumonia or 
bronchopneumonia not 
requiring mechanical 
ventilation 
Any acute pneumonia 
requiring mechanical 
ventilation 


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Type of Infection/ 
Severity grade 
Grade 1 
Grade 2 
Grade 3 
  
Typhlitis 
  
  
  
Severe sepsis*** without 
an identified organism 
*Concomitant or multimicrobial infections are graded according to the grade of the infection with the higher 
grade of severity. 
**Therapy includes both PO and IV formulations. 
***Severe sepsis definition (adults): 
● Hypotension: A systolic blood pressure of <90 mmhg="" or="" a="" reduction="" of="">40 mmhg from 
baseline in the absence of other causes for hypotension 
● Multiple Organ Dysfunction Syndrome: 2 or more of the following 
 
● Renal failure requiring dialysis 
 
● Respiratory failure requiring BiPAP or intubation 
 
● Heart failure requiring pressors 
 
● Liver failure  
Disseminated Infections: 
● Two or more non-contiguous sites with the SAME organism 
● A disseminated infection can occur at any level of severity, but most will be grade 2 or 3. 
Recurrence intervals to determine whether an infection is the same or new: 
1. CMV, HSV, EBV, HHV6: 2 months (< 60 days) 
2. VZV, HZV: 2 weeks (< 14 days) 
3. Bacterial, non-C. difficile: 1 week (< 7 days) 
4. Bacterial, C. difficile: 1 month (< 30 days) 
5. Yeast: 2 weeks (< 14 days) 
6. Molds: 3 months (< 90 days) 
7. Helicobacter: 1 year (< 365 days) 
8. Adenovirus, Enterovirus, Influenza, RSV, Parainfluenza, Rhinovirus: 2 weeks (< 14 days) 
9. Polyomavirus (BK virus): 2 months (< 60 days) 
For infections coded as “Disseminated” per the Infection Form, any previous infection with the same organism 
but different site within the recurrence interval for that organism will be counted as part of the disseminated 
infection. 


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16.4 
Appendix 4: Prohibited medications and Concomitant 
medications to be used with caution and/or requiring actions 
during study drug treatment 
In general, the use of any concomitant medication deemed necessary for the care of the 
participants is permitted in this trial, except as specifically prohibited in Section 6.2.2 and in 
Table 16-4 below. Refer to Section 6.2.2 for detailed guidance on restrictions. Some 
concomitant therapy to be used with caution or requiring action are described 
in Section 6.2.2.1 and in Table 16-5 below. 
The list is adapted from the Novartis PK Sciences internal memorandum (2021): drug-drug 
interactions (DDI) database, which is compiled primarily from the Indiana University School 
of Medicine’s “Clinically Relevant” Table (medicine.iupui.edu/flockhart/table.htm), the 
University of Washington’s Drug Interaction Database (druginteractioninfo.org), and the 
FDA’s “Guidance for Industry, Drug Interaction Studies”. 
These lists are not comprehensive and are only meant to be used as a guide. Please contact the 
medical monitor with any questions. 
If a medication appears on both the list of prohibited and the list of medications to be used with 
caution, the medication is prohibited. 
Table 16-4 
List of prohibited medications during study treatment 
Mechanism of Interaction 
Drug Names 
Narrow therapeutic index 
substrates of CYP3A 
abemaciclib, acalabrutinib, alectinib, amiodarone, amitriptyline, astemizole, 
axitinib, baricitinib, bosutinib, brigatinib, cabazitaxel, cabozantinib, 
carbamazepine, ceritinib, clomipramine, cobimetinib, conivaptan, copanlisib, 
crizotinib, dabrafenib, dasatinib, dihydroergotamine, docetaxel, dronedarone, 
entrectinib, erdafitinib, ergotamine, everolimus, imipramine, ivosidenib, 
ixazomib, lomitapide, midostaurin, neratinib, nilotinib, panobinostat, 
pexidartinib, pimozide, ponatinib, quinidine, regorafenib, romidepsin, sonidegib, 
sorafenib, sunitinib, tamoxifen, temsirolimus, tolvaptan, trabectedin, vinblastine, 
zanubrutinib 
Strong inducers of CYP3A 
carbamazepine, enzalutamide, lumacaftor, phenobarbital, phenytoin, rifabutin, 
rifampicin, mitotane, St. John’s wort (Hypericum perforatum)1, avasimibe, 
rifapentine, apalutamide, ivosidenib 
Moderate inducers of CYP3A 
asunaprevir / beclabuvir / daclatasvir, bosentan, cenobamate, dabrafenib, 
elagolix, efavirenz, etravirine, lesinurad, lersivirine, lopinavir, nafcillin, 
phenobarbital, primidone, rifabutin, talviraline, telotristat ethyl, thioridazine, 
tipranavir/ritonavir2 
1 Herbal product 
2Combination therapy  
Table 16-5 
List of medications to be used with caution and/or requiring actions 
during study treatment 
Narrow therapeutic index 
substrates of CYP3A 
cyclosporine, sirolimus, tacrolimus 
Strong inhibitors of CYP3A 
boceprevir, clarithromycin, cobicistat, danoprevir/ritonavir2 
elvitegravir/ritonavir2, grapefruit juice1, idelalisib, indinavir, indinavir/ritonavir2 
itraconazole, josamycin, ketoconazole, lopinavir/ritonavir2, mibefradil, 
mifepristone, nefazodone, nelfinavir, ombitasvir/paritaprevir/dasabuvir/ritonavir 
(Viekira Pak)2, posaconazole, ribociclib, ritonavir, saquinavir, 


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saquinavir/ritonavir2, telaprevir, telithromycin, troleandomycin, tucatinib, 
voriconazole  
Moderate inhibitors of 
CYP3A 
aprepitant, amprenavir, atazanavir, atazanavir/ritonavir2, casopitant, cimetidine, 
ciprofloxacin, darunavir, darunavir/ritonavir2, diltiazem, duvelisib, erythromycin, 
faldaprevir, fedratinib, fluconazole, grapefruit juice1, imatinib, isavuconazole, 
istradefylline, lefamulin, letermovir, Magnolia vine (Schisandra sphenanthera)3, 
netupitant, ravuconazole, tofisopam, verapamil, voxelotor 
1 The effect of grapefruit juice varies widely among brands and is concentration-, dose-, and preparation-
dependent. 
2Combination therapy 
3 Herbal product 


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16.5 
Appendix 5: Patient Past History and Disease Characteristics 
AML diagnosis: diagnosis of AML will be reported as defined by the 2016 World Health 
Organization (WHO) AML classification (Arber et al 2016). 
Table 16-6 
2016 WHO AML classification 
1 
AML with recurrent genetic 
abnormalities 
● AML with t(8;21)(q22;q22), RUNX1-RUNX1T1. 
● AML with inv(16)(p13.1;q22) or t(16;16)(p13.1;q22), CBFB-MYH11. 
● Acute promyelocytic leukemia (APL) with PML-RARA. 
● AML with t(9;11)(p21.3;q23.3), MLLT3-KMT2A. 
● AML with t(6;9)(p23;q34.1), DEK-NUP214. 
● AML with inv(3)(q21.3;q26.2) or t(3;3)(q21.3;q26.2), GATA2, 
MECOM. 
● AML (megakaryoblastic) with t(1;22)(p13.3;q13.3), RBM15-MKL1. 
● AML with BCR-ABL1 (provisional entity). 
● AML with mutated NPM1. 
● AML with biallelic mutations of CEBPA. 
● AML with mutated RUNX1 (provisional entity). 
2 
AML with myelodysplasia-
related features 
  
3 
Therapy-related myeloid 
neoplasms 
  
4 
AML, Not Otherwise 
Specified (NOS) 
● AML with minimal differentiation (FAB classification M0). 
● AML without maturation (FAB classification M1). 
● AML with maturation (FAB classification M2). 
● Acute myelomonocytic leukemia (FAB classification M4). 
● Acute monoblastic/monocytic leukemia (FAB classification M5a and 
M5b). 
● Pure erythroid leukemia (FAB classification M6a and M6b). 
● Acute megakaryoblastic leukemia (FAB classification M7). 
● Acute basophilic leukemia. 
● Acute panmyelosis with myelofibrosis. 
5 
Myeloid sarcoma 
  
6 
Myeloid proliferations 
related to Down syndrome: 
● Transient abnormal myelopoiesis (TAM). 
● Myeloid leukemia associated with Down syndrome. 
7 
Acute Leukemias of 
Ambiguous Lineage 
● Acute undifferentiated leukemia. 
● Mixed phenotype acute leukemia (MPAL) with 
t(9;22)(q34.1;q11.2); BCR-ABL1. 
● MPAL with t(v;11q23.3); KMT2A rearranged. 
● MPAL, B/myeloid, NOS. 
● MPAL, T/myeloid, NOS. 
Cytogenetics and risk stratification: cytogenetic risk category will be reported according to 
the 2017 European LeukemiaNet (ELN) recommendations (Döhner et al 2017). 
Table 16-7 
2017 ELN risk stratification by genetics 
Risk category* 
Genetic abnormality 
Favorable 
t(8;21)(q22;q22.1); RUNX1-RUNX1T1 
inv(16)(p13.1q22) or t(16;16)(p13.1;q22); CBFB-MYH11 
Mutated NPM1 without FLT3-ITD or with FLT3-ITDlow† 
Biallelic mutated CEBPA 
Intermediate 
Mutated NPM1 and FLT3-ITDhigh† 
Wild-type NPM1 without FLT3-ITD or with FLT3-ITDlow† (without adverse-risk genetic 
lesions) 


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Risk category* 
Genetic abnormality 
t(9;11)(p21.3;q23.3); MLLT3-KMT2A‡ 
Cytogenetic abnormalities not classified as favorable or adverse 
Adverse 
t(6;9)(p23;q34.1); DEK-NUP214 
t(v;11q23.3); KMT2A rearranged 
t(9;22)(q34.1;q11.2); BCR-ABL1 
inv(3)(q21.3q26.2) or t(3;3)(q21.3;q26.2); GATA2,MECOM(EVI1) -5 or del(5q); -7; -
17/abn(17p) 
Complex karyotype,§ monosomal karyotype|| 
Wild-type NPM1 and FLT3-ITDhigh† 
Mutated RUNX1{ 
Mutated ASXL1{ 
Mutated TP53# 
Frequencies, response rates, and outcome measures should be reported by risk category, and, if sufficient 
numbers are available, by specific genetic lesions indicated. 
*Prognostic impact of a marker is treatment-dependent and may change with new therapies. 
†Low, low allelic ratio (,0.5); high, high allelic ratio ($0.5); semiquantitative assessment of FLT3-ITD allelic ratio 
(using DNA fragment analysis) is determined as ratio of the area under the curve “FLT3-ITD” divided by area 
under the curve “FLT3-wild type”; recent studies indicate that AML with NPM1 mutation and FLT3-ITD low 
allelic ratio may also have a more favorable prognosis and participants should not routinely be assigned to 
allogeneic HCT. 
‡The presence of t(9;11)(p21.3;q23.3) takes precedence over rare, concurrent adverse-risk gene mutations. 
§Three or more unrelated chromosome abnormalities in the absence of 1 of the WHO-designated recurring 
translocations or inversions, that is, t(8;21), inv(16) or t(16;16), t(9;11), t(v;11)(v;q23.3), t(6;9), inv(3) or t(3;3); 
AML with BCR-ABL1. 
||Defined by the presence of 1 single monosomy (excluding loss of X or Y) in association with at least 1 
additional monosomy or structural chromosome abnormality (excluding core-binding factor AML). 
{ These markers should not be used as an adverse prognostic marker if they co-occur with favorable-risk AML 
subtypes. 
#TP53 mutations are significantly associated with AML with complex and monosomal karyotype.  
Molecular markers and risk stratification:  
In addition to basic cytogenetic analysis, molecular markers that can help refining prognostics 
groups, particularly in participants with a normal karyotype, include: NPM1, FLT3 (FLT3-ITD 
and FLT3-TKD), CEBPA, isocitrate dehydrogenase 1 and 2 (IDH1/2), DNA methyltransferase 
3A 
(DNMT3A), 
c-KIT, 
MLL, 
TP53, 
RUNX1, 
and 
ASXL1 
gene 
mutations 
(National Comprehensive Cancer Network (2021)). 


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16.6 
Appendix 6: Statistical details on the Bayesian Logistic 
Regression Model (BLRM) 
Details of the statistical model, the derivation of prior distributions from historical data, the 
results of the Bayesian analyses and respective dosing decisions for some hypothetical data 
scenarios are included. A simulation study of the operating characteristics of the model is also 
presented. 
16.6.1 
Statistical model for single agent 
The statistical model comprises a single-agent toxicity part for siremadlin, which allows the 
incorporation of single-agent toxicity information. The proposed statistical model uses a meta-
analytic framework (Spiegelhalter et al 2004, Neuenschwander et al 2016) to combine all 
historical and concurrent data. 
Let π(d) be the risk of DLT for siremadlin given as a single agent dose at dose d. The single 
agent dose-DLT models are logistic: 
logit(π(d))=log(α)+β log(d/d*) (1) 
where d*, the reference dose, is used to scale the doses of siremadlin. The reference dose is 
defined in the appropriate model specifications sections. 
Hence, α (>0) is the single-agent odds of a DLT at d* and β (>0) are the increase in the log-odds 
of a DLT by a unit increase in log-dose. 
16.6.2 
Prior specifications 
The Bayesian approach requires the specification of prior distributions for the model parameters 
log(α) and log(β). A meta-analytic framework approach was used to derive the prior distribution 
for these model parameters. 
16.6.2.1 The meta-analytic framework approach 
Assume we have data from historical or concurrent trials, which we want to use in combination 
with data in the new treatment arm. 
Let πj(dj) be the risk of single-agent DLT in group j (j = 1, ... , J) as defined in (1). A trial may 
consist of multiple groups, e.g, groups with different dose regimen. 
The model assumes exchangeable parameters (“random effects”), and introduces a variance 
component accounting for between-group heterogeneity. Therefore, in order to borrow 
information across groups, an exchangeability structure is assumed across θj = (log(αj),log(βj)). 
θj~ BVN (μ, Γ). μ = (μα, μβ) and Γ are the mean and between-group covariance matrix for the 
logistic parameters, the latter with standard deviations τα, τβ and correlation ρ. 
However, as historical studies may involve different regimens/patient population with 
concurrent studies, they can have different safety profile. Therefore, stratification between 
historical studies and concurrent studies is used to differentially discount data from each stratum 
through the covariance, with sj = 1, 2 noting the stratum. 


