Clinical trial NCT02520011
Conditions: Acute Myeloid Leukemia
Keywords: Refractory AML Relapsed AML AML
Sponsor: Sumitomo Pharma America, Inc.
Start date: 2016-03-14; Completion date: 2020-02-12
Enrollment: 104 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this two-stage Phase 2 study is to assess the clinical response (Complete Remission) of ACM (Alvocidib/Cytarabine/Mitoxantrone) compared to CM (Cytarabine/Mitoxantrone) treatment in refractory or relapsed AML patients with demonstrated MCL-1 dependence of ≥ 30% by mitochondrial profiling in bone marrow.

Detailed description:
In Stage 1 of the study, all eligible AML patients with demonstrated MCL-1 dependence of ≥ 30% by mitochondrial profiling in bone marrow will receive treatment with ACM.

In Stage 2, all eligible AML patients with demonstrated MCL-1 dependence of ≥ 30% by mitochondrial profiling in bone marrow will be randomized 1:1 to receive either treatment with ACM or CM.

Arms: arm 1: A: alvocidib, 30 mg/m2 as a 30 minute intravenous (IV) bolus followed by 60 mg/m2 over 4 hours as an IV infusion administered daily on Days 1-3; C: cytarabine (ara-c), 2 gm/m2 by continuous IV infusion over 72 hours on Days 6-8; M: mitoxantrone (mitoxantrone hydrochloride), 40 mg/m2 by IV infusion over 1-2 hours starting 12 hours after completing cytarabine arm 2: C: cytarabine (ara-c), 2 gm/m2 by continuous IV infusion over 72 hours on Days 1-3; M: mitoxantrone (mitoxantrone hydrochloride), 40 mg/m2 by IV infusion over 1-2 hours starting 12 hours after completing cytarabine
Interventions: intervention 1: Alvocidib intervention 2: Cytarabine intervention 3: Mitoxantrone
Intervention descriptions: intervention 1: None intervention 2: None intervention 3: None

Protocol documents:
Prot_000.pdf: 


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PROTOCOL SIGNATURE PAGE
SPONSOR SIGNATURE
I have carefully read the protocol, TPI-ALV-201 Amendment 11 titled “A Phase 2, 
Randomized, Biomarker-driven, Clinical Study in Patients with Relapsed or Refractory 
Acute Myeloid Leukemia (AML) with MCL-1 Dependence 30%” and confirm this is 
the approved current version. 
Sponsor’s Signature
Date (DD/MMM/YYYY)
Printed Name
INVESTIGATOR’S SIGNATURE
I have carefully read this protocol, TPI-ALV-201 Amendment 11, and commit to 
conduct the study as outlined herein, in accordance with the International Council on 
Harmonisation (ICH), Good Clinical Practices (GCPs) and the Declaration of Helsinki, 
and comply with the obligations and requirements of the Clinical Investigator and other 
requirements as listed in Title 21 of the United States Code of Federal Regulations 
(CFR) and other applicable regulations.
Investigator’s Signature
Date (DD/MMM/YYYY)
Printed Name
Name of Institution/Research Facility


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TABLE OF CONTENTS
ABBREVIATIONS ...................................................................................................7 
STUDY SUMMARY ................................................................................................. 9 
1. 
INTRODUCTION.............................................................................................19 
1.1 Acute Myeloid Leukemia (AML).............................................................................. 19 
1.2 Relapsed/refractory AML........................................................................................ 19 
1.3 Role of MCL-1 in AML............................................................................................ 20 
1.4 Rationale................................................................................................................ 20 
2. 
DRUG INFORMATION – ALVOCIDIB............................................................22 
2.1 Background............................................................................................................ 22 
2.2 Chemistry............................................................................................................... 22 
2.3 Drug Description .................................................................................................... 22 
2.4 Mechanism of Action.............................................................................................. 23 
2.5 Preclinical Studies.................................................................................................. 23 
2.5.1 In vitro/in vivo studies......................................................................................................... 23 
2.5.2 Safety Pharmacology......................................................................................................... 24 
2.5.3 Nonclinical Absorption, Distribution, Metabolism and Excretion........................................ 25 
2.5.4 Animal Toxicology.............................................................................................................. 25 
2.5.5 Genotoxicity ....................................................................................................................... 26 
2.5.6 Reproductive and Developmental Toxicity ........................................................................ 26 
2.5.7 Other Toxicity Studies........................................................................................................ 26 
2.6 Clinical Studies ...................................................................................................... 27 
2.6.1 Phase 1 and 2 Clinical Studies of Bolus and Hybrid FLAM Regimens in Patients with 
AML.................................................................................................................................... 27 
2.6.2 Data Summaries from Phase 1 and 2 Clinical Studies in Patients with 
Relapsed/Refractory AML.................................................................................................. 30 
2.6.3 Newly Diagnosed High-Risk AML...................................................................................... 34 
2.7 Justification for Study Treatment Plan.................................................................... 34 
2.8 Summary of Risk and Benefits ............................................................................... 36 
3. 
STUDY OBJECTIVES ....................................................................................37 
4. 
INVESTIGATIONAL PLAN.............................................................................38 
4.1 Overall Study Design ............................................................................................. 38 
4.2 Randomization Criteria........................................................................................... 41 
4.3 Controls ................................................................................................................. 41 
4.4 Patient Population.................................................................................................. 41 
4.4.1 Number of Patients ............................................................................................................ 41 
4.4.2 Inclusion Criteria ................................................................................................................ 42 
4.4.3 Exclusion Criteria ............................................................................................................... 43 
4.5 Study Treatments................................................................................................... 44 
4.5.1 Calculation of Dose............................................................................................................ 44 
4.5.2 Treatment Plan .................................................................................................................. 44 
4.5.3 Treatment Schema ............................................................................................................ 44 
4.5.3.1 
Stage 1:  Treatment with ACM over Days 1-9 ..............................................................44 
4.5.3.2 
Stage 2:  Treatment with ACM or CM ..........................................................................45 
4.5.3.3 
Evaluation After Cycle 1...............................................................................................45 
4.5.3.4 
Crossover (Stage 2).....................................................................................................45 


