Conditions: Oncology Acute Myeloid Leukemia
Allocation: NA | Intervention model: SEQUENTIAL
Enrollment: 17
Healthy volunteers: no

Brief summary:
A Phase 1 Dose-Escalation Study of LAM-003 in Patients with Acute Myeloid Leukemia

Detailed description:
This clinical trial is a Phase 1 study evaluating the safety, pharmacokinetics, pharmacodynamics, and antitumor activity of LAM-003 across a range of LAM-003 dose levels when administered to subjects with previously treated relapsed or refractory cute Myeloid Leukemia (AML).

Subjects will self-administer oral LAM-003 either once or twice per day as long as they are safely benefitting from therapy. Cohorts of 3 to 6 subjects will be sequentially enrolled at progressively higher dose levels of LAM-003 using a standard 3+3 dose-escalation design. Based on the pattern of dose-limiting toxicities observed in the first 4 weeks of therapy, escalation will proceed to define a recommended LAM-003 dosing regimen.

Arms:
arm 1: Open label LAM-003 at three sequentially increasing starting dose levels of 200, 300 and 450 mg.

Interventions: intervention 1: Open Label LAM-003
Intervention descriptions: intervention 1: LAM-003

Protocol document:
Prot_000.pdf: 
CONFIDENTIAL
Page 1 of 184
Version 8 (4 Nov 2019)
TITLE PAGE
CLINICAL STUDY PROTOCOL
Protocol Title
A Phase 1 Dose-Escalation Study of LAM-003 in Patients with 
Acute Myeloid Leukemia
Study Sponsor
AI Therapeutics, Inc. (formerly LAM Therapeutics, Inc.)
530 Old Whitfield St
Guilford CT, 06437
Investigational Product
LAM-003
Protocol Number
LAM-003-HEM-CLN02
Developmental Phase
Phase 1b
US IND Number
112055
Protocol Versions (Dates)
Version 1 – Original (27 Sep 2017)
Version 2 (19 Nov 2017)
Version 3 (17 Feb 2018)
Version 4 (15 Jun 2018)
Version 5 (  2 Jul 2018)
Version 6 (10 Sep 2018)
Version 7 (11 Jun 2019)
Version 8 ( 4 Nov 2019)
Confidentiality Statement
This document contains confidential information belonging to AI Therapeutics, Inc. Except as may be 
otherwise permitted in writing, by accepting or reviewing these materials, it is agreed that this 
information should not be disclosed to others (except if required by applicable law or regulation) and 
should not be used for unauthorized purposes. 


Investigational Product: LAM-003 
Study Protocol: LAM-003-HEM-CLN02 
AI Therapeutics, Inc.
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Page 4 of 184 
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PRINCIPAL INVESTIGATOR APPROVAL PAGE
Title 
A Phase 1 Dose-Escalation Study of LAM-003 in Patients with Acute 
Myeloid Leukemia 
Protocol Number
LAM-003-HEM-CLN02
Version (Date) 
Version 8 (4 Nov 2019)
I have reviewed the protocol. On behalf of my institution, I agree to conduct the study as 
outlined in the study protocol and in compliance with Good Clinical Practices (GCP) and all 
applicable regulatory requirements. 
 
 
 
 
Principal Investigator Signature 
 
Date 
 
 
Principal Investigator Printed Name 
 
 
Institution:
 
Address:
 


Investigational Product: LAM-003 
Study Protocol: LAM-003-HEM-CLN02 
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TABLE OF CONTENTS
TITLE PAGE ..................................................................................................................................1
AI THERAPEUTICS PROJECT PERSONNEL .............................................................................2
AI THERAPEUTICS, INC. APPROVAL PAGE ...........................................................................3
PRINCIPAL INVESTIGATOR APPROVAL PAGE .....................................................................4
TABLE OF CONTENTS .................................................................................................................5
LIST OF IN-TEXT TABLES........................................................................................................11
LIST OF IN-TEXT FIGURES.......................................................................................................11
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ................................................12
PROTOCOL SYNOPSIS...............................................................................................................15
1
INTRODUCTION ................................................................................................................29
1.1
Acute Myeloid Leukemia ................................................................................................29
1.2
FMS-Like Tyrosine Kinase-3 Receptor and Ligand in AML .........................................29
1.3
Heat Shock Proteins as Clinical Targets for AML Therapy ............................................30
1.4
LAM-003/LAM-003A.....................................................................................................30
1.4.1
Background.................................................................................................................30
1.4.2
Chemistry ....................................................................................................................31
1.4.3
Nonclinical Experience...............................................................................................32
1.4.4
Clinical Experience.....................................................................................................41
1.5
Conclusions .....................................................................................................................43
2
STUDY DESIGN AND CONDUCT ...................................................................................43
2.1
Study Design ...................................................................................................................43
2.2
Study Conduct .................................................................................................................44
2.3
Rationale for Study Design .............................................................................................44
3
STUDY OBJECTIVES........................................................................................................45
3.1
Primary Objective ............................................................................................................45
3.2
Secondary Objectives ......................................................................................................45
3.3
Exploratory Objectives....................................................................................................45
4
STUDY ENDPOINTS .........................................................................................................45
4.1
Primary Endpoints ...........................................................................................................45
4.2
Secondary Endpoints .......................................................................................................46
4.2.1
Drug Administration, Safety, and Supportive Care Profiles ......................................46


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4.2.2
Pharmacokinetics ........................................................................................................46
4.2.3
Antitumor Activity and Survival ................................................................................46
4.2.4
Exploratory Endpoints ................................................................................................47
4.3
Rationale for Selection of Endpoints ...............................................................................47
5
RECRUITMENT AND SELECTION OF STUDY SUBJECTS ........................................49
5.1
Planned Number of Subjects ...........................................................................................49
5.2
Recruitment of Subjects ..................................................................................................49
5.3
Informed Consent Process ...............................................................................................49
5.4
Enrollment and Replacement of Study Subjects .............................................................50
5.5
Subject Selection Criteria ................................................................................................50
5.5.1
Inclusion Criteria ........................................................................................................50
5.5.2
Exclusion Criteria.......................................................................................................52
5.6
Rationale for Subject Selection .......................................................................................54
6
STUDY DRUG INFORMATION, ADMINISTRATION, AND SUPPORT .....................55
6.1
LAM-003 .........................................................................................................................55
6.1.1
Description ..................................................................................................................55
6.1.2
Source .........................................................................................................................55
6.1.3
Packaging and Labelling.............................................................................................55
6.1.4
Shipping, Storage, and Stability .................................................................................55
6.1.5
Dispensing ..................................................................................................................55
6.1.6
Return and Compliance Assessment ..........................................................................56
6.1.7
Accountability.............................................................................................................56
6.1.8
Overdose Precautions .................................................................................................56
6.1.9
Inadvertent Exposure Precautions ..............................................................................56
6.2
Study Drug Administration .............................................................................................57
6.2.1
Premedications ............................................................................................................57
6.2.2
LAM-003 Administration...........................................................................................58
6.2.3
Dose Schedule Interruptions and Vomited Doses ......................................................58
6.2.4
Starting Dose Levels and Dose Escalation .................................................................58
6.2.5
Definition of DLTs .....................................................................................................60
6.2.6
Definitions of MTD and RDR ....................................................................................61
6.2.7
Dose Modification Recommendations .......................................................................61
6.3
Supportive Care ...............................................................................................................62


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6.3.1
General Recommendations .........................................................................................62
6.3.2
Antibiotics, Antifungals, and Antivirals .....................................................................63
6.3.3
Anticancer Therapies Other than the Study Drugs .....................................................63
6.3.4
Anticoagulants............................................................................................................63
6.3.5
Antidiarrheals .............................................................................................................63
6.3.6
Antiemetics .................................................................................................................63
6.3.7
Antihistamine, Antiinflammatory, or Antipyretic, Drugs ..........................................64
6.3.8
Corticosteroids............................................................................................................64
6.3.9
Drugs with Drug-Drug Interaction Potential ..............................................................64
6.3.10 
Drugs Known to Prolong the QT Interval ..................................................................65
6.3.11 
Hematopoietic Support ...............................................................................................65
6.3.12 
Immunization..............................................................................................................66
6.3.13 
Ophthalmological Symptom Management .................................................................66
6.3.14 
TLS Management .......................................................................................................66
6.4
Study Restrictions ............................................................................................................67
6.4.1
Breast Feeding ............................................................................................................67
6.4.2
Contraception/Reproduction .......................................................................................67
6.4.3
Diet .............................................................................................................................68
6.5
Duration of Study Drug Administration and Study Participation ...................................69
6.6
Rationale for Study Drug Administration and Supportive Care .....................................69
7
STUDY ACTIVITIES AND ASSESSMENTS ...................................................................70
8
SAFETY ASSESSMENTS ..................................................................................................75
8.1
Definitions .......................................................................................................................75
8.1.1
Adverse Event .............................................................................................................75
8.1.2
Serious Adverse Event................................................................................................76
8.1.3
Unexpected Adverse Event.........................................................................................77
8.1.4
Treatment-Emergent Adverse Event ..........................................................................77
8.1.5
Adverse Events of Special Interest .............................................................................77
8.2
Eliciting Adverse Event Information...............................................................................77
8.3
Recording Adverse Events ..............................................................................................77
8.4
Grading of the Severity of an Adverse Event ..................................................................78
8.5
Describing Adverse Event Relationship to Study Drug and Study Procedures ..............78
8.6
Adverse Event Reporting Period .....................................................................................79


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8.7
Study Center Reporting Requirements ............................................................................80
8.7.1
Adverse Event Reporting Requirements ....................................................................80
8.7.2
Pregnancy ...................................................................................................................81
8.7.3
Contact Information for Reporting an SAE or Pregnancy ..........................................82
8.8
Sponsor Reporting Requirements ....................................................................................82
9
LABORATORY AND OTHER ASSESSMENTS ..............................................................83
9.1
Methods and Analytes .....................................................................................................83
9.2
Sample Shipping, Storage, and Retention.......................................................................85
10
EFFICACY ASSESSMENTS..............................................................................................86
10.1
Overview .........................................................................................................................86
10.2
Methods of Assessment ...................................................................................................86
10.3
Timing of Assessments....................................................................................................87
10.4
Definitions of Tumor Remission and Progression ..........................................................87
10.4.1 
Complete Remission without Minimal Residual Disease ..........................................87
10.4.2 
Complete Remission ...................................................................................................88
10.4.3 
Complete Remission with Incomplete Blood Count Recovery..................................88
10.4.4 
Partial Remission ........................................................................................................88
10.4.5 
Treatment Failure........................................................................................................89
10.4.6 
Disease Relapse or Progression ..................................................................................89
10.4.7 
Nonevaluable ..............................................................................................................89
11
STATISTICAL CONSIDERATIONS .................................................................................90
11.1
Analysis Conventions ......................................................................................................90
11.1.1 
Analysis Sets ...............................................................................................................90
11.1.2 
Data Handling Conventions ........................................................................................90
11.2
Analysis Plan ...................................................................................................................91
11.2.1 
Subject Disposition and Baseline Characteristics.......................................................91
11.2.2 
Study Drug Exposure and Concomitant Medications ................................................91
11.2.3 
Safety ..........................................................................................................................92
11.2.4 
Pharmacokinetics ........................................................................................................95
11.2.5 
Pharmacodynamics .....................................................................................................96
11.2.6 
Efficacy Analyses .......................................................................................................96
11.2.7 
Other Analyses............................................................................................................97
11.3
Timing of Analyses .........................................................................................................97


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11.3.1 
Interim Analyses.........................................................................................................97
11.3.2 
Final Analyses ............................................................................................................98
11.3.3 
Follow-up Analyses....................................................................................................98
11.4
Basis for the Planned Sample Sizes .................................................................................98
12
STUDY ADMINISTRATION AND RESPONSIBILITIES ...............................................99
12.1
General Investigator Responsibilities ..............................................................................99
12.2
Protocol Compliance .......................................................................................................99
12.3
Compliance with Ethical and Regulatory Guidelines .....................................................99
12.4
Institutional Review Board/Independent Ethics Committee (IRB/IEC) .......................100
12.5
Informed Consent ..........................................................................................................101
12.6
Confidentiality ...............................................................................................................101
12.7
Study Files and Retention of Records and Biological Samples ....................................102
12.8
Subject Screening Log ...................................................................................................103
12.9
Modifications of the Protocol or Informed Consent Documents ..................................103
12.10 
Case Report Forms ........................................................................................................103
12.11 
Study Drug Accountability ............................................................................................104
12.12 
Monitoring .....................................................................................................................105
12.13 
Inspections .....................................................................................................................105
12.14 
Data Management ..........................................................................................................105
12.15 
Clinical Trial Insurance .................................................................................................106
12.16 
Communications with Regulatory Authorities ..............................................................106
12.17 
Public Notification of Study Conduct ...........................................................................106
12.18 
Study Reporting and Publication ...................................................................................106
12.19 
Study Discontinuation ...................................................................................................107
13
BIBLIOGRAPHY ..............................................................................................................108
14
APPENDICES ....................................................................................................................113
14.1
ECOG Performance Status ............................................................................................114
14.2
Cockcroft-Gault Method for Estimating Creatinine Clearance .....................................115
14.3
Substrates of CYP3A4 ...................................................................................................116
14.4
Strong Inhibitors and Inducers of CYP3A4 ..................................................................117
14.5
Drugs Known to Prolong the Cardiac QT Interval ........................................................118
14.6
Summary of Changes to Protocol – Amended Version 2..............................................121
14.6.1 
Overview of Changes ...............................................................................................121


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14.6.2 
Specific Changes ......................................................................................................123
14.7
Summary of Changes to Protocol – Amended Version 3..............................................147
14.7.1 
Overview of Changes ...............................................................................................147
14.7.2 
Specific Changes ......................................................................................................148
14.8
Summary of Changes to Protocol – Amended Version 4..............................................151
14.8.1 
Overview of Changes ...............................................................................................151
14.8.2 
Specific Changes ......................................................................................................152
14.9
Summary of Changes to Protocol – Amended Version 5..............................................158
14.9.1 
Overview of Changes ...............................................................................................158
14.9.2 
Specific Changes ......................................................................................................159
14.10 
Summary of Changes to Protocol – Amended Version 6..............................................161
14.10.1 
Overview of Changes ...............................................................................................161
14.10.2 
Specific Changes ......................................................................................................162
14.11 
Summary of Changes to Protocol – Amended Version 7..............................................168
14.11.1 
Overview of Changes ...............................................................................................168
14.11.2 
Specific Changes ......................................................................................................171
14.12 
Summary of Changes to Protocol – Amended Version 8..............................................182
14.12.1 
Overview of Changes ...............................................................................................182
14.12.2 
Specific Changes ......................................................................................................182


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Study Protocol: LAM-003-HEM-CLN02 
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LIST OF IN-TEXT TABLES
Table 1: 
LAM-003 Starting Dose Levels .................................................................................59
Table 2: 
Protocol-Recommended Contraceptive Methods.......................................................68
Table 3: 
Schedule of Activities ................................................................................................71
Table 4: 
Grading of Adverse Event Severity ............................................................................78
Table 5: 
Relationship of Study Drug to Adverse Event ...........................................................79
Table 6: 
Study Center Reporting Requirements for Adverse Events .......................................80
Table 7: 
Contact Information for Reporting SAEs or Pregnancies..........................................82
Table 8: 
Laboratory and Other Parameters to Be Assessed .....................................................84
Table 9: 
Statistical Basis for 3+3 Dose-Escalation Paradigm ..................................................98
LIST OF IN-TEXT FIGURES 
Figure 1. 
LAM-003 Structure ....................................................................................................31
Figure 2: 
In Vivo Conversion of LAM-003 to LAM-003A and L-Alanine ..............................32
Figure 3: 
LAM-003 Demonstrates Potent Antileukemic Activity in AML Cells......................32
Figure 4. 
LAM-003 In Vitro Efficacy in Cancer Cells from a Patient with Gilteritinib- 
and Sorafenib-Resistant AML ....................................................................................34
Figure 5. 
LAM-003 Efficacy in a Subcutaneous MV4-11 Human AML Xenograft 
Model in Immunodeficient Mice ................................................................................35


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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS
Abbreviation 
Definition
AE
adverse event 
AML 
acute myeloid leukemia 
ALP 
alkaline phosphatase
ALT 
alanine aminotransferase 
ANC 
absolute neutrophil count 
ANCOVA 
analysis of covariance 
aPTT 
activated partial thromboplastin time 
AST 
aspartate aminotransferase 
ATC 
Anatomical-Therapeutic-Chemical (drug coding system)
ATP 
adenosine triphosphate 
AUC 
area under the concentration-time curve 
AUC0-24
area under the concentration-time curve from time 0 to 24 hours postdose 
AUC0-inf
area under the concentration-time curve from time 0 to infinity 
AUC0-t
area under the concentration-time curve from time 0 to the time of last measurable concentration 
AV
atrioventricular
BID 
twice per day 
BUN 
blood urea nitrogen 
CD
cluster of differentiation 
CFR 
Code of Federal Regulations
CHO 
Chinese hamster ovary (cells) 
CI 
confidence interval 
CK
creatine kinase
Cl 
clearance 
CLIA 
Clinical Laboratory Improvement Amendments (certification) 
Cmax
maximum concentration 
CR
complete remission
CRc 
composite complete remission 
CRi 
complete remission with incomplete blood count recovery 
CRMRD- 
complete remission without minimal residual disease 
CRO 
contract research organization 
CT 
computed tomography 
CTCAE
Common Terminology Criteria for Adverse Events
CYP
cytochrome P450 (enzyme)
DLT
dose-limiting toxicity
DNA
deoxyribonucleic acid
DOR 
duration of remission 
DRP 
disease recurrence or progression 
EC50
half-maximal effective concentration 
ECG 
Electrocardiogram, electrocardiographic
eClCR
estimated creatinine clearance 
ECOG 
Eastern Cooperative Oncology Group
eCRF 
electronic case report form 
EDC 
electronic data capture 
EFS 
event-free survival 
ELN 
European Leukemia Network 
EU
European Union
FDA 
Food and Drug Administration
FDAMA 
Food and Drug Modernization Act of 1997 
FDG 
fluorodeoxyglucose 
FL
FLT3 ligand 


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Abbreviation
Definition
FLT3
FMS-like tyrosine kinase-3
FSH
follicle-stimulating hormone
GCP
Good Clinical Practice
G-CSF
granulocyte colony-stimulating factor
GGT
gamma-glutamyl transferase
GLP
Good Laboratory Practices
GM-CSF
granulocyte-macrophage colony-stimulating factor
GVHD
graft-versus-host disease
HBc
hepatitis B core (antibody)
HBsAg
hepatitis B surface antigen
HBV
hepatitis B virus
HCV
hepatitis C virus
HDPE
high-density polyethylene
hERG
human ether-à-go-go-related gene
HIV
human immunodeficiency virus
HNSTD
highest non-severely toxic dose
HSP
Heat shock protein
IC50 
half-maximal inhibitory concentration
ICH 
International Conference on Harmonization
ICMJE
International Committee of Medical Journal Editors
 
interferon-gamma
IND 
investigational new drug application 
IRB/IEC 
institutional review board/independent ethics committee 
ITD
internal tandem duplications 
IUD 
intrauterine device
IV
intravenous, intravenously 
JAK/STAT 
Janus kinase/signal transducer and activator of transcription 
Kd
equilibrium disassociation constant 
LDH 
lactate dehydrogenase 
LLQ 
lower limit of quantitation 
MedDRA 
Medical Dictionary for Regulatory Activities 
MRD 
minimal residual disease 
MRI 
magnetic resonance imaging 
MTD 
maximum tolerated dose 
NCI 
National Cancer Institute 
NE
nonevaluable 
NGS 
next-generation sequencing
NK 
natural killer (cells) 
NOAEL 
no-observed-adverse-effect level 
NSAID 
nonsteroidal anti-inflammatory drug 
OR
objective remission
OS 
overall survival
PCR 
polymerase chain reaction
PD-L1 
programmed death ligand 1 
PET 
positron emission tomography 
pKa
logarithm of the acid dissociation constant 
PR
partial remission 
PT
prothrombin time
QD 
once per day
QTc 
cardiac QT interval corrected for heart rate
QTcB 
cardiac QT interval corrected for heart rate using Bazett formula 
QTcF 
cardiac QT interval corrected for heart rate using Fridericia formula


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Abbreviation
Definition
PI3K/AKT
phosphoinositide 3-kinase/protein kinase B
RDR
recommended dosing regimen
RNA
ribonucleic acid
SAE
serious adverse event
SRC
safety review committee
SUSAR
suspected, unexpected, serious adverse reaction
t1/2
elimination half-life
TEAE
treatment-emergent adverse event
TF
treatment failure
TKD
tyrosine kinase domain
TLS
tumor lysis syndrome
Tmax
time of maximum concentration
TTR
time to remission
ULN
upper limit of normal
US(A)
United States (of America)
Vd
volume of distribution
WHODRUG
World Health Organization Drug Dictionary 
WT 
wild-type
 
beta human chorionic gonadotropin 
z 
terminal elimination rate constant


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PROTOCOL SYNOPSIS
Protocol Number 
LAM-003-HEM-CLN02 
Title of Study 
A Phase 1 Dose-Escalation Study of LAM-003 in Patients with Acute 
Myeloid Leukemia 
Investigational Product 
LAM-003 
US IND Number 
112055 
Study Background 
Acute myeloid leukemia (AML) is a clonal disease characterized by the 
proliferation and accumulation of myeloid progenitor cells in the bone 
marrow, resulting in hematopoietic failure with attendant neutropenia, 
thrombocytopenia, and anemia. Clinical manifestations of the disease can 
include thrombotic complications due to leukemic blast cell 
hyperleukocytosis, bacterial and fungal infections, bleeding, and fatigue. The 
incidence is highest between 55 and 85 years of age. Of all leukemias, AML 
has the lowest survival rate, particularly in elderly patients, who more 
frequently present with poor prognostic features and cannot tolerate intensive 
therapy. Five-year survival rates for all patients are <30%.  
Current standard of care treatment in younger, fit patients who can tolerate 
intensive therapy is daunorubicin and cytarabine chemotherapy as induction 
followed by high-dose cytarabine consolidation. Allogeneic bone marrow 
transplantation is also used for treating poor-prognosis, high-risk disease in 
younger adults. In older patients, most of whom are not able to tolerate 
intense chemotherapy, monotherapy with low-dose cytarabine or decitabine 
are among the therapeutic alternatives. Unfortunately, most patients will 
eventually experience disease relapse and – despite use of sequential 
therapies to control disease manifestations – are likely to die of their cancers.  
FMS-like tyrosine kinase-3 (FLT3) is a cell-surface receptor that is 
overexpressed in nearly all cases of AML. Activating mutations in FLT3 
occur in ~30% of patients and represent the most frequent genetic alteration 
in this disease. About 75% of the activating mutations are internal tandem 
duplications (FLT3-ITD) and 25% are point mutations in the activation loop 
of the tyrosine kinase domain (TKD) (consisting mostly of D835 mutations). 
Both types of mutations have been shown to constitutively activate FLT3 and 
are linked to a poor prognosis. Midostaurin, a FLT3 tyrosine kinase inhibitor, 
was recently approved as a first-line therapy in combination with standard 
induction chemotherapy, and other FLT3 inhibitors are in clinical 
development. However, resistance to these inhibitors develops through the 
acquisition of secondary mutations in FLT3, upregulation of other molecular 
pathways, or stimuli from the tumor microenvironment. Thus, novel 
mechanisms of action are needed to address these resistance mechanisms. 
Heat shock protein (HSP)90 is a highly conserved, ubiquitously expressed, 
molecular chaperone that plays an important role in regulating post-
translational folding, stability, and function of cellular proteins (often referred 
to as “client proteins”). Folding of client proteins is dependent on the ATPase 
activity of HSP90, and inhibitors of HSP90 can result in degradation of 
oncogenic client proteins through the ubiquitin-proteasome pathway. Mutant 
FLT3 is a client protein of HSP90. Mutant FLT3 expression is associated 


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with higher levels of HSP90 expression in primary AML cells, and HSP90 
appears to be important in mutant FLT3 stability and function.  
AI Therapeutics, Inc. is developing LAM-003 as a clinical HSP90 inhibitor. 
LAM-003 is the L-alanine prodrug of the active moiety LAM-003A. 
Following oral administration, removal of L-alanine by esterases in the 
intestinal tract leads to systemic absorption of LAM-003A. Nonclinical 
studies indicate that LAM-003A demonstrates FLT3-ITD client protein 
degradation and cytotoxicity toward FLT3-ITD-expressing AML cell lines 
and primary AML cells. LAM-003 shows significant efficacy in mouse 
xenografts bearing the FLT3-ITD-containing MV4-11 AML cell line. Of 
importance, LAM-003A is also active in cells that have become resistant to 
FLT3-ITD inhibitors due to receptor mutation, upregulation of “work-
around” pathways, or the influence of stromal cells that support AML 
survival and growth. LAM-003A also shows cytotoxicity toward FLT3-TKD 
and FLT3-wild-type (WT) AML. In cells transfected with FLT-TKD mutants, 
LAM-003 induced FLT3-TKD degradation and reduced cell surface 
expression with identical potency to FLT3-ITD. In FLT3-WT AML cell lines 
and patient-derived cells, many were as sensitive to LAM-003A as FLT3-ITD 
cell lines as measured by cytotoxicity assays. Hence, while FLT3-ITD AML 
is uniformly sensitive to LAM-003A, additional AML subtypes, driven by 
different oncogenic drivers that are client proteins of HSP90, are also 
sensitive. Further, LAM-003A downregulates the immunosuppressive 
protein, programmed death-ligand 1 (PD-L1) in AML cell lines, suggesting 
the potential for salutary immunomodulatory effects.  
Nonclinical pharmacokinetic studies indicate that LAM-003 should deliver 
comparable plasma exposures of LAM-003A as oral administration of 
LAM-003A. In vitro, LAM-003A is both a substrate and inhibitor of 
cytochrome P450 (CYP) 3A4. In nonclinical toxicology studies, the primary 
adverse effects of potential clinical relevance included gastrointestinal 
toxicities and lymphoid depletion.  
A Phase 1 dose-ranging study of LAM-003A evaluated 26 patients with 
advanced solid tumors. Doses as high as 320 mg twice per day (BID) 
(640 mg total per day) given daily in repeated 28-day cycles were evaluated. 
Based on pre-established definitions of dose-limiting toxicity (DLT), an 
MTD was not determined. However, at total doses >600 mg per day, 
Grade 1-3 gastrointestinal adverse events (AEs) occurred in 10/10 subjects 
and Grade 1-2 recoverable vision changes of light/dark adaptation difficulty, 
dark/dimmed vision, white ocular crescents, and/or floaters were observed in 
3/10 subjects (consistent with a known class effect for HSP90 inhibitors).  
Pharmacokinetic data from the study indicated that plasma maximum 
concentration (Cmax) and area under the concentration-time curve (AUC) 
values increased in a nearly dose-proportional manner. Day 21 exposures 
were 1- to 2-fold more than on Day 1, indicating modest drug accumulation. 
The average half-life (t1/2) after repeated dosing was 11.2 hours, supporting 
once-per-day (QD) or BID dosing. The recommended starting dose level was 
240 mg BID (480 mg total daily dose).  
Collectively, these nonclinical and clinical data provide a foundation for 
development of LAM-003 to characterize the drug’s safety, pharmacology, 
and antitumor activity in patients with AML. 


Investigational Product: LAM-003 
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Study Design 
This clinical trial is a Phase 1 study evaluating the safety, pharmacokinetics, 
pharmacodynamics, and antitumor activity of LAM-003 across a range of 
dose levels when administered to subjects with previously treated relapsed or 
refractory AML. Subjects will self-administer oral LAM-003 QD or BID 
continuously in repeated 28-day cycles. Cohorts of 3 to 6 subjects will be 
sequentially enrolled at progressively higher dose levels of LAM-003 using a 
standard 3+3 dose-escalation design. The initial cohort of subjects in this 
study will be prescribed 200 mg QD; this dose level is 2.4-fold below the 
recommended dosing regimen (RDR) of 480 mg total daily dose established 
in the prior Phase 1 study of LAM-003A in patients with solid tumors. Based 
on the pattern of DLTs observed in Cycle 1, escalation in this study will 
proceed to define an MTD and an RDR that may be at the MTD or a lower 
dose within the tolerable dose range.  
  
Study Objectives 
 
 Primary Objective 
 To determine the MTD and/or RDR of LAM-003 
 Secondary Objectives 
 To characterize the drug administration, safety, and supportive care 
profiles of LAM-003 
  
 To evaluate the pharmacokinetic profile of LAM-003 
  
 To characterize the onset, magnitude, and duration of antitumor activity 
and to assess survival in subjects with AML receiving LAM-003 
 Exploratory Objectives 
 To assess the effects of LAM-003 on pharmacodynamic markers relating to 
drug mechanism, disease, and immune status 
  
 To explore associations between baseline AML characteristics and 
outcomes in subjects administered LAM-003 
Study Endpoints 
 
 Primary Endpoints 
 MTD and/or RDR within the tested LAM-003 dose range  
 Secondary Endpoints 
Drug Administration, Safety, and Supportive Care Profiles 
  
 LAM-003 drug administration as assessed by prescribing records and 
subject compliance records 
  
Type, frequency, severity, timing of onset, duration, and relationship to 
study drug of any treatment-emergent adverse events (TEAEs); laboratory 
abnormalities; vital sign/oxygen saturation abnormalities; adverse 
electrocardiogram (ECG) findings; DLTs; SAEs; adverse events of special 
interest; or AEs leading to interruption, modification, or discontinuation of 
study treatment (referencing the Common Terminology Criteria for 
Adverse Events [CTCAE], Version 4.03, for grading of the severity of AEs 
and laboratory abnormalities) 
  
 Type, frequency, and timing of use of supportive care and other 
concomitant medications 
  
Pharmacokinetics 
  
 LAM-003 and LAM-003A plasma concentrations (as measured using a 
validated bioanalytical assay) 


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 Derived LAM-003 and LAM-003A pharmacokinetic parameters (including 
AUC, Cmax, time of maximum concentration [Tmax], volume of distribution 
[Vd], t1/2, terminal elimination rate constan
apparent clearance 
[Cl/F]) (as determined using noncompartmental methods) 
  
Antitumor Activity and Survival 
  
Efficacy will be evaluated using standard response and progression criteria as 
adapted for use in the context of protocol therapy for relapsed or refractory 
AML. Efficacy endpoints will include: 
  
 Complete remission without minimal residual disease (CRMRD-), defined as 
complete remission (see definition below) with no evidence of AML by 
flow cytometry 
  
Complete remission (CR), defined as <5% bone marrow blasts; no blasts in 
the peripheral blood; no blasts with Auer rods; no extramedullary disease; 
and peripheral blood meeting both of the following criteria: ANC 
 × 109/L and 
 × 109/L 
  
 Complete remission with incomplete count recovery (CRi), defined as <5% 
bone marrow blasts; no blasts in the peripheral blood; no blasts with Auer 
rods; no extramedullary disease; but with peripheral blood meeting either 
of the following criteria: ANC <1.0 × 109/L or platelet count <100 × 109/L 
  
 Composite complete remission (CRc), defined as CRMRD-, CR, or CRi 
  
 Partial remission (PR), defined as leukemia disease status meeting all of 
the following requir
to 25% or <5% bone marrow blasts but with Auer rods present; no blasts in 
the peripheral blood; no new or worsening extramedullary disease; and 
peripheral blood meeting both of the following criteria: ANC 
 × 109/L 
and 
 × 109/L 
  
 Overall remission (OR), defined as achievement of any of CR, CRi, or PR 
  
 Time to remission (TTR), defined as the interval from the start of study 
therapy to the first documentation of an objective remission 
  
Duration of remission (DOR), defined as the interval from the first 
documentation of objective remission to the earliest of the first 
documentation of disease relapse, disease progression, or death from any 
cause 
  
 Event-free survival (EFS), defined as the interval from the start of study 
therapy to the earliest of the first documentation of disease relapse, disease 
progression, treatment failure, or death from any cause 
  
 Overall survival (OS), defined as the interval from the start of study 
therapy to death from any cause 
 Exploratory Endpoints 
Pharmacodynamics 
  
 Changes in FLT3 and HSP (eg, HSP90, HSP70) protein expression and 
activation of downstream pathway components in AML blasts (as 
measured using flow cytometry and/or protein immunoblotting) 


Investigational Product: LAM-003 
Study Protocol: LAM-003-HEM-CLN02 
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CONFIDENTIAL 
Page 19 of 184 
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 Changes in HSP gene expression in AML blasts (as measured using 
quantitative polymerase chain reaction [PCR]) 
  
Changes in plasma FLT3 ligand (FL) concentration (as measured using an 
immunoassay) 
  
Changes in PD-L1 expression in AML blasts (as measured using flow 
cytometry) 
  
 Changes in the numbers, cell surface markers, and function of circulating 
B-cell, T-cell, natural killer (NK) cell, monocyte, and other immune 
subsets (as measured using flow cytometry) 
  
Biomarkers 
  
 Baseline AML blast FLT3 mutation type and FLT3 mutation-to-WT allele 
ratio  
  
 Baseline mutational profile in AML blasts (with germ-line control in 
saliva) (as assessed with next-generation sequencing [NGS]) 
Selection and Enrollment of Study Subjects 
 Planned Number of 
Subjects 
The total number of subjects will depend upon the numbers of subjects 
accrued to each dose level and the number of dose levels evaluated. If 
6 subjects are enrolled at all 5 planned starting dose levels and 6 additional 
subjects are enrolled at the MTD or RDR, as many as 36 subjects could be 
enrolled. If an additional dose level or an additional schedule (eg, twice-per-
day [BID]) administration is explored in 6 subjects per cohort, as many as 
12 additional subjects could be enrolled, bringing the potential sample size to 
48 subjects. To allow for the possibility that some subjects may not be fully 
evaluable, up to 60 subjects may be enrolled. 
 
 Target Population 
The target population comprises adult subjects with adequate performance 
status and organ function who have histologically confirmed AML that has 
progressed after appropriate prior therapy and have no potential for cure with 
currently available treatments. 
 Enrollment Criteria 
Inclusion Criteria 
  
Study candidates must meet all of the following inclusion criteria to be 
eligible for participation in this study: 
  
1)
 
  
2) Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, 
or 2 (see Appendix 14.1). 
  
3)
Current diagnosis of AML. 
  
4) AML has been previously treated and has progressed during or relapsed 
after prior therapy. 
  
5)
Presence of measurable AML, defined as the presence of >5% blasts in 
 nucleated 
cells and bone marrow spicules) and/or >1.0 × 109/L blasts in the 
peripheral blood. 


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6)
All acute toxic effects of any prior antitumor therapy (except 
hydroxyurea, cytarabine, and/or cyclophosphamide given to control blast 
count proliferation) resolved to Grade 1 before the start of study therapy 
(with the exception of alopecia [Grade 
 permitted], neurotoxicity 
[Grade 
 permitted], or bone marrow parameters [Grade 1 to 4 
permitted]). Note: For subjects with rapidly proliferative disease, use of 
hydroxyurea, cytarabine, and/or cyclophosphamide is allowed before 
the start of study therapy and during Cycle 1, but must be discontinued 
thereafter.  
  
7) Adequate hepatic profile: 
  
a) 
 
  
b) 
 
  
c) Serum bilirubi
 
  
8) Adequate renal function: 
  
a) Serum creatinine <1.5 × ULN (Grade 1), or 
  
b) Estimated creatinine clearance (eClCR
60 mL/min (eCLCR to be 
calculated by the Cockcroft-Gault formula [see Appendix 14.2]). 
  
9) Adequate coagulation profile: 
  
a)
  
b) 
(Grade 
 
  
10) Negative antiviral serology: 
  
a) Negative human immunodeficiency virus (HIV) antibody. 
  
b) Negative hepatitis B surface antigen (HBsAg) and negative hepatitis 
B core (HBc) antibody or undetectable hepatitis B (HBV) 
deoxyribonucleic acid (DNA) by quantitative PCR testing. 
  
c) Negative hepatitis C virus (HCV) antibody or negative HCV 
ribonucleic acid (RNA) by quantitative PCR. 
  
11) For female subjects of childbearing potential, a negative serum pregnancy 
test. 
  
12) For female subjects of childbearing potential, willingness to use a 
protocol-recommended method of contraception from the start of the 
screening perio
 days after the final dose of study therapy. 
Note: A female subject is considered to be of childbearing potential 
unless she has had a hysterectomy, bilateral tubal ligation, or bilateral 
oophorectomy; has medically documented ovarian failure (with serum 
estradiol and follicle-stimulating hormone [FSH] levels within the 
institutional laboratory postmenopausal range and a negative serum or 
 
 
  
13) For male subjects who can father a child and are having intercourse with 
females of childbearing potential who are not using adequate 
contraception, willingness to use a protocol-recommended method of 


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Study Protocol: LAM-003-HEM-CLN02 
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Page 21 of 184 
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contraception from the start of study therapy un
days after the final 
dose of study therapy and to refrain from sperm donation from the start of 
 days after administration of the final dose of 
study therapy. Note: A male subject is considered able to father a child 
unless he has had a bilateral vasectomy with documented aspermia or a 
bilateral orchiectomy. 
  
14) Willingness and ability of the subject to comply with scheduled visits, 
drug administration plan, protocol-specified laboratory tests, other study 
procedures (including all bone marrow biopsy/aspirations and 
radiographic studies), and study restrictions. 
  
15) Evidence of a personally signed informed consent indicating that the 
subject is aware of the neoplastic nature of the disease and has been 
informed of the procedures to be followed, the experimental nature of the 
therapy, alternatives, potential risks and discomforts, potential benefits, 
and other pertinent aspects of study participation. 
  
Exclusion Criteria 
  
Study candidates who meet any of the following criteria will not be eligible 
for participation in this study: 
  
1) Peripheral blood leukemic blast cell count >50 × 109/L before the start of 
study therapy and despite the use of hydroxyurea, cytarabine, and/or 
cyclophosphamide. 
  
2) Presence of known central nervous system (CNS) leukemia. Note: 
Radiographic imaging or cerebrospinal fluid analysis is not required as 
a condition of enrollment into the study. 
  
3) Presence of another cancer with disease manifestations or therapy that 
could adverse effect subject safety or longevity, create the potential for 
drug-drug interactions, or compromise the interpretation of study results. 
  
4) Ongoing Grade >1 proliferative or nonproliferative retinopathy (eg, due 
to diabetes mellitus, hypertension, macular degeneration, prematurity, 
genetic disorder).  Note: Subjects with resolved retinal tears due to age-
related vitreous humor shrinkage are not excluded. 
  
5)
Significant cardiovascular disease (eg, myocardial infarction, arterial 
thromboembolism, cerebrovascular thromboembolism) within 3 months 
prior to start of study therapy; angina requiring therapy; symptomatic 
peripheral vascular disease; New York Heart Association Class 3 or 4 
congestive heart failure; or uncontrolled G
 mmHg or sy
 mmHg) 
despite antihypertensive therapy. 
  
6) Significant screening ECG abnormalities, including unstable cardiac 
arrhythmia requiring medication, atrial fibrillation/flutter, left 
bundle-branch block, 2nd-degree atrioventricular (AV) block type II, 
3rd-
Fridericia method) >480 msec (Grade >1).  


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7)
Gastrointestinal disease (eg, gastric or intestinal bypass surgery, 
pancreatic enzyme insufficiency, malabsorption syndrome, symptomatic 
inflammatory bowel disease, chronic diarrheal illness, bowel obstruction) 
that might interfere with drug absorption or with interpretation of 
gastrointestinal AEs. 
8) Uncontrolled, ongoing systemic bacterial, fungal, or viral infection 
(including upper respiratory tract infections) at the time of start of study 
therapy. Note: Subjects with localized fungal infections of skin or nails 
are not excluded. Subjects may be receiving prophylactic or therapeutic 
antibiotics if there is no occurrence of fever within 48 hours before 
starting study therapy, and if antibiotics are not proscribed due to the 
potential for drug-drug interactions (see Exclusion Criterion 
.
  
9) Pregnancy or breastfeeding. 
  
10) Major surgery within 4 weeks before the start of study therapy. 
  
11) Subject is a candidate for hematopoietic stem cell transplantation 
(HSCT), has an appropriate HSC donor, and is willing to undergo HSCT.  
  
12) In subjects with prior HSCT, evidence of graft-versus-host disease 
 
study therapy. 
  
13) Prior solid organ transplantation. 
  
14) Prior HSP inhibitor therapy.  
  
15) Ongoing immunosuppressive therapy other than corticosteroids. Note: At 
study entry, subjects may be using systemic, intraarticular, inhaled, or 
topical corticosteroids. During study therapy, subjects may use systemic, 
enteric, intraarticular, inhaled, or topical corticosteroids as required for 
intercurrent conditions. 
  
16) Use of a strong inhibitor or inducer of cytochrome P450 (CYP) 3A4 
(including itraconazole, ketoconazole, posaconazole, or voriconazole) 
within 7 days prior to the start of study therapy or expected requirement 
for chronic use of a strong CYP3A4 inhibitor or inducer during Cycle 1 
of study therapy (see Appendix 14.4). Note: For subjects requiring 
antifungal prophylaxis/therapy, oral fluconazole or isavuconazonium 
can be considered. Echinocandins (eg, caspofungin, anidulafungin, or 
requirement for intravenous administration. 
  
17) Use within 7 days prior to the start of study therapy of a drug known to 
prolong the QT interval (see Appendix 14.5). Note: For subjects 
requiring antifungal prophylaxis/therapy, oral fluconazole is permitted 
given that the risk of QT prolongation is considered low (as 
documented in product labeling .  
  
18) Concurrent participation in another therapeutic or imaging clinical trial. 
Note: Subjects are not precluded from undergoing evaluations 
involving observation, noninvasive diagnostic procedures or sampling, 
or questionnaires as follow-up to a prior study or as components of a 
concurrent noninterventional study. 


Investigational Product: LAM-003 
Study Protocol: LAM-003-HEM-CLN02 
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CONFIDENTIAL 
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19) Any illness, medical condition, organ system dysfunction, or social 
situation, including mental illness or substance abuse, deemed by the 
investigator to be likely to interfere with a subject’s ability to provide 
informed consent, adversely affect the subject’s ability to cooperate and 
participate in the study, or compromise the interpretation of study results. 
Study Treatment
 Study Drug Dosage 
Forms, Strength, 
Storage and Supply 
The sponsor will supply LAM-003 as white, 0.25”, round, convex, film-
coated tablets containing 50 mg of drug substance. Inactive ingredients 
include: microcrystalline cellulose, lactose monohydrate, crospovidone, 
hydroxypropyl cellulose, colloidal silicon dioxide, sodium starch glycolate, 
compritol 888 ATO, Opadry clear and Opadry white. Tablets are packaged in 
high-density polyethylene (HDPE) bottles containing 28 tablets per bottle. 
During shipping and storage, bottles should remain refrigerated at 
temperatures of 2 to 8°C [35.6 to 46.4°F]).  
 Premedications 
Administration of antiemetics, antidiarrheals, or medical prophylaxis for 
tumor lysis syndrome (TLS) should be provided as indicated in Section 6.2.1 
of the protocol. 
 Study Drug 
Administration 
Dose Administration, Schedule, and Dosing Conditions 
 
In each 28-day cycle, subjects are to self-administer LAM-003 starting on 
Day 1 and then continuously thereafter (28 total doses/cycle). Subjects should 
take the study drug at approximately the same time each day, ideally at 
~24-hour intervals (eg, ~8AM every day) for the planned QD schedule or at 
12-hour intervals (eg, ~8AM and ~8PM every day) if a BID schedule is 
evaluated. In conjunction with frequent pharmacokinetic assessments on 
C1D1, C1D2, and C1D8, subjects should take the drug at the study center 
under the supervision of study personnel and the timing of drug 
administration must be documented in the clinic notes and/or in the subject 
diary. While variations in dosing schedule may occur in the outpatient setting, 
the prescribed regimen should be followed as closely as possible. 
At each dose administration, the number of LAM-003 tablets corresponding 
to the appropriate doses of each drug should be swallowed whole with 100 to 
200 mL (~4 to 8 ounces) of water. Subjects should be instructed not to bite or 
chew on the tablets. In case of breakage of the tablets in the oral cavity, 
additional water should be taken as a rinse. 
In conjunction with frequent pharmacokinetic assessments on C1D1, C1D2, 
and C1D8, subjects should ingest the drug while fasting (defined as no food 
with the exception of clear liqu
 
dosing). Pending the evaluation of the effect of food on LAM-003 absorption, 
subjects are encouraged to take the drug while fasting on other days. 
  
Starting Dose Levels 
  
Cohorts of 3 to 6 subjects will be sequentially enrolled at progressively 
higher starting dose levels of LAM-003 using a standard 3+3 design, as 
indicated in Table S-1. The initial cohort of subjects will be prescribed 
LAM-003 at Dose Level 1 (200 mg). Dose Levels -1 (100 mg) and 
-2 (50 mg) are provided to permit dose decrements if a subject experiences a 
TEAE requiring dose modifications to levels below Dose Level 1.  


Investigational Product: LAM-003 
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Table S-1. LAM-003 Starting Dose Levels 
 
Dose  
Level 
LAM-003 
Dosing Regimen 
Dose Change  
Relative to  
Prior Dose
 
-2  
50 QD
0.50
 
-1 
100 QD 
0.50
 
1 (initial dose level) 
200 QD 
Not applicable 
 
2 
300 QD 
1.50
 
3 
450 QD 
1.50
 
4 
600 QD 
1.33
 
5 
750 QD 
1.25
 
Abbreviations: QD=once per day
  
The following dose-escalation rules will be employed, considering DLTs 
observed in Cycle 1 of therapy: 
  
 Each dose level cohort will initially enroll 3 subjects. 
  
 If 0 of the first 3 subjects has a DLT, the next cohort of 3 subjects will be 
treated at the next higher dose level. 
  
 If 1 of the first 3 subjects in a cohort experiences a DLT, an additional 
3 subjects will be treated at that same dose level. If 0 of the additional 
3 subjects experience a DLT, the next cohort of 3 subjects will be treated at 
the next higher dose level. 
  
 If 2 of 3 or 2 of 6 subjects experience a DLT, the MTD will have been 
exceeded and 3 more subjects will be treated at the next lower dose level 
(if only 3 subjects were previously treated at that prior dose level). If 
6 subjects were previously treated at the prior dose level, that prior dose 
level will provisionally be considered the MTD. 
  
 An additional 6 subjects (up to 12 total) may be enrolled at the MTD or 
RDR. 
  
 With the concurrence of the Safety Review Committee (SRC) (comprising 
the investigators and clinical representatives of the sponsor), additional 
subjects (up to 12 subjects per dose level) may be accrued at dose levels at 
or below the MTD to refine the estimation of the RDR and further define 
the pharmacology of LAM-003. Such accrual may occur: 
  
o At Dose Level -1 or -2 (100 or 50 mg of LAM-003, respectively). 
  
o At an initially planned dose level (as indicated in Table S-1) or at a 
dose level that lies between the initially planned dose levels. 
  
o Using an alternative schedule (eg, BID) with a total daily dose that 
does not exceed the total daily MTD (rounded up or down to the 
nearest even multiple of 50 mg). 
  
The following additional procedures will be followed during the dose 
escalation: 
  
 The first subject to be treated at Dose Level 1 will 
 week 
after initiation of LAM-003 before any subsequent subjects are treated at 
the same dose level. 


Investigational Product: LAM-003 
Study Protocol: LAM-003-HEM-CLN02 
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for a QD schedule or 42/56 doses for a BID schedule) of planned Cycle 1 
LAM-003 doses per subject and must be observed for a minimum period of 
~4 weeks throughout this treatment period without DLT before subsequent 
subjects are enrolled at the next higher dose level. Any subject without 
DLT who does not complete these requirements may be replaced.  
  
 Escalation to the next dose level can only occur upon review of the safety 
data from all ongoing and previous subjects and with the concurrence of 
the SRC. 
  
Intrasubject dose escalation above the initially assigned dose level will be 
permitted as defined in Section 6.2.7 of the protocol. 
Accrual of additional subjects to a treatment cohort may be considered by 
the SRC with the concurrence of the study sponsor. 
 Definition of DLTs 
The SRC will meet when each cohort has completed Cycle 1 and will review 
safety, and any available pharmacokinetic or pharmacodynamic data. The 
sponsor, working in consultation with the investigators and SRC, will 
determine whether a TEAE meets a definition of DLT as defined in the 
protocol. Reference will be made to the CTCAE, Version 4.03, for grading 
the severity of TEAEs, treatment-emergent laboratory abnormalities, and 
DLTs, considering the known safety profiles of the study drug and other 
medical factors.  
The existing clinical experience indicates that nausea, vomiting, diarrhea, 
tachycardias, respiratory distress, and visual disturbances can occur in 
association with LAM-003A administration and may be dose-limiting at total 
daily doses >600 mg. Visual symptoms observed with LAM-003A have 
included darkening or dimming of vision, difficulties with light/dark 
adaptation, appearance of intermittent bilateral white ocular crescents, and 
visual floaters. Dose-dependent ocular symptoms described with other HSP90 
inhibitors have included visual dimming, difficulties with light/dark 
adaptation, nyctalopia (night blindness), photopsia (perceived flashes of 
light), photophobia (light sensitivity), and blurred vision.  
Based on this information but considering the limited experience with 
LAM-003/LAM-003A, DLTs for the purposes of establishing the MTD and 
RDR in this study will be defined as any of the following TEAEs occurring in
Cycle 1 of LAM-003 therapy that cannot be considered incontrovertibly 
related to the underlying malignancy, a comorbid condition, an intercurrent 
illness, or a concomitant medication: 
  
 
 
  
 
antiemetic support 
  
 
 
  
 
2 visual disturbances 
  
 
 
  
 Grade 3 TLS despite adequate prophylaxis (unless TLS results in no 
Grade 2 renal dysfunction or other Grade 2 end-organ injury and 
 


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 Grade 4 TLS despite adequate prophylaxis 
  
 
tion of 
asymptomatic Grade 
 laboratory abnormalities that improve to Grade 
within 72 hours) 
  
The occurrence of either of the following circumstances during Cycle 1:
  
o 
42/56 dose for a BID schedule) of planned LAM-003 doses due to an 
AE that is not primarily related to the underlying malignancy, a 
comorbid condition, an intercurrent illness, or a concomitant 
medication 
  
o Following a dose interruption starting in Cycle 1, failure to recover to 
baseline within 2 weeks from the last dose of LAM-003 due to a 
TEAE that is not primarily related to the underlying malignancy, a 
comorbid condition, an intercurrent illness, or a concomitant 
medication; occurrence of such a TEAE should also result in 
permanent discontinuation of study drug (see Section 6.5) 
 Definitions of MTD and 
RDR 
treated and which is associated with a Cycle 1 DL
The RDR may be the MTD or may be a lower dose within the tolerable dose 
range. Selection of the RDR will be based on consideration of short- and 
long-term safety information together with available pharmacokinetic, 
pharmacodynamic, and efficacy data. 
 Duration of Therapy 
Subjects may receive study therapy until the earliest of any of the following 
events: subject request to withdraw from study treatment; documented 
objective evidence of treatment failure or of AML relapse or progression 
while receiving study treatment at the highest individually tolerated dose 
level; for a subject in PR, continued red blood cell transfusion dependence at 
Week 20; intolerable toxicity despite appropriate supportive care and/or dose 
modification; fa
 weeks from 
the last dose of LAM-003 following interruption for a TEAE that is not 
primarily related to the underlying malignancy, a comorbid condition, an 
intercurrent illness, or a concomitant medication; the development of 
intercurrent illness or other substantial change in the subject’s condition or 
circumstances that would place the subject at unacceptable risk as determined 
by the study investigator in consultation with the medical monitor; initiation 
of treatment for the subject’s cancer with an off-study therapeutic regimen; 
pregnancy or breastfeeding; substantial noncompliance with study drug 
administration, study procedures, or study requirements in circumstances that 
increase risk or substantially compromise the interpretation of study results; 
discontinuation of the study by the study center, the study sponsor, relevant 
regulatory agencies, or the IRB/IEC.  


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Statistical Methods 
 
 Analysis Conventions 
Analysis Sets 
  
Appropriate data analysis sets will be defined. The full-analysis set will 
include data from all subjects who recei
analysis sets (responder and evaluable analysis sets) will be defined, as 
appropriate, and will include data from subjects who have the necessary 
baseline and on-study measurements to provide interpretable results for 
specific parameters of interest. 
  
Data Handling 
  
Data will be described and summarized by dosing regimen and cohort.  
Descriptive summaries for continuous variables will contain N (number in 
population); n (number with data); mean (with standard deviation and 
confidence intervals [CIs] on the mean); median; minimum; and maximum. 
Descriptive summaries for categorical variables will include N, n, percentage, 
and CIs on the percentage.  
The baseline value used in each analysis will be the last (most recent) predose 
value. As appropriate, changes from baseline to each subsequent time point 
will be described and summarized. Similarly, as appropriate, the most 
extreme change from baseline during the study will also be described and 
summarized. Shift tables or graphical techniques (eg, bar charts, line graphs) 
may be used when such methods are appropriate and informative.  
Data from all participating study centers will be pooled for all analyses. 
Analyses will be based upon the observed data unless methods for handling 
missing data are specified. If there is a significant degree of non-normality, 
analyses may be performed on log-transformed data or nonparametric tests 
may be applied, as appropriate. Unless otherwise indicated, CI for binary 
variables will be calculated using the binomial distribution (exact method) 
and will be 2-sided. Unless otherwise specified, statistical testing will be 
2-sided at a nominal 0.05 level of significance. Given the exploratory nature 
of this study, adjustments for multiple comparisons need not be applied. 
 Analysis Plan 
Subject Disposition and Baseline Characteristics 
  
Based on the full-analysis set, information regarding subject disposition, 
demographics, cancer history, tumor characteristics, and other baseline 
characteristics will be described. 
  
Study Drug Exposure, Concomitant Medications, and Safety 
  
Study drug administration and compliance, concomitant medication use, 
supportive care use, AEs, laboratory abnormalities, vital signs/oxygen 
saturation, body weight, and ECOG performance status will be described and 
summarized. For safety analyses, AEs will be classified using the Medical 
Dictionary for Regulatory Activities (MedDRA). The severity of AEs will be 
graded by the investigator according to the Common Terminology Criteria 
for Adverse Events (CTCAE), Version 4.03. Standard regulatory definitions 
of seriousness will be applied to AEs. Laboratory abnormalities will be 
graded according to CTCAE severity grade whenever applicable.  
 


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Quantitative and qualitative ECG assessments of rhythm abnormalities, 
cardiac intervals, wave form abnormalities, and ectopy will be reported. 
Concomitant medication use will be coded using the World Health 
Organization Drug Dictionary into Anatomical Therapeutic-Chemical 
classification (ATC) codes; data descriptions may particularly focus on 
supportive medications and care provided in response to any study-therapy-
induced adverse effects and any drugs that might represent a risk for a 
CYP3A4-mediated drug-drug interaction. 
  
Pharmacokinetics 
  
Noncompartmental methods will be used to derive pharmacokinetic 
parameters. LAM-003A concentrations and derived pharmacokinetic 
parameters will be described and will be summarized using appropriate 
graphical and tabular methods. Dose-exposure relationships will be 
characterized. 
  
Efficacy 
  
Efficacy analyses will be based on the full-analysis and responder data sets. 
Tumor response and progression will be assessed using standard response and 
progression criteria for AML as adapted to this protocol. Response rates will 
be presented with relevant CIs. Time-to-event endpoints will be summarized 
using Kaplan-Meier methods with appropriate censoring. Medians, ranges, 
and corresponding CIs will be presented. 
  
Other Analyses 
  
Using appropriate regression techniques, possible relationships between 
subject characteristics (eg, sex, race, age, weight, tumor characteristics, dose) 
and outcome measures (eg, pharmacokinetic parameters, pharmacodynamic 
parameters, efficacy) may be assessed. Similarly, associations between 
outcome measures (eg, relationships between pharmacokinetic and 
pharmacodynamic parameters) may be evaluated.  
 Basis for the Planned 
Sample Sizes 
In the dose escalation, the cohort sizes of 3 to 6 subjects allow evaluation of 
regimen safety using a standard definition of MTD (ie, a starting dose 
associated with DLT in 
Based on the planned 3+3 dose-escalation scheme, there is a high probability 
of dose escalation to the next dose level if the true underlying proportion of 
DLT is low at the current dose level. Conversely, there is a low probability of 
escalation to the next dose level if the true underlying proportion of DLT is 
high at the current dose level. 