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16.6.2.2 Prior specification 
In Part 1, monotherapy of siremadlin is used. The Bayesian model consists of siremadlin single 
agent component. 
Weakly informative priors are assumed for log(α) and log(β), with mean μα 
equal to logit (0.15) corresponding to the anticipated DLT rate at the reference dose 
(d1*=siremadlin 150 mg corresponding to 30 mg QD Day 1-5 28-day cycle) and with mean μβ 
equal to 0 corresponding to a doubling in the dose of siremadlin leading to a doubling in the 
odds of the risk of a DLT. Priors for τ1 and τ2 are assigned such that (1) their medians correspond 
to large or moderate between trial heterogeneity for historical trials and concurrent trials 
respectively, and (2) their uncertainty (95% prior interval) cover plausible between trial 
standard deviations (Neuenschwander et al 2014). Full exchangeability is assumed. 
The prior distributions for the model used for deriving the meta-analytic priors are specified in 
Table 16-8 below. 
Table 16-8 
Prior distributions for single-agent parameters 
Parameter 
Prior distribution 
μα (Siremadlin) 
N(mean = logit(0.15), sd = 2) 
μβ (Siremadlin) 
N(mean = 0, sd=0.75) 
τα1 (Historical stratum) 
log-normal(mean = 1, sd = log(4)/1.96) 
τβ1 (Historical stratum) 
log-normal(mean = 0.5, sd = log(2)/1.96) 
τα2 (Concurrent stratum) 
log-normal(mean = 0.25, sd = log(4)/1.96) 
τβ2 (Concurrent stratum) 
log-normal(mean = 0.125, sd = log(2)/1.96) 
ρ1(Historical stratum) 
uniform (-1,1) 
ρ2(Concurrent stratum) 
uniform (-1,1) 
16.6.2.3 Historical data 
The prior described above was then updated by using the dose-DLT data from a Novartis 
study [CHDM201X2101] in post-SCT participants with AML treated with siremadlin single 
agent, and a Novartis study [CHDM201H12101C] in participants with AML or high-risk MDS 
treated with siremadlin in combination with sabatolimab. Historical data are presented 
in Table 16-9, andTable 16-10 . Data in the Novartis study [CHDM201H12101C] is assumed 
to be generated from siremadlin alone regardless of sabatolimab. 
Table 16-9 
Historical data from [CHDM201X2101] for siremadlin single agent 
Siremadlin dose regimen  
Number of participants for 
DDS 
Number of participants with 
a DLT 
250 mg Q3W* 
3 
1 
350 mg Q3W* 
1 
0 
400 mg Q3W* 
2 
2 
120 mg QD on D1 and D8, 28-day cycle 
2 
0 
150 mg QD on D1 and D8, 28-day cycle 
1 
0 
20 mg QD 2 weeks on/ 2 weeks off 
1 
0 
30 mg QD 2 weeks on/ 2 weeks off 
1 
0 
*Doses are normalized to 28-day cycle  


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Table 16-10 
Historical data from [CHDM201H12101C] for siremadlin and 
sabatolimab combination  
Siremadlin dose regimen 
Sabatolimab 
dose regimen 
Number of 
participants for DDS 
Number of participants 
with a DLT 
20 mg QD Day 1 to 5, 28-day cycle 
400 mg Q2W 
4 
0 
40 mg QD Day 1 to 5, 28-day cycle 
800 mg Q4W 
4 
0 
40 mg QD Day 1 to 5, 28-day cycle 
400 mg Q2W 
3 
0 
16.6.2.4 Summary of prior distributions 
The prior summaries for DLT rates are summarized in Table 16-11. 
Table 16-11 
Summary of prior distributions 
Siremadlin 
QD dose  
Prior probabilities that p(DLT) is in the 
interval: 
Mean 
SD 
Quantiles 
[0,0.16) 
[0.,16,0.33) 
[0.33,1] 
2.5% 
50% 
97.5% 
20 mg 
0.971 
0.025 
0.004 
0.037 
0.050 
0.001 
0.020 
0.172 
30 mg 
0.943 
0.050 
0.008 
0.055 
0.062 
0.002 
0.035 
0.220 
40 mg 
0.894 
0.093 
0.013 
0.074 
0.075 
0.004 
0.051 
0.275 
16.6.2.5 Hypothetical dose scenarios for siremadlin single agent 
To illustrate the performance of the model used to guide the dose escalation, hypothetical dose 
escalations scenarios are presented in Table 16-12. In each scenario, the recommended dose for 
the next cohort of participants is shown (dose escalation rules described in Section 6.6 of the 
study protocol). 


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Table 16-12 
Probability of excessive toxicity estimated by the Bayesian model 
after each cohort 
Scenario 
Cohort 
Siremadlin 
QD dose 
Day 1-5 
(mg) 
Number of 
Siremadlin 
dose level 
for the next 
cohort 
P(target 
toxicity) at 
highest 
siremadlin 
dose 
P(excessive 
toxicity) at 
highest 
siremadlin 
dose 
Evaluable 
participants 
DLTs* 
1 
Cohort 1 
30 
3 
1 
40 
0.244 
0.047 
2 
Cohort 1 
30 
4 
1 
40 
0.223 
0.039 
3 
Cohort 1 
30 
5 
1 
40 
0.204 
0.023 
4 
Cohort 1 
30 
3 
1 
- 
- 
- 
Cohort 2 
40 
6 
1 
40 
0.295 
0.027 
5 
Cohort 1 
30 
3 
1 
- 
- 
- 
Cohort 2 
40 
6 
2 
40 
0.484 
0.098 
6 
Cohort 1 
30 
4 
1 
- 
- 
- 
Cohort 2 
40 
6 
1 
40 
0.277 
0.020 
7 
Cohort 1 
30 
4 
1 
- 
- 
- 
Cohort 2 
40 
6 
2 
40 
0.466 
0.084 
8 
Cohort 1 
30 
3 
2 
- 
- 
- 
Cohort 2 
20 
6 
1 
40 
0.506 
0.189 
9 
Cohort 1 
30 
3 
2 
- 
- 
- 
Cohort 2 
20 
6 
1 
- 
- 
- 
Cohort 3 
40 
6 
2 
40** 
0.597 
0.243 
* Number of participants with at least one DLT. 
** Probability of overdose at 20 mg is 0.042; probability of overdose at 30 mg is 0.121 
16.6.3 
Operating characteristics 
16.6.3.1 Scenarios 
In order to show how the design performs, four hypothetical scenarios are investigated: 
 Scenario 1: True DLT rate is aligned to the mean of the prior distribution. 
 Scenario 2: Higher toxicity profile for all the doses. True DLT rate of toxic doses is 
increased across the dose range. 
 Scenario 3: Higher toxicity profile for all the doses and the last dose a much larger DLT 
rate than in scenario 1. 
 Scenario 4: High toxicity profile for all the doses and all doses have excessive toxicity. 
Hypothetical true DLT rate are shown in Table 16-13.  
Table 16-13 
 Hypothetical true probabilities of DLT for different scenarios 
Siremadlin QD 
dose Day 1-5 (mg)  
Scenario 
1. Prior means 
2. Higher toxicity 
profile 
3. Steep increase 
4. High toxicity all  
20 
0.037 
0.1 
0.1 
0.4 
30 
0.055 
0.2 
0.22 
0.5 
40 
0.074 
0.3 
0.55 
0.6 


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16.6.3.2 Simulation results 
Operating characteristics are reviewed based on the simulation results under the four scenarios. 
The metrics reviewed are: 
 Probability of participants receiving an overdose. 
 Probability that identified RD at the end of the trial is in the target toxicity interval. 
 Probability that identified RD is an overdose. 
 Probability that identified RD is an underdose. 
 Percentage of trials stopped without RD declaration. 
 Average sample size. 
Operating characteristics for the four scenarios are presented in Table 16-14.  
Table 16-14 
Operating characteristics for different true values of DLT rate * 
Scenario 
participants 
receiving an 
overdose 
Probability to declare RD 
Probability 
to stop for 
toxicity 
Average 
sample 
size 
Over-
dose  
Target 
toxicity 
Under-
dose 
1. Prior means 
0 
0 
0 
1 
0 
10 
2. Higher toxicity profile 
0 
0 
0.956 
0.022 
0.022 
15 
3. Steep increase in toxicity 
for the last dose 
0.450 
0.288 
0.449 
0.115 
0.148 
20 
4. High toxicity all doses 
1 
0.246 
0 
0 
0.754 
13 
* Only evaluable participants. 1000 simulations were performed in R3.6.1 with option to de-escalate when >= 2 
DLTs in a cohort are observed for the first time at that dose combination. In the simulated trials, first 3 
participants were enrolled at the starting dose level of 30 mg. A second cohort of 3 participants was enrolled if 
30 mg was maintained. If the decision was to escalate, a cohort of 6 participants was enrolled at 40 mg or 
another cohort of 6 participants at 20 mg if de-escalating. A dose level may be declared as RD after 6 
participants were tested. The maximum number of participants was set at 100 for the simulation. Run time was 
22:02 minutes. 


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16.7 
Appendix 7: Statistical details on the Bayesian Time-to-DLT 
Model 
Rationale of implementing the time-to-first-DLT approach is included as well as details of the 
statistical model, the derivation of prior distributions from historical data, the results of the 
Bayesian analyses and respective dosing decisions for some hypothetical data scenarios. A 
simulation study of the operating characteristics of the model is also presented. 
By the study design, if participants meet the eligibility criteria for DLI in Part 2, they will enter 
combination phase at the siremadlin dose tolerated in the last cycle of priming phase. The 
addition of DLI in the combination phase may increase the risk of GvHD. Participants may 
undergo different number of priming cycles and have acute or cumulative toxicities before 
entering the combination phase, which leads to changed population characteristics from the 
beginning of priming phase. Therefore, it is necessary to establish a safe maximum dose level 
for siremadlin in the combination phase which spans multiple cycles. 
During combination phase, participants may receive up to 3 DLIs. The number of DLI cycles 
depends on various reasons besides DLTs. The DLIs will be administered in a ramp-up way 
starting with a relatively small dose. Thus, a conventional binomial model would be inadequate 
as it implies that the exposure time per participant is a single cycle only. Here we consider 
instead a multi-cycle model, which generalizes the binomial model. The multi-cycle model is 
realized as a simplified time-to-first-DLT model. Instead of a full time-to-event model, the time 
observation process is aligned with a respective binomial model in that time always lapses in at 
least full cycles. The model will be updated continuously with data when a cohort of 3 
participants complete the first cycle of combination phase throughout the trial except the final 
assessment (for declaration of the maximum recommended dose for combination) will be 
conducted when the last participant in the final cohort completes the combination phase (below 
table). This approach allows participants to continue their treatment without operational 
interruptions and enables the close monitoring of all participants. 
Table 16-15 
Time point for the safety analysis in the combination Phase* 
Safety 
assessment 
Number evaluable 
participants 
Timepoint 
Decisions 
1 
3 
The3rd participant has completed C1 or had a DLT 
Maximum dose 
2 
(3 +) 3 
The 6th participant has completed C1 or had a DLT 
Maximum dose 
3 
(6 +) 3 
The9th participant has completed C1 or had a DLT 
Maximum dose 
n 
N 
N participants have completed the combination 
phase 
Declaration of 
maximum RD** 
(final 
assessment) 
*There will be n safety assessments in total with N participants who enter combination phase. 
** Declaration of maximum RD for combination requires at least 9 evaluable participants. 
16.7.1 
Statistical model 
The statistical model is a piece-wise constant Poisson process, which is censored for each 
participant after the first event in case an event occurs. Each cycle defines a piece of the 
parametric hazard function. The model is specified via the instantaneous hazard h(t) which is 
transformed to the log scale to ensure positivity. As two independent factors contribute to the 


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overall DLT event rate in the combination phase, we use specifically a compound Poisson 
process. The siremadlin and DLI treatment contribute independently from each other to the 
overall event rate. For a compound Poisson process the total counting rate is the sum of the 
individual counting rates on the linear scale. Therefore we have 
Ym,n = event counter for participant m in cycle n 
tm,n = Time duration in days of cycle n of participant m 
Ym,n ~Poisson((λ1 + λ2,n) * tm,n) 
The linear predictor on the log-scale for the event counting rate for siremadlin is modelled with 
an intercept and positive slope as a function of the standardized dose of siremadlin 
log(λ1) = α + exp(β) * log(d/dref) 
, where d is siremadlin dose and dref is the siremadlin reference dose. 
The DLI treatment is not modelled in dependence of a dose such that no slope is used. However, 
a cycle specific DLT event rate accounts for potential carry over effects of previous DLI 
treatments. The carry over effect reflects the ordering of the cycles through its structural form 
of 
log(λ2,n) = γ + I(n=2) * 2*θ * x + I(n=3) *2* x, 
where γ is the overall intercept representing the DLI event rate in cycle 1, x being the average 
difference between cycles in the DLT event rate and θ being a percentage of the total Cycle 3 
difference of 2 * x(modelled on the 0-1 scale). 
The likelihood accounts for participants being in the risk set for each cycle as only terms are 
included in the likelihood for a given participant if still at risk of an event. 
Importantly, time tm,n is being counted in at least full cycles for each participant. That is, the 
observation process is aligned with the commonly used binomial BLRM in that for each 
participant an exposure time of a full cycle is assumed. In consequence, tm,n is always at least 
42 days (6 weeks) for any participant and cycle. The exact value of tm,n depends on the start of 
the follow-up cycle n+1, which is determined by constraints of the clinical context of the 
participant. 
16.7.2 
Prior specifications 
The Bayesian approach requires the specification of prior distributions for the model 
parameters. A meta-analytic framework approach was used to derive the prior distribution for 
these model parameters. 
Table 16-16 
Prior distributions for single-agent and interaction parameters 
Parameter 
Prior distribution 
μ1α (siremadlin) 
N(mean = -6.7, sd = 2.5) 
μ1β (siremadlin) 
N(mean = 0, sd = 1) 
μ2α (DLI) 
N(mean = -6.1, sd = 2.5) 
t1α1, t2α1 
log-normal(mean = log(2.5/4.0), sd = log(2)/1.96) 
t1β1 
log-normal(mean = log(2.5/8.0), sd = log(2)/1.96) 
x 
N(mean = 0, sd = 1) 
θ 
Beta(alpha = 1, beta = 1) 