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4.6 Management of Toxicities and Dosage Modifications............................................. 46 
4.6.1 Management of Nonhematologic Toxicities....................................................................... 46 
4.6.1.1 
Hyperkalemia and Tumor Lysis Syndrome ..................................................................46 
4.6.1.2 
Diarrhea .......................................................................................................................50 
4.6.1.3 
Nausea/Vomiting..........................................................................................................50 
4.6.1.4 
Infection Prevention .....................................................................................................50 
4.6.2 Management of Hematologic Toxicities............................................................................. 51 
4.6.3 Dose Modifications............................................................................................................. 51 
4.7 Concomitant Medications and Therapies ............................................................... 51 
4.7.1 Previous Therapies ............................................................................................................ 51 
4.7.2 Concomitant Therapies...................................................................................................... 52 
4.7.2.1 
Mandated / Permitted Therapies..................................................................................52 
4.7.2.2 
Prohibited Therapies....................................................................................................53 
4.7.3 Birth Control Requirements for Fertile Patients ................................................................. 53 
4.8 Protocol Deviations ................................................................................................ 53 
4.9 Other Precautions .................................................................................................. 53 
5. 
ON-STUDY CLINICAL AND LABORATORY EVALUATIONS ......................54 
5.1 Prescreening (Stage 1, Stage 2) ............................................................................ 54 
5.2 Screening (Stage 1, Stage 2) ................................................................................. 54 
5.2.1 Within 2 Weeks Prior to First Dose.................................................................................... 54 
5.2.2 Within 72 Hours Prior to First Dose (Stage 1, Stage 2) ..................................................... 55 
5.3 Stage 1 Assessments ............................................................................................ 55 
5.3.1 Assessments Required Prior to First Dose........................................................................ 55 
5.3.1.1 
Cycle 1 – At Least 10 Hours Prior to First Dose...........................................................56 
5.3.1.2 
Cycle 1, Day 1 – Just Prior to First Dose .....................................................................56 
5.3.2 Cycle 1, Day 1 – Dosing .................................................................................................... 57 
5.3.2.1 
Cycle 1 – Daily during Hospitalization for Chemotherapy ............................................57 
5.3.3 Cycle 1 – Weekly after Completion of Chemotherapy Regimen ....................................... 58 
5.3.4 Cycle 1 – At Hematologic Recovery .................................................................................. 58 
5.3.5 Cycles 2 - 4 ........................................................................................................................ 58 
5.3.5.1 
Cycles 2 - 4, Day 1 – At Least 10 Hours Prior to First Dose ........................................59 
5.3.5.2 
Cycles 2 - 4, Day 1 – Just Prior to First Dose ..............................................................59 
5.3.5.3 
Cycles 2 - 4, Day 1 – Dosing........................................................................................60 
5.3.5.4 
Cycles 2 - 4 – Daily during Hospitalization for Chemotherapy .....................................60 
5.3.5.5 
Cycles 2 - 4 – Weekly after Completion of Chemotherapy Regimen ...........................61 
5.3.5.6 
Cycles 2 - 4 – At Hematologic Recovery......................................................................61 
5.4 Stage 2 Assessments ............................................................................................ 62 
5.4.1 Assessments Required Prior to First Dose........................................................................ 62 
5.4.1.1 
Cycle 1, Day 1 – At Least 10 Hours Prior to First Dose ...............................................62 
5.4.1.2 
Cycle 1, Day 1 – Just Prior to First Dose .....................................................................62 
5.4.2 Cycle 1, Day 1 – Dosing .................................................................................................... 63 
5.4.2.1 
Cycle 1 – Daily during Hospitalization for Chemotherapy ............................................63 
5.4.3 Cycle 1 – Weekly after Completion of Chemotherapy Regimen ....................................... 64 
5.4.4 Cycle 1 – At Hematologic Recovery .................................................................................. 64 
5.4.5 Cycles 2 - 4 ........................................................................................................................ 64 
5.4.5.1 
Cycles 2 - 4, Day 1 – Within 10 Hours Prior to First Dose ...........................................65 
5.4.5.2 
Cycles 2 - 4, Day 1 – Just Prior to First Dose ..............................................................65 
5.4.5.3 
Cycles 2 - 4, Day 1 – Dosing........................................................................................66 
5.4.5.4 
Cycles 2 - 4 – Daily during Hospitalization for Chemotherapy .....................................66 
5.4.5.5 
Cycles 2 - 4 – Weekly after Completion of Chemotherapy Regimen ...........................67 
5.4.5.6 
Cycles 2 - 4 – At Hematologic Recovery......................................................................67 
5.5 End of Study Assessments (Stage 1, Stage 2)....................................................... 68 
5.6 Follow-up Assessments (Stage 1, Stage 2 and Exploratory Arms)......................... 68 


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6. 
OFF-STUDY CRITERIA..................................................................................69 
6.1 Withdrawal of Patients ........................................................................................... 69 
6.2 Reasons for Withdrawal ......................................................................................... 69 
6.3 Follow-up for Patients Withdrawn from Study......................................................... 70 
7. 
CRITERIA FOR EVALUATION AND ENDPOINT DEFINITIONS...................71 
7.1 Efficacy Endpoints.................................................................................................. 71 
7.1.1 Primary Efficacy Endpoint.................................................................................................. 71 
7.1.2 Secondary Efficacy Endpoints ........................................................................................... 71 
7.2 Safety Endpoints.................................................................................................... 71 
8. 
ADVERSE EVENTS .......................................................................................72 
8.1 Definitions .............................................................................................................. 72 
8.2 Causality ................................................................................................................ 74 
8.3 Serious Adverse Events......................................................................................... 74 
8.4 Eliciting and Reporting Adverse Events.................................................................. 75 
8.5 Serious Adverse Events and/or Adverse Events Requiring Discontinuation of 
Study Drug............................................................................................................. 76 
8.6 Follow-up of Adverse Events.................................................................................. 76 
8.7 Patient Deaths ....................................................................................................... 77 
8.8 Reporting Adverse Events to the Regulatory Authorities ........................................ 77 
9. 
STUDY DRUG MANAGEMENT .....................................................................78 
9.1 Study Drug............................................................................................................. 78 
9.2 Study Drug Dispensing and Accountability............................................................. 78 
9.3 Preparation and Administration .............................................................................. 79 
9.4 Storage at Study Center......................................................................................... 79 
9.5 Compliance............................................................................................................ 79 
10. RECORD MANAGEMENT..............................................................................80 
10.1 Data Collection....................................................................................................... 80 
10.2 Source Document Maintenance ............................................................................. 80 
10.3 Record Maintenance.............................................................................................. 81 
10.4 Study Center File Management.............................................................................. 82 
11. STATISTICAL ANALYSIS..............................................................................83 
11.1 Statistical Methods................................................................................................. 83 
11.2 Sample Size........................................................................................................... 83 
11.2.1 
Sample Size in Stage 1................................................................................................ 83 
11.2.2 
Sample Size in Stage 2................................................................................................ 84 
11.3 Analysis Populations.............................................................................................. 84 
11.4 Data Analyses........................................................................................................ 85 
11.4.1 
Demographics and Baseline Characteristics............................................................... 86 
11.4.2 
Efficacy Analyses......................................................................................................... 86 
11.4.3 
Pharmacodynamic Endpoint Analyses ........................................................................ 87 
11.4.4 
Safety Analyses ........................................................................................................... 88 
12. PROTOCOL AMENDMENTS .........................................................................89 
13. MONITORING................................................................................................. 90 
14. AUDITING.......................................................................................................91 