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1
INTRODUCTION
1.1 
Acute Myeloid Leukemia 
Acute myeloid leukemia (AML) is a clonal disease characterized by the proliferation and 
accumulation of myeloid progenitor cells in the bone marrow, resulting in hematopoietic failure 
with attendant neutropenia, thrombocytopenia, and anemia [Liesveld 2016]. Clinical 
manifestations of the disease can include thrombotic complications due to leukemic blast cell 
hyperleukocytosis, bacterial and fungal infections, bleeding, and fatigue. Occurring 
predominately in adults, the incidence increases with increasing age, most commonly affecting 
those between 55 and 85 years of age [SEER 2017, Siegel 2017]. Of all leukemias, AML has the 
lowest survival rate, particularly in elderly patients, who more frequently present with poor 
prognostic features and cannot tolerate intensive therapy [Podoltsev 2017]. Five-year survival 
rates for all patients are <30% [SEER 2017].  
Current standard of care treatment in younger, fit patients who can tolerate intensive therapy is 
daunorubicin and cytarabine chemotherapy as induction followed by high-dose cytarabine 
consolidation [Döhner 2017, NCCN 2017]. Allogeneic bone marrow transplantation is also used 
for treating poor-prognosis, high-risk disease in younger adults. In older patients, most of whom 
are not able to tolerate intense chemotherapy, monotherapy with low-dose cytarabine or 
decitabine are among the therapeutic alternatives. Unfortunately, most patients will eventually 
experience disease relapse and despite use of sequential therapies to control disease 
manifestations are likely to die of their cancers. 
1.2 
FMS-Like Tyrosine Kinase-3 Receptor and Ligand in AML 
FMS-like tyrosine kinase-3 (FLT3) is a cell-surface receptor that dimerizes on binding its
cognate ligand, the cytokine FLT3 ligand (FL), resulting in autophosphorylation and 
transduction of signals promoting proliferation and survival via the Janus kinase/signal 
transducer and activator of transcription (JAK/STAT), phosphoinositide 3-kinase/protein 
kinase B (PI3K/AKT), and other pathways [Lyman 1998, Janke 2014, Tsapogas 2017]. Its 
ligand, FL, is a cytokine that promotes the expansion of hematopoietic precursors 
[Tsapogas 2017]. Circulating concentrations of FL are normally low, but rise in response to 
chemotherapy-induced or other bone marrow aplasia [Wodnar-Filipowicz 1996].  
FLT3 is overexpressed in nearly all cases of AML [Carow 1996]. Mutations in FLT3 occur in 
~30% of patients and represent the most frequent genetic alteration in this disease 
[Papaemmanuil 2016]. About 75% of these mutations are internal tandem duplications 
(FLT3-ITD) and 25% are point mutations in the activation loop of the tyrosine kinase domain 
TKD (consisting mostly of D835 mutations) [Pratz 2017]. The mutations are activating and the 
presence of a FLT-ITD mutation confers an adverse prognosis [Kiyoi 1999, Thiede 2002, 
Schnittger 2002, Fröhling 2002]. In addition to enzyme autoactivation arising from the mutation, 
FLT3-ITD receptors remain highly responsive to FL and progressive increases in circulating FL 
following sequential regimens of myelotoxic therapy [Wodnar-Filipowicz 1996] may impair the 
efficacy of drugs targeting FLT3 mutations in AML [Sato 2011].  
Given the importance of FLT3 in AML pathophysiology, FLT3 inhibitors have been developed 
and are undergoing clinical evaluation. Midostaurin, a multi-targeted tyrosine kinase inhibitor, 


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was recently approved as a first-line therapy in combination with standard induction 
chemotherapy [Stone 2017, Levis 2017]. Another clinically available multitargeted tyrosine 
kinase inhibitor, sorafenib, has been evaluated alone and in combination therapy in several AML 
treatment settings and is commonly administered off-label to patients with FLT3-mutant AML 
[Antar 2017]. Several potent and selective FLT3 inhibitors (eg, quizartinib, gilteritinib, 
crenolanib) are undergoing active clinical development as investigational agents [Garcia 2017]. 
Unfortunately, resistance to all of these types of inhibitors commonly develops through the 
acquisition of secondary mutations in FLT3, upregulation of other molecular pathways, or the 
influence of the bone marrow microenvironment [Ghiaur 2017]. Thus, novel drugs are needed 
that can circumvent these mechanisms of resistance. 
1.3
Heat Shock Proteins as Clinical Targets for AML Therapy
Heat shock protein (HSP)90 is a highly conserved, ubiquitously expressed, molecular chaperone 
that plays an important role in regulating post-translational folding, stability, and function of 
cellular proteins (often referred to as “client proteins”) [Nahleh 2012]. Cancer cells experience 
high levels of proteotoxic stress and rely upon stress-response pathways for survival and 
proliferation, thereby becoming dependent on stress-inducible proteins, such as HSP90. Because 
folding of client proteins is dependent on HSP90-mediated hydrolysis of adenosine triphosphate 
(ATP), inhibitors that disrupt the ATPase function of HSP90 can cause degradation of oncogenic 
client proteins through the ubiquitin-proteasome pathway, thereby offering a therapeutic 
approach to cancer. 
Mutant FLT3 is a client protein of HSP90 [Minami 2002, Yao 2003, Al Shaer 2008]. Mutant 
FLT3 expression is associated with higher levels of HSP90 expression in primary AML cells 
[Reikvam 2011]. Treatment with an HSP90 inhibitor induces mutant FLT3 degradation and 
tumor cytotoxicity [Yao 2003, Zong 2015], leading to enhanced sensitivity of AML blasts 
harboring this oncogenic mutation [Zong 2015].  
1.4 
LAM-003/LAM-003A 
Based on the collective knowledge regarding the roles of FLT3 and HSP90 in AML, 
AI Therapeutics, Inc. is developing LAM-003 as a clinical HSP90 inhibitor for patients with 
AML. The initial goal of development is to offer a novel treatment approach that can circumvent 
resistance in patients who have experienced failure of other drugs. Ultimately, it is hoped that 
LAM-003 administered alone or in combination can supplement or complement current 
treatment methods. 
1.4.1 
Background 
Myrexis Pharmaceuticals, Inc., Salt Lake City, Utah, USA (Myrexis) originally began 
development of the drug in the form of MPC-3100 (hereafter designated LAM-003A). IND-
enabling nonclinical studies supported a first-in-human study of LAM-003A in 26 patients with 
advanced solid tumors under IND 104348. Subsequently, Myrexis began nonclinical 
development of a prodrug, MPC-0767 (now designated LAM-003), to enhance aqueous 
solubility and LAM-003A delivery. Myrexis demonstrated that LAM-003 undergoes hydrolysis 
to LAM-003A in the gastrointestinal tract. Nonclinical studies using a xenograft model of gastric 
cancer showed that oral dosing of LAM-003 had comparable antitumor activity to oral dosing of 
LAM-003A. Pharmacokinetic studies in mice, rats, and monkeys showed similar plasma 


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exposures of LAM-003A when delivered as the prodrug or the active moiety, and that exposure 
to the prodrug (LAM-003) in the systemic circulation was negligible. For business reasons, 
Myrexis did not pursue further development of LAM-003. AI Therapeutics, Inc. subsequently 
acquired the rights to the drug with the intent of developing LAM-003 in patients with 
hematological cancers.  
1.4.2 
Chemistry 
LAM-003 has the chemical name of 
[(1S)-2-[4-[2-[6-amino-8-[(6-bromo-1,3-benzodioxol-5-yl)sulfanyl]purin-9-yl]ethyl]-1-
piperidyl]-1-methyl-2-oxo-ethyl] (2S)-2-aminopropanoate mono-mesylate, mono-hydrate]. The 
structure is shown in Figure 1. 
Figure 1. LAM-003 Structure 
N
N
N
N
NH2
S
O
O
Br
N
(S)
O
O
O
(S) NH2
Me
Me
MsOH
H2O
The molecular formula is C25H30BrN7O5S•CH4O3S•H2O and the molecular weight is 
734.64 g/mole. LAM-003 is modestly soluble in water (350 
logarithm of the acid 
dissociation constant (pKa) is 6.91. 
LAM-003 is the L-alanine prodrug of the active moiety LAM-003A. LAM-003 is converted by 
esterases to LAM-003A. This conversion occurs in vitro in culture media and in vivo at the brush 
border of the intestine as shown in Figure 2. Based on a LAM-003A molecular weight of 549.44, 
and assuming complete conversion, administration of LAM-003 is expected to result in delivery 
of ~75% of the LAM-003A that would occur with direct administration of LAM-003A. 


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Figure 2: In Vivo Conversion of LAM-003 to LAM-003A and L-Alanine
1.4.3
Nonclinical Experience
1.4.3.1
Efficacy Pharmacology
In support of clinical development, the pharmacology of LAM-003/LAM-003A has been 
extensively characterized in in vitro and in vivo nonclinical models of AML. 
1.4.3.1.1
In Vitro Studies
In vitro studies indicated that LAM-003 demonstrates mutant FLT3 client protein degradation 
and preferential cytotoxicity toward AML cell lines and primary AML cells harboring a 
FLT3-ITD mutation (Figure 3); in these experiments, the geometric mean EC50 values were 
576 nM for FLT3-ITD-mutant cells (n=8) vs 1525 nM for FLT3-wild-type (WT) cells (n = 11).
However, as also shown in (Figure 3), multiple FLT3-WT AML cell lines and patient-derived 
tumors share the enhanced sensitivity to LAM-003 displayed by FLT3-ITD AML cells in vitro.
Figure 3: LAM-003 Demonstrates Potent Antileukemic Activity in AML Cells 
Abbreviation: AML=acute myeloid leukemia, EC50=median effective concentration, FLT3=FMS-like tyrosine 
kinase 3, ITD=internal tandem duplication, WT=wild type


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To further characterize the ability of LAM-003 to cause FLT3-mutant degradation, testing was 
performed on BaF3 murine cells made dependent on several oncogenic FLT3 mutations 
(including: FLT3-WT, FLT3-ITD, FLT3 D835V, FLT3-ITD D835V, FLT3 D835Y, FLT3-ITD 
D835Y, FLT3 D835H, FLT3-ITD D835H, FLT3 F691L, and FLT3-ITD F691L). As assessed by 
flow cytometry, LAM-003 caused similar dose-dependent reductions in FLT3 cell surface 
expression on all mutant cell lines but had relatively little effect on BaF3 cells expressing a 
FLT3-WT receptor. By this measure, FLT3-TKD mutants are as sensitive to LAM-003 
degradation as FLT3-ITD mutations. 
To demonstrate that LAM-003 can degrade FLT3-ITD and diminish FLT3-mediated signaling, 
FLT3-ITD-mutant MV-4-11 and MOLM-13 AML cells were treated with 1 
-003 for 
24 hours. Cell surface FLT3 and downstream phosphorylation of the PI3K/AKT pathway 
enzyme S6 were evaluated by flow cytometry. In both MV-4-11 and MOLM-13 cell lines, there 
was a >65% reduction in cell surface FLT3 protein and corresponding >70% reduction in 
phospho-S6, confirming the expected drug effects on receptor expression and function. 
Importantly, LAM-003 is also active in cells that have become resistant to FLT3-ITD due to 
receptor mutation, upregulation of “work-around” pathways, or the influence of stromal cells that 
support AML survival and growth. Using the BaF3 system, LAM-003 activity was compared 
with that of crenolanib in a crenolanib-resistant FLT3-ITD F691L mutant. As expected, the BaF3 
cells harboring the FLT3-ITD-F691L mutant displayed a 23-fold resistance to crenolanib therapy 
as compared with the cells harboring FLT3-ITD. In contrast, LAM-003 had similar 
antiproliferative activity against the 2 FLT3-ITD mutant cell lines. LAM-003 cytotoxicity was 
also compared in parental MOLM-13 cells, which harbor FLT3-ITD and are midostaurin-
sensitive, to cytotoxicity in a MOLM-13 cell line grown in midostaurin to generate a 
midostaurin-resistant cell line. The MOLM-13 resistant cell line showed respective 2.5-fold and 
3-fold increases in EC50 values relative to the sensitive line for midostaurin and crenolanib, while 
the increase for LAM-003 was only 1.5-fold. In addition, when MOLM-14 FLT3-ITD-mutant 
cells were seeded in bone-marrow-stroma-conditioned medium, the FLT3 inhibitors gilteritinib 
and crenolanib showed marked loss of activity (increases in EC50 by >15- and >30-fold); in 
contrast, LAM-003 retained antiproliferative activity under stromal conditions, with only a 
1.6-fold increase in EC50. Particularly important in support of the proposed study was an 
evaluation of cancer cells from a patient who had primary refractory FLT-3-mutant AML
progressing after cytarabine/idarubicin induction chemotherapy, high-dose chemotherapy/total 
body irradiation with hematopoietic progenitor cell transplantation, gilteritinib, and sorafenib. In 
vitro analysis of cell viability (using Annexin V/7-AAD exclusion) confirmed resistance to 
gilteritinib but showed that the AML cells from this patient remained sensitive to LAM-003 
(see Figure 4). 


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Figure 4. LAM-003 In Vitro Efficacy in Cancer Cells from a Patient with Gilteritinib- and 
Sorafenib-Resistant AML
Abbreviation: AML=acute myeloid leukemia
T-cell-derived interferon gamma (IF
programmed death-ligand 1 (PD-L1) in a variety of cancer cell types, thus providing a
mechanism by which tumor cells can evade immune detection. To test whether LAM-003 can 
block IFN- -induced PD-L1 expression, 6 primary AML samples (FLT3-WT, n=2; FLT3-ITD, 
n=4) wer
alone, LAM-003 
LAM-003 for 24 hours. At this timepoint, LAM-003 did not affect the viability of the AML 
blasts. Samples from all
-
L1 on the cell surface (5- to 25-fold). LAM-003 alone did not affect basal PD-L1 cell surface 
protein. 
LAM-003 significantly r
-induced 
PD-L1 cell surface expression. These data show that, in addition to possessing cytotoxic activity 
against AML, LAM-003 may also possesses salutary immunopotentiating activity.
1.4.3.1.2
In Vivo Study
A xenograft study using the MV-4-11 AML cell line was performed in mice to demonstrate the 
in vivo efficacy of LAM-003. In animals with baseline subcutaneous tumor volumes of 80 to 
120 mm3, LAM-003 (200 mg/kg once per day [QD]
150 mg/kg QD × 16 days), 
resulted in tumor regression on Day 24. Cells had regressed relative to baseline by a mean of
83.7% and relative to control animal by 99% (p<0.001, unpaired t-test) (see Figure 5). 
Particularly notable was that 5 of the 10 animals in the LAM-003 group had complete tumor 
regressions. Also notable was that these highly significant anti-tumor effects were achieved 
without adverse effects on mean animal body weights. 


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Figure 5. LAM-003 Efficacy in a Subcutaneous MV4-11 Human AML Xenograft Model in 
Immunodeficient Mice
Abbreviations: QD=once per day, SEM=standard error of the mean
1.4.3.2
Safety Pharmacology
In a Good Laboratory Practices (GLP) study evaluating the potential effects of LAM-003A on 
cardiac repolarization, LAM-003A concentrations of 1 and 3 µM inhibited the human 
ether-à-go-go-related gene (hERG) potassium current by 12% and 21%, respectively. The 50% 
inhibitory concentration (IC50) of LAM-003A could not be determined because of solubility 
limitations. The results suggest minimal clinical potential for QT prolongation as predicted by 
this assay and when adjusting for protein binding (see Section 1.4.3.3).
The potential cardiovascular effects of LAM-003A were evaluated in vivo in female cynomolgus 
monkeys administered single doses of 0 (vehicle), 25, 50, and 100 mg/kg of LAM-003A by oral 
gavage. No biologically significant changes were observed in any hemodynamic measurement 
(systolic or diastolic blood pressure, mean arterial pressure, or heart rate), qualitative or 
quantitative electrogram (ECG) parameters, or troponin I levels after administration of any dose 
of LAM-003A. Based on these results, the no-observed-adverse-effect level (NOAEL) was 
considered to be 100 mg/kg (the highest dose tested).
Respiratory effects were evaluated in a single-dose study in Sprague-Dawley rats administered 
single doses of 0 (vehicle), 100, 200, or 350 mg/kg of LAM-003A by oral gavage. No adverse 
effects of any dose were observed on clinical signs, respiratory rate, tidal volume, or minute 
volume. Based on these results, the NOAEL was considered to be 350 mg/kg (the highest dose 
tested).


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Acute neurobehavioral effects were evaluated in a single-dose study in Sprague-Dawley rats 
administered single doses of 0 (vehicle), 100, 200, or 350 mg/kg of LAM-003A by oral gavage. 
No adverse clinical effects were observed on any parameter of the functional observation battery 
(autonomic function, reactivity and sensitivity, excitability, gait and sensorimotor coordination, 
and grip strength) at any dose. Based on these results, the NOAEL was considered to be 
350 mg/kg (the highest dose tested). 
1.4.3.3 
Pharmacokinetics, Metabolism, and Drug-Drug Interactions 
Pharmacokinetic and toxicokinetic nonclinical studies of LAM-003 and/or LAM-003A were 
performed in mouse, rat, dog, and monkey species and all documented systemic exposure to the 
drug when administered the oral route.  
Following oral administration of the LAM-003 prodrug to mice, rats, and dogs, systemic 
exposure to LAM-003A was equivalent to systemic exposure when LAM-003A was given 
directly by the oral route in equimolar doses. As anticipated, the systemic exposure to the 
prodrug LAM-003 was negligible.  
The pharmacokinetics of LAM-003A were investigated in mice, rats, dogs and monkeys 
following oral and intravenous (IV) dosing. Oral bioavailability was approximately 100% for 
high doses in mice, ranged from 46 to 68% in rats, and 41 to 56% in cynomolgus monkeys. In 
toxicokinetics studies, time of maximum concentration (Tmax) values typically ranged from 1 to 
2 hours in the rat and from 2 to 3.7 hours in the monkey. Exposures increased with increasing 
dose across species; in monkey, increases in mean values for maximum concentration (Cmax) and 
area under the concentration-time curve (AUC) appeared greater than dose proportional. 
Plasma protein binding data in humans indicated that LAM-003 shows 91.6% protein binding 
(ie, an unbound plasma fraction of 8.4%). 
There was no evidence of drug accumulation during oral dosing in the toxicokinetic studies, 
consistent with half-life (t1/2) values of LAM-003A ranging from 2.6 to 13.9 hours in mice, 3.0 to 
5.5 hours in rats, 3.3 to 9.4 hours in rats, and 4.5 to 9.3 hours in monkeys. 
When metabolism was evaluated in human liver microsomes, 7 unique chromatographic peaks 
were detected by mass spectrometric-detection and the identities of 4 of these peaks were 
established. All metabolites detected in human microsomes were also detected in rat and/or 
monkey microsomes. These data confirmed that there were no unique human metabolites relative 
to toxicology species and that rat and monkey were appropriate species for nonclinical 
toxicology assessments of LAM-003A.
When evaluated in rats, the primary route of elimination for LAM-003A and metabolites 
appeared to be through biliary elimination. Renal elimination was negligible (<1%) in rat, dog, 
and monkey. 
To assess for the possibility that LAM-003A metabolism might be altered by other drugs, an in 
vitro characterization with recombinant cytochrome P450 (CYP) enzymes was performed. This 
study concluded that LAM-003A was a substrate for the CYP3A4 and CYP3A5 isoforms. Until 
clinical drug-drug interaction data are available, these nonclinical findings suggest that 
coadministration of LAM-003 with strong inhibitors or inducers of CYP3A4/5 might perturb 
LAM-003A exposure and should be minimized (see Section 6.3.9). 


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The potential for LAM-003 acting as to perpetrate a drug-drug interaction was evaluated in vitro
using recombinant CYP enzymes. LAM-003A did not inhibit CYP1A2, CYP2C8, CYP2C9, 
CYP2C19, or CYP2D6 at concentrations that are likely to be achieved clinically. Inhibition of 
CYP3A4 was observed with an IC50 value of 
, suggesting the possibility that LAM-003 
could increase systemic exposures to drugs that are sensitive substrates of this enzyme. In a 
further study in pooled human liver microsomes, LAM-003A did not show direct inhibitory 
effects on CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, and CYP3A4/5. 
LAM-003A did not show time-dependent inhibition potential against CYP1A2, CYP2B6, 
CYP2C8, CYP2C19, or CYP2D6. However, LAM-003A demonstrated some evidence of time-
dependent inhibition against CYP2C9 with an IC50 value of 21.3 µM and more substantial time-
dependent inhibition against CYP3A4/5 with IC50 values of 0.636 µM (midazolam probe 
substrate) and 0.499 µM (testosterone probe substrate). Because the prior LAM-003A Phase 1 
clinical experience did not demonstrate time-dependent changes in LAM-003A Cmax and AUC 
following repeated dosing, the potential for clinically significant effects of LAM-003 on drugs 
that are metabolized by CYP3A4 appears to be low. However, investigators are advised to use 
caution when administering drugs that are sensitive or low-therapeutic-index CYP3A4 substrates 
(see Section 6.3.9). 
1.4.3.4 
General Toxicology 
In support of clinical development in patients with cancers, LAM-003A underwent toxicological 
evaluation in conformance with the International Conference on Harmonization (ICH) S9 
guidance on nonclinical assessments of anticancer pharmaceuticals [FDA 2010]. This evaluation 
included 28-day and 16-week GLP toxicology studies in rats and monkeys that formed the 
central basis for Phase 1, first-in-human dose selection and clinical safety monitoring.  In 
addition, a 28-day study compared the toxicology and toxicokinetics of LAM-003 and 
LAM-003A in rats. 
1.4.3.4.1 
28-Day LAM-003A Toxicology Study in Rats 
In this GLP study, rats were administered either vehicle or LAM-003A QD by oral gavage for 
28 days. Dose levels were 50, 100, or 200 mg/kg/day. The study included a 14-day recovery 
period.  
Deaths were observed after 10 days at 200 mg/kg/day and the dose was reduced in survival 
animals to 100 mg/kg/day. These animals had moderate adipose tissue depletion. 
Ophthalmoscopic examinations were negative for all animals. 
The primary effects of LAM-003A appeared to be generalized lymphoid depletion and 
erosion/ulcer/inflammation of the stomach; and slight changes in hematology, electrolytes, and 
minimal or sporadic increases in serum aspartate aminotransferase (AST), alanine 
aminotransferase (ALT), blood urea nitrogen (BUN), creatinine, or sorbitol dehydrogenase. At 
termination, there were mild dose-dependent decreases in potassium in both sexes at all dose 
levels. Chloride was also mildly decreased in males at 100 mg/kg/day. Clinical findings resolved 
during the recovery period except for continued cell depletion of the bone marrow of some 
animals. 


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Following 28 days of oral dosing of LAM-003A in rats at dose levels of 0, 50, 100 or 
200 mg/kg/day, the NOAEL was determined to be 100 mg/kg/day based on mortality noted at 
200 mg/kg/day. 
1.4.3.4.2 
16-Week LAM-003A Toxicology Study in Rats 
In this GLP study, rats were administered either vehicle or LAM-003A QD by oral gavage for 
16 weeks. Dose levels were 25, 50, or 100 mg/kg/day. The study included a 4-week recovery 
period.  
LAM-003A-related mortality occurred in males at the 100-mg/kg/day dose level (3 males in the 
main study and 6 toxicokinetic males). Clinical findings before death generally indicated a 
debilitated condition of these animals. At necropsy, the animals showed atrophy of the seminal 
vesicles, erosion/ulceration in the non-glandular stomach, and adipose tissue depletion in the skin 
and subcutaneous tissues. No other significant clinical findings were noted in this study except 
for decreased food consumption and body weights in animals in the 100-mg/kg/day dosing 
group. No ophthalmoscopic findings related to LAM-003A were observed.  
Notable clinical pathology changes that were considered related to LAM-003A in males and/or 
females at the 100-mg/kg/day dose level included increased neutrophils in both sexes on Day 90 
Serum alkaline phosphatase and gamma-glutamyltransferase (GGT) levels tended to be 
increased, particularly in males, on Day 90. Elevations in serum AST, ALT, and sorbitol 
dehydrogenase were also observed in males on Day 90 and in both sexes at termination. All 
changes resolved after the recovery period, and none was considered adverse. 
Thymus gland weights were lower (relative and absolute) in both sexes in the 100-mg/kg/day 
dose group at termination. These correlated with lymphoid depletion in males. Increased adrenal 
weights were noted in males in the 100-mg/kg/day dose group, and decreased pituitary weights 
were noted in females at all LAM-003A dose levels in a dose-dependent manner. There were no 
microscopic correlates for the changes in adrenal or pituitary weights. All changes resolved after 
the recovery period, and none was considered adverse. 
Microscopic changes related to LAM-003A were noted in both sexes in the 100-mg/kg/day dose 
group and in females in the 50-mg/kg/day dose group. These included multifocal erosions/ulcers 
with or without perforations (sometimes accompanied by inflammation, hemorrhage, and/or 
bacterial colonies) in males in the 100-mg/kg/day dose group; mixed hematopoietic cell 
depletion of the femur and sternum bone marrow in both sexes in the 100-mg/kg/day dose group; 
and generalized lymphoid depletion of the spleen with pigmented macrophages in both sexes in 
the 100-mg/kg/day dose group and in females in the 50-mg/kg/day dose group. Most of these 
findings resolved during the recovery period. 
Following 16 weeks of oral dosing of LAM-003A in rats at dose levels of 0, 25, 50, or 
100 mg/kg/day, the NOAEL was determined to be 50 mg/kg/day  
1.4.3.4.3 
28-Day LAM-003A Toxicology Study in Monkeys 
In this GLP study, cynomolgus monkeys were administered either vehicle or LAM-003A QD by 
oral gavage for 28 days. Dose levels were 10, 25, or 50/35 mg/kg/day. The study included a 
28-day recovery period.  


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One male and one female in the 50-mg/kg dose group were euthanized in extremis on Day 5 of 
dosing. Clinical signs, including soft and/or watery feces, inappetence, decreased activity, and 
abnormal posture, were observed in the animals in the 50-mg/kg/day dose group before death. 
The remaining animals in the 50-mg/kg dose group were allowed a dose holiday of 6 days and 
then received a reduced dose of 35 mg/kg/day for 21 days. Body weight gain was lower during 
 mg/kg/day than in those 
who were administered the 10-mg/kg/day dose; weight rebounded during the recovery period. 
No LAM-003A-related ophthalmoscopic findings or effects on urinalysis parameters were 
observed. 
No effect of LAM-003A was observed on qualitative ECG parameters, heart rate, PR or RR 
interval, or QRS duration. A mild dose-related increase in QTc interval, relative to prestudy 
values, was observed at the terminal intervals, but postdose values were not different from 
predose values. The effect on the QTc interval was reversible, and the increase in the QTc 
interval never exceeded 10%. 
Blood samples that were collected before early termination on Day 5 from the animals in the 
50-mg/kg/day dose group that had declining health status exhibited increased levels of total 
leukocytes (primarily neutrophils). Decreased values for erythrocytes, hemoglobin, and/or 
hematocrit were noted in the 25- and 50/35-mg/kg/day dose groups on Day 5 and at termination. 
Reticulocyte values tended to be higher than in controls on Day 5 and at termination, but the 
response was inadequate relative to the decreased red cell mass. Macroscopic observations 
included red discoloration/foci in the stomach and generalized lymphoid depletion. All these 
observations appeared to be reversible with cessation of treatment except for thymic depletion in 
1 female in the 50/35-mg/kg/day dose group, which remained at the end of the recovery period. 
Following 28 days of oral dosing of LAM-003A in monkeys at dose levels of 10, 25, or 
50/35 mg/kg/day, the NOAEL was determined to be 50 mg/kg/day.  
1.4.3.4.4 
16-Week LAM-003A Toxicology Study in Monkeys 
In this GLP study, cynomolgus monkeys were administered either vehicle or LAM-003A QD by 
oral gavage for 16 weeks. Dose levels were 6.25, 12.5, or 25 mg/kg/day. The study included a 
4-week recovery period.  
Soft/watery feces were evident in all groups, including the control group, although the incidence 
and severity were greater in the 25-mg/kg/day dose group than in the control group. Three 
animals (12.5-mg/kg/day dose group, 1 female; 25-mg/kg/day dose group, 1 male and 1 female) 
were euthanized in extremis secondary to the consequences of the watery/soft feces. Additional 
findings noted at the 25-mg/kg/day dose level included hypothermia and dehydration. Body 
weight gain among both sexes was lower during in the 25-mg/kg/day dose group than in the 
other dose groups, but this generally resolved during the recovery period. There were no 
ophthalmoscopic findings during the study. 
No effects on qualitative or quantitative ECG parameters were observed. No adverse effects of 
LAM-003A were observed on any clinical pathology parameter. At necropsy, there were no 
organ weight effects or definitive microscopic findings that were attributable to LAM-003A.  
Following 16 weeks of oral dosing of LAM-003A in monkeys at dose levels of 6.25, 12.5, or 
25 mg/kg/day, the NOAEL was determined to be 12.5 mg/kg/day. The dose level of 
25 mg/kg/day was considered the highest non-severely toxic dose (HNSTD) in this study. 


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1.4.3.4.5 
Comparative Repeat-Dose Study of LAM-003 and LAM-003A 
This study was conducted to evaluate the potential toxicity and toxicokinetics of LAM-003 and 
LAM-003A in rats when administered orally for 28 days followed by a 14-day recovery period 
Two groups of Sprague-Dawley rats were administered LAM-003 at dose levels of 67 and 
134 mg/kg/day (respective molar equivalent doses of 50 and 100 mg/kg/day of LAM-003A). 
One group of animals was administered LAM-003A at a dose level of 100 mg/kg/day (the 
NOAEL of LAM-003A in a previous study). One additional group of animals was administered 
vehicle. Following 28 days of administration, recovery animals were maintained for a 14-day 
recovery period.  
No early deaths occurred. A lower body weight gain was observed in males given 100 mg/kg/day 
LAM-003A and in males given 134 mg/kg/day LAM-003 during the dosing period. Further loss 
was not observed during recovery. No effects on food consumption or changes in ophthalmology 
were noted in any group. 
Minimal to mild decreases in lymphocytes, eosinophils, basophils and platelets were observed in 
both sexes receiving 134 mg/kg/day LAM-003 and 100 mg/kg/day LAM-003A. The changes 
were similar in magnitude between animals receiving LAM-003 and LAM-003A. Minimal 
increases in serum AST and ALT were observed at termination in both sexes given 
100 mg/kg/day LAM-003A. Although these changes were considered related to treatment, they 
were not considered biologically relevant based on their small magnitude and/or and lack of 
histopathologic correlates. These changes had resolved by the recovery interval. 
Spleen and thymus weights were decreased in both sexes at 67 and 134 mg/kg/day of LAM-003 
and at 100 mg/kg/day LAM-003A. Similar microscopic findings were observed in rats given 
LAM-003 or LAM-003A orally for 28 days, including minimal to mild cortical lymphoid 
necrosis and/or minimal to mild generalized lymphoid depletion of the thymus; minimal to mild 
mixed depletion of the bone marrow; and minimal edema, minimal hyperkeratosis, minimal 
epithelial hyperplasia and/or mild erosion/ulceration of the stomach in both sexes, primarily in 
the high dose groups (100 mg/kg/day equimolar dose). Minimal to moderate physeal thickening 
was observed in the growth plate of the femur in males in all LAM-003 and LAM-003A groups 
and minimal bilateral follicular cell hypertrophy in the thyroid gland was observed in females in 
the high-dose groups. All findings generally resolved during the recovery period. There were no 
toxicities observed in animals given LAM-003 that were not also observed in animals given 
equimolar doses of LAM-003A.
1.4.3.5 
Genotoxicity 
The mutagenic potential of LAM-003A was examined in the in vitro bacterial reverse gene 
mutation assay (Ames assay), with and without metabolic activation. LAM-003 was not 
mutagenic as indicated by the results of this assay.  
The effects of LAM-003A were evaluated in the in vitro Chinese hamster ovary (CHO) cell 
chromosomal aberration assay (with and without metabolic activation). With 3 hours of 
treatment, LAM-003A was considered negative for inducing chromosomal aberrations without 
metabolic activation and showed an equivocal result due to the presence of aberrations in the 
cultures treated with 62.5 µg/mL with metabolic activation (but in the context of cytotoxicity and 
drug precipitation)  With 18 hours of treatment, LAM-003A significant increases in cells with 


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chromosomal aberrations were observed in the cultures treated with the 2 higher concentrations 
of 5.0 and 15.0 µg/mL without metabolic activation. 
In the in vivo bone marrow micronucleus assay, LAM-003A was assessed for potential 
clastogenic activity and/or disruption of the mitotic apparatus by evaluation of micronuclei in 
polychromatic erythrocytes. In this assay, LAM-003A was administered orally at 0, 125, 250, or
500 mg/kg to Hsd:ICR (CD-1) mice. LAM-003A did not induce statistically significant increases 
in micronucleated polychromatic erythrocytes in the bone marrow of the test animals. Thus, 
LAM-003A was considered negative for clastogenic activity as indicated by this assay. 
1.4.3.6
Phototoxicity
The phototoxic potential of LAM-003 has not yet been evaluated. 
1.4.3.7 
Reproductive Toxicology 
Twenty-eight-day and 16-week general toxicology studies in rats and monkey indicated no 
adverse effects of LAM-003A on female organs of reproduction. In male rats that died while 
receiving the high dose of 100 mg/kg in a 16-week toxicology study, atrophy of the seminal 
vesicles was noted, but similar effects were not described in surviving animals or those 
administered lower doses of LAM-003A (see Section 1.4.3.4.2). These data suggest that the risk 
of adverse LAM-003 effects on human fertility may be low, however, nonclinical studies have 
not been performed to determine specifically whether LAM-003 or its metabolites might 
decrease reproductive function or potential. 
LAM-003 or LAM-003A has not yet been evaluated in embryo-fetal development studies. In 
addition, there is no information about whether the drug or its metabolites are excreted in breast 
milk during lactation.
Based on the information currently available, study participants will be informed of the potential 
for reproductive risks. Pregnant or breast-feeding women will be excluded from study 
participation. 
1.4.4 
Clinical Experience 
1.4.4.1 
Phase 1 Study of LAM-003A 
A Phase 1, multicenter (3 centers), open-label, dose-ranging, multiple-dose study was conducted 
by the previous sponsor (Myrexis) to evaluate the safety and pharmacokinetics and to determine 
the maximum tolerated dose (MTD) of LAM-003A in patients with advanced solid tumors.  
Twenty-six subjects (13 males and 13 females) of median age 63.5 years (range: 45 to 85 years) 
with diverse types of tumor histologies (ie, cancers of the breast, colon, lung, prostate, kidney, 
salivary gland; melanoma, mesothelioma, sarcoma; unknown primary) were enrolled to receive 
repeated 21- to 28-day cycles of LAM-003A self-administered orally on a QD or twice-per-day 
(BID) schedule. Dosing regimens included 50 mg/m2 QD (n=1), 100 mg/m2 QD (n=1), 
165 mg/m2 QD (n=1), 245 mg/m2 QD (n=6), 340 mg/m2 QD (n=2), 340 mg/m2 BID (n=6), 
240 mg BID (n=4), and 320 mg BID (n=5). Subjects received a mean of 1.7 cycles of therapy 
(range, 0 to 13 cycles).  


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Based on pre-established definitions of dose-limiting toxicity (DLT), an MTD was not 
determined. However, the drug was not well tolerated at total doses of >600 mg per day due to 
Grade 1-3 gastrointestinal adverse events (AEs) of nausea, vomiting, abdominal pain, diarrhea, 
and/or enteritis in 10/10 subjects.  
Cardiovascular-related AEs were considered possibly related to the study drug in 3 subjects; 
these events included Grade 1 sinus tachycardia in 2 subjects in the 640-mg dose group and 
Grade 3 supraventricular tachycardia in 1 subject in the 245-mg/m2 dose group. 
Electrocardiograms that were monitored on Days 1 and 21 for 8 to 12 hours indicated corrected 
QT intervals by the Fridericia correction method (QTcF) of >450 msec and 480 msec (Grade 1) 
in 4 of the 26 subjects. A prolonged QTcF interval (>500 msec) was noted in 1 subject; however, 
this subject had a pacemaker and the finding was not considered clinically relevant. 
At doses of >600 mg per day, Grade 1-2 recoverable vision changes of light/dark adaptation 
difficulty, dark/dimmed vision, white ocular crescents, and/or floaters were observed in 
3/10 subjects (consistent with known class effects for HSP90 inhibitors [Pacey 2011, 
Rajan 2011, Sessa 2013, Infante 2014, Bendell 2015, Shapiro 2015, Bendell 2016, Kong 2016]). 
Other notable potentially drug-related AEs included renal failure (1 subject) and respiratory 
failure (1 subject).  
Pharmacokinetic findings indicated median Tmax values in the range of 1 to 3 hours. Cmax and 
AUC increased in a nearly dose-proportional manner across the dose levels. Exposures were 
generally 1- to 2-fold greater on Day 21 than on Day 1, indicating minimal to modest drug 
accumulation. The average t½ based on all cohorts after repeated dosing was 11.2 hours, 
supporting QD or BID dosing. 
1.4.4.2 
Phase 1 Study of LAM-003 (Current Study) 
This ongoing Phase 1 multicenter, open-label, 3+3 dose-escalation study is being conducted by 
AI Therapeutics to evaluate the safety and pharmacokinetics and to determine the MTD of 
LAM-003 in patients with previously treated, relapsed or refractory AML. As of a cut-off date of 
10 Jun 2019, 9 subjects (6 males and 3 females) ranging in age from 26 to 82 years had received 
LAM-003 self-administered orally on a QD schedule. Dosing regimens included 200 mg QD 
(total n=6, DLT evaluable n=3) and 300 mg QD (total n=3, DLT evaluable n=3). Durations of 
LAM-003 administration at 200 mg QD were 2, 9, 12, 28, 56, and 57 days. Durations of 
LAM-003 administration at 300 mg QD were 21, 28, and 36 days. Reasons for discontinuation 
were progressive disease or lack of sufficient treatment response (n=8) or intercurrent illness due 
to AML complications (n=1).  
AEs appeared to be primarily related to AML, comorbid medical conditions, intercurrent illness 
or concomitant medications. Obvious LAM-003-related toxicities were not evident and no DLTs 
occurred. Laboratory or ECG abnormalities clearly attributable to the study drug were not 
observed. No drug-related ophthalmological findings were described. 
Pharmacokinetic data were available from subjects at LAM-003 dose levels of 200 mg QD 
(Day 1, n=4; Day 8, n=3) and 300 mg QD (Day 1, n=3; Day 8, n=3). As expected, exposure to 
the prodrug (LAM-003) in the systemic circulation was below the lower limit of quantitation of 
the assay (<1.0 ng/mL). LAM-003A exposures in the plasma was observed in all subjects. 
Increases in LAM-003A exposures were generally proportional to increases in LAM-003 dose. It 


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appeared that LAM-003A steady state was achieved between Day 1 and Day 8; LAM-003A 
concentrations at 24 hours following the first dose on Day 1 were comparable to trough levels on 
Day 8 and LAM-003A AUC values were similar on Days 1 and 8. The pharmacokinetic profile 
of LAM-003A following LAM-003 administration was consistent with that observed with 
LAM-003A administration in the prior Phase 1 experience in patients with solid tumors.  
1.5
Conclusions
The conduct of this Phase 1 study of LAM-003 in patients with AML is founded on a current 
understanding of the natural history and current therapies for patients with this malignancy; 
knowledge of the importance of FLT3 and HSP90 cellular pathways in the pathophysiology of 
this disease; and nonclinical and clinical information regarding the efficacy and safety of 
LAM-003 and LAM-003A. The collective data support the following conclusions:  
 Relapsed or refractory AML is a serious, disabling, and life-threatening disorder. Existing 
therapies can induce complete tumor regressions but often lose effectiveness over time. 
Through its effects as an HSP90 inhibitor and immunopotentiator, LAM-003 offers the 
potential for overcoming disease resistance and improving clinical outcomes for patients with 
previously treated AML. 
Clinical evaluation of LAM-003 in patients with AML has sound scientific rationale based 
on evaluation of its therapeutic potential in in vitro and in vivo models relevant to human 
leukemia.  
 Advancing the development of LAM-003 in this study is well supported by nonclinical 
evaluations of LAM-003 and LAM-003A pharmacology, pharmacokinetics, and toxicology 
and by Phase 1 assessment of the safety and pharmacokinetics of LAM-003A in patients with 
solid tumors. This collective information provides a basis for subject enrollment criteria; 
starting dose selection and dose escalation; administration of an appropriate dosing regimen 
and supportive care; and for safety, pharmacodynamic, pharmacokinetic, and efficacy 
monitoring within this study. 
 Given the seriousness of previously treated, progressive AML and the aggregate potential 
benefits considered in the context of potential risks, clinical development of LAM-003 in 
patients with AML is justified. 
The rationale for specific design features of the study is provided in relevant sections of the 
protocol, including Section 2.3 (Rationale for Study Design), Section 4.3 (Rationale for Selection 
of Endpoints), Section 5.6 (Rationale for Subject Selection), and Section 6.6 (Rationale for Study 
Drug Administration and Supportive Care). 
2 
STUDY DESIGN AND CONDUCT 
2.1 
Study Design 
This clinical trial is a Phase 1 study evaluating the safety, pharmacokinetics, pharmacodynamics, 
and antitumor activity of LAM-003 across a range of LAM-003 dose levels when administered 
to subjects with previously treated relapsed or refractory AML. Subjects will self-administer oral 
LAM-003 QD or BID continuously in repeated 28-day cycles. Cohorts of 3 to 6 subjects will be 
sequentially enrolled at progressively higher dose levels of LAM-003 using a standard 3+3 dose-


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escalation design. Based on the pattern of DLTs observed in Cycle 1, escalation will proceed to 
define an MTD and a recommended dosing regimen (RDR) that may be at the MTD or a lower 
dose within the tolerable dose range.  
2.2 
Study Conduct 
The study will be performed in accordance with the principles as set forth under the requirements 
of 21 Code of Federal Regulations (CFR) 50 and the ICH E6 GCP guideline. The research will 
be overseen by an institutional review board/independent ethics committee (IRB/IEC). The study 
protocol, any protocol amendments, informed consent documents, and any material used to 
describe the trial to potential subjects will be reviewed and approved by the IRB/IEC prior to the 
performance of any study-related procedures.  
AI Therapeutics, Inc. will serve as the regulatory sponsor for the study and will maintain an 
investigational new drug (IND) application with the FDA. The protocol will be submitted to an 
IND for LAM-003 (IND#112055) and the trial design and results will be subject to review by the 
FDA. 
AI Therapeutics, Inc. will also serve as the operational coordinator of the study and will oversee 
conduct of the study at participating study centers and through contract research organization 
(CROs). The CROs will perform activities relating to medical monitoring; pharmacovigilance; 
site monitoring; data management and study reporting; sample handling; and centralized 
performance of pharmacokinetic and pharmacodynamic assays, evaluation of ECG data, and 
reviews of drug efficacy. 
During the study, assessments of safety and trial conduct will be performed by a safety review 
committee (SRC) comprising the investigators and clinical representatives of the sponsor. AEs 
and serious adverse events (SAEs) will be reviewed on an ongoing basis to identify any safety 
concerns. Conference calls among the members of the SRC will be conducted periodically to 
discuss study progress, exchange study information, and review safety events (in particular, 
DLTs; SAEs; adverse events of special interest; and AEs leading to dose interruption, dose 
reduction, or therapy discontinuation), determine whether additional dose levels should be 
evaluated, and discuss potential amendments to the protocol. It is expected that these discussions 
will be scheduled at intervals of ~2 to 4 weeks unless accrual to the study and decisions 
regarding study conduct or transitions between the dosing cohorts indicate the need for an 
alternative schedule of reviews.  
A central histopathological review of bone marrow and peripheral blood results will be 
established to evaluate changes in AML disease status. The review will be performed by a board-
certified hematopathologist and will be managed by a CRO selected by the sponsor. The findings 
of the central review (considered together with any pertinent radiographic or clinical information 
regarding extramedullary disease) will be considered primary for analyses of efficacy endpoints. 
2.3 
Rationale for Study Design 
The study has been designed to provide critical dosing, safety, pharmacokinetic, 
pharmacodynamic, and early efficacy data in support of future clinical development of LAM-003
in larger clinical trials.  


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Dose-ranging in cohorts of 3 to 6 subjects using a 3+3 design is consistent with usual oncologic 
drug development in the Phase 1 evaluation of various types of anticancer agents; this method 
provides efficient dose escalation while limiting the number of subjects who are exposed to 
excessively toxic doses of study drug.  
Centralized conduct of the study using experienced sites, investigators, CROs and laboratories is 
intended to provide a consistent approach to assessments of LAM-003 safety, pharmacology, and 
efficacy. Establishment of an SRC ensures collective investigator and sponsor input into critical 
assessments and decisions affecting trial conduct. Central histopathological review of AML 
disease status offers a systematic expert interpretation of efficacy results. 
3
STUDY OBJECTIVES
3.1 
Primary Objective 
 To determine the MTD and/or RDR of LAM-003
3.2 
Secondary Objectives 
 To characterize the drug administration, safety, and supportive care profiles of LAM-003
 To evaluate the pharmacokinetic profile of LAM-003 
To characterize the onset, magnitude, and duration of antitumor activity and to assess 
survival in subjects with AML receiving LAM-003 
3.3 
Exploratory Objectives 
 To assess the effects of LAM-003 on pharmacodynamic markers relating to drug mechanism, 
disease, and immune status 
 To explore associations between baseline AML characteristics and outcomes in subjects 
administered LAM-003 
4 
STUDY ENDPOINTS 
4.1 
Primary Endpoints 
 MTD and/or RDR within the tested LAM-003 dose range  


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4.2
Secondary Endpoints
4.2.1
Drug Administration, Safety, and Supportive Care Profiles
LAM-003 drug administration as assessed by prescribing records and subject compliance 
records 
 Type, frequency, severity, timing of onset, duration, and relationship to study drug of any 
treatment-emergent adverse events (TEAEs); laboratory abnormalities; vital sign/oxygen 
saturation abnormalities; adverse ECG findings; DLTs; SAEs; adverse events of special 
interest; or AEs leading to interruption, modification, or discontinuation of study treatment 
(referencing the Common Terminology Criteria for Adverse Events [CTCAE], Version 4.03 
[NCI 2010], for grading of the severity of AEs and laboratory abnormalities) 
 Type, frequency, and timing of use of supportive care and other concomitant medications 
4.2.2
Pharmacokinetics
 LAM-003 and LAM-003A plasma concentrations (as measured using a validated 
bioanalytical assay) 
 Derived LAM-003 and LAM-003A pharmacokinetic parameters (including area under the 
plasma AUC, Cmax, time of maximum concentration [Tmax], volume of distribution [Vd], 
terminal elimination half-life [t1/2], terminal elimination rate co
clearance [Cl/F]) (as determined using noncompartmental methods)
4.2.3 
Antitumor Activity and Survival 
Efficacy will be evaluated using standard remission and progression criteria [Cheson 2003, 
Döhner 2017] as adapted for use in the context of protocol therapy for relapsed or refractory 
AML. Efficacy endpoints will include: 
 Complete remission without minimal residual disease (CRMRD-), defined as complete 
remission (see definition below) with no evidence of AML by flow cytometry 
 Complete remission (CR), defined as <5% bone marrow blasts; no blasts in the peripheral 
blood; no blasts with Auer rods; no extramedullary disease; and peripheral blood meeting 
both of the following cr
1.0 × 109/L and 
 × 109/L 
 Complete remission with incomplete count recovery (CRi), defined as <5% bone marrow 
blasts; no blasts in the peripheral blood; no blasts with Auer rods; no extramedullary disease; 
but with peripheral blood meeting either of the following criteria: ANC <1.0 × 109/L or 
platelet count <100 × 109/L 
 Composite complete remission (CRc), defined as CRMRD-, CR, or CRi 
 Partial remission (PR), defined as leukemia disease status meeting all of the following 
requireme
blasts but with Auer rods present; no blasts in the peripheral blood; no new or worsening 
extramedullary disease; and peripheral blood meeting both of the following criteria: 
ANC 
.0 × 109/L and 
 × 109/L 
 Overall remission (OR), defined as achievement of any of CR, CRi, or PR 


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 Time to remission (TTR), defined as the interval from the start of study therapy to the first 
documentation of an objective remission 
 Duration of remission (DOR), defined as the interval from the first documentation of 
objective remission to the earliest of the first documentation of disease relapse, disease 
progression, or death from any cause 
 Event-free survival (EFS), defined as the interval from the start of study therapy to the 
earliest of the first documentation of disease relapse, disease progression, treatment failure,
or death from any cause 
 Overall survival (OS), defined as the interval from the start of study therapy to death from 
any cause 
4.2.4 
Exploratory Endpoints 
4.2.4.1 
Pharmacodynamics 
 Changes in FLT3 and HSP (eg, HSP90, HSP70) protein expression and activation of 
downstream pathway components in AML blasts (as measured using flow cytometry and/or 
protein immunoblotting) 
 Changes in HSP gene expression in AML blasts (as measured using quantitative polymerase 
chain reaction [PCR]) 
 Changes in plasma FL concentration (as measured using an immunoassay) 
 Changes in PD-L1 expression in AML blasts (as measured using flow cytometry) 
 Changes in the numbers, cell surface markers, and function of circulating B-cell, T-cell, 
natural killer (NK) cell, monocyte, and other immune subsets (as measured using flow 
cytometry) 
4.2.4.2 
Biomarkers 
 Baseline AML blast FLT3 mutation type and FLT3 mutation-to-WT allele ratio  
 Baseline mutational profile in AML blasts (with germ-line control in saliva) (as assessed 
with next-generation sequencing [NGS])
4.3 
Rationale for Selection of Endpoints 
The proposed endpoints have been chosen based on relevance to the pathophysiology and 
clinical manifestations of AML; the known pharmacology of LAM-003/LAM-003A; and the 
goals of the study in establishing an appropriate LAM-003 dosing regimen and providing 
information regarding its efficacy. These types of endpoints have been employed in prior studies 
evaluating LAM-003A or other anticancer agents and can be evaluated with acceptable accuracy 
and reliability. 
Determination of an optimal dosing regimen is critical to ensuring adequate benefit:risk for 
future development. Selection of a final RDR will focus on evaluation of any DLTs in the first 
4 weeks of therapy (Cycle 1) but will also seek to balance short- and long-term safety 


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information with treatment administration, general feasibility, pharmacology, and efficacy 
findings. 
In defining the therapeutic ratio of a treatment for use in a clinical setting, it is imperative that its 
safety profile be fully characterized. Proper description of each AE or laboratory abnormality 
requires an understanding of the type, incidence, timing, severity, and relatedness to study drug. 
In this study, particular focus will be placed on monitoring for toxicities that were encountered in 
the nonclinical studies and prior clinical study of LAM-003A. For consistency of interpretation, 
AEs will be coded using the standard Medical Dictionary for Regulatory Activities (MedDRA). 
The severity of AEs and laboratory abnormalities will be graded using the well-defined CTCAE, 
Version 4.03 [NCI 2010]. Standard definitions for seriousness will be applied (see Section 8.1.2). 
interruption, dose modification, or discontinuation of the study drugs; and to SAEs. ECG 
evaluations will be performed to evaluate for any drug-related dysrhythmias, wave-form 
abnormalities, or perturbations of cardiac intervals; obtaining ECG data in coordination with 
pharmacokinetic analyses will permit exploration of exposure-QTc relationships. 
Ophthalmologic monitoring is consistent with recommendations for the characterization of 
findings in patients receiving antineoplastic agents with potential ocular toxicities 
[Renouf 2012], considering the potential mechanisms of HSP90 inhibitor effects on vision 
[Ochoa 2002, Sakai 2003, Zhou 2013, Kanamaru 2014]. 
Blood sampling for derivation of pharmacokinetic parameters is intended to provide 
characterization of LAM-003/LAM-003 exposure and disposition; evaluate for dose-exposure, 
pharmacokinetic-pharmacodynamic, and exposure-response relationships; assess drug 
accumulation with repeated dosing; and consider the implications of exposure analyses in 
establishing an optimal dosing regimen. Sampling is planned on Cycle 1 Day 1 (C1D1) and 
C1D8 (see Section 7) to generate acute and steady-state LAM-003 exposure information within a 
time period that will allow an assessment of LAM-003 accumulation but is sufficiently short so 
as to minimize loss of data due to subject dropout. On those days, frequent sampling for 8 hours 
postdose will provide detailed plasma concentration-time curves and permit generation of 
pharmacokinetic parameters while minimizing inconvenience for study participants and study 
center staff. Evaluation of LAM-003 plasma concentrations will be performed using liquid 
chromatography with tandem mass spectrometry as established in animal studies and validated 
for human plasma. Plasma samples will be retained for potential later analyses of LAM-003A
metabolites. 
Determinations of the magnitude and duration of changes in AML disease status will be based on 
well-established remission and progression criteria [Cheson 2003, Döhner 2017] as applied to 
bone marrow and peripheral blood laboratory measurements (and to radiographic or clinical 
information in subjects with extramedullary AML). Beyond assessing the ability of the study 
drug to control cancer growth, AML assessments will also be considered in defining the proper 
duration of treatment for each study participant. The specific endpoints of overall cancer control 
evaluated in this trial are customarily assessed and reported in studies of new therapies in 
patients with AML. CRMRD-, CR, CRi, and PR provide convenient categorization of the 
magnitude of clinically meaningful reductions in the extent of AML. TTR, DOR, and EFS offer 
well-established outcome measures that directly evaluate treatment effect, convey important 
information regarding the rapidity and duration of clinical benefit, can be characterized in all 
subjects using intention-to-treat principles, and are readily analyzed using statistical methods 


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such as Kaplan-Meier techniques. The 8- to 12-week cadence of tumor assessments is consistent 
with the expected natural history of remission and progression in relapsed AML, current clinical 
practice, and the goals of the trial in documenting meaningful LAM-003-mediated AML 
regression 
Changes in FLT3 expression, FLT3 pathway activation, HSP protein and gene expression, and 
PD-L1 expression in AML blasts are assessed during C1 therapy to provide evidence of drug 
mechanism, offer context for efficacy findings, and assist in final dose and schedule selection. 
Changes in plasma FL concentrations are intended to provide information that may corroborate 
drug effects on cellular alterations in FLT3. Immunophenotyping assays for changes in 
circulating B-cell, T-cell, NK cell, and monocyte subsets will characterize the peripheral immune 
status of the subject and any possible LAM-003 effects on these parameters. Baseline evaluations 
of FLT3 and overall mutational status in AML blasts are intended to generate subject selection 
hypotheses for future studies. 
5
RECRUITMENT AND SELECTION OF STUDY SUBJECTS
5.1 
Planned Number of Subjects 
The total number of subjects will depend upon the numbers of subjects accrued to each dose 
level and the number of dose levels evaluated. If 6 subjects are enrolled at all 5 planned starting 
dose levels and 6 additional subjects are enrolled at the MTD or RDR, as many as 36 subjects 
could be enrolled. If an additional dose level or an additional schedule (eg, BID) administration 
is explored in 6 subjects per cohort, as many as 12 additional subjects could be enrolled, bringing 
the potential sample size to 48 subjects. To allow for the possibility that some subjects may not 
be fully evaluable, up to 60 subjects may be enrolled. 
5.2 
Recruitment of Subjects 
Subjects will be enrolled, dosed, and evaluated by study center personnel who are experienced in 
the conduct of studies in subjects with relapsed AML. Patients who are being followed at each 
study center or are referred to the study center are candidates for the study. Study center 
coordinators may recruit appropriate candidates for screening by study physicians. The principal 
investigator, designated sub-investigators, or other designees at the study center will discuss the 
possibility of participation directly with patients who may be appropriate candidates for the 
study. 
Any recruitment or advertising materials will meet criteria as outlined in 21 CFR 50, “Protection 
of Human Subjects,” and will be approved by an IRB/IEC before implementation. These 
materials will not be coercive or offer undue inducements and will accurately reflect information 
regarding the study. 
The sponsor will post a description of the study on the ClinicalTrials.gov website. 
5.3 
Informed Consent Process 
Study candidates will be given a written informed consent document that describes study 
procedures, potential risks, and potential benefits, and informs them of their rights if they elect to 
become participants in the study. The informed consent document will be provided to them in a 
language that they understand well.  


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Prior to study candidate screening for enrollment in the study, the investigator or designee at the 
study center will describe the risks and benefits of participation in the study. Adequate time will 
be given to study candidates to read the informed consent document and to decide whether or not 
to participate in the study. Study candidates will be encouraged to ask questions of the study 
physician during the consent process and throughout the trial. They will be offered the option to 
take a copy of the informed consent document home to discuss the study with family, friends, 
and/or health care providers before deciding to take part in the study. If they agree to participate 
in the study, they will be required to sign and date the consent document and will be given a 
signed and dated copy to keep. Signing of the informed consent document by the study candidate 
will be required prior to initiation of any study activities that are not part of routine medical care. 
5.4
Enrollment and Replacement of Study Subjects
Inclusion and exclusion criteria will be reviewed for each potential subject by qualified study 
center personnel. If the consented study candidate is considered eligible for study participation, 
the study center will transmit a study-specific eligibility and enrollment form to the sponsor (or a 
designee). If medically appropriate, study candidates who do not initially meet screening criteria 
may be rescreened with the approval of the medical monitor. 
The sponsor (or a designee) will acknowledge receipt of the study candidate’s eligibility form 
and will complete the enrollment form indicating the LAM-003 dosing regimen. The enrollment 
form will be transmitted to the study center. Once the study center receives the completed 
enrollment form, the subject can begin treatment.  
Subjects who do not have the necessary baseline and on-study measurements to provide 
interpretable results for safety, pharmacodynamic, pharmacokinetics, or efficacy parameters may 
be replaced at the discretion of the SRC. In general, this will mean that subjects who do not 
complete study drug administration and protocol evaluation through Week 4 of therapy will be 
considered for replacement. The replacement subject will be assigned to the same treatment 
cohort as the original subject. Accrual of additional subjects to a cohort may also be considered 
at the discretion of the SRC. Replacement subjects or additional subjects may be accrued if there 
is agreement that treatment of such subjects is unlikely to constitute an unacceptable safety risk. 
5.5
Subject Selection Criteria
This clinical trial can fulfill its objectives only if appropriate participants are enrolled. The 
protocol-specified eligibility criteria are designed to select subjects for whom study participation 
is considered appropriate. All relevant medical and non-medical conditions should be taken into 
consideration when deciding whether this protocol is suitable for a study candidate. Eligibility 
criteria may not be waived by the investigator and conformance to the eligibility criteria will be 
reviewed in the case of a GCP or a regulatory authority audit. Any questions regarding a study 
candidate’s eligibility should be discussed with the medical monitor before enrollment. 
5.5.1 
Inclusion Criteria 
Study candidates must meet all of the following inclusion criteria to be eligible for participation 
in this study:
1. 


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2. Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2 
(see Appendix 14.1). 
3. Current diagnosis of AML. 
4. AML has been previously treated and has progressed during or relapsed after prior therapy. 
5. Presence of measurable AML, defined as the presence of >5% blasts in the bone marrow 
 nucleated cells and bone marrow spicules) 
and/or >1.0 × 109/L blasts in the peripheral blood. 
6. All acute toxic effects of any prior antitumor therapy (except hydroxyurea, cytarabine, and/or 
cyclophosphamide given to control blast count proliferation) resolved to Grade 1 before the 
start of study therapy (with the exception of alopecia [Grade 
tted], neurotoxicity 
[Grade
 Note: For 
subjects with rapidly proliferative disease, use of hydroxyurea, cytarabine, and/or 
cyclophosphamide is allowed before the start of study therapy and during Cycle 1, but must 
be discontinued thereafter. 
7. Adequate hepatic profile: 
a. Serum 
  
b. 
 
c. 
8. Adequate renal function: 
a. Serum creatinine <1.5 × ULN (Grade 1), or 
b. Estimated creatinine clearance (eClCR) >60 mL/minute (with eClCR to be calculated by 
the Cockcroft-Gault formula [see Appendix 14.2]). 
9. Adequate coagulation profile: 
a. 
b. 
 
 
10. Negative antiviral serology: 
a. Negative human immunodeficiency virus (HIV) antibody. 
b. Negative hepatitis B surface antigen (HBsAg) and negative hepatitis B core (HBc) 
antibody or undetectable hepatitis B (HBV) deoxyribonucleic acid (DNA) by quantitative 
polymerase chain reaction (PCR) testing. 
c. Negative hepatitis C virus (HCV) antibody or negative HCV ribonucleic acid (RNA) by 
quantitative PCR.
11. For female subjects of childbearing potential, a negative serum pregnancy test. 