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16.7.2.1 Historical data 
The prior described above was then updated by using the dose-DLT data in Section 16.6.2.3 as 
well an external study (Guillaume et al 2019) where post-allo-SCT HR AML and HR MDS 
participants 
treated 
with 
azacitidine 
and 
DLI. 
Historical 
data 
are 
presented 
in Table 16-9, Table 16-10 and Table 16-17. Data in the Guillaume study is assumed to be 
generated from DLI alone regardless of azacitidine.  
Table 16-17 
Historical data from [Guillaume et al (2019)] for DLI 
DLI* 
DLI received 
Number participants 
Number participants with DLT 
Cycle 1 
1 
17 
2 
Cycle 2 
1 
12 
0 
Cycle 3 
1 
10 
0 
*DLI is given1 per cycle of 8 weeks with 3 DLIs of 5e6 CD3+/kg, 1e7 CD3+/kg and 5e7 CD3+/kg for matched 
related donors and 1e6 CD3+/kg, 5e6 CD3+/kg and 1e7 CD3+/kg for matched unrelated donors. 
16.7.2.2 Summary of prior distributions 
The prior summaries for DLT rates are summarized in Table 16-18.  
Table 16-18 
Summary of prior distributions 
Siremadlin 
QD dose  
Cycle 
number 
DLT rate 
Quantiles / (%) 
Mean/(%) 
SD/(%) 
25% 
50% 
75% 
20 mg 
1 
13.1 
13.5 
4.5 
8.8 
16.7 
20 mg 
2 
8.4 
10.2 
2.3 
5.0 
10.6 
20 mg 
3 
7.1 
9.8 
1.4 
3.7 
8.7 
30 mg 
1 
15.4 
14.3 
6.0 
11.0 
19.9 
30 mg 
2 
10.9 
11.7 
3.4 
7.2 
14.0 
30 mg 
3 
9.6 
11.4 
2.6 
5.8 
12.5 
40 mg 
1 
19.1 
16.0 
8.0 
14.5 
24.5 
40 mg 
2 
14.7 
14.2 
5.3 
10.1 
19.2 
40 mg 
3 
13.5 
14.0 
4.2 
8.8 
17.8 
16.7.2.3 Hypothetical dose scenarios for siremadlin/DLI combination 
To illustrate the performance of the model used to guide the dose escalation, hypothetical dose 
escalations scenarios are presented in Table 16-19. In each scenario, the maximum dose for the 
next cohort of participants is shown (dose escalation rules described in Section 6.6 of the study 
protocol). 
Table 16-19 
Predicted DLT rate estimated by the Bayesian model after each cohort 
Scenari
o 
Cohor
t 
Siremadli
n QD dose 
Day 1-5 
(mg) 
#evaluable 
participant
s 
#DLT
s 
Siremadli
n dose 
level for 
next 
cohort 
Cycle 
numbe
r 
Mean 
DLT rate 
at highest 
siremadli
n dose 
75th 
percentil
e 
1 
Cohort 
1 
30 
3 
1 
40 
1 
0.220 
0.288 
  
  
  
  
  
  
2 
0.170 
0.225 


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Scenari
o 
Cohor
t 
Siremadli
n QD dose 
Day 1-5 
(mg) 
#evaluable 
participant
s 
#DLT
s 
Siremadli
n dose 
level for 
next 
cohort 
Cycle 
numbe
r 
Mean 
DLT rate 
at highest 
siremadli
n dose 
75th 
percentil
e 
  
  
  
  
  
  
3 
0.155 
0.207 
2 
Cohort 
1 
30 
3 
2 
20 
1 
0.237 
0.317 
  
  
  
  
  
  
2 
0.154 
0.213 
  
  
  
  
  
  
3 
0.128 
0.181 
3 
Cohort 
1 
30 
2 
1 
40 
1 
0.212 
0.276 
  
  
40 
1 
0 
  
2 
0.161 
0.214 
  
  
 
 
 
  
3 
0.145 
0.193 
16.7.3 
Operating characteristics 
16.7.3.1 Scenarios 
In order to show how the design performs, four hypothetical scenarios are investigated: 
 Scenario 1: True DLT rate is aligned to the mean of the prior distribution. 
 Scenario 2: Higher toxicity profile for all the doses. True DLT rate of toxic doses is 
increased across the dose range. 
 Scenario 3: Higher toxicity profile for all the doses and the last dose a much larger DLT rate 
than in scenario 1. 
 Scenario 4: High toxicity profile for all the doses and all doses have excessive toxicity. 
Constant DLT rates were assumed over the 3 cycles. Hypothetical true DLT rate are shown in 
Table 16-20.  
Table 16-20 
Hypothetical true probabilities of DLT for different scenarios 
Siremadlin QD 
dose Day 1-5 
(mg)  
Scenario 
  
  
  
1. Prior means 
2. Higher toxicity 
profile 
3. Steep increase 
4. High toxicity all  
20 
0.13 
0.21 
0.15 
0.4 
30 
0.152 
0.28 
0.23 
0.5 
40 
0.183 
0.38 
0.5 
0.6 
16.7.3.2 Simulation results 
Operating characteristics are reviewed based on the simulation results under the four scenarios. 
The metrics reviewed are: 
 Probability of participants receiving an overdose. 
 Probability that identified maximum RD at the end of the trial is an overdose. 
 Probability that the trial is stopped early due to toxicity. 
 Probability that the trial reaches maximum number of participants without declaring a 
maximum RD. 


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 Average sample size. 
At least 9 evaluable participants are required to determine the maximum recommended dose of 
siremadlin in combination with DLI. A dose level to be declared as maximum RD for 
combination must be tested with at least 3 evaluable participants treated at or above that dose 
level. However, the actual number of evaluable participants is not known. Thus, operating 
characteristics for the four scenarios are presented for 9 and 18 evaluable participants in 
Table 16-21 and Table 16-22 respectively. 
Table 16-21 
Operating characteristics for different true values of DLT rate for n=9 
patients * 
Scenario 
Participants 
receiving an 
overdose 
Probability of 
the declared 
maximum RD 
being an OD 
Probability to 
stop for 
toxicity 
Probability of 
inconclusive 
results 
Average 
sample size 
1. Prior means 
0.0 
0.0 
0.035 
0 
8.826 
2. Higher 
toxicity profile 
2.195 
0.244 
0.15 
0.019 
8.43 
3. Steep 
increase 
2.23 
0.214 
0.117 
0.016 
8.538 
4. High toxicity 
all 
6.735 
0.289 
0.687 
0.024 
6.735 
* Only evaluable participants. 1000 simulations were performed in R3.6.1 
Table 16-22 
Operating characteristics for different true values of DLT rate based 
on n=18 patients* 
Scenario 
Participants 
receiving an 
overdose 
Probability of 
the declared 
maximum RD 
being an OD 
Probability to 
stop for 
toxicity 
Probability of 
inconclusive 
results 
Average 
sample size 
1. Prior means 
0.0 
0.0 
0.036 
0 
17.505 
2. Higher 
toxicity profile 
3.503 
0.306 
0.187 
0.002 
15.933 
3. Steep 
increase 
3.597 
0.325 
0.127 
0 
16.443 
4. High toxicity 
all 
8.943 
0.15 
0.850 
0 
8.943 
* Only evaluable participants. 1000 simulations were performed in R3.6.1 
 

SAP_001.pdf: 
Official Title:  A Phase Ib/II, Open Label Study of Siremadlin Monotherapy and in Combination 
With Donor Lymphocyte Infusion as a Treatment for Patients With Acute 
Myeloid Leukemia Post-allogeneic Stem Cell Transplantation Who Are in 
Complete Remission But at High Risk for Relapse.
NCT Number: 
 NCT05447663 
Document Date: Statistical Analysis Plan Amendment 1: 29-November-2023


 
 
 
 
Clinical Development 
HDM201/Siremadlin 
CHDM201K12201 
A phase Ib/II, open label study of siremadlin monotherapy 
and in combination with donor lymphocyte infusion as a 
treatment for patients with acute myeloid leukemia post-
allogeneic stem cell transplantation who are in complete 
remission but at high risk for relapse 
Statistical Analysis Plan (SAP) 
Document type: 
SAP Documentation 
Document status: 
Final Version 2.0 – Amendment 1 
Release date: 
29-Nov-2023 
Number of pages: 
36 
Property of Novartis 
 Confidential 
May not be used, divulged, published or otherwise disclosed 
without the consent of Novartis 
 
Template Version 4.0, Effective from 23-Apr-2021 


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Document History – Changes compared to previous final version of SAP 
 
Date 
Time 
point 
Reason for update 
Outcome for 
update 
Section and title impacted 
(Current) 
29-Nov-
2023 
Prior to 
final 
CSR 
DBL 
Creation of Version 2.0 to 
adjust the final CSR due to 
the permanent hold of 
recruitment after completion 
of the first cohort in safety 
run-in Part 1   
Amendment 1 
1. Section 1: added rationale for 
this amendment and clarified 
the scope of planned analysis 
for the final CSR 
2. Section 2: revised the analyses 
to report only primary and 
secondary objectives for Part 
1 (excluding time to event 
endpoints which require a 
recommended dose) 
3. Section 4: added changes to 
protocol specified analyses 
4. Section 5: updated date of last 
exposure derivation to 
harmonize with program 
standards 
 
 
 


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Table of contents 
 
Table of contents ................................................................................................................. 3 
List of tables ........................................................................................................................ 4 
List of abbreviations ............................................................................................................ 5 
1 
Introduction ......................................................................................................................... 7 
1.1 
Study design ............................................................................................................ 7 
1.2 
Study objectives, endpoints and estimands ........................................................... 10 
1.2.1 
Primary estimand(s) .............................................................................. 12 
1.2.2 
Secondary estimand .............................................................................. 15 
2 
Statistical methods ............................................................................................................. 15 
2.1 
Data analysis general information ......................................................................... 15 
2.1.1 
General definitions ................................................................................ 15 
2.2 
Analysis sets .......................................................................................................... 17 
2.2.1 
Subgroup of interest .............................................................................. 19 
2.3 
Patient disposition, demographics and other baseline characteristics ................... 19 
2.3.1 
Patient disposition ................................................................................. 19 
2.3.2 
Demographics and other baseline characteristics ................................. 19 
2.4 
Treatments (study treatment, rescue medication, concomitant therapies, 
compliance)............................................................................................................ 20 
2.4.1 
Study treatment and DLI / compliance ................................................. 20 
2.4.2 
Prior, concomitant and post therapies ................................................... 21 
2.5 
Analysis supporting primary objective(s) .............................................................. 21 
2.5.1 
Primary endpoint(s) ............................................................................... 21 
2.5.2 
Statistical hypothesis, model, and method of analysis .......................... 22 
2.5.3 
Handling of intercurrent events ............................................................. 24 
2.5.4 
Handling of missing values not related to intercurrent event ............... 24 
2.5.5 
Sensitivity analyses ............................................................................... 24 
2.5.6 
Supplementary analyses ........................................................................ 24 
2.6 
Analysis supporting secondary objectives ............................................................. 24 
2.6.1 
Secondary endpoint(s) ........................................................................... 24 
2.6.2 
Sensitivity analyses ............................................................................... 26 
2.6.3 
Supplementary analyses ........................................................................ 26 
2.7 
Safety analyses [Part 1] ......................................................................................... 26 
2.7.1 
Adverse events (AEs) ............................................................................ 26 
2.7.2 
Deaths .................................................................................................... 28 
2.7.3 
Laboratory data ..................................................................................... 28 


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2.7.4 
Other safety data ................................................................................... 28 
2.8 
Pharmacokinetic endpoints .................................................................................... 29 
2.9 
PD and PK/PD analyses ........................................................................................ 30 
2.10 
Patient-reported outcomes ..................................................................................... 30 
2.11 
Biomarkers ............................................................................................................. 31 
2.12 
Other Exploratory analyses.................................................................................... 31 
2.13 
Interim analysis ...................................................................................................... 31 
3 
Sample size calculation ..................................................................................................... 32 
4 
Change to protocol specified analyses .............................................................................. 33 
5 
Appendix ........................................................................................................................... 34 
5.1 
General definitions ................................................................................................ 34 
5.2 
Laboratory parameters derivations ........................................................................ 35 
6 
Reference ........................................................................................................................... 35 
 
List of tables 
Table 1-1 
Objectives and related endpoints .......................................................... 10 
Table 2-1 
Last contact date data sources ............................................................... 17 
Table 2-2 
Response classification in AML at a given evaluation time (based 
on IWG Cheson et al 2003, ELN 2017 Döhner et al 2017) .................. 22 
Table 2-3 
Notable ECG values .............................................................................. 29 
Table 2-4 
Notable vital sign values ....................................................................... 29 
Table 2-5 
Non-compartmental pharmacokinetic parameters* .............................. 30 
Table 3-1 
Data scenarios, inferential results and decisions (n=26) ....................... 33 
Table 3-2 
Operating characteristics for true CR/CRi rate (n=26) ......................... 33 
 