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15. ETHICS AND RESPONSIBILITY ...................................................................92 
15.1 Principal Investigator’s Responsibilities.................................................................. 92 
15.2 Informed Consent................................................................................................... 92 
15.3 Institutional Review Board/Independent Ethics Committee..................................... 93 
16. CONFIDENTIALITY........................................................................................94 
17. NONPROTOCOL RELATED RESEARCH.....................................................95 
18. PUBLICATIONS .............................................................................................96 
19. REFERENCES................................................................................................97 
APPENDIX A – SCHEDULE OF ACTIVITIES – STAGE 1, Cycle 1 (ACM 
only) ..........................................................................................100 
APPENDIX B – ECOG PERFORMANCE STATUS SCALE...............................108 
APPENDIX C – NCI COMMON TERMINOLOGY CRITERIA FOR ADVERSE 
EVENTS.....................................................................................109 
APPENDIX D – LABORATORY TESTS .............................................................110 
APPENDIX E – RESPONSE CRITERIA .............................................................111 
APPENDIX F – MULTIVARIATE ANALYSIS AND RISK SCORE 
PREDICTION MODEL FOR DEVELOPMENT OF TUMOR 
LYSIS SYNDROME IN AML......................................................115 
APPENDIX G –ASSESSMENT OF PRIOR AND CUMULATIVE 
ANTHRACYCLINE/ANTHRACENEDIONE EXPOSURE*.........116 
LIST OF TABLES
TABLE 1: 
OVERVIEW OF ALVOCIDIB PHASE 1 & 2 CLINICAL STUDIES 
IN AML (IN CHRONOLOGIC ORDER)............................................ 28 
TABLE 2: 
ALVOCIDIB/FLAM IN AML (DEMOGRAPHICS AND DOSING IN 
RELAPSED/REFRACTORY PATIENTS)........................................ 31 
TABLE 3: 
ALVOCIDIB/FLAM IN AML (EFFICACY PARAMETERS IN 
RELAPSED/REFRACTORY PATIENTS)........................................ 32 
TABLE 4: 
ALVOCIDIB/FLAM IN AML (SAFETY DATA IN 
RELAPSED/REFRACTORY PATIENTS)........................................ 33 


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ABBREVIATIONS
7&3
Refers to the regimen of Ara-c: Days 1-7 & Daunorubicin: Days 1, 2, 
3
ACM
Alvocidib/Cytarabine/Mitoxantrone (previously referred to as FLAM)
AE
Adverse event
AGC
Absolute granulocyte count
ALT
Alanine aminotransferase
AM
Ara-c/Mitoxantrone (now referred to as CM)
AML
Acute myeloid leukemia
ANC
Absolute neutrophil count
ANOVA
Analysis of variance
AP
Accelerated phase
APL
Acute promyelocytic leukemia
Ara-c
Cytarabine
AST
Aspartate aminotransferase
AUC
Area under the curve
BID
Every 12 hours
BM
Bone marrow
BUN
Blood urea nitrogen
CBC
Complete blood count
CHR
Complete hematologic remission
Cl
Clearance
CLL
Chronic lymphocytic leukemia
CM
Cytarabine/Mitoxantrone (previously referred to as AM)
CNS
Central nervous system
COV
Close out visit
CR
Complete remission/response
CRA
Clinical research associate
CRi
Complete remission with residual neutropenia (ANC <1000 μL) or 
lack of recovery of any other hematopoietic cell
CRF
Case report form
CRp
Complete remission with incomplete platelet recovery
CTCAE
Common Terminology Criteria for Adverse Events
DCF
Data clarification form
DLT
Dose-limiting toxicity
DNA
Deoxyribonucleic acid
DSMB
Data Safety Monitoring Board
ECHO
Echocardiogram
ECOG
Eastern Cooperative Oncology Group
EFS
Event-free survival
EMD
Extramedullary disease
FDA
Food and Drug Administration
FLAM
Alvocidib (Flavopiridol)/Ara-c/Mitoxantrone (now referred to as 
ACM)
GCP
Good Clinical Practice
GCSF
Granulocyte colony stimulating factor
GM-CSR
Granulocyte-macrophage colony stimulating factor
GVHD
Graft versus host disease
HCG
Human chorionic gonadotropin
HCT
Hematocrit


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Hgb
Hemoglobin
HI
Hematologic improvement
IC50
Inhibitory concentration in 50% of animals
IEC
Independent Ethics Committee
IND
Investigational New Drug Application
IP
Intraperitoneal
IRB
Institutional Review Board
IT
Intrathecal (chemotherapy)
ITT
Intent to treat (population)
LD50
Lethal dose in 50% of animals
LDH
Lactate dehydrogenase
LR
Logistic regression
LVEF
Left ventricular ejection fraction
MedDRA
Medical Dictionary for Regulatory Activities
MDS
Myelodysplastic syndrome
MRD
Minimal residual disease
MTD
Maximum tolerated dose
MUGA
Multigated acquisition (scan)
NCCN
National Comprehensive Cancer Network
NCI
National Cancer Institute
OS
Overall survival
PR
Partial remission/response
PS
Performance status
RBC
Red blood cell
RFS
Relapse-free survival
RNA
Ribonucleic acid
RT-PCR
Reverse transcription-polymerase chain reaction
SAE
Serious adverse event
SAS
Statistical Analysis System (software)
SGOT (AST)
Serum glutamic-oxaloacetic transaminase
SGPT (ALT)
Serum glutamic-pyruvic transaminase
SIV
Study initiation visit
SOP
Standard operating procedure(s)
T1/2
Half-life
Tmax
Time to maximum concentration
TRM
Treatment-related mortality
TST
Timed sequential therapy
ULN
Upper limit of normal
Vd
Volume of distribution
Vss
Volume at steady state
WBC
White blood cell
WHO
World Health Organization


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STUDY SUMMARY
Title of Study:
A Phase 2, Randomized, Biomarker-driven, Clinical Study in Patients 
with Relapsed or Refractory Acute Myeloid Leukemia (AML) with 
MCL-1 Dependence 30% 
Study Indication:
x 
Relapsed or primary refractory AML with MCL-1 dependence of 
30% demonstrated by mitochondrial profiling
Objectives: 
Stage 1: Primary Objective
x
To determine the CR rate in patients with relapsed or refractory 
AML with MCL-1 dependence of 30%  
Stage 2: Primary Objective
x
To compare CR rates between patients with relapsed or 
refractory AML with MCL-1 dependence of 30% receiving 
1 cycle of ACM treatment and those receiving 1 cycle of CM. 
Exploratory Objective (Stage 2):  
x
To determine if treatment with ACM can induce CR in patients 
with relapsed or refractory AML with MCL-1 dependence of 30% 
who failed to achieve CR following 1 cycle of CM. 
Clinical Phase:
2 
Study Design:
“FLAM” (alvocidib, cytarabine, mitoxantrone hydrochloride) will now 
be referred to as “ACM”.
“AM” (cytarabine, mitoxantrone hydrochloride) will now be referred to 
as “CM”.
This is an open-label, randomized, multicenter two-stage study of 
ACM (Stage 1) and ACM versus CM (Stage 2) in patients with acute 
myeloid leukemia (AML) with demonstrated MCL-1 dependence of 
30% by mitochondrial profiling in bone marrow who are either in first 
relapse (within 24 months of CR) or have failed induction therapy* (no 
CR or CRi after
treatment with an
intensive regimen [eg,
anthracycline/cytarabine ± etoposide, gemtuzumab ozogamicin, or 
cladribine]). 
*Induction therapy may involve 1 or 2 cycles of the same regimen. 
Efficacy assessment of induction therapy must be >21 days from 
the start of the previous induction cycle.
Stage 1 of the study will be single arm, conducted similarly to the first 
stage of a Simon 2-stage design. All patients with relapsed or 
refractory AML enrolled in this stage will receive ACM. 
Once patients enrolled in Stage 1 exhibit a CR, CRi, or CRp, 
enrollment into Stage 1 will close and additional patients will be 
enrolled in Stage 2 of the study.
Enrollment into Stage 1 will be limited to no more than 23 evaluable 
patients, however enrollment into Stage 2 may be initiated at any 