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12. For female subjects of childbearing potential, willingness to use a protocol-recommended 
method of contraception from the start of the screening period un
 days after the final 
dose of study therapy. Note: A female subject is considered to be of childbearing potential 
unless she has had a hysterectomy, bilateral tubal ligation, or bilateral oophorectomy; has 
medically documented ovarian failure (with serum estradiol and follicle-stimulating 
hormone [FSH] levels within the institutional laboratory postmenopausal range and a 
 
. 
13. For male subjects who can father a child and are having intercourse with females of 
childbearing potential who are not using adequate contraception, willingness to use a 
protocol-recommended method of contraception from the start of study therapy until 
 days after the final dose of study therapy and to refrain from sperm donation from the 
 days after administration of the final dose of study therapy. 
Note: A male subject is considered able to father a child unless he has had a bilateral 
vasectomy with documented aspermia or a bilateral orchiectomy. 
14. Willingness and ability of the subject to comply with scheduled visits, drug administration 
plan, protocol-specified laboratory tests, other study procedures (including all bone marrow 
biopsy/aspirations and radiographic studies), and study restrictions. 
15. Evidence of a personally signed informed consent indicating that the subject is aware of the 
neoplastic nature of the disease and has been informed of the procedures to be followed, the 
experimental nature of the therapy, alternatives, potential risks and discomforts, potential 
benefits, and other pertinent aspects of study participation. 
5.5.2 
Exclusion Criteria 
Study candidates who meet any of the following criteria will not be eligible for participation in 
this study: 
1. Peripheral blood leukemic blast cell count >50 × 109/L before the start of study therapy and 
despite the use of hydroxyurea, cytarabine, and/or cyclophosphamide. 
2. Presence of known central nervous system (CNS) leukemia. Note: Radiographic imaging or 
cerebrospinal fluid analysis is not required as a condition of enrollment into the study. 
3. Presence of another cancer with disease manifestations or therapy that could adverse effect 
subject safety or longevity, create the potential for drug-drug interactions, or compromise the 
interpretation of study results. 
4. Ongoing Grade >1 proliferative or nonproliferative retinopathy (eg, due to diabetes mellitus, 
hypertension, macular degeneration, prematurity, genetic disorder).  Note: Subjects with 
resolved retinal tears due to age-related vitreous humor shrinkage are not excluded. 
5. Significant cardiovascular disease (eg, myocardial infarction, arterial thromboembolism, 
cerebrovascular thromboembolism) within 3 months prior to start of study therapy; angina 
requiring therapy; symptomatic peripheral vascular disease; New York Heart Association 
Class 3 or 4 congestive heart failure; or uncontrolled Grade 
 
 mmHg) despite antihypertensive 
therapy. 


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6. Significant screening ECG abnormalities, including unstable cardiac arrhythmia requiring 
medication, atrial fibrillation/flutter, left bundle-branch block, 2nd-degree atrioventricular 
(AV) block type II, 3rd-
Fridericia method) >480 msec (Grade >1). 
7. Gastrointestinal disease (eg, gastric or intestinal bypass surgery, pancreatic enzyme 
insufficiency, malabsorption syndrome, symptomatic inflammatory bowel disease, chronic 
diarrheal illness, bowel obstruction) that might interfere with drug absorption or with 
interpretation of gastrointestinal AEs.
8. Uncontrolled ongoing systemic bacterial, fungal, or viral infection (including upper 
respiratory tract infections) at the time of start of study therapy. Note: Subjects with 
localized fungal infections of skin or nails are not excluded. Subjects may be receiving 
prophylactic or therapeutic antibiotics if there is no occurrence of fever within 48 hours 
before starting study therapy, and if antibiotics are not proscribed due to the potential for 
drug-drug interactions (see Exclusion Criterion 
.
9. Pregnancy or breastfeeding. 
10. Major surgery within 4 weeks before the start of study therapy. 
11. Subject is a candidate for hematopoietic stem cell transplantation (HSCT), has an appropriate 
HSC donor, and is willing to undergo HSCT. 
12. In subjects with prior HSCT, evidence of graft-versus-host disease (GVHD) manifesting as 
NCI 
Grade 
 at the start of study therapy. 
13. Prior solid organ transplantation. 
14. Prior HSP inhibitor therapy. 
15. Ongoing immunosuppressive therapy other than corticosteroids. Note: At study entry, 
subjects may be using systemic, intraarticular, inhaled, or topical corticosteroids. During 
study therapy, subjects may use systemic, enteric, intraarticular, inhaled, or topical 
corticosteroids as required for intercurrent conditions. 
16. Use of a strong inhibitor or inducer of cytochrome P450 (CYP) 3A4 (including itraconazole, 
ketoconazole, posaconazole, or voriconazole) within 7 days prior to the start of study therapy 
or expected requirement for chronic use of a strong CYP3A4 inhibitor or inducer during 
Cycle 1 of study therapy (see Appendix 14.4). Note: For subjects requiring antifungal 
prophylaxis/therapy, oral fluconazole or isavuconazonium can be considered. 
Echinocandins (eg, caspofungin, 
realizing the disadvantage of the requirement for intravenous administration. 
17. Use within 7 days prior to the start of study therapy of a drug known to prolong the QT 
interval (see Appendix 14.5). Note: For subjects requiring antifungal prophylaxis/therapy, 
oral fluconazole is permitted given that the risk of QT prolongation is considered low (as 
documented in product labeling . 


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18. Concurrent participation in another therapeutic or imaging clinical trial. Note: Subjects are 
not precluded from undergoing evaluations involving observation, noninvasive diagnostic 
procedures or sampling, or questionnaires as follow-up to a prior study or as components 
of a concurrent noninterventional study. 
19. Any illness, medical condition, organ system dysfunction, or social situation, including 
mental illness or substance abuse, deemed by the investigator to be likely to interfere with a 
subject’s ability to provide informed consent, adversely affect the subject’s ability to 
cooperate and participate in the study, or compromise the interpretation of study results. 
5.6 
Rationale for Subject Selection  
In general, the eligibility criteria are designed to maximize the likelihood that study participation 
is appropriately matched to disease risk. The criteria limit enrollment to subjects who have 
incurable advanced AML, are appropriate candidates for a Phase 1 investigational therapy, are 
likely to tolerate study procedures, and will provide interpretable results. Investigators are 
requested to make appropriate judgements as to whether study enrollment is suitable for a subject 
considering an integrated assessment of disease status, medical condition, prior therapies, 
comorbidities, and other relevant factors in determining eligibility or ineligibility. 
The requirement that study candidates be adults largely limits participation to subjects who can 
consent on their own behalf. The lack of an upper bound on the age range permits enrollment of 
subjects across the full spectrum of ages for which therapy with LAM-003 might be applicable. 
To ensure that subjects are able to perform basic self-care, they must have ECOG performance 
scores of 0, 1, or 2.  
The requirement for the presence of AML that is measurable ensures that subjects have disease 
that can be fully assessed for evidence of drug efficacy.
Based on the nonclinical and clinical profile of LAM-003, subjects must not have serious prior or 
ongoing organ dysfunction, comorbidities, or comedication use that would compromise safety, 
compliance, or evaluation; such factors might mask, exacerbate, or confound the interpretation of 
the safety, pharmacokinetic, or efficacy profiles of study therapy. Baseline clinical safety 
laboratory studies are intended to ensure that subjects have adequate organ function for study 
participation. Screening tests such as serum virology assays are performed to exclude subjects 
who might be at increased risk for adverse hepatic effects or immunological effects. Pregnancy 
testing and restrictions on eligibility relating to reproduction, pregnancy, and nursing are 
important because there is no knowledge regarding the potential for LAM-003 to have adverse 
effects on conception, fetal development, or the health of a breast-feeding infant.  
Exclusion of subjects who have undergone prior HSP inhibitor therapy is intended to avoid 
enrolling subjects with AML that is likely to be resistant to LAM-003. Avoidance of 
concomitant immunosuppressives at baseline minimizes the potential that such therapy would 
depress the potential immunotherapeutic effects of LAM-003 or confound adequate profiling of 
the LAM-003 safety profile. Restrictions on concomitant administration of CYP3A4 inhibitors 
are important because in vitro data suggest that LAM-003A is primarily metabolized by 
CYP3A4 (see Section 1.4.3.3). Exclusions for cardiac waveform or rhythm abnormalities are 
intended to ensure that subjects do not have conduction system disorders that would increase risk 
or confound on-study ECG evaluations. 


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To minimize missing data and premature discontinuations, subjects should have sufficient 
psychological and social resources to comply with study procedures and restrictions. Consistent 
with GCP guidelines, subjects must provide informed consent before initiation of any study 
procedures that are not part of routine medical care.
6
STUDY DRUG INFORMATION, ADMINISTRATION, AND SUPPORT
6.1 
LAM-003 
6.1.1 
Description 
LAM-003 is formulated in white, 0.25”, round, convex, film-coated tablets containing 50 mg of 
drug substance. Inactive ingredients include: microcrystalline cellulose, lactose monohydrate, 
crospovidone, hydroxypropyl cellulose, colloidal silicon dioxide, sodium starch glycolate, 
compritol 888 ATO, Opadry clear and Opadry white. Flaking of the non-functional surface 
coating may be observed on some tablets, but does not affect tablet safety, quality, purity, or 
potency. 
6.1.2 
Source 
LAM-003 will be provided by the study sponsor. 
6.1.3 
Packaging and Labelling 
LAM-003 tablets are supplied in high density polyethylene (HDPE) bottles, each of which is 
closed with a child-resistant, tamper-evident plastic screw cap. Each bottle contains 28 tablets 
and includes a silica gel desiccant packet. 
Labels for LAM-003 bottles meet all applicable requirements of the Food and Drug 
Administration (FDA) and/or other local regulations, as applicable. 
6.1.4 
Shipping, Storage, and Stability 
During shipping study drug bottles should remain refrigerated at temperatures of 2 to 8°C [35.6 
to 46.4°F]). 
LAM-003 tablets should be stored at refrigerated temperatures of 2 to 8°C [35.6 to 46.4°F]) in 
the bottles in which they are supplied. Desiccant packets should be retained in opened bottles and 
bottles should remain closed when not in use to avoid absorption by the tablets of moisture from 
the air. To maximize product stability, subjects should be instructed to leave the desiccant 
packets in the bottles and to use the entire contents of one bottle before opening another bottle.  
The study sponsor will provide study centers with initial and updated product stability data, 
when available. 
6.1.5 
Dispensing  
A pharmacist or other qualified staff member will dispense bottles containing LAM-003 tablets. 
Sufficient bottles will be dispensed to the subject to provide an adequate drug supply until the 
subject’s next planned clinic visit at which drug will be dispensed (generally at 28-day intervals). 
If it is anticipated that a subject may have a potential delay in returning to the study center (eg, 


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due to a holiday), an additional bottle may be provided at the start of therapy so that the subject 
has an overage supply to cover any potential delays in returning to the study center.  Sites should 
take care to minimize waste. 
For LAM-003 doses that are taken in the study center, subjects will take the dose from the drug 
dispensed to them for that specific dispensing interval. All other LAM-003 doses will be taken at 
home. 
6.1.6 
Return and Compliance Assessment 
At the completion of each dispensing interval, empty, partially used, or full bottles of LAM-003
should be retrieved from the subject. The quantities of unused LAM-003 and the date when these 
study supplies are returned by the subject should be recorded in the study drug accountability 
records. In addition, the subject’s dosing diary should be reviewed at each visit, any incomplete 
or inconsistent entries should be addressed, and the dosing diary should be photocopied. 
Returned bottles may be redispensed to the same subject but not to another subject. Returned 
tablets and bottles may be destroyed according to the site’s standard operating procedures (see 
Section 12.11).  
6.1.7 
Accountability 
See Section 12.11 for information regarding LAM-003 drug accountability. 
6.1.8 
Overdose Precautions 
An overdose is defined as a dose taken (accidentally or intentionally) exceeding the overdose 
limit. In the case of a discrepancy in drug accountability, an overdose will be established only 
when it is clear that the subject has received an excess dose or the investigator has reason to 
suspect that the subject has received an excess dose. 
There are limited data on the effects of LAM-003 overdose. LAM-003A doses as high as 
320 mg BID (640 mg QD) were achieved in a prior Phase 1 study.  
For this protocol, an overdose of LAM-003 is defined as administration of a daily dose 50 mg 
above the prescribed dose. In a subject who experiences an overdose, consideration should be 
given as to whether LAM-003 administration should be temporarily interrupted. If the overdose 
is recent and substantial, and if there are no medical contraindications, use of gastric lavage or 
induction of emesis may be considered. Observation for any symptomatic side effects should be 
instituted, and safety laboratory parameters should be followed closely (consistent with the 
protocol or more frequently, as needed). Appropriate supportive management should be 
instituted to mitigate adverse effects. The subject should remain under observation until adverse 
effects have recovered to baseline. There is no specific antidote for LAM-003. 
The medical monitor should be contacted if a study drug overdose occurs. The occurrence of an 
overdose does not preclude further protocol therapy if the subject appears to be safely benefiting 
from treatment and the circumstances that led to the initial overdose are unlikely to recur. 
6.1.9 
Inadvertent Exposure Precautions 
Based on available data, LAM-003 is not expected to be acutely toxic, irritating, or genotoxic at 
levels that are likely to result from inadvertent exposure. However, personnel handling the drug 


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should use reasonable precautions to avoid eye contact, skin contact, inhalation, or ingestion of 
LAM-003. Subjects should be instructed to keep the drug secured such that it is out of the reach 
of children and is not inadvertently taken by others. The LAM-003 investigator brochure can be 
consulted for further information regarding exposure and spill precautions. 
6.2
Study Drug Administration
6.2.1
Premedications
6.2.1.1 
Antidiarrheal or Antiemetics 
Prophylactic administration of antidiarrheals or antiemetics on or before C1D1 should be 
avoided unless the emerging safety profile of the study drug indicates that initial antidiarrheal or 
antiemetic prophylaxis is warranted. On other days, antidiarrheals and/or antiemetics may be 
given to minimize any potential study-drug-related nausea (see Section 6.3.5 and Section 6.3.6).
6.2.1.2
Tumor Lysis Syndrome (TLS) Prophylaxis
The general risk for TLS can be characterized according to the following criteria, considering 
established algorithms relevant to AML [Cairo 2010, MDACC 2013, Ejaz 2015]:
 Low risk: Serum lactate dehydrogenase (LDH) <2 × ULN, serum uric acid <5.5 mg/dL, and 
WBC <25 × 109/L. 
 Intermediate risk
5.5 mg/dL and <7 mg/dL, or 
 × 109/L to <100 × 109/L.
 High risk
 mg/dL or WBC 
 × 109/L. 
If TLS is observed during study conduct, subjects who are at intermediate or high risk of TLS 
should receive medical prophylaxis according to the following prophylaxis regimen or an 
institutional regimen customarily used at the study center:
 Intermediate Risk: These subjects should receive allopurinol, 100 to 300 mg orally every 
8
o 48 hours before the start of study drug therapy; of note, the maximum 
daily allopurinol dose is 800 
hyperuricemia may receive rasburicase, 3 to 4.5 mg by IV infusion.  
 High Risk: These subjects should receive allopurinol, 100 to 300 mg orally every 8 hours 
allopurinol dose is 8
high-
insufficiency. In addition, high-risk subjects may receive rasburicase, 3 to 4.5 mg by IV 
infusion, administered 3 to 4 hours prior to the first dose of study drug. 
Subjects must be monitored for TLS during C1D1 through C1D5 with assessments of vital signs, 
AEs, and serum chemistry and hematology laboratory studies as described in Section 7. Study 
centers may wish to provide additional hydration and in-patient monitoring for TLS, particularly 
in subjects who are at high risk.  
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6.2.2 
LAM-003 Administration 
In each 28-day cycle, subjects are to self-administer LAM-003 starting on Day 1 and then 
continuously thereafter (28 total doses/cycle). Subjects should take the study drug at 
approximately the same time each day, ideally at ~24-hour intervals (eg, ~8AM every day) for 
the planned QD schedule or at 12-hour intervals (eg, ~8AM and ~8PM every day) if a BID 
schedule is evaluated. In conjunction with frequent pharmacokinetic assessments on C1D1, 
C1D2, and C1D8, subjects should take the drug at the study center under the supervision of study 
personnel and the timing of LAM-003 administration must be documented in the clinic notes 
and/or in the subject diary. On C1D2, C1D3, C1D4, and C1D5, LAM-003 is to be administered 
in the study center and only after the serum chemistry results from that day have been evaluated 
to exclude Grade 4 TLS or Grade 3 TLS associated with 
-organ injury. While variations in dosing schedule may occur in the outpatient 
setting, the prescribed regimen should be followed as closely as possible. 
At each dose administration, the number of LAM-003 tablets corresponding to the appropriate 
doses of each drug should be swallowed whole with 100 to 200 mL (~4 to 8 ounces) of water. 
Subjects should be instructed not to bite or chew the tablets. In case of breakage of the tablets in 
the oral cavity, additional water should be taken as a rinse. 
In conjunction with frequent pharmacokinetic assessments on C1D1, C1D2, and C1D8, subjects 
should ingest the drug while fasting (defined as no food with the exception of clear liquids for 
 
r dosing). Pending the evaluation of the effect of food on 
LAM-003 absorption, subjects are encouraged to take the drug while fasting on other days. 
6.2.3 
Dose Schedule Interruptions and Vomited Doses 
For the QD schedule, subjects who have a delay in administration of <12 hours should take the 
planned dose as soon as possible after the intended time of administration. For subjects who have 
2 hours, the dose should not be taken. The planned timing of 
subsequent drug administration should not be altered.  
If a BID schedule is evaluated, subjects who have a delay in administration of <6 hours should 
take the planned dose as soon as possible after the intended time of administration. For subjects 
 hours, the dose should not be taken. The planned 
timing of subsequent drug administration should not be altered. 
For subjects who vomit shortly after taking the study drugs, the vomited dose should not be 
replaced. The planned timing of subsequent drug administration should not be altered. 
6.2.4 
Starting Dose Levels and Dose Escalation 
Cohorts of 3 to 6 subjects will be sequentially enrolled at progressively higher starting dose 
levels of LAM-003 using a standard 3+3 design, as indicated in Table 1. The initial cohort of 
subjects will be prescribed LAM-003 at Dose Level 1 (200 mg). Dose Levels -1 (100 mg) and 
-2 (50 mg) are provided to permit dose decrements if a subject experiences a TEAE requiring 
dose modifications to levels below Dose Level 1.  


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Table 1: LAM-003 Starting Dose Levels 
Dose 
Level 
LAM-003
Dosing Regimen 
Dose Change 
Relative to  
Prior Dose 
-2
50 QD
0.50
-1
100 QD
0.50
1 (initial dose level)
200 QD
Not applicable
2
300 QD
1.50
3
450 QD
1.50
4
600 QD
1.33
5
750 QD
1.25
Abbreviations: QD=once per day
The following dose-escalation rules will be employed, considering DLTs observed in Cycle 1 of 
therapy: 
 Each dose level cohort will initially enroll 3 subjects.  
 If 0 of the first 3 subjects has a DLT, the next cohort of 3 subjects will be treated at the next 
higher dose level.  
 If 1 of the first 3 subjects in a cohort experiences a DLT, an additional 3 subjects will be 
treated at that same dose level. If 0 of the additional 3 subjects experience a DLT, the next 
cohort of 3 subjects will be treated at the next higher dose level. 
 
subjects experience a DLT, the MTD will have been exceeded and 
3 more subjects will be treated at the next lower dose level (if only 3 subjects were 
previously treated at that prior dose level). If 6 subjects were previously treated at the prior 
dose level, that prior dose level will provisionally be considered the MTD. 
 An additional 6 subjects (up to 12 total) may be enrolled at the MTD or RDR. 
 With the concurrence of the SRC, additional subjects (up to 12 subjects per dose level) may 
be accrued at dose levels at or below the MTD to refine the estimation of the RDR and 
further define the pharmacology of LAM-003. Such accrual may occur: 
o At Dose Level -1 or -2 (100 or 50 mg of LAM-003, respectively). 
o At an initially planned dose level (as indicated in Table 1) or at a dose level that lies 
between the initially planned dose levels. 
o Using an alternative schedule (eg, BID) with a total daily dose that does not exceed the 
total daily MTD (rounded up or down to the nearest even multiple of 50 mg). 
The following additional procedures will be followed during the dose escalation: 
 The first subject to be treated at Dose Level 1 will be observed for 
 week after initiation of 
LAM-003 before any subsequent subjects are treated at the same dose level. 
 Each 
or 42/56 doses for a BID schedule) of planned Cycle 1 LAM-003 doses per subject and must 
be observed for a minimum period of ~4 weeks without DLT before subsequent subjects are 
enrolled at the next higher dose level. Any subject without DLT who does not complete these 
requirements may be replaced. 


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 Escalation to the next dose level can only occur upon review of the available safety data from 
all ongoing and previous subjects and with the concurrence of the SRC. 
 Intrasubject dose escalation above the initially assigned dose level will be permitted  as 
defined in Section 6.2.7 below. 
 Accrual of additional subjects to a treatment cohort may be considered by the SRC with the 
concurrence of the study sponsor. 
6.2.5 
Definition of DLTs 
When each cohort has completed Cycle 1, the SRC will review safety and may review any 
available pharmacokinetic or pharmacodynamic data. The sponsor, working in consultation with 
the SRC, will determine whether a TEAE meets a definition of DLT as defined in the protocol. 
Reference will be made to the CTCAE, Version 4.03 [NCI 2010], for grading the severity of 
TEAEs, treatment-emergent laboratory abnormalities, and DLTs, considering the known safety 
profiles of the study drug and other medical factors.  
The existing clinical experience indicates that nausea, vomiting, diarrhea, tachycardias, 
respiratory distress, and visual disturbances can occur in association with LAM-003A 
administration and may be dose-limiting at total daily doses >600 mg. Visual symptoms 
observed with LAM-003A have included darkening or dimming of vision, difficulties with 
light/dark adaptation, appearance of intermittent bilateral white ocular crescents, and visual 
floaters. Dose-dependent ocular symptoms described with other HSP90 inhibitors have included 
visual dimming, difficulties with light/dark adaptation, nyctalopia (night blindness), photopsia 
(perceived flashes of light), photophobia (light sensitivity), and blurred vision [Pacey 2011, 
Rajan 2011, Sessa 2013, Infante 2014, Bendell 2015, Shapiro 2015, Bendell 2016, Kong 2016].  
Based on this information but considering the limited experience with LAM-003/LAM-003A, 
DLTs for the purposes of establishing the MTD and RDR in this study will be defined as any of 
the following TEAEs occurring in Cycle 1 of LAM-003 therapy that cannot be considered 
incontrovertibly related to the underlying malignancy, a comorbid condition, an intercurrent 
illness, or a concomitant medication: 
 
s 
 
despite recommended antiemetic support 
 
 
 
2 visual disturbances 
 
 
 Grade 3 TLS despite adequate prophylaxis (unless TLS results in no Grade 2 renal 
dysfunction or other Grade 2 end-
 
 Grade 4 TLS despite adequate prophylaxis 
 
Es (with the exception of asymptomatic 
Grade 
 laboratory abnormalities that improve to Grade 
within 72 hours) 


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 The occurrence of either of the following circumstances during Cycle 1: 
o 
 dose for a BID 
schedule) of planned LAM-003 doses due to an AE that is not primarily related to the 
underlying malignancy, a comorbid condition, an intercurrent illness, or a concomitant 
medication 
o Following a dose interruption starting in Cycle 1, failure to recover to baseline within 
2 weeks from the last dose of LAM-003 due to a TEAE that is not primarily related to the 
underlying malignancy, a comorbid condition, an intercurrent illness, or a concomitant 
medication; occurrence of such a TEAE should also result in permanent discontinuation 
of study drug (see Section 6.5)
6.2.6
Definitions of MTD and RDR
associated with a Cycle 
lower dose within the tolerable dose range. Selection of the RDR will be based on consideration 
of short- and long-term safety information together with available pharmacokinetic, 
pharmacodynamic, and efficacy data. 
6.2.7 
Dose Modification Recommendations 
If a subject experiences an AE that is suspected to be related to the study drug, appropriate 
monitoring and supportive care (eg, antiemetics, antidiarrheals, therapy for TLS) should be 
instituted consistent with the nature of the event.  
If a subject experiences a Grade 4 toxicity (other than Grade 4 TLS recovering with no adverse 
sequalae), then the study drug administration should be permanently discontinued. If a subject 
experiences a DLT or a less severe AE that the investigator believes warrants dose modification, 
then the study drug administration should be inter
or baseline.  In addition, subjects who develop treatment-emergent dose-limiting visual 
symptoms should undergo more frequent ophthalmological consultation (eg, at ~2-week 
intervals or more frequently, as appropriate) (see Section 6.3.13). If the drug is resumed after a 
dosing interruption, the dose of LAM-003 should be reduced by 1 dose level (reference Table 1). 
Two successive adjustments to progressively lower dose levels can be made. If the subject 
cannot tolerate LAM-003 after a decrease in dose by 2 dose levels or to Dose Level -2 
(50 mg/day), then the subject should be discontinued from study drug therapy.  
In general, after the LAM-003 dose is reduced, the dose should be maintained at that dose level, 
even if there is minimal or no toxicity with the reduced dose. However, if the subject tolerates a 
reduced dose of LAM-003 for 
 weeks with no toxicities of 
then the LAM-003
dosing regimen may be reescalated to the next higher dose level if the AE that prompted the dose 
reduction comprised TLS or if further evaluation reveals that the AE that led to the dose 
reduction was incontrovertibly related to the underlying malignancy, a comorbid condition, an 
intercurrent illness, or a concomitant medication. Successive adjustments to progressively higher 
dose levels can be made. However, during the first 2 cycles of therapy, the escalated dose cannot 
exceed the starting dose level for that subject.  


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Individual subjects may have the LAM-003 dose escalated to the next higher dose level after 
1 cycle of therapy if both the principal investigator and the medical monitor agree that the 
subject is tolerating the current dose level 
 and that a dose 
escalation is medically warranted to try to obtain better disease control (eg, for a subject who has 
not shown an improvement in AML disease burden by the end of the cycle). In such subjects, 
successive ad
 weeks 
with the caveat that the escalated dose cannot exceed 750 mg QD (highest plan dose level) or the 
established MTD (if lower). As directed by the medical monitor, certain safety and other studies 
(eg, serum chemistry, hematology, ECG, ophthalmology, pharmacokinetic, and 
pharmacodynamic evaluations) may be repeated at the higher dose level per the Cycle 1 schedule 
for these tests. 
In a subject who experiences an AE precluding resumption of LAM-003 therapy by Day 29 of 
the current cycle (planned Day 1 of the next cycle), the new cycle of treatment may only begin 
when AEs or laboratory abnormalities have returned to baseline levels and if the subject does not 
meet criteria for permanent discontinuation of study therapy (see Section 6.5). Upon initiation of 
a new cycle, the current cycle will be considered completed. 
Investigators are requested to discuss modifications in the dosing regimen with the medical 
monitor. The appropriate clinic staff should dispense the study drug for the new dose level and 
instruct the subject/caregiver about the change in dose level.
6.3 
Supportive Care 
6.3.1 
General Recommendations 
Consistent with subject safety and comfort, administration of any prescription or over-the-
counter drug products other than study medication will be minimized during the study period. 
Subjects should be discouraged from use of herbal remedies, self-prescribed drugs, tobacco 
products, or street drugs during their participation in the clinical study and should be counseled 
to minimize use of alcohol or nonmedical marijuana. 
If considered necessary for the subject’s well-being, drugs for concomitant medical conditions or 
for symptom management may be given at the discretion of the investigator. The investigator’s 
decision to authorize the use of any drug other than study drug should take into account subject 
safety, the medical need, the potential for drug interactions, the possibility for masking 
symptoms of a more significant underlying event, and whether use of the drug will compromise 
interpretation of study endpoints. 
Subjects will be instructed about the importance of the need to inform the clinic staff of the use 
of any drugs or remedies (whether prescribed, over-the-counter, or illicit) before and during the 
study.  
Recommendations regarding specific types of concomitant therapies, supportive care, diet, and 
other interventions are provided below. To minimize variations in supportive care, the 
recommended supportive care agents should be considered unless there is a medical rationale in 
a specific subject for use of an alternative product. 


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6.3.2 
Antibiotics, Antifungals, and Antivirals 
Local practices or guidelines regarding infection prophylaxis may be followed. Subjects 
developing an intercurrent infection during study drug treatment may receive therapeutic 
antibacterial, antiviral, or antifungal drugs as needed. However, care should be taken to avoid or 
minimize concomitant administration of prophylactic or therapeutic antibacterial, antifungal, or 
antiviral, agents that are strong CYP3A4 inhibitors or inducers (see Section 6.3.9 and 
Appendix 14.4). Continuation of study therapy during treatment for an intercurrent infection is at 
the discretion of the investigator. 
6.3.3 
Anticancer Therapies Other than the Study Drugs 
Other than hydroxyurea, cytarabine, and/or cyclophosphamide used during Cycle 1 to control 
AML blast counts, no systemic anticancer therapies (including chemotherapy, antibody therapy, 
hormonal therapy, immunotherapy, radiotherapy, or other experimental therapies) for the 
subject’s cancer are permitted while the subject is receiving study treatment. Subjects are not 
allowed to participate concurrently in any other therapeutic clinical study. 
6.3.4 
Anticoagulants 
As a precaution, subjects are required to have normal coagulation parameters before enrolling in 
this study. Use of local anticoagulation or antithrombotic agents to maintain a venous access 
catheter is permitted. In addition, subjects who develop conditions that require anticoagulant 
therapy are permitted to receive such drugs and are not required to discontinue study 
participation if they appear to be safely benefiting from study therapy. 
6.3.5 
Antidiarrheals 
Subjects experiencing diarrhea (and/or abdominal cramping) may take loperamide at the earliest 
sign of a loose stool, an increase in bowel movements by 1 to 2 episodes compared to baseline, 
or an increase in stool volume or liquidity. The recommended regimen is 4 mg at the first onset 
of diarrhea, then 2 mg with each succeeding diarrheal stool until the subject is diarrhea-free for 
at least 12 hours.  
Additional antidiarrheal measures may be implemented at the discretion of the investigator. 
Subjects should also be instructed to maintain oral fluid intake to help sustain fluid and 
electrolyte balance during episodes of diarrhea. 
6.3.6 
Antiemetics 
While prophylactic antiemetics can be considered, it is preferred that antiemetics not be given 
prophylactically before initial study drug administration on C1D1.  
If antiemetics are needed, it is recommended that subjects be offered 1 to 2 mg of the serotonin 
antagonist, granisetron (Kytril®, Granisol®), as an oral tablet or solution every 6 to 8 hours as 
needed. If subjects have persistent nausea or vomiting, consideration can be given to a 10-mg 
subcutaneous injection of the extended release form of granisetron (Sustol®). Alternatively, 
application of a 31.3-mg granisetron transdermal patch (Sancuso®) every 3 to 7 days can be 
considered. For transdermal prophylaxis, 24 to 48 hours may be necessary to allow a sufficient 
period to achieve effective granisetron systemic concentrations. Use of the serotonin antagonists, 
ondansetron (Zofran®, Zuplenz®) or dolasetron (Anzemet®), is discouraged before C2 due to 


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the possibility that such agents could prolong the cardiac QT interval during Cycle 1 ECG 
assessments.  
The dopamine antagonist, olanzapine (Zyprexa®), at doses of 2.5 to 10 mg, may be considered 
alone or in conjunction with serotonin antagonists or other types of antiemetic agents. Doses of 
10 mg may be sedating, which could be helpful for certain subjects, but may represent a concern 
for others, particularly for those who are elderly.  
Based on currently available information regarding LAM-003 metabolism, the neurokinin 1 
receptor antagonist, rolapitant (Varubi®), can be considered together with other anti-emetic 
agents, but aprepitant (Emend®) or netupitant+palonosetron (Akynzeo®) should be avoided 
because these drugs may inhibit CYP3A4 activity.  
Benzodiazepines may be considered if such drugs do not pose risks of QT prolongation during 
Cycle 1 or drug-drug interactions.  
Corticosteroids can be introduced if other types of antiemetic agents are not sufficiently 
effective. 
6.3.7 
Antihistamine, Antiinflammatory, or Antipyretic, Drugs 
Antihistamines (eg, cetirizine, diphenhydramine), and antiinflammatory/antipyretic drugs (eg, 
acetaminophen [paracetamol], nonsteroidal anti-inflammatory drugs [NSAIDs]), may be used 
during the study, as medically warranted. 
6.3.8 
Corticosteroids 
At study entry, subjects may be using systemic, intraarticular, inhaled, or topical corticosteroids. 
During study therapy, subjects may use systemic, intraarticular, enteric, inhaled, or topical 
corticosteroids as required for intercurrent conditions.  
6.3.9 
Drugs with Drug-Drug Interaction Potential 
In vitro experiments indicate that LAM-003A can inhibit CYP3A4. While no clinical drug-drug 
interaction data are available, these nonclinical data suggest that LAM-003 could increase 
exposure to drugs that undergo metabolism via CYP3A4, potentially resulting in exaggerated 
pharmacological or toxic responses to such drugs. 
A list of substrates of CYP3A4 is provided in Appendix 14.3. During study participation, 
coadministration of LAM-003 and any of the listed drugs should be minimized to the extent 
possible, particularly for drugs that are sensitive substrates of CYP3A4 or have low therapeutic 
indices. If medically appropriate, subjects receiving the listed drugs should have therapeutically 
equivalent drugs substituted, when available. If a subject develops a condition that requires use 
of a CYP3A4 substrate, investigators should evaluate for toxicity due to the coadministered drug 
and modify the dosage of that drug, as appropriate.  
While clinical data are not yet available, in vitro data suggest that LAM-003 is metabolized by 
CYP3A. Based on these findings, protocol candidates who require therapy with the strong 
CYP3A4 inhibitors or inducers listed in Appendix 14.4 should not be enrolled into the study. If 
medically justified, protocol candidates may be enrolled if such inhibitors or inducers can be 
discontinued or alternative drugs that do not strongly affect this enzyme can be substituted 
>7 days before initiation of LAM-003.  


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During study participation, coadministration of LAM-003 with the strong CYP3A4 inhibitors or 
inducers listed in Appendix 14.4 should be avoided, if possible. However, a subject who 
develops a condition that may require use of such drugs is not required to permanently 
discontinue LAM-003 if the subject is experiencing clinical benefit and other options for treating 
the subject’s cancer are limited. If medically appropriate, investigators may wish to use a 
therapeutic alternative that would not be expected to affect these enzymes.  
For subjects who require temporary use of a drug that does affect these enzymes (eg, treatment 
with a systemic antifungal agent), LAM-003 therapy can be temporarily interrupted and then 
resumed after completion of the other drug. For subjects who require initiation of chronic 
therapy with a drug that strongly affects these enzymes, investigators must consult with the 
medical monitor to consider the best course of action. If subjects do receive a CYP3A4 inhibitor 
concomitantly with LAM-003, they should be monitored closely for signs of LAM-003 toxicity. 
Based on consultation with the medical monitor, such subjects may be required to undergo 
additional pharmacokinetic testing and may require a LAM-003 dose modification. 
6.3.10 Drugs Known to Prolong the QT Interval 
Available nonclinical and clinical data do not suggest a high risk that LAM-003 will alter the QT 
interval. However, data are limited and, as a precaution, the clinical potential of LAM-003 to 
prolong the QT interval will be assessed in this study. Accordingly, co-administration of 
LAM-003 and known QT-prolonging drugs is to be minimized during Cycle 1 because use of 
such drugs might confound interpretation of QT data from the trial.  
Based on these considerations, protocol candidates who require therapy with drugs known to 
prolong the QT interval (as listed in Appendix 14.5) should not be enrolled into the study. If 
medically justified, protocol candidates may be enrolled if such drugs are unlikely to result in QT 
prolongation in the specific study subject (as judged by the medical monitor),  can be 
discontinued, or alternative drugs that do not affect QT can be substituted >7 days before the first 
dose of LAM-003.  
After the subject is enrolled to the protocol and has been monitored for 24 hours after receiving 
the first dose of LAM-003, there is no specific restriction on use of drugs (eg, antiemetics) that 
might prolong QT interval; however, use of such drugs should be minimized. 
6.3.11 Hematopoietic Support 
LAM-003 is not expected to cause myelosuppression based on nonclinical and clinical 
experience with LAM-003A. However, subjects may experience hematological AEs related to 
the underlying AML or prior therapy.  
Granulocyte colony-stimulating factor (G-CSF) (eg, filgrastim, filgrastim-snd, peg-filgrastim, 
lenograstim) or granulocyte-macrophage colony-stimulating factor (GM-CSF) (eg, 
sargramostim) may be administered in response to neutropenic complications, as appropriate and 
consistent with current guidelines [NCCN 2017a, NCCN 2017c].  
Use of erythropoietic agents (eg, erythropoietin or darbepoetin) is not recommended based on 
current guidelines [NCCN 2017b].  
Red blood cell or platelet transfusions may be administered as medically indicated. 


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6.3.12 Immunization 
For subjects who are at risk of an infection (eg, influenza, herpes zoster) that might be prevented 
by immunization, consideration should be given to providing the vaccine prior to initiation of 
study therapy.  
Whether the study drug would increase the risk of live viral vaccines during study therapy is 
unknown. Pending the acquisition of additional information, live viral vaccination during study 
therapy should be avoided. 
6.3.13 Ophthalmological Symptom Management 
Grade 1 and 2 visual disturbances are an expected effect of HSP90 inhibitor administration. 
Known ocular symptoms described with LAM-003A and other HSP90 inhibitors have included 
visual dimming, difficulties with light/dark adaptation, nyctalopia (night blindness), photopsia 
(perceived flashes of light), photophobia (light sensitivity), and blurred vision [Pacey 2011, 
Rajan 2011, Sessa 2013, Infante 2014, Bendell 2015, Shapiro 2015, Bendell 2016, Kong 2016]. 
These effects are likely an on-target consequence of HSP90 inhibition in the retina [Zhou 2013,
Kanamaru 2014] based on a physiological role for this protein in retinal function under normal 
and stressed conditions [Ochoa 2002, Sakai 2003].  
During the study, subjects will undergo screening and periodic ophthalmological examinations 
(including visual symptom assessment, visual acuity testing, electroretinography, tonometry, slit 
lamp examination, and electrical coherence tomography) according to the schedule of activities 
provided in Section 7. As noted in Section 6.2.7, subjects who develop treatment-emergent dose-
limiting visual symptoms should have drug interrupted and should undergo more frequent 
ophthalmological consultation (eg, at ~2-week intervals or more frequently, as appropriate). 
Symptoms should resolve to Grade 
 of study drug and study drug should 
only be resumed if such resolution occurs within 2 weeks of interruption of study drug and the 
subject appears to be otherwise safely benefiting from study therapy. 
6.3.14 TLS Management 
Information regarding TLS prophylaxis is provided in Section 6.2.1.2.
Subjects must be monitored for TLS on C1D1 through C1D5 with assessment of vital signs, 
AEs, and serum chemistry and hematology laboratory studies as described in Section 7. Subjects 
who develop TLS may experience hyperkalemia, hypocalcemia, hyperuricemia, 
hyperphosphatemia, acute renal failure, and cardiac dysrhythmias; thus, close monitoring of 
electrolytes, serum creatinine, and vital signs is particularly important after initial therapy. ECG 
monitoring should also be instituted in subjects with biochemical abnormalities suggestive of 
TLS.  
Subjects with TLS should receive IV hydration, rapid reversal of hyperkalemia, 
antihyperuricemic agents, and appropriate cardiac and renal support, including dialysis as 
indicated. LAM-003 administration may continue except in those who develop Grade 4 TLS or 
end-organ injury. 
Upon recovery to baseline functioning and as medically appropriate, subjects who develop TLS 
should continue with protocol therapy to maintain tumor control. 


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6.4
Study Restrictions
6.4.1
Breast Feeding
There is no information regarding the presence of LAM-003, LAM-003A, or other metabolites in 
human milk; the potential effects of the drug or its metabolites on the breastfed infant, or the 
potential effects of the drug or its metabolites on milk production. For these reasons women who 
are nursing are not eligible to participate in this study. Lactating women who do participate in 
this clinical trial must discontinue nursing during study therapy. 
6.4.2 
Contraception/Reproduction 
In general toxicology studies, LAM-003A administration was not associated with adverse 
histopathological effects on organs of reproduction at exposures that are likely to be achieved 
clinically. However, no studies evaluating drug effects on reproductive function in animals or 
humans are available. Thus, subjects should be advised that the risks of LAM-003 for future 
reproduction are unknown. 
No nonclinical data or clinical data are available regarding LAM-003 or LAM-003A effects 
during embryo-fetal development. Accordingly, female subjects cannot be pregnant at the time 
of study entry and must be removed from study therapy if they do become pregnant. 
Sexually active females of childbearing potential must agree to use a protocol-recommended 
method of contraception during heterosexual intercourse from the start of the screening period 
until 
 final dose of study therapy. In the context of this protocol, a female 
subject is considered to be of childbearing potential unless she has had a hysterectomy, bilateral 
tubal ligation, or bilateral oophorectomy; has medically documented ovarian failure (with serum 
estradiol and follicle-stimulating hormone [FSH] levels within the institutional laboratory 
postmenopausal range and a negative serum or urine beta human chorionic gonadotropin 
 
Sexually active male subjects who can father a child and are having intercourse with females of 
childbearing potential who are not using adequate contraception must agree to use a protocol-
recommended method of contraception from th
final dose of the study therapy and to refrain from sperm donation from the start of study therapy 
protocol, a male subject is considered able to father a child unless he has had a bilateral 
vasectomy with documented aspermia or a bilateral orchiectomy. 


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Protocol-recommended contraceptive methods are described in Table 2. 
Table 2: Protocol-Recommended Contraceptive Methods
Individual Methods 
Combination Methods 
Hormonal Methods 
(One method to be used  
with a barrier method) 
Barrier Methods 
(Both methods to be used OR one 
method to be used with one 
hormonal method)
IUD (eg, Copper T380A, LNg20)
Estrogen and progesterone 
Diaphragm with spermicide 
Tubal sterilization
Oral contraceptives
Male condom (with spermicide) 
Hysterectomy
Transdermal patch 
 
Vasectomy 
Vaginal ring
 
 
Progesterone injection or implant
 
Abbreviation: IUD=intrauterine device 
6.4.3 
Diet 
Pending the acquisition of information regarding the effects of food on LAM-003 
pharmacokinetics, subjects should be encouraged to fast (with the exception of clear liquids) for 
our after each LAM-003 dose.  
Subjects should be advised to avoid ingestion of grapefruit, grapefruit juice, Seville oranges, or 
starfruit (all of which contain CYP3A4 inhibitors) and should not use St. John’s wort (which is a 
potent CYP3A4 inducer).  
No other specific dietary restrictions are required. 


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6.5
Duration of Study Drug Administration and Study Participation
Subjects may receive LAM-003 therapy indefinitely. However, the occurrence of any of the 
following events requires treatment discontinuation: 
 Subject request to withdraw from study treatment  
 Documented objective evidence of treatment failure or of AML relapse or progression (see 
Section 10.4.5 and Section 10.4.6 for definitions) while receiving study treatment at the 
highest individually tolerated dose level 
 For a subject in PR, continued red blood cell transfusion dependence at Week 20 
 Intolerable toxicity despite appropriate supportive care and/or dose modification 
 Failure to recover to Grade 
baseline within 2 weeks from the last dose of LAM-003 
following interruption for a TEAE that is not primarily related to the underlying malignancy, 
a comorbid condition, an intercurrent illness, or a concomitant medication 
 The development of intercurrent illness or other substantial change in the subject’s condition 
or circumstances that would place the subject at unacceptable risk as determined by the study 
investigator in consultation with the medical monitor
 Initiation of treatment for the subject’s cancer with an off-study therapeutic regimen 
 Pregnancy or breastfeeding 
 Substantial noncompliance with study drug administration, study procedures, or study 
requirements in circumstances that increase risk or substantially compromise the 
interpretation of study results 
 Discontinuation of the study by the study center, the study sponsor, relevant regulatory 
agencies, or the IRB/IEC 
Unless they withdraw consent for further follow-up, subjects who discontinue study therapy will 
continue on study for acquisition of safety 
study treatment, and for further collection of information regarding additional therapies for their 
cancer and OS. 
6.6 
Rationale for Study Drug Administration and Supportive Care 
The initial cohort of subjects in this study will be prescribed 200 mg QD; this dose level is 
2.4-fold below the RDR of 480 mg total daily dose established as tolerable in the prior Phase 1 
study of LAM-003A in patients with solid tumors. While offering all participants the potential 
for antitumor efficacy, this starting dose level provides a safety margin to account for the status 
of LAM-003 as a previously untested prodrug of LAM-003A and the lack of experience with use 
of the drug in a hematological cancer (for which TLS could represent a potential safety concern). 
Both one-per-day (QD) and twice-per-day (BID) dosing were explored in the Phase 1 study of 
LAM-003A in patients with solid tumors. It appeared that the total daily dose of LAM-003A was 
most important in defining the safety profile; the study did not suggest a schedule-dependent 
safety concern with either the QD or BID dosing regimen. Further, the average half-life (t1/2) 
after repeated dosing of LAM-003A was 11.2 hours, supporting use of either QD or BID dosing. 
Based on these observations, the current study will initially evaluate LAM-003 using a QD 


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dosing regimen because such dosing could potentially minimize the likelihood of TLS (by 
avoiding administration of a C1D1 evening dose in the face of potential TLS-mediated renal 
dysfunction). In addition, food-effect data are not yet available; thus, QD dosing in the morning 
is appropriate to increase the likelihood that the drug will consistently be administered in a 
fasting state. Further, QD dosing offers convenience advantages for patients. BID dosing may be 
explored in this protocol once there is more safety, pharmacokinetics, and pharmacodynamic 
experience with the drug using the initial QD regimen. 
The dose modification provisions are designed to balance a primary concern for subject safety 
with the potential for observing pharmacological and antitumor activity in circumstances in 
which a subject experiences an AE that justifies a dose reduction but can continue on therapy at a 
lower LAM-003 dose level. Focusing dose modifications to the prespecified dose levels permit 
the acquisition of greater chronic safety experience at the dose levels prescribed by the protocol. 
Allowing sequential dose reductions is consistent with typical oncological practice and permits 
maximum benefit for participants. Further, this approach generates additional chronic safety data 
and information regarding rechallenge or tachyphylaxis to drug effects. This method also 
provides dose modification data that can inform the dose modification plan in future LAM-003 
development.  
Supportive care recommendations consider widely used approaches in the management of 
toxicities relating LAM-003 and other cancer products in patients with hematological cancers. 
Suggestions for TLS prophylaxis are based on established guidelines relevant to AML 
[Cairo 2010, MDACC 2013, Ejaz 2015]. Management of ophthalmologic adverse events is 
consistent with approaches taken in the development of other HSP90 inhibitors [Sessa 2013, 
Bendell 2015, Shapiro 2015, Bendell 2016, Kong 2016]). A systematic approach to use of 
concomitant medications minimizes confounding effects on evaluation of study therapy 
pharmacokinetics and pharmacodynamics while establishing supportive care regimens to 
maintain subject safety and inform toxicity management recommendations for further 
development.  
7 
STUDY ACTIVITIES AND ASSESSMENTS 
The specific study procedures and time of activities to be conducted for each subject enrolled in 
the study are presented in tabular form in Table 3. Physical examinations, other clinical 
evaluations, and additional laboratory studies or more frequent assessments may be performed 
consistent with appropriate medical care for the subject, but these data will not necessarily be 
collected unless specified in Table 3. 
Missed or delayed procedures or evaluations should be performed as close to the originally 
scheduled date/time as possible. Based on the investigator’s judgment, an exception can be made 
when rescheduling becomes medically unnecessary because it is too close in time to the next 
scheduled procedure or evaluation. In that case, the missed evaluation may be omitted after 
consultation with the medical monitor. 


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Table 3: Schedule of Activities 
Study Period/Cycle 
Screening 
Therapy
Posttherapy 
Follow-up
Cycle 1 
Cycle 2 
End of 
Therapy 
Visit 
Day 
-28 to -1 [a] 1 [b] 
2 
3 
4 
5 
8 
15 
1 
15 
1 
 
Long-
term 
Visit Window, days
±2
±3
±3
±3
±3
+14
General Eligibility/Safety Assessments 
 
 
 
 
 
 
 
 
 
 
 
 
 
Written informed consent [c] 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history [d] 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Height [e] 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Weight [f] 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
X 
X
 
 
Vital signs/oxygen saturation [g]
X
X
X
X
X
X
X
X
X
X
Performance status [h] 
X 
X 
 
 
 
 
X 
 
X 
 
X 
X
 
 
AE assessment [i] 
X 
X 
X 
X 
X 
X 
X 
X [i] 
X 
X [i] 
X 
X
X 
 
Concomitant medications [j]
X
X
X
X
X
X
X
X [j]
X
X [j]
X
X
X
12-lead ECG [k] 
X 
X 
X 
 
 
 
X 
 
X 
 
 
X
 
 
Ophthalmological examination [l] 
X 
 
 
 
 
 
 
 
X [l] 
 
X [l] 
X
 
 
Study Drug Administration/Dispensing/Return 
 
 
 
 
 
 
 
 
 
 
 
 
 
TLS prophylaxis as needed [m] 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
LAM-003 administration in clinic [n] 
 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
 
Dispensing of LAM-003 [o] 
 
 
 
 
 
X 
 
 
X 
 
X 
 
 
 
LAM-003 return/compliance and diary check [p] 
 
 
 
 
 
 
 
 
X 
 
X 
X
 
 
Laboratory Assessments
Urinalysis [q]
X
X
X
X
X
Serum virology [r] 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Serum pregnancy test [s]
X
X
X
X
X
Serum chemistry [t] 
X 
X 
X 
X 
X 
X 
X 
X [t] 
X 
X [t] 
X 
X
 
 
Hematology [u] 
X 
X 
X 
X 
X 
X 
X 
X [u] 
X 
X [u] 
X 
X
 
 
Coagulation [v]
X
X
X
X
X
Plasma for LAM-003 pharmacokinetics [w] 
 
X 
X 
 
 
 
X 
 
 
 
 
 
 
Blood for AML FLT3/HSP protein expression [x]
X
X
X
X
Blood for AML HSP gene expression [y]
X
X
X
X
Plasma for FL concentrations [z] 
 
X 
X 
 
 
 
X 
 
X 
 
 
 
 
 
Blood for AML PD-L1 expression [aa]
X
X
X
X
Blood for immune cell profiling [bb] 
 
X 
 
 
 
 
X 
 
X 
 
 
 
 
 
Disease-Related Assessments 
 
 
 
 
 
 
 
 
 
 
 
 
 
AML genetic profiling data from records [cc] 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Blood and/or bone marrow for FLT3 mutation [dd]
X
Blood/saliva for AML/control mutation profiling [ee]
X
Blood and bone marrow aspiration/biopsy [ff] 
X 
 
 
 
 
 
 
 
 
X [ff]
X [ff] 
 
 
Radiology examination [gg]
X
X [gg]
X [gg]
Posttherapy Follow-up
Posttherapy safety assessment [hh]
X
Long-term follow-up [ii] 
 
 
 
 
 
 
 
 
 
 
 
 
X 


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Footnotes 
Note: For scheduled visits after C1D1, permitted visit windows are indicated in the table. For procedures to be performed at a specified time postdose, the acceptable 
ossible to the specified time. 
a.
To optimize scheduling convenience for the subject and for the study center staff, Screening procedures may be performed over as many days as necessary provided that 
screening activities (excepting prestudy tumor evaluation) are completed within 28 days before C1D1 of the study.  
b. 
If obtained within 3 days prior to the start of therapy, urinalysis and serum pregnancy, serum chemistry, hematology, and coagulation studies collected during Screening 
need not be repeated on C1D1. 
c. 
Written informed consent will be obtained before performance of any study procedures that are not part of routine medical care.
d.
Medical history to include recording of cancer history, previous therapy for cancer, past and ongoing medical conditions, review of systems, and relevant social history.
e.
Height (in centimeters) will be obtained at Screening only. 
f.
Weight (in kilograms) will be obtained once on each designated day.
g.
Vital signs (blood pressure, pulse, temperature, and oxygen saturation via pulse oximetry) will be obtained with the subject resting in a supine position while breathing 
room air. Vital signs will be assessed at Screening, C1D1 (predose, and at 1, 2, 4, 6, and 8 hours postdose), C1D2 (24 hours postdose/predose for next drug administration), 
C1D3, C1D4, C1D5, 
h.
Performance status will be assessed using ECOG scale (see Appendix 14.1) once on each designated day.
i. 
AEs will be described using concise medical terminology, including whether serious, the date of onset, the date of resolution, severity based on the CTCAE (Version 4.03) 
[NCI 2010], a description of potential relatedness to the study drug or to a study procedure, the action taken due, and the outcome. On C1D15 and C2D15, AE information 
may be obtained via telephone contact with the subject. 
j.
Concomitant medication assessments should include information regarding all prescription, nonprescription, illicit, and alternative medications (health foods). Use of any 
supportive care (eg, antiproliferative drugs, antidiarrheals, antiemetics, hematopoietic growth factors, transfusions) should be noted. On C1D15 and C2D15, concomitant 
medication information may be obtained via telephone contact with the subject. 
k. 
12-lead ECGs will be obtained with the subject resting in a supine position. ECGs will be collected at Screening, C1D1 (predose [in triplicate], and at 1, 2, 4, 6, and 8 hours 
postdose), C1D2 (24 hours postdose/predose for next drug administration), C1D8 (predose, and at 1, 2, 4, 6, and 8 hours postdose), C2D1, and at End of Therapy. 
l. 
Ophthalmologic evaluations (including visual symptom assessment, visual acuity testing, electroretinography, tonometry, slit lamp examination, and electrical coherence 
tomography) should be performed by an ophthalmologist, optometrist, or other qualified specialist during Screening, within 14 days before C2D1 (4-week interval), within 
14 days before C4D1 (8-week interval), and then within 14 days before C7D1, C10D1, C13D1, C16D1, etc (12-week intervals), and at End-of-Therapy. An End-of-
Therapy ophthalmologic evaluation may be omitted with the approval of the medical monitor. 
m. If TLS is observed during study conduct, subjects who are at intermediate or high risk of TLS should receive medical prophylaxis according to the protocol-recommended 
or an institutional regimen customarily used at the study center (see Section 6.2.1.2).  
n.
The dose of LAM-003 will be administered to the subject in the study center (with recording of the date and actual clock time of the LAM-003 administration). On C1D2, 
C1D3, C1D4, and C1D5, LAM-003 should only be administered after the serum chemistry results from that day have been evaluated to exclude Grade 4 TLS or Grade 3 
TLS associa
-organ injury. 
o.
Study centers will ensure that subjects have a sufficient supply of LAM-003 and are provided with instructions for self-administration at home. 
p. 
Empty, partially used, or full bottles of LAM-003 will be retrieved from the subject and drug compliance will be assessed. In addition, the subject’s dosing diary should be 
reviewed, any incomplete or inconsistent entries should be addressed, and the dosing diary should be photocopied. 
q.
Urinalysis to include specific gravity, pH, protein, glucose, ketones, bilirubin, urobilinogen, blood, nitrite, leukocyte esterase as assessed by dipstick and white blood cells, 
red blood cells, epithelial cells, bacteria, cast and crystals as assessed by microscopy. Urinalysis should be performed once on each designated day. 
r. 
Virology evaluation to include serum HIV antibody, HbsAg antibody, HBc antibody, HCV antibody. Subjects with a positive antibody evaluation for HBc or HCV should 
undergo evaluation for HBV DNA and for HCV RNA to determine if the antibody test may be falsely positive.
s.
Serum pregnancy testing will be performed in women of childbearing potential only. Pregnancy testing should be performed once on each designated day.
t. 
Serum chemistry studies to include sodium, potassium, chloride, bicarbonate, BUN, creatinine, glucose, calcium, phosphorus, magnesium, total protein, albumin, ALT, 


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AST, ALP, CK, LDH, total bilirubin, uric acid. Serum chemistry studies should be performed once on each designated day. On C1D2, C1D3, C1D4, C1D5, serum 
chemistry results from that day should be evaluated for evidence of 
-organ 
injury before the subject is administered LAM-003 in the clinic. On C1D15 and C2D15, serum chemistry studies may be obtained at a local laboratory. 
u. 
Hematology to include hematocrit, hemoglobin, erythrocyte count; absolute counts of leukocytes, neutrophils, lymphocytes, monocytes, eosinophils, basophils; platelet 
count. Hematology testing should be performed once on each designated day. On C1D15 and C2D15, hematology studies may be obtained at a local laboratory. 
v. 
Coagulation studies to include PT and aPTT. Coagulation studies should be performed once on each designated day. 
w. Plasma for LAM-003 pharmacokinetics will be collected on C1D1 (predose, and at 0.5, 1, 2, 4, 6, and 8 hours postdose), C1D2 (24 hours postdose/predose for next drug 
administration), and on C1D8 (predose, and at 0.5, 1, 2, 4, 6, and 8 hours postdose). 
x. 
Blood for FLT3 /HSP protein expression in AML blasts will be collected on C1D1 (predose and 8 hours postdose), C1D2 (24 hours postdose/predose for next drug 
administration), C1D8 (predose and 8 hours postdose), and C2D1.
y. 
Blood for HSP gene expression will be collected on C1D1 (predose and 8 hours postdose), C1D2 (24 hours postdose/predose for next drug administration), C1D8 (predose 
and 8 hours postdose), and C2D1. 
z. 
Plasma for FLT3 ligand concentrations will be collected on C1D1 (predose and 8 hours postdose), C1D2 (24 hours postdose/predose for next drug administration), 
C1D8 (predose and 8 hours postdose), and C2D1. 
aa.
Blood for AML PD-L1 expression will be collected on C1D1 (predose and 8 hours postdose), C1D2 (24 hours postdose/predose for next drug administration), 
C1D8 (predose and 8 hours postdose), and C2D1.
bb. Blood for immune cell profiling will be collected on C1D1 (predose), C1D8 (predose), and C2D1. 
cc. Any available information in medical records regarding AML genetic profiling (eg, for FLT3 mutation status) to be collected for sponsor review. 
dd. Blood and/or bone marrow aspirate for FLT3 mutation confirmation in AML blasts using a sponsor-specified assay will be obtained during Screening.
ee. Blood for AML cell mutation profiling with collection of saliva as a germline DNA control will be obtained on C1D1 (predose). 
ff.
Blood for peripheral blood AML blast count evaluation and bone marrow aspiration/biopsy will be performed during Screening (unless the requirement for screening bone 
marrow aspirate/biopsy is waived by the medical monitor because sufficient bone marrow material is available for response determination). Post-baseline, a peripheral 
blood AML blast count evaluation and a bone marrow aspirate/biopsy is required within 14 days before C3D1, C5D1, C7D1 (8-week intervals), and then within 14 days 
before C10D1, C13D1, C16D1, etc (12-week intervals). An End-of-Therapy peripheral blood AML blast count evaluation and a bone marrow aspirate/biopsy should be 
performed unless the subject already has hematological or radiographic confirmation of TF or DRP 8 weeks before permanent study drug discontinuation or the medical 
monitor approves omission of such End-of-Therapy testing. At all AML evaluations, the extent of involvement with AML in peripheral blood and bone marrow, the 
presence of Auer rods, and bone marrow cellularity will be assessed. Bone aspirate aliquots obtained at Screening and within 14 days before C3D1 may also be evaluated 
for FLT3/HSP protein and gene expression, PD-L1, and AML mutations. 
gg. Radiology examination is required in subjects with extramedullary disease that is radiographically assessable. FDG-PET/CT is the preferred method of evaluation but other 
methods (diagnostic CT, MRI) may be used if appropriate for the type of lesion. The baseline evaluation should occur within 28 days before C1D1. Post-baseline 
evaluations should be performed within 7 days before C3D1, C5D1, C7D1 (8-week intervals), and then within 7 days before C10D1, C13D1, C16D1, etc (12-week 
intervals). An End-of-Therapy radiology assessment should be performed unless a subject with extramedullary disease already has hematological or radiographic 
confirmation of TF or DRP 8 weeks before permanent study drug discontinuation or the medical monitor approves omission of such End-of-Therapy testing. 
hh. Posttherapy safety assessment will be performed after permanent cessation of study therapy to follow subjects for any drug-related AE and/or ongoing SAEs. Subjects will 
be followed until the later of either 30 days after the last dose of study treatment or until resolution/stabilization of any ongoing drug-related AEs and/or SAEs. Follow-up 
may be obtained in person or by telephone contact. 