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List of abbreviations 
AE 
Adverse event 
AESI 
Adverse events of special interest 
aGvHD 
Acute Graft versus Host Disease 
Allo-SCT 
Allogeneic Stem Cell Transplantation 
ALP 
Alkaline Phosphatase 
ALT 
Alanine aminotransferase 
AML 
Acute myeloid leukemia 
AST 
Aspartate aminotransferase 
ATC 
Anatomical therapeutic classification 
AUC 
Area under the curve 
BLRM 
Bayesian Logistic Regression Model 
BMI 
Body mass index 
BP 
Blood pressure 
BSA 
Body surface area 
CI 
Confidence interval 
cGvHD 
Chronic Graft versus Host Disease  
CR 
Complete remission 
CRi 
Complete remission with incomplete hematologic recovery 
CRF 
Case report form 
CSR 
Clinical study report 
CTC 
Common toxicity criteria 
CTCAE 
Common terminology criteria for adverse events 
CYP 
Cytochrome P450 
CV 
Coefficient of variation 
DDS 
Dose-determining set 
DLI 
Donor lymphocyte infusion 
DLT 
Dose limiting toxicity 
DMS 
Document management system 
eCRF 
Electronic case report form 
eCRS 
Electronic case retrieval strategy 
ECG 
Electrocardiogram 
ECOG 
Eastern cooperative oncology group  
ELN 
European Leukemia Net 
EOT 
End of treatment  
EWOC 
Escalation with overdose control 
FAS 
Full analysis set 
G-CSF 
Granulocyte colony stimulating factor  
 
 
HR 
High risk 
IA 
Interim analyses 
IRT 
Interactive response technology 
MedDRA 
Medical Dictionary for Drug Regulatory Affairs 
 
 
OS 
Overall survival 
PAS 
Pharmacokinetic analysis set 


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PD 
Progressive disease 
PK 
Pharmacokinetic(s) 
PR 
Partial response/remission 
PT 
Preferred term 
QD 
Latin abbreviation for every day 
RAP 
Report and analysis process 
RBC 
Red blood cells 
RD 
Recommended dose  
RFS 
Relapse free survival  
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SAS 
Statistical Analysis System 
SMQ 
Standardized MedDRA queries 
SOC 
System organ class 
SoC 
Standard of Care  
TP53 
Tumor protein P53 
TFLs 
Tables, figures, listings 
TLS 
Tumor lysis syndrome 
WHO 
World Health Organization 


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1 
Introduction 
This statistical analysis plan (SAP) describes the planned analyses for the Clinical Study Report 
(CSR) of the study CHDM201K12201, a phase Ib/II, open label, proof of concept study of 
siremadlin in combination with donor lymphocyte infusion (DLI) as a treatment for patients 
with 
acute 
myeloid 
leukemia 
(AML) 
post-allogeneic 
stem 
cell 
transplantation  
(allo-SCT) who are in complete remission but at high risk for relapse. 
The content of this SAP is based on the CHDM201K12201 Protocol Amendment 2  
(release date: 18-Nov-2022). All decisions regarding the analysis, as defined in the SAP 
document, were made prior to database lock. 
As specified in Section 12.7 of the study protocol, no formal interim analyses are planned. The 
monitoring of safety data was planned to be conducted after each dose level cohort of the 
siremadlin monotherapy in Part 1 as well as after each cohort of 3 participants who completed 
at least one siremadlin/DLI treatment cycle in combination phase in Part 2. This SAP served as 
the basis for those analyses as well. A separate selection of tables, figures, and listings (TFLs) 
will be provided. The first safety review meeting was held on 18-Sep-2023 for Cohort 1 at 
siremadlin monotherapy 30 mg QD Days 1-5 of a 28-day cycle, where no new safety concern 
was identified.  
However, Novartis decided to permanently halt the recruitment of new participants into study 
CHDM201K12201 in September 2023 (recruitment halt letter dated 21-Sep-2023 was sent to 
investigators on 25-Sep-2023). As a result, Part 1 was discontinued after the Cohort 1 safety 
review meeting, and Part 2 of the study will not be opened. This decision was not based on any 
safety findings or safety concerns with siremadlin but rather on a Novartis strategic 
consideration. The decision about the permanent recruitment halt was documented in the Early 
Termination Plan for the study. The study data will be analyzed and reported based on all 
available data up to the data cut-off date of the final DBL in a synoptic final CSR. 
1.1 
Study design 
This is a Phase Ib/II, single arm, open label, multi-center study of siremadlin as monotherapy 
and in combination with DLI, in adult participants with AML who are in complete remission 
(CR) or CR with incomplete count recovery (CRi) post allo-SCT but are at high risk for relapse 
based on the presence of pre-transplant risk factors (as specified in Protocol Section 5.1). 
The study will enroll approximately 38 participants and will start with the dose confirmation of 
siremadlin monotherapy (Part 1) followed by a treatment strategy with siremadlin/DLI (Part 2) : 
 Part 1- Dose confirmation siremadlin monotherapy: using siremadlin as a single agent, 
to explore a maximal of 3 dose levels (starting dose 30 mg/day on days 1-5 of a 28-day 
treatment cycle, dose level +1 at 40 mg/day and dose level -1 at 20 mg/day). It is assumed 
that approximately 12 participants will be enrolled in 2 cohorts to obtain at least 3 evaluable 
participants in each cohort. Based on the observed dose limiting toxicity (DLT) rate, overall 
safety, tolerability, available pharmacokinetic (PK) (and preliminary efficacy) data 
generated, the participating investigators and Novartis Team will make decisions regarding 
the siremadlin dose to be given to participants in the next cohort(s), as guided by a Bayesian 


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Logistic Regression model (BLRM). A minimum of 6 evaluable participants are required 
to confirm the siremadlin monotherapy dose level that will be declared as the recommended 
dose for Part 2.  
For each dose level in Part 1, once the required number of evaluable participants has been 
confirmed, enrollment will be held until participants have completed the DLT observation 
period of one treatment cycle. Nevertheless, each participant will continue treatment at 
his/her tolerated siremadlin dose. 
DLI in combination with siremadlin will not be permitted on study for participants in dose 
confirmation Part 1. Each participant treated in these dose confirmation cohorts (Part 1) will 
continue with siremadlin monotherapy for the entire duration of treatment (up to a 
maximum of 24 cycles).  
Once the recommended siremadlin dose is determined in Part 1, enrollment in Part 2 will start 
after obtaining Health Authority’s approval as applicable. Enrollment in Part 2 will not be 
applicable to the participating sites in the United States and Germany. 
 Part 2 - Treatment strategy (siremadlin/DLI): will enroll approximately 26 participants and 
will not start until the recommended dose for Part 2 is confirmed. Participants enrolled in 
Part 2 will follow a treatment strategy, which contains siremadlin monotherapy (priming 
phase), potentially followed by siremadlin in combination with DLI then maintenance with 
siremadlin monotherapy (as shown in Figure 1.1): 
 A priming phase with siremadlin monotherapy. Participants will be administered 
siremadlin orally on Days 1-5 of a 28-day cycle (for at least 2 cycles). Participants who 
are not eligible for the combination phase of siremadlin/DLI may continue priming 
phase with siremadlin monotherapy for up to a maximum of 24 cycles. 
 A combination phase of siremadlin in combination with DLI (siremadlin/DLI) for 
participants who are eligible to receive DLI (up to a total of 3 combination cycles). 
Criteria to start DLI/siremadlin combination phase are detailed in Protocol Section 6.1.4. 
Participants will be administered siremadlin orally on Days 1-5, at the dose that was 
received and tolerated in the last cycle of priming phase, in combination with DLI on 
Day 3 of every 42-day (6-week) cycle (see Protocol Section 6.3.2 for details of DLI 
starting dose and ramp-up dosing instructions). 
 A maintenance phase with siremadlin monotherapy. After completion of 
siremadlin/DLI combination phase, participants may enter maintenance phase with 
siremadlin monotherapy orally on Days 1-5 of a 28-day cycle starting at the dose that 
was tolerated in the last cycle in combination phase (refer to Protocol Section 6.1.4 for 
eligibility for maintenance phase). 
Intraparticipant dose escalation is not allowed in the trial: each participant will keep his/her 
allocated siremadlin dose throughout the treatment phases, provided it is well tolerated by the 
participant (dose modifications are allowed in case of toxicity, see Protocol Section 6.6.4).  
Study treatment will be administered for up to a maximum of 24 cycles in Part 2 (including 
priming phase, with or without combination phase, and maintenance phase) or until a participant 
experiences hematologic relapse, unacceptable toxicity, or withdrawal of consent, whichever is 
earlier. 


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Figure 1-1 
Study design 
 
* Criteria to proceed with siremadlin dose increase or decrease or Go/No Go for the next Cohort (s): based on 
incidence of DLTs during the first cycle of study treatment in Cohort 1.  
** Go criteria to start treatment in Part 2 at the recommended dose (RD) for Part 2 determined based on incidence 
of DLTs during the first cycle of study treatment in Cohort 2, after obtaining Health Authority’s approval as applicable. 
Enrollment in Part 2 will not be applicable to the participating sites in the United States and Germany. 
*** The decision of DLI administration will be at the discretion of the treating investigator per standard of 
practice/institutional guidelines; however, participant must fulfill the combination phase eligibility criteria after 
completion of at least 2 cycles of priming. 
Safety, tolerability, available PK (if applicable) outcomes of siremadlin in combination with 
DLI will be analyzed in all participants (refer to Protocol Section 6.6.2 for evaluability criteria) 
when they complete at least the first cycle in combination phase. A Time-to-(first) DLT 
approach will be used to continuously assess the safety of the combination in individual 
participants and decide the maximum dose of siremadlin for combination phase. Afterwards, 
participants entering the combination phase must be treated at a siremadlin dose not 
exceeding the maximum dose for combination. The maximum recommended dose for 
siremadlin/DLI combination will be declared after all evaluable participants have completed 
combination phase and requires a minimum of 9 evaluable participants. Enrollment will not be 
held for safety assessment of the combination phase. 
Safety and tolerability data from all participants in combination phase will continue to be 
monitored on an ongoing basis following the same approach. (Refer to Protocol Section 6.6.2 
for details) 
 


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1.2 
Study objectives, endpoints and estimands  
Table 1-1 (which is a copy of the Table 2-1 from the study protocol) outlines the primary, 
secondary 
 objectives and belonging endpoints. Due to the permanent 
recruitment halt for Part 1 and Part 2, only the first cohort of participants treated at siremadlin 
30 mg monotherapy in Part 1 was completed, and the recommended siremadlin dose was not 
determined in Part 1.  Consequently, only primary and secondary objectives for Part 1 will be 
analyzed for the synoptic CSR, excluding time to event endpoints which require the 
recommended siremadlin dose (as further detailed in Section 2). All primary and secondary 
objectives for Part 2 will not be analyzed 
 
  
Table 1-1 
Objectives and related endpoints 
Objective(s) 
Endpoint(s) 
Primary objective(s) 
Endpoint(s) for primary objective(s) 
● Safety:  
 
● To determine the dose and schedule of 
siremadlin monotherapy that are tolerable without 
unacceptable toxicities (recommended dose for 
Part 2) [Part 1 - siremadlin monotherapy]. 
 
● To determine the dose and schedule of 
siremadlin in combination with DLI that are 
tolerable without unacceptable toxicities 
(recommended dose for combination) [Part 2 - 
siremadlin/DLI treatment strategy].   
 
● Incidence of DLTs with siremadlin monotherapy in dose 
confirmation [Part 1] 
 
 
● Time to DLT with siremadlin/DLI in combination phase 
[Part 2] 
● Efficacy: 
 
● To evaluate the preliminary efficacy of study 
treatment strategy (siremadlin monotherapy, as 
priming and/or maintenance, with or without 
siremadlin in combination with DLI)) on prevention 
of hematologic relapse [Part 2 – siremadlin/DLI 
treatment strategy]. 
 
● Proportion of participants who are alive and maintained 
CR or CRi with no evidence of hematologic relapse over 
at least 6 months after start of study treatment strategy 
(siremadlin monotherapy, as priming and/or maintenance, 
with or without siremadlin in combination with DLI) [Part 
2].  
 
Secondary objective(s) 
 
To evaluate the preliminary efficacy of 
siremadlin monotherapy on prevention of 
hematologic relapse [Part 1 - siremadlin 
monotherapy at the recommended dose for 
Part 2]. 
 
 
Endpoint(s) for secondary objective(s) 
 
Participants who are alive and maintained CR or CRi 
with no evidence of hematologic relapse over at least 
6 months after start of siremadlin monotherapy [Part 
1 - siremadlin monotherapy at the recommended 
dose for Part 2]. 
 
● To assess relapse free survival (RFS) [Part 2]. 
● Time from start of study treatment to the date of first 
documented hematologic relapse or death due to any 
cause, whichever occurs first 
● To assess cumulative incidence of relapse at 1 
year and at 2 years after start of study treatment 
[Part 1, Part 2]. 
● Cumulative incidence of AML relapse at 1 year and at 2 
years after start of study treatment  
● To assess overall survival (OS) [Part 2]. 
● Time from start of study treatment to the date of death 
from any cause.  
.  
 