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point after confirming CR, CRi or CRp responses in 13 Stage-1
patients.
The sample size of 23 eligible patients for Stage 1 was selected 
because it allows estimation of the remission rate by means of a 90% 
confidence interval with maximum width of ±17%. Although this study 
does not follow a Simon 2-stage design, 23 patients is consistent with 
the sample size for Stage 1 of the Simon 2-stage minimax design with 
80% power for testing the null hypothesis that the remission rate is 
50% against a one-sided alternative at the 5% level of significance 
when the actual remission rate is 70%. 
In the Simon 2-stage design described, the study would continue to 
Stage 2 only if 13 patients achieve remission out of 23 eligible 
patients. Therefore, this was selected as the requirement to proceed 
to Stage 2 of this study. However, the study may proceed to Stage 2 
as soon as 13 patients achieve remission.
In Stage 2, patients will be randomized to receive either ACM or CM. 
The planned sample size of 56 patients (28 per treatment arm) in 
Stage 2 of this study provides 90% power to reject the null hypothesis 
of equal CR rates across treatment arms under the following 
conditions:
x
CR rates of 70% and 30% for patients receiving ACM and CM,
respectively
x
One-sided 2.5% significance level
x
Randomization based on a 1:1 patient allocation ratio (ACM to 
CM) 
x
No interim analysis
Randomization to treatment arm will be stratified by:  
x 
Response to first-line therapy:
O Refractory: persistent disease or complete remission [CR] 
duration <90 days
O Early relapse: CR duration 90 days to 1 year
O
Late relapse: CR duration >1 year but <24 months
Response assessments in Stage 1 are defined by the International 
Working Group Criteria and 2010 European LeukemiaNet (ELN). The 
2017 ELN criteria will be used to determine patient responses during 
Stage 2. Response assessments will include:
x
CR rate = Percentage of patients achieving CR 
x
Combined CR rate (CR+CRp†+CRi)  
x
Combined Response Rate (CR+CRp†+CRi+PR)  
x
Overall Survival (OS) 
x
Event-free Survival (EFS)
x
Rate of Stem Cell Transplantation


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†Note that CRp has been retained in definitions for Combined CR 
Rate and Combined Remission Rate because Stage-1 patients 
were assessed using the IWG criteria. CRp will not be used for 
assessing response in Stage-2 patients and, therefore, will not be 
included in the definitions of Combined CR Rate and Combined 
Remission Rate in Stage 2.
Safety assessments will include:
x
Mortality from any cause at 30 and 60 days
x
Adverse events graded according to National Cancer 
Institute’s Common Terminology Criteria for Adverse Events 
(NCI CTCAE), version 4.03 in Stage 1 and version 5.0 in 
Stage 2 
o
The multivariate analysis and risk score prediction model 
by Montesinos and colleagues [22] will be used to assess 
the potential for development of TLS (Appendix F) 
Treatment assessments will include: 
x
Bone marrow biopsies and/or aspirates will be performed 
before treatment and at hematologic recovery (ie, absolute 
neutrophil count (ANC) >1000 μL and platelet count 
>100,000 μL) or Day 45, whichever occurs first.
x
Complete blood counts and chemistries assessed daily during 
hospitalization for chemotherapy administration and weekly 
thereafter 
x
Overall survival (OS) monitored monthly during year 1, every 
2 months during year 2
x
Intensive monitoring of renal function, electrolytes, potassium,
and uric acid levels
Pharmacodynamic assessments will include: 
x
Determination of MCL-1 dependence at baseline using bone
marrow
Patients who achieve CR, CRi, CRp, or PR after the first cycle 
(completion of all doses) may receive up to 3 additional optional 
cycles of treatment. After completing the first cycle of treatment, 
continued use of mitoxantrone is optional. Mitoxantrone must be 
omitted from subsequent cycles if the patient’s lifetime daunorubicin
equivalent exceeds 460 mg/m2 (see Appendix G for conversion table)
or the left ventricular ejection fraction (LVEF) drops below 45%.
Patients not demonstrating evidence of CR, CRi, CRp, or PR after the 
first cycle of treatment will be considered for removal from the study, 
although with permission of the Medical Monitor, induction treatment 


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may continue if clinically indicated and provided there is no evidence 
RIWR[LFLW\NCI CTCAE grade 4.  
Crossover: Patients randomized to CM with progressive disease or 
no response after 1 cycle of CM may cross over to receive ACM. In 
addition, patients randomized to CM with a best response of PR after 
2 cycles of CM may also cross over to receive ACM. Patients who 
cross over to ACM may receive up to a combined total (CM + ACM)
of 4 cycles. 
Results from Stage 1 (ie, the Primary Relapsed/Refractory AML 
Study Arm) will be analyzed using descriptive statistics and 
confidence intervals.   
In Stage 2, complete remission (CR) rates will be compared across 
treatment groups using the Cochran-Mantel-Haenszel
general 
association test stratified by response to most recent induction 
therapy. The same test will be applied to assess the statistical 
significance of the secondary response rate endpoints. Control of the 
overall one-sided 2.5% type-1 error rate for multiple comparisons will 
be achieved using the hierarchical closed test procedure. 
Primary statistical comparisons of efficacy results will use only data 
from Stage 2; however, data from Stage 1 patients will be combined 
with data from patients receiving ACM in Stage 2 for secondary 
efficacy analyses.
Treatment-group distributions of time-to-event endpoints will be 
compared using the log-rank test stratified by response to most recent 
induction therapy. Patients who are lost to follow-up or have not had 
the event of interest at the time of analysis will have their event time 
censored (see Statistical Methods).
Patient 
Population:
Patients will be prescreened to determine percent MCL-1
dependence. 
x
Patients with AML with demonstrated MCL-1 dependence of 
30% by mitochondrial profiling in bone marrow who are either in 
first relapse (within 24 months of CR) or have failed induction 
therapy* (no CR or CRi after treatment with an intensive regimen
(eg,
anthracycline/cytarabine 
± 
etoposide, 
gemtuzumab 
ozogamicin, or cladribine)
o
*Induction therapy may involve 1 or 2 cycles of the same 
regimen. Efficacy assessment of induction therapy must be 
>21 days from the start of the previous induction cycle.
Inclusion Criteria:
To be eligible for participation in the study, patients must meet all of 
the following inclusion criteria:
During Prescreening:
1. %HEHWZHHQWKHDJHVRIDQG\HDUV  