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ii.
Long-term follow-up information will be obtained in all surviving subjects who permanently discontinue study therapy. Data on post-study therapies for the AML and on 
survival will be collected. Such information may be collected at ~3- to 6-month intervals through 3 years. This long-term follow-up information will be gathered during 
routine clinic visits, other study site contact with the subjects, or via telephone or e-mail with the subjects/caregivers or referring physician offices.  
Abbreviations: AE=adverse event, ALP=alkaline phosphatase, ALT=alanine aminotransferase, AML=acute myeloid leukemia, aPTT=activated partial thromboplastin time, 
AST=aspartate aminotransferase, BUN=blood urea nitrogen, CK=creatine kinase,  CT=computed tomography, CTCAE=Common Terminology Criteria for Adverse Events, 
DNA=deoxyribonucleic acid, ECG=electrocardiogram, ECOG=Eastern Cooperative Oncology Group, FDG=fluorodeoxyglucose, FL=FLT3 ligand concentration, FLT3= FMS-
like tyrosine kinase-3, HBc antibody=hepatitis B core antibody, HbsAg=hepatitis B surface antigen, HBV=hepatitis B virus, HCV=hepatitis C virus, HIV=human 
immunodeficiency virus, HSP=heat shock protein, LDH=lactate dehydrogenase, MRI=magnetic resonance imaging, PD-L1=programmed death-ligand 1, PET=positron 
emission tomography, PT=partial thromboplastin time, RNA=ribonucleic acid, SAE=serious adverse event, TLS=tumor lysis syndrome 
 


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8
SAFETY ASSESSMENTS
8.1 
Definitions 
8.1.1
Adverse Event
An AE is any untoward medical occurrence in a clinical investigation subject administered a 
medicinal product; the event does not necessarily have a causal relationship with study drug 
administration or usage. An AE can therefore be any unfavorable and unintended sign (including 
an abnormal laboratory finding), symptom, or disease temporally associated with the use of a 
medicinal product, whether or not considered related to the medicinal product. 
In this study, any of the following events will be considered an AE: 
 Any complication that occurs as a result of a protocol-mandated procedure (eg, venipuncture, 
ECG). 
 Any preexisting condition that increases in severity or changes in nature during or as a 
consequence of study drug administration. Worsening manifestations of the underlying 
cancer (eg, increase in pain, tumor flare reaction, TLS) may be considered AEs in this study.  
 Any injury or accident. If a medical condition is known to have caused the injury or accident 
(eg, a fall secondary to dizziness), the medical condition (dizziness) and the accident (fall) 
should be reported as 2 separate AEs.  
 Any abnormality in physiological testing or a physical examination finding that requires 
clinical intervention or further investigation (beyond ordering a repeat [confirmatory] test). 
 Any laboratory (eg, clinical chemistry, hematology, urinalysis) or investigational abnormality 
(eg, ECG, X-ray) independent of the underlying medical condition that requires clinical 
intervention, results in further investigation (beyond ordering a repeat [confirmatory] test), or 
leads to investigational medicinal product interruption or discontinuation unless it is 
associated with an already reported clinical event. If the laboratory abnormality is part of a 
syndrome, the syndrome or diagnosis (eg, anemia) not the laboratory result (eg, decreased 
hemoglobin) should be recorded.  
 A complication related to pregnancy or termination of a pregnancy (see Section 8.7.2 for 
additional information).
None of the following events is considered an AE: 
 Asymptomatic hyperleucocytosis 
 Cancer progression without worsening disease manifestations. In cases of SAEs, cancer 
progression may be reported if there is no alternative term that can be satisfactorily 
substituted. In such cases, the AE description should match the SAE description. 
 Laboratory abnormalities not requiring clinical intervention or further investigation. Such 
abnormalities will be captured as part of laboratory monitoring. 


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 A diagnostic, medical or surgical procedure (eg, surgery, endoscopy, tooth extraction, 
transfusion). However, the medical condition for which the procedure was performed should 
be reported if it meets the definition of an AE. For example, an acute appendicitis that begins 
during the AE reporting period should be reported as the AE and the resulting appendectomy 
should be recorded in the source documents.  
 A preexisting disease or condition or laboratory abnormality present or detected before the 
initial screening visit and that does not worsen. 
 An intervention not associated with an untoward medical occurrence (eg, hospitalization for 
elective surgery or for social and/or convenience reasons).
 An overdose without clinical sequelae. 
8.1.2 
Serious Adverse Event 
An SAE is defined as an untoward medical occurrence that results in any of the following 
outcomes: 
 Death (ie, all deaths occurring between signing of the consent form to within 30 days after 
last study drug administration), including deaths due to cancer progression if no other event 
more satisfactorily explains the reason for death. Deaths that occur as a result of an AE that 
started during the study period should be reported. Death is not an SAE term; the reported 
AE should be the event that caused the death. Death is the outcome of this SAE. 
 Life-threatening situation (ie, with an immediate risk of death from the event as it occurred 
but not including an event that, had it occurred in a more serious form, might have caused 
death).
 In-patient hospitalization or prolongation of existing hospitalization. Of note, an untoward 
medical occurrence that occurs during hospitalization is an AE but a complication that 
prolongs hospitalization is an SAE. In-subject hospitalization comprises formal admission to 
a hospital for medical reasons, for any length of time, whether or not hospitalization extends 
overnight. However, hospital admissions or prolongations of hospitalization for 
administration of the study drug or procedures required by the study protocol, diagnostic 
observations or procedures, administration of concomitant or subsequent therapy for the 
cancer, logistical issues (eg, lengthy travel), or the convenience of the subject or clinical 
personnel are not considered serious.  
 Persistent or significant disability/incapacity.
 Congenital anomaly/birth defect in the offspring of a subject who received the investigational 
medicinal product. 
 Other medically significant event. Such events may not be immediately life-threatening or 
result in death or hospitalization, but based upon appropriate medical and scientific 
judgment, may jeopardize the subject or may require medical or surgical intervention to 
prevent one of the outcomes listed above. Examples of such events might include: 
o Allergic bronchospasm requiring intensive treatment in an emergency room or at home 
o New cancers or blood dyscrasias 


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o Convulsions that do not result in hospitalization 
o Development of drug dependency or drug abuse 
8.1.3 
Unexpected Adverse Event 
An unexpected AE is defined as an event that has a nature, severity, or specificity that is not 
consistent with the applicable investigator brochure, or that is symptomatically and 
pathophysiologically related to a known toxicity but differs because of greater severity or 
specificity. For example, under this definition, hepatic necrosis would be unexpected (by virtue 
of greater severity) if the investigator brochure only referred to elevated hepatic enzymes or 
hepatitis. Similarly, cerebral thromboembolism and cerebral vasculitis would be unexpected (by 
virtue of greater specificity) if the investigator brochure only listed cerebral vascular accidents. 
“Unexpected,” as used in this definition, refers to an adverse drug experience that has not been 
previously observed and reported rather than an experience that has not been anticipated based 
on the pharmacological properties of the study drug. 
8.1.4 
Treatment-Emergent Adverse Event  
A TEAE is defined as an AE that occurs or worsens in the period from the first dose of study 
drug administration to 30 days after the final dose of study drug administration. 
8.1.5 
Adverse Events of Special Interest 
The major AEs of special interest in this protocol will be any occurrences of TLS or 
ophthalmological symptoms or signs. In addition to descriptions in listings and tables, narratives 
will be prepared to describe the clinical and laboratory manifestations of these outcomes. 
8.2 
Eliciting Adverse Event Information 
The investigator is to report all directly observed AEs and all AEs spontaneously reported by the 
study subject. In addition, each study subject should be questioned about AEs at each scheduled 
study center visit or during any telephone contact with the subject. The type of question asked 
should typically be open-ended, eg, “Have you had any new health problems?” or a similar type 
of query.  
8.3 
Recording Adverse Events 
All AEs will be assessed by the investigator or qualified designee and recorded in the electronic 
case report forms (eCRFs). The following considerations apply in collecting AE information:
 Recognized medical terms (not colloquialisms, abbreviations, or jargon) should be used 
when recording AEs. Ideally the description should be consistent with MedDRA 
nomenclature. 
 The medical diagnosis (ie, disease or syndrome) should be recorded instead of signs and 
symptoms (eg, pneumonia instead of shortness of breath, coughing, and fever). 
 Any sign or symptom considered as unrelated to an encountered disease or syndrome should 
be recorded as an individual AE (eg, if nausea and severe headache are observed at the same 
time, each event should be recorded as a separate AE).


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 If an AE resolves and reoccurs at a later date, a new AE must be documented and reported, as 
appropriate. 
The following information should be recorded:
 Description as to whether the AE is serious, if applicable (see Section 8.1.2) 
 The start date (date of AE onset)
The stop date (date of AE resolution)
The severity of the AE (see Section 8.4)
 A description of the relatedness of the AE to the study drug or to a study procedure (see 
Section 8.5) 
 The action taken due to the AE 
 The outcome of the AE 
8.4 
Grading of the Severity of an Adverse Event 
The severity of AEs will be graded and reported using the CTCAE, Version 4.03 [NCI 2010].  
If a CTCAE criterion does not exist, the investigator should use the grade or adjectives: Grade 1 
(mild), Grade 2 (moderate), Grade 3 (severe), Grade 4 (life-threatening), or Grade 5 (fatal) to 
describe the maximum intensity of the AE. For purposes of consistency with the CTCAE, these 
intensity grades are defined in Table 4.
Table 4:
Grading of Adverse Event Severity 
Grade
Adjective 
Description 
Grade 1 
Mild 
Sign or symptom is present, but it is easily tolerated, is not expected to 
have a clinically significant effect on the subject’s overall health and 
well-being, does not interfere with the subject’s usual function, and is 
not likely to require medical attention. 
Grade 2 
Moderate 
Sign or symptom causes interference with usual activity or affects 
clinical status, and may require medical intervention. 
Grade 3 
Severe 
Sign or symptom is incapacitating or significantly affects clinical status 
and likely requires medical intervention and/or close follow-up. 
Grade 4 
Life-threatening
Sign or symptom results in a potential threat to life. 
Grade 5 
Fatal 
Sign or symptom results in death. 
The distinction between the seriousness and the severity of an AE should be noted. Severity is a 
measure of intensity; thus, a severe reaction is not necessarily a serious reaction. For example, a 
headache may be severe in intensity, but would not be classified as serious unless it met one of 
the criteria for serious events (as listed in Section 8.1.2). 
8.5 
Describing Adverse Event Relationship to Study Drug and Study 
Procedures 
The investigator will evaluate the causal relationship of each AE to a study drug and/or to a 
study procedure (eg, venipuncture or ECG evaluation) and record that relationship on the 
appropriate CRFs. Causality will be assessed considering whether the AE is reasonably related to 


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the study drug or procedure or whether the AE is not reasonably related to the study drug or 
procedure considering the definitions in Table 5. 
Table 5: Relationship of Study Drug to Adverse Event 
Relationship
Description
Definite 
A clinical event in which a relationship to the use of the study drug seems definite because 
of such factors as consistency with known effects of the drug; a clear temporal association 
with the use of the drug; lack of alternative explanations for the event; improvement upon 
withdrawal of the drug (de-challenge); and recurrence upon resumption of the drug 
(rechallenge). 
Probable 
A clinical event in which a relationship to the study drug seems probable because of such 
factors as consistency with known effects of the drug; a reasonable temporal association 
with the use of the drug; lack of alternative explanations for the event; and improvement 
upon withdrawal of the drug (de-challenge). 
Possible 
A clinical event with a reasonable temporal association with administration of the study 
drug, and that is not likely to be explained by concurrent disease or other drugs or 
chemicals. Information on drug withdrawal may be lacking. 
Unlikely 
A clinical event with a temporal relationship to study drug administration that makes a 
causal relationship improbable and for which other factors suggesting an alternative etiology 
exist. Such factors might include a known relationship of the clinical event to a concomitant 
drug, past medical history of a similar event, the subject’s disease state, intercurrent illness, 
or environmental factors. 
Unrelated 
A clinical event in which a relationship to the study drug seems improbable because of 
factors such as inconsistency with known effects of the study drug; lack of a temporal 
association with study drug administration; lack of association of the event with study drug 
withdrawal or rechallenge; and/or presence of alternative explanations for the event. 
Alternative explanations might include a known relationship of the clinical event to a 
concomitant drug, past medical history of a similar event, the subject’s disease state, 
intercurrent illness, or environmental factors. 
8.6 
Adverse Event Reporting Period 
The start of the AE reporting for a study subject will coincide with signing of the informed 
consent for this study. Between the time of informed consent and the first administration of study 
drug, only AEs (nonserious and serious) assessed as related to study procedures should be 
reported. After the first administration of study drug, all AEs (serious and nonserious, related and 
unrelated) should be reported. Unless a subject withdraws consent for follow-up, each subject
must be followed until the end of the AE reporting period at 30 days after the final LAM-003 
administration or when any ongoing drug-related AEs and/or SAEs have resolved or become 
stable. The investigator should use appropriate judgment in ordering additional tests as necessary 
to monitor the resolution of events. The medical monitor or the sponsor may request that certain 
AEs be followed longer.  
Investigators are not obligated to actively seek information regarding the occurrence of new 
SAEs beginning after the 30-day post-LAM-003 period. However, if the investigator learns of 
such an SAE and that event is deemed relevant to the use of LAM-003, he/she should promptly 
document and report the event. A longer reporting period applies in the case of pregnancy (see 
Section 8.7.2). 


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8.7
Study Center Reporting Requirements
8.7.1
Adverse Event Reporting Requirements
Classification of an event as serious or nonserious (see Section 8.1) determines the reporting 
procedures to be followed by the study center. Study center reporting requirements for AEs are 
summarized in Table 6.
Table 6:
Study Center Reporting Requirements for Adverse Events
Classification
Reporting Time 
Reporting Action 
Serious 
Within 24 hours of becoming aware 
of the event 
E-mail report on designated SAE report form to the 
sponsor or designee [a] and to the study center IRB, 
as per local IRB/IEC requirements
Within 10 working days 
E-mail copies of relevant source documents (eg, 
progress notes, laboratory and diagnostic test 
results, discharge summaries) [b] to the sponsor or 
designee [a].  
Per eCRF submission procedure 
Record and submit information on appropriate 
eCRFs.
Nonserious 
Per eCRF submission procedure 
Record and submit information on appropriate 
eCRFs.
a. 
See contact information in Table 7. 
b. Subject name, address, and other personal identifiers should be obscured but without losing the traceability of a 
document to the study subject identifiers. 
Abbreviations: eCRF=case report form; IRB/IEC= institutional review board/independent ethics committee; 
SAE=serious adverse event 
For SAEs, in addition to completing the AE portion of the eCRF, an SAE report form must also 
be completed and emailed within 24 hours of first awareness of the event to the sponsor (or 
designee) (see Table 7). 
Investigators must also submit written safety reports as required by the IRB/IEC within timelines 
set by local and regional regulations. The study site should retain documentation of the 
submission of expedited safety reports to the IRB/IEC, and their receipt. Study site personnel 
should not wait to receive complete information or the investigator’s signature before notifying 
the sponsor (or designee) and the IRB/IEC of an SAE.
The following minimum information is required: 
 Subject identification (ie, subject number, sex, age)
 Description of the SAE (diagnosis preferred, symptoms, etc) 
 Study drug and causal relationship of the SAE to the study drugs or study procedures
 Investigator name 
Collection of complete information concerning SAEs is extremely important. The information in 
the AE portion of the eCRF and the SAE report form must match or be reconciled. Where the 
same data are collected, the forms must be completed in a consistent manner. For example, the 
same AE term should be used on both forms.  
All available and relevant supporting documentation (eg, progress notes, pertinent laboratory and 
diagnostic test results, discharge summaries) should also be provided. The subject’s name, 


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address, and other personal identity information should be obscured on any source documents 
(eg, progress notes, nurses’ notes, laboratory and diagnostic test results, discharge summaries). 
The subject’s unique study number should be included on each page of any document provided.  
The sponsor (or designee) will review SAE reports for missing information and send queries to 
the site for resolution as indicated. The study site is responsible for obtaining pertinent follow-up 
information missing from initial reports and forwarding the information within 24 hours of 
receipt to the sponsor (or designee). Follow-up information to the SAE should be clearly 
documented as “follow-up” in the SAE report form.  
The original SAE form and any follow-up forms must be kept on file at the study site. An SAE is 
followed until it is considered resolved, it returns to baseline, is chronically ongoing, or 
explained otherwise by the principal investigator. 
8.7.2 
Pregnancy  
Each female subject should be instructed to inform the investigator immediately if she becomes 
pregnant at any time between the start of study screening until 30 days after the last 
administration of study drug.  
The investigator should counsel the subject regarding the possible effects of study drug exposure 
on the fetus and the need to inform the study center, the medical monitor, and the sponsor (or 
designee) of the outcome of the pregnancy. 
Neither the pregnancy itself nor an induced elective abortion to terminate the pregnancy without 
medical reasons is considered an AE; such occurrences should be reported on the appropriate 
pregnancy report forms. However, if the outcome of the pregnancy meets the criteria for 
classification as an SAE (ie, spontaneous abortion, induced abortion due to complications, 
stillbirth, neonatal death, or congenital anomaly [including that in an aborted fetus]), the 
investigator should follow the procedures for reporting SAEs (ie, report the event to the sponsor 
[or designee] and follow up by submission of the appropriate AE eCRFs (see Section 8.7.1).  


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Additional information about pregnancy outcomes that are classified as SAEs includes: 
 Any spontaneous abortion, including miscarriage and missed abortion, will be reported as an 
SAE. 
 An induced therapeutic abortion to terminate any pregnancy due to complications or other 
medical reasons will be recorded as an SAE. The underlying medical reason for this 
procedure should be recorded as the AE term. 
 All neonatal deaths that occur within 1 month of birth should be reported, without regard to 
causality, as SAEs. In addition, any infant death after 1 month that the investigator assesses 
as possibly related to the in-utero exposure to the study drug should also be reported. 
 In the case of a live birth, the “normality” of the newborn can be assessed at the time of birth 
(ie, there is no required minimum follow-up of a presumably normal infant before the 
pregnancy outcome report eCRF can be completed). 
 The “normality” of an aborted fetus can be assessed by gross visual inspection unless there 
are pre-abortion laboratory findings suggestive of a congenital anomaly, in which case 
pathologic examination should be requested.  
Information regarding any pregnancy in a study subject or the female partner of a male subject 
must be documented on a pregnancy report form and forwarded to the sponsor (or designee) (see 
Table 7) within 24 hours of becoming aware of the pregnancy. Monitoring of the pregnancy in 
both female study subjects and female partners of male study subjects should continue until the 
conclusion of the pregnancy. For female partners of male study subjects, such monitoring applies 
if the pregnancy occurs in the period from the subject’s start of study drug until 30 days after the 
subject’s last dose of study drug. The outcome of the pregnancy should be reported on the 
pregnancy outcome report form within 5 days of the conclusion of the pregnancy. If the end of 
the pregnancy occurs after the study has been completed, the outcome should be reported to the 
sponsor (or designee) (see Table 7). 
8.7.3 
Contact Information for Reporting an SAE or Pregnancy 
Contact information for reporting an SAE or pregnancy is provided in Table 7. 
Table 7: Contact Information for Reporting SAEs or Pregnancies 
Pharmacovigilance CRO
Contact Information
Pharmalex US, LLC, Guilford, CT, USA 
E-mail: 
Vigicare@pharmalex.com 
Facsimile:
+1 (617) 315-4825 
CRO=contract research organization, SAE=serious adverse event 
8.8 
Sponsor Reporting Requirements 
Each SAE or special situation report received from the investigator will be evaluated by the 
sponsor (or designee). The sponsor (or designee) will assess the seriousness of the event (see 
Section 8.1.2), the expectedness of the event (see Section 8.1.3), and the relationship to 
participation in the study (see Section 8.5). The sponsor (or designee) will also indicate whether 
there is concurrence with the details of the report provided by the investigator.  
The sponsor (or designee) will provide information for reporting of suspected, unexpected, 
serious adverse reactions (SUSARs) to regulatory authorities worldwide consistent with relevant 


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legislation or regulations, including the applicable US FDA CFR, the European Commission 
Clinical Trials Directive (2001/20/EC, and revisions), and other country-specific legislation or 
regulations. SUSARS will be reported to regulatory authorities within 7 calendar days for 
life-threatening and fatal events, or 15 calendar days for all others. These timeframes begin with 
the first notification of the event from the reporting investigator to the sponsor (or designee), 
which represents the start of the regulatory clock (Day 0).  
The sponsor (or designee) will also provide all investigators with a safety letter describing the 
SUSAR. The information will be provided by e-mail, fax, or overnight mail within 15 calendar 
days from Day 0. Investigators will be requested to provide written notification of the event to 
the relevant IRB/IEC as soon as is practical and consistent with local regulatory requirements 
and local institutional policy.  
9 
LABORATORY AND OTHER ASSESSMENTS 
9.1 
Methods and Analytes 
Samples to be obtained and parameters to be analyzed are indicated in Table 8. 
General safety laboratory assays (serum virology, serum pregnancy test, serum chemistry, 
hematology, coagulation, urinalysis) will be performed using standard clinical pathology 
methods at Clinical Laboratory Improvement Amendments (CLIA)-certified laboratories 
associated with the study centers.  
For pharmacokinetic analyses, evaluation of LAM-003 serum concentrations will be performed 
using a validated immunoassay at a contract laboratory designated by the sponsor.  
Cellular pharmacodynamic assessments from peripheral blood and bone marrow will be assessed 
at the sponsor or at contract laboratories designated by the sponsor. Similarly, plasma analyses 
for FL3 ligand will be analyzed by immunoassays at the sponsor or sponsor-specified contract 
laboratories.  
FLT3 mutation analysis in AML blasts using a FLT3 mutation assay will be performed at the 
sponsor or at a sponsor-designated contract laboratory.  
Any available information in the subject medical records regarding AML genetic profiling (eg, 
for FLT3 mutation status) will be provided in redacted format for sponsor review. 
Efficacy evaluations of bone marrow aspirates and biopsies will be performed by a sponsor-
specified CRO specializing in central pathology review of AML clinical trials.  
Clinical assessments (body weight and height, vital signs, oxygen saturation) will be obtained 
using standard clinical equipment available at each study center.  
Ophthalmological examinations should be performed by a consulting ophthalmologist, 
optometrist, or other qualified specialist with the necessary facilities and equipment to perform 
appropriate testing (including visual symptom assessment, visual acuity testing, 
electroretinography, tonometry, slit lamp examination, and electrical coherence tomography); 
interpretations of ophthalmological findings will be provided by a consulting specialist.   
ECGs will be performed at the clinical sites using ECG machines provided by a LAM-specified 
CRO; study-specific interpretations of the ECG findings will be provided by a cardiologist at the 
CRO.  


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Radiography testing performed in subjects with extramedullary disease will be performed and 
interpreted at study centers. 
Table 8: Laboratory and Other Parameters to Be Assessed 
Test/Procedure 
Parameters
Laboratory – Safety 
Serum virology 
 Serum HIV antibody 
 Serum HbsAg antibody, HBc antibody (if positive, then serum HBV DNA by PCR) 
 Serum HCV antibody (if positive, then serum HCV RNA by PCR) 
Serum pregnancy test 
 
-HCG  
Serum chemistry
 Sodium, potassium, chloride, bicarbonate, BUN, creatinine, glucose, calcium, 
phosphorus, magnesium, total protein, albumin, ALT, AST, ALP, CK, LDH, total 
bilirubin, uric acid.  
Hematology 
 Hematocrit, hemoglobin, erythrocyte count 
 Absolute counts of leukocytes, neutrophils, lymphocytes, monocytes, eosinophils, 
basophils 
 Platelet count 
Coagulation 
 PT 
 aPTT 
Urinalysis 
 Dipstick: specific gravity, pH, protein, glucose, ketones, bilirubin, urobilinogen, 
blood, nitrite, leukocyte esterase 
 Microscopy: White blood cells, red blood cells, epithelial cells, bacteria, casts, 
crystals 
Laboratory – Pharmacokinetic
Plasma pharmacokinetics 
 Plasma LAM-003 and LAM-003A concentrations (as assessed by validated 
bioassays) 
 Retention of plasma for potential metabolite analyses 
Laboratory – Pharmacodynamic 
Peripheral blood and bone 
marrow aspirate cellular 
pharmacodynamics 
 FLT3 and HSP (eg, HSP90, HSP70) protein expression and activation of 
downstream pathway components in AML blasts (as measured using flow 
cytometry and/or protein immunoblotting) 
 HSP gene expression in AML blasts (as measured using quantitative PCR) 
 PD-L1 expression in AML blasts (as measured using flow cytometry) 
Plasma 
pharmacodynamics 
 Plasma concentrations FL (as measured using an immunoassay) 
 Retention of plasma for potential additional cytokine/chemokine analyses, 
LAM-003 concentration analysis, or alternative safety parameter analysis 
Peripheral blood 
immunoprofiling 
 Numbers of circulating B-cell, T-cell, NK, and monocyte subsets, potentially 
including (but not limited to): B cells (CD19, B regulatory cells (CD19+, CD38+, 
CD1d+, IgM+, CD147+), total T cells (CD3+), cytotoxic T cells (CD3+, CD8+), 
activated cytot
 
NK cells (CD3-, CD56+, CD16+), mature/activated NK cells (CD3-, CD56 dim, 
-T cells (CD3+, CD56+) 
(as measured using flow cytometry) 


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Table 8: Laboratory and Other Parameters to Be Assessed 
Test/Procedure
Parameters
Laboratory – Disease-related
Peripheral blood or bone 
marrow cellular AML 
FLT3 mutation analysis 
 Peripheral blood or bone marrow AML blast FLT3 mutation type and FLT3 
mutation-to-WT allele ratio (as evaluated using a sponsor-specified FLT3 mutation 
assay) 
Baseline biomarker 
assessment 
 Mutational profiling in DNA from peripheral blood AML blasts with saliva as 
germ-line DNA control (with sample analysis using NGS) 
Peripheral blood smears 
and bone marrow aspirate 
and biopsy for efficacy 
assessments 
 Peripheral blood smears and bone marrow aspirate and biopsy for analysis of AML 
disease status (blast percentage, presence of Auer rods, bone marrow cellularity, 
MRD) (as assessed by Wright stain for peripheral blood and bone marrow aspirate, 
hematoxylin and eosin for bone marrow biopsy, flow cytometry, and 
immunohistochemistry [as needed for ambiguous blast analysis]) 
Other 
Body weight/height
 Weight in kilograms, height in centimeters  
Body temperature  
 Temperature in degrees Celsius 
Blood pressure  
 Diastolic and systolic blood pressure in mm Hg 
Oxygen saturation  
 % saturation 
Ophthalmology 
examination 
 Examination by an ophthalmologist, optometrist, or other qualified specialist 
(including visual symptom assessment, visual acuity testing, electroretinography, 
tonometry, slit lamp examination, and electrical coherence tomography)) 
12-lead ECG  
 Heart rate, cardiac intervals, wave form abnormalities, ectopy 
Radiology examination  
 FDG-PET/CT (preferred), MRI, or diagnostic CT imaging for subjects with 
extramedullary disease that is radiographically assessible. 
Abbreviations: ALP=alkaline phosphatase, ALT=alanine aminotransferase, AML=acute myeloid leukemia, 
aPTT=activated partial thromboplastin time, AST=aspartate aminotransferase, BUN=blood urea nitrogen, 
CD=cluster of differentiation, CK=creatine kinase, CT=computed tomography, DNA=deoxyribonucleic acid, 
ECG=electrocardiogram, FDG=fluorodeoxyglucose, FL=FLT3 ligand, FLT3= FMS-like tyrosine kinase-3, 
HBc antibody=anti-hepatitis B core antibody, HbsAg=hepatitis B surface antigen, HBV=hepatitis B virus, 
HCV=hepatitis C virus, HIV=human immunodeficiency virus, HSP=heat shock protein, 
-
LDH=lactate dehydrogenase, MRD=minimal residual disease, MRI=magnetic resonance imaging, NGS=next-
generation sequencing, NK=natural killer (cells), PET=positron emission tomography, PCR=polymerase chain 
reaction, PD-L1=programmed death (receptor) ligand-1, PT=prothrombin time, RNA=ribonucleic acid, WT=wild-
type, -
-human chorionic gonadotropin. 
9.2 
Sample Shipping, Storage, and Retention 
Routine clinical safety samples (for serum virology, serum pregnancy test, serum chemistry, 
hematology, and coagulation) will be analyzed at the clinical laboratory at the study center and 
will not be shipped. These samples will not be stored and will be discarded promptly after 
analysis.  
Other samples (plasma for pharmacokinetics; blood, bone marrow, and plasma for 
pharmacodynamics and immune profiling; bone marrow for disease characterization) will be 
prepared following the instructions outlined in a detailed clinical study laboratory manual.  
These samples will be shipped to the sponsor or the contract analytical laboratories using a 
shipping service designated by the sponsor and as specified in the study laboratory manual. For 


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the duration of the sample analysis campaign, samples will be stored at these contract laboratory 
facilities or sent for long-term storage at a storage facility designated by the sponsor. Samples 
will be retained as described for study records (see Section 12.7). 
As described for other study records (see Section 12.7), copies of data relating to body weight 
and height, vital signs, oxygen saturation, and radiography will be retained on file at the study 
centers. The sponsor may request copies of primary radiography images (redacted of subject 
personal identifying information) for storage at the company. Copies of data relating to ECG 
parameters and bone marrow biopsy/aspirate data will be retained on file at the CROs 
responsible for analysis of those data. 
10
EFFICACY ASSESSMENTS
10.1 Overview  
The determination of remission and progression for AML in this study will be based on 
standardized criteria [Cheson 2003, Döhner 2017] as modified for use in the context of protocol 
therapy for relapsed or refractory AML. During the study, investigators will periodically 
determine AML disease status. Treatment decisions by the investigator in this study will be 
based, in part, on these assessments. Bone marrow assessments will be subject to independent 
review and together with peripheral blood and any radiographic information these data will be 
considered primary for analyses of tumor control. 
10.2 Methods of Assessment 
Evaluation of peripheral blood cell counts and bone marrow aspirates will be used in this study 
as the primary basis of AML assessment, but with consideration of extramedullary disease for 
subjects who have such involvement.  
The peripheral blood smear will be reviewed by a pathologist because reliance cannot be placed 
on automated differential blood counts. For assessment of the bone marrow, examination of an 
aspirate is preferred. Trephine biopsy of the bone marrow will also be obtained because a biopsy 
allows more bone marrow tissue to be examined and permits identification of clusters of blasts. 
Biopsy evaluation can also provide a back-up to aspirate findings if the aspirate is dilute, 
hypocellular, or inaspirable or if spicules are absent from the aspirate sample. Routine 
cytochemical evaluation (eg, with peroxidase and esterase) will be carried out. 
Immunophenotyping by flow cytometry (preferred) or immunohistochemistry can be included 
for determination of cellular lineage determination.  
For evaluation of systemic extramedullary disease by radiography, PET-CT is the preferred 
method [Ohanian 2013], but other methods (eg, MRI, diagnostic CT) may be used, as 
appropriate. If performed, whole-body FDG PET-CT scanning should be extended from the base 
of the skull to mid-thigh. Other testing for extramedullary disease (eg, biopsy, cytological 
assessment of cerebral-spinal fluid or effusions) may be employed 
All relevant information required to make each tumor status assessment must be made available 
for source verification as requested by the study sponsor. 


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10.3
Timing of Assessments
During screening, clinical and imaging-based tumor assessments should be performed within the 
specified screening period. On-study tumor assessments should be performed as indicated in 
Section 7. An end-of-therapy tumor assessment should be performed unless the subject already 
has confirmation of TF or DRP 8 weeks prior to study drug discontinuation or the medical 
monitor has waived the requirement. If a subject permanently discontinues treatment prior to 
objective documentation of AML progression, investigators should continue further follow-up of
tumor status with assessments at ~8- to 12-week intervals until disease progression is 
documented or until the initiation of a new post-study therapy for the subject’s AML. 
10.4 Definitions of Tumor Remission and Progression 
Responses will be categorized as complete remission without minimal residual disease (CRMRD-), 
complete remission (CR), complete remission with incomplete blood count recovery (CRi), 
partial remission (PR), disease recurrence or progression (DRP), or treatment failure (TF). In 
addition, a remission category of nonevaluable (NE) is provided for situations in which there is 
inadequate information to otherwise categorize remission status.  
The best overall response will be determined. The best overall response is the best on-treatment 
response from baseline recorded from the start of treatment until DRP or TF. The baseline status 
will be taken as a reference for determinations of response. The best on-study measurement will 
be taken as a reference for DRP; the best on-study measurement constitutes the measurement 
with the least tumor involvement, including the baseline measurement if this is the measurement 
meeting this criterion.  
10.4.1 Complete Remission without Minimal Residual Disease 
To satisfy criteria for CRMRD-, all of the following conditions must be attained: 
 Leukemia disease status meeting all of the following requirements: 
o Absence of evidence of AML in bone marrow aspirate by flow cytometry 
o <5% bone marrow blasts (based on a bone marrow aspirate/biopsy sample with 
 nucleated cells and the presence of bone marrow spicules)   
o No blasts in the peripheral blood 
o No blasts with Auer rods 
o No extramedullary disease 
 Peripheral blood meeting both of the following requirements: 
o 
× 109/L 
o 
× 109/L  


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10.4.2 Complete Remission 
To satisfy criteria for CR, all of the following conditions must be attained: 
 Leukemia disease status meeting all of the following requirements: 
o <5% bone marrow blasts (based on a bone marrow aspirate/biopsy sample with 
 nucleated cells and the presence of bone marrow spicules)   
o No blasts in the peripheral blood 
o No blasts with Auer rods 
o No extramedullary disease 
 Peripheral blood meeting both of the following requirements: 
o 
× 109/L 
o 
× 109/L  
10.4.3 Complete Remission with Incomplete Blood Count Recovery 
To satisfy criteria for CRi, all of the following conditions must be attained: 
 Leukemia disease status meeting all of the following requirements: 
o <5% bone marrow blasts (based on a bone marrow aspirate/biopsy sample with 
 nucleated cells and the presence of bone marrow spicules)   
o No blasts in the peripheral blood 
o No blasts with Auer rods
o No extramedullary disease
 Peripheral blood meeting either of the following requirements:
o ANC <1.0 x 109/L 
o Platelet count <100 x 109/L 
10.4.4 Partial Remission 
To satisfy criteria for PR, all of the following conditions must be attained: 
 Leukemia disease status meeting either of the following requirements: 
o 
e 
marrow aspirate/biopsy sample
 nucleated cells and the presence of bone 
marrow spicules)  
o <5% bone marrow blasts but with Auer rods present (based on a bone marrow 
spicules)   
o No blasts in the peripheral blood 
o No new or worsening extramedullary disease 


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 Peripheral blood meeting both of the following requirements: 
o 
× 109/L 
o 
× 109/L  
10.4.5 Treatment Failure 
The occurrence of any of the following events indicates TF:
In a subject without DRP, inability to qualify for a CRMRD-. CR, CRi, or PR by 8 weeks from 
start of study therapy 
 In a subject without a CRMRD-. CR, CRi, PR, or DRP, permanent cessation of study therapy 
due to an AE
 In a subject without a CRMRD-. CR, CRi, PR, or DRP, death from any cause 
10.4.6 Disease Relapse or Progression 
The occurrence of any of the following events indicates DRP: 
 Reappearance of bone marrow blasts to >5% in a subject who had experienced a CR or CRi 
 Reappearance of blasts in the peripheral blood in a subject who had experienced a CR, CRi, 
or PR 
 An absolute 20% increase in bone marrow blasts to >25% (based on a bone marrow 
in a subject who had experienced a PR  
 Development of new or worsening existing extramedullary disease 
Reoccurrence or worsening of MRD, as assessed by flow cytometry, will not be considered in 
the definition of DRP, but will be recorded. 
10.4.7 Nonevaluable 
In a subject who does not have TF or DRP, the occurrence of any of the following conditions 
indicates a remission status of NE:  
 Bone marrow aspiration/biopsy data are inadequate or missing 
 Peripheral blood data are inadequate or missing 
 Information for a known site of extramedullary disease is inadequate or missing 


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11
STATISTICAL CONSIDERATIONS
11.1 Analysis Conventions 
11.1.1
Analysis Sets
11.1.1.1 Full-Analysis Set 
The full-
. This analysis set 
will be used in the analyses of subject characteristics, study drug administration and compliance, 
safety, OR, CRc, CRMRD-, CR, CRi, PR, EFS, and OS. 
11.1.1.2 Responding Analysis Set 
The responding analysis set includes subjects in the full analysis set who have measurable 
disease, who can be evaluated for tumor response with both baseline and on-study tumor 
evaluations, and who achieve a CRMRD-, CR, CRi, or PR. This analysis set will be used in the 
analyses of TTR and DOR. 
11.1.1.3 Evaluable Analysis Sets 
The evaluable analysis sets include subjects in the full analysis set who have the necessary 
baseline and on-study measurements to provide interpretable results for specific parameters of 
interest. These analysis sets will be used in the analyses of pharmacokinetic, pharmacodynamic, 
and biomarker parameters.  
11.1.2 Data Handling Conventions 
By-subject listings will be created for important variables from each eCRF module. Data will be 
described and summarized by dosing regimen and time point.  
Descriptive summaries for continuous variables will contain N (number in population); 
n (number with data); mean (with standard deviation and confidence intervals [Cis] on the 
mean); median; minimum; and maximum. Descriptive summaries for categorical variables will 
include N, n, percentage, and CIs on the percentage.  
The baseline value used in each analysis will be the last (most recent) predose value. As 
appropriate, changes from baseline to each subsequent time point will be described and 
summarized. Similarly, as appropriate, the most extreme change from baseline during the study 
will also be described and summarized. Shift tables or graphical techniques (eg, bar charts, line 
graphs) may be used when such methods are appropriate and informative.  
Data from all study centers will be pooled for all analyses. Analyses will be based upon the 
observed data unless methods for handling missing data are specified. If there is a significant 
degree of non-normality, analyses may be performed on log-transformed data or nonparametric 
tests may be applied, as appropriate. Unless otherwise indicated, CIs for binary variables will be 
calculated using the binomial distribution (exact method) and will be 2-sided. Unless otherwise 
specified, statistical testing will be 2-sided at a nominal 0.05 level of significance. Given the 
exploratory nature of this study, adjustments for multiple comparisons need not be applied. 


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11.2
Analysis Plan
Details of the statistical analyses will be fully described in a statistical analysis plan to be 
finalized prior to the analyses. 
11.2.1 Subject Disposition and Baseline Characteristics 
A listing of all full analysis subjects will be generated to describe study center, subject number, 
first screening date, first treatment date, dosing regimen, the longest duration of treatment with 
LAM-003, and the reason for discontinuing LAM-003. Available information on subjects who 
were screened but not administered study drug may be listed separately. A table will be created 
summarizing these categories in terms of number and percent for the full analysis set.
Subject baseline characteristics (eg, subject demographics, medical history, disease history, prior 
therapy, FLT3 mutational status and mutant-to-WT allele ratio, peripheral AML blast count, 
bone marrow blast percentage, peripheral blood ANC, peripheral blood platelet count, peripheral 
blood hemoglobin, baseline TLS risk status, etc) will be listed and summarized for the full 
analysis set. 
11.2.2 Study Drug Exposure and Concomitant Medications 
11.2.2.1 Treatment Administration and Study Drug Compliance 
Descriptive information will be provided regarding the number of doses of LAM-003 prescribed; 
the number of days of LAM-003 treatment, the number and timing of prescribed LAM-003 dose 
modifications and interruptions; and the reasons for LAM-003 dose modifications and 
interruptions. 
LAM-003 compliance will be described based on diary information and bottle and tablet counts 
in terms of the number (%) of study drug doses actually taken relative to the amount that was 
dispensed (taking into account physician-prescribed reductions and interruptions). 
11.2.2.2 Prior and Concomitant Medication Use 
Prior, concomitant, and postdose medications will be coded by means of the World Health 
Organization Drug Dictionary (WHODRUG) into Anatomical Therapeutic-Chemical 
classification (ATC) codes. 
Descriptions of prior medication use will be focused on drugs and regimens used as treatments 
for AML. As appropriate and if available, information on the sequencing, type, dose, schedule, 
timing, duration of use, and efficacy of prior regimens will be provided. Descriptions of prior 
medications used during the screening period will also be provided. 
The type and timing of use of concomitant medications and supportive care will be listed and 
summarized. Information regarding the type and amounts of specific supportive medications or 
measures (eg, antifungal prophylaxis, antiemetics, TLS prophylaxis, corticosteroid usage) may 
be described. Use of drugs representing a risk for a CYP3A4-mediated drug-drug interactions 
may be described. 
The number, type, and timing of poststudy treatment regimens for AML will be summarized, 
characterizing the disposition of all subjects who are eligible for poststudy treatment and those 


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who are not eligible for poststudy treatment (eg, subjects who are never treated at all, die while 
on study treatment, are still on study, or are lost to follow-up). 
11.2.3 Safety 
11.2.3.1 Adverse Events 
All AEs will be listed. The focus of AE summarization will be on TEAEs as defined in 
Section 8.1.4. AEs that occur before the first dose of study drug administration or >30 days after 
the final study drug administration will be included in data listings.
AEs will be classified using MedDRA with descriptions by System Organ Class and Preferred 
Term. The severity of AEs will be graded by the investigator according to the CTCAE, 
Version 4.03 [NCI 2010], whenever possible. If a CTCAE criterion does not exist for a specific 
type of AE, the grade corresponding to the appropriate adjective will be used by the investigator 
to describe the maximum intensity of the AE: Grade 1 (mild), Grade 2 (moderate), Grade 3 
(severe), Grade 4 (life threatening), or Grade 5 (fatal). The relationship of the AE to the study 
drug will be described based on the categories as outlined in Table 5. As necessary, attributions 
of “definitely”, “probably”, or “possibly” related may be aggregated as “related” and attributions 
of “unlikely” or “unrelated” may be aggregated as “unrelated” to provide a dichotomous 
description of causal relationships. 
Summary tables will be presented to show the number of subjects reporting TEAEs by severity 
grade and corresponding percentages. A subject who reports multiple TEAEs within the same 
Preferred Term (or System Organ Class) is counted only once for that Preferred Term (or System 
Organ Class) using the worst severity grade. AE descriptions will be presented in order of 
decreasing frequency for System Organ Class, and by decreasing frequency in the overall or total 
column for a given Preferred Term. 
Separate listings and summaries will be prepared for the following types of AEs: 
 Study-drug-related AEs 
 AEs that are Grade 3, 4, or 5 in severity 
 AEs leading to study drug interruption and/or dose modification 
 AEs leading to study drug discontinuation 
 SAEs (with categorization of the primary outcome that results in the AE being considered 
serious, eg, life-threatening, requiring hospitalization) 
 AEs of special interest (see Section 8.1.5) 
Separate listings and summaries will be prepared for long-term follow-up safety data (see 
Section 7).
11.2.3.2 Laboratory Evaluations 
All laboratory data will be listed. Summaries of laboratory data will be based on observed data 
and will be reported using conventional units. The focus of laboratory data summarization will 
be on treatment-emergent laboratory abnormalities. A treatment-emergent laboratory 
abnormality is defined as an abnormality that, compared to baseline, worsens by 


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period from the first study drug administration to 30 days after the last study drug administration. 
If baseline data are missing, then any graded abnormality (ie, an abnormality that is Grade
severity) will be considered treatment-emergent. Laboratory abnormalities that occur before the 
administration of study drug or >30 days after the final administration of study drug will be 
included in data listings. 
Hematological, serum biochemistry, and coagulation data will be programmatically graded 
according to CTCAE severity grade, when applicable. For parameters for which a CTCAE scale 
does not exist, reference ranges from the laboratory will be used to determine programmatically 
if a laboratory parameter is below, within, or above the normal range for the subject’s age, sex, 
etc. 
Hematological, serum biochemistry, and coagulation data will be summarized in tables and may 
be summarized in figures showing values over time, if informative. Summary tables will be 
presented for each relevant assay to show the number of subjects by CTCAE severity grade with 
corresponding percentages. For parameters for which a CTCAE scale does not exist, the 
frequency of subjects with values below, within, and above the normal ranges will be 
summarized. Subjects will be characterized only once for a given assay, based on their worst 
severity grade observed during a period of interest (eg, during the study or during a cycle). 
Shift tables for hematology, serum biochemistry, and coagulation data will also be presented by 
showing change in CTCAE severity grade from baseline to each time point. For parameters for 
which a CTCAE scale does not exist, shift tables will be presented showing change in results 
from baseline (normal, low and high [or abnormal]) to each time point (normal, low and high [or 
abnormal]). For selected variables of interest, tables may be prepared to show frequencies 
adjusted for baseline values; for these frequencies, subjects with the same or worse grade at 
baseline are not considered. 
Urinalysis data will be summarized in tables. The overall urinalysis assessment will be reported 
as “Normal” or “Abnormal” with respect to relevant abnormalities based on the reference 
laboratory ranges provided by the study center. A shift table comparing the urinalysis assessment 
over the on-study period (ever abnormal) to baseline will be presented with the types of 
abnormalities tabulated. 
11.2.3.3 Vital Signs and Oxygen Saturation 
Vital sign data and oxygen saturation data will be listed. Blood pressure data will be specifically 
categorized in terms of systolic and diastolic blood pressures. Reference ranges will be used to 
determine programmatically if a vital sign is below, within, or above the normal range. Normal 
ranges for vital signs will be referenced as follows:
 Systolic blood pressure (>90 mm Hg and <140 mm Hg), 
 Diastolic blood pressure (>50 mm Hg and <90 mm Hg) 
 P
 T
C) 
Blood pressure and body temperature data will also be graded according to CTCAE severity 
grade.  


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Oxygen saturation data will be reported as percent saturation and 
5% will be categorized programmatically. 
Data will be summarized in tables and may be summarized in figures showing values over time 
or most extreme values on study, if appropriate. The frequencies of subjects with values below, 
within, and above the normal ranges for vital signs and of subjects with oxygen saturation values 
will be summarized in tables. For blood pressure 
and body temperature data, summary tables will be presented to show the number of subjects by 
CTCAE severity grade with corresponding percentages. Subjects will be characterized only once 
for a given parameter, based on their worst severity grade observed during a period of interest 
(eg, during the study, during a cycle, or at a specific time point). 
For vital signs, shift tables will be presented showing change in results from baseline (normal, 
low and high [or abnormal]) to each time point (normal, low and high [or abnormal]). For blood 
pressure and body temperature, data will also be presented by showing change in CTCAE 
severity grade from baseline to each time point. Tables may be prepared to show frequencies 
adjusted for baseline values; for these frequencies, subjects with the same or worse grade at 
baseline are not considered. 
For oxygen saturation, shift tables will be presented showing change in results from baseline to 
each time point considering categorization of values based on values 
% and declines from 
.  
11.2.3.4 Electrocardiography 
The overall quantitative and qualitative ECG assessment of heart rate, cardiac intervals, wave 
form abnormalities, and ectopy will be reported as “Normal” or “Abnormal” with respect to the 
description of the official ECG reading provided by the CRO performing the ECG analyses. A 
shift table comparing the ECG assessment over the on-study period (ever abnormal) to baseline 
will be presented with the types of abnormalities tabulated.  
Quantitative ECG parameters (heart rate, PR interval, QRS interval, QT interval, and QTc 
interval) at each time recorded as well as the change from screening will be summarized with 
descriptive statistics. The QT interval will be corrected by the Fridericia method for purposes of 
analysis. The following formula will be employed for correction: 
 Fridericia: QTcF in msec = QT/(RR/1000)1/3 
The QTc data obtained by using the Fridericia correction will be categorized separately into the 
following classifications and summarized by time point: 
 QTc interval >450 msec and 
 (Grade 1) 
 
 (Grade 2) 
 QTc interval >500 msec (Grade 3) 
The change of the QTc values obtained by using the Fridericia correction will also be 
categorized separately as follows: 
 QTc interval increases from baselin
 
 QTc interval increases from baseline by >60 msec 


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QTc data will be presented in shift tables consistent with these categories.
11.2.3.5 Body Weight and Performance Status 
Body weight and performance status data will be listed. Data will be summarized in tables.
11.2.3.6 Other Clinical Variables Relating to Safety  
Baseline height, baseline calculated body-mass index (in kg/m2 based on body weight/height2), 
baseline serum virology data, and all pregnancy test data will be listed and summarized.  
11.2.4
Pharmacokinetics
Pharmacokinetic parameters will be calculated using non-compartmental methods. Only serum
concentrations greater than or equal to the validated lower limit of quantitation (LLQ) will be 
used in the pharmacokinetic analyses. Per-protocol times will be used to calculate mean serum 
concentrations for graphical displays. Actual blood sampling times will be used in all 
pharmacokinetic analyses.  
The Cmax and Tmax 
z will be calculated as the 
negative of the slope of the terminal log-linear segment of the serum concentration-time curve. 
The range of data to be used for each subject will be determined by visual inspection of a semi-
logarithmic plot of concentration versus time and will comprise any available data points along 
the elimination phase. Elimination t½ will be calculated according to the following equation:  
z
0.693
t½
The AUC to the final sample with a concentration LLQ (AUC0-t) will be calculated using the 
linear trapezoidal method and extrapolated to infinity (AUCinf) using: 
z
C
AUC
AUC
tf
t
0
inf
 
where the final concentration greater than the lower limit of quantitation (Ctf) is LLQ. 
CL and Vd will be calculated according to the following respective formulas:
inf
AUC
Dose
CL
and
inf
AUC
Dose
V
z
d
Serum concentrations and derived pharmacokinetic parameters will be listed and graphs of 
individual subject concentrations will be presented on linear and semi-logarithmic axes. 
Pharmacokinetic data will be summarized using graphical and tabular methods. The data may 
also be described by baseline variables such as sex, age, weight, and body-mass index.  
The relationship between the parameters Cmax, AUC0-inf, and AUC0-24 and the dose may be 
examined using the power model, ie, 
P = a  Doseb
where P represents the parameter and a and b are constants. A value of b of approximately 1 
indicates linear pharmacokinetics.  


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11.2.5 Pharmacodynamics 
For each pharmacodynamic variable, the value at each assessment will be described. Changes 
from baseline to each assessment and the most extreme changes from baseline during the study 
will be summarized using tabular and graphical methods. The data may also be described by 
baseline variables such as sex, age, weight, and body-mass index.
As appropriate, changes in the pharmacodynamic parameters will be assessed using paired t-tests 
or analysis of covariance (ANCOVA) with baseline values as covariates; in these analyses, both 
changes from baseline to each subsequent time point and most extreme on study changes will be 
evaluated.  
11.2.6 Efficacy Analyses 
Tumor control will be documented at each assessment by remission category (eg, CRMRD-, CR, 
CRi, PR, TF, DRP, or NE, as defined for each response parameter (see Section 10.4), date that 
response is first documented, and date of tumor progression/failure. MRD status, as assessed by
flow cytometry, will be recorded. 
11.2.6.1 Categorical Endpoints  
OR, CRc, CRMRD-, CR, CRi, and PR rates will be described. In analyses of response rates in the 
full analysis set, subjects who have best responses of TF, DRP, or NE will be counted as failures. 
For all analyses of response rates, the relevant CIs will be presented. 


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11.2.6.2 Time-to-Event Tumor Control and OS Endpoints 
For time-to-event endpoints, the following definitions and censoring conventions will be applied: 
 TTR will be defined as the interval from the start of study therapy to the first documentation 
of an objective remission. TTR data will not be censored. 
 DOR will be defined as the interval from the first documentation of objective remission to 
the earlier of the first documentation of DRP or death from any cause. Data from surviving, 
non-progressing subjects will be censored at the earliest of the time of initiation of anti-AML 
treatment other than the study treatment or the last time that lack of DRP was objectively 
documented. Data from subjects who have DRP 
AML 
assessments will be censored at the last time prior to the missing assessments that lack of 
DRP was objectively documented. 
 EFS will be defined as the interval from start of study therapy to the earliest of the first 
documentation of TF, DRP, or death from any cause. Data from surviving subjects who do 
not have TF or DRP will be censored at the earliest of the time of initiation of anti-AML 
treatment other than the study treatment or the last on-therapy time that lack of TF or DRP 
was objectively documented. Data from subjects who have DRP 
 consecutive 
missing AML assessments will be censored at the last time prior to the missing assessments 
that lack of DRP was objectively documented.
 OS will be defined as the interval from the start of study therapy to death from any cause. 
Data from surviving subjects will be censored at the last time that the subject was known to 
be alive. 
Time-to-event endpoints will be described in the appropriate analysis sets using Kaplan-Meier 
methods with appropriate censoring. Medians, ranges, and relevant corresponding Cis will be 
presented.  
11.2.7 Other Analyses 
Using appropriate regression techniques, possible relationships between subject characteristics 
(eg, sex, race, age, weight, tumor characteristics, dose) and outcome measures (eg, 
pharmacodynamic and pharmacokinetic parameters) may be assessed. Similarly, associations 
between outcome measures (eg, relationships between pharmacokinetic and pharmacodynamic 
parameters) may be evaluated. 
11.3 Timing of Analyses 
11.3.1 Interim Analyses 
No formal interim analyses are planned. As described in Section 2.2, conference calls among the 
members of the SRC will be conducted periodically to discuss study progress, exchange study 
information, and review safety events, determine whether additional dose levels should be 
evaluated, and discuss potential amendments to the protocol. It is expected that these discussions 
will be scheduled at intervals of ~2 to 4 weeks unless accrual to the study and decisions 
regarding study conduct or transitions between the dosing cohorts indicate the need for an 
alternative schedule of reviews. As needed for scientific or business reasons, the sponsor may 
collate and summarize available study results during conduct of the study. 


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11.3.2 Final Analyses 
Final study reporting is expected to occur after all subjects have discontinued study treatment or 
 weeks after accrual of the final subject (whichever occurs earlier).  
11.3.3 Follow-up Analyses 
After the final analyses, additional supplemental analyses may be performed to assess long-term 
PFS, OS, and to satisfy regulatory requirements. 
11.4 Basis for the Planned Sample Sizes 
Sample sizes the cohorts of the study are not based on a specific statistical hypothesis but on 
experience from similar types of Phase 1 dose-ranging studies in patients with cancer. 
In the dose escalation, the cohort sizes of 3 to 6 subjects allow evaluation of regimen safety using 
a standard definition of MTD (ie, a starting dose associated with DLT in <17% of subjects 
during the first cycle of therapy). Based on the planned 3+3 dose-escalation scheme, Table 9 
shows the probability of escalating to the next dose level or proceeding to the next cohort, based 
on the true rate of DLT at the current dose level. 
Table 9:
Statistical Basis for 3+3 Dose-Escalation Paradigm 
True Incidence of DLT 
Probability of Escalating 
10%
0.91 
20%
0.71 
30%
0.49 
40%
0.31 
50%
0.17 
60%
0.08 
Abbreviation: DLT=dose-limiting toxicity 
Thus, if the true underlying proportion of DLT is low (eg, 10% at the current dose level, there 
is a high probability ( 0.91) of dose escalation to the next dose level. Conversely, if the true 
underlying proportion of DLT is high (eg, 60%) at the current dose level, there is a low 
probability ( 0.08) of escalation to the next dose level. 


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12
STUDY ADMINISTRATION AND RESPONSIBILITIES
12.1 General Investigator Responsibilities 
The principal investigator must ensure that: 
 He or she will personally conduct or supervise the study. 
His or her staff and all persons who assist in the conduct of the study clearly understand their 
responsibilities and have their names included in the relevant Study Personnel documents.
The study is conducted according to the protocol and all applicable regulations.
The protection of each subject’s rights and welfare is maintained.
 Signed and dated informed consent and, when applicable, permission to use protected health 
information are obtained from each subject before conducting study procedures. If a subject 
withdraws permission to use protected health information, the investigator will obtain a 
written request from the subject and will ensure that no further data be collected from the 
subject. 
 The consent process is conducted in compliance with all applicable regulations and privacy 
acts. 
 The IRB/IEC complies with applicable regulations and conducts initial and ongoing reviews 
and approvals of the study. 
Any amendment to the protocol is submitted promptly to the IRB/IEC.
Any significant protocol deviations are reported to the medical monitor, the sponsor, and the 
IRB/IEC according to the guidelines at each study center.
eCRF pages are completed in a timely fashion.
All SAEs are reported to the sponsor (or designee) within 24 hours of knowledge and to the 
IRB/IEC per IRB/IEC requirements. 
 All safety reports are submitted promptly to the IRB/IEC. 
12.2 Protocol Compliance 
The investigator is responsible for ensuring the study is conducted in accordance with the 
procedures and evaluations described in this protocol. 
12.3 Compliance with Ethical and Regulatory Guidelines 
The investigator will ensure that this study is conducted in accordance with ICH guidelines, or 
with the laws and regulations of the country in which the research is conducted, whichever 
affords the greater protection to the study subject. For studies conducted under a US IND, the 
investigator will ensure adherence to the basic principles of GCP as outlined in 21 CFR 312, 
subpart D, “Responsibilities of Sponsors and Investigators,” 21 CFR, Part 50, 1998, and 21 CFR, 
Part 56, 1998. 