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Objective(s) 
Endpoint(s) 
● To assess safety and tolerability of siremadlin 
monotherapy (during dose confirmation; priming 
and maintenance) and in combination with DLI 
[Part 1, Part 2]. 
● Incidence and severity of AEs and SAEs, changes in 
laboratory values and vital signs. 
● To assess the proportion of participants 
stopping study treatment due to GvHD or other 
adverse events [Part 1, Part 2]. 
● Proportion of participants with permanent 
discontinuation of study treatment due to GvHD or other 
adverse events. 
● To assess the incidence of grade III and IV 
aGvHD, moderate and severe cGvHD [Part 1, 
Part 2]. 
● Incidence of treatment emergent grade III or grade IV 
aGvHD. 
Incidence of treatment emergent moderate to severe 
cGvHD. 
● To assess GvHD-free/relapse-free survival 
(GRFS) [Part 1, Part 2]. 
● Time from start of study treatment to the date of first 
documented occurrence or worsening of treatment 
emergent grade III or IV aGvHD, cGvHD requiring 
initiation of systemic immunosuppressive treatment, 
occurrence of disease relapse, or death due to any cause, 
whichever occurs first. 
● To characterize the PK of siremadlin in 
monotherapy and in combination with DLI [Part 1, 
Part 2]. 
● Pharmacokinetic parameters (e.g., AUC, Cmax, Tmax) 
and concentration vs time profiles of siremadlin in 
monotherapy and in combination with DLI. 


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1.2.1 
Primary estimand(s) 
The estimand is the precise description of the treatment effect and reflects strategies to address 
events occurring during trial conduct, which could impact the interpretation of the trial results 
(e.g., premature discontinuation of treatment). 
Primary safety estimands: 
Dose confirmation siremadlin monotherapy (Part 1): 
The primary clinical question of interest is: Can siremadlin be safely administered as 
monotherapy on Days 1-5 of a 28-day cycle (at the starting dose level of 30 mg QD) to adult 
participants with AML who are in CR or CRi starting no earlier than ≥ Day 60 after allo-SCT? 
The justification for the primary safety estimand is that we wish to determine whether 
siremadlin leads to unacceptable level of toxicity (DLT) when administered as monotherapy in 
Part 1 and determine the siremadlin recommended dose (RD) for Part 2 as monotherapy. 
The primary estimand of safety for dose confirmation (Part 1) is described by the following 
attributes: 
1. Population: Adult participants with AML who are in CR/CRi after allo-SCT and meet 
eligibility as defined by the inclusion/exclusion criteria. 
2. Primary variable: DLT between the first dose of siremadlin until end of Cycle 1. Any DLT 
from participants who initiated siremadlin during Cycle 1 will be considered. 
3. Treatment of interest: Siremadlin monotherapy. 
4. Handling of remaining intercurrent events: 
 Dose modifications, dose interruptions or discontinuations due to reasons other than 
DLT leading to less than minimum exposure: such participants will be considered non-
evaluable. (Refer to Protocol Section 6.6 and Section 12.1) 


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 Withdrawal from study before completion of cycle 1 with no DLT prior to completing 
sufficient scheduled safety assessments: such participants will be considered non-
evaluable. 
5. The summary measure: incidence of DLTs. 
Combination phase (in Part 2): 
The primary clinical question of interest is: Following the priming phase with at least 2 cycles 
of siremadlin monotherapy at the RD for Part 2, can siremadlin be safely administered to adult 
participants with AML at the tolerated dose from the last priming cycle in combination with 
DLI? 
The justification for the primary safety estimand of combination phase is that we wish to 
determine whether siremadlin in combination with DLI leads to an unacceptable level of 
toxicity (DLT) when administered after priming phase and determine the siremadlin maximum 
recommended dose (RD) for combination considering the time to first DLT, dose and schedule. 
The primary estimand of safety for combination phase is described by the following attributes: 
1. Population: Adult participants with AML who completed at least 2 cycles of siremadlin 
priming phase and meet combination phase eligibility to receive DLI as defined in Protocol 
Section 6.1.4. 
2. Primary variable: Time-to-DLT, defined as time from start of combination phase to first 
DLT observed during the entire combination phase. 
3. Treatment of interest: Siremadlin, at the dose tolerated in the last cycle of priming phase, 
when administered in combination with DLI. 
4. Handling of remaining intercurrent events: 
 Dose modifications, dose interruptions or discontinuations due to reasons other than 
DLT leading to less than minimum exposure: 
 Participants who do not satisfy at least one cycle of minimum exposure and do not 
experience a DLT will be considered non-evaluable. 
 Participants who satisfy at least one cycle of minimum exposure will be censored 
at the last safety assessment at the end of the last cycle where minimum exposure 
to study treatment was satisfied. E.g., for a participant who received 2 cycles of 
combination therapy without any DLT and only met the minimum exposure for the 
first cycle, this participant will be censored at the end of the first cycle. 
 Death (not caused by study treatment) or withdrawal from study without experiencing 
DLT: participants will be censored at the last safety assessment at the end of the last 
cycle preceding death or withdrawal from study (while-on-treatment). 
 End of combination phase without experiencing DLT: participants will be censored at 
the last safety assessment in the combination phase. 
5. The summary measure: probability of DLT 
Based on safety/tolerability outcomes of siremadlin/DLI combination, the study may identify a 
siremadlin maximum RD for combination. 


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Primary efficacy estimand: 
The primary clinical question of interest is: Does siremadlin given in a treatment strategy 
consisting of priming, combination and maintenance therapy have activity in preventing 
hematologic relapse or death (i.e., maintenance of CR/CRi) in adult participants with AML who 
are in CR/CRi after allo-SCT irrespective of treatment discontinuation? 
The justification for the primary efficacy estimand is that we wish to estimate the effect of the 
study treatment and to assess it in the context of published data (included in the dual-criterion 
for efficacy assessment; more details in Protocol Section 12.8.1) of the same patient population 
treated with Best Available Therapy (BAT) in preventing early relapse of AML post-allo-SCT. 
The activity of siremadlin is assessed based on the absence of hematologic relapse (maintenance 
of CR/CRi), which is the most clinically meaningful endpoint in this post-transplant setting 
(CRi is also acceptable as complete hematologic recovery may be delayed early post-transplant 
(Dominietto et al 2001)). Patients requiring new antineoplastic therapy (including a second 
allo-SCT) before completing 6 months after start of study treatment are considered as failure to 
study treatment. Similarly, withdrawing consent before completing 6 months after start of study 
treatment could also be attributed to effects of the study treatment and are considered as failure. 
Discontinuation of study treatment due to other criteria or dose modification might not preclude 
maintenance of CR/CRi. Medical care of this life-threatening condition is provided also in the 
context of a pandemic. The primary estimand will therefore assess the treatment effect 
regardless of any impact by a pandemic. 
The primary estimand of efficacy is described by the following attributes: 
1. Population: Adult participants with AML who are in CR/CRi after allo-SCT participating in 
Part 2 and meet priming phase eligibility as described in the inclusion/exclusion criteria who 
initiated priming phase at siremadlin RD for Part 2. 
2. Primary variable: CR/CRi per investigator assessment after completing 6 months from start 
of study treatment. Participants who die, relapse, start new antineoplastic therapy or withdrawal 
of consent prior to completing 6 months after start of study treatment will be considered as non-
responders. (Döhner et al 2017, Cheson et al 2003). 
3. Treatment of interest: Siremadlin starting as priming monotherapy for at least 2 cycles, 
followed by combination of siremadlin with DLI for eligible participants, and then siremadlin 
monotherapy for maintenance. 
4. Handling of remaining intercurrent events: 
 Dose modification or treatment discontinuation due to any reason: All assessments will be 
taken into account regardless of any treatment  interruption, dose adjustment or permanent 
discontinuation (treatment policy strategy). 
 Any Public Health emergency as declared by Local or Regional authorities i.e., pandemic, 
epidemic or natural disaster: All assessments will be taken into account regardless of any 
disruptions resulting from public health emergencies (refer to Protocol Section 4.6) 
(treatment policy strategy) 
5. The summary measure: Proportion of participants who maintained CR or CRi after at least 6 
months from start of study treatment and its 95% confidence interval. 


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1.2.2 
Secondary estimand 
Not applicable 
2 
Statistical methods 
2.1 
Data analysis general information 
The primary analysis, as well as the analyses that will be used for the safety review meetings of 
the Part 1 and combination phase of the Part 2 of the study will be performed by Novartis. 
SAS 9.4 (or higher version) or R 3.6.1 (or higher version) will be used to perform all data 
analyses and to generate tables, figures, and listings. 
The study data will be analyzed and reported based on all available data up to the cut-off date 
of the final DBL in a synoptic final CSR. 
General analysis conventions 
Qualitative data (e.g., gender, race) will be summarized by means of contingency tables; a 
missing category will be included as applicable. Percentages will be calculated using the 
number of participants in the relevant population or subgroup as the denominator. 
Quantitative data (e.g., age, body weight) will be summarized by appropriate descriptive 
statistics (e.g., mean, standard deviation, median, 25th and 75th percentiles, minimum, and 
maximum). 
Data included in the analysis / data cut-off handling  
For each of the safety review meetings in Part 1, a data cut-off date will be determined after the 
targeted number of participants has completed 1 cycle of treatment.  All safety data (including 
duration of exposure to study treatment, dose modifications, study treatment discontinuation, 
etc.), demographics, disease history (including cytogenetics, risk category, acute/chronic GvHD, 
etc.), concomitant medications,  hematology data, extramedullary disease assessment, blast 
counts from bone marrow and PK data (if available) with an assessment date or event start date 
(e.g., laboratory assessment date or start date of an adverse event) prior to or on the cut-off 
date will be included in the analysis. The list of analyses to be presented at the time of the 
safety review meetings is provided in Section 2.13. 
For the synoptic CSR, all data collected up to the cut-off date of the final DBL will be included 
in the analysis. 
2.1.1 
General definitions  
Both “Investigational drug” and “Study treatment” refer to siremadlin. 
Donor Lymphocyte Infusion (DLI)  
DLI given in combination phase of Part 2 is not a part of the study treatment and should be 
administered according to standard local clinical practice or institutional guidelines. However, 
all dosages prescribed, administered to the participant and all dose changes during the study 


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including the reason for any treatment must be recorded on the appropriate electronic case report 
form (eCRF) page. 
Date of first administration of study treatment   
The date of the first administration of study treatment is defined as the first date when a non-
zero dose of the respective study treatment is administered and recorded on the study treatment 
eCRF page.  
Date of last administration of study treatment  
The date of the last administration of the study treatment is defined as the last date when a non-
zero dose of the respective study treatment is administered and recorded on the study treatment 
eCRF page.  
Study day 
The study day describes the day of the event or assessment date, relative to the reference start 
date (start date of study treatment).  
The study day is calculated as follows: 
 The date of the event (visit date, onset date of an event, assessment date etc.) − reference 
start date + 1 if event is on or after the reference start date; 
 The date of the event (visit date, onset date of an event, assessment date etc.) − reference 
start date if event precedes the reference start date. 
The reference start date for safety assessments (e.g., adverse event onset, laboratory or ECG 
assessment, vital sign measurement) is the start of study treatment. The same reference start 
date will be used for efficacy (e.g., response assessment, time-to-event endpoints). 
The study day will be displayed in the data listings. If an event starts before the reference start 
date, the study day displayed on the listing will be negative. 
Baseline 
For efficacy evaluations, the last non-missing assessment post-allo-SCT, including unscheduled 
assessments on or within 28 days before the date of start of study treatment is taken as “baseline” 
value or “baseline” assessment.   
For safety evaluations, the last available assessment including unscheduled assessments on or 
before the date of start of study treatment is taken as “baseline” assessment.  
If participants have no value as defined above, the baseline result will be missing.  
Last contact date  
The last contact date will be used for censoring of participants in the analysis of relapse free 
survival and overall survival. 


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The last contact date is defined as the latest complete date from the below list on or before the 
data cut-off date (Table 2-1). The cut-off date will not be used for last contact date unless the 
participant was seen or contacted on that date. No date post cut-off date will be used. 
Completely imputed dates (e.g., the analysis cut-off date programmatically imputed to replace 
the missing end date of a dose record) will not be used to derive the last contact date. Partial 
date imputation is allowed for event (death)/censoring only if coming from the ‘Survival’ eCRF. 
The last contact date will be derived for participants not known to have died at the analysis cut-
off using the last complete date among the following: 
Table 2-1 
Last contact date data sources  
Source data 
Conditions 
Last date participant was known to be alive from 
Survival Follow-up page  
Participant status is reported to be alive or unknown 
Start/End dates from antineoplastic therapy 
Non-missing medication/procedure term 
Start/End dates from drug administration record  
Non-missing dose  
Response assessment date 
Response marked as ‘done’ 
Laboratory/PK collection dates 
Sample collection marked as ‘done’ 
Vital signs date 
At least one non-missing parameter value 
ECOG performance status date 
Non-missing performance status 
Start/End dates of AE  
Non-missing verbatim term 
Other general definitions are detailed in Appendix Section 5.1. 
2.2 
Analysis sets  
The Full Analysis Set (FAS) comprises all participants who received any study drug (i.e., at 
least one dose of siremadlin with or without DLI). 
The Safety Set includes all participants from the FAS. 
The Dose-Determining Set (DDS) includes all participants during the dose determination phase 
of the study (DLT assessment) who met the minimum required number of treatment cycles, met 
the minimum exposure criteria (MEC), met the minimum follow up/ DLT observation after 
treatment and have sufficient safety evaluations, or have experienced a DLT during the 
observation period.  
MEC for Part 1 (MEC1) is defined as a participant who has received, during the first cycle, at 
least 75% of the total planned doses of siremadlin (e.g., ≥ 4 out of  5 daily doses of siremadlin).  
MEC for Part 2 (MEC2) is defined as a participant who has received at least one dose of DLI 
and at least 75% of the total planned doses of siremadlin for a given combination cycle.  
There are two DDSs: DDS1 for Part 1 and DDS2 for Part 2: 
 DDS1 (siremadlin monotherapy in Part 1): consists of participants from each siremadlin 
dose level cohort who met the MEC1, met the minimum DLT observation period and had 
sufficient safety evaluations, or had a DLT during Cycle 1. Participants receiving a reduced 
dose of siremadlin due to co-administration of strong or moderate CYP3A4 inhibitors as 