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2.
Have an established, pathologically confirmed diagnoses of AML 
by World Health Organization (WHO) criteria excluding acute 
promyelocytic leukemia (APL-M3) with a bone marrow of >5% 
blasts based on histology or flow cytometry
3.
Be in first relapse (within 24 months of CR) or have failed 
induction therapy* (no CR or CRi after treatment with an intensive 
regimen [eg, anthracycline/cytarabine ± etoposide, gemtuzumab 
ozogamicin, or cladribine])
*Induction therapy may involve 1 or 2 cycles of the same 
regimen. Efficacy assessment of induction therapy must be 
>21 days from the start of the previous induction cycle.
4.
Demonstrate MCL-1 dependence RI 30% by mitochondrial 
profiling in bone marrow
During Screening:
5.
Have an Eastern Cooperative Oncology Group (ECOG) 
SHUIRUPDQFHVWDWXV36
6.
Have a serum creatinine levHO1.8 mg/dL
7.
Have 
an 
alanine 
aminotransferase 
(ALT)/aspartate 
DPLQRWUDQVIHUDVH$67OHYHOWLPHVXSSHUOLPLWRIQRUPDO8/1
8.
+DYHDWRWDOELOLUXELQOHYHOPJG/XQOHVVVHFRQGDU\WRGilbert 
syndrome, hemolysis, or leukemia)
9.
Have a left ventricular ejection fraction (LVEF) >45% by 
echocardiogram (ECHO) or multigated acquisition (MUGA) scan
10. Be nonfertile or agree to use an adequate method of 
contraception. Sexually active patients and their partners must 
use an effective method of contraception associated with a low 
failure rate during and for at least 6 months after completion of 
study therapy (see Section 4.7.3). 
11. Be able to comply with the requirements of the entire study.
12. Provide written informed consent prior to any study related 
procedure. (In the event that the patient is re-screened for study 
participation or a protocol amendment alters the care of an 
ongoing patient, a new informed consent form must be signed.)
Exclusion 
Criteria: 
 
Patients meeting any one of these exclusion criteria will be prohibited 
from participating in this study.
1. Received more than 2 cycles of induction therapy for AML. 
Investigational agents as part of front-line therapy for AML may by 
acceptable following discussion with the Medical Monitor. 
Hydroxyurea is permitted (see #5 below).
2. Received any previous treatment with alvocidib or any other CDK 
inhibitor
3. Received a hematopoietic stem cell transplant within the previous 
2 months


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4. Have clinically significant graft versus host disease (GVHD), or 
GVHD requiring initiation or escalation of treatment within the last 
21 days
5. Require concomitant chemotherapy, radiation therapy, or 
immunotherapy. Hydroxyurea is allowed up to the evening before 
starting (but not within 12 hours) of starting treatment on either 
arm.
6. Received >360 mg/m2
equivalents of daunorubicin
(see 
Appendix G for conversion table)
7. Have a peripheral blast count of >30,000/mm3 (may use 
hydroxyurea as in #5 above)
8. Received antileukemic therapy within the last 3 weeks (with the 
exception of hydroxyurea or if the patient has definite refractory 
disease).  Refractory patients who received therapy within the last 
3 weeks may be eligible with prior approval of the Medical Monitor.
9. Diagnosed with acute promyelocytic leukemia (APL, M3)
10. Have active central nervous system (CNS) leukemia
11. Have evidence of uncontrolled disseminated intravascular 
coagulation
12. Have an active, uncontrolled infection
13. Have other life-threatening illness
14. Have other active malignancies or diagnosed with other 
malignancies within the last 6 months, except nonmelanoma skin 
cancer or cervical intraepithelial neoplasia
15. Have mental deficits and/or psychiatric history that may 
compromise the ability to give written informed consent or to 
comply with the study protocol.
16. Are pregnant and/or nursing
17. Have received any live vaccine within 14 days prior to first study 
drug administration
Study Treatment:
Stage 1 (the Primary Relapsed/Refractory AML Study Arm): 
x
All patients enrolled in Stage 1 will receive ACM.
A: alvocidib (formerly flavopiridol), 30 mg/m2 as a 30-minute 
(±10 minutes) intravenous (IV) bolus followed by 60 mg/m2 over 
4 hours (±15 minutes) as an IV infusion administered daily on 
Days 1-3 
C: cytarabine (Ara-c), 2 gm/m2 by continuous IV infusion over 
72 hours (±2.5 hours) on Days 6-8 (ie, 667 mg/m2 daily on 
Days 6, 7, and 8 for total of 2 gm/m2) 
M: mitoxantrone (mitoxantrone hydrochloride), 40 mg/m2 by IV 
infusion over 1-2 hours (±10 minutes) starting 12 hours after 
completing cytarabine


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Stage 2 (ACM vs AM): 
x
Patients with AML with demonstrated MCL-1 dependence of 
E\PLWRFKRQGULDOprofiling in bone marrow, who are enrolled 
in Stage 2, will be randomized 1:1 to receive either ACM (dosing 
as described in Stage 1) or CM.
C: cytarabine (Ara-c), 2 gm/m2 by continuous IV infusion over 
72 hours (±2.5 hours) on Days 1-3 (ie, 667 mg/m2 daily on 
Days 1, 2, and 3 for total of 2 gm/m2)
M: mitoxantrone (mitoxantrone hydrochloride), 40 mg/m2 by IV 
infusion over 1-2 hours (±10 minutes) starting 12 hours after 
completing cytarabine
x
Crossover: Patients randomized to CM who exhibit progressive 
disease or no response after a single cycle of CM may cross over 
to receive ACM. In addition, patients randomized to CM with a 
best response of PR after two cycles of CM may also cross over 
to receive ACM. Patients who cross over to ACM may receive up 
to a combined total (CM + ACM) of 4 cycles.
Supportive care will be provided including:
x
Tumor Lysis Prevention and Treatment
o
Mandatory IV hydration with 0.45% NaCl (or similar hydration 
fluid per institutional standard) sterile solution at 100 cc/hour 
for at least 10 hours prior to initiation of first dose of 
chemotherapy during Cycle 1 (optional for subsequent 
cycles) in both treatment arms. If, by Day 4, there is no 
evidence of tumor lysis syndrome, the hydration rate can be 
reduced to a maintenance level.
x
Diligent monitoring of urine output frequently to ensure that it 
equals fluid input. If input is greater than output by 10%, 
administration of diuretics is encouraged. Replacement of 
excessive fluid losses, including from diarrhea, should be done 
unless otherwise clinically indicated.
x
Mandatory allopurinol orally each day of dosing during Cycle 1 
(optional in subsequent cycles) to be started at same time as 
initiation of IV hydration in all treatment arms.
x
Mandatory oral phosphate binder to be started at the same time 
as initiation of IV hydration during Cycle 1 (optional in subsequent 
cycles) in all treatment arms, unless contraindicated. 
x
Evaluation of laboratory indicators of tumor lysis syndrome (TLS) 
during Cycle 1:
o
Tumor lysis laboratory evaluations (tumor lysis labs) include 
electrolytes (sodium, potassium, chloride, and carbon 
dioxide) 
as 
well 
as 
creatinine, 
calcium, 
lactate 
dehydrogenase (LDH), uric acid, and phosphorus levels 