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This study is also subject to and will be conducted in accordance with 21 CFR, Part 320, 1993, 
“Retention of Bioavailability and Bioequivalence Testing Samples.”
Because this is a “covered” clinical trial, the investigator will ensure adherence to 21 CFR, 
Part 54, 1998; a covered clinical trial is any “study of a drug or device in humans submitted in a 
marketing application or reclassification petition subject to this part that the applicant or FDA 
relies on to establish that the product is effective (including studies that show equivalence to an 
effective product) or that make a significant contribution to the demonstration of safety.” This 
requires that investigators and all sub-investigators must provide documentation of their financial 
interest or arrangements with the sponsor, or proprietary interests in the drug being studied. This 
documentation must be provided before participation of the investigator and any sub-investigator 
in the trial. The investigator or sub-investigator agrees to notify the sponsor of any change in 
reportable financial interests during the study and for 1 year following completion of the study. 
Study completion is defined as the date that the last subject has completed the protocol-defined 
activities. 
12.4 Institutional Review Board/Independent Ethics Committee (IRB/IEC) 
This protocol and any accompanying material to be provided to the subject (such as 
advertisements, subject information sheets, or descriptions of the study used to obtain informed 
consent) will be submitted by the investigator to an IRB/IEC. Approval from the IRB/IEC must 
be obtained before starting the study and should be documented in a letter from the IRB/IEC to 
the investigator specifying the protocol number, protocol version, protocol date, documents 
reviewed, and date on which the committee met and granted the approval. A signed protocol 
approval page, a letter confirming IRB/IEC approval of the protocol and informed consent, and a 
statement that the IRB/IEC is organized and operates according to GCP and the applicable laws 
and regulations must be forwarded to the sponsor before screening subjects for the study. 
Additionally, study centers must forward a signed Form FDA 1572 (Investigator Obligation 
Form) to the sponsor before screening subjects for study enrollment. 
Any modifications or amendments made to the protocol or informed consent document after 
receipt of the initial IRB/IEC approval must also be submitted to the IRB/IEC for approval 
before implementation. Only changes necessary to eliminate apparent immediate hazards to the 
subjects may be initiated prior to IRB/IEC approval. In that event, the investigator must notify 
the IRB/IEC, the medical monitor, and the sponsor in writing within 5 working days after 
implementation. If a change to the protocol in any way increases the risk to the subject or 
changes the scope of the study, then written documentation of IRB/IEC approval must be 
received by the sponsor before the amendment may take effect. Additionally, under this 
circumstance, information on the increased risk and/or change in scope must be provided to 
subjects already actively participating in the study, and they must read, understand, and sign any 
revised informed consent document confirming willingness to remain in the trial. 
The investigator shall submit a progress report at least once yearly to the IRB/IEC, and must 
provide a copy to the sponsor. As soon as possible after completion or termination of the study, 
the investigator will submit a final report to the IRB/IEC and to the sponsor. This report should 
include the dates of initiation and completion of the trial, a description of any changes in study 
procedures or amendments to the protocol, any deviations from the protocol, the number and 
type of subjects evaluated, the number of subjects who discontinued (and the reasons for 
discontinuation), the number of subjects who completed the trial, and the results of the trial, 


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including a description of any AEs. The sponsor will assist the investigator in the preparation of 
this report, as needed. 
12.5 Informed Consent 
The investigator, or a designee (designee must be listed in the relevant in the relevant study 
personnel documents), must explain to each subject the purpose and nature of the study, the 
study procedures, the possible adverse effects, and all other elements of consent as defined in 
21 CFR Part 50 and other applicable national and local regulations governing informed consent. 
Each subject must provide a signed and dated informed consent before enrollment into this 
study. Signed consent forms must remain in each subject’s study file and be available for 
verification by study monitors at any time. 
A copy of the IRB/IEC-approved informed consent must be forwarded to the sponsor or designee 
for regulatory purposes.  
12.6 Confidentiality 
Every effort will be made to maintain the anonymity and confidentiality of all subjects during 
this clinical study. However, because of the experimental nature of this study drug, the 
investigator agrees to allow the IRB/IEC, representatives of the sponsor and its designated 
agents, and authorized employees of appropriate regulatory agencies to inspect the facilities used 
in this study and, for purposes of verification, allow direct access to the study center records of 
all subjects enrolled into this study. This includes providing by fax, email, or regular mail 
de-identified copies of clinical, laboratory, ECG, radiology, pathology, and/or other test results 
when requested by the sponsor. A statement to this effect will be included in the informed 
consent and a permission form authorizing the use of protected health information will also be 
included. 
In accordance with local and national subject privacy regulations, the investigator or designee 
must explain to each subject that in order to evaluate study results, the subject’s protected health 
information obtained during the study may be shared with IRB/IECs, the sponsor and its 
designees, and regulatory agencies. It is the investigator’s or designee’s responsibility to obtain 
written permission to use protected health information from each subject. If a subject withdraws 
permission to use protected health information, it is the investigator’s responsibility to obtain the 
withdrawal request in writing from the subject and to ensure that no further data will be collected 
from the subject. Any data collected on the subject before withdrawal will be used in the analysis 
of study results. The sponsor will only use or disclose the subject’s protected health information 
as defined in the informed consent document. 
The investigator must assure that each subject’s anonymity will be strictly maintained and that 
each subject’s identity is protected from unauthorized parties. Only subject initials, date of birth, 
and an identification code (but no subject names) should be recorded on any form or biological 
sample submitted to the IRB/IEC, to the sponsor or its designees (eg, laboratories), or to 
regulatory authorities. However, sufficient information must be retained at the study center to 
permit sample data and data in the database to be connected with the unique subject number 
assigned to each study participant. 
The investigator agrees that all information received from the sponsor, including but not limited 
to the study drug, the investigator brochure, this protocol, the eCRFs, and any other study 


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information remain the sole and exclusive property of the sponsor during the conduct of the 
study and thereafter. This information is not to be disclosed to any third party (except employees 
or agents directly involved in the conduct of the study or as required by law) without prior 
written consent from the sponsor. The investigator further agrees to take all reasonable 
precautions to prevent the disclosure by any employee or agent of the study center to any third 
party or otherwise into the public domain. 
12.7 Study Files and Retention of Records and Biological Samples 
The investigator must maintain adequate and accurate records to enable the conduct of the study 
to be fully documented and the study data to be subsequently verified by the IRB/IEC, 
representatives of the sponsor and its designated agents, and authorized employees of appropriate 
regulatory agencies. These documents should be classified into at least the following 
2 categories: (1) investigator’s study file, and (2) subject clinical source documents.  
The investigator’s study file will contain the protocol/amendments, eCRF and query forms, the 
IRB/IEC and governmental approval with correspondence, signed informed consent documents, 
drug accountability records, staff curriculum vitae and authorization forms (eg, Form 
FDA 1572), and other appropriate documents and correspondence pertaining to the conduct of 
the study.  
The required source data referenced in the monitoring plan for the study should include 
sequential notes containing at least the following information for each subject: 
 Subject identification (name, date of birth, gender) 
 Documentation that the subject meets eligibility criteria, eg, history, physical examination, 
and confirmation of diagnosis (to support inclusion and exclusion criteria) 
 Participation in trial (including trial number) 
 Trial discussed and date of informed consent 
 Dates of all visits 
 Documentation that protocol-specific procedures were performed 
 Results of efficacy parameters, as required by the protocol 
 Start and end date (including dose regimen) of study drug (including relevant drug 
dispensing information) 
 Record of all AEs and other safety parameters (including start and end date, causality and 
intensity) 
 Concomitant medications (including start and end date and dose if relevant dose changes 
occur) 
 Date of trial completion and reason for discontinuation, if applicable 
All clinical study documents must be retained by the investigator until at least 2 years after the 
last approval of a marketing application in an ICH region (ie, the United States, Europe, or 
Japan) and until there are no pending or contemplated marketing applications in an ICH region; 
or, if no application is filed or if the application is not approved for such indication, until 2 years 


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after the investigation is discontinued and regulatory authorities have been notified or for 
15 years, whichever is longer. Investigators may be required to retain documents longer if 
required by applicable regulatory requirements, by local regulations, or by an agreement with the 
sponsor. The investigator must notify the sponsor and obtain written approval from the sponsor 
before destroying any clinical study records. The investigator will promptly notify the sponsor in 
the event of accidental loss or destruction of any study records. The sponsor will inform the 
investigator of the date that study records may be destroyed or returned to the sponsor. 
The sponsor must be notified in advance and must provide express written approval of any 
change in the maintenance of the foregoing documents if the investigator wishes to move study 
records to another location or assign responsibility for record retention to another party.  
If the investigator cannot guarantee this archiving requirement at the study center for any of the 
documents, special arrangements must be made between the investigator and the sponsor to store 
these in sealed containers outside of the study center so that they can be returned sealed to the 
investigator in case of a regulatory audit. When source documents are required for the continued 
care of the subject, appropriate copies should be made for storage outside of the study center. 
Biological samples retained by the investigator will be stored and maintained by the investigator 
until notification is received from the sponsor that the retained samples and records no longer 
need to be retained. The investigator must obtain written permission from the sponsor before 
disposing of any retained samples. The investigator should promptly notify the sponsor in the 
event of accidental loss or destruction of any study samples. With the permission of the sponsor, 
the retained samples may be transferred to an acceptable designee, such as another investigator, 
another institution, a contract laboratory, a contract storage site, or to the sponsor. 
12.8 Subject Screening Log 
The investigator must keep a record that lists all subjects who signed the informed consent 
(including those who did not undergo screening). For those subjects who declined to participate 
or were subsequently excluded from enrollment, the reasons for not enrolling in the study must 
be described. 
12.9 Modifications of the Protocol or Informed Consent Documents 
Protocol modifications, except those intended to reduce immediate risk to study participants, will 
be made only by the sponsor. All protocol modifications must be submitted to the IRB/IEC in 
accordance with local requirements. Except as noted in Section 12.4, IRB/IEC approval must be 
obtained before changes can be implemented.  
Informed consent documents cannot be changed without prior approval by the sponsor and the 
study center IRB/IEC. 
12.10 Case Report Forms 
Authorized study center personnel will complete eCRFs designed for this study according to the
completion guidelines that will be provided. An eCRF is required and must be completed for 
each enrolled subject, with all required study data accurately recorded such that the information 
matches the data contained in medical records (eg, physicians’ notes, nurses’ notes, study center 
charts, or other study-specific source documents). The investigator will ensure that the eCRFs 


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are accurate, complete, legible, and completed in a timely fashion after each subject’s visit. The 
investigator will ensure that source documents that are required to verify the validity and 
completeness of data transcribed on the eCRFs are never obliterated or destroyed. As required by 
the protocol, eCRFs should also be completed for those subjects who fail to complete the study 
(even during the screening period). If a subject withdraws from the study, the reason must be 
noted on the eCRF and thorough efforts should be made to clearly document outcome. 
The eCRFs for this study will exist within a web-based electronic data capture (EDC) system. 
After the investigator or the investigator’s designees (eg, research coordinators) have been 
appropriately trained, they will be given access to the EDC system and will enter the data 
required by the protocol into the EDC system. Any change of data will be made via the EDC 
system, with all changes tracked by the system to provide an audit trail. 
The eCRF must be completed and signed by the principal investigator or sub-investigator (as 
appropriate) within a reasonable time period after data collection. This signature serves to attest 
that the information contained in the eCRF is true. 
12.11 Study Drug Accountability  
The disposition of all investigational LAM-003 should be documented from the time of receipt at 
the study center through subject administration. An investigational drug accountability log must 
be maintained for drug accountability. It is acceptable to use a protocol-specific form or a study 
center form that captures the relevant information. Within the drug accountability log, the 
responsible study center personnel must maintain accurate records of the receipt of all LAM-003
shipped by the sponsor (or its designee), including, but not limited to, the date received, lot 
number, amount received, pertinent details about the condition of the study drug upon receipt 
based on visual inspection, and the disposition of the drug (eg, to storage). If a LAM-003 drug 
shipment arrives damaged, or if there are any other complaints relating specifically to the drug, a 
product complaint should be emailed to the sponsor or the sponsor’s representative. LAM-003 
accountability records must also be maintained that include the subject number to whom the 
study drug was administered and the date, quantity and lot number of the LAM-003
administered. 
Study personnel must ensure that LAM-003 is kept in a secure locked area with access limited to 
authorized personnel. The study drug must not be used outside the context of this protocol. 
Under no circumstances should the investigator or study center personnel supply LAM-003 to 
other investigators, subjects, or clinics, or allow the study drug to be used other than as directed 
by this protocol without the prior authorization from the sponsor.  
Depending upon the decision of the sponsor, remaining unused LAM-003 supply will be 
returned to the sponsor or its designee after the study is completed or will be discarded or 
destroyed at the study center. After investigational product accountability has been performed, 
LAM-003 may be returned or destroyed on an ongoing basis during the study if appropriate. If 
the study drug is discarded or destroyed at the study center, standard institutional policy should 
be followed. At study initiation, the monitor will evaluate the study center’s standard operating 
procedure for study drug disposal/destruction in order to ensure that it complies with sponsor 
requirements. At the end of the study, following final drug inventory reconciliation by the 
monitor, the study center will dispose of and/or destroy all unused study drug supplies, including 
empty containers, according to these procedures. If the study center cannot meet sponsor 


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requirements for disposal, arrangements will be made between the study center and the sponsor 
or its representative for destruction or return of unused study drug supplies. 
All study drug supplies and associated documentation will be periodically reviewed and verified 
by the study monitor over the course of the study. Study drug accountability records must be 
readily available for inspection by the study monitor or other representatives of the sponsor or by 
regulatory authorities. 
12.12 Monitoring 
Representatives of the sponsor or its designee will monitor this study until completion. 
Monitoring will be conducted through personal visits with the investigator and study center staff 
as well as any appropriate communications by mail, fax, email, or telephone. The monitor is 
responsible for routine review of the eCRFs at regular intervals throughout the study to verify 
adherence to the protocol and the completeness, consistency, and accuracy of the data being 
entered on them. The purpose of monitoring is to ensure compliance with the protocol and the 
quality and integrity of the data. 
In accordance with GCP, the study monitor must have direct access to the investigator’s source 
documentation in order to verify the data recorded in the eCRFs for consistency. The investigator 
agrees to cooperate with the monitor to ensure that any problems detected in the course of these 
monitoring visits are resolved. 
12.13 Inspections 
The source documents for this trial must be made available to appropriately qualified personnel 
from the sponsor or its representatives, to IRB/IECs, and to regulatory authority or health 
authority inspectors as a part of their responsibility to protect human subjects in research. The 
investigator agrees to provide access to records, facilities, and personnel for the effective conduct 
of any inspection or audit to representatives of the sponsor and regulatory agencies. It is 
important that the investigator and relevant institutional personnel are available during 
monitoring visits and possible audits or inspections and that sufficient time is devoted to the 
process. If the investigator is notified of an inspection by a regulatory authority the investigator 
agrees to notify the sponsor immediately.  
12.14 Data Management 
Electronic data capture will be used to enter study data into eCRFs and to transfer the data into a 
study-specific electronic database. During the data collection process, automated quality 
assurance programs will be used to identify missing data, out-of-range data, and other data 
inconsistencies. Requests for data clarification or correction will be forwarded to the 
investigative study center for resolution. As appropriate, eCRFs, listings, tables, and SAS 
datasets will be provided to the study centers for review. 
Quality assurance and quality control systems will be implemented and maintained according to 
written standard operating procedures to ensure that the data are generated, recorded, and 
reported in compliance with the protocol, GCP, and applicable regulatory requirements. Data 
collection and storage systems will provide audit trail, security mechanisms, and electronic 
signature capabilities that meet the requirements of FDA Title 21 of CFR Part 11 regarding 
electronic records and electronic signatures.  


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Data security will be controlled through appropriate and specific restriction of access only to data 
and systems required by individual users to accomplish their roles in the data management 
process. Individual login and password protections will be employed at study centers and at the 
sponsor or its designee. The database will exist on physically secured servers. Data backups will 
be done regularly and will be stored in separate facilities. Printed documents relating to the study 
will be secured when not under review.  
12.15 Clinical Trial Insurance 
The sponsor will secure clinical trial insurance. An insurance certificate will be made available 
to the participating study centers before study initiation. 
12.16 Communications with Regulatory Authorities 
The sponsor (or its designee) will assume responsibility for interactions with the FDA and any 
other relevant regulatory authorities. The sponsor will maintain an IND for LAM-003 in support 
of the study in the US and will maintain similar regulatory applications with other regulatory 
authorities as required for conduct of the study. In fulfilling these responsibilities, the sponsor (or 
a designee) will collect and assemble all required regulatory documents (eg, Form FDA 1572, 
investigator financial disclosure forms, protocol and protocol amendments, investigator 
brochures, informed consent documents, annual reports) as required by regulation. The sponsor 
(or a designee) will also assume responsibility for AE reporting to regulatory authorities (as 
described in Section 8.8).
12.17 Public Notification of Study Conduct 
Consistent with Section 113 of the Food and Drug Modernization Act of 1997 (FDAMA) and to 
ensure meeting the requirement of the International Committee of Medical Journal Editors 
(ICMJE) as a condition of consideration for publication of study results, the sponsor will register 
this protocol at the ClinicalTrials.gov website (or equivalent). If the protocol is registered at 
ClinicalTrials.gov, the sponsor will appropriately update the information at the website relating 
to study design and conduct during the course of the study. In order to facilitate this process, 
investigators will need to supply the sponsor with appropriate contact information for study 
center personnel. 
12.18 Study Reporting and Publication
The sponsor may make information obtained during this study available in order to further the 
scientific or business needs of the company or as required by law or regulation. In this regard, 
the sponsor may provide study information to private or public organizations (eg, business 
partners, collaborators, consultants, CROs, investors, other physicians who are conducting 
similar studies, funding organizations, regulatory authorities, or other government authorities). 
The results may also be used for papers, abstracts, posters or other material presented at 
scientific meetings or published in professional journals or as part of an academic thesis. 
The sponsor will prepare a clinical study report for submission to relevant regulatory agencies. 
The sponsor will ensure that the report meets the standards set out in the ICH Guideline for 
Structure and Content of Clinical Study Reports (ICH E3). An abbreviated report may be 
prepared in certain cases, as appropriate. 


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The sponsor intends that the data from this study will be presented and published. Because the 
study will ultimately part of a multicenter clinical trial, data from all study centers will be pooled 
and analyzed for a primary publication of the study results. The sponsor will coordinate and 
prepare this primary publication. The investigator agrees that the primary publication, which will 
be coordinated by the sponsor, will be the first publication to present the pooled study results. 
Other ancillary publications or presentations relating to the pooled data from this study may be 
suggested by the investigator, but can only be published with the express consent of the sponsor 
and the other investigators; such ancillary publications will also be coordinated by the sponsor.  
After the primary publication, or if the primary publication is not published within 2 years of 
termination of the study, the investigator may freely publish or present the results of his or her 
work conducted under the clinical trial agreement, subject to providing the sponsor with the 
opportunity to review the contents of any proposed presentation, abstract, or publication about 
such work, including any results of this study, in advance of any presentation or submission for 
publication. Within that advance notice period, the sponsor may review the proposed publication 
to identify patentable subject matter and/or any inadvertent disclosure of its confidential 
information, which must be redacted from any final publication or presentation. If necessary, to 
permit the preparation and filing of patent applications, the sponsor may elect an additional 
review period. The durations of the review periods will be specified in contractual agreements 
between each study center and the sponsor. 
In most cases, the principal investigators at the study centers with the highest accruals of eligible 
subjects and/or who have provided significant intellectual input into the study design, shall be 
listed as lead or senior authors on publications and presentations of study results. Sponsor 
clinical personnel, lead statistician, scientific personnel, or other staff members meeting the 
requirements for authorship may also be included in the list of authors. This custom can be 
adjusted upon mutual agreement of the authors and the sponsor. 
12.19 Study Discontinuation 
Both the investigator and the sponsor reserve the right to terminate the study at any time. Should 
this be necessary, both parties will arrange discontinuation procedures. The investigator will be 
responsible for notifying the relevant study center IRB/IEC. The sponsor will be responsible for 
notifying the appropriate regulatory authorities. In terminating the study, the investigator and the 
sponsor will assure that adequate consideration is given to the protection of the subjects’ 
interests. As directed by the sponsor, all study materials must be collected and all eCRFs 
completed to the greatest extent possible.  


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APPENDICES
14.1
ECOG Performance Status 
14.2
Cockcroft-Gault Method for Estimating Creatinine Clearance 
14.3
Substrates of CYP3A4 
14.4
Strong Inhibitors and Inducers of CYP3A4
14.5
Drugs Known to Prolong the Cardiac QT Interval 
14.6
Summary of Changes to Protocol – Amended Version 2 
14.7
Summary of Changes to Protocol – Amended Version 3 
14.8
Summary of Changes to Protocol – Amended Version 4 
14.9
Summary of Changes to Protocol – Amended Version 5 
14.10 
Summary of Changes to Protocol – Amended Version 6 
14.11 
Summary of Changes to Protocol – Amended Version 7 


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14.1
ECOG Performance Status
Grade 
Description 
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, eg, light house work, office work 
2
Ambulatory and capable of all self-care but unable to carry out any work activities. Up and about 
more than 50% of waking hours 
3
Capable of only limited self-care, confined to bed or chair more than 50% of waking hours
4
Completely disabled. Cannot carry on any self-care. Totally confined to bed or chair
5
Dead
Reference: [Oken 1982] 


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Page 115 of 184 
Version 8 (4 Nov 2019)
14.2
Cockcroft-Gault Method for Estimating Creatinine Clearance
Formulas for calculating the estimated creatinine clearance (eCcr) are provided below. The 
formula appropriate to the units in which serum creatinine was measured and the subject’s sex 
should be used. 
Cockcroft-Gault Formulas for Calculating Estimated Creatinine Clearance
Serum  
Creatinine Units
Sex 
Formula
mg/dL
Males 
eClCR
[mL/min]
= (140-subject age [years])  subject weight [kilograms] 1.0 
72 subject serum creatinine [mg/dl]
 
 
 
 
 
 
Females
eClCR 
[mL/min] 
= (140-subject age [years])  subject weight [kilograms] 0.85
72 subject serum creatinine [mg/dl] 
 
 
 
 
 
 
µM/dL 
Males 
eClCR 
[mL/min] 
= (140-subject age [years])  subject weight [kilograms] 1.23
Subject serum creatinine [µM/dL] 
 
 
 
 
 
 
Females 
eClCR 
[mL/min] 
= (140-subject age [years])  subject weight [kilograms] 1.04
Subject serum creatinine [µM/dL] 
 
 
 
 
Abbreviation: eClCR=estimated creatinine clearance 


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Page 116 of 184 
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14.3
Substrates of CYP3A4
Alfentanil (Alfenta) [b] 
Alfuzosin (Uroxatral) [a] 
Almotriptan (Axert) [a]
Alprazolam (Xanax) [a] [c] 
Amiodarone (Cordarone) [a] 
Amlodipine (Norvasc) 
Apixaban 
Aprepitant (Emend) [c] 
Astemizole
Atazanavir (Reyataz)
Atorvastatin (Lipitor) [a] [c] 
Avanafil [a] [b]
Axitinib (Inlyta) [a] 
Bedaquiline (Sirturo) [a] 
Bepridil (Vascor) 
Bexarotene (Targretin) 
Bosentan (Tracleer) 
Brexpiprazole (Rexulti) 
Bromocriptine (Parlodel) 
Budesonide (Entocort) [a] [b] 
Buprenorphine (Subutex) 
Bupropion (Buspar, Zyban, 
Wellbutrin, Voxra) 
Buspirone 
Cabazitaxel (Jevtana) 
Carbamazepine (eg, Tegretol) 
[a] 
Cevimeline (Evoxac) 
Cilostazol (Pletal) 
Cisapride (Propulsid) 
Clarithromycin (Biaxin) 
Clonazepam (Klonopin) 
Clopidogrel (Plavix) 
Colchicine [a] [c] 
Conivaptan [b] 
Cyclophosphamide (Cytoxan) 
Cyclosporine (Neoral) [a] 
Dabrafenib 
Daclatasvir (Daklinza) 
Dapsone (Avlosulfon) 
Darifenacin [b]  
Darunavir (Prezista) [b] 
Dasatinib (Sprycel) [b] 
Delavirdine (Rescriptor)
Dexamethasone (Decadron)
[a] 
Dihydroergotamine 
Diltiazem (Cardizem) 
Disopyramide (Norpace) [a] 
Docetaxel (Taxotere) 
Donepezil (Aricept)
Doxorubicin (Adriamycin) 
Dronedarone [b]
Droperidol 
Dutasteride (Avodart) 
Ebastine (Kestine) [b]
Efavirenz (Sustiva) 
Eletriptan (Relpax) [b] 
Eliglustat [c]Elvitegravir 
(Stribild) 
Eplerenone (Inspra) [a] [b] 
Ergotamine (Ergomar) [a] [a] 
Erlotinib 
(Tarceva)Erythromycin 
Estazolam (ProSom) 
Eszopiclone (Lunesta) 
Ethinyl Estradiol 
Ethosuximide (Zarontin) 
Etoposide (Vepesid)
Etravirine (Intelence)
Everolimus (Afinitor) [b]
Exemestane (Aromasin) 
Felodipine (Plendil) [b] 
Fentanyl (Sublimaze) [a] 
Finasteride (Proscar) 
Flurazepam (Dalmane) 
Fluticasone (Flovent) [a] 
Fosamprenavir (Lexiva) 
Fosamprenavir (Lexiva) 
Galantamine (Reminyl) 
Gefitinib (Iressa) 
Granisetron (Kytril) 
Halofantrine (Halfan) 
Ibrutinib (Imbruvica) [b] 
Ifosfamide (Ifex) 
Imatinib (Gleevec) 
Indinavir (Crixivan) [b] 
Irinotecan (Camptosar) [a]  
Isradipine (DynaCirc) 
Itraconazole (Sporanox) 
Ixabepilone (Ixempra) 
Ixabepilone (Ixempra) 
Ketoconazole (Nizoral)
Lapatinib (Tykerb) 
Levomethadyl (Orlaam) 
Lomitapide [a] [b] 
Lopinavir (Kaletra)
Loratadine (Claritin) 
Lovastatin (Mevacor) [a] [b] 
Lurasidone [b] 
Maraviroc (Selzentry) [b]
Mefloquine (Lariam) 
Methylprednisolone [a] 
Midazolam (Versed) [a] [b] 
Mifepristone (Mifeprex) [a] 
Modafinil (Provigil) 
Naloxegol [b] 
Nefazodone 
Nevirapine (Viramune) 
Nicardipine (Cardene) 
Nifedipine (Adalat) 
Nimodipine (Nimotop) 
Nisoldipine (Sular) [b] 
Nitrendipine (Baypress) 
Oxycodone (Percodan) [a] 
Paclitaxel (Taxol) 
Paricalcitol 
(Zemplar)Paritaprevir (in 
Technivie) 
Pimozide (Orap) [a] 
Praziquantel (Biltricide) 
Prednisolone 
Prednisone 
Propoxyphene (Darvon) 
Quazepam (Doral) 
Quetiapine (Seroquel) [b] 
Quinacrine 
Quinidine [a] 
Quinine 
Ranolazine (Ranexa) [a]
Regorafenib (Stivarga) 
Repaglinide (Prandin) [a] 
Rifabutin (Rimactane) [a] 
Rilpivirine [c] 
Riociguat 
Ritonavir (Norvir) 
Rivaroxaban [c] 
Saquinavir (Invirase) [b] 
Saxagliptin (Onglyza) [a] 
Sibutramine (Meridia) 
Sildenafil (Viagra) [a] [b] 
Simvastatin (Zocor) [a] [b]
Sirolimus (Rapamune) [b] 
Sitagliptin (Janumet) [a] 
Solifenacin (Vesicare)
Sorafenib 
(Nexavar)Sufentanil 
(Sufenta) 
Sunitinib (Sutent)
Suvorexant (Belsomra) 
Tacrolimus (Prograf) [a] [b] 
Tadalafil (Cialis) [a] [c] 
Tamoxifen (Nolvadex) 
Tamsulosin (Flomax) 
Teniposide (Vumon) 
Testosterone 
Testosterone
Tiagabine (Gabitril) 
Ticagrelor [b] 
Tinidazole (Tindamax) 
Tipranavir (Aptivus) [b] 
Tofacitinib 
Tolvaptan [b] 
Topiramate (Topamax) 
Triazolam (Halcion) [a] [b] 
Vardenafil (Levitra) [a] [b] 
Vemurafenib (Zelboraf) 
Verapamil (Calan) 
Vilazodone (Viibryd) 
Vinblastine (Velbane) [a] 
Vincristine (Oncovin) [a] 
Ziprasidone (Geodon) 
Zolpidem (Ambien) 
Zonisamide (Zonegran)
Zopiclone (Imovane) 
a. 
CYP3A4 substrates producing potentially serious toxicity when combined with CYP3A4 inhibitors
b. 
-fold with strong CYP3A4 inhibitors) 
c. 
- to <5-fold with strong CYP3A4 
inhibitors) 
References: [Horn 2015, FDA 2016]  
Abbreviation: CYP=cytochrome P450 enzyme 


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Study Protocol: LAM-003-HEM-CLN02 
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CONFIDENTIAL 
Page 117 of 184 
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14.4
Strong Inhibitors and Inducers of CYP3A4
Effect on CYP3A  
Drug 
Strong CYP3A Inhibitors 
boceprevir, cobicistat, conivaptan, danoprevir and ritonavir, elvitegravir and 
ritonavi), grapefruit juice, indinavir and ritonavir, itraconazole, ketoconazole, 
lopinavir and ritonavir, paritaprevir and ritonavir and (ombitasvir and/or 
dasabuvir), posaconazole, ritonavir, saquinavir and ritonavir, telaprevir, tipranavir 
and ritonavir, troleandomycin, voriconazole 
Strong CYP3A Inducers
carbamazepine, enzalutamide, mitotane, phenytoin, rifampin, St. John’s wort
Reference: [FDA 2017] 
Abbreviation: CYP=cytochrome P450 enzyme 


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CONFIDENTIAL 
Page 118 of 184 
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14.5
Drugs Known to Prolong the Cardiac QT Interval
Generic Name
Brand Names (Partial List) 
Drug Class 
Therapeutic Use 
Amiodarone 
Cordarone®, Pacerone®, 
Nexterone® 
Antiarrhythmic 
Abnormal heart rhythm 
Anagrelide
Agrylin®, Xagrid®
Phosphodiesterase 3 
inhibitor
Thrombocythemia 
Arsenic trioxide 
Trisenox® 
Anticancer 
Cancer (leukemia) 
Astemizole (Removed 
from Market)
Hismanal® 
Antihistamine
Allergic rhinitis
Azithromycin
Zithromax®, Zmax® 
Antibiotic 
Bacterial infection 
Bepridil (Removed 
from Market)
Vascor® 
Antianginal 
Angina Pectoris (heart pain) 
Chloroquine 
Aralen® 
Antimalarial
Malaria 
Chlorpromazine 
Thorazine®, Largactil®, 
Megaphen® 
Antipsychotic / 
Antiemetic
Schizophrenia, nausea, 
many others 
Cilostazol 
Pletal® 
Phosphodiesterase 3 
inhibitor 
Intermittent claudication 
Ciprofloxacin
Cipro®, Cipro-XR®, 
Neofloxin®
Antibiotic 
Bacterial infection 
Cisapride (Removed 
from Market)
Propulsid®
Gastrointestinal 
stimulant
Increase gastrointestinal 
motility 
Citalopram 
Celexa®, Cipramil®
Antidepressant, 
selective serotonin 
reuptake inhibitor 
Depression 
Clarithromycin
Biaxin®, Prevpac®
Antibiotic 
Bacterial infection 
Cocaine
Cocaine
Local anesthetic 
Anesthesia (topical) 
Disopyramide
Norpace® 
Antiarrhythmic 
Abnormal heart rhythm 
Dofetilide 
Tikosyn® 
Antiarrhythmic 
Abnormal heart rhythm 
Domperidone (Only on 
Non-US Market) 
Motilium®, Motillium®, 
Motinorm Costi®, Nomit® 
Antinausea 
Nausea, vomiting 
Donepezil 
Aricept®
Cholinesterase 
inhibitor
Dementia (Alzheimer’s 
Disease)
Dronedarone
Multaq®
Antiarrhythmic
Abnormal heart rhythm
Droperidol
Inapsine®, Droleptan®,
Dridol®, Xomolix®
Antipsychotic / 
Antiemetic
Anesthesia (adjunct), nausea
Erythromycin
E.E.S.®, Robimycin®, 
Emycin®, Erymax®, Ery-
Tab®, Eryc Ranbaxy®, 
Erypar®, Eryped®, Erythrocin 
Stearate Filmtab®, 
Erythrocot®, 
E-Base®, Erythroped®, 
Ilosone®, MY-E®, 
Pediamycin®, Zineryt®, 
Abboticin®, Abboticin-ES®, 
Erycin®, PCE Dispertab®, 
Stiemycine®, Acnasol®, 
Tiloryth® 
Antibiotic 
Bacterial infection, increase 
gastrointestinal motility 


Investigational Product: LAM-003 
Study Protocol: LAM-003-HEM-CLN02 
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CONFIDENTIAL 
Page 119 of 184 
Version 8 (4 Nov 2019)
Generic Name
Brand Names (Partial List)
Drug Class
Therapeutic Use
Escitalopram
Cipralex®, Lexapro®, 
Nexito®, Anxiset-E® (India), 
Exodus® (Brazil), Esto® 
(Israel), Seroplex®, Elicea®, 
Lexamil®, Lexam®, Entact® 
(Greece), Losita® 
(Bangladesh), Reposil® (Chile), 
Animaxen® (Colombia), 
Esitalo® (Australia), Lexamil® 
(South Africa) 
Antidepressant, 
selective serotonin 
reuptake inhibitor 
Depression (major), anxiety 
disorders 
Flecainide 
Tambocor®, Almarytm®, 
Apocard®, Ecrinal®, 
Flécaine® 
Antiarrhythmic 
Abnormal heart rhythm 
Fluconazole 
Diflucan®, Trican® 
Antifungal 
Fungal infection 
Gatifloxacin 
(Removed from 
Market) 
Tequin® 
Antibiotic 
Bacterial infection 
Grepafloxacin 
Raxar® 
Antibiotic 
Bacterial infection 
Halofantrine 
Halfan® 
Antimalarial
Malaria 
Haloperidol
Haldol® (US & UK), 
Aloperidin®, Bioperidolo®, 
Brotopon®, Dozic®, 
Duraperidol® (Germany), 
Einalon S®, Eukystol®, 
Halosten®, Keselan®, Linton®, 
Peluces®, Serenace®, 
Serenase®, Sigaperidol® 
Antipsychotic 
Schizophrenia, agitation
Ibutilide 
Corvert® 
Antiarrhythmic 
Abnormal heart rhythm 
Levofloxacin
Levaquin®, Tavanic® 
Antibiotic 
Bacterial infection 
Levomepromazine 
(Only on Non-US 
Market) 
Nosinan®, Nozinan®, 
Levoprome® 
Antipsychotic 
Schizophrenia 
Levomethadyl 
(Removed from 
Market) 
Orlaam®
Opioid agonist 
Narcotic dependence
Mesoridazine 
(Removed from 
Market) 
Serentil® 
Antipsychotic 
Schizophrenia 
Methadone 
Dolophine®, Symoron®, 
Amidone®, Methadose®, 
Physeptone®, Heptadon® 
Opioid agonist 
Narcotic dependence, pain
Moxifloxacin 
Avelox®, Avalox®, Avelon® 
Antibiotic 
Bacterial infection 
Ondansetron
Zofran®, Anset®, Ondemet®, 
Zuplenz®, Emetron®, 
Ondavell®, Emeset®, 
Ondisolv®, Setronax®
Antiemetic
Nausea, vomiting 
Oxaliplatin 
Eloxatin® 
Antineoplastic Agent
Cancer
Papaverine HCl
none 
Vasodilator, 
Coronary 
Diagnostic adjunct 
Pentamidine 
Pentam® 
Antifungal 
Fungal infection 
(Pneumocystis pneumonia) 
Pimozide
Orap®
Antipsychotic 
Tourette’s Disorder


Investigational Product: LAM-003 
Study Protocol: LAM-003-HEM-CLN02 
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CONFIDENTIAL 
Page 120 of 184 
Version 8 (4 Nov 2019)
Generic Name
Brand Names (Partial List)
Drug Class
Therapeutic Use
Probucol (Removed 
from Market)
Lorelco®
Antilipemic
Hypercholesterolemia
Procainamide
Pronestyl®, Procan® 
Antiarrhythmic 
Abnormal heart rhythm 
Propofol 
Diprivan®, Propoven®
Anesthetic, general 
Anesthesia 
Quinidine 
Quinaglute®, Duraquin®, 
Quinact®, Quinidex®, Cin-
Quin®, Quinora®
Antiarrhythmic 
Abnormal heart rhythm 
Roxithromycin (Only 
on Non-US Market) 
Rulide®, Xthrocin®, Roxl-
150®, Roxo®, Surlid®, 
Rulide®, Biaxsig®, Roxar®, 
Roximycinv®, Roxomycin®, 
Rulid®, Tirabicin®, Coroxin® 
Antibiotic 
Bacterial infection 
Sevoflurane 
Ulane®, Sojourn®
Anesthetic, general 
Anesthesia 
Sotalol 
Betapace®, Sotalex®, Sotacor®
Antiarrhythmic 
Abnormal heart rhythm 
Sparfloxacin 
(Removed from 
Market) 
Zagam® 
Antibiotic 
Bacterial infection 
Sulpiride (Only on 
Non-US Market) 
Dogmatil®, Dolmatil®, 
Eglonyl®, Espiride®, Modal®, 
Sulpor® 
Antipsychotic, 
atypical 
Schizophrenia 
Terfenadine (Removed 
from Market)
Seldane® 
Antihistamine
Allergic rhinitis
Thioridazine 
Mellaril®, Novoridazine®, 
Thioril® 
Antipsychotic 
Schizophrenia 
Vandetanib
Caprelsa® 
Anticancer 
Cancer (thyroid) 
Note: Includes those drugs known to prolong the cardiac QT interval [Woosley 2016]. 


Investigational Product: LAM-003 
Study Protocol: LAM-003-HEM-CLN02 
AI Therapeutics, Inc.
CONFIDENTIAL 
Page 121 of 184 
Version 8 (4 Nov 2019)
14.6
Summary of Changes to Protocol – Amended Version 2
14.6.1
Overview of Changes
Modifications from Version 1 to Version 2 of the protocol included the following: 
 The title of the study was simplified prior to listing of the study at clinicaltrials.gov. 
 The LAM-003 chemical name was changed to follow the naming convention of the 
International Union of Pure and Applied Chemistry. 
 Figure 3 (LAM-003 In Vitro Efficacy in Cancer Cells from a Patient with Gilteritinib- and 
Sorafenib-Resistant AML) was updated to match the final figure that was included in the 
investigator brochure and IND. 
 The study design was revised to remove Part 2 (cohort expansion) based on the FDA 
recommendation not to conduct the cohort expansion portion of the study until additional 
information is available to develop an appropriate plan for assessing the long-term safety of 
LAM-003. All references to Part 2 of the study were removed from the protocol consistent 
with the change in the study design. 
 The efficacy endpoints were expanded to include the categories of and definitions for 
complete remission without minimal residual disease (CRMRD) and composite complete 
remission (CRc), as recommended by FDA, and to remove references to red blood cell 
(RBC) transfusions as a component of response (for consistency with 2017 European 
Leukemia Net [ELN] proposals for response criteria). 
 The inclusion and exclusion criteria were modified as follows: 
o Inclusion Criterion 9 was modified to change the allowable value for estimated creatinine 
clearance (eClCR) from >50 mL/minute to >60 mL/minute, as recommended by FDA 
based on observations in nonclinical studies (renal excretion and increases in serum 
creatinine levels) and an event of renal failure in the earlier study of LAM-003A in 
subjects with solid tumors.
o Exclusion Criterion 4 was modified to clarify that only subjects with Grade >1 
proliferative or nonproliferative retinopathy would be excluded at the request of the 
consulting ophthalmologist for the study. 
 The following changes to the dose levels of LAM-003 and recommendations for dose 
modifications of LAM-003 were made based on FDA review of Version 1 of the protocol: 
o The dose levels of LAM-003 after Dose Level 1 were revised to reflect 1.5-fold increases 
in dose (rather than 1.75-fold increments), resulting in a maximum dose level of 
<480 mg/day, which was the MTD in the earlier study of LAM-003A in subjects with 
solid tumors. 
o The previous dose modification recommendations for LAM-003 were revised to 1) make 
dose modifications for toxicities mandatory, 2) ensure that dose reductions are done in 
accordance with the protocol-specified dose levels, 3) state that subjects who cannot 
tolerate LAM-003 after 2 progressive dose reductions or a decrease to Dose Level -2 
(50 mg/day) should be discontinued from study drug therapy, 4) clarify that subjects 


Investigational Product: LAM-003 
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Page 122 of 184 
Version 8 (4 Nov 2019)
whose dose is de-escalated are not eligible for dose re-escalation if they have experienced 
Grade >2 toxicities at the current dose level, 5) clarify resumption of LAM-003 therapy 
in subjects who experience adverse events (AEs) that preclude resumption of therapy by 
Day 29, and 6) provide additional dose-modification guidelines for subjects who 
experience treatment-emergent visual toxicities. 
 Additional information on the rationale for exploring the one-per-day (QD) and 
twice-per-day (BID) dosing regimens was provided. 
 At the request of the FDA, hematologic toxicity (Grade 4) neutropenia was added as a DLT 
and the DLT criteria for visual disturbances and TLS were revised.  
 At the request of the FDA, the previous guidance on the use of hematopoietic agents and 
other growth factors as supportive care was revised to conform to National Comprehensive 
Cancer Network (NCCN) guidelines.  
 As requested by the FDA, specific guidance on ophthalmologic follow-up (including 
appropriate assessment methods) and resumption of LAM-003 therapy in subjects who 
experience dose-limiting visual toxicity was added. 
 As requested by the FDA, additional monitoring for TLS, including assessment of vital signs, 
AEs, and laboratory studies (hematology and serum chemistry), was added. 
 As requested by the FDA, the reasons for treatment discontinuation were clarified and 
expanded. 


Investigational Product: LAM-003 
Study Protocol: LAM-003-HEM-CLN02 
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CONFIDENTIAL 
Page 123 of 184 
Version 8 (4 Nov 2019)
14.6.2 Specific Changes 
In preparing Amended Version 2 of the protocol document, the following specific changes were 
made. Explanations of the changes are provided in italics as “Changes/Rationale”. Inserted text 
is indicated by double-underlining. Deleted text is indicated by strikeout. Revisions to the 
synopsis are not described. Changes to protocol versions, dates, the list of abbreviations and 
definitions of terms, and minor typographical or syntax corrections are not indicated. 
Changes to: Title Page, 
 Therapeutics Project Personnel, 
Page 
Changes/Rationale: The title of the study has been simplified prior to listing of the study at
clinicaltrials.gov. 
Protocol Title 
A Phase 1 Dose-Escalation and Cohort-Expansion Study of the 
Heat Shock Protein 90 Inhibitor, LAM-003, in Patients with 
Acute Myeloid Leukemia 
Changes to: 
 
Changes/Rationale: The LAM-
 
LAM-003 has the chemical name of 
[(1S)-2-[4-[2-[6-amino-8-[(6-bromo-1,3-benzodioxol-5-yl)sulfanyl]purin-9-yl]ethyl]-1-
piperidyl]-1-methyl-2-oxo-ethyl] (2S)-2-aminopropanoate mono-mesylate, mono-hydrate](2S)-
1-[4-(2-{6-amino-8-[(6-bromo-1,3-benzodioxol-5-yl) sulfanyl]-9H-purin-9-yl}ethyl)piperidin-1-
yl]-1-oxopropan-2-yl L-alaninate mono-mesylate, mono-hydrate). 
Changes to: 
cy 
,
-
 Efficacy in 
- and Sorafenib-
Changes/Rationale: 
updated to match the final figure that was in included in the 
in
 
0 .1
1
1 0
1 0 0
0
2 0
4 0
6 0
8 0
1 0 0
G ilte ritin ib  (n M )
Gilteritinib (nM)
1 0
1 0 0
1 0 0 0
1 0 0 0 0
0
2 0
4 0
6 0
8 0
1 0 0
L A M -0 0 3  (n M )
LAM-003 (nM)
 


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CONFIDENTIAL 
Page 124 of 184 
Version 8 (4 Nov 2019)
0 . 1
1
1 0
1 0 0
0
2 0
4 0
6 0
8 0
1 0 0
G i l t e r i t i n i b  ( n M )
1 0
1 0 0
1 0 0 0
1 0 0 0 0
0
2 0
4 0
6 0
8 0
1 0 0
L A M - 0 0 3  ( n M )
Changes to: Section 
 and 
Rationale for Study Design 
Changes/Rationale: The study design was revised to remove Part 
 of the 
study in accordance with FDA guidance not to conduct 
 study until additional 
information was available 
. 
2.1
Study Design 
This clinical trial is a Phase 1 study of the safety, pharmacokinetics, pharmacodynamics, and 
antitumor activity of LAM-003. The study will be conducted in 2 parts comprising an initial dose 
escalation followed by a subsequent cohort expansion. 
2.1.1
Part 1 Dose Escalation
This clinical trial is a Phase 1 study evaluating the safety, pharmacokinetics, pharmacodynamics, 
and antitumor activity of LAM-003 across This portion of the study will evaluate the safety and 
pharmacology of a range of LAM-003 dose levels when administered to subjects with previously 
treated relapsed or refractory FLT3-ITD-mutant AML. Subjects will self-administer oral 
LAM-003 QD or BID continuously in repeated 28-day cycles. Cohorts of 3 to 6 subjects will be 
sequentially enrolled at progressively higher dose levels of LAM-003 using a standard 3+3 dose-
escalation design. Based on the pattern of DLTs observed in Cycle 1, escalation will proceed to 
define an MTD and a recommended dosing regimen (RDR) that may be at the MTD or a lower 
dose within the tolerable dose range.  
2.1.2
Part 2 Cohort Expansion 
This portion of the study will further explore the safety, pharmacology, and clinical activity of 
LAM-003 monotherapy in patients with FLT3-ITD-mutant AML. Study subjects will self-
administer LAM-003 orally using the RDR derived from Part 1 of the study. The planned sample 
size will be based on a futility analysis testing if there is antitumor activity sufficient to warrant 
further development of LAM-003 for FLT3-ITD-mutant AML. A continuous reassessment of 
safety will be used to confirm the selection of the RDR. 


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2.3
Rationale for Study Design
The study has been designed to provide critical dosing, safety, pharmacokinetic, 
pharmacodynamic, and early efficacy data in support of future clinical development of LAM-003 
in larger clinical trials.  
In Part 1 of the study, dDose-ranging in cohorts of 3 to 6 subjects using a 3+3 design is 
consistent with usual oncologic drug development in the Phase 1 evaluation of various types of 
anticancer agents; this method provides efficient dose escalation while limiting the number of 
subjects who are exposed to excessively toxic doses of study drug.  
In Part 2 of the study, enrollment of an expansion cohort provides confirmation of starting dose 
selection and permits evaluations of drug safety and pharmacology while generating preliminary 
observations regarding drug activity. The intent is to confirm safety and seek an efficacy signal 
but to limit total enrollment using a continuous reassessment of safety and a futility analysis of 
efficacy to protect subjects against excessive drug toxicity or insufficient drug activity. 
Changes to: Section 
 
Changes/Rationale: The primary objectives were revised to remove the objectives for Part
revised study design. 
3.1
Primary Objectives 
3.1.1
Part 1 (Dose Escalation)
 To determine the MTD and/or RDR of LAM-003
3.1.2
Part 2 (Cohort Expansion) 
 To evaluate the antitumor activity of LAM-003 in subjects with FLT3-ITD-mutant AML
Changes to: Section 
TS, 4.1 Primary Endpoints
Changes/Rationale: The primary endpoints were revised to remove the primary endpoint for 
Part
revised study design. 
4.1
Primary Endpoints 
4.1.1
Part 1 (Dose Escalation)
 MTD and/or RDR within the tested LAM-003 dose range 
4.1.2
Part 2 (Cohort Expansion) 
 Composite complete remission (CRc), defined as complete remission (CR) or complete 
remission with incomplete count recovery (CRi) 
Changes to: Section 
Antitumor Activity and Survival 
Changes/Rationale: The efficacy endpoints categories were expanded and the definitions 
provided for CRMRD and CRc, as recommended by FDA, and references to RBC transfusions 
as a component of response were removed (for consisten
response criteria . 
Efficacy will be evaluated using standard remission and progression criteria [Cheson 2003, 
Döhner 2017] as adapted for use in the context of protocol therapy for relapsed or refractory 


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AML. Besides the Part 2 primary endpoint (defined in Section 4.1.2 above), other e Efficacy 
endpoints will include: 
 Complete remission without minimal residual disease (CRMRD-), defined as complete 
remission (see definition below) with no evidence of AML by flow cytometry 
 Complete remission (CR), defined as <5% bone marrow blasts; no blasts in the peripheral 
blood; no blasts with Auer rods; no extramedullary disease; and peripheral blood meeting all 
both of the follo
1.0 × 109/L and,
× 109/L, and no 
requirement for red blood cell transfusions to maintain hemoglobin 
Complete remission with incomplete count recovery (CRi), defined as <5% bone marrow 
blasts; no blasts in the peripheral blood; no blasts with Auer rods; no extramedullary disease; 
but with peripheral blood meeting either any of the following criteria: ANC <1.0 × 109/L or, 
platelet count <100 × 109/L, or requirement for red blood cell transfusions to maintain 
hemoglobin
 Composite complete remission (CRc), defined as CRMRD-, CR, or CRi 
 Partial remission (PR), defined as leukemia disease status meeting all of the following 
blasts but with Auer rods present; no blasts in the peripheral blood; no new or worsening 
extramedullary disease; and peripheral blood meeting all both of the following criteria: 
ANC 
 × 109/L and, 
 × 109/L, and no requirement for red blood cell 
transfusions to maintain hemoglobin 
 Overall remission (OR), defined as achievement of any of CR, CRi, or PR 
 Time to remission (TTR), defined as the interval from the start of study therapy to the first 
documentation of an objective remission 
 Duration of remission (DOR), defined as the interval from the first documentation of 
objective remission to the earliest of the first documentation of disease relapse, disease 
progression, or death from any cause 
 Event-free survival (EFS), defined as the interval from the start of study therapy to the 
earliest of the first documentation of disease relapse, disease progression, treatment failure,
or death from any cause 
 Overall survival (OS), defined as the interval from the start of study therapy to death from 
any cause 
Changes to: Section 
 
Changes/Rationale: 
of CRMRD to the list of 
efficacy endpoints.
Determinations of the magnitude and duration of changes in AML disease status will be based on 
well-established remission and progression criteria [Cheson 2003, Döhner 2017] as applied to 
bone marrow and peripheral blood laboratory measurements (and to radiographic or clinical 
information in subjects with extramedullary AML). Beyond assessing the ability of the study 
drug to control cancer growth, AML assessments will also be considered in defining the proper 
duration of treatment for each study participant. The specific endpoints of overall cancer control 


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evaluated in this trial are customarily assessed and reported in studies of new therapies in 
patients with AML. CRMRD, CR, CRi, and PR provide convenient categorization of the magnitude 
of clinically meaningful reductions in the extent of AML. TTR, DOR, and EFS offer well-
established outcome measures that directly evaluate treatment effect, convey important 
information regarding the rapidity and duration of clinical benefit, can be characterized in all 
subjects using intention-to-treat principles, and are readily analyzed using statistical methods 
such as Kaplan-Meier techniques. The 8- to 12-week cadence of tumor assessments is consistent 
with the expected natural history of remission and progression in relapsed AML, current clinical 
practice, and the goals of the trial in documenting meaningful LAM-003-mediated AML 
regression 
Changes to: 
Planned Number of Subjects
Changes/Rationale: The number of subjects who were to be enrolled in Part 
revised study design. 
5.1
Planned Number of Subjects
5.1.1
Part 1 (Dose Escalation) 
The total number of subjects will depend upon the numbers of subjects accrued to each dose 
level and the number of dose levels evaluated. If 6 subjects are enrolled at all 3 planned starting 
dose levels and 6 additional subjects are enrolled at the MTD or RDR, as many as 24 subjects 
could be enrolled. If an additional dose level or an additional schedule (eg, BID) administration 
is explored in 6 subjects per cohort, as many as 12 additional subjects could be enrolled, bringing 
the potential sample size to 36 subjects. To allow for the possibility that some subjects may not 
be fully evaluable, up to 48 subjects may be enrolled. 
5.1.2
Part 2 (Cohort Expansion) 
It is planned that the RDR will be evaluated in 12 evaluable subjects. To allow for the possibility 
that some subjects may not be fully evaluable, up to 18 subjects may be enrolled.
Changes to: 
Changes/Rationale: 
usion criterion 9 was revised to change the allowable value for eClCR 
 
mL/minute as recommended by FDA based on observations in 
renal failure in the earlier study of LAM-
in subjects with solid tumors.
9. Adequate renal function: 
a. Serum creatinine <1.5 × ULN (Grade 1), or 
b. Estimated creatinine clearance (eClCR) >60 50 mL/minute (with eClCR to be calculated by 
the Cockcroft-Gault formula [see Appendix 14.2]). 


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Changes to:
 
 Exclusion Criteria 
Changes/Rationale: Exclusion criterion  was modified to clarify that only subjects with 
 >1 proliferative or nonproliferative retinopathy would be excluded at the request of the 
consulting ophthalmologist for the study.
4. Ongoing Grade >1 proliferative or nonproliferative retinopathy (eg, due to diabetes mellitus, 
hypertension, macular degeneration, prematurity, genetic disorder).  Note: Subjects with 
resolved retinal tears due to age-related vitreous humor shrinkage are not excluded.
Changes to: Section 
 
 
 Tumor 
 
Changes/Rationale: The paragraph after the last bulleted point (high risk of TLS
to provide additional guidance on monitoring for TLS, as recommended by FDA.
Subjects must be monitored for TLS during on C1D1 through C1D5 with assessments of 
vital signs, AEs, and serum chemistry and hematology laboratory studies as described in 
Section 7. In addition, at the discretion of the investigator, s Study centers may wish to 
provide additional hydration and in-patient monitoring for TLS, particularly in subjects who 
are at high risk.  
Changes to: Section 
 
 LAM-
 
Changes/Rationale: Additional information related to monitoring for TLS before 
administration of LAM-
, as recommended by FDA.  
In each 28-day cycle, subjects are to self-administer LAM-003 starting on Day 1 and then 
continuously thereafter (28 total doses/cycle). Subjects should take the study drug at 
approximately the same time each day, ideally at ~24-hour intervals (eg, ~8AM every day) for 
the planned QD schedule or at 12-hour intervals (eg, ~8AM and ~8PM every day) if a BID 
schedule is evaluated. In conjunction with frequent pharmacokinetic assessments on C1D1, 
C1D2, and C1D8, subjects should take the drug at the study center under the supervision of study 
personnel. On C1D2, C1D3, C1D4, and C1D5, LAM-003 is to be administered in the study 
center and only after the serum chemistry results from that day have been evaluated to exclude 
TLS. While variations in dosing schedule may occur in the outpatient setting, the prescribed 
regimen should be followed as closely as possible. 
Changes to: Section 
N, AND 
 
 Starting Dose Levels and Dose 
Escalation 
Changes/Rationale: As requested by FDA, the dose levels of LAM-
after Dose Level 1 
-
-fold i
lting 
in a maximum dose level of <
 mg/day, which was the MTD dose level in the earlier study of 
LAM-
in subjects with solid tumors. References to Part
removed consistent with the revised study design.  