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described in Protocol Section 6.2.1.1, will be considered to have received the full planned 
dose.  
DLT observation period for DDS1 starts from the first dose administration of siremadlin 
(Cycle 1 Day 1) until the end of Cycle 1 (planned on Cycle 1 Day 28):  
 For participants who started Cycle 2, the end of the DLT observation period will be the 
day before the initiation of Cycle 2 Day 1 (whatever the status of the patient: on-
treatment or on drug interruption period).  
 For participants who did not start Cycle 2, the end of the DLT observation period will 
be Cycle 1 Day 28 or the last on-treatment day within Cycle 1 (up to 42 days after Cycle 
1 Day 1), whichever comes later. 
Participants who do not experience a DLT during Cycle 1 are considered to have 
sufficient safety evaluations if they have met the DLT observation period in Cycle 1 (as 
defined above), and are considered by both the sponsor and investigators to have enough 
safety data to conclude that a DLT did not occur. 
 DDS2 (combination phase in Part 2): consists of participants who met the MEC2 for at 
least Cycle 1 of combination, met the minimum DLT observation period after treatment 
and had sufficient safety evaluations, or had a DLT during combination 
phase.  Participants receiving a reduced dose of siremadlin due to co-administration of 
strong or moderate CYP3A4 inhibitors as described in Protocol Section 6.2.1.1, will be 
considered to have received the full planned dose.  
DLT observation period for DDS2 starts from the first study treatment or first DLI 
administration during the first combination cycle  until the end of combination Phase (Day 
42 of the last combination cycle) [i.e., over the entire siremadlin/DLI combination phase]. 
Participants who do not experience a DLT during cycle(s) of DLI administration 
(combination phase) are considered to have sufficient safety evaluations if they have met 
the DLT observation period (as defined above), and are considered by both the sponsor 
and investigators to have enough safety data to conclude that a DLT did not occur. For a 
participant who experiences a DLT prior to the first DLI in the first cycle of their 
combination phase, this DLT will be assigned to siremadlin monotherapy. However, for 
subsequent combination cycles, if a DLT occurs before the DLI has been received, the 
DLT attribution to the earlier combination cycle will be evaluated. Participants will be 
analyzed according to the study treatment received as defined for FAS.  
The Pharmacokinetic analysis set for all (PAS-all) includes all participants in the safety set who 
provide at least one evaluable PK concentration of siremadlin. 
For a concentration to be evaluable: 
 Dosing information must be properly documented (data and time of administration) 
 Participant takes the dose of study treatments as described in Protocol Section 6.3.2 
 Participant did not vomit within 4 hours after the oral dosing of siremadlin 
 For pre-dose samples: the sample is collected before the next dose administration 
 For post-dose samples: the planned dose of siremadlin must be taken prior to sampling. 


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2.2.1 
Subgroup of interest 
No specific subgroups of interest will be considered for the synoptic CSR. 
2.3 
Patient disposition, demographics and other baseline 
characteristics 
The FAS will be used for the analyses below. Participant disposition, demographics and other 
baseline characteristics will be summarized by dose level of siremadlin for participants in Part 
1. 
2.3.1 
Patient disposition 
Number (%) of participants screened and enrolled will be summarized by country and center. 
For participants who did not complete screening, the reasons for not completing screening will 
be summarized based on “Screening Phase” page in “Disposition” eCRF. 
The number (%) of participants in the FAS who started treatment, are still on treatment, who 
entered and discontinued post-treatment follow-up and the study after survival follow-up will 
be summarized together with the respective reasons for discontinuation from treatment/post-
treatment follow-up/end of study (which corresponds to end of survival follow-up). The number 
(%) of participants by dose level of siremadlin in Part 1will be also summarized.  
The number (%) of participants in the FAS with any protocol deviation will be tabulated by 
deviation category. All protocol deviations will be listed. 
2.3.2 
Demographics and other baseline characteristics 
Demographic (age, sex, country, ethnicity, race and Eastern Cooperative Oncology 
Group (ECOG)) performance status and other baseline data including disease characteristics 
will be listed and summarized descriptively for all participants from the FAS. The summary by 
dose level of siremadlin in Part 1will be provided. 
BMI (kg/m2) at baseline will be calculated as weight[kg] / (height[m]²) using weight at baseline 
and height at screening. Body Surface Area (BSA) is based on the Mosteller formula described 
below: 
BSA (m2) = ඥWeight ሺkgሻ∗Height at screening ሺcmሻ/3600 
Details on AML diagnosis / disease history [date of initial diagnosis, WHO classification, ELN 
classification (Döhner et al 2017), cytogenetic abnormalities, and molecular genetic 
abnormalities] will be listed and summarized.  
Allogeneic transplant characteristics (disease remission status at time of transplant, 
transplantation timing, donor type, donor-host HLA match) will be tabulated and time since 
transplant will be listed. 
Relevant medical histories and current medical conditions at baseline will be summarized by 
system organ class and preferred term. Medical history and current medical conditions will be 
coded using the Medical Dictionary for Regulatory Activities (MedDRA) terminology. The 


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MedDRA version used for reporting will be specified in the CSR and as a footnote in the 
applicable outputs.  
2.4 
Treatments (study treatment, rescue medication, concomitant 
therapies, compliance) 
2.4.1 
Study treatment and DLI / compliance 
The Safety set will be used for the analyses below and summary tables will be presented by 
dose level of siremadlin in part 1. “Cycle(s)” in this document refers to the cycle(s) with at least 
one non-zero dose of any study treatment. Each treatment cycle in dose confirmation siremadlin 
monotherapy (Part 1), priming and maintenance phase (Part 2) is 28 days. Each treatment cycle 
in combination phase (Part 2) is 42 days 
Duration of exposure 
The duration of exposure (in months) will be summarized for study treatment based on summary 
statistics and categorical analyses. Details on start and end dates used for derivations are 
outlined in Section 5.1. 
Cumulative dose 
For siremadlin, the actual cumulative dose in mg is the sum of “dose administered -Siremadlin” 
from the eCRF of all cycles during the exposure to siremadlin. 
Dose intensity and relative dose intensity 
Dose intensity is defined for participants with non-zero duration of exposure. For participants 
who did not take the drug, the dose intensity is by definition equal to zero. The actual dose 
intensity is computed as the ratio of actual cumulative dose received and duration in days from 
first to last cycle.  
The planned dose intensity for siremadlin is computed as the ratio of planned cumulative dose 
in a cycle over the duration in days from first to last cycle [42 days for each combination cycle 
in Part 2, and 28 days for each siremadlin monotherapy cycle in Part 1 or Part 2].  
The relative dose intensity is then computed as the ratio of actual dose intensity and planned 
dose intensity.  
As an example, if a participant received siremadlin at 25 mg QD D1-D5 on average throughout 
the study (instead of the 30 mg QD D1-D5 as planned per protocol, which corresponds to a 
planned dose intensity of 150 mg/28 days), the relative dose intensity for this participant is 0.83. 
Participants receiving a reduced dose of siremadlin due to co-administration of strong or 
moderate CYP3A inhibitors as described in Protocol Section 6.2.1.1, will be considered to have 
received the full planned siremadlin dose. 
Details on the duration in days from the first to last cycle for the derivation of the dose 
intensity and the relative dose intensity are provided in Appendix Section 5.1. 


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Dose reduction, dose interruption and permanent discontinuations 
The number (%) of participants with any dose changes (incl. reductions, interruptions, or 
permanent discontinuations) and the reasons (e.g., AE, dosing error, dispensing error) will be 
taken from the eCRF “Study Treatment Siremadlin” and summarized.  The total duration of 
interruptions by participant will be summarized for the study population by time intervals, e.g., 
<1week, ≥1-<2 weeks, ≥2-<3 week, etc. (these time intervals may be adjusted depending on the 
observed data). 
Cycle initiated 
The number of cycles initiated by a participant will be summarized. A cycle is delayed if the 
first dose of study treatment within a cycle is administered > 3 days after the scheduled date. 
For the eCRF, a cycle delay will be recorded as a dose interruption between the planned start 
date of the cycle and the day before the actual date of the first dose of any study treatment within 
the cycle. 
2.4.2 
Prior, concomitant and post therapies 
Prior or concomitant medications and significant non-drug therapies within 28 of starting study 
treatment until 30 days after the last dose of siremadlin will be summarized according to the 
Anatomical Therapeutic Chemical (ATC) classification system.  
Prior anti-neoplastic medications/radiotherapy will be summarized using the FAS. Medications 
will be summarized by ATC class and preferred term.   
Anti-neoplastic therapies after discontinuation of study treatment during follow-up within the 
study will be listed using the FAS by ATC class and preferred term.  
All transfusions of blood products (incl. those not related to AML) prior (during screening) and 
after start of study treatment will be listed using the FAS.  
2.5 
Analysis supporting primary objective(s) 
The primary safety objective is to confirm the dose and schedule that are tolerable and safe 
without unacceptable toxicities (dose limiting toxicities [DLTs]) of siremadlin monotherapy in 
Part 1 and for siremadlin in combination with DLI in Part 2.  
The primary efficacy objective is to evaluate the preliminary efficacy of siremadlin study 
treatment strategy (siremadlin monotherapy, as priming and/or maintenance, with or without 
siremadlin in combination with DLI) in Part 2, on prevention of hematologic relapse. 
2.5.1 
Primary endpoint(s) 
The primary safety endpoints are the incidence of DLTs in Part 1 and time-to-DLT in Part 2, 
respectively, during DLT evaluation period for participants included in the DDS1 or DDS2. 
The definition of DLT evaluation period is defined in Section 5.1 and the details of DLT are 
defined in Protocol Section 6.6.3 which are captured in eCRF. 
The primary efficacy endpoint of the study is the proportion of participants who are alive and 
remain in CR/CRi at least 6 months after the of start study treatment among participants who 


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initiated priming phase at the siremadlin RD for priming in Part 2 (Cheson et al 2003, 
Döhner et al 2017). Details on the definition of response categories which are to be captured in 
the eCRF by the investigator were defined in the Study Protocol Table 8-4 that was copied into 
Table 2-2. 
Table 2-2 
Response classification in AML at a given evaluation time (based on 
IWG Cheson et al 2003, ELN 2017 Döhner et al 2017) 
Response Category 
Definition1 
Complete Remission 
Bone marrow: 
 
< 5% blasts 
 
no blasts with Auer rods 
Peripheral blood: 
 
neutrophils ≥ 1.0x109/L 
 
platelets ≥ 100x109/L 
 
no circulating blasts 
No evidence of extramedullary disease (such as CNS 
or soft tissue involvement). 
Complete remission with incomplete hematologic 
recovery (CRi) 
Bone marrow: 
 
< 5% blasts 
 
no blasts with Auer rods 
Peripheral blood: 
 
neutrophils < 1.0x109/L or platelets < 100x109/L 
 
no circulating blasts 
No evidence of extramedullary disease (such as CNS 
or soft tissue involvement). 
Relapse from CR or CRi 
Only in participants with a CR or CRi. Any of the 
following: 
 
Reappearance of blasts in peripheral blood 
OR 
 
≥ 5% blasts in bone marrow 
OR 
 
(Re-)appearance of extramedullary disease 
Unknown 
In case the response assessment was not done or the 
assessment was incomplete 
1 If not defined otherwise, all of these criteria apply 
2.5.2 
Statistical hypothesis, model, and method of analysis  
Primary safety analysis (incidence of DLT and time-to-DLT) 
As Novartis decided to permanently halt the enrollment and consequently, Part 2 was not 
opened, time-to-DLT analysis will not be performed for the synoptic CSR. 
For participants in the Cycle 1 of Part 1, assessing whether siremadlin at the tested dose levels 
does not lead to an unacceptable level of toxicity (DLTs) when administered as monotherapy 
will be based on the estimation of the probability of DLT within the DLT evaluation period  for 
participants in the DDS1. The assessment will be guided by a Bayesian analysis of DLT data 
for siremadlin monotherapy within the DLT evaluation period of treatment. The probability of 


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DLT is modeled using a Bayesian approach detailed in the Study Protocol Appendix 
Section 16.1. 
After each cohort in Part 1 is completed, posterior distributions for the risk of DLT will be 
summarized to provide the posterior probability that the risk of excessive toxicity (DLT rate 
≥ 33%) 
is 
less 
than 
25% 
(Escalation 
with 
Overdose 
Control 
(EWOC) 
principle, Babb et al 1998). 
The standard EWOC defines overdosing as the probability of having a DLT >33% and limits 
the probability of overdosing under 25% (i.e., probability to observe a DLT rate exceeding 33% 
is below 25%). 
A full assessment of the prior risk to participants and a summary of the operating characteristics 
of the models is given in Protocol Section 16.6 
For participants who complete the combination phase in Part 2, assessing whether siremadlin 
at the tested dose levels does not lead to an unacceptable level of toxicity (DLTs) when 
administered in combination with DLI will be based on the estimation of the probability of DLT 
for participants in the DDS2 for combination phase in Part 2. Dose confirmation of siremadlin 
in combination with DLI (siremadlin/DLI combination phase in Part 2) will be based on time-
to-DLT using Bayesian time to first DLT model with the EWOC principle considering all 
available information for up to 3 cycles.  
The standard EWOC defines overdosing as the probability of having a DLT >33% and limits 
the probability of overdosing under 25% (i.e., probability to observe a DLT rate exceeding 33% 
is below 25%). The conditional probabilities (given that the patient made it to the start of that 
cycle without a DLT) of overdosing/target/underdosing probabilities per-cycle will be 
summarized. 
A full assessment of the prior risk to participants and a summary of the operating characteristics 
of the models is given in Protocol Section 16.7. 
Primary efficacy analysis (proportion of participants who remain in CR/CRi 6 
months after the start of study treatment) (in Part 2) 
As Novartis decided to permanently halt the enrollment and consequently, Part 2 was not 
opened, this primary efficacy analysis will not be performed for the synoptic CSR.  
The efficacy of study treatment will be based on the proportion of participants in Part 2 
remaining in CR/CRi as per investigator assessment for at least 6 months after the start study 
treatment among participants who initiated priming phase at the siremadlin RD for 
priming with/without DLI. Assuming a minimally informative prior distribution (Beta(0.67,1)) 
with mean 40% based on the null value in the statistical criterion, the distribution of the CR/CRi 
rate will be updated with all available data from participants who are in the FAS and have 
initiated siremadlin (at RD for priming or a tolerated siremadlin dose lower than RD for priming) 
as monotherapy with or without siremadlin/DLI combination. 
Decision criteria for trial success (dual-criterion) are based on proportion of participants who 
remain in CR/CRi by investigator assessment and are alive at least 6 months after the start of 
study treatment): 