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o
Monitor tumor lysis labs at the start of treatment (alvocidib for 
ACM, cytarabine for CM) and throughout the treatment cycle 
according to the schedule outlined in Section 4.6.1.1. [Note: 
there are different blood collection schedules for monitoring 
of TLS labs for patients at high risk of TLS and for those NOT 
at high risk for TLS.] 
o
Monitor fibrinogen levels at baseline and then as clinically 
indicated
x
Infection Prevention
o
Prophylactic antibiotics including levofloxacin (or equivalent) 
500 mg orally once daily and valacyclovir (or equivalent) 
500 mg orally BID each day should be administered to 
patients in all treatment arms at the start of chemotherapy.
Alternative prophylactic antibiotic and antiviral therapy is left 
to the discretion of the treating physician and institutional 
standards.  

Testing for Clostridioides difficile (C. difficile) should start 
with first episode of diarrhea. GI antibiotics should then be 
initiated based on the results of the C. difficile testing. 
o
To prevent cytarabine-related conjunctivitis, corticosteroid 
eye drops per institutional formulary (eg, prednisolone 0.1%) 
must begin 1 day prior to institution of cytarabine infusion (ie,
Day 6 for ACM; Day 1 for CM) and continue for at least 7 days
o
Antifungal prophylaxis to be administered according to each 
institution’s standard of care 
o
Routine growth factor support is QRW DOORZHG 'D\ 35 of 
therapy. Growth factor support can be given at the discretion 
of the Investigator >Day 35 of therapy in the presence of life-
threatening infection with ongoing neutropenia.  
o
Donor lymphocyte infusions are not allowed unless discussed 
and approved by the medical monitor. 
Suggested doses of these supportive care therapies are provided in 
the protocol; however, adjustment of the dosages based on the 
patient’s clinical condition or each institution’s standard of care is 
permitted.
Efficacy 
Evaluations:
Primary Endpoint
The primary endpoint is the rate of Complete Remission (CR) after 
Cycle 1 as defined in Stage 1 by the International Working Group 
Criteria and 2010 ELN criteria and in Stage 2 by the 2017 ELN criteria
(Appendix E).  
Secondary Endpoints
x
Combined CR Rate = Percentage of patients achieving:
o
CR = Bone marrow blasts <5%; absence of blasts with Auer 
rods; absence of extramedullary disease; hematologic 


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recovery (absolute neutrophil count [ANC] >1000 μL and 
platelet count >100,000 μL); independence of red cell 
transfusions (In Stage 2, per 2017 ELN, independence of red 
cell transfusions is not a requirement for CR); plus
o
CRi = Meets all CR criteria except for residual neutropenia 
(ANC <1000 μL) or lack of recovery of any other 
hematopoietic cell; plus
o
CRp = Meets all CR criteria except for residual
thrombocytopenia (platelet count <100,000 μL) †
x
Combined Response Rate = Percentage of patients achieving:
o
CR
o
CRi
o
CRp †
o
PR = Meets all hematologic values required for CR but with a 
GHFUHDVHRIDWOHDVWLQWKHSHUFHQWDJHRIEODVWVWR
WRLQbone marrow
x
Overall Survival (OS) = Time from randomization (Day 1) until 
death from any cause
x
Event-free Survival (EFS) = Time from randomization (Day 1) 
until (a) treatment failure, (b) relapse after CR, or (c) death from 
any cause, whichever occurs first, censored at 2 years
x
Rate of Stem Cell Transplantation = Percentage of patients 
proceeding directly to stem cell transplantation
†Note that CRp has been retained in definitions for Combined CR 
Rate and Combined Remission Rate because Stage-1 patients 
were assessed using the IWG criteria. CRp will not be used for 
assessing response in Stage-2 patients and, therefore, will not be 
included in the definitions of Combined CR Rate and Combined 
Remission Rate in Stage 2.
The CR rate in patients failing 1-2 cycles of CM and crossing over to 
receive ACM will also be determined. 
The Complete Remission (CR) rate, defined as the percentage of 
patients achieving CR, will be determined. Secondary endpoints 
described for Stage 1 will also be assessed.
Complete details of the planned analysis will be documented in a full 
Statistical Analysis Plan, which will be finalized before locking the 
study database. 
Safety 
Evaluations:
Safety and tolerability of the ACM and CM regimens will be assessed 
by analyzing the incidence rates of treatment-emergent adverse 
events summarized within treatment groups at the MedDRA preferred 
term and primary system organ class levels. Similar summaries will 
be made for subsets of AEs such as (1) those judged by the 
Investigator to be related to study treatment, and (2) serious adverse 
events (SAEs). The multivariate analysis and risk score prediction 


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model by Montesinos and colleagues [22] will be used to assess the 
potential for development of TLS (Appendix F).
Other routine safety assessments (eg, clinical laboratory parameters 
and vital signs) will be summarized by shift tables and treatment 
group using mean, standard deviation, median, minimum and 
maximum changes from baseline values.
Mortality (all causes) at 30 and 60 days will also be calculated.  
A Data Safety Monitoring Board (DSMB) will monitor key outcomes 
from the study.
Study Duration:
The study is expected to take 20-24 months to enroll up to 
137 patients: 25 patients in Stage 1; 56 patients in the 4 Exploratory 
Arms (closed after Amendment 8); and 56 patients (28 patients in 
each of two treatment arms in Stage 2.