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In Part 1, c Cohorts of 3 to 6 subjects will be sequentially enrolled at progressively higher 
starting dose levels of LAM-003 using a standard 3+3 design, as indicated in Table 1. The initial 
cohort of subjects will be prescribed LAM-003 at Dose Level 1 (200 mg). Dose Levels -1 
(100 mg) and -2 (50 mg) are provided to permit dose decrements if a subject experiences a 
TEAE requiring dose modifications to levels below Dose Level 1. In Part 2, expansion cohorts 
will receive the RDR established in Part 1 of the study.  
Table 1: 
LAM-003 Starting Dose Levels 
Dose 
Level 
LAM-003
Dosing Regimen 
Dose Change 
Relative to  
Prior Dose 
Part 1 (Dose Escalation)
-2
50 QD
0.50
-1
100 QD
0.50
1 (initial dose level)
200 QD
Not applicable
2 
350 300 QD 
1.751.50 
3 
500 450 QD 
1.751.50 
Part 2 (Cohort Expansion)
Not applicable 
RDR 
Not applicable 
Abbreviations: QD=once per day, RDR=recommended dosing regimen
During Part 1 of the study, theThe following dose-escalation rules will be employed, considering 
DLTs observed in Cycle 1 of therapy: 
 Each dose level cohort will initially enroll 3 subjects.  
 If 0 of the first 3 subjects has a DLT, the next cohort of 3 subjects will be treated at the next 
higher dose level.  
 If 1 of the first 3 subjects in a cohort experiences a DLT, an additional 3 subjects will be 
treated at that same dose level. If 0 of the additional 3 subjects experience a DLT, the next 
cohort of 3 subjects will be treated at the next higher dose level. 
 
subjects experience a DLT, the MTD will have been exceeded and 
3 more subjects will be treated at the next lower dose level (if only 3 subjects were 
previously treated at that prior dose level). If 6 subjects were previously treated at the prior 
dose level, that prior dose level will provisionally be considered the MTD. 
 An additional 6 subjects (up to 12 total) may be enrolled at the MTD or RDR. 
 With the concurrence of the SRC, additional subjects (up to 12 subjects per dose level) may 
be accrued at dose levels at or below the MTD to refine the estimation of the RDR and 
further define the pharmacology of LAM-003. Such accrual may occur: 
o At Dose Level -1 or -2 (100 or 50 mg of LAM-003, respectively). 
o At an initially planned dose level (as indicated in Table 1) or at a dose level that lies 
between the initially planned dose levels. 
o Using an alternative schedule (eg, BID) with a total daily dose that does not exceed the 
total daily MTD. 
The following additional procedures will be followed during the dose escalation: 


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 The first subject to be treated at Dose Level 1 will be observed for 
 week after initiation of 
LAM-003 before any subsequent subjects are treated at the same dose level. 
 
or 42/56 doses for a BID schedule) of planned Cycle 1 LAM-003 doses per subject and must 
be observed for a minimum period of 4 weeks without DLT before subsequent subjects are 
enrolled at the next higher dose level. Any subject without DLT who does not complete these 
requirements may be replaced. 
Escalation to the next dose level or progression to the expansion portion of the study can only 
occur upon review of the available safety data from all ongoing and previous subjects and 
with the concurrence of the SRC. 
Intrasubject dose escalation above the initially assigned dose level will be not be permitted 
except as defined in Section 6.2.7 below. 
Accrual of additional subjects to a treatment cohort may be considered by the SRC with the 
concurrence of the study sponsor. 
Changes to: Section 
 
 Definition of DLTs
Changes/Rationale: 
 
added as a DLT and the DLT criteria for visual disturbances and TLS were revised. 
Based on this information but considering the limited experience with LAM-003/LAM-003A, 
DLTs for the purposes of establishing the MTD and RDR in this study will be defined as any of 
the following TEAEs occurring in Cycle 1 of LAM-003 therapy that cannot be considered 
incontrovertibly related to the underlying malignancy, a comorbid condition, an intercurrent 
illness, or a concomitant medication: 
 Grade 4 neutropenia persisting for 
 
 
 
23 visual disturbances 
 
 Grade 3 TLS despite adequate prophylaxis (unless TLS results in no Grade 2 renal 
dysfunction or other Grade 2 end-
 
 Grade 4 TLS despite adequate prophylaxis 
 
AEs (with the exception of asymptomatic 
Grade 
 laboratory abnormalities that improve to Grade 
 hours) 
 The occurrence of either of the following circumstances during Cycle 1: 
o 
 dose for a BID 
schedule) of planned LAM-003 doses due to an AE that is not primarily related to the 
underlying malignancy, a comorbid condition, an intercurrent illness, or a concomitant 
medication 


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o Following a dose interruption starting in Cycle 1, failure to recover to baseline within 
32 weeks from the last dose of LAM-003 due to a TEAE that is not primarily related to 
the underlying malignancy, a comorbid condition, an intercurrent illness, or a 
concomitant medication; occurrence of such a TEAE should also result in permanent 
discontinuation of study drug (see Section 6.5) 
Hematological findings will not be considered as DLTs given preexisting disease-related 
myelosuppression in patients with AML and the lack of concerning hematological toxicity 
observed within the planned dose range based on the prior clinical experience with LAM-003A. 
Changes to: Section 
 
 Dose Modification 
Recommendations
Changes/Rationale: As recommended by FDA, the previous dose modification 
recommendations for LAM-
 make dose modifications for toxicities 
mandatory, 
ensure that dose reductions are done in accordance with the protocol-specified 
dose levels, 
 state that subjects who cannot tolerate LAM-
reductions or a decrease to Dose Level -
 
therapy
clarify that subjects whose dose is de-escalated are not eligible for dose 
re-escalation i
 >
, 
 clarify 
resumption of LAM-
AEs that preclude resumption of 
therapy by Day
provide additional dose-modification guidelines for subjects who 
experience treatment-emergent visual toxicities. 
Recommendations for modifications of study drug dosing comprise guidelines; variations from 
these recommendations may be warranted based on judgments in considering potential risks, 
benefits, and therapeutic alternatives available to each subject. In addition, investigators should 
consider and eliminate other potential causes for AEs (eg, underlying malignancy, intercurrent 
illness, comorbid conditions, or concomitant medications).  
If a subject experiences an AE that is suspected to be related to the study drug, appropriate 
monitoring and supportive care (eg, antiemetics, antidiarrheals, therapy for TLS) should be 
instituted consistent with the nature of the event. 
If a subject experiences a Grade 4 toxicity (other than Grade 4 TLS recovering with no adverse 
sequalae), then the study drug administration should be permanently discontinued. If a subject 
experiences a DLT or a less severe AE that the investigator believes warrants dose modification, 
then the study drug administration should be interrupted until the toxicity r
or baseline. A decision should be made as to whether the subject can reasonably continue with 
the study drug based upon the nature and severity of the AE.  In addition, subjects who develop 
treatment-emergent dose-limiting visual symptoms should undergo more frequent 
ophthalmological consultation (eg, at ~2-week intervals or more frequently, as appropriate) (see 
Section 6.3.13). If the drug is resumed after a dosing interruption, the dose of LAM-003 should 
be reduced by 1 dose level (reference Table 1)-unless a lesser decrement in dose is permitted by 
the medical monitor. Two successive adjustments to progressively lower dose levels can be 
made. If the subject cannot tolerate LAM-003 after a decrease in dose by 2 dose levels or to 
Dose Level -2 (50 mg/day), then the subject should be discontinued from study drug therapy 
unless continued treatment is permitted by the medical monitor.  


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In general, after the LAM-003 dose is reduced, the dose should be maintained at that dose level, 
even if there is minimal or no toxicity with the reduced dose. However, if the subject tolerates a 
reduced dose of LAM-003 
 weeks 
 then the LAM-003 
dosing regimen may be reescalated to the next higher dose level at the discretion of the 
investigator if the AE that prompted the dose reduction comprised TLS or if further evaluation 
reveals that the AE that led to the dose reduction was incontrovertibly related to the underlying 
malignancy, a comorbid condition, an intercurrent illness, or a concomitant medication. 
Successive adjustments to progressively higher dose levels can be made. However, during the 
first 2 cycles of therapy, the escalated dose cannot exceed the starting dose level for that subject.  
Individual subjects who initiated treatment at a dose level below the lower of the currently 
established MTD may have the LAM-003 dose escalated to the next higher dose level after 
 cycles of therapy if both the principal investigator and the medical monitor agree that the 
subject is tolerating the current dose level 
 and that a dose 
escalation is medically warranted (egie, for a subject with a partial remissionPR). In such 
subjects, successive adjustments to progressively higher dose levels can be made at intervals of 
 weeks with the caveat that the escalated dose level cannot exceed the currently established 
MTD.  
In a subject who experiences a DLT precluding resumption of LAM-003 therapy during a cycle, 
a new cycle of treatment may begin at the later of Day 29 of the current cycle or when AEs or 
laboratory abnormalities have returned to baseline levels. If AEs or laboratory abnormalities 
preventing further administration of study drug are not resolved to baseline by Day 29 of the 
current cycle, week-by-week delays in initiating the new cycle of treatment should be instituted. 
When AEs and laboratory abnormalities have returned to baseline, the next cycle of therapy can 
be initiated. Upon initiation of a new cycle, the prior cycle of therapy will be considered 
completed. In a subject who experiences an AE precluding resumption of LAM-003 therapy by 
Day 29 of the current cycle (planned Day 1 of the next cycle), the new cycle of treatment may 
only begin when AEs or laboratory abnormalities have returned to baseline levels and if the 
subject does not meet criteria for permanent discontinuation of study therapy (see Section 6.5). 
Upon initiation of a new cycle, the current cycle will be considered completed. 
Changes to: Section  
 Supportive Care
 
Changes/Rationale: As requested by the FDA , the use of hematopoietic agents as supportive 
care was revised to conform to NCCN guidelines. 
LAM-003 is not expected to cause myelosuppression based on nonclinical and clinical 
experience with LAM-003A. However, subjects may experience hematological AEs related to 
the underlying AML or prior therapy.  
Granulocyte colony-stimulating factor (G-CSF) (eg, filgrastim, filgrastim-snd, peg-filgrastim, 
lenograstim) or granulocyte-macrophage colony-stimulating factor (GM-CSF) (eg, 
sargramostim) may be administered in response to neutropenic complications, as appropriate and 
consistent with current guidelines [NCCN 2017a, NCCN 2017c]. 
GM-CSF should not be administered given the potential for GM-CSF-related inflammatory 
symptoms. 


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Use of erythropoietic agents (eg, erythropoietin or darbepoetin) is not recommended based on 
current guidelines [NCCN 2017b].  
Red blood cell or platelet transfusions may be administered as medically indicated. 
Changes to: Section 
 Supportive Care, 
 Ophthalmological Symptom Management 
Changes/Rationale: As requested by the FDA, the section was revised to provide additional 
guidance on ophthalmologic follow-up for subjects who experience dose-limiting visual 
toxicities and to clarify resumption of LAM-
 
During the study, subjects will undergo screening and periodic ophthalmological examinations 
(eg, visual acuity testing, with electroretinography, and slit lamp examination and dark 
adaptometry) according to the schedule of activities provided in Section 7. As noted in 
Section 6.2.7In addition, subjects who develop treatment-emergent dose-limiting visual 
symptoms should have drug interrupted and should undergo more frequent ophthalmological 
consultation (eg, at ~2-week intervals or more frequently, as appropriate). Symptoms should 
resolve to Grade 
 of study drug and study drug should only be resumed if 
such resolution occurs within 2 weeks of interruption of study drug and the subject appears to be 
otherwise safely benefiting from study therapy.
Changes to: Section 
 Supportive Care, 
4 TLS Management 
Changes/Rationale: As requested by the FDA, additional guidance for monitoring of TLS was 
included. 
Subjects must be monitored for TLS during on C1D1 through C1D5 with assessment of vital 
signs, AEs, and serum chemistry and hematology laboratory studies as described in Section 7. 
Subjects who develop TLS may experience hyperkalemia, hypocalcemia, hyperuricemia, 
hyperphosphatemia, acute renal failure, and cardiac dysrhythmias, and acute renal failure; thus, 
close monitoring of electrolytes, serum creatinine, and vital signs is particularly important after 
initial therapy. ECG monitoring should also be instituted in subjects with biochemical 
abnormalities suggestive of TLS. 
Changes to: Section 
D 
 Duration of Study Drug Administration and Study Participation
Changes/Rationale: The reasons for treatment discontinuation were clarified and expanded 
based on FDA recommendations. 
Subjects may receive LAM-003 therapy indefinitely. However, the occurrence of any of the 
following events requires treatment discontinuation: 
 Subject request to withdraw from study treatment  
 Documented objective evidence of treatment failure or of AML relapse or progression (see 
Section 10.4.5 and Section 10.4.6 for definitions) while receiving study treatment 
 For a subject in PR, continued red blood cell transfusion dependence at Week 20 
 Intolerable toxicity despite appropriate supportive care and/or dose modification 


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hin 2 weeks from the last dose of LAM-003 
following interruption for a TEAE that is not primarily related to the underlying malignancy, 
a comorbid condition, an intercurrent illness, or a concomitant medication 
 The development of intercurrent illness or other substantial change in the subject’s condition 
or circumstances that would place the subject at unacceptable risk as determined by the study 
investigator in consultation with the medical monitor
 Initiation of treatment for the subject’s cancer with an off-study therapeutic regimen 
 Pregnancy or breastfeeding 
 Substantial noncompliance with study drug administration, study procedures, or study 
requirements in circumstances that increase risk or substantially compromise the 
interpretation of study results 
 Discontinuation of the study by the study center, the sponsor, relevant regulatory agencies, or 
the IRB/IEC 
Unless they withdraw consent for further follow-up, subjects who discontinue study therapy will 
continue on study for acquisition of safety information throug
study treatment, and for further collection of information regarding additional therapies for their 
cancer and OS. 
Changes to: Section 
 Rationale for Study Drug Administration and Supportive Care 
Changes/Rationale: Additional rationale was provided 
on a comment from FDA.
Both one-per-day (QD) and twice-per-day (BID) dosing were explored in the Phase 1 study of 
LAM-003A in patients with solid tumors. It appeared that the total daily dose of LAM-003A was 
most important in defining the safety profile; the study did not suggest a schedule-dependent 
safety concern with either the QD or BID dosing regimen. Further, the average half-life (t1/2) 
after repeated dosing of LAM-003A was 11.2 hours, supporting use of either QD or BID dosing. 
Based on these observations, the current study will initially evaluate LAM-003 using a QD 
dosing regimen because such dosing could potentially minimize the likelihood of TLS (by 
avoiding administration of a C1D1 evening dose in the face of potential TLS-mediated renal 
dysfunction). In addition, food-effect data are not yet available; thus, QD dosing in the morning 
is appropriate to increase the likelihood that the drug will consistently be administered in a 
fasting state. Further, QD dosing offers convenience advantages for patients. BID dosing may be 
explored in this protocol once there is more safety, pharmacokinetics, and pharmacodynamic 
experience with the drug using the initial QD regimen. 
Changes to: 
 
Changes/Rationale: The schedule of activities (Table 
 to reflect additional TLS 
quest. 


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Table 3: Schedule of Activities 
 
Screening 
Therapy 
Posttherapy  
Follow-up 
Cycle 1 
Cycle 2 
End of 
Therapy 
Visit 
Day 
-28 to -1 [a] 1 [b] 
2 
3 
4 
5 
8 
15 
1 
15 
1 
 
Long-
term
Visit Window, days
±2
±23
±23
±23
±23
+14
General Eligibility/Safety Assessments
Written informed consent [c]
X
Medical history [d] 
X 
 
 
 
 
 
 
 
 
 
 
 
Height [e] 
X 
 
 
 
 
 
 
 
 
 
 
 
Weight [f] 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
X 
X 
 
 
Vital signs/oxygen saturation [g] 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
X 
X 
 
 
Performance status [h] 
X 
X 
 
 
 
 
X 
 
X 
 
X 
X 
 
 
AE assessment [i] 
X 
X 
X 
X 
X 
X 
X 
X [i] 
X 
X [i] 
X 
X 
X 
 
Concomitant medications [j]
X
X
X
X
X
X
X
X [j]
X
X [j]
X
X
X
12-lead ECG [k] 
X 
X 
X 
 
 
 
X 
 
X 
 
 
X 
 
 
Ophthalmological examination [l] 
X 
 
 
 
 
 
 
 
X [l] 
 
X [l]
X 
 
 
Study Drug Administration/Dispensing/Return 
 
 
 
 
 
 
 
 
 
 
 
 
TLS prophylaxis as needed [m] 
X 
X 
 
 
 
 
 
 
 
 
 
 
LAM-003 administration in clinic [n]
X
X
X
X
X
X
Dispensing of LAM-003 [o] 
 
 
X 
 
 
X 
 
 
X 
 
X 
 
 
LAM-003 return/compliance check [p] 
 
 
 
 
 
 
 
 
X 
 
X 
X 
 
 
Laboratory Assessments 
 
 
 
 
 
 
 
 
 
 
 
 
Urinalysis [q] 
X 
X 
X 
 
 
 
 
 
X 
 
 
X 
 
 
Serum virology [r] 
X 
 
 
 
 
 
 
 
 
 
 
 
Serum pregnancy test [s] 
X 
X 
 
 
 
 
 
 
X 
 
X 
X 
 
 
Serum chemistry [t]
X
X
X
X
X
X
X
X [t]
X
X [t]
X
X
Hematology [u] 
X 
X 
X 
X 
X 
X 
X 
X [u] 
X 
X [u] 
X 
X 
 
 
Coagulation [v]
X
X
X
X
X
Plasma for LAM-003 pharmacokinetics [w]
X
X
X
Blood for AML FLT3-ITD/HSP protein expression [x] 
 
X 
X 
 
 
 
X 
 
X 
 
 
 
 
Blood for AML HSP gene expression [y]
X
X
X
X
Plasma for FL concentrations [z] 
 
X 
X 
 
 
 
X 
 
X 
 
 
 
 
Blood for AML PD-L1 expression [aa] 
 
X 
X 
 
 
 
X 
 
X 
 
 
 
 
Blood for immune cell profiling [bb]
X
X
X
Disease-Related Assessments
Blood for FLT3-ITD mutation [dd]
X
Blood/saliva for AML/control mutation profiling [ee] 
 
X 
 
 
 
 
 
 
 
 
 
 
Blood and bone marrow aspiration/biopsy [ff]
X
X [ff]
X [ff]
Radiology examination [gg] 
X 
 
 
 
 
 
 
 
 
X [gg]
X [gg] 
 
 
Posttherapy Follow-up 
 
 
 
 
 
 
 
 
 
 
 
 
Posttherapy safety assessment [hh] 
 
 
 
 
 
 
 
 
 
 
X 
 
Long-term follow-up [ii]
X


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Footnotes 
Note: For scheduled visits after C1D1, permitted visit windows are indicated in the table. For procedures to be performed at a specified time postdose, the acceptable 
 
 
 
 
 
 
 
same timepoint, the 
fied time.  
a. 
To optimize scheduling convenience for the subject and for the study center staff, Screening procedures may be performed over as many days as necessary provided that 
screening activities (excepting prestudy tumor evaluation) are completed within 28 days before C1D1 of the study.  
b. 
If obtained within 3 days prior to the start of therapy, urinalysis and serum pregnancy, serum chemistry, hematology, and coagulation studies collected during Screening 
need not be repeated on C1D1. 
c. 
Written informed consent will be obtained before performance of any study procedures that are not part of routine medical care. 
d. 
Medical history to include recording of cancer history, previous therapy for cancer, past and ongoing medical conditions, review of systems, and relevant social history. 
e.
Height (in centimeters) will be obtained at Screening only. 
f. 
Weight (in kilograms) will be obtained once on each designated day. 
g.
Vital signs (blood pressure, pulse, temperature, and oxygen saturation via pulse oximetry) will be obtained with the subject resting in a supine position while breathing 
room air. Vital signs will be assessed at Screening, C1D1 (predose, and at 1, 2, 4, 6, and 8 hours postdose), C1D2 (24 hours postdose/predose for next drug administration), 
C1D3, C1D4, C1D5, 
 
h.
Performance status will be assessed using ECOG scale (see Appendix 14.114.1) once on each designated day.
i. 
AEs will be described using concise medical terminology, including whether serious, the date of onset, the date of resolution, severity based on the CTCAE (Version 4.03) 
[NCI 2010], a description of potential relatedness to the study drug or to a study procedure, the action taken due, and the outcome. On C1D15 and C2D15, AE information 
may be obtained via telephone contact with the subject.
j. 
Concomitant medication assessments should include information regarding all prescription, nonprescription, illicit, and alternative medications (health foods). Use of any 
supportive care (eg, antidiarrheals, antiemetics, hematopoietic growth factors, transfusions) should be noted. On C1D15 and C2D15, concomitant medication information 
may be obtained via telephone contact with the subject. 
k.
12-lead ECGs will be obtained with the subject resting in a supine position. ECGs will be collected at Screening, C1D1 (predose [in triplicate], and at 1, 2, 4, 6, and 8 hours 
postdose), C1D2 (24 hours postdose/predose for next drug administration), C1D8 (predose, and at 1, 2, 4, 6, and 8 hours postdose), C2D1, and at End of Therapy. 
l. 
Ophthalmologic evaluations (eg, with visual acuity testing, electroretinography, slit lamp examination dark adaptometry) should be performed by an ophthalmologist during 
Screening, within 14 days before C2D1, within 14 days before C4D1 (8-week interval), and then within 14 days before C7D1, C10D1, C13D1, C16D1, etc (12-week 
intervals), and at End-of-Therapy. 
m. If TLS is observed during study conduct, subjects who are at intermediate or high risk of TLS should receive medical prophylaxis according to the protocol-recommended 
or an institutional regimen customarily used at the study center (see Section 6.2.1.2). 
n. 
The dose of LAM-003 will be administered to the subject in the study center (with recording of the date and actual clock time of the LAM-003 administration). On C1D2, 
C1D3, C1D4, and C1D5, LAM-003 should only be administered after the serum chemistry results from that day have been evaluated to exclude TLS.
o.
Study centers will ensure that subjects have a sufficient supply of LAM-003 and are provided with instructions for self-administration at home. 
p. 
Empty, partially used, or full bottles of LAM-003 will be retrieved from the subject and drug compliance will be assessed. 
q.
Urinalysis to include specific gravity, pH, protein, glucose, ketones, bilirubin, urobilinogen, blood, nitrite, leukocyte esterase as assessed by dipstick and white blood cells, 
red blood cells, epithelial cells, bacteria, cast and crystals as assessed by microscopy. Urinalysis should be performed once on each designated day.
r. 
Virology evaluation to include serum HIV antibody, HbsAg antibody, HBc antibody, HCV antibody. Subjects with a positive antibody evaluation for HBc or HCV should 
undergo evaluation for HBV DNA and for HCV RNA to determine if the antibody test may be falsely positive. 
s.
Serum pregnancy testing will be performed in women of childbearing potential only. Pregnancy testing should be performed once on each designated day.
t. 
Serum chemistry studies to include sodium, potassium, chloride, bicarbonate, BUN, creatinine, glucose, calcium, phosphorus, magnesium, total protein, albumin, ALT, 
AST, ALP, CK, LDH, total bilirubin, uric acid. Serum chemistry studies should be performed once on each designated day. On C1D2, C1D3, C1D4, C1D5, serum 
chemistry results from that day should be evaluated to exclude TLS before the subject is administered LAM-003 in the clinic. On C1D15 and C2D15, serum chemistry 
studies may be obtained at a local laboratory.
u. 
Hematology to include hematocrit, hemoglobin, erythrocyte count; absolute counts of leukocytes, neutrophils, lymphocytes, monocytes, eosinophils, basophils; platelet 


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count. Hematology testing should be performed once on each designated day. On C1D15 and C2D15, hematology studies may be obtained at a local laboratory.
v. 
Coagulation studies to include PT and aPPT. Coagulation studies should be performed once on each designated day. 
w.
Plasma for LAM-003 pharmacokinetics will be collected on C1D1 (predose, and at 0.5, 1, 2, 4, 6, and 8 hours postdose), C1D2 (24 hours postdose/predose for next drug 
administration), and on C1D8 (predose, and at 0.5, 1, 2, 4, 6, and 8 hours postdose). 
x. 
Blood for FLT3-ITD/HSP protein expression in AML blasts will be collected on C1D1 (predose and 8 hours postdose), C1D2 (24 hours postdose/predose for next drug 
administration), C1D8 (predose and 8 hours postdose), and C2D1. 
y. 
Blood for HSP gene expression will be collected on C1D1 (predose and 8 hours postdose), C1D2 (24 hours postdose/predose for next drug administration), C1D8 (predose 
and 8 hours postdose), and C2D1. 
z. 
Plasma for FLT3 ligand concentrations will be collected on C1D1 (predose and 8 hours postdose), C1D2 (24 hours postdose/predose for next drug administration), 
C1D8 (predose and 8 hours postdose), and C2D1.
aa. Blood for AML PD-L1 expression will be collected on C1D1 (predose and 8 hours postdose), C1D2 (24 hours postdose/predose for next drug administration), 
C1D8 (predose and 8 hours postdose), and C2D1. 
bb. Blood for immune cell profiling will be collected on C1D1 (predose), C1D8 (predose), and C2D1.
cc. Blood for FLT3-ITD mutation confirmation in AML blasts using the LeukoStrat® CDx FLT3 mutation assay will be obtained during Screening.
dd. Blood for AML cell mutation profiling with collection of saliva as a germline DNA control will be obtained on C1D1 (predose).
ee. Blood for peripheral blood AML blast count evaluation and bone marrow aspiration/biopsy will be performed during Screening (unless the requirement for screening bone
marrow aspirate/biopsy is waived by the medical monitor because sufficient bone marrow material is available for response determination). Post-baseline, a bone marrow 
aspirate/biopsy is required within 14 days before C3D1, C5D1, C7D1 (8-week intervals), and then within 14 days before C10D1, C13D1, C16D1, etc (12-week intervals). 
An End-of-Therapy bone marrow aspirate/biopsy should be performed unless the subject already has hematological or radiographic confirmation of DRP 8 weeks before 
permanent study drug discontinuation. At all AML evaluations, the extent of involvement with AML in peripheral blood and bone marrow, the presence of Auer rods, and 
bone marrow cellularity will be assessed. Bone aspirate aliquots obtained at Screening and within 14 days before C3D1 may also be evaluated for FLT3-ITD, HSP protein 
and gene expression, PD-L1, and AML mutations.
ff. 
Radiology examination is required in subjects with extramedullary disease that is radiographically assessable. FDG-PET/CT is the preferred method of evaluation but other 
methods (diagnostic CT, MRI) may be used if appropriate for the type of lesion. The baseline evaluation should occur within 28 days before C1D1. Post-baseline 
evaluations should be performed within 7 days before C3D1, C5D1, C7D1 (8-week intervals), and then within 7 days before C10D1, C13D1, C16D1, etc (12-week 
intervals). An End-of-Therapy radiology assessment should be performed unless a subject with extramedullary disease already has hematological or radiographic 
confirmation of DRP 8 weeks before permanent study drug discontinuation. 


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gg. Posttherapy safety assessment will be performed after permanent cessation of study therapy to follow subjects for any drug-related AE and/or ongoing SAEs. Subjects will 
be followed until the later of either 30 days after the last dose of study treatment or until resolution/stabilization of any ongoing drug-related AEs and/or SAEs. Follow-up 
may be obtained in person or by telephone contact. 
hh. Long-term follow-up information will be obtained in all surviving subjects who permanently discontinue study therapy. Data on post-study therapies for the AML and on 
survival will be collected. Such information may be collected at ~3- to 6-month intervals through 3 years. This long-term follow-up information will be gathered during 
routine clinic visits, other study site contact with the subjects, or via telephone or e-mail with the subjects/caregivers or referring physician offices. 
Abbreviations: AE=adverse event, ALP=alkaline phosphatase, ALT=alanine aminotransferase, AML=acute myeloid leukemia, aPTT=activated partial thromboplastin time, 
AST=aspartate aminotransferase, BUN=blood urea nitrogen, CK=creatine kinase,  CT=computed tomography, CTCAE=Common Terminology Criteria for Adverse Events, 
DNA=deoxyribonucleic acid, ECG=electrocardiogram, ECOG=Eastern Cooperative Oncology Group, FDG=fluorodeoxyglucose, FL=FLT3 ligand concentration, FLT3= FMS-
like tyrosine kinase-3, HBc antibody=hepatitis B core antibody, HbsAg=hepatitis B surface antigen, HBV=hepatitis B virus, HCV=hepatitis C virus, HIV=human 
immunodeficiency virus, HSP=heat shock protein, ITD=internal tandem duplications, LDH=lactate dehydrogenase, MRI=magnetic resonance imaging, NK=natural killer 
(cells), PD-L1=programmed death-ligand 1, PET=positron emission tomography, PT=partial thromboplastin time, RNA=ribonucleic acid, SAE=serious adverse event, 
TLS=tumor lysis syndrome 


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Changes to: Section 8
Study Center Reporting Requirements, 
 
ancy 
Changes/Rationale: The facsimile number of the pharmacovigilance group was added. 
Contact information for reporting an SAE or pregnancy is provided in Table 7. 
Table 7: 
Contact Information for Reporting SAEs or Pregnancies 
Pharmacovigilance CRO 
Contact Information 
Pharmalex US, LLC, Guilford, CT, USA 
E-mail: 
Vigicare@pharmalex.com 
Facsimile:
+1 (617) 315-4825 
CRO=contract research organization, SAE=serious adverse event 
Changes to: Section 9 
Methods and 
Analytes 
Changes/Rationale: Text in the body of this section and in Table 8 was updated to describe the 
ophthalmological examinations and the appropriate testing equipment. The disease-related 
laboratory parameters in Table 8 were revised to include an assessment of minimal residual 
disease. 
Ophthalmological examinations should be performed by a consulting ophthalmologist or 
optometrist with the necessary facilities and equipment to perform appropriate testing (eg, visual 
acuity testing, electroretinography, slit lamp examination dark adaptometry); interpretations of 
ophthalmological findings will be provided by a consulting ophthalmologist). 


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Table 8: 
Laboratory and Other Parameters to Be Assessed 
Laboratory – Disease-related
Peripheral blood or bone 
marrow cellular AML 
FLT3-ITD mutation 
analysis 
 Peripheral blood or bone marrow AML blast FLT3 mutation type and FLT3 ITD 
mutation-to-WT allele ratio (as evaluated using the LeukoStrat® CDx FLT3 
mutation assay) 
Baseline biomarker 
assessment 
 Mutational profiling in DNA from peripheral blood AML blasts with saliva as 
germ-line DNA control (with sample analysis using NGS) 
Peripheral blood smears 
and bone marrow aspirate 
and biopsy for efficacy 
assessments 
Peripheral blood smears and bone marrow aspirate and biopsy for analysis of AML 
disease status (blast percentage, presence of Auer rods, bone marrow cellularity, 
MRD) (as assessed by Wright stain for peripheral blood and bone marrow aspirate, 
hematoxylin and eosin for bone marrow biopsy, flow cytometry, and 
immunohistochemistry or flow cytometry [as needed for ambiguous blast analysis]) 
Other 
Body weight/height 
 Weight in kilograms, height in centimeters  
Body temperature  
 Temperature in degrees Celsius 
Blood pressure  
 Diastolic and systolic blood pressure in mm Hg 
Oxygen saturation  
 % saturation 
Ophthalmology 
examination 
 Examination by an ophthalmologist (to includeeg, visual acuity testing, 
electroretinography, slit lamp examination and dark adaptometry, if appropriate)
12-lead ECG  
 Heart rate, cardiac intervals, wave form abnormalities, ectopy 
Radiology examination  
 FDG-PET/CT (preferred), MRI, or diagnostic CT imaging for subjects with 
extramedullary disease that is radiographically assessible. 
Abbreviations: ALP=alkaline phosphatase, ALT=alanine aminotransferase, AML=acute myeloid leukemia, 
aPTT=activated partial thromboplastin time, AST=aspartate aminotransferase, BUN=blood urea nitrogen, 
CD=cluster of differentiation, CK=creatine kinase, CT=computed tomography, DNA=deoxyribonucleic acid, 
ECG=electrocardiogram, FDG=fluorodeoxyglucose, FL=FLT3 ligand, FLT3= FMS-like tyrosine kinase-3, 
HBc antibody=anti-hepatitis B core antibody, HbsAg=hepatitis B surface antigen, HBV=hepatitis B virus, 
HCV=hepatitis C virus, HIV=human immunodeficiency virus, HSP=heat shock protein, 
-
LDH=lactate dehydrogenase, MRD=minimal residual disease, ITD=internal tandem repeat, MRI=magnetic 
resonance imaging, NGS=next-generation sequencing, NK=natural killer (cells), PET=positron emission 
tomography, PCR=polymerase chain reaction, PD-L1=programmed death (receptor) ligand-1, PT=prothrombin 
time, RNA=ribonucleic acid, WT=wild type, -
-human chorionic gonadotropin.  
Changes to: Section 1
and Progression 
Changes/Rationale: The criteria for CRMRD were added, references to RBC transfusions as a 
component of response were removed from the definitions of complete remission with 
incomp
MRD were added. 
10.4
Definitions of Tumor Remission and Progression 
Responses will be categorized as complete remission without minimal residual disease (CRMRD), 
complete remission (CR), complete remission with incomplete blood count recovery (CRi), 
partial remission (PR), disease recurrence or progression (DRP), or treatment failure (TF). In 


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addition, a remission category of nonevaluable (NE) is provided for situations in which there is 
inadequate information to otherwise categorize remission status.
The best overall response will be determined. The best overall response is the best on-treatment 
response from baseline recorded from the start of treatment until DRP or TF. The baseline status 
will be taken as a reference for determinations of response. The best on-study measurement will 
be taken as a reference for DRP; the best on-study measurement constitutes the measurement 
with the least tumor involvement, including the baseline measurement if this is the measurement 
meeting this criterion.  
10.4.1 
Complete Remission without Minimal Residual Disease
To satisfy criteria for CRMRD, all of the following conditions must be attained: 
 Leukemia disease status meeting all of the following requirements: 
o Absence of evidence of AML in bone marrow aspirate by flow cytometry 
o <5% bone marrow blasts (based on a bone marrow aspirate/biopsy sample with 
 nucleated cells and the presence of bone marrow spicules)   
o No blasts in the peripheral blood 
o No blasts with Auer rods 
o No extramedullary disease 
 Peripheral blood meeting both of the following requirements: 
o 
9/L 
o 
9/L  
10.4.2 
Complete Remission 
To satisfy criteria for CR, all of the following conditions must be attained: 
 Leukemia disease status meeting all of the following requirements: 
o
<5% bone marrow blasts (based on a bone marrow aspirate/biopsy sample with 
 nucleated cells and the presence of bone marrow spicules)   
o No blasts in the peripheral blood 
o No blasts with Auer rods
o No extramedullary disease
 Peripheral blood meeting all both of the following requirements: 
o A
9/L 
o 
9/L  
o No requirement for red blood cell transfusions to maintain hemoglobin 


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10.4.3 
Complete Remission with Incomplete Blood Count Recovery 
To satisfy criteria for CRi, all of the following conditions must be attained: 
 Leukemia disease status meeting all of the following requirements: 
o <5% bone marrow blasts (based on a bone marrow aspirate/biopsy sample with 
 nucleated cells and the presence of bone marrow spicules)   
o No blasts in the peripheral blood 
o No blasts with Auer rods
o No extramedullary disease
 Peripheral blood meeting any either of the following requirements: 
o ANC <1.0 x 109/L 
o Platelet count <100 x 109/L
o Requirement for red blood cell transfusions to maintain hemoglobin 
10.4.4 
Partial Remission 
To satisfy criteria for PR, all of the following conditions must be attained: 
 Leukemia disease status meeting either of the following requirements: 
o 
 nucleated cells and the presence of bone 
marrow spicules)  
o <5% bone marrow blasts but with Auer rods present (based on a bone marrow 
asp
spicules)   
o No blasts in the peripheral blood 
o No new or worsening extramedullary disease
Peripheral blood meeting all both of the following requirements:
o 
9/L 
o Platele
9/L  
o No requirement for red blood cell transfusions to maintain hemoglobin 
10.4.5 
Treatment Failure 
The occurrence of any of the following events indicates TF: 
 In a subject without DRP, inability to qualify for a CRMRD. CR, CRi, or PR by 56 days 
8 weeks from start of study therapy 
 In a subject without a CRMRD. CR, CRi, PR, or DRP, permanent cessation of study therapy 
due to an AE
 In a subject without a CRMRD. CR, CRi, PR, or DRP, death from any cause 


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10.4.6 
Disease Relapse or Progression
The occurrence of any of the following events indicates DRP:
 Reappearance of bone marrow blasts to >5% in a subject who had experienced a CR or CRi
 Reappearance of blasts in the peripheral blood in a subject who had experienced a CR, CRi, 
or PR
An absolute 20% increase in bone marrow blasts to >25% (based on a bone marrow 
in a subject who had experienced a PR 
Development of new or worsening existing extramedullary disease
 Recurrence or worsening of MRD, as assessed by flow cytometry, will not be considered in 
the definition of DRP, but will be recorded. 
10.4.7 
Nonevaluable 
In a subject who does not have TF or DRP, the occurrence of any of the following conditions 
indicates a remission status of NE:  
 Bone marrow aspiration/biopsy data are inadequate or missing 
 Peripheral blood data are inadequate or missing 
 Information for a known site of extramedullary disease is inadequate or missing 
Changes to: Section 
 Analysis Conventions, 
11.1.1 Analysis Sets 
Changes/Rationale: The definitions of the full analysis set and responding analysis set were 
modified to include CRMRD as a response category. 
11.1.1 Analysis Sets 
11.1.1.1 
Full-Analysis Set 
The full-analysis set includes all subjects who receive 
will be used in the analyses of subject characteristics, study drug administration and compliance, 
safety, OR, CRc, CRMRD, CR, CRi, PR, EFS, and OS. 
11.1.1.2 
Responding Analysis Set
The responding analysis set includes subjects in the full analysis set who have measurable 
disease, who can be evaluated for tumor response with both baseline and on-study tumor 
evaluations, and who achieve a CRMRD, CR, CRi, or PR. This analysis set will be used in the 
analyses of TTR and DOR 


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Changes to: Section
Data Handling 
Changes/Rationale: The text was revised to reflect the change in study design (removal of 
Part
 
11.1.2 Data Handling Conventions
By-subject listings will be created for important variables from each eCRF module. Data will be 
described and summarized by dosing regimen study part (Part 1 or 2), dose level (Part 1), and 
time point.  
11.2.1 Subject Disposition and Baseline Characteristics 
A listing of all full analysis subjects will be generated to describe study center, subject number, 
first screening date, first treatment date, study part (Part 1 or 2), dose level (Part 1) dosing 
regimen, the longest duration of treatment with LAM-003, and the reason for discontinuing 
LAM-003. Available information on subjects who were screened but not administered study 
drug may be listed separately. A table will be created summarizing these categories in terms of 
number and percent for the full analysis set. 
Changes to: Section 
 Analysis Plan, 
 Categorical Endpoints
Changes/Rationale: The text was revised to reflect the addition of the CRMRD response 
category. 
11.2.6 
Efficacy Analyses 
Tumor control will be documented at each assessment by remission category (eg, CRMRD, CR,
CRi, PR, TF, DRP, or NE, as defined for each response parameter (see Section 10.4), date that 
response is first documented, and date of tumor progression/failure. MRD status, as assessed by 
flow cytometry, will be recorded. 
11.2.6.1 
Categorical Endpoints  
OR, CRc, CRMRD,CR, CRi, and PR rates will be described. In analyses of response rates in the 
full analysis set, subjects who have best responses of TF, DRP, or NE will be counted as failures. 
For all analyses of response rates, the relevant Cis will be presented. 
Changes to: Section 
 Timing of Analyses, 
 Final Analyses 
Changes/Rationale: The sections were revised to remove references to Part 
cohort 
expansion
11.3.1 
Interim Analyses 
In Part 1 of the study,N no formal interim analyses are planned. As described in Section 2.2, 
conference calls among the members of the SRC will be conducted periodically to discuss study 
progress, exchange study information, and review safety events, determine whether additional 
dose levels should be evaluated, and discuss potential amendments to the protocol. It is expected 
that these discussions will be scheduled at intervals of ~2 to 4 weeks unless accrual to the study 
and decisions regarding study conduct or transitions between the dosing cohorts indicate the 


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need for an alternative schedule of reviews. As needed for scientific or business reasons, LAM 
may collate and summarize available study results during conduct of the study. 
In Part 2 of the study, a rate of discontinuations of therapy due to AEs 
excessive toxicity due to study therapy. Sequential Pocock-type boundaries will be used to 
continuously monitor the rate of AE discontinuations and to test the null hypothesis, after each 
subject (to the maximum potential sample of 18 subjects), that the event rate is 
1-sided significance test of <0.05. AE discontinuation rates will be considered excessive if the 
following n/N values are observed: -/1, -/2, 3/3, 4/4, 4/5, 4/6, 5/7, 5/8, 5/9, 6/10, 6/11, 6/12, 7/13, 
7/14, 7/15, 8/16, 8/17, 8/18. With this method, the probability of detecting an AE discontinuation 
excessive levels of AE discontinuation are observed, the study sponsor, working in collaboration 
with the investigators, will take appropriate actions (eg, continuation with modifications in 
design, dosing regimen, and/or monitoring plan; interruption of expansion cohort accrual; 
discontinuation of expansion cohort therapy). 
11.3.2 
Final Analyses 
As appropriate, Part 1 may be reported separately from Part 2 of the study. Final study reporting 
for Part 1 is expected to occur after all Part 1 subjects have discontinued study treatment or 
 weeks after accrual of the final subject (whichever occurs earlier). Final study reporting for 
Part 
after accrual of the final subject (whichever occurs earlier).
Section
 Basis for the Planned Sample Sizes
Changes/Rationale: The sections were revised to remove references to Part 
cohort 
expansion
esign. 
11.4.1 
Part 1 (Dose Escalation)
Sample sizes for Part 1 of the cohorts of the study are not based on a specific statistical 
hypothesis but on experience from similar types of Phase 1 dose-ranging studies in patients with 
cancer.
In the dose escalation, the cohort sizes of 3 to 6 subjects allow evaluation of regimen safety using 
a standard definition of MTD (ie, a starting dose associated with DLT in <17% of subjects 
during the first cycle of therapy). Based on the planned 3+3 dose-escalation scheme, Table 9
shows the probability of escalating to the next dose level or proceeding to the next cohort, based 
on the true rate of DLT at the current dose level.
Table 9: Statistical Basis for 3+3 Dose-Escalation Paradigm 
True Incidence of DLT 
Probability of Escalating 
10%
0.91 
20%
0.71 
30%
0.49 
40%
0.31 
50%
0.17 
60%
0.08 
Abbreviation: DLT=dose-limiting toxicity 
Thus, if the true underlying proportion of DLT is low (eg, 10% at the current dose level, there 
is a high probability ( 0.91) of dose escalation to the next dose level. Conversely, if the true 


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underlying proportion of DLT is high (eg, 60%) at the current dose level, there is a low 
probability ( 0.08) of escalation to the next dose level. 
11.4.2 
Part 2 (Cohort Expansion) 
Enrollment of 12 evaluable subjects offers the opportunity to determine if there is antitumor 
activity sufficient to warrant further development of LAM-003 for FLT3-ITD AML. A CRc rate 
exp
(1-sided exact binomial 90% CI upper bound=17.5%). 
Changes to: Section 
 
Changes/Rationale: The following modifications or additions were made to the bibliography to 
support the revisions that were made in this amendment:
NCCN (National Comprehensive Cancer Network). NCCN clinical practice guidelines in 
oncology: cancer- and chemotherapy-induced anemia. Version 1.2018. 2017b Jun 23. Available 
at: https://www.nccn.org/professionals/physician_gls/pdf/anemia.pdf (accessed 2017 Nov 10). 
NCCN (National Comprehensive Cancer Network). NCCN clinical practice guidelines in 
oncology: myeloid growth factors. Version 2.2017. 2017c Oct 13. Available at: 
https://www.nccn.org/professionals/physician_gls/pdf/myeloid_growth.pdf (accessed 
2017 Nov 10). 


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14.7
Summary of Changes to Protocol – Amended Version 3
14.7.1
Overview of Changes
The modifications from Version 2 to Version 3 of the protocol included the following: 
 Information and implications were included in the protocol regarding additional in vitro 
drug-drug interaction studies performed with LAM-003A. 
 Enrollment procedures were clarified. 
At the request of the investigators, a clarification was included to indicate the extent of TLS 
that would result in interruption of study drug administration. 
 Information regarding severity grading of AEs was corrected. 


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14.7.2 Specific Changes 
In preparing Amended Version 3 of the protocol document, the following specific changes were 
made. Explanations of the changes are provided in italics as “Changes/Rationale”. Inserted text 
is indicated by double-underlining. Deleted text is indicated by strikeout. Revisions to the 
synopsis are not described. Changes to protocol versions and dates, modifications to the list of 
abbreviations and definitions of terms, routine bibliographic reference updates, or minor 
typographical or syntax corrections are not indicated.  
Changes to: 
-
-
Pharmacokinetics, Metabolism, and Drug-
Changes/Rationale: Additional in vitro drug-drug interaction studies were performed with 
LAM-
regarding the results of these studies and their implications. 
(No change to Paragraphs 1-5)
When metabolism was evaluated in human liver microsomes, 7 unique chromatographic peaks 
were detected by mass spectrometric-detection and the identities of 4 of these peaks were 
established. The data suggested that LAM-003A is a substrate of cytochrome P450 (CYP) 3A4. 
All metabolites detected in human microsomes were also detected in rat and/or monkey 
microsomes. These data confirmed that there were no unique human metabolites relative to 
toxicology species and that rat and monkey were appropriate species for nonclinical toxicology 
assessments of LAM-003A. 
When evaluated in rats, the primary route of elimination for LAM-003A and metabolites 
appeared to be through biliary elimination. Renal elimination was negligible (<1%) in rat, dog, 
and monkey. 
To assess for the possibility that LAM-003A metabolism might be altered by other drugs, an in 
vitro characterization with recombinant cytochrome P450 (CYP) enzymes was performed. This 
study concluded that LAM-003A was a substrate for the CYP3A4 and CYP3A5 isoforms. Until 
clinical drug-drug interaction data are available, these nonclinical findings suggest that 
coadministration of LAM-003 with strong inhibitors or inducers of CYP3A4/5 might perturb 
LAM-003A exposure and should be minimized (see Section 6.3.9).
The potential for LAM-003 acting as to perpetrate a drug-drug interaction was evaluated in vitro
using recombinant CYP enzymes. LAM-003A did not inhibit CYP1A2, CYP2C8, CYP2C9, 
CYP2C19, or CYP2D6 at concentrations that are likely to be achieved clinically. Inhibition of 
CYP3A4 was observed with an IC50 value of 
, suggesting the possibility that LAM-003 
could increase systemic exposures to drugs that are sensitive substrates of this enzyme. In a 
further study in pooled human liver microsomes, LAM-003A did not show direct inhibitory 
effects on CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, and CYP3A4/5. 
LAM-003A did not show time-dependent inhibition potential against CYP1A2, CYP2B6, 
CYP2C8, CYP2C19, or CYP2D6. However, LAM-003A demonstrated some evidence of time-
dependent inhibition against CYP2C9 with an IC50 value of 21.3 µM and more substantial time-
dependent inhibition against CYP3A4/5 with IC50 values of 0.636 µM (midazolam probe 
substrate) and 0.499 µM (testosterone probe substrate). Because the prior LAM-003A Phase 1 
clinical experience did not demonstrate time-dependent changes in LAM-003A Cmax and AUC 


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following repeated dosing, the potential for clinically significant effects of LAM-003 on drugs 
that are metabolized by CYP3A4 appears to be low. However, investigators are advised to use 
caution when administering drugs that are sensitive or low-therapeutic-index CYP3A4 substrates 
(see Section 6.3.9). 
Changes to: 
Replacement of Study Subjects 
Changes/Rationale: Clarifications were included regarding the enrollment procedures. 
Inclusion and exclusion criteria will be reviewed for each potential subject by qualified study 
center personnel. If the consented study candidate is considered eligible for study participation, 
the study center will transmit a study-specific elegibility eligibility and enrollment form to LAM 
(or designee).  
LAM (or designee) will acknowledge receipt of the study candidate’s eligibility form and will 
complete an the enrollment form indicating the subject identification number, the study part, and 
the LAM-003 dosing regimen. The enrollment form will be transmitted to the study center. Once 
the study center receives the completed enrollment form, the subject can begin treatment.  
Changes to: 
, 
-
tration, 
Changes/Rationale: A clarification was included to indicate the extent of TLS that should be 
evaluated to determine the need for interruption of study drug 
administration. The wording of the change ensured consistency with the 
TLS DLT definition i
by the FDA. 
In each 28-day cycle, subjects are to self-administer LAM-003 starting on Day 1 and then 
continuously thereafter (28 total doses/cycle). Subjects should take the study drug at 
approximately the same time each day, ideally at ~24-hour intervals (eg, ~8AM every day) for 
the planned QD schedule or at 12-hour intervals (eg, ~8AM and ~8PM every day) if a BID 
schedule is evaluated. In conjunction with frequent pharmacokinetic assessments on C1D1, 
C1D2, and C1D8, subjects should take the drug at the study center under the supervision of study 
personnel. On C1D2, C1D3, C1D4, and C1D5, LAM-003 is to be administered in the study 
center and only after the serum chemistry results from that day have been evaluated to exclude 
-
organ injury TLS. While variations in dosing schedule may occur in the outpatient setting, the 
prescribed regimen should be followed as closely as possible. 
Changes to: 
 
Changes/Rationale: A clarification was included to indicate the extent of TLS that would 
result in interruption of study drug administration. The wording of the 
change ensured consistency with the TLS DLT definition in 
Section
.
(No change to Paragraphs 1 or 2) 


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Subjects with TLS should receive IV hydration, rapid reversal of hyperkalemia, 
antihyperuricemic agents, and appropriate cardiac and renal support, including dialysis as 
indicated. LAM-003 administration may continue except in those who develop Grade 4 TLS or 
-organ injury. 
Upon recovery to baseline functioning and as medically appropriate, such subjects who develop 
TLS should continue with protocol therapy to maintain tumor control. 
Changes to: 
 
Changes/Rationale: To match other instructions in the protocol related to TLS detection and 
were updated. 
n. 
The dose of LAM-003 will be administered to the subject in the study center (with recording of the date and actual clock 
time of the LAM-003 administration). On C1D2, C1D3, C1D4, and C1D5, LAM-003 should only be administered after 
the serum chemistry results from that day have been evaluated to exclude Grade 4 TLS or Grade 3 TLS associated with 
-organ injury TLS. 
t. 
Serum chemistry studies to include sodium, potassium, chloride, bicarbonate, BUN, creatinine, glucose, calcium, 
phosphorus, magnesium, total protein, albumin, ALT, AST, ALP, CK, LDH, total bilirubin, uric acid. Serum chemistry 
studies should be performed once on each designated day. On C1D2, C1D3, C1D4, C1D5, serum chemistry results from 
that day should be evaluated for evidence of 
 
-organ injury to exclude TLS before the subject is administered LAM-003 in the clinic. On C1D15 and 
C2D15, serum chemistry studies may be obtained at a local laboratory. 
Changes to: 
n Adverse Event 
Changes/Rationale:
would report changes in the 
severity of AEs, a limitation was removed that sites were to report only 
the highest severity grade for an AE. 
The severity of AEs will be graded and reported using the CTCAE, Version 4.03 [NCI 2010].
For each episode, the highest severity grade attained should be reported. 
(No change to Paragraphs 2 or 3, or to Table 4)


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14.8
Summary of Changes to Protocol – Amended Version 4
14.8.1
Overview of Changes
The modifications from Version 3 to Version 4 of the protocol included the following: 
 Information regarding a comparative toxicology study of LAM-003 and LAM-003A in rats 
was added to the protocol introduction section. 
 The enrollment procedures were clarified to indicate that study candidates could be 
rescreened if such rescreening was medically appropriate and was approved by the medical 
monitor. 
 The minimum FLT3-ITD mutant-to-WT allele ratio cutoff allowing subject enrollment to the 
study was lowered from >0.40 to 
 and it was explicitly indicated that either peripheral 
blood or bone marrow could be used to evaluate subject elegibility. 
 It was clarified that a leukemic blast cell count >50 × 109/L in the peripheral blood could be 
the basis for a study candidate exclusion from study participation. 
 Descriptions were included of the specific tests to be performed during ophthalmological 
evaluations. 
 Enrollment criteria text was corrected to indicate that study candidates likely to receive 
strong CYP3A4 inhibitors or inducers chronically be excluded from study participation. 
Relevant supportive care text was corrected, and the associated appendix table was updated 
to describe strong CYP3A4 inhibitors and inducers based on the most recent listing of such 
drugs in FDA guidance. 
 It was clarified that a peripheral blood sample and/or a bone marrow aspirate sample could 
be submitted for confirmation of FLT3-ITD mutation status. 


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14.8.2 Specific Changes 
In preparing Amended Version 4 of the protocol document, the following specific changes were 
made. Explanations of the changes are provided in italics as “Changes/Rationale”. Inserted text 
is indicated by double-underlining. Deleted text is indicated by strikeout. Revisions to the 
synopsis are not described. Changes to protocol versions and dates, modifications to the list of 
abbreviations and definitions of terms, routine bibliographic reference updates, or minor 
typographical or syntax corrections are not indicated.  
Changes/Rationale: 
comparative toxicology study of LAM-
LAM-
section.
Changes to:  
-
-
 
In support of clinical development in patients with cancers, LAM-003A underwent toxicological 
evaluation in conformance with the International Conference on Harmonization (ICH) S9 
guidance on nonclinical assessments of anticancer pharmaceuticals [FDA 2010]. This evaluation 
included 28-day and 16-week GLP toxicology studies in rats and monkeys that formed the 
central basis for Phase 1, first-in-human dose selection and clinical safety monitoring. In 
addition, a 28-day study compared the toxicology and toxicokinetics of LAM-003 and 
LAM-003A in rats. 
Changes to:  
-
-
-Dose 
Study of LAM-
-
 
1.4.3.4.5 
Comparative Repeat-Dose Study of LAM-003 and LAM-003A 
This study was conducted to evaluate the potential toxicity and toxicokinetics of LAM-003 and 
LAM-003A in rats when administered orally for 28 days followed by a 14-day recovery period 
Two groups of Sprague-Dawley rats were administered LAM-003 at dose levels of 67 and 
134 mg/kg/day (respective molar equivalent doses of 50 and 100 mg/kg/day of LAM-003A). 
One group of animals was administered LAM-003A at a dose level of 100 mg/kg/day (the 
NOAEL of LAM-003A in a previous study). One additional group of animals was administered 
vehicle. Following 28 days of administration, recovery animals were maintained for a 14-day 
recovery period.  
No early deaths occurred. A lower body weight gain was observed in males given 100 mg/kg/day 
LAM-003A and in males given 134 mg/kg/day LAM-003 during the dosing period. Further loss 
was not observed during recovery. No effects on food consumption or changes in ophthalmology 
were noted in any group. 
Minimal to mild decreases in lymphocytes, eosinophils, basophils and platelets were observed in 
both sexes receiving 134 mg/kg/day LAM-003 and 100 mg/kg/day LAM-003A. The changes 
were similar in magnitude between animals receiving LAM-003 and LAM-003A. Minimal 
increases in serum AST and ALT were observed at termination in both sexes given 
100 mg/kg/day LAM-003A. Although these changes were considered related to treatment, they 
were not considered biologically relevant based on their small magnitude and/or and lack of 
histopathologic correlates. These changes had resolved by the recovery interval. 


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Spleen and thymus weights were decreased in both sexes at 67 and 134 mg/kg/day of LAM-003 
and at 100 mg/kg/day LAM-003A. Similar microscopic findings were observed in rats given 
LAM-003 or LAM-003A orally for 28 days, including minimal to mild cortical lymphoid 
necrosis and/or minimal to mild generalized lymphoid depletion of the thymus; minimal to mild 
mixed depletion of the bone marrow; and minimal edema, minimal hyperkeratosis, minimal 
epithelial hyperplasia and/or mild erosion/ulceration of the stomach in both sexes, primarily in 
the high dose groups (100 mg/kg/day equimolar dose). Minimal to moderate physeal thickening 
was observed in the growth plate of the femur in males in all LAM-003 and LAM-003A groups 
and minimal bilateral follicular cell hypertrophy in the thyroid gland was observed in females in 
the high-dose groups. All findings generally resolved during the recovery period. There were no 
toxicities observed in animals given LAM-003 that were not also observed in animals given 
equimolar doses of LAM-003A.
Changes/Rationale: The enrollment procedures were clarified to indicate that study candidates 
could be rescreened if such rescreening was medically appropriate and was approved by the 
medical monitor.
Changes to:  
 Enrollment and Replacement of Study Subjects 
Inclusion and exclusion criteria will be reviewed for each potential subject by qualified study 
center personnel. If the consented study candidate is considered eligible for study participation, 
the study center will transmit a study-specific eligibility and enrollment form to LAM (or 
designee). If medically appropriate, study candidates who do not initially meet screening criteria 
may be rescreened with the approval of the medical monitor. 
(No changes to Paragraphs 2 or 3)
Changes/Rationale: Based on discussions with the investigators, it was elected to decrease the 
minimum 
mutant-to-WT allele ratio cutoff allowing subject enrollment to the study 
 and permit diagnosis based on peripheral blood or bone marrow. 
Changes to:
 
 
3. Current dDiagnosis of FLT3-ITD-mutant AML (with a mutant-to-WT allele ratio of 
>0.40
 in peripheral blood or bone marrow at screening as documented by the 
LeukoStrat® CDx FLT3 mutation assay). 
Changes/Rationale: 
9/L in the 
peripheral blood could be the basis for a study candidate exclusion from study participation.
Changes to:  
 
 
1. Peripheral blood lLeukemic blast cell count >50 × 109/L before the start of study therapy and 
despite the use of hydroxyurea. 


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Changes/Rationale: Descriptions were included of the specific tests to be performed during 
ophthalmological evaluations.  
Changes to:  
Ophthalmological Symptom 
Management 
(No change to Paragraph 1)
During the study, subjects will undergo screening and periodic ophthalmological examinations 
(including visual symptom assessment, visual acuity testing, electroretinography, tonometry, slit 
lamp examination, and electrical coherence tomographyeg, visual acuity testing, 
electroretinography, and slit lamp examination) according to the schedule of activities provided 
in Section 7. As noted in Section 6.2.7, subjects who develop treatment-emergent dose-limiting 
visual symptoms should have drug interrupted and should undergo more frequent 
ophthalmological consultation (eg, at ~2-week intervals or more frequently, as appropriate). 
Symptoms should resolve to Grade 
 of study drug and study drug should 
only be resumed if such resolution occurs within 2 weeks of interruption of study drug and the 
subject appears to be otherwise safely benefiting from study therapy. 
Changes to: 
 
 
l.  Ophthalmologic evaluations (including visual symptom assessment, visual acuity testing, electroretinography, tonometry, slit lamp 
examination, and electrical coherence tomographyeg, with visual acuity testing, electroretinography, slit lamp examination) should 
be performed by an ophthalmologist during Screening, within 14 days before C2D1, within 14 days before C4D1 (8-week interval), 
and then within 14 days before C7D1, C10D1, C13D1, C16D1, etc (12-week intervals), and at End-of-Therapy
Changes to: 9
, 9.1 Methods and Analytes
(No change to Paragraphs 1-7, 9 or 10)
Ophthalmological examinations should be performed by a consulting ophthalmologist or 
optometrist with the necessary facilities and equipment to perform appropriate testing (including 
visual symptom assessment, visual acuity testing, electroretinography, tonometry, slit lamp 
examination, and electrical coherence tomographyeg, visual acuity testing, electroretinography, 
slit lamp examination); interpretations of ophthalmological findings will be provided by a 
consulting ophthalmologist. 
Changes to: 9
, 9.1 Methods and Analytes, 
Table 8 
Ophthalmology 
examination 
 Examination by an ophthalmologist or optometrist (including visual symptom 
assessment, visual acuity testing, electroretinography, tonometry, slit lamp 
examination, and electrical coherence tomographyeg, visual acuity testing, 
electroretinography, slit lamp examination) 


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Changes/Rationale: Erroneous text was present indicating that study candidates likely to 
inhibitors or inducers chronically be excluded from study participation. Accordingly, the text 
in the relevant exclusion criterion was corrected, supportive care text was corrected, the 
rs, and a 
more recent reference was included in support of the appendix table. 
Changes to:  
 
16. Use of a strong inhibitor or inducer of cytochrome P450 (CYP) 3A4 (including itraconazole, 
ketoconazole, posaconazole, or voriconazole) within 7 days prior to the start of study therapy 
or expected requirement for chronic use of a moderate or strong CYP3A4 inhibitor or inducer 
during Cycle 1 of study therapy (see Appendix 14.4). Note: For subjects requiring 
antifungal prophylaxis/therapy, oral fluconazole or isavuconazonium can be considered. 
Echinocandins (eg, caspofungin, anidulafungin, or micafungin
realizing the disadvantage of the requirement for intravenous administration. 
Changes to:  
 
Local practices or guidelines regarding infection prophylaxis may be followed. Subjects 
developing an intercurrent infection during study drug treatment may receive therapeutic 
antibacterial, antiviral, or antifungal drugs as needed. However, care should be taken to avoid or 
minimize concomitant administration of prophylactic or therapeutic antibacterial, antifungal, or 
antiviral, agents that are moderate or strong CYP3A4 inhibitors or inducers (see Section 6.3.9 
and Appendix 14.4). Continuation of study therapy during treatment for an intercurrent infection 
is at the discretion of the investigator. 
Changes to:  
-
Potential
(No change to Paragraphs 1,2, 3, or 4)
For subjects who require temporary use of a drug that does affect these enzymes (eg, treatment 
with a systemic antifungal agent), LAM-003 therapy can be temporarily interrupted and then 
resumed after completion of the other drug. For subjects who require initiation of chronic 
therapy with a drug that moderately or strongly affects these enzymes, investigators must consult 
with the medical monitor to consider the best course of action. If subjects do receive a CYP3A4 
inhibitor concomitantly with LAM-003, they should be monitored closely for signs of LAM-003 
toxicity. Based on consultation with the medical monitor, such subjects may be required to 
undergo additional pharmacokinetic testing and may require a LAM-003 dose modification. 