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 Bayesian statistical significance: probability (CR/CRi rate > 40% | data) ≥ 0.975 (the one-
sided p-value must be less than 2.5%) (null value), and 
 Clinical relevance: posterior median of CR/CRi rate ≥ 60% (decision value) 
2.5.3 
Handling of intercurrent events  
Handling of intercurrent events of the primary efficacy and safety estimands is described in 
Section 1.2.1 
2.5.4 
Handling of missing values not related to intercurrent event 
For the determination of CR/CRi, an adequate response assessment is considered any disease 
assessment indicating response status apart from “unknown” or “not done”. If no subsequent 
assessment or the subsequent assessment of an inadequate response does not show CR/CRi, the 
inadequate response will be regarded as no CR/CRi. 
2.5.5 
Sensitivity analyses  
Not applicable 
2.5.6 
Supplementary analyses 
Not applicable 
2.6 
Analysis supporting secondary objectives  
The secondary objectives for Part 1 and Part 2 are to assess the effect of siremadlin with/without 
DLI on safety and tolerability, cumulative incidence of relapse, proportion of participants 
stopping study treatment due to GvHD/AE, incidence of treatment-emergent grade III/IV 
aGvHD and moderate/severe cGvHD, GvHD-free/relapse-free survival (GRFS), and PK. A 
separate objective for Part 1 siremadlin monotherapy is to evaluate the preliminary efficacy of 
siremadlin monotherapy (in participants treated at the RD for Part 2) on prevention of 
hematologic relapse. Secondary objectives for Part 2 only are relapse free survival (RFS) and 
overall survival (OS). 
2.6.1 
Secondary endpoint(s) 
Efficacy endpoints will be analyzed and summarized in FAS and by dose level of siremadlin in 
Part 1 unless otherwise specified. Responses per investigator assessment (Table 2-2) will be 
used unless specified otherwise. 
Time-to-event endpoints will not be analyzed given siremadlin RD for priming was not 
determined and Part 2 was not opened. 
No formal statistical tests will be performed for any of the secondary efficacy endpoints and 
hence no multiplicity adjustment will be applied.  


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Relapse-Free Survival (RFS) [Part 2 only] 
RFS is defined as the time from start of study treatment to the date of first documented 
hematologic relapse or death due to any cause, whichever occurs first. RFS will be censored if 
no RFS event is observed before the first to occur between: 
1. the analysis cut-off date, and  
2. the date when a new anti-neoplastic therapy is started. The censoring date will be the date 
of the last adequate response assessment. The handling of intercurrent events will be the 
same as the primary estimand (Section 1.2.1). 
Cumulative incidence of relapse [Part 1 and 2] 
Cumulative incidence of relapse (CIR) is defined as the time from start of study treatment to 
the date of first documented hematologic relapse. Participants will be censored if no relapse is 
observed before the first to occur between:  
1. the analysis cut-off date, and  
2. the date when a new anti-neoplastic therapy is started. The censoring date will be the date 
of the last adequate response assessment. 
Overall Survival (OS) [Part 2 only] 
OS is defined as the time from start date of treatment to date of death due to any cause. If a 
participant is not known to have died, then OS will be censored at the latest date the 
participant was known to be alive (on or before the cut-off date). All deaths will be taken into 
account whenever the death occurred, i.e., even after new anti-neoplastic therapy, allo-SCT, 
interruptions, or discontinuation of study treatment due to any reason.  
GvHD-free/relapse-free survival (GRFS) [Parts 1 and 2] 
GRFS is defined as the time from start of treatment to the date of first documented occurrence 
or worsening of treatment emergent grade III or IV aGvHD or cGvHD requiring initiation of 
systemic immunosuppressive treatment, hematologic relapse, or death due to any cause, 
whichever occurs first. GRFS will be censored if no GRFS event is observed before the first to 
occur between:  
1. the analysis cut-off date, and  
2. the date when a new anti-neoplastic therapy is started. The censoring date will be the date 
of the last GvHD assessment given confirmed remission in a subsequent efficacy assessment. 
The details of aGvHD and cGvHD are defined in Study Protocol Section 16.1 and Section 
16.2 which are captured in eCRF page. 
Participants remaining in CR/CRi (in Part 1) 
The participants who remain in CR/CRi at least 6 months after the start of study treatment 
among participants in Part 1 treated with siremadlin monotherapy at the recommended dose for 
Part 2 will be listed. 
Handling of intercurrent events will follow the same rule in the primary efficacy estimand. 


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2.6.2 
Sensitivity analyses 
Not applicable 
2.6.3 
Supplementary analyses 
Not applicable 
2.7 
Safety analyses [Part 1] 
Safety analyses will be summarized for the Safety Set by dose level of siremadlin in Part 1. 
Safety summaries (tables, figures) include only data from the on-treatment period with the 
exception of baseline data which will also be summarized where appropriate (e.g., change from 
baseline summaries). In addition, a separate summary for death including on-treatment and post 
treatment deaths will be provided. In particular, summary tables for adverse events (AEs) will 
summarize only on-treatment events, with a start date during the on-treatment period 
(treatment-emergent AEs). 
The overall observation period will be divided into three mutually exclusive segments: 
1. Pre-treatment period: from day of participant's informed consent to the day before first 
administration of study treatment 
2. On-treatment period: from date of first administration of study treatment to 30 days after 
date of last administration of study treatment 
3. Post-treatment period: any observation starting at day 31 after last administration of study 
treatment 
2.7.1 
Adverse events (AEs) 
Summary tables for adverse events (AEs) will include only AEs that started or worsened during 
the on-treatment period.  
The number (and percentage) of participants with treatment emergent adverse events will be 
summarized by primary system organ class (SOC), preferred term (PT) and maximum severity. 
A participant with multiple occurrences of an AE will be counted only once in the respective 
AE category. A participant with multiple CTCAE grades for the same PT will be summarized 
under the maximum CTCAE grade recorded for the event. AEs will be assessed according to 
the Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. 
In the AE summaries, the primary SOC will be presented alphabetically, and the PT will be 
sorted within primary SOC in descending frequency. The sort order for the PT will be based on 
their frequency in the “overall” column (combining all dose levels of siremadlin). The 
summaries will show ‘All grades’ (including AEs with missing grade) and ‘Grades ≥ 3’. 
The following adverse event summaries will be produced selecting all or a subset of AEs 
depending on seriousness, relationship to study treatment, outcome or action taken:  
 AEs (by SOC and by PT) and separately those considered related to study treatment  
 SAEs and separately those considered related to study treatment  


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 SAEs with number of occurrences (an occurrence is defined as >1 day between start and 
prior end date of record of same PT) 
 Non-SAEs 
 SAEs with fatal outcome and separately those considered related to study treatment  
 AEs leading to permanent study treatment discontinuation by study treatment  
 AEs leading to dose adjustment/interruption 
 AEs requiring additional therapy  
All reported AEs will be listed and those that started during the pre-treatment, and post-
treatment period will be flagged. 
Acute GvHD and chronic GvHD will be listed separately. Post-treatment period will be flagged. 
For the legal requirements of ClinicalTrials.gov and EudraCT, two tables on on-treatment 
adverse events which are not serious adverse events with an incidence greater than 5% and on 
on-treatment serious adverse events and SAE suspected to be related to study treatment will be 
provided by system organ class and preferred term on the safety set population. 
If for a patient several consecutive AEs (irrespective of study treatment causality, seriousness 
and severity) occurred with the same SOC and PT: 
 a single occurrence will be counted if there is ≤ 1 day gap between the end date of the 
preceding AE and the start date of the consecutive AE 
 more than one occurrence will be counted if there is > 1 day gap between the end date of 
the preceding AE and the start date of th consecutive AE 
For occurrence, the presence of at least one SAE / SAE suspected to be related to study 
treatment / non-SAE has to be checked in a block e.g., among AEs in a ≤ 1 day gap block, if at 
least one SAE is occurring, then one occurrence is calculated for that SAE. 
The number of on-treatment deaths resulting from SAEs suspected to be related to study 
treatment and SAEs irrespective of study treatment relationship will be provided by SOC and 
PT. 
2.7.1.1 
Adverse events of special interest / grouping of AEs 
An adverse event of special interest (AESI) is a grouping of adverse events that are of scientific 
and medical concern specific to siremadlin. These groupings are defined using MedDRA terms, 
SMQs (standardized MedDRA queries), HGLTs (high level group terms), HLT (high level 
terms) and PTs (preferred terms). Customized MedDRA queries (CMQs) and/or Novartis 
MedDRA queries (NMQs) may also be used. These are customized group of search terms which 
defines a medical concept for which there is no official SMQ available or the available SMQ 
does not completely fit the need. It may include a combination of single terms and/or an existing 
SMQ, narrow or broad. These searches will be defined in the eCRS (electronic Case Retrieval 
Sheet) and a listing of search terms will be provided in the DMS (Document Management 
System).  The eCRS version used events retrieval will be specified as a footnote in the 
applicable outputs. 


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For each specified AESI, the number (%) of participants with at least one event of the AESI 
occurring during the on treatment period will be summarized together with the individual 
preferred terms in that grouping. In addition, number (%) of participants with at least one AESIs 
by maximum CTCAE grade, related AESIs, serious AESIs as well as action taken and outcome 
of the respective AESI will be summarized.  
2.7.2 
Deaths 
Separate summaries for on-treatment and all deaths (including post-treatment deaths not in the 
AE CRF but in the survival CRF) will be produced showing deaths reasons by primary reason 
and PT. All deaths will be listed for all screened participants. Post treatment deaths and prior to 
starting treatment death will be flagged.  
2.7.3 
Laboratory data 
Grading of laboratory values will be assigned programmatically as per National Cancer Institute 
(NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. The 
calculation of CTCAE grades will be based on the observed laboratory values only, clinical 
assessments will not be taken into account. 
CTCAE Grade 0 will be assigned for all non-missing values not graded as 1 or higher. 
For laboratory tests where grades are not defined by CTCAE version 5.0, results will be 
categorized as low/normal/high based on laboratory normal ranges. 
For laboratory tests where grades are defined by CTCAE v5.0: 
 Shift tables using CTCAE v5.0 grades to compare baseline to the worst on-treatment value 
For laboratory tests where grades are not defined by CTCAE v5.0: 
 Shift tables using the low/normal/high classification to compare baseline to the worst on-
treatment value 
Liver function parameters of interest are total bilirubin, Direct Bilirubin, ALT, AST, gamma-
glutamyl transferase (GGT) and alkaline phosphatase. The number (%) of participants with 
worst post-baseline values as per Novartis Liver Toxicity guidelines will be summarized. 
All CTCAE grade ≥ 3 laboratory toxicities will be flagged. 
2.7.4 
Other safety data 
2.7.4.1 
ECG and cardiac imaging data 
ECGs are collected as 12-lead triplicate using the ECG machines supplied by the central 
laboratory and then transmitted electronically to the central laboratory for central review by an 
independent reviewer.  
HR and QTcF will be obtained from 12-lead ECGs for each participant at screening and during 
the study. ECG data will be read and interpreted centrally. If a participant has more than one 
measurement at a specific time point, the average of all available measurements associated with 
the nominal time point will be used for the analyses.  