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1.
INTRODUCTION
1.1
Acute Myeloid Leukemia (AML)
The clinical objective of induction chemotherapy is to obtain ‘first CR’ 
(complete remission with recovery of blood counts) in as many newly 
diagnosed AML patients as possible. Attaining initial CR enables application 
of further therapies of curative intent (consolidation and transplant). Once CR 
is obtained, survival also varies as a function of age, cytogenetic risk status, 
and possibly, by minimal residual disease (MRD). In patients with unfavorable 
risk AML, <60% achieve CR, many patients relapse quickly, and survival 
among responders is woefully low with 5% to 10% experiencing 
chemotherapy-related deaths due to severe toxicity. These data amplify the 
decades’ long tragedy and debilitating nature of available treatments for newly 
diagnosed AML patients, particularly for older patients >60 years, those with 
adverse and complex cytogenetics, and patients with secondary AML.
1.2
Relapsed/refractory AML
As described above, a significant number of patients receiving initial induction 
chemotherapy for AML either do not achieve remission or relapse after 
induction of remission. 
Beginning in the late 1990s, intermediate- and high-dose cytarabine has 
produced approximately 45% CRs and 5 months median survival in 
relapsed/refractory AML patients. Several combinations with experimental 
agents in the 2000s did not achieve any added benefit, in fact, the CR rates 
for these combinations were lower than 40%, and this observation continued 
in 2010 with the publication of E4999, where the CR rates for three 
combination regimens did not exceed 12%. In 2012, MD Anderson published 
results with combination of clofarabine and intermediate-dose cytarabine
which produced a 47% CR and over 6 months’ survival. In 2012, The 
University of Chicago published results of age-specific doses of intermediate 
and high-dose cytarabine in combination with mitoxantrone. Among the 
19 relapsed/refractory patients treated, the CR + CRi rate was 58%.  
At the ASH 2014 meeting, the randomized Phase 3 VALOR trial was 
presented, comparing intermediate-dose cytarabine with or without vosaroxin 
in 711 relapsed/ refractory AML patients. The vosaroxin combination produced 
30% CR, compared to 16% CR with intermediate-dose cytarabine alone. OS 
was higher for the vosaroxin combination (7.5 months versus 6 months, 
although not statistically (p=0.06).


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1.3
Role of MCL-1 in AML
The ability to resist cell death is an important hallmark of all cancer cells, 
allowing them to divide uncontrollably [1, 2]. The BCL-2 family of polypeptides 
has been widely studied as regulators of cell death [3]. Because members of 
this protein family can exhibit pro- or anti-apoptotic functions, they are highly 
involved in the development of cancer and in mechanisms of resistance to 
many therapeutic agents. The myeloid leukemia cell-1 (MCL-1) gene is the 
predominant BCL2 family member expressed in primary AML samples. Tumor 
resistance to targeted therapies limits effectiveness of current clinical 
regimens. Overexpression of MCL-1 has been shown to convey resistance to 
apoptosis induced by a number of different treatments, including etoposide, in 
vitro [4, 5]. Other studies have indicated that MCL-1 expression can be induced 
rapidly in response to a number of DNA-damaging agents [6, 7].
Alvocidib (flavopiridol), a potent cyclin-dependent kinase (CDK) inhibitor, 
downregulates the expression of MCL-1 through inhibition of CDK 9, which, in 
turn, inhibits tumor growth. Studies have shown that alvocidib suppresses 
MCL-1 expression [8, 9] and acts synergistically with other chemotherapeutic 
agents like daunorubicin. Through use of mitochondrial (BH3) profiling, the 
mechanism by which apoptosis is suppressed in a population of cells can be 
determined. Mitochondrial sensitivity to NOXA BH3 peptides suggests
dependence on MCL-1 to mediate resistance to apoptosis. Early studies have 
shown that MCL-1 dependence can predict the clinical activity of alvocidib in 
AML patient samples and suggests an important role for MCL-1 activity in 
predicting alvocidib activity. 
In light of these findings, Tolero is conducting this Phase 2 study to determine 
if MCL-1 dependency determined by mitochondrial profiling of bone marrow 
samples will increase the Complete Remission (CR) rate after FLAM (ACM) 
treatment. 
1.4
Rationale
Acute myeloid leukemia continues to be one of the highest unmet medical 
needs, due to very short survival from time of diagnosis (median <1 to 2 years). 
Short survival in AML patients is directly correlated with the presence of 
unfavorable cytogenetics and multiple adverse clinical features (age >60, prior 
MDS, treatment-related or secondary AML, FLT3-ITD positivity, and monocytic 
phenotype). Attainment of initial complete remission still remains unachievable 
in approximately 40-60% of AML patients, and progression, rapid relapse and 
short survival are too frequent consequences from currently available, but 
inadequate, antileukemic therapy.
Tolero’s position remains that the existing AML therapies developed decades 
ago, which remain the standard of care, do not adequately attain sufficiently 
high rates of first CR, long-term remission nor survival for the majority of AML 
patients. In treating relapsed/refractory AML, current therapies produce 


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modest complete remission rates, and almost all of these patients succumb to 
disease-related mortality. As noted in the 2014 National Comprehensive 
Cancer Network (NCCN) Guidelines for patients with AML, the best option for 
patients with relapsed or refractory AML is a clinical trial.
Our experience to date with alvocidib, as part of the FLAM regimen, clearly 
shows that this novel treatment can produce exceptionally high complete 
remission rates:
•
62 - 80% in newly diagnosed unfavorable risk AML patients based on 
three Phase 2 studies
•
29 - 92% in patients with relapsed AML
•
28 - 43% in combined populations of relapsed/refractory AML
In relapsed AML patients, where no standard of care exists, FLAM has 
produced CR rates as high as 75 - 92%. Among relapsed/refractory AML 
patients treated with the alvocidib/FLAM hybrid dosing regimen, a 50% CR 
rate was observed among 24 patients treated at dose level 5 (30 and 40 mg/m2
hybrid dosing in FLAM) [10]. This clinical activity has allowed many patients 
the opportunity to undergo stem cell transplantation, who otherwise may not 
have had this option.












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2.6
Clinical Studies
Alvocidib has now been evaluated in solid tumors and hematologic 
malignancies. Eight Phase 1 and 2 clinical trials have been completed in 
patients with intermediate and poor-risk AML, including more than 400 patients 
with both relapsed/refractory and newly diagnosed AML. In these trials, 
alvocidib has been evaluated as a single agent as well as in combination with 
cytarabine and mitoxantrone.
2.6.1
Phase 1 and 2 Clinical Studies of Bolus and Hybrid FLAM 
Regimens in Patients with AML 
Initially, Phase 1 clinical trials in AML patients incorporated alvocidib into the 
“Timed Sequential Therapy” (TST) AML induction therapy approach from the 
1990s, which had utilized cytarabine and later added mitoxantrone (AM) [11]. 
Investigators at the University of Maryland, and then at Johns Hopkins, added 
alvocidib to AM for the dual purpose of initial cytoreduction and enhancing the 
cell cycle progression of the remaining leukemic cell cohort, followed by the 
cycle-dependent agents cytarabine and mitoxantrone (FLAM regimen). Two 
alvocidib dosing schedules have been evaluated: by 1-hour bolus infusion, and 
by a hybrid dosing schedule consisting of a 30-minute short IV bolus dose 
followed by a 4-hour IV infusion. A listing of all eight (8) clinical studies of FLAM 
in relapsed/refractory patients and newly diagnosed patients is provided in 
Table 1.