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Changes to:
14.4 Strong Potent Inhibitors and Inducers of CYP3A4 
Effect on 
CYP3A 
Drug Class 
Medications 
Moderate to 
Strong CYP3A 
Inhibitors 
Antibiotics 
chloramphenicol, ciprofloxacin, clarithromycin, erythromycin, 
telithromycin 
Antiemetic 
aprepitant
Antifungals 
ketoconazole, fluconazole, itraconazole, posaconazole, 
voriconazole 
Antiviral 
protease inhibitors 
amprenavir, atazanavir, boceprevir, cobicistat, darunavir, 
elvitegravir, fosamprenavir, indinavir, lopinavir, nelfinavir, 
ritonavir, saquinavir, telaprevir, tenofovir, tipranavir 
Calcium-channel blockers 
diltiazem, mibifradil, verapamil 
Foods/herbs 
grapefruit, grapefruit juice, Seville oranges 
Serotonin antagonist 
nefazodone
Tyrosine kinase inhibitor 
imatinib 
Vasopressin antagonist 
conivaptan 
Moderate to 
Strong CYP3A 
Inducers 
Antibiotics 
nafcillin, rifampin 
Anticonvulsants 
carbamazepine, phenobarbital, phenytoin 
Antiviral reverse 
transcriptase inhibitors
efavirenz, etravirine 
Endothelin receptor 
antagonist 
bosentan  
Foods/herbs 
St. John’s wort 
Wakefulness-promoting 
agent
modafinil 
Reference: [FDA 2016] 
Abbreviation: CYP=cytochrome P450 enzyme 
Effect on CYP3A  
Drug 
Strong CYP3A Inhibitors 
boceprevir, cobicistat, conivaptan, danoprevir and ritonavir, elvitegravir and 
ritonavi), grapefruit juice, indinavir and ritonavir, itraconazole, ketoconazole, 
lopinavir and ritonavir, paritaprevir and ritonavir and (ombitasvir and/or 
dasabuvir), posaconazole, ritonavir, saquinavir and ritonavir, telaprevir, tipranavir 
and ritonavir, troleandomycin, voriconazole
Strong CYP3A Inducers 
carbamazepine, enzalutamide, mitotane, phenytoin, rifampin, St. John’s wort 
Abbreviation: CYP=cytochrome P450 enzyme 
Reference: [FDA 2017] 
Changes to:  
 
FDA (Food and Drug Administration). Drug development and drug interactions: table of 
substrates, inhibitors and inducers. 2016 Sep 27. Available at: 
https://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/DrugInteracti
onsLabeling/ucm093664.htm (accessed 2017 Sep 20). 
Food and Drug Administration (FDA). Drug development and drug interactions: Table of 
substrates, inhibitors and inducers. 2017 Nov 14. Available at: 
http://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/DrugInteractio
nsLabeling/ucm093664.htm#4 (accessed 2018 June 11). 


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Changes/Rationale: The Schedule of Activities was clarified to indicate that a peripheral 
blood sample and/or a bone marrow aspirate sample could be submitted 
-
 
Changes to:  Section 
 
 
Blood and/or bone marrow for FLT3-ITD mutation [dd] 
cc. Blood and/or bone marrow aspirate for FLT3-ITD mutation confirmation in AML blasts using the LeukoStrat® CDx 
FLT3 mutation assay will be obtained during Screening. 


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14.9
Summary of Changes to Protocol – Amended Version 5
14.9.1
Overview of Changes
The modifications from Version 4 to Version 5 of the protocol included the following: 
 Based on discussions with study investigators, it was noted that study candidates who had 
undergone HSCT could have persistent need for systemic corticosteroids for low-grade 
GVHD and that such corticosteroid use was precluding participation in the study. Because 
there was no specific safety, efficacy, or drug-drug interaction concern regarding 
coadministration of LAM-003 and corticosteroids, the protocol was modified in 2 ways: 
o It was specified that study candidates with high-grade GVHD would be excluded from 
the study. 
o
It was indicated that study candidates who had completed other immunosuppressive 
therapy but required continued corticosteroids would not be excluded from protocol 
participation. 
o Other sections of the protocol describing corticosteroid use were modified in accordance 
with the changes to the enrollment criteria. 


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14.9.2 Specific Changes 
In preparing Amended Version 5 of the protocol document, the following specific changes were 
made. Explanations of the changes are provided in italics as “Changes/Rationale”. Inserted text 
is indicated by double-underlining. Deleted text is indicated by strikeout. Revisions to the 
synopsis are not described. Changes to protocol versions and dates, modifications to the list of 
abbreviations and definitions of terms, routine bibliographic reference updates, or minor 
typographical or syntax corrections are not indicated.  
Changes/Rationale: 
was specified that study candidates with high-
excluded from the study based on disease manifestations rather than based on use of 
immunosuppressive drugs. 
Change to:  
 
 
 
12. In subjects with prior HSCT, evidence of graft-versus-host disease (GVHD) manifesting as 
NCI 
 involvement, or 
Grade 
 at requiring immunosuppressive therapy within 4 weeks prior to the start 
of study therapy. 
Changes/Rationale: t was indicated that study candidates who had completed other 
immunosuppressive therapy but required continued corticosteroids would not be excluded 
from protocol participation. Text relating to incidental use of intraarticular corticosteroids 
was also incorporated. 
Change to:  
Subject Selection Criteria,
 
 
15. Ongoing immunosuppressive therapy other than corticosteroids, including systemic or 
enteric corticosteroids. Note: At study entry, subjects may be using systemic,  
intraarticular, inhaled, or topical corticosteroids. During study therapy, subjects may use 
systemic, enteric, intraarticular, inhaled, or topical corticosteroids as required for 
intercurrent conditions. 
Changes/Rationale: Text in this section was modified in accordance with the changes to the 
enrollment criteria.
Change to:  
Rationale for Subject Selection 
(No change to Paragraphs 1,2, 3, 4, or 6) 
Exclusion of subjects who have undergone prior HSP inhibitor therapy is intended to avoid 
enrolling subjects with AML that is likely to be resistant to LAM-003. Avoidance of 
concomitant corticosteroid therapy immunosuppressives at baseline minimizes the potential that 
such therapy would depress the potential immunotherapeutic effects of LAM-003 or confound 
adequate profiling of the LAM-003 safety profile. Restrictions on concomitant administration of 
CYP3A4 inhibitors are important because in vitro data suggest that LAM-003A is primarily 
metabolized by CYP3A4 (see Section 1.4.3.3). Exclusions for cardiac waveform or rhythm 


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abnormalities are intended to ensure that subjects do not have conduction system disorders that 
would increase risk or confound on-study ECG evaluations. 
Changes/Rationale: Text in this section was modified in accordance with the changes to the 
enrollment criteria.
Change to:  
(No change to Paragraphs 1,2, 3, 4, or 5) 
Use of systemic corticosteroids (eg, dexamethasone) should be minimized to avoid interference 
with the potential immunopotentiating effects of study therapy; however, c Corticosteroids can 
be introduced if other types of antiemetic agents are not sufficiently effective.
Changes/Rationale: Text in this section was modified in accordance with the changes to the 
enrollment criteria.
Change to:  
 
At study entry, subjects may not be using systemic, intraarticular, or enteric corticosteroids but 
may be receiving inhaled, or topical corticosteroids. During study therapy, subjects may use 
systemic, intraarticular, enteric, inhaled, or topical or enteric corticosteroids as required for 
treatment-emergent intercurrent conditions.  


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14.10 Summary of Changes to Protocol – Amended Version 6
14.10.1 Overview of Changes
The modifications from Version 5 to Version 6 of the protocol included the following: 
 The protocol had originally focused on enrolling only patients with FLT3-ITD AML. 
However, this restriction was constraining accrual to the study. Because nonclinical data 
indicate that LAM-003 has the potential for activity in patients with FLT3-ITD, FLT3-TKD, 
and FLT3-WT AML, it was elected to expand accrual to permit enrollment of patients with 
any of these forms of AML. The change was endorsed by study investigators and conformed 
with a suggestion from the FDA at the time of opening the LAM-003 IND. As a consequence 
of this study modification, the type of screening testing was altered and the requirement that 
study candidates must have previously received FLT3 kinase inhibitors was removed.  
 At the request of the investigators, the protocol was modified to allow use of any of 
hydroxyurea, cytarabine, or cyclophosphamide to control blast count proliferation during 
Cycle 1.  
 To conserve supplies of study drug, modifications were made to the dispensing instructions.  
 To encourage adequate review of the subject dosing diary by site personnel, additional 
instructions regarding dosing diary review and documentation were included in protocol text.  
 To encourage collection of historical data regarding AML genetic profiling, instructions for 
acquisition of this information were included in the protocol.  


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14.10.2 Specific Changes 
In preparing Amended Version 6 of the protocol document, the following specific changes were 
made. Explanations of the changes are provided in italics as “Changes/Rationale”. Inserted text 
is indicated by double-underlining. Deleted text is indicated by strikeout. Revisions to the 
synopsis are not described. Changes to protocol versions and dates, modifications to the list of 
abbreviations and definitions of terms, routine bibliographic reference updates, or minor 
typographical or syntax corrections are not indicated. 
Changes/Rationale: The protocol had originally focused on enrolling only patients with 
-
 However, this restriction was constraining accrual to the study. Because 
nonclinical data indicate that LAM-
l for activity in patients with 
-
-
-WT AML, it was elected to expand accrual to permit 
enrollment of patients with any of these forms of AML. The change was endorsed by study 
investigators and conformed with a suggestion from the FDA at the time of opening the 
LAM-
 As a consequence of this study modification, the type of screening testing was 
altered 
inhibitors was removed.
1 INTRODUCTION, 1.3 Heat Shock Proteins as Clinical Targets for AML Therapy, 
2nd Paragraph 
Mutant FLT3-ITD is a client protein of HSP90 [Minami 2002, Yao 2003, Al Shaer 2008]. 
Mutant FLT3FLT3-ITD expression is associated with higher levels of HSP90 expression in 
primary AML cells [Reikvam 2011]. Treatment with an HSP90 inhibitor induces mutant FLT3-
ITD degradation and tumor cytotoxicity [Yao 2003, Zong 2015], leading to enhanced sensitivity 
of AML blasts harboring this oncogenic mutation [Zong 2015].  
1 INTRODUCTION, 1.4 LAM-003/LAM-003A, 1st Paragraph 
Based on the collective knowledge regarding the roles of FLT3 and HSP90 in AML, 
LAM Therapeutics, Inc (LAM) is developing LAM-003 as a clinical HSP90 inhibitor for patients 
with FLT3-ITD-mutant AML. The initial goal of development is to offer a novel treatment 
approach that can circumvent FLT3-ITDresistance in patients who have experienced failure of 
FLT3 inhibitors other drugs. Ultimately, it is hoped that LAM-003 administered alone or in 
combination can supplement or complement current treatment methods. 
1 INTRODUCTION, 1.4 LAM-003/LAM-003A, 1.4.3 Nonclinical Experience, 
1.4.3.1 Efficacy Pharmacology, 1.4.3.1.1 in Vitro Studies, 1st, 2nd, and 5th Paragraphs
In vitro studies indicated that LAM-003 demonstrates mutant FLT3-ITD client protein 
degradation and preferential cytotoxicity toward AML cell lines and primary AML cells 
harboring a FLT3-ITD mutation (Figure 3); in these experiments, the geometric mean EC50 
values were 576 nM for FLT3-ITD-mutant cells (n=8) vs 1525 nM for FLT3-wild-type (WT) 
cells (n = 11).  However, as also shown in (Figure 3), multiple FLT3-WT AML cell lines and 
patient-derived tumors share the enhanced sensitivity to LAM-003 displayed by FLT3-ITD AML 
cells in vitro.


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Figure 3: LAM-003 Demonstrates Potent Antileukemic Activity in AML Cells  
 
Abbreviation: AML=acute myeloid leukemia, EC50=median effective concentration, FLT3=FMS-like tyrosine 
kinase 3, ITD=internal tandem duplication, WT=wild type 
To further characterize the ability of LAM-003 to cause FLT3-mutant degradation, testing was 
performed on BaF3 murine cells made dependent on several oncogenic FLT3 mutations 
(including: FLT3-WT, FLT3-ITD, FLT3 D835V, FLT3-ITD D835V, FLT3 D835Y, FLT3-ITD 
D835Y, FLT3 D835H, FLT3-ITD D835H, FLT3 F691L, and FLT3-ITD F691L). As assessed by 
flow cytometry, LAM-003 caused similar dose-dependent reductions in FLT3 cell surface 
expression on all mutant cell lines but had relatively little effect on BaF3 cells expressing a 
FLT3-WT receptor. By this measure, FLT3-TKD mutants are as sensitive to LAM-003 
degradation as FLT3-ITD mutations. 
T-cell-
programmed death-ligand 1 (PD-L1) in a variety of cancer cell types, thus providing a 
mechanism by which tumor cells can evade immune detection. To test whether LAM-003 can 
block IFN- -induced PD-L1 expression, 6 primary AML samples (FLT3-WT, n=2; FLT3-ITD, 
n=4) wer
alone, LAM-003 
LAM-003 for 24 hours. At this timepoint, LAM-003 did not affect the viability of the AML 
blasts. Samples from all
-
L1 on the cell surface (5- to 25-fold). LAM-003 alone did not affect basal PD-L1 cell surface 
protein. 
LAM-003 significantly r
-induced 
PD-L1 cell surface expression. These data show that, in addition to possessing cytotoxic activity 
against AML FLT3-ITD, LAM-003 may also possesses salutary immunopotentiating activity.


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1 INTRODUCTION, 1.5 Conclusions, 1st and 4th Bullet Points
The conduct of this Phase 1 study of LAM-003 in patients with AML is founded on a current 
understanding of the natural history and current therapies for patients with this malignancy;
knowledge of the importance of FLT3 and HSP90 cellular pathways in the pathophysiology of 
this disease; and nonclinical and clinical information regarding the efficacy and safety of 
LAM-003 and LAM-003A. The collective data support the following conclusions:  
 Relapsed or refractory AML is a serious, disabling, and life-threatening disorder. Existing 
therapies can induce complete tumor regressions but often lose effectiveness over time. 
Through its effects as an HSP90 inhibitor and immunopotentiator, LAM-003 offers the 
potential for overcoming disease resistance and improving clinical outcomes for patients with 
previously treated FLT3-ITD-mutant AML. 
 Clinical evaluation of LAM-003 in patients with AML has sound scientific rationale based 
on evaluation of its therapeutic potential in in vitro and in vivo models relevant to human 
leukemia.  
 Advancing the development of LAM-003 in this study is well supported by nonclinical 
evaluations of LAM-003 and LAM-003A pharmacology, pharmacokinetics, and toxicology 
and by Phase 1 assessment of the safety and pharmacokinetics of LAM-003A in patients with 
solid tumors. This collective information provides a basis for subject enrollment criteria; 
starting dose selection and dose escalation; administration of an appropriate dosing regimen 
and supportive care; and for safety, pharmacodynamic, pharmacokinetic, and efficacy 
monitoring within this study. 
 Given the seriousness of previously treated, progressive AML and the aggregate potential 
benefits considered in the context of potential risks, clinical development of LAM-003 in 
patients with FLT3-ITD-mutant AML is justified. 
The rationale for specific design features of the study is provided in relevant sections of the 
protocol, including Section 2.3 (Rationale for Study Design), Section 4.3 (Rationale for Selection 
of Endpoints), Section 5.6 (Rationale for Subject Selection), and Section 6.6 (Rationale for Study 
Drug Administration and Supportive Care). 
2 STUDY DESIGN AND CONDUCT, 2.2 Study Design
This clinical trial is a Phase 1 study evaluating the safety, pharmacokinetics, pharmacodynamics, 
and antitumor activity of LAM-003 across a range of LAM-003 dose levels when administered 
to subjects with previously treated relapsed or refractory FLT3-ITD-mutant AML. Subjects will 
self-administer oral LAM-003 QD or BID continuously in repeated 28-day cycles. Cohorts of 3 
to 6 subjects will be sequentially enrolled at progressively higher dose levels of LAM-003 using 
a standard 3+3 dose-escalation design. Based on the pattern of DLTs observed in Cycle 1, 
escalation will proceed to define an MTD and a recommended dosing regimen (RDR) that may 
be at the MTD or a lower dose within the tolerable dose range. 
3 STUDY OBJECTIVES, 3.2 Secondary Objectives 
 To characterize the drug administration, safety, and supportive care profiles of LAM-003
 To evaluate the pharmacokinetic profile of LAM-003 


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 To characterize the onset, magnitude, and duration of antitumor activity and to assess 
survival in subjects with FLT3-ITD-mutant AML receiving LAM-003 
4 STUDY ENDPOINTS, 4.2 Secondary Endpoints, 4.2.4 Exploratory Endpoints, 
4.2.4.1 Pharmacodynamics, 1st Bullet
Changes in FLT3-ITD and HSP (eg, HSP90, HSP70) protein expression and activation of 
downstream pathway components in AML blasts (as measured using flow cytometry and/or 
protein immunoblotting) 
4 STUDY ENDPOINTS, 4.2 Secondary Endpoints, 4.2.4 Exploratory Endpoints, 
4.2.4.2 Biomarkers 
 Baseline AML blast FLT3 mutation type and FLT3-ITD mutation-to-WT allele ratio (as 
evaluated using the LeukoStrat® CDx FLT3 mutation assay) 
4 STUDY ENDPOINTS, 4.3 Rationale for Selection of Endpoints, 7th Paragraph 
Changes in FLT3-ITD expression, FLT3 pathway activation, HSP protein and gene expression, 
and PD-L1 expression in AML blasts are assessed during C1 therapy to provide evidence of drug 
mechanism, offer context for efficacy findings, and assist in final dose and schedule selection. 
Changes in plasma FL concentrations are intended to provide information that may corroborate 
drug effects on cellular alterations in FLT3. Immunophenotyping assays for changes in 
circulating B-cell, T-cell, NK cell, and monocyte subsets will characterize the peripheral immune 
status of the subject and any possible LAM-003 effects on these parameters. Baseline evaluations 
of FLT3 and overall mutational status in AML blasts are intended to generate subject selection 
hypotheses for future studies. 
5 RECRUITMENT AND SELECTION OF STUDY SUBJECTS, 5.5 Subject Selection 
Criteria, 5.5.1 Inclusion Criteria, Criteria 3 and 5 
3. Current diagnosis of FLT3-ITD-mutant AML (with a mutant-to-wild-type allele ratio of 
screening as documented by the LeukoStrat® 
CDx FLT3 mutation assay). 
5.
midostaurin, sorafenib, lestaurtinib, quizartinib, crenolanib, or gilteritinib) given as 
monotherapy or in combination. 
5 RECRUITMENT AND SELECTION OF STUDY SUBJECTS, 5.6 Rationale for Subject 
Selection, 3rd Paragraph 
A fundamental premise of the study is that LAM-003 HSP90 inhibition will cause degradation of 
ITD-mutated FLT3 in patients who have become resistant to existing FLT3 inhibitors. 
Accordingly, subjects must have a current diagnosis of FLT3-ITD-mutant AML and have 
undergone prior therapy with a FLT3 kinase inhibitor (eg, midostaurin, sorafenib, lestaurtinib 
quizartinib, crenolanib, or gilteritinib). The requirement for the presence of AML that is 
measurable ensures that subjects have disease that can be fully assessed for evidence of drug 
efficacy. 


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7 STUDY ACTIVITIES AND ASSESSMENTS, Table 3, Body of Table and Footnotes
Blood for AML FLT3-ITD/HSP protein expression [x] 
x. Blood for FLT3-ITD/HSP protein expression in AML blasts will be collected on C1D1 (predose and 8 hours postdose), C1D2 
(24 hours postdose/predose for next drug administration), C1D8 (predose and 8 hours postdose), and C2D1. 
Blood and/or bone marrow for FLT3-ITD mutation [dd]
x. Blood and/or bone marrow aspirate for FLT3-ITD mutation confirmation in AML blasts using a sponsor-specified  the 
LeukoStrat® CDx FLT3 mutation assay will be obtained during Screening.
ee.
Blood for peripheral blood AML blast count evaluation and bone marrow aspiration/biopsy will be performed during 
Screening (unless the requirement for screening bone marrow aspirate/biopsy is waived by the medical monitor because 
sufficient bone marrow material is available for response determination). Post-baseline, a bone marrow aspirate/biopsy is 
required within 14 days before C3D1, C5D1, C7D1 (8-week intervals), and then within 14 days before C10D1, C13D1, 
C16D1, etc (12-week intervals). An End-of-Therapy bone marrow aspirate/biopsy should be performed unless the subject 
already has hematological or radiographic confirmation of DRP
ontinuation. At 
all AML evaluations, the extent of involvement with AML in peripheral blood and bone marrow, the presence of Auer rods, 
and bone marrow cellularity will be assessed. Bone aspirate aliquots obtained at Screening and within 14 days before C3D1 
may also be evaluated for FLT3-ITD/ HSP protein and gene expression, PD-L1, and AML mutations. 
9 LABORATORY AND OTHER ASSESSMENTS, 9.1 Methods and Analytes, 5th 
Paragraph, and Body of Table 8. 
FLT3 mutation analysis in AML blasts using the LeukoStrat® CDxa FLT3 mutation assay will 
be performed at LAM or at a LAM-designated contract laboratory.  
Peripheral blood and bone 
marrow aspirate cellular 
pharmacodynamics 
 FLT3-ITD and HSP (eg, HSP90, HSP70) protein expression and activation of 
downstream pathway components in AML blasts (as measured using flow 
cytometry and/or protein immunoblotting) 
 HSP gene expression in AML blasts (as measured using quantitative PCR) 
 PD-L1 expression in AML blasts (as measured using flow cytometry) 
Peripheral blood or bone 
marrow cellular AML 
FLT3-ITD mutation 
analysis 
 Peripheral blood or bone marrow AML blast FLT3 mutation type and FLT3 ITD 
mutation-to-WT allele ratio (as evaluated using a sponsor-specified the 
LeukoStrat® CDx FLT3 mutation assay) 
11 Statistical Considerations, 11.2 Analysis Plan, 11.2.1 Subject Disposition and Baseline 
Characteristics, 2nd Paragraph
Subject baseline characteristics (eg, subject demographics, medical history, disease history, prior 
therapy, FLT3-ITD mutational status and mutant-to-WT allele ratio, peripheral AML blast count, 
bone marrow blast percentage, peripheral blood ANC, peripheral blood platelet count, peripheral 
blood hemoglobin, baseline TLS risk status, etc) will be listed and summarized for the full 
analysis set. 


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Changes/Rationale: At the request of the investigators, the protocol was modified to allow use 
of any of hydroxyurea, cytarabine, or cyclophosphamide to control blast count proliferation 
during Cycle 1.  
5 RECRUITMENT AND SELECTION OF STUDY SUBJECTS, 5.5 Subject Selection 
Criteria, 5.5.1 Inclusion Criteria, Criterion 7 (Now Criterion 6) 
7. All acute toxic effects of any prior antitumor therapy (except hydroxyurea, cytarabine, and/or 
cyclophosphamide given to control blast count proliferation) resolved to Grade
1 before the 
star
[G
Note: For 
subjects with rapidly proliferative disease, use of hydroxyurea, cytarabine, and/or 
cyclophosphamide is allowed before the start of study therapy and during Cycle 1, but must 
be discontinued thereafter. 
5 RECRUITMENT AND SELECTION OF STUDY SUBJECTS, 5.5 Subject Selection 
Criteria, 5.5.2 Exclusion Criteria, Criterion 1
1. Peripheral blood leukemic blast cell count >50 × 109/L before the start of study therapy and 
despite the use of hydroxyurea, cytarabine, and/or cyclophosphamide. 
6 STUDY DRUG INFORMATION, ADMINISTRATION, AND SUPPORT, 6.3 Supportive 
Care, 6.3.3 Anticancer Therapies Other than the Study Drugs 
Other than hydroxyurea, cytarabine, and/or cyclophosphamide used during Cycle 1 to control 
AML blast counts, noNo systemic anticancer therapies (including chemotherapy, antibody 
therapy, hormonal therapy, immunotherapy, radiotherapy, or other experimental therapies) for 
the subject’s cancer are permitted while the subject is receiving study treatment. Subjects are not 
allowed to participate concurrently in any other therapeutic clinical study. 
7 STUDY ACTIVITIES AND ASSESSMENTS, Table 3, Footnote c 
c.
Concomitant medication assessments should include information regarding all prescription, nonprescription, illicit, and 
alternative medications (health foods). Use of any supportive care (eg, antiproliferative drugs, antidiarrheals, antiemetics, 
hematopoietic growth factors, transfusions) should be noted. On C1D15 and C2D15, concomitant medication information 
may be obtained via telephone contact with the subject. 
Changes/Rationale: To conserve supplies of study drug, modifications were made to the 
dispensing instructions.  
6 STUDY DRUG INFORMATION, ADMINISTRATION, AND SUPPORT, 
6.1.5 Dispensing, 1st Paragraph 
A pharmacist or other qualified staff member will dispense bottles containing LAM-003 tablets. 
Sufficient bottles will be dispensed to the subject to provide an adequate drug supply until the 
subject’s next planned clinic visit at which drug will be dispensed (generally at 28-day intervals). 
If it is anticipated that a subject may have a potential delay in returning to the study center (eg, 
due to a holiday), an One additional bottle may should be provided at the start of therapy so that 
the subject has an overage supply to cover any potential delays in returning to the study center.
Sites should take care to minimize waste. 


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Changes/Rationale: To encourage adequate review of the subject dosing diary by site 
personnel, additional instructions regarding dosing diary review and documentation were 
included in protocol text. 
6 STUDY DRUG INFORMATION, ADMINISTRATION, AND SUPPORT, 6.1.6 Return 
and Compliance Assessment
At the completion of each dispensing interval, empty, partially used, or full bottles of LAM-003
should be retrieved from the subject. The quantities of unused LAM-003 and the date when these 
study supplies are returned by the subject should be recorded in the study drug accountability 
records. In addition, and the subject’s dosing diary should be reviewed at each visit, any 
incomplete or inconsistent entries should be addressed, and the dosing diary should be 
photocopied. Returned bottles may be redispensed to the same subject but not to another subject. 
Returned tablets and bottles may be destroyed according to the site’s standard operating 
procedures (see Section 12.11). 
7 STUDY ACTIVITIES AND ASSESSMENTS, Table 3, Body of Table and Footnote p 
LAM-003 return/compliance and diary check [p] 
p. Empty, partially used, or full bottles of LAM-003 will be retrieved from the subject and drug compliance will be assessed. In 
addition, the subject’s dosing diary should be reviewed, any incomplete or inconsistent entries should be addressed, and the 
dosing diary should be photocopied. 
Changes/Rationale: To encourage collection of historical data regarding AML genetic 
profiling, instructions for acquisition of this information were included in the protocol. 
7 STUDY ACTIVITIES AND ASSESSMENTS, Table 3, Body of Table and Footnote cc
AML genetic profiling data from records [cc] 
cc. Any available information in medical records regarding AML genetic profiling (eg, for FLT3 mutation status) to be 
collected for sponsor review. 
9 LABORATORY AND OTHER ASSESSMENTS, 9.1 Methods and Analytes, 6th 
Paragraph
Any available information in the subject medical records regarding AML genetic profiling (eg, 
for FLT3 mutation status) will be provided in redacted format for sponsor review. 
14.11 Summary of Changes to Protocol – Amended Version 7
14.11.1 Overview of Changes 
The modifications from Version 6 to Version 7 of the protocol are summarized as follows:
 The introduction to the protocol was updated to document the expected 
LAM-003
LAM-003A conversion ratio and summarize the available clinical and 
pharmacokinetic experience with LAM-003 from this clinical trial; these changes were made 
to support the plan to evaluate additional LAM-003 dose levels. 
 Information regarding the number of subjects to be accrued was modified consistent with 
other changes to the protocol. 


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 During accrual to the study, investigational sites had occasionally noted spuriously high 
values for cardiac QT interval when correcting with the Bazett formula (QTcB). These 
findings are consistent with published literature indicating that the QTcB tends to 
overestimate the QT interval and that correction using the Fridericia formula (QTcF) 
provides more accurate data in adults. In addition, the FDA had indicated that the QTcF 
alone is acceptable in analyzing QT data from clinical trials in adults. Based on these 
observations and considerations, it was elected to use only the QTcF value for purposes of 
establishing eligibility, determining DLT, assessing potential critical QT alerts, and statistical 
analyses. 
 In post-marketing surveillance, rare instances of cardiac QT prolongation and ventricular 
dysrhythmias had been observed in patients taking fluconazole. For this reason, fluconazole 
was listed in Appendix 14.5 as a drug having a known association with QT prolongation and 
thus its use was proscribed per protocol. However, as documented in fluconazole product 
labeling, most of the case reports of increases in QT interval were limited to patients with 
confounding disease, drug, or electrolyte risk factors. Accordingly, the protocol was updated 
to indicate that concomitant use of fluconazole prophylaxis/therapy would be permitted in 
subjects enrolled to the study. Further, it was indicated that the medical monitor could 
sanction use of certain concomitant drugs if the risk of QT prolongation in a specific study 
subject was likely to be negligible. 
 The exclusion criterion relating to participation in another therapeutic or imaging clinical 
trial was clarified. 
 The need for documentation of the timing of LAM-003 administration in conjunction with 
frequent pharmacokinetic assessments was emphasized 
 The definition of an overdose was changed to accommodate changes in the dose range of 
LAM-003 being explored in the study.   
 Prior Phase 1 clinical dose ranging with the active LAM-003 metabolite, LAM-003A, 
established an MTD in the range of 480 mg/day to 600 mg/day. LAM-003A dosing was not 
limited by high-grade DLTs but by reversible low-grade nausea vomiting at doses 
>600 mg/day. In the current LAM-003 study, it was considered possible that administration 
of LAM-003 as a prodrug for LAM-003A might result in lower effective drug exposure at 
higher dose levels than was previously observed when administering the metabolite directly. 
LAM-003 administration in this study at dose levels of 200 mg QD and 300 mg QD 
demonstrated no discernable toxicity, justifying an increment in dose level to a planned 450 
mg QD. Based on these considerations and the evolving LAM-003 safety profile, it was 
anticipated that exploration of higher LAM-003 dose levels might be warranted. 
Accordingly, it was elected to add LAM-003 dose levels of 600 mg (1.33-fold increment) 
and 750 mg QD (1.25-fold increment) to the dose escalation-scheme. Actual dose escalation 
continued using the existing 3+3 paradigm, DLT definitions, and safety monitoring; thus, all 
existing safety protections remained in place. 


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 Exploration of BID dosing was permitted per the existing protocol with the expectation that 
study subjects would receive divided doses that were half of the total daily dose in multiple 
of 50 mg (considering the 50-mg LAM-003 tablet size). The introduction of a potential total 
dose of 750 mg/day could result in unequal morning and evening dosing on a BID schedule. 
Thus, a provision for rounding up or down was introduced into the protocol (eg, 750 mg/day 
could be evaluated as 350 mg BID or 400 mg BID depending upon the emerging safety and 
pharmacokinetic profile of the drug). 
 The requirement for a minimum period of 4 weeks of observation was made approximate to 
allow some latitude in the DLT observation period consistent with the allowed visit window 
(±3 days). 
 Changes were incorporated into dose modification recommendations to maximize the 
potential for clinical benefit in individual subjects who proved to be tolerating therapy at a 
lower dose level and might safely benefit from a dose-escalation. In making these changes, 
safeguards were maintained: subjects must have tolerated therapy with no toxicities of 
Grade 
-level adjustments were permitted, the dose could not have 
exceeded an established MTD, the potential for additional monitoring was incorporated, and 
both the investigator and the medical monitor must have agreed that the dose escalation was 
medically appropriate. 
 It was clarified that ophthalmological testing could be performed by ophthalmologists or 
optometrists but also by other specialists with the relevant expertise (eg, a neurologist for 
ERG testing).  
 
It was also noted that the medical monitor could approve omission of an End-of-Therapy 
ophthalmological evaluation; this change was implemented to provide some flexibility to 
deal with extenuating circumstance (eg, avoid repeat testing in a subject who had recently 
undergone ophthalmological testing or was too ill due to AML to be transported to the 
ophthalmology clinic). 
 It was clarified that both peripheral blood and bone marrow should be evaluated at each 
AML disease assessment. The type of testing and the conditions of testing at the End-of-
Therapy were also clarified for peripheral blood, bone marrow, and radiological assessments 
of AML disease status. 
 It was clarified that hospital admissions or prolongations of hospitalization for administration 
of concomitant or subsequent therapy for the cancer would not be considered serious. 


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14.11.2 Specific Changes 
In preparing Amended Version 7 of the protocol document, the following specific changes were 
made. Explanations of the changes are provided in italics as “Changes/Rationale”. Inserted text 
is indicated by double-underlining. Deleted text is indicated by strikeout. Revisions to the 
synopsis are not described because analogous changes were made in the body of the protocol.. 
Changes to the protocol versions and dates, modifications to the list of abbreviations and 
definitions of terms, routine bibliographic reference updates, or minor typographical or syntax
corrections are not indicated. References to the former company name (LAM Therapeutics, Inc.) 
were updated to the current company name (AI Therapeutics, Inc.) without indicating the 
specific locations of these changes. 
Changes/Rationale: The introduction to the protocol was updated to document the expected 
LAM-
LAM-
summarize the available clinical experience with 
LAM-
; these changes were made to support the plan to evaluate 
additional LAM-
.
1 INTRODUCTION, 1.4 LAM-003/LAM-003A, 1.4.2. Chemistry 
LAM-003 has the chemical name of 
[(1S)-2-[4-[2-[6-amino-8-[(6-bromo-1,3-benzodioxol-5-yl)sulfanyl]purin-9-yl]ethyl]-1-
piperidyl]-1-methyl-2-oxo-ethyl] (2S)-2-aminopropanoate mono-mesylate, mono-hydrate]. The 
structure is shown in Figure 1. 
Figure 1. LAM-003 Structure 
N
N
N
N
NH2
S
O
O
Br
N
(S)
O
O
O
(S) NH2
Me
Me
MsOH
H2O
The molecular formula is C25H30BrN7O5S•CH4O3S•H2O and the molecular weight is 
734.64 g/mole. LAM-003 is modestly soluble in water (350 g/mL). The logarithm of the acid 
dissociation constant (pKa) is 6.91. 
LAM-003 is the L-alanine prodrug of the active moiety LAM-003A. LAM-003 is converted by 
esterases to LAM-003A. This conversion occurs in vitro in culture media and in vivo at the brush 
border of the intestine as shown in Figure 2. Based on a LAM-003A molecular weight of 549.44, 
and assuming complete conversion, administration of LAM-003 is expected to result in delivery 
of ~75% of the LAM-003A that would occur with direct administration of LAM-003A. 


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Figure 2: In Vivo Conversion of LAM-003 to LAM-003A and L-Alanine
1 INTRODUCTION, 1.4 LAM-003/LAM-003A, 1.4.4 Clinical Experience
1.4.4.1 Phase 1 Study of LAM-003A
No studies of LAM-003 have been conducted. A Phase 1, multicenter (3 centers), open-label, 
dose-ranging, multiple-dose study was conducted by the previous sponsor (Myrexis) to evaluate 
the safety and pharmacokinetics and to determine the maximum tolerated dose (MTD) of 
LAM-003A in patients with advanced solid tumors. 
Twenty-six subjects (13 males and 13 females) of median age 63.5 years (range: 45 to 85 years) 
with diverse types of tumor histologies (ie, cancers of the breast, colon, lung, prostate, kidney, 
salivary gland; melanoma, mesothelioma, sarcoma; unknown primary) were enrolled to receive 
repeated 21- to 28-day cycles of LAM-003A self-administered orally on a QD or twice-per-day 
(BID) schedule. Dosing regimens included 50 mg/m2 QD (n=1), 100 mg/m2 QD (n=1),
165 mg/m2 QD (n=1), 245 mg/m2 QD (n=6), 340 mg/m2 QD (n=2), 340 mg/m2 BID (n=6),
240 mg BID (n=4), and 320 mg BID (n=5). Subjects received a mean of 1.7 cycles of therapy 
(range, 0 to 13 cycles). 
Based on pre-established definitions of dose-limiting toxicity (DLT), an MTD was not 
determined. However, the drug was not well tolerated at total doses of >600 mg per day due to 
Grade 1-3 gastrointestinal adverse events (AEs) of nausea, vomiting, abdominal pain, diarrhea, 
and/or enteritis in 10/10 subjects.
Cardiovascular-related AEs were considered possibly related to the study drug in 3 subjects; 
these events included Grade 1 sinus tachycardia in 2 subjects in the 640-mg dose group and 
Grade 3 supraventricular tachycardia in 1 subject in the 245-mg/m2 dose group.
Electrocardiograms that were monitored on Days 1 and 21 for 8 to 12 hours indicated corrected 
QT intervals by the Fridericia correction method (QTcF) of >450 msec and 480 msec (Grade 1) 
in 4 of the 26 subjects. A prolonged QTcF interval (>500 msec) was noted in 1 subject; however, 
this subject had a pacemaker and the finding was not considered clinically relevant.
At doses of >600 mg per day, Grade 1-2 recoverable vision changes of light/dark adaptation
difficulty, dark/dimmed vision, white ocular crescents, and/or floaters were observed in 


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3/10 subjects (consistent with known class effects for HSP90 inhibitors [Pacey 2011, 
Rajan 2011, Sessa 2013, Infante 2014, Bendell 2015, Shapiro 2015, Bendell 2016, Kong 2016]). 
Other notable potentially drug-related AEs included renal failure (1 subject) and respiratory 
failure (1 subject).  
Pharmacokinetic findings indicated median Tmax values in the range of 1 to 3 hours. Cmax and 
AUC increased in a nearly dose-proportional manner across the dose levels. Exposures were 
generally 1- to 2-fold greater on Day 21 than on Day 1, indicating minimal to modest drug 
accumulation. The average t½ based on all cohorts after repeated dosing was 11.2 hours, 
supporting QD or BID dosing. 
1.4.4.1   Phase 1 Study of LAM-003 (Current Study) 
This ongoing Phase 1 multicenter, open-label, 3+3 dose-escalation study is being conducted by 
AI Therapeutics to evaluate the safety and pharmacokinetics and to determine the MTD of 
LAM-003 in patients with previously treated, relapsed or refractory AML. As of a cut-off date of 
10 Jun 2019, 9 subjects (6 males and 3 females) ranging in age from 26 to 82 years had received 
LAM-003 self-administered orally on a QD schedule. Dosing regimens included 200 mg QD 
(total n=6, DLT evaluable n=3) and 300 mg QD (total n=3, DLT evaluable n=3). Durations of 
LAM-003 administration at 200 mg QD were 2, 9, 12, 28, 56, and 57 days. Durations of 
LAM-003 administration at 300 mg QD were 21, 28, and 36 days. Reasons for discontinuation 
were progressive disease or lack of sufficient treatment response (n=8) or intercurrent illness due 
to AML complications (n=1). 
AEs appeared to be primarily related to AML, comorbid medical conditions, intercurrent illness 
or concomitant medications. Obvious LAM-003-related toxicities were not evident and no DLTs 
occurred. Laboratory or ECG abnormalities clearly attributable to the study drug were not 
observed. No drug-related ophthalmological findings were described. 
Pharmacokinetic data were available from subjects at LAM-003 dose levels of 200 mg QD 
(Day 1, n=4; Day 8, n=3) and 300 mg QD (Day 1, n=3; Day 8, n=3). As expected, exposure to 
the prodrug (LAM-003) in the systemic circulation was below the lower limit of quantitation of 
the assay (<1.0 ng/mL). LAM-003A exposures in the plasma was observed in all subjects. 
Increases in LAM-003A exposures were generally proportional to increases in LAM-003 dose. It 
appeared that LAM-003A steady state was achieved between Day 1 and Day 8; LAM-003A 
concentrations at 24 hours following the first dose on Day 1 were comparable to trough levels on 
Day 8 and LAM-003A AUC values were similar on Days 1 and 8. The pharmacokinetic profile 
of LAM-003A following LAM-003 administration was consistent with that observed with 
LAM-003A administration in the prior Phase 1 experience in patients with solid tumors.  
Changes/Rationale: 
consistent with other changes to the protocol. 
5 RECRUITMENT AND SELECTION OF STUDY SUBJECTS, 5.1 Planned Number of 
Subjects 
The total number of subjects will depend upon the numbers of subjects accrued to each dose 
level and the number of dose levels evaluated. If 6 subjects are enrolled at all 3 5 planned 
starting dose levels and 6 additional subjects are enrolled at the MTD or RDR, as many as 24 36 
subjects could be enrolled. If an additional dose level or an additional schedule (eg, BID) 


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administration is explored in 6 subjects per cohort, as many as 12 additional subjects could be 
enrolled, bringing the potential sample size to 36 48 subjects. To allow for the possibility that 
some subjects may not be fully evaluable, up to 48 60 subjects may be enrolled. 
Changes/Rationale: During accrual to the study, investigational sites had occasionally noted 
spuriously high values for cardiac QT interval when correcting with the Bazett formula 
(QTcB . These findings are consistent with published literature indicating that the QTcB tends 
to overestimate the QT interval and that correction using the Fridericia formula (QTcF  
provides more accurate 
ddition, the FDA had indicated that the QTcF 
alone is acceptable in analyzing QT data from clinical trials in adults. Based on these 
observations and considerations, it was elected to use only the QTcF value for purposes of 
establishing eligibility, determining DLT, assessing potential critical QT alerts, and statistical 
analyses.  
5 RECRUITMENT AND SELECTION OF STUDY SUBJECTS, 5.5. Subject Selection 
Criteria, 5.5.2 Exclusion Criteria, Exclusion Criterion 6 
6. Significant screening ECG abnormalities, including unstable cardiac arrhythmia requiring 
medication, atrial fibrillation/flutter, left bundle-branch block, 2nd-degree atrioventricular 
(AV) block type II, 3rd-
dycardia, or corrected QT (QTc by 
Fridericia or Bazett method) >480 msec (Grade >1). 
11 STATISTICAL CONSIDERATIONS, 11.2 Analysis Plan, 11.2.3 Safety, 11.2.3.4 
Electrocardiography
The overall quantitative and qualitative ECG assessment of heart rate, cardiac intervals, wave 
form abnormalities, and ectopy will be reported as “Normal” or “Abnormal” with respect to the 
description of the official ECG reading provided by the CRO performing the ECG analyses. A 
shift table comparing the ECG assessment over the on-study period (ever abnormal) to baseline 
will be presented with the types of abnormalities tabulated.  
Quantitative ECG parameters (heart rate, PR interval, QRS interval, QT interval, and QTc 
interval) at each time recorded as well as the change from screening will be summarized with 
descriptive statistics. The QT interval will be corrected by the Fridericia method for purposes of 
analysis. The following formula will be employed for correction: The QT interval will be 
corrected by both the Bazett and Fridericia method as follows: 
 Bazett: QTcB = QT/(RR)1/2 
 Fridericia: QTcF in msec = QT/(RR/1000)1/3 
The QTc data obtained by using the Bazett and Fridericia correction will be categorized 
separately into the following classifications and summarized by time point: 
 
(Grade 1)
 QTc interval >480 msec and 
(Grade 2)
 QTc interval >500 msec (Grade 3)


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The change of the QTc values obtained by using the Bazett’s and Fridericia’s correction will also 
be categorized separately as follows: 
 
msec 
 QTc interval increases from baseline by >60 msec 
QTc data will be presented in shift tables consistent with these categories.
n post-marketing surveillance, rare instances of cardiac QT prolongation and ventricular 
dysrhythmias had been observed in patients taking fluconazole. For this reason, fluconazole 
was listed in Appendix 
 as a drug having a known association with QT prolongation and 
thus its use was proscribed per protocol. However, as documented in fluconazole product 
labeling, most of the case reports of increases in QT interval were limited to patients with 
confounding disease, drug, or electrolyte risk factors. Accordingly, the protocol was updated to 
indicate that concomitant use of fluconazole prophylaxis/therapy would be permitted in 
subjects enrolled to the study. Further, it was indicated that the medical monitor could 
sanction use of certain concomitant drugs if the risk of QT prolongation in a specific study 
subject was likely to be negligible. 
5 RECRUITMENT AND SELECTION OF STUDY SUBJECTS, 5.5. Subject Selection 
Criteria, 5.5.2 Exclusion Criteria, Exclusion Criterion 17
17. Use within 7 days prior to the start of study therapy of a drug known to prolong the QT 
interval (see Appendix 14.5). Note: For subjects requiring antifungal prophylaxis/therapy, 
oral fluconazole is permitted given that the risk of QT prolongation is considered low (as 
documented in product labeling .
6 STUDY DRUG INFORMATION, ADMINISTRATION, AND SUPPORT, 6.3 Supportive 
Care, 6.3.10 Drugs Known to Prolong the QT Interval
Available nonclinical and clinical data do not suggest a high risk that LAM-003 will alter the QT 
interval. However, data are limited and, as a precaution, the clinical potential of LAM-003 to 
prolong the QT interval will be assessed in this study. Accordingly, co-administration of 
LAM-003 and known QT-prolonging drugs is to be minimized during Cycle 1 because use of 
such drugs might confound interpretation of QT data from the trial.  
Based on these considerations, protocol candidates who require therapy with drugs known to 
prolong the QT interval (as listed in Appendix 14.5) should not be enrolled into the study. If 
medically justified, protocol candidates may be enrolled if such drugs are unlikely to result in QT 
prolongation in the specific study subject (as judged by the medical monitor), can be 
discontinued, or alternative drugs that do not affect QT can be substituted >7 days before the first 
dose of LAM-003. 
After the subject is enrolled to the protocol and has been monitored for 24 hours after receiving 
the first dose of LAM-003, there is no specific restriction on use of drugs (eg, antiemetics) that 
might prolong QT interval; however, use of such drugs should be minimized. 


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Changes/Rationale: The exclusion criterion relating to participation in another therapeutic or 
imaging clinical trial was clarified.  
5 RECRUITMENT AND SELECTION OF STUDY SUBJECTS, 5.5. Subject Selection 
Criteria, 5.5.2 Exclusion Criteria, Exclusion Criterion 18 
18. Concurrent participation in another therapeutic or imaging clinical trial. Note: Subjects are 
not precluded from undergoing evaluations involving observation, noninvasive diagnostic 
procedures or sampling, or questionnaires as follow-up to a prior study or as components 
of a concurrent noninterventional study. 
Changes/Rationale: The need for documentation of the timing of LAM-
 in conjunction with 
frequent pharmacokinetic assessments was emphasized 
6 STUDY DRUG INFORMATION, ADMINISTRATION, AND SUPPORT, 6.2 Study 
Drug Administration, 6.2.2 LAM-003 Administration
In each 28-day cycle, subjects are to self-administer LAM-003 starting on Day 1 and then 
continuously thereafter (28 total doses/cycle). Subjects should take the study drug at 
approximately the same time each day, ideally at ~24-hour intervals (eg, ~8AM every day) for 
the planned QD schedule or at 12-hour intervals (eg, ~8AM and ~8PM every day) if a BID 
schedule is evaluated. In conjunction with frequent pharmacokinetic assessments on C1D1, 
C1D2, and C1D8, subjects should take the drug at the study center under the supervision of study 
personnel and the timing of LAM-003 administration must be documented in the clinic notes 
and/or in the subject diary. On C1D2, C1D3, C1D4, and C1D5, LAM-003 is to be administered 
in the study center and only after the serum chemistry results from that day have been evaluated 
to exclude Grade 4 TLS or Grade 3 TLS associated with G
-organ injury. While variations in dosing schedule may occur in the outpatient 
setting, the prescribed regimen should be followed as closely as possible. 
Changes/Rationale: The definition of an overdose was changed to accommodate changes in 
the dose range of LAM-
plored in the study.  
6 STUDY DRUG INFORMATION, ADMINISTRATION, AND SUPPORT, 6.1 LAM-003, 
6.1.8 Overdose Precautions
An overdose is defined as a dose taken (accidentally or intentionally) exceeding the overdose 
limit. In the case of a discrepancy in drug accountability, an overdose will be established only 
when it is clear that the subject has received an excess dose or the investigator has reason to 
suspect that the subject has received an excess dose. 
There are limited data on the effects of LAM-003 overdose. LAM-003A doses as high as 
320 mg BID (640 mg QD) were achieved in a prior Phase 1 study.  
For this protocol, an overdose of LAM-003 is defined as administration of a daily dose 600 
mg 50 mg above the prescribed dose. In a subject who experiences an overdose, consideration 
should be given as to whether LAM-003 administration should be temporarily interrupted. If the 
overdose is recent and substantial, and if there are no medical contraindications, use of gastric 
lavage or induction of emesis may be considered. Observation for any symptomatic side effects 
should be instituted, and safety laboratory parameters should be followed closely (consistent 
with the protocol or more frequently, as needed). Appropriate supportive management should be 


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instituted to mitigate adverse effects. The subject should remain under observation until adverse 
effects have recovered to baseline. There is no specific antidote for LAM-003. 
The medical monitor should be contacted if a study drug overdose occurs. The occurrence of an 
overdose does not preclude further protocol therapy if the subject appears to be safely benefiting 
from treatment and the circumstances that led to the initial overdose are unlikely to recur. 
Changes/Rationale: Prior Phase 1 clinical dose ranging with the active LAM-
LAM-
-
dosing was not limited by high-grade DLTs but by reversible low-grade nausea vomiting at 
-
was considered possible that 
administration of LAM-
-
ight result in lower effective drug 
exposure at higher dose levels than was previously observed when administering the 
metabolite directly. LAM-
mg QD demonstrated no discernable toxicity, justifying an increment in dose level to a 
 mg QD. Based on these considerations and the evolving LAM-
it was anticipated that exploration of higher LAM-
dose levels might be warranted. 
Accordingly, it was elected to add LAM-
-
and 
-fold increment
-scheme. Actual dose escalation 
existing safety protections remained in place.  
6 STUDY DRUG INFORMATION, ADMINISTRATION, AND SUPPORT, 6.2 Study 
Drug Administration, 6.2.4 Starting Dose Levels and Dose Escalation, Table 1 (LAM-003 
Starting Dose Levels) 
Cohorts of 3 to 6 subjects will be sequentially enrolled at progressively higher starting dose 
levels of LAM-003 using a standard 3+3 design, as indicated in Table 1. The initial cohort of 
subjects will be prescribed LAM-003 at Dose Level 1 (200 mg). Dose Levels -1 (100 mg) and 
-2 (50 mg) are provided to permit dose decrements if a subject experiences a TEAE requiring 
dose modifications to levels below Dose Level 1.  
Table 1: LAM-003 Starting Dose Levels 
Dose  
Level 
LAM-003 
Dosing Regimen 
Dose Change 
Relative to  
Prior Dose
-2
50 QD
0.50
-1 
100 QD 
0.50 
1 (initial dose level) 
200 QD 
Not applicable 
2 
300 QD 
1.50 
3 
450 QD 
1.50 
4 
600 QD 
1.33 
5 
750 QD 
1.25 
Abbreviations: QD=once per day 


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Changes/Rationale: 
h 
the expectation that study subjects would receive divided doses that were half of the total daily 
dose 
-mg LAM-
 The introduction of a 
potential total 
ing and evening dosing on a 
 Thus, a provision for rounding up or down was introduced into the protocol 
6 STUDY DRUG INFORMATION, ADMINISTRATION, AND SUPPORT, 6.2 Study 
Drug Administration, 6.2.4 Starting Dose Levels and Dose Escalation, Sub-bullet 
The following dose-escalation rules will be employed, considering DLTs observed in Cycle 1 of 
therapy: 
 Each dose level cohort will initially enroll 3 subjects.  
 If 0 of the first 3 subjects has a DLT, the next cohort of 3 subjects will be treated at the next 
higher dose level.  
 If 1 of the first 3 subjects in a cohort experiences a DLT, an additional 3 subjects will be 
treated at that same dose level. If 0 of the additional 3 subjects experience a DLT, the next 
cohort of 3 subjects will be treated at the next higher dose level. 
 
subjects experience a DLT, the MTD will have been exceeded and 
3 more subjects will be treated at the next lower dose level (if only 3 subjects were 
previously treated at that prior dose level). If 6 subjects were previously treated at the prior 
dose level, that prior dose level will provisionally be considered the MTD. 
 An additional 6 subjects (up to 12 total) may be enrolled at the MTD or RDR. 
 With the concurrence of the SRC, additional subjects (up to 12 subjects per dose level) may 
be accrued at dose levels at or below the MTD to refine the estimation of the RDR and 
further define the pharmacology of LAM-003. Such accrual may occur: 
o At Dose Level -1 or -2 (100 or 50 mg of LAM-003, respectively). 
o At an initially planned dose level (as indicated in Table 1) or at a dose level that lies 
between the initially planned dose levels. 
o Using an alternative schedule (eg, BID) with a total daily dose that does not exceed the 
total daily MTD (rounded up or down to the nearest even multiple of 50 mg).


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Changes/Rationale: The requirement for a minimum period of 4 weeks of observation was 
made approximate to allow some latitude in the DLT observation period consistent with the 
.
6 STUDY DRUG INFORMATION, ADMINISTRATION, AND SUPPORT, 6.2 Study 
Drug Administration, 6.2.4 Starting Dose Levels and Dose Escalation, Bullet 
The following additional procedures will be followed during the dose escalation: 
 The first subject to be treated at Dose Level 1 will be observed for 
 week after initiation of 
LAM-003 before any subsequent subjects are treated at the same dose level. 
 Each group of 3 subjects within a cohort must receive 
or 42/56 doses for a BID schedule) of planned Cycle 1 LAM-003 doses per subject and must 
be observed for a minimum period of ~4 weeks without DLT before subsequent subjects are 
enrolled at the next higher dose level. Any subject without DLT who does not complete these 
requirements may be replaced.
 Escalation to the next dose level can only occur upon review of the available safety data from 
all ongoing and previous subjects and with the concurrence of the SRC. 
 Intrasubject dose escalation above the initially assigned dose level will be not be permitted 
except as defined in Section 6.2.7 below. 
 Accrual of additional subjects to a treatment cohort may be considered by the SRC with the 
concurrence of the study sponsor. 
Changes/Rationale: Changes were incorporated into dose modification recommendations to 
maximize the potential for clinical benefit in individual subjects who proved to be tolerating 
therapy at a lower dose level and might safely benefit from a dose-
changes, safeguards were maintained: subjects must have tolerated therapy with no toxicities 
-level adjustments were permitted, the dose could not have 
exceeded an established MTD, the potential for additional monitoring was incorporated, and 
both the investigator and the medical monitor must have agreed that the dose escalation was 
medically appropriate.
6 STUDY DRUG INFORMATION, ADMINISTRATION, AND SUPPORT, 6.2 Study 
Drug Administration, 6.2.7 Dose Modification Recommendations, 4th Paragraph
Individual subjects who initiated treatment at a dose level below the dose currently under study 
or the established MTD (if lower) may have the LAM-003 dose escalated to the next higher dose 
level 
 cycles of therapy if both the principal investigator and the medical monitor agree 
that the subject is tolerating the current dose level 
and that a dose 
escalation is medically warranted (ie eg, for a subject with a PR). In such subjects, successive 
 weeks with the 
caveat that the escalated dose level cannot exceed the dose level currently under study or the 
established MTD (if lower). If considered necessary by the medical monitor, certain safety and 
other studies (eg, serum chemistry, hematology, ECG, pharmacokinetic, and pharmacodynamic 
evaluations) may be repeated at the higher dose level per the Cycle 1 schedule for these tests. 