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Categorical analysis of QTcF interval and HR data will be based on the summary of number of 
participants meeting or exceeding predefined limits. 
Notable ECG values during on-treatment period in participants with normal values at baseline 
(for the respective QTc value) will be summarized using the following criteria: 
Table 2-3 
Notable ECG values 
ECG parameter (unit) 
Clinically notable criteria 
QTcF (ms) 
Increase >30 and ≤ 60 ms 
Increase >60 ms 
New >450 to ≤ 480 ms 
New >480 to ≤ 500 ms 
New >500 ms 
 
HR (bpm) 
Increase >25% and HR >100 bpm 
Decrease >25% and HR<50 bpm 
 
2.7.4.2 
Vital signs 
Notable vital sign values during on-treatment period will be summarized using the following 
criteria: 
Table 2-4 
Notable vital sign values 
Vital sign (unit) 
Clinically notable criteria 
 
above normal value  
below normal value 
Systolic blood pressure 
(mmHg) 
≥ 180 with increase from baseline of 
≥20 
≤ 90 with decrease from baseline of 
≥20 
 
Diastolic blood pressure 
(mmHg) 
≥105 with increase from baseline of ≥15 
≤ 50 with decrease from baseline of 
≥15 
 
Pulse rate (bpm) 
≥100 with increase from baseline 
of >25% 
≤ 50 with decrease from baseline of > 
25% 
 
Weight (kg) 
Increase ≥10% from baseline 
Decrease ≥ 10% from baseline 
Body Temperature 
>=39.1 °C 
 
2.7.4.3 
ECOG PS 
ECOG PS categorical data will be displayed by timepoint in listing.  
2.8 
Pharmacokinetic endpoints   
The PAS-all will be used in all pharmacokinetic data analysis. 
Siremadlin drug concentrations 
Pharmacokinetic parameters will be derived from the individual concentration versus time 
profile using a non-compartmental method as implemented in Phoenix WinNonlin (Version 8.0 
or higher; Pharsight, Mountain View, CA). The pharmacokinetic parameters described in 


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Table 2-5 will be determined as deemed appropriate. Additional PK parameters may be 
estimated as needed. Pharmacokinetic parameters will be determined using the actual recorded 
sampling times and non-compartmental method(s) with Phoenix WinNonlin. 
Table 2-5 
Non-compartmental pharmacokinetic parameters* 
AUC0-t 
The area under the concentration vs. time Curve (AUC) from time zero to specified time point. 
Note: when the last sampling time of the PK profiles at Cycle 1 Day 1 is 24h post-dose (in CONF 
or PRIM), AUC0-24h will be determined (when feasible) for siremadlin; For the PK profiles 
collected at Day 1 and Day 5 of other cycles, AUC0-8h will be determined (when feasible) for 
siremadlin 
AUClast 
The AUC from time zero to the last quantifiable concentration point (Tlast) (mass x time x volume-1) 
Ctrough 
Concentration that is just prior to the beginning of, or at the end, of a dosing interval; 
corresponding to the pre-dose concentration (when feasible) 
Cmax 
The maximum (peak) observed plasma, blood, serum, or other body fluid drug concentration 
following drug administration (mass x volume-1) 
C3h 
Concentration at 3 hours post-dose (when feasible) 
Tlast 
Time at which the last measurable concentration was observed (time) 
Note: for the PK profiles of selected cycles 
Tmax 
The time to reach maximum (peak) plasma, blood, serum, or other body fluid drug concentration 
after drug administration (time) 
* Details of sampling time are included in Table 8-10a and Table 8-10b. 
The respective PAS for siremadlin will be used in all pharmacokinetic data analyses. 
Siremadlin concentration data will be listed by participant, by dose level of siremadlin, and by 
Cycle/Day, sampling time point (See Protocol Section 8.5.1 for details). Descriptive summary 
statistics for siremadlin concentrations will be provided by dose level of siremadlin, by 
Cycle/Day, /sampling time point. Summary statistics will include mean (arithmetic and 
geometric), standard deviation (SD), coefficient of variation (CV) (arithmetic and geometric), 
median, minimum, and maximum, as well as the frequency (n, %) of concentrations below the 
lower limit of quantification (LLOQ) and reported as zero. Values below the LLOQ will be 
treated as missing for the calculation of the geometric means and geometric CV%. 
The PAS will be used for the PK data analysis and PK summary statistics. Descriptive statistics 
of all pharmacokinetic parameters (e.g., AUCs, Cmax) will include arithmetic and geometric 
mean, median, SD, and CV, geometric CV, minimum and maximum. Zero concentrations will 
not be included in the geometric mean calculation. Since Tmax is generally evaluated by a 
nonparametric method, median values and ranges will be given for this parameter. 
Missing values for any PK parameters or concentrations will not be imputed and will be treated 
as missing. 
All concentration vs. time profiles data for siremadlin will be displayed graphically. 
2.9 
PD and PK/PD analyses 
Not applicable. 
2.10 
Patient-reported outcomes 
Not applicable 


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2.11 
Biomarkers 
Not applicable. 
2.12 
Other Exploratory analyses 
Not applicable. 
2.13 
Interim analysis 
No formal interim analysis is planned for this trial. 
However, safety review meetings will be conducted after each dose level cohort of the 
siremadlin monotherapy in Part 1 as well as after each cohort of 3 participants who completed 
at least one siremadlin/DLI treatment cycle in combination phase in Part 2. 
The decision to start enrollment in the subsequent cohort and to continue with the siremadlin 
RDE in the expansion phase will be guided by a Bayesian analysis based on the incidence of 
DLT data. 
For each cohort of the safety run-in part, the following information (summaries and/or listings) 
will be provided as far as data is available: 
 Number (%) of participants treated and included in the analysis sets 
 Basic demographic and background data 
 Disease characteristics (including cytogenetics, molecular genetics, and ELN risk 
category) 
 Allogeneic transplant characteristics  
 Medical history 
 Prior and concomitant medications (including immunosuppressive therapy)  
 Participant disposition 
 Protocol deviations 
 Duration of exposure to study treatment 
 Dose intensity and relative dose intensity 
 Number (%) of participants with any dose changes (incl. reductions, interruptions, or 
permanent discontinuations) and the reasons 
 DLTs, AEs, treatment related AEs, SAEs, on-treatment deaths reported during the DLT 
evaluation period, as well as DLTs, AEs, treatment related AEs, SAEs, on-treatment 
deaths reported up to the data cut-off date 
 AESI overview  
 Posterior distribution for the risk of DLT for new participants at the dose level tested (see 
Section 2.5.2) 
 Laboratory data and vital signs abnormalities 
 Blast counts from bone marrow, peripheral blood (CBC and differential), extramedullary 
disease assessment and investigator’s response assessment (if available) 


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 Siremadlin concentrations (if available) 
 Antineoplastic therapies since discontinuation of study treatment (medication and cellular 
therapies) 
For the regular safety review meetings, the same information as listed above will be provided  
The exact list of tables, listings and figures prepared for those safety review meetings will be 
defined in a separate planning document. 
3 
Sample size calculation 
Primary safety endpoint 
No formal statistical power calculations to determine sample size were performed for this study. 
For Part 1, initially, 3-6 participants will be enrolled at the starting dose level (siremadlin 30 
mg QD D1-5) to have at least 3 evaluable participants. Upon observation of specific toxicities 
(see Protocol Section 6.6 for details), the participating Investigators and Novartis study 
personnel will decide to increase/decrease the dose or expand at 30 mg QD siremadlin. For a 
dose level to be considered for RD for Part 2, at least 6 evaluable participants are required. For 
combination phase in Part 2, the maximum RD for siremadlin/DLI combination will be decided 
with data from all evaluable participants (at least 9 evaluable participants are required) when 
they have completed siremadlin/DLI combination phase or experienced a DLT. For a dose level 
to be declared as maximum RD for combination it must be tested with at least 3 evaluable 
participants treated at or above that dose level. 
Primary efficacy endpoint 
The efficacy of study treatment will be based on the proportion of participants remaining in 
CR/CRi as per investigator assessment in Part 2. Decision criteria for trial success (dual 
criterion) are based on proportion of participants who remain in CR/CRi by investigator 
assessment and are alive at least 6 months after the start of study treatment): 
 Bayesian statistical significance: probability (CR/CRi rate > 40% | data) ≥ 0.975 (the one-
sided p-value must be less than 2.5%) (null value; details about rationale in Section 2.5.2), 
and 
 Clinical relevance: posterior median of CR/CRi rate ≥ 60% (decision value) 
With two criteria stated above the minimally required sample size (nmin) is 22, and the final 
sample size was set to 26 including participants who initiated priming phase at siremadlin RD 
for priming. For 26 participants (included for the primary efficacy analysis), the table below 
shows data scenarios (number of participants remaining in CR/CRi) with respective inferential 
results and decisions.  
Based on simulations, a total of 16 responders out of 26 participants (62%) is required for trial 
success, with estimates of 60% for the posterior median CR/CRi rate and 98% for the posterior 
probability for a positive effect (CR/CRi >40%). If the number of participants with CR/CRi is 
less than 16, both criteria are not met (NO-GO).  


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Table 3-1 
Data scenarios, inferential results and decisions (n=26) 
Observed CR/CRi rate 
Posterior median 
CR/CRi 
Posterior probability for 
a positive effect 
(CR/CRi >40%) 
Decision for trial 
success 
10/26 (0.38) 
0.38 
0.43 
Failed 
11/26 (0.42) 
0.42 
0.58 
Failed 
12/26 (0.46) 
0.46 
0.73 
Failed 
13/26 (0.5) 
0.49 
0.84 
Failed 
14/26 (0.54) 
0.53 
0.92 
Failed 
15/26 (0.58) 
0.57 
0.96 
Failed 
16/26 (0.62) 
0.6 
0.98 
Successful 
17/26 (0.65) 
0.64 
0.99 
Successful 
A minimally informative prior distribution (Beta (0.67,1)) with mean 40% based on the null value in the statistical 
criteria has been used in these calculations. Operating characteristics for various true CR/CRi rates are presented 
in Table 12-3  below. The type-I error under the null value (CR/CRi rate = 40%) is 2% and power is 52% assuming 
a true CR/CRi rate of 60%. 
Table 3-2 
Operating characteristics for true CR/CRi rate (n=26) 
True proportion of participants 
in CR/CRi 
Probability of success (Go) 
Probability of futility (No Go) 
0.30 
0.00 
1.00 
0.35 
0.01 
0.99 
0.40* 
0.02 
0.98 
0.45 
0.07 
0.93 
0.50 
0.16 
0.84 
0.55 
0.32 
0.68 
0.60** 
0.52 
0.48 
0.65 
0.72 
0.28 
0.70 
0.88 
0.12 
0.75 
0.96 
0.04 
0.80 
0.99 
0.01 
For a true CR/CRi rate of 40% (null value), the probability for a trial success is 2% (type-I error). **For a true 
CR/CRi rate of 60%, the probability for a trial success is 52% (power). These calculations were made using the 
software R (version 3.6.1) using the RBestT package. 
4 
Change to protocol specified analyses 
As Novartis decided to permanently halt the enrollment of the study HDM201K12201 in 
September 2023, the following analyses as per protocol will not be performed: 
 The primary safety analysis to determine RD for Part 2, 
 The primary efficacy analysis of CR rate in Part 2, 
 Secondary time-to-event endpoints for Part 1 RD and Part 2, including RFS, cumulative 
incidence of relapse, OS, and GRFS, 
 
 


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5 
Appendix 
5.1 
General definitions 
End date of the last cycle  
The end date of the last cycle is the maximum date between: 
 The planned end date (Day 28 for Part 1, priming and maintenance phase of Part 2; 42 
days of combination phase of Part 2) of the last cycle when the last non-zero dose of 
siremadlin) is administered, 
 The actual date of the last administration of a non-zero dose of siremadlin. 
The end date of the last cycle initiated will be applicable even if this date goes beyond the 
data cut-off date. 
Date of last exposure to study treatment  
One cycle planned length is 28 days for Part 1 and Part 2 (priming, maintenance), and one cycle 
planned length is 42 days for combination phase in Part 2. The start date of a cycle is defined 
as the first administration of siremadlin within a cycle. Siremadlin is planned to be administered 
QD D1-D5.  
The date of last exposure to siremadlin is therefore calculated as: 
 Minimum (date of last administration of siremadlin + 23 days, date of death, last contact 
date in case participant is lost to follow-up), as siremadlin is given QD D1-D5. 
Date of last exposure and duration of exposure to study treatment combination 
For the calculation of the duration of exposure to study treatment combination (siremadlin + 
DLI), the date of last exposure to study treatment combination will be derived as the minimum 
date between: 
 End date of the last cycle, 
 Date of death, 
 Last contact date in case participant is lost to follow-up. 
The duration of exposure to study treatment combination will be calculated as follow: date of 
last exposure to study treatment combination - date of first administration of study treatment 
combination + 1.  
Duration from first to last cycle to calculate dose intensity and the relative dose 
intensity 
For the calculation of the dose intensity and relative dose intensity, the duration in days from 
first to last cycle will be calculated as follows: end date of the last cycle - date of first 
administration of study treatment + 1. 
Thus, this derivation will be irrespective of date of death or last contact date (i.e., it should not 
be truncated to the date of death or date of last contact date). 


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Time unit 
A year length is defined as 365.25 days. A month length is 30.4375 days (365.25/12). If duration 
is reported in months, duration in days will be divided by 30.4375. If duration is reported in 
years, duration in days will be divided by 365.25. 
5.2 
Laboratory parameters derivations 
If laboratory values are provided as ‘<X’ (i.e., below limit of detection) or ‘>X’, prior to 
conversion of laboratory values to SI unit, these numeric values are set to X. 
The following rules will be applied to derive the WBC differential counts when only 
percentages are available for a xxx differential 
xxx count = (WBC count) * (xxx %value / 100) 
The following rules will be applied to derive the WBC differential percentages when only 
absolute differential counts are available for a xxx differential 
xxx %value = (xxx count * 100) / WBC count 
Further derivation of laboratory parameters might be required for CTCAE grading. For instance, 
if only serum calcium is collected, the corrected calcium can be derived using the total serum 
calcium value and serum albumin at the same assessment using the following formula (after 
values had been converted to SI units): 
Corrected Calcium (mmol/L) = Calcium (mmol/L) + 0.02 (40 – [Albumin (g/L)] 
For laboratory CTC grade derivations, the normal range for derived corrected calcium is set to 
the same limits (in mmol/L) as for serum calcium. 
6 
Reference 
References are available upon request 
Babb J, Rogatko A, Zacks S (1998) Cancer phase I clinical trials: efficient dose escalation 
with overdose control. Stat Med p. 1103-20. 
Cheson BD, Bennett JM, Kopecky KJ, et al (2003) Revised recommendations of the 
International Working Group for Diagnosis, Standardization of Response Criteria, Treatment 
Outcomes, and Reporting Standards for Therapeutic Trials in Acute Myeloid Leukemia. J 
Clin Oncol p. 4642-9. 
Clopper CJ, Pearson ES (1934) The use of confidence or fiducial limits illustrated in the case 
of the binomial p. 404-413. 
Dominietto, A., Raiola, A.M., Van Lint, M.T., et al (2001) Factors influencing haematological 
recovery after allogeneic haemopoietic stem cell transplants: graft-versus-host disease, donor 
type, cytomegalovirus infections and cell dose. p. 219-227. 
Döhner H, Estey E, Grimwade D, et al (2017) Diagnosis and management of AML in adults: 
2017 ELN recommendations from an international expert panel. Blood p. 424-447.