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Changes/Rationale: 
ophthalmologists or optometrists but also by other specialists with the relevant expertise (eg, a 
neurol
 
d that the medical monitor could approve omission of an End-of-Therapy 
ophthalmological evaluation; this change was implemented to provide some flexibility to deal 
with extenuating circumstance (eg, avoid repeat testing in a subject who had recently 
undergone ophthalmological testing or was too ill due to AML to be transported to the 
 
7 STUDY ACTIVITIES AND ASSESSMENTS, Table 3 (Schedule of Activities), Footnote l. 
l. 
Ophthalmology evaluations (including visual symptom assessment, visual acuity testing, electroretinography, tonometry, 
slit lamp examination, and electrical coherence tomography) should be performed by an ophthalmologist, or optometrist, 
or other qualified specialist during Screening, within 14 days before C2D1 (4-week interval), within 14 days before C4D1 
(8-week interval), and then within 14 days before C7D1, C10D1, C13D1, C16D1, etc (12-week intervals), and at End-of-
Therapy. An End-of-Therapy ophthalmologic evaluation may be omitted with the approval of the medical monitor. 
9 LABORATORY AND OTHER ASSESSMENTS, 9.1 Methods and Analytes, 
Paragraph 9.
Ophthalmological examinations should be performed by a consulting ophthalmologist,  or 
optometrist, or other qualified specialist with the necessary facilities and equipment to perform
appropriate testing (including visual symptom assessment, visual acuity testing, 
electroretinography, tonometry, slit lamp examination, and electrical coherence tomography); 
interpretations of ophthalmological findings will be provided by a consulting ophthalmologist 
specialist. 
9 Laboratory and Other Assessments, 9.1 Methods and Analytes, Table 8 (Laboratory and 
Other Parameters to Be Assessed), Body of Table. 
Ophthalmology 
examination 
 Examination by an ophthalmologist,  or optometrist, or other qualified specialist 
(including visual symptom assessment, visual acuity testing, electroretinography, 
tonometry, slit lamp examination, and electrical coherence tomography))


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Changes/Rationale: 
at both peripheral blood and bone marrow should be 
evaluated at each AML disease assessment. The type of testing and the conditions of testing at 
the End-of-Therapy were also clarified for peripheral blood, bone marrow, and radiological 
assessments of AML disease status. 
7 STUDY ACTIVITIES AND ASSESSMENTS, Table 3 (Schedule of Activities), 
Footnotes ff and gg. 
ff. 
Blood for peripheral blood AML blast count evaluation and bone marrow aspiration/biopsy will be performed during 
Screening (unless the requirement for screening bone marrow aspirate/biopsy is waived by the medical monitor because 
sufficient bone marrow material is available for response determination). Post-baseline, a peripheral blood AML blast count 
evaluation and a bone marrow aspirate/biopsy is required within 14 days before C3D1, C5D1, C7D1 (8-week intervals), and 
then within 14 days before C10D1, C13D1, C16D1, etc (12-week intervals). An End-of-Therapy peripheral blood AML 
blast count evaluation and a bone marrow aspirate/biopsy should be performed unless the subject already has hematological 
or radiographic confirmation of TF or DRP 
 or the medical monitor 
approves omission of such End-of-Therapy testing. At all AML evaluations, the extent of involvement with AML in 
peripheral blood and bone marrow, the presence of Auer rods, and bone marrow cellularity will be assessed. Bone aspirate 
aliquots obtained at Screening and within 14 days before C3D1 may also be evaluated for FLT3/HSP protein and gene 
expression, PD-L1, and AML mutations. 
gg. Radiology examination is required in subjects with extramedullary disease that is radiographically assessable. FDG-PET/CT 
is the preferred method of evaluation but other methods (diagnostic CT, MRI) may be used if appropriate for the type of 
lesion. The baseline evaluation should occur within 28 days before C1D1. Post-baseline evaluations should be performed 
within 7 days before C3D1, C5D1, C7D1 (8-week intervals), and then within 7 days before C10D1, C13D1, C16D1, etc 
(12-week intervals). An End-of-Therapy radiology assessment should be performed unless a subject with extramedullary 
disease already has hematological or radiographic confirmation of TF or DRP 
discontinuation or the medical monitor approves omission of such End-of-Therapy testing. 
10 EFFICACY ASSESSMENTS, 10.3 Timing of Assessments 
During screening, clinical and imaging-based tumor assessments should be performed within the 
specified screening period. On-study tumor assessments should be performed as indicated in 
Section 7. An end-of-therapy tumor assessment should be performed unless the subject already 
has confirmation of TF or DRP 8 weeks prior to study drug discontinuation or the medical 
monitor has waived the requirement. If a subject permanently discontinues treatment prior to 
objective documentation of AML progression, investigators should continue further follow-up of
tumor status with assessments at ~8- to 12-week intervals until disease progression is 
documented or until the initiation of a new post-study therapy for the subject’s AML. 
Changes/Rationale: 
hospital admissions or prolongations of 
hospitalization for administration of concomitant or subsequent therapy for the cancer would 
not be considered serious.
8. SAFETY ASSESSMENTS, 8.1 Definitions, 8.1.2 Serious Adverse Events, Bullet 
 In-patient hospitalization or prolongation of existing hospitalization. Of note, an untoward 
medical occurrence that occurs during hospitalization is an AE but a complication that 
prolongs hospitalization is an SAE. In-subject hospitalization comprises formal admission to 
a hospital for medical reasons, for any length of time, whether or not hospitalization extends 
overnight. However, hospital admissions or prolongations of hospitalization for 
administration of the study drug or procedures required by the study protocol, diagnostic 
observations or procedures, administration of concomitant or subsequent therapy for the 
cancer, logistical issues (eg, lengthy travel), or the convenience of the subject or clinical 
personnel are not considered serious. 


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14.12 Summary of Changes to Protocol – Amended Version 8
14.12.1 Overview of Changes
The modifications from Version 7 to Version 8 of the protocol are summarized as follows:
 The contact information for the clinical operations manager for the study was updated.  
 The intrapatient dose-escalation provisions and duration of study drug administration 
instructions were altered to maximize the potential for clinical benefit in individual subjects 
who proved to be tolerating therapy at a lower dose level and might safely benefit from a 
dose-escalation.  
14.12.2 Specific Changes 
In preparing Amended Version 8 of the protocol document, the following specific changes were 
made. Explanations of the changes are provided in italics as “Changes/Rationale”. Inserted text 
is indicated by double-underlining. Deleted text is indicated by strikeout. Revisions to the 
synopsis are not described because these are described in the body of the protocol. Changes to 
the protocol versions and dates, modifications to the list of abbreviations and definitions of 
terms, routine bibliographic reference updates, or minor typographical or syntax corrections are 
not indicated.  
Changes/Rationale: Due to changes in study personnel, the contact information for the 
clinical operations manager for the study was updated. 
AI THERAPEUTICS PROJECT PERSONNEL 
AI Therapeutics, Inc. 
Study Director 
Langdon L Miller, MD
Medical Advisor 
AI Therapeutics, Inc.
Seattle, WA, USA
Mobile telephone: +1 (908) 906-6471
E-mail: lmiller@ai-thera.com 
AI Therapeutics, Inc. 
Clinical Operations Manager 
Candace Fuchs, BS 
Head, Clinical Operations and Project 
Management 
AI Therapeutics, Inc. 
Guilford, CT, USA 
Mobile telephone: +1 (860) 389-3749
E-mail: cfuchs@ai-thera.com 
Kate Flanders, BS 
Clinical Operations Manager 
AI Therapeutics, Inc. 
Guilford, CT, USA 
Mobile telephone: +1 (206) 795-6514
E-mail: kflanders@lamthera.com 


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Changes/Rationale: The intrapatient dose-escalation provisions and duration of study drug 
administration instructions were altered to maximize the potential for clinical benefit in 
individual subjects who proved to be tolerating therapy at a lower dose level and might safely 
benefit from a dose-escalation. 
subjects must have tolerated therapy with 
-level 
adjustments were permitted, the dose was limited t
there is experience in a prior Phase 1 study of LAM-
the investigator and the medical monitor must have agreed that the dose escalation was 
medically appropriate, and additional safety and other monitoring was mandated.
6.2.4 Starting Dose Levels and Dose Escalation, Bullet Point
Intrasubject dose escalation above the initially assigned dose level will be permitted will not 
be permitted except as defined in Section 6.2.7 below. 
Section 6.2.7 Dose Modification Recommendations, Paragraph 4 
Individual subjects may have the LAM-003 dose escalated to the next higher dose level after 
1 cycle of therapy if both the principal investigator and the medical monitor agree that the 
subject is tolerating the current dose level 
 and that a dose 
escalation is medically warranted to try to obtain better disease control (eg, for a subject who has 
not shown an improvement in AML disease burden by the end of the cycle). In such subjects, 
successive adjustments to progressively higher dose levels can be mad
 weeks 
with the caveat that the escalated dose cannot exceed 750 mg QD (highest plan dose level) or the 
established MTD (if lower). As directed by the medical monitor, certain safety and other studies 
(eg, serum chemistry, hematology, ECG, ophthalmology, pharmacokinetic, and 
pharmacodynamic evaluations) may be repeated at the higher dose level per the Cycle 1 schedule 
for these tests.
Individual subjects who initiate treatment at a dose level below the dose currently under study or 
the established MTD (if lower) may have the LAM-003 dose escalated to the next higher dose 
level after 2 cycles of therapy if both the principal investigator and the medical monitor agree 
that the subject is tolerating the current dose level 
 and that a dose 
escalation is medically warranted (eg, for a subject with a PR). In such subjects, successive 
 weeks with the 
caveat that the escalated dose cannot exceed the dose level currently under study or the 
established MTD (if lower). If considered necessary by the medical monitor, certain safety and 
other studies (eg, serum chemistry, hematology, ECG, pharmacokinetic, and pharmacodynamic 
evaluations) may be repeated at the higher dose level per the Cycle 1 schedule for these tests.  
6.2.5 Duration of Study Drug Administration and Study Participation 
Subjects may receive LAM-003 therapy indefinitely. However, the occurrence of any of the 
following events requires treatment discontinuation: 
 Subject request to withdraw from study treatment  
 Documented objective evidence of treatment failure or of AML relapse or progression (see 
Section 10.4.5 and Section 10.4.6 for definitions) while receiving study treatment at the 
highest individually tolerated dose level 
 For a subject in PR, continued red blood cell transfusion dependence at Week 20 


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 Intolerable toxicity despite appropriate supportive care and/or dose modification 
 Failure to recover to Grade 
baseline within 2 weeks from the last dose of LAM-003 
following interruption for a TEAE that is not primarily related to the underlying malignancy, 
a comorbid condition, an intercurrent illness, or a concomitant medication 
 The development of intercurrent illness or other substantial change in the subject’s condition 
or circumstances that would place the subject at unacceptable risk as determined by the study 
investigator in consultation with the medical monitor 
 Initiation of treatment for the subject’s cancer with an off-study therapeutic regimen 
 Pregnancy or breastfeeding 
 Substantial noncompliance with study drug administration, study procedures, or study 
requirements in circumstances that increase risk or substantially compromise the 
interpretation of study results 
 Discontinuation of the study by the study center, the study sponsor, relevant regulatory 
agencies, or the IRB/IEC 
Unless they withdraw consent for further follow-up, subjects who discontinue study therapy will 
continue on study for acquisition of safety 
e last dose of 
study treatment, and for further collection of information regarding additional therapies for their 
cancer and OS. 

SAP_001.pdf: 
Statistical Analysis Plan
AI Therapeutics, Inc.
Study: LAM-003-HEM-CLN02
Ce3, Inc.
CONFIDENTIAL
Page 1 of 28
Version 1 (21 August 2020)
STATISTICAL ANALYSIS PLAN
Protocol Title
A Phase 1 Dose-Escalation Study of LAM-003 in Patients with 
Acute Myeloid Leukemia
Investigational Product
LAM-003
Protocol Number/Version
LAM-003-HEM-CLN02, Version 8 (4 November 2019)
Study Sponsor 
AI Therapeutics, Inc.
530 Old Whitfield Street
Guilford, CT 06437
Biometric Service 
Provider
Ce3, Inc.
6 Post Office Square
Clinton, CT 06413
Statistical Analysis Plan 
(SAP) Version
Version 1 (21 August 2020)
Confidentiality Statement
This document is the property of AI Therapeutics, Inc and Ce3, Inc. This document and all information 
contained herein are to be considered and treated as strictly confidential. This document shall be used 
only for the purpose of the disclosure herein provided. No disclosure or publication shall be made 
without the prior written consent of AI Therapeutics, Inc. and Ce3, Inc.


Statistical Analysis Plan 
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DOCUMENT HISTORY 
Protocol Title: 
A Phase 1 Dose-Escalation Study of LAM-003 in Patients with Acute 
Myeloid Leukemia 
Protocol Number 
LAM-003-HEM-CLN02 
 
SAP Version Number 
Version Date 
Description of Changes 
1.0
21 August 2020 
 
Not applicable 
 


Statistical Analysis Plan 
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TABLE OF CONTENTS 
STATISTICAL ANALYSIS PLAN ................................................................................................1
REVIEW AND APPROVAL ..........................................................................................................2
DOCUMENT HISTORY .................................................................................................................3
TABLE OF CONTENTS .................................................................................................................4
LIST OF IN-TEXT TABLES..........................................................................................................6
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ..................................................7
1.
INTRODUCTION ........................................................................................................9
1.1.
Purpose and Scope of this Document...........................................................................9
1.2.
Study Design .................................................................................................................9
1.3.
Study Objectives.........................................................................................................10
1.3.1. 
Primary Objective .......................................................................................................10
1.3.2. 
Secondary Objectives .................................................................................................10
1.3.3. 
Exploratory Objectives ...............................................................................................10
1.4.
Study Endpoints ..........................................................................................................11
1.4.1. 
Primary Endpoints ......................................................................................................11
1.4.2. 
Secondary Endpoints ..................................................................................................11
1.4.3. 
Exploratory Endpoints ................................................................................................12
1.5.
Sample Size Justification............................................................................................13
1.6.
Timing of Analyses .....................................................................................................13
1.6.1. 
Interim Analyses.........................................................................................................13
1.6.2. 
Final Analyses ............................................................................................................13
1.6.3. 
Follow-up Analysis .....................................................................................................14
2.
ANALYSIS CONVENTIONS ...................................................................................14
2.1.
Analysis Sets ...............................................................................................................14
2.1.1. 
Full Analysis Set .........................................................................................................14
2.1.2. 
Responding Analysis Set............................................................................................14
2.1.3. 
Evaluable Analysis Sets ..............................................................................................14
2.2.
Data Handling Conventions ........................................................................................14
3.
ANALYSIS PLAN .....................................................................................................15
3.1.
Subject Disposition and Baseline Characteristics.......................................................15
3.1.1. 
Disposition..................................................................................................................15


Statistical Analysis Plan 
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3.1.2. 
Demography and Baseline Characteristics .................................................................15
3.2.
Protocol Deviations ....................................................................................................16
3.3.
Study Drug Exposure and Concomitant Medications ................................................16
3.3.1. 
Study Drug Administration and Compliance .............................................................17
3.3.2. 
Prior and Concomitant Medications ...........................................................................18
3.4.
Safety..........................................................................................................................19
3.4.1. 
Adverse Events ...........................................................................................................19
3.4.2. 
Laboratory Data ..........................................................................................................21
3.4.3. 
Vital Signs and Oxygen Saturation.............................................................................22
3.4.4.
Electrocardiography....................................................................................................22
3.4.5. 
Body Height, Body Weight, and Performance Status ................................................24
3.4.6. 
Other Clinical Variables Relating to Safety ...............................................................24
3.5.
Pharmacodynamics .....................................................................................................25
3.6.
Pharmacokinetics ........................................................................................................25
3.7.
Efficacy .......................................................................................................................25
3.7.1. 
Categorical Tumor Assessment Variables ..................................................................25
3.7.2. 
Time-to-Event Tumor Control and Survival Endpoints .............................................26
4.
REFERENCES ...........................................................................................................28
5.
TABLES, FIGURES, AND LISTINGS.....................................................................28
 


Statistical Analysis Plan 
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LIST OF IN-TEXT TABLES 
Table 1:
LAM-003 Starting Dose Levels..................................................................................10
Table 2: 
Statistical Basis for 3 + 3 Dose-Escalation Paradigm ................................................13
Table 3: 
Censoring Rules for Time-to-Event Endpoints ..........................................................27
 


Statistical Analysis Plan 
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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
Abbreviation 
Definition 
AE 
adverse event 
AESI
adverse event of special interest
AMA 
American Medical Association  
AML 
acute myeloid leukemia 
ANC 
Absolute neutrophil count 
ATC
Anatomical-Therapeutic-Chemical (drug coding system)
AUC 
area under curve 
BMI 
body mass index 
BOR 
best overall response 
C1/F 
apparent clearance 
CI 
confidence interval 
Cmax  
maximum concentration 
CR 
complete remission 
CRc 
composite complete remission 
CRi 
complete remission with incomplete blood count recovery 
CRMRD- 
complete remission without minimal residual disease 
CSR 
clinical study report 
CT 
computed tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
DLT 
dose-limiting toxicity 
DOR 
duration of remission 
DRP 
disease recurrence or progression 
ECG 
electrocardiogram, electrocardiographic 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
electronic case report form 
EFS 
event-free survival 
FAS 
full analysis set 
FDA 
Food and Drug Administration 
FLT3 
FMS-like tyrosine kinase-3 
HSP90 
heat shock protein-90 
ICH 
International Conference on Harmonization 
ITD 
internal tandem duplications 
MedDRA 
Medical Dictionary for Regulatory Activities 


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Abbreviation 
Definition 
MTD 
maximum tolerated dose 
NCI 
 
National Cancer Institute 
NE 
nonevaluable 
NGS 
next-generation sequencing 
NK 
natural killer (cell) 
OR 
objective remission 
ORR 
overall remission rate 
OS 
overall survival 
PCR 
polymerase chain reaction 
PD-L1 
programmed death ligand 1 
PR 
partial remission 
PT 
preferred term 
QD 
once per day 
QTc 
cardiac QT interval corrected for heart rate 
QTcF 
cardiac QT interval corrected for heart rate using Fridericia formula 
RDR 
recommended dosing regimen  
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SAS 
Statistical Analysis System (software) 
SOC 
(MedDRA) System Organ Class 
t½  
half-life 
TEAE 
treatment-emergent adverse event 
TF
treatment failure
tmax
time of maximum concentration
TTR 
time to remission 
Vd 
volume of distribution 
WHODRUG 
World Health Organization Drug Dictionary 
z  
terminal elimination rate constant  
 


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1. 
INTRODUCTION 
1.1. 
Purpose and Scope of this Document 
As per International Conference on Harmonization (ICH) E9 guidelines [FDA 1998] the purpose 
of this statistical analysis plan (SAP) is to provide a more technical and detailed elaboration of 
the principal features of the analysis described in the protocol document for 
Study LAM-003-HEM-CLN02 and to include detailed procedures for executing the statistical 
analysis of the study endpoints and other collected data.  
This SAP describes only the statistical summaries that are to be performed by Ce3, Inc. 
Statistical summaries to be provided by AI Therapeutics, Inc., including summaries of 
pharmacokinetic and pharmacodynamic data, are not described in this document.  
This SAP is based on Version 8.0 of the clinical trial protocol (dated 4 November 2019) and on 
the version of the electronic case report forms (eCRFs) current as of the date of this version of 
the SAP. If there are additional amendments to the protocol or eCRFs, this SAP will be updated, 
as appropriate.  
The results of the analyses described in this SAP will be included in the clinical study report 
(CSR). Any post-hoc or unplanned analyses performed to provide results for inclusion in 
publications or other reports but not identified in this prospective SAP will be identified in the 
relevant documents. 
Activities related to the development, approval, and maintenance of the SAP, along with study 
analysis and reporting will be the responsibility of the assigned study team members. After 
completion of the cohort review and evaluation and sign-off of the final CSR, all applicable 
datasets, outputs, programs, and specification documents will be transferred to the study sponsor 
for archiving.
1.2. 
Study Design 
Based on the knowledge regarding the role of heat shock protein-90 (HSP90) in acute myeloid 
leukemia (AML), AI Therapeutics, Inc has developed LAM-003 as a clinical HSP90 inhibitor for 
patients with relapsed or refractory AML. The goal of development has been to offer a novel 
treatment approach that can circumvent drug resistance in patients who have experienced failure 
of other therapies. Ultimately, it is hoped that LAM-003 administered alone or in combination 
can supplement or complement current treatment methods. 
This clinical trial is a Phase 1 study evaluating the safety, pharmacokinetics, pharmacodynamics, 
and antitumor activity of LAM-003 across a range of LAM-003 dose levels when administered 
to subjects with previously treated relapsed or refractory AML. Subjects self-administer oral 
LAM-003 once per day (QD) continuously in repeated 28-day cycles. Cohorts of 3 to 6 subjects 
are sequentially enrolled at progressively higher starting dose levels of LAM-003 using a 
standard 3 + 3 design, as indicated in Table 1. The initial cohort of subjects is prescribed 
LAM-003 at Dose Level 1 (200 mg). Dose Levels -1 (100 mg) and -2 (50 mg) are provided to 
permit dose decrements if a subject experiences a treatment-emergent adverse event (TEAE) 
requiring dose modifications to levels below Dose Level 1. 


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Table 1:
LAM-003 Starting Dose Levels
Dose Level 
LAM-003 
Dosing Regimen 
Dose Change  
Relative to Prior Dose 
-2 
50 QD 
0.50 
-1 
100 QD 
0.50 
1 (initial dose level) 
200 QD 
Not applicable 
2 
300 QD 
1.50 
3 
450 QD 
1.50 
4 
600 QD 
1.33 
5 
750 QD 
1.25 
Abbreviation: QD=once per day
Individual subjects who are tolerating the current dose level with no toxicities of Grade 
2 have 
had the LAM-003 dose escalated to the next higher dose level after 1 cycle of therapy. In such 
subjects, successive adjustments to progressively higher dose levels are allowed at intervals of 
4 weeks with the caveat that the escalated dose cannot exceed 750 mg QD (highest plan dose 
level) or the established maximum tolerated dose (MTD) (if lower). 
Based on the pattern of dose-limiting toxicities (DLTs) observed in Cycle 1, escalations proceed 
to define the MTD and a recommended dosing regimen (RDR) that could be at the MTD or a 
lower dose within the overall tolerable dose range. 
1.3. 
Study Objectives 
1.3.1. 
Primary Objective 
 To determine the MTD and/or RDR of LAM-003 
1.3.2. 
Secondary Objectives 
To characterize the drug administration, safety, and supportive care profiles of LAM-003
 To evaluate the pharmacokinetic profile of LAM-003 
 To characterize the onset, magnitude, and duration of antitumor activity and to assess 
survival in subjects with AML receiving LAM-003 
1.3.3.
Exploratory Objectives
 To assess the effects of LAM-003 on pharmacodynamic markers relating to drug mechanism, 
disease, and immune status
 To explore associations between baseline AML characteristics and outcomes in subjects 
administered LAM-003


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1.4. 
Study Endpoints 
1.4.1. 
Primary Endpoints 
 MTD and/or RDR within the tested LAM-003 dose range 
1.4.2. 
Secondary Endpoints 
1.4.2.1. 
Drug Administration, Safety, and Supportive Care Profiles 
 LAM-003 drug administration as assessed by prescribing records and subject compliance 
records 
 Type, frequency, severity, timing of onset, duration, and relationship to study drug of any 
TEAEs; laboratory abnormalities; vital sign/oxygen saturation abnormalities; adverse 
electrocardiogram (ECG) findings; DLTs; serious adverse events (SAEs); adverse events of 
special interest (AESIs); or adverse events (AEs) leading to interruption, modification, or 
discontinuation of study treatment (referencing the Common Terminology Criteria for 
Adverse Events [CTCAE], Version 4.03, for grading of the severity of AEs and laboratory 
abnormalities) [NCI 2010]. 
 Type, frequency, and timing of use of supportive care and other concomitant medications 
1.4.2.2. 
Pharmacokinetics 
 LAM-003 and LAM-003A plasma concentrations (as measured using a validated 
bioanalytical assay) 
Derived LAM-003 and LAM-003A pharmacokinetic parameters (including area under the 
concentration-time curve [AUC], maximum concentration [Cmax], time of maximum 
concentration [tmax], volume of distribution [Vd], half-life [t1/2], terminal elimination rate 
z], and apparent clearance [Cl/F]) (as determined using noncompartmental
methods) 
1.4.2.3. 
Antitumor Activity and Survival 
Efficacy will be evaluated using standard response and progression criteria as adapted for use in 
the context of protocol therapy for relapsed or refractory AML. Efficacy endpoints will include: 
 Complete remission without minimal residual disease (CRMRD-), defined as complete 
remission (see definition below) with no evidence of AML by flow cytometry 
 Complete remission (CR), defined as < 5% bone marrow blasts; no blasts in the peripheral 
blood; no blasts with Auer rods; no extramedullary disease; and peripheral blood meeting 
both of the following criteria:  Absolute neutrophil count (ANC)  1.0 × 109/L and platelet 
count 100 × 109/L 
 Complete remission with incomplete count recovery (CRi), defined as < 5% bone marrow 
blasts; no blasts in the peripheral blood; no blasts with Auer rods; no extramedullary disease; 
but with peripheral blood meeting either of the following criteria; ANC < 1.0 × 109/L or 
platelet count < 100 × 109/L 


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 Composite complete remission (CRc), defined as CRMRD-, CR, or Cri
 Partial remission (PR), defined as leukemia disease status meeting all of the following 
requirements: a 
50% decrease in bone marrow blasts to 5% to 25% or < 5% bone marrow 
blasts but with Auer rods present; no blasts in the peripheral blood; no new or worsening 
extramedullary disease; and peripheral blood meeting both of the following criteria: ANC 
1.0 × 109/L and platelet count 
100 × 109/L 
 Overall remission (OR), defined as achievement of any of CR, CRi, or PR 
Time to remission (TTR), defined as the interval from the start of study therapy to the first 
documentation of an objective remission
Duration of remission (DOR), defined as the interval from the first documentation of 
objective remission to the earliest of the first documentation of disease relapse, disease 
progression, or death from any cause
Event-free survival (EFS), defined as the interval from the start of study therapy to the 
earliest of the first documentation of disease relapse, disease progression, treatment failure, 
or death from any cause 
 Overall survival (OS), defined as the interval from the start of study therapy to death from 
any cause 
1.4.3. 
Exploratory Endpoints 
1.4.3.1. 
Pharmacodynamics 
 Changes in FMS-like tyrosine kinase-3 (FLT3) and HSP (eg, HSP90, HSP70) protein 
expression and activation of downstream pathway components in AML blasts (as measured 
using flow cytometry and/or protein immunoblotting) 
 Changes in HSP gene expression in AML blasts (as measured using quantitative polymerase 
chain reaction [PCR]) 
 Changes in plasma FLT3 ligand concentration (as measured using an immunoassay) 
 Changes in programmed death ligand 1 (PD-L1) expression in AML blasts (as measured 
using flow cytometry) 
 Changes in the numbers, cell surface markers, and function of circulating B-cell, T-cell, 
natural killer (NK) cell, monocyte, and other immune subsets (as measured using flow 
cytometry) 
1.4.3.2. 
Biomarkers 
 Baseline AML blast FLT3 mutation type and FLT3 mutation-to-wild-type allele ratio (as 
evaluated using the LeukoStrat® CDx FLT3 mutation assay) 
 Baseline mutational profile in AML blasts (with germ-line control in saliva) (as assessed with 
next-generation sequencing [NGS]) 


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1.5. 
Sample Size Justification 
Cohort sample sizes for this study are not based on a specific statistical hypothesis but on 
experience in the conduct of similar types of Phase 1 dose-ranging studies in subjects with 
cancer. The total number of subjects will depend upon the numbers of subjects accrued to each 
dose level and the number of dose levels evaluated.  
Cohort sizes of 3 to 6 subjects allow evaluation of regimen safety using a standard method to 
determine MTD (ie, the hig
 6 subjects have been treated and 
which is associated with a DLT in  17% of subjects during the first cycle of therapy). Based on 
the planned 3 + 3 dose-escalation scheme, Table 2 shows the probability of escalating to the next 
dose level based on the true rate of DLT at the current dose level. 
Table 2: 
Statistical Basis for 3 + 3 Dose-Escalation Paradigm 
True Incidence of DLT 
Probability of Escalating 
10%
0.91
20% 
0.71 
30% 
0.49 
40% 
0.31 
50% 
0.17 
60% 
0.08 
 Abbreviation: DLT=dose-limiting toxicity
Thus, if the true underlying proportion of DLT is low (eg, 
10% at the current dose level, there 
is a high probability ( 0.91) of dose escalation to the next dose level. Conversely, if the true 
underlying proportion of DLT is high (eg, 
60%) at the current dose level, there is a low 
probability ( 0.08) of escalation to the next dose level.  
1.6. 
Timing of Analyses 
1.6.1. 
Interim Analyses 
No formal interim analyses are planned.  As described in Section 2.2 of the study protocol, 
conference calls among the members of the safety review committee will be conducted 
periodically to discuss study progress, exchange study information,  review safety events, 
determine whether additional dose levels should be evaluated, and discuss potential amendments 
to the protocol. It is expected that these discussions will be scheduled at intervals of ~2 to 
4 weeks unless accrual to the study and decisions regarding study conduct or transitions between 
the dosing cohorts indicate the need for an alternative schedule of reviews. As needed for 
scientific or business reasons, AI Therapeutics, Inc.  may collate and summarize available study 
results during conduct of the study. 
1.6.2. 
Final Analyses 
Final study reporting is expected to occur after all subjects have discontinued study treatment or 
 48 weeks after accrual of the final subjects (whichever occurs earlier). 


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1.6.3. 
Follow-up Analysis 
After the final analyses, additional supplemental analyses may be performed to assess long-term 
outcomes and to satisfy regulatory requirements. 
2.
ANALYSIS CONVENTIONS
2.1. 
Analysis Sets 
The analysis of clinical data will focus on the following analysis sets. 
2.1.1. 
Full Analysis Set
The full analysis set includes all subjects who receive 
1 dose of study drug. This analysis set 
will be used in the analyses of subject characteristics, study drug administration and compliance, 
safety, OR, CRc, CRMRD-, CR, CRi, PR, EFS, and OS. 
2.1.2. 
Responding Analysis Set
The responding analysis set includes subjects in the full analysis set who have measurable 
disease, who can be evaluated for tumor response with both baseline and on-study tumor 
evaluations, and who achieve a CRMRD-, CR, CRi, or PR. This analysis set will be used in the 
analyses of TTR and DOR. 
2.1.3. 
Evaluable Analysis Sets 
The evaluable analysis sets include subjects in the full analysis set who have the necessary 
baseline and on-study measurements to provide interpretable results for specific parameters of 
interest. These analysis sets will be used in the analyses of pharmacokinetic, pharmacodynamic, 
and biomarker parameters. 
2.2. 
Data Handling Conventions 
Analyses will be performed using SAS® Version 9.3 or higher (SAS Institute, Cary, NC, USA).
The clinical database will be locked prior to the initiation of the statistical analyses. A database 
lock is defined as a stable database that can be analyzed and reported. Changes to a locked 
database must be authorized in writing by the study sponsor and Ce3 according to Ce3 standard 
operating procedures. 
The data conventions include the following: 
 Data will be described and summarized by starting dose level. 
 Summary tables for continuous variables will contain the following statistics: N (number of 
subjects in the population); n (number of subjects with data); mean; standard deviation; 
median; minimum; and maximum. Selected statistics may also include a 2-sided 95% normal 
approximation confidence intervals (CIs) on the mean. 
 Summary tables for categorical variables will include: N (number of subjects in the 
denominator); n (number of subjects in the numerator); and percent. Selected statistics also 
may include 2-sided 95% CIs for the percent.  


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 The baseline value for a given parameter is the last value prior to the first dose. A value is 
post-baseline if it is obtained after the first dose. A value is considered to be post dose on a 
given cycle day if it is obtained after the dose is administered on that day. 
 Data from all study centers will be pooled for all analyses.  
 Unless otherwise specified, statistical testing will be 2-sided at a nominal 0.05 level of 
significance. 
 Study day is defined as calendar date – date of first treatment + 1 if the calendar date is on or 
after the date of first treatment, and calendar date – date of first treatment if the calendar date 
is before the date of first treatment 
 Measurements from unscheduled visits will be included in listings but not in summary tables.
 Missing data conventions for individual endpoints are described in the SAP section for the 
endpoint.
 Additional exploratory analyses may be performed as deemed appropriate after review of the 
pre-specified analyses. Log transformations or nonparametric tests may be applied to 
measurements displaying a significant degree of non-normality. 
 Listings will be provided of all data collected in the eCRFs. 
3. 
ANALYSIS PLAN 
3.1. 
Subject Disposition and Baseline Characteristics 
3.1.1. 
Disposition
The number of subjects in each of the following subsets will be presented by cohort and overall.  
 Full analysis set 
 Responding analysis set 
Discontinued study treatment (overall and by reason)
Discontinued study (overall and by reason)
Follow-up status
A listing of full analysis set subjects will be provided that includes starting dose level, study 
center, subject number, consent date, first treatment date, duration of study treatment, and reason 
for treatment discontinuation
The number and percent of full analysis subjects by starting dose level will be summarized. 
3.1.2.
Demography and Baseline Characteristics
Baseline characteristics will be listed and will be summarized for the full analysis set as follows: 
 Demographics (age, sex, race, and ethnicity) and physical characteristics (weight in kg, 
height in cm, and body mass index [BMI] in kg/m2) 


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 Number and percent of subjects by baseline Eastern Cooperative Oncology Group (ECOG) 
performance status 
 Number and percent of subjects having Medical Dictionary for Regulatory Activities 
(MedDRA) coded medical history conditions by System Organ Class (SOC) and Preferred 
Term (PT). 
 Years from date of diagnosis for primary disease to Day 1 of protocol therapy 
 Number of regimens of prior systemic therapy for cancer 
 Time from completion of last prior regimen of systemic therapy for cancer to Day 1 of 
protocol therapy 
 Number of episodes of prior radiation for cancer 
 Number of prior transfusions 
 Number of prior transplants  
 FLT3 allelic ratio 
 Internal tandem duplication (ITD) insertion length 
 Peripheral AML blast count 
 Peripheral AML blast percentage 
 Peripheral blood white blood count 
 Peripheral blood ANC 
 Peripheral blood platelet count 
 Peripheral blood hemoglobin 
 Bone marrow aspirate blast percentage by morphology/immunohistochemistry 
 Bone marrow aspirate blast percentage by flow cytometry  
 Baseline TLS risk status 
3.2. 
Protocol Deviations 
Details of protocol deviations will be provided in a listing.  
3.3. 
Study Drug Exposure and Concomitant Medications 
The analysis population for study drug exposure and concomitant medications is the full analysis 
set.   
Concomitant medications other than cancer treatment will be summarized by starting dose level 
and by World Health Organization Drug Dictionary (WHODRUG) Anatomical-Therapeutic-
Chemical (ATC3) Term and Preferred Drug Name (ATC2 Term will be used for any 
investigational medications or medications not having ATC3).   
Data regarding LAM-003 administration is to be categorized by starting dosing level.  


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The LAM-003 Dosing Log eCRF records actual dose administration from Cycle 1 Day 1 through 
to the last day of LAM-003 administration, including all dose modifications (increases, 
reductions, delays, or interruptions) and reasons for modification.  
The actual length of Cycle n may be calculated as follows from the dates recorded on the visit 
eCRF. 
 
 
 =
 
 
 
 
 +  1 
where the End Date of Cycle is the last date of drug administration in that cycle if no subsequent 
cycle is administered, or is the last date before the start date of the next cycle if a subsequent 
cycle is administered. 
3.3.1. 
Study Drug Administration and Compliance 
The following summaries of treatment cycles will be provided: 
 Number and percent of subjects by number of cycles administered, where a cycle is 
con
 1 dose is received during the cycle 
 Number and percent of subjects by number of completed cycles, where a cycle is considered 
to be completed if either (a) dosing has begun in the following cycle, or (b) the subject has 
completed the end-of-treatment visit. 
 Number and percent of subjects by number of prolonged cycles, where a cycle is considered 
to be prolonged if the cycle is > 28 days in duration. 
 Prescribed and actual dosing will be summarized by descriptive statistics for the following: 
 Number of doses prescribed (defined as the number of cycles started × 28) 
 Number of doses of actual treatment (defined as the total number of doses actually 
administered by the clinic staff and self-administered by the subject) 
 Dose modifications and interruptions will be summarized as follows: 
 Number and percent of subjects having a dose interruption  
 Number and percent of subjects by reason for dose interruption  
 Descriptive statistics for the number of days to the first dose interruption (for subjects having 
a dose interruption) 
 Number and percent of subjects having a dose reduction 
 Number and percent of subjects by reason for dose reduction 
 Descriptive statistics for the number of days to the first dose reduction (for subjects having a 
dose reduction) 
 Number and percent of subjects having a dose increase
 Number and percent of subjects by reason for dose increase 
 Descriptive statistics for the number of days to the first dose increase (for subjects having a 
dose increase)


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The following definition will be used to calculate compliance rate for each subject. 
 
= 100
 
 
 
 
 
  
 
 
 
 
 
 
 
 
  
 
 
 
 
 
, 
Where: 
=
+ 1.
Descriptive statistics for the compliance rate will be provided. 
Study drug administration data will be listed. 
3.3.2. 
Prior and Concomitant Medications 
Medication use and other therapies are collected on 6 eCRFs: 
 Prior Anti-Cancer Therapy 
 Prior and Concomitant Medications 
 Prior Radiation Therapy 
 Non-Drug Treatments/Procedures 
 Prior Therapy Transplants 
Prior Transfusion History
Medications collected on the Prior Anti-Cancer Therapy and Prior and Concomitant Medications 
eCRFs will be coded by means of the World Health Organization Drug Dictionary (WHODrug) 
to WHODrug preferred drug name. 
Prior anti-cancer therapies will be summarized by descriptive statistics for the number of prior 
regimens per subject, best response, duration of treatment, type of therapy, and the time in years 
from the end of the last therapy to date of the first dose of LAM-003. The Prior Anti-Cancer 
Therapy eCRF also will be summarized by a listing containing the verbatim medication term, 
WHODrug preferred drug name, therapy start and end dates, study drug start date, duration of 
therapy, type of therapy, and best overall response (BOR).  
Prior radiation therapy will be summarized by number of treatments per subject. 
Data from the, Prior Radiation Therapy, Non-Drug Treatments/Procedures, Prior Therapy 
Transplants, and Prior Transfusion eCRFs will be listed. The Non-Drug Treatment Procedures 
listing will also include the MedDRA SOC and PT terms. 
Medications collected on the Prior and Concomitant Medications eCRF will be presented as a 
listing containing the verbatim medication term, WHODrug preferred drug name, start and end 
dates and study days, indication, duration of therapy, and flags to indicate if the medication was 
prior, concomitant, or both. The following conventions will be used: 
 Prior medications are medications having a start date prior to the date of the first dose of 
study drug.  
 Concomitant medications are medications having a start on or after the date of the first dose 
of study drug.  


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 A medication can be both prior and concomitant. 
Additional descriptions of supportive care (eg, anti-diarrheal drug administration) may be 
provided as deemed appropriate after review of the concomitant medication data. 
3.4. 
Safety  
The analysis population for safety is the full analysis set. 
3.4.1. 
Adverse Events 
AEs are recorded by the site in the eCRFs. AEs will be summarized and listed.
AEs will be classified using MedDRA with descriptions by SOC and PT. The severity of AEs 
will be graded by the investigator according to the CTCAE, Version 4.03, whenever possible. If 
a CTCAE criterion does not exist for a specific type of AE, the grade corresponding to the 
appropriate adjective will be used by the investigator to describe the maximum intensity of the 
AE: Grade 1 (mild), Grade 2 (moderate), Grade 3 (severe), Grade 4 (life threatening), or Grade 5 
(fatal). The eCRFs also identify the following characteristics of each AE: 
 The start date and end dates of the AE 
 The outcome of the AE (Fatal, Not Recovered or Not Resolved, Recovered or Resolved, 
Recovered or Resolved with Sequelae, Unknown) 
 The relationship of the AE to study treatment (Related or Unrelated)
 The action taken regarding the study treatment (Dose Not Changed, Dose Reduced, Drug 
Interrupted, Drug Withdrawn, Dose Increased, Not Applicable, Unknown)
 Whether the AE was a DLT (as defined in Section 6.2.5 of the study protocol) 
 Whether the AE was an SAE (as defined in Section 8.1.2 of the study protocol)  
 Whether the AE was an AESI  (as defined in Section 8.1.5 of the study protocol) 
All DLTs, including those defined by laboratory toxicity grades, are to be recorded as AEs. 
Verbatim AE terms will be coded into MedDRA SOC and PT (using MedDRA Version 19 or 
higher). 
TEAEs are defined as AEs having a start date on or after the date of the first dose of study drug. 
The focus of AE summarization will be on TEAEs. AEs that occur before the first dose of study 
drug administration or > 30 days after the final study drug administration will be included in data 
listings.   
An overview summary will be provided of the number and percent of subjects in each of the 
following categories: 
1 AE; 
1 TEAE; 
1 TEAE of Grade 
3; 
1 study-drug-related TEAE; 
1 study-drug-related TEAE of Grade 
3; 
1 SAE; 
1 treatment-emergent SAE; 
1 
study-drug-related treatment-emergent SAE; 1 AE leading to study drug withdrawal; 
1 AE 
leading to study drug interruption or reduction; and 1 AE leading to death. 
The following summaries of AEs will be provided by starting dose and overall: 
 TEAEs by SOC and PT  


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 Study-drug-related TEAEs by SOC and PT 
 Cycle 1 DLTs by SOC and PT 
 TEAEs leading to study drug interruption by SOC and PT  
TEAEs leading to study drug reduction and/or dose modification by SOC and PT
TEAEs leading to study drug discontinuation by SOC and PT
Treatment-emergent SAEs by SOC and PT
 Treatment-emergent AESIs by SOC and PT
 TEAEs that are Grade 3, 4, or 5 in severity 
SOCs and PT in summaries will be displayed in order of decreasing total frequency of AEs. 
Summaries by SOC and PT will count subjects at most once for each SOC/PT. Summaries by 
SOC, PT, and severity grade at most once for each SOC/PT at the highest severity experienced. 
Listings of all AEs, SAEs, AESIs, AEs that led to study drug discontinuation, and AEs leading to 
death will be provided. Separate listings and summaries will be prepared for long-term follow-up 
safety data.   
Hematologic abnormalities reported as AEs that were coded to preferred terms in the Blood and 
Lymphatic Systems Disorders SOC have been mapped to the appropriate laboratory preferred 
term in the Investigations SOC for summary counts in relevant tables and listings, including the 
following:  
 Thrombocytopenia = Platelet count decreased 
 Neutropenia = Neutrophil count decreased 
 Leukopenia = White blood cell count decreased 
 Lymphopenia = Lymphocyte count decreased 
 Anemia = Hemoglobin decreased 
Any additional terms added to this list will be noted in the CSR.   
Abnormalities reported as AEs that were coded to preferred terms in the Metabolism and 
nutrition disorders SOC have been mapped to the appropriate laboratory preferred term in the 
Investigations SOC for summary counts in relevant tables and listings, including the following: 
 Hyperglycaemia = Blood glucose increased 
 Hypernatraemia = Blood sodium increased 
 Hyperphosphataemia = Blood phosphorus increased 
 Hyperuricaemia = Blood uric acid increased 
 Hypoalbuminaemia = Blood albumin decreased 
 Hypocalcaemia = Blood calcium decreased 
 Hypogammaglobulinaemia = Immunoglobulins decreased 


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 Hypoglycaemia = Blood glucose decreased 
 Hypokalaemia = Blood potassium decreased 
 Hyponatraemia = Blood sodium decreased
Any additional terms added to this list will be noted in the CSR. 
3.4.2. 
Laboratory Data 
Laboratory results are recorded by the site in the eCRFs. Laboratory results will be summarized 
and listed. 
All laboratory data will be reported using conventional units. Severity grades will be 
programmatically calculated using standard American Medical Association’s (AMA) laboratory 
normal ranges [AMA 2020] and the quantitative NCI CTCAE 4.03 criteria (when available for a 
specific laboratory abnormality). Laboratory values considered to be normal by CTCAE criteria, 
meaning they do not qualify as Grade 1 - 4, will be assigned a severity grade of 0. For laboratory 
tests without any CTCAE criteria, toxicity grades will be recorded as 99. For parameters for 
which a CTCAE scale does not exist, reference ranges from the laboratory will be used to 
determine programmatically if a laboratory parameter is below, within, or above the normal 
range for the subject’s age, sex, etc. 
The focus of laboratory data summarization will be on treatment-emergent laboratory 
abnormalities. A treatment-emergent laboratory abnormality is defined as an abnormality that 
occurs or continues in the period from the first study drug administration to 30 days after the last 
study drug administration. Any post-baseline abnormality (ie, an abnormality that is Grade 
1 in 
severity) will be considered treatment-emergent. Laboratory abnormalities that occur before the 
administration of study drug or > 30 days after the final administration of study drug will be 
included in data listings but not in summary tables.  
The incidence of CTCAE treatment-emergent laboratory abnormalities will be summarized by 
laboratory category (eg, hematology, chemistry), laboratory parameter, and CTCAE severity 
grade, when applicable. The summary will present the number and percent of subjects in each 
category. Subjects will be characterized only once for a given study or parameter, based on the 
worst post-baseline severity grade observed. For parameters for which a CTCAE scale does not 
exist, the incidence of treatment-emergent laboratory abnormalities will be summarized by 
laboratory category (eg, hematology, chemistry), laboratory parameter, and number going from 
normal to high, and those going from normal to low. 
Hematological and serum biochemistry data will be summarized in tables and may be 
summarized in figures showing values over time, if informative. Summary tables will be 
presented for each relevant assay to show the number of subjects by CTCAE severity grade with 
corresponding percentages. For parameters for which a CTCAE scale does not exist, the 
frequency of subjects with values below, within, and above the normal ranges will be 
summarized. Subjects will be characterized only once for a given assay, based on their worst 
severity grade observed during a period of interest (eg, during the study or during a cycle).  
Shift tables for hematology and serum biochemistry data will also be presented by showing 
change in CTCAE severity grade from baseline to each time point. For parameters for which a 


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CTCAE scale does not exist, shift tables will be presented showing change in results from 
baseline (normal, low and high [or abnormal]) to each time point (normal, low and high [or 
abnormal]). For selected variables of interest, tables may be prepared to show frequencies 
adjusted for baseline values; for these frequencies, subjects with the same or worse grade at 
baseline are not considered.  
All laboratory data will be displayed in listings. Values meeting CTCAE severity criteria, outside 
of normal ranges, or assessed as abnormal will be flagged in the listings. 
3.4.3. 
Vital Signs and Oxygen Saturation 
Vital signs are assessed at Screening, C1D1 (predose, and at 1, 2, 4, 6, and 8 hours postdose), 
C1D2 (24 hours postdose/predose for next drug administration), C1D3, C1D4, C1D5, C1D8 
(predose, and at 1, 2, 4, 6, and 8 hours postdose), and at End of Therapy. 
Vital sign data and oxygen saturation data are recorded by the site in the eCRFs. Vital sign data 
and oxygen saturation data will be listed. Blood pressure data will be specifically categorized in 
terms of systolic and diastolic blood pressures. Reference ranges will be used to determine 
programmatically if a vital sign is below, within, or above the normal range. Normal ranges for 
vital signs will be referenced as follows:  
 Systolic blood pressure (> 90 mm Hg and < 140 mm Hg),  
 Diastolic blood pressure (> 50 mm Hg and < 90 mm Hg)  
 Pulse ( 50 bpm and 
100 bpm)  
 Temperature (
37.5°C) 
 Oxygen saturation (> 92%) 
The listings will include the normal range categories described above. 
3.4.4. 
Electrocardiography 
ECGs will be collected at Screening, C1D1 (predose [in triplicate, at least 5 minutes apart], and 
at 1, 2, 4, 6, and 8 hours postdose), C1D2 (24 hours postdose/predose for next drug 
administration), C1D8 (predose, and at 1, 2, 4, 6, and 8 hours postdose), C2D1, and at End of 
Therapy. 
ECG data are recorded by the site in the eCRFs. ECG data will be summarized and listed. 
The following qualitative measurements are to be recorded for each ECG: 
 Overall Result (Normal/Abnormal) 
 If Abnormal, was the abnormal result clinically significant? (Yes/No) 
The Overall Result of Normal or Abnormal will be summarized by the following shift tables: 
 Predose and End-of-Treatment measurements: Shift from baseline to worst post-baseline 
result 
 Cycle 1 Day 1 measurements: Shift from Cycle 1 Day 1 predose result to worst postdose 
result  


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 Cycle 1 Day 8 measurements: Shift from Cycle 1 Day 8 predose result to worst postdose 
result  
Sites are also to record the following quantitative measurements for each ECG: 
 Heart Rate (bpm) 
 RR Interval (msec) 
 PR Interval (msec)
 QRS Duration (msec) 
QT Interval (msec)
The quantitative ECG parameters (Heart Rate, RR, PR, QRS, QT, and QTcF) will be 
summarized by descriptive statistics as follows: 
 Predose and End-of-Treatment measurements: observed and change from baseline values at 
each cycle day and at End of Treatment
 Cycle 1 Day 1 measurements: observed and change from Cycle 1 Day 1 predose values at 
each timepoint 
 Cycle 1 Day 8 measurements: observed and change from Cycle 1 Day 8 predose values at 
each timepoint  
If not recorded by the site, the QT with Fridericia correction (QTcF) will calculated from the 
recorded measurements using the following formula:
 QTcF = QT/(RR)1/3
If the RR Interval value is missing, but the Heart Rate value is present, then RR in the QTcF 
formula will be replaced by 60,000/Heart Rate. 
QTcF categories will be summarized as follows:
 Predose and End-of-Treatment measurements: QTcF interval category at each visit 
 Cycle 1 Day 1 measurements: QTcF interval category at each timepoint 
 Cycle 1 Day 8 measurements: QTcF interval category at each timepoint 
QTcF categories also will be summarized by shift tables as follows: 
 Predose and End-of-Treatment measurements: Shift from baseline QTcF category at each 
visit 
 Cycle 1 Day 1 measurements: Shift from Cycle 1 Day 1 predose QTcF category at each 
timepoint
Cycle 1 Day 8 measurements: Shift from Cycle 1 Day 8 predose QTcF category at each 
timepoint
These categorical changes in QTcF will be summarized as follows:
 Predose and End-of-Treatment measurements: QTcF change from baseline value at each 
cycle day and at End of Treatment


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 Cycle 1 Day 1 measurements: QTcF change from Cycle 1 Day 1 predose value at each 
timepoint 
 Cycle 1 Day 8 measurements: QTcF change from Cycle 1 Day 8 predose value at each 
timepoint 
The QTcF data will be categorized separately into the following classifications and summarized 
by time point:
 QTcF interval 
450 msec
 QTcF interval > 450 msec and 
480 msec (Grade 1)  
 QTcF interval > 480 msec and 
500 msec (Grade 2)  
 QTcF interval > 500 msec (Grade 3) 
The change of the QTcF values obtained by using the Fridericia correction will also be 
categorized separately as follows:  
 QTcF interval change from baseline by 
30 msec 
 QTcF interval increases from baseline by > 30 msec and 
60 msec  
 QTcF interval increases from baseline by > 60 msec  
QTcF data will be presented in shift tables consistent with these categories. 
3.4.5. 
Body Height, Body Weight, and Performance Status 
Body height, body weight, and ECOG performance status data are recorded by the site in the 
eCRFs. All body height, body weight, and ECOG performance status data will be presented in 
listings.  
3.4.6. 
Other Clinical Variables Relating to Safety 
3.4.6.1. 
Body Mass Index (BMI) 
The BMI in kg/m2 at baseline will be calculated using baseline body height and body weight 
data. Baseline BMI will be listed. 
3.4.6.2. 
Pregnancy Tests 
The results of pregnancy tests are recorded by the site in the eCRFs. The results of pregnancy 
test results at each visit will be listed. 
3.4.6.3. 
Serum Virology 
The baseline serum virology test results are recorded by the site in the eCRFs. These data will be 
listed.   
3.4.6.4. 
Ophthalmological Testing 
Ophthalmological results from testing performed by consulting ophthalmologists are recorded on 
study-specific worksheets. The data on these worksheets is recorded by the site in the eCRFs. 


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Results of eye exams will be listed for Visual Symptoms, Snellen Visual Acuity, Full Field 
Electroretinography, Multifocal Electroretinography, Tonometry, Optical Coherence 
Tomography, and Eye/Slit Lamp Exam.  
3.5. 
Pharmacodynamics 
Pharmacodynamic analyses will be performed by the study sponsor and are not described in this 
SAP. 
3.6. 
Pharmacokinetics 
Pharmacokinetic analyses will be performed by the study sponsor and are not described in this 
SAP. 
3.7.
Efficacy
Peripheral blood and bone marrow findings are the central bases for efficacy assessments in 
patients with AML. In support of efficacy assessments, peripheral blood hematology data are 
recorded by the sites in the eCRFs. In addition, peripheral blood and bone marrow samples are 
sent from the sites for processing and analysis at a central laboratory; data from the central 
laboratory are transferred electronically to Ce3, Inc.   
Listings will be provided for all efficacy data collected, including data collected for peripheral 
blood hematological and bone marrow used for tumor assessments. The following parameters 
will be listed for each subject and efficacy assessment time point:
 Peripheral AML blast count 
 Peripheral AML blast percentage 
 Peripheral blood white blood count
 Peripheral blood ANC 
 Peripheral blood platelet count 
 Peripheral blood hemoglobin 
 Bone marrow aspirate blast percentage by morphology/immunohistochemistry
 Bone marrow aspirate blast percentage by flow cytometry  
3.7.1. 
Categorical Tumor Assessment Variables 
For each tumor assessment, the sponsor medical monitor will categorize tumor response. In 
addition, for each subject, the medical monitor will determine the best overall response (BOR) 
considering the results across all tumor assessments. Based on the relevant criteria for AML
[Cheson 2003, Döhner 2017], the possible categories for each time point and for the BOR are:  
 Complete response (CR) 
 Complete remission without minimal residual disease (CRMRD-) 
 Complete response with incomplete count recovery (CRi) 


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 Partial response (PR) 
 Treatment failure (TF)
 Disease recurrence or progression (DRP) 
Nonevaluable (NE) 
Listings describing the by-time-point tumor assessment and BOR for each subject will be 
provided. 
The BOR assessment will be used to calculate an overall remission rate (ORR) and composite 
complete remission (CRc) rate for each starting dose cohort and overall. ORR and CRc rate have 
the following definitions: 
= 100
 
 
 
 
 
 
,
MRD-,
,
 
 
 
 
 
= 100
 
 
 
 
 
 
,
MRD-,
 
 
 
 
 
All subjects (including those with a BOR of NE) are included in the denominators in these 
calculations. For all analyses of response rates, the relevant CIs will be presented. 
3.7.2. 
Time-to-Event Tumor Control and Survival Endpoints 
The time-to-event endpoints measured in this study are defined in terms of the following dates, 
which will be listed for each subject: 
 Date of first LAM-003 dose as recorded on the LAM-003 Dosing Log eCRF 
 Date of first response (for subjects with a BOR of CR, CR MRD-, CRi, or PR)
 Date of first DRP 
 Date of first TF 
 Date of last non-DRP response assessment (with assessment of CR, CRMRD-, CRi, or PR)
 Date of first initiation of another therapy identified by sponsor as being an antitumor 
treatment administered concomitantly or after study treatment (not including hydroxyurea, 
cyclophosphamide, or cytarabine started at baseline or during Cycle 1 of study therapy)
 Date of death as recorded on the End of Study Page eCRF
 Date last known alive (for subjects not having a date of death) as recorded on the Post-
Treatment Survival eCRF, or date of last visit if date last known alive is missing 
The following time-to-event endpoints will be calculated for each subject and displayed in 
listings. 
 Time to response (TTR) = date of first response - date of first LAM-003 dose + 1 (TTR will 
only be calculated for subjects having a BOR of CR, CRMRD-, CRi, or PR) 
 Duration of response (DOR) = min (date of first DRP, date of death) – date of response + 1 
(DOR will only be calculated for subjects having a BOR of CR, CRMRD-, CRi, or PR)


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 Event-free survival (EFS) = min (date of first DRP, date of first TF, date of death) - date of 
first LAM-003 dose + 1
 Overall survival (OS) = date of death - date of first LAM-003 dose + 1 
For time-to-event endpoints having missing dates, the censoring rules described in Table 3 will 
be applied. 
Table 3: 
Censoring Rules for Time-to-Event Endpoints 
Endpoint 
Censor  
Condition 
Censoring Date = Minimum of Indicated Dates 
Date of Last 
Non-DRP 
Assessment 
Date of 
DRP 
Date of Last 
Assessment 
Date of 
Initiation of 
Other 
Antitumor 
Treatment 
Date Last 
Known 
Alive 
TTR 
None 
 
 
 
 
 
DOR 
Surviving and no DRP 
 
 
X 
X 
 
Either DRP or death 
preceded by 2 missing or 
NE tumor assessments 
X 
 
 
 
 
EFS 
Surviving and no DRP or 
TF 
 
 
X 
X 
 
Either DRP or death 
preceded by 2 missing or 
NE tumor assessments 
X 
 
 
 
 
OS 
Surviving 
 
 
 
 
X 
Abbreviations: DOR = duration of response, DRP = disease recurrence or progression, EFS = event-free 
survival, NE = nonevaluable, OS = overall survival, TF = treatment failure, TTR = time to response 
Time-to-event endpoints will be described in the appropriate analysis sets using Kaplan-Meier 
methods with appropriate censoring. Medians, ranges, and relevant corresponding CIs will be 
presented. 


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4. 
REFERENCES 
American Medical Association (AMA). AMA manual of style: a guide for authors and editors 
(11th edition). 2020 Feb. Available at: 
https://www.amamanualofstyle.com/view/10.1093/jama/9780190246556.001.0001/med-
9780190246556-chapter-17-div2-32 (accessed on 2020 Aug 10).   
Cheson BD, Bennett JM, Kopecky KJ, Buchner T, William CI, Estery EH, Schiffer CA, Doehner 
H Tallman MS, Lister TA, Lo-Coco F, Wilemze R, Biondi A, Hiddemann W, Larson RA, 
Lowenberg B, Sanz MA, Head DR, Ohno R, Bloomfield CD; International Working Group for 
Diagnosis, Standardization of Response Criteria, Treatment Outcomes, and Reporting Standards 
for Therapeutic Trials in Acute Myeloid Leukemia. Revised recommendations of the 
international working group for diagnosis, standardizations of response criteria, treatment 
outcomes, and reporting standards for therapeutic trials in acute myeloid leukemia. J Clin Oncol. 
2003 Dec 15;21(24):4642-9. Erratum in: J Clin Oncol. 2004 Feb 1;22(3);576. PMID: 14673054. 
Döhner H, Estey E, Grimwade D, Amadori S, Appelbaum FR, Büchner T, Dombret H, Ebert BL, 
Fenaux P, Larson RA, Levine RL, Lo-Coco F, Naoe T, Niederwieser D, Ossenkoppele GJ, Sanz 
M, Sierra J, Tallman MS, Tien HF, Wei AH, Löwenberg B, Bloomfield CD. Diagnosis and 
management of AML in adults: 2017 ELN recommendations from an international expert panel. 
Blood. 2017 Jan 26;129(4):424-447. PMID: 27895058. 
Food and Drug Administration (FDA). E9 statistical principles for clinical trials. 1998 Sep. 
Available at: https://www.fda.gov/media/71336/download (accessed on 2020 Aug 10). 
National Cancer Institute (NCI). Common Terminology Criteria for Adverse Events (CTCAE), 
Version 4.03. 2010 Jun 14. Available at:
https://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03/CTCAE_4.03_2010-06-
14_QuickReference_5x7.pdf (accessed on 2020 Aug 10). 
5. 
TABLES, FIGURES, AND LISTINGS 
A separate document will be maintained that identifies all tables, figures, and listings to be 
provided. This document will be updated as appropriate during development of tables, figures, 
and listings.