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Table 1: Overview of Alvocidib Phase 1 & 2 Clinical Studies in AML
(In Chronologic Order)
Study (Reference)
N
Treatment Regimen
Patient Population
Study 1: 
JHOC J0254/
NCI-3170 
Phase 1 FLAM [12] 
Total: 
34
AML: 
26
Alvocidib Bolus 1 hr IV:
40, 50, 60 mg/m2/d on Days 1-3 
Ara-c: 2 gm/m2/72h by CIV given 
Days 6-8 
Mitoxantrone: 40 mg/m2 given by 
60-120 min IV on day 9
Adults median age 54, 
primary refractory, multi-
refractory or relapsed AML 
(26) ALL (7) CML (1) 
Study 2:
JHOC J0254/
NCI-3170 
Phase 2 FLAM [13] 
62
AML
Alvocidib Bolus 1 hr IV: 
50 mg/m2/d on Days 1-3 
Ara-c: 2 gm/m2/72h by CIV given 
Days 6-8 
Mitoxantrone: 40 mg/m2 given by 
60-120 min IV on day 9
Adults median age 58, 
primary refractory (13), 
multirefractory (10), 
relapsed (24), newly 
diagnosed secondary AML
(15)
Study 3:
OSU-0479/
NCI-6947 
Phase 1 Alvocidib  
Monotherapy [14] 
Total: 
24
AML: 
19
Alvocidib monotherapy 
dose-escalation, Hybrid regimen:
20 mg/m2 & 30 mg/m2  
30 mg/m2 & 35 mg/m2
30 mg/m2 & 50 mg/m2
40 mg/m2 & 60 mg/m2
50 mg/m2 & 75 mg/m2
30 min bolus followed by 4-hr 
infusion/day on Days 1,2,3
Adults median age 62, 
relapsed or refractory 
non-M3 AML (19), ALL (5)
Study 4:
JHOC J0669/
NCI-7845 
Phase 2 FLAM [15] 
45
AML
Alvocidib Bolus 1hr IV: 50 mg/m2/d 
Days 1-3 
Ara-c: 2 gm/m2/72h by CIV given 
Days 6-8 
Mitoxantrone: 40 mg/m2 given by 
60-120 min IV on day 9
Adults median age 61, 
newly diagnosed, 
pathologically confirmed, 
previously untreated 
intermediate/poor risk AML
Study 5:
JHOC J06133/
NCI-7889 
Phase 1 FLAM [10] 
Total: 
55
AML: 
49
Alvocidib dose-escalation in Hybrid 
regimen
20 mg/m2 & 30 mg/m2  
25 mg/m2 & 35 mg/m2 
30 mg/m2 & 40 mg/m2
30 mg/m2 & 50 mg/m2
30 mg/m2 & 60 mg/m2
30 mg/m2 & 70 mg/m2
given as: 
30-min bolus followed by 4-hr 
infusion/d on Days 1,2,3 
Ara-c: 2 gm/m2/72h by CIV given 
Days 6-8 
Mitoxantrone: 40 mg/m2 given by 
60-120 min IV on day 9
Adults median age 54, 
pathologically confirmed 
relapsed and refractory 
AML (49), ALL (3), ABL (3)


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Table 1: Overview of Alvocidib Phase 1 & 2 Clinical Studies in AML 
(In Chronologic Order) (cont)
Study (Reference)
N
Treatment Regimen
Patient Population
Study 6:
ECOG 1906 
Phase 2 
Randomized Trial 
of Carboplatin and 
Topotecan; 
Alvocidib, 
Mitoxantrone and 
Cytosine 
Arabinoside; and 
Sirolimus, 
Mitoxantrone, 
Etoposide and 
Cytosine 
Arabinoside for the 
Treatment of Adults 
With Primary 
Refractory or Initial 
Relapse of AML [16] 
Ongoing follow-up
AML
Total:
111
Arm B 
FLAM:
36
Arm A: CT
carboplatin and topotecan IV 
continuously over 24 hours on days 
1-5 
Arm B: Hybrid FLAM
Alvocidib: 30 mg/m2 by 30-min bolus 
followed by & 60 mg/m2  
by 4-hr CIV/day on Days 1,2,3
Ara-c: 2 gm/m2/72h by CIV given 
Days 6-8 
Mitoxantrone: 40 mg/m2 given by 
60-120 min IV on day 9
Arm C: Sirolimus-MEC
sirolimus PO QD on days 2-9, 
mitoxantrone hydrochloride IV over 
15 minutes QD, etoposide IV over 1 
hour QD, and Ara-c IV over 3 hours 
QD on days 4-8 or 5-9 
Adults 18-70 years, 
relapsed or refractory AML 
(36 on FLAM arm); 
median age 58
Study 7:
JHOC J0856/
NCI-8237
Phase 2 FLAM [17] 
AML
78
Arm A: Bolus FLAM
Alvocidib Bolus 1 hr IV: 
50 mg/m2/d on Days 1-3 
Ara-c: 2 gm/m2/72h by CIV given 
Days 6-8 
Mitoxantrone: 40 mg/m2 given by 
60-120 min IV on day 9
Arm B: Hybrid FLAM
Alvocidib: 30 mg/m2 by 30-min bolus 
followed by 40 mg/m2  
by 4-hr CIV/day on Days 1,2,3
Ara-c: 2 gm/m2/72h by CIV given 
Days 6-8 
Mitoxantrone: 40 mg/m2 given by 
60-120 min IV on day 9
Adults median age 61, 
newly diagnosed, 
pathophysiologically 
confirmed, previously 
untreated 
intermediate/poor risk AML
Study 8:
JHOC J1101/ 
NCI-8972 
Randomized 
Phase 2 
FLAM vs 7&3 [18] 
Ongoing follow-up
AML
Total:
165
FLAM:
109
7&3:
56
Arm A: Bolus FLAM
Alvocidib Bolus 1-hr IV: 
50 mg/m2/d on Days 1-3 
Ara-c: 2 gm/m2/72h by CIV given 
Days 6-8 
Mitoxantrone: 40 mg/m2 given by 
60-120 min IV on day 9
Arm B: 7&3
Ara-c: 100 mg/m2/day IV infusion 
Days 1-7 
Daunorubicin 90 mg/m2 /day IV over 
30-60 minutes Days 1, 2, 3
Adults median age 60 
(FLAM), newly diagnosed, 
pathologically confirmed, 
previously untreated 
intermediate/poor risk AML
(including Secondary 
AML)


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2.6.2 
Data Summaries from Phase 1 and 2 Clinical Studies in Patients 
with Relapsed/Refractory AML
Table 2, Table 3, and Table 4 provide details regarding the demographics, 
efficacy, and safety data, respectively, summarized from the five trials of FLAM 
in relapsed/refractory AML patients (ie, Studies 1, 2, 3, 5, and 6). 


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Table 2: Alvocidib/FLAM in AML (Demographics and Dosing in Relapsed/Refractory Patients)


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Table 3: Alvocidib/FLAM in AML (Efficacy Parameters in Relapsed/Refractory Patients)


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Table 4: Alvocidib/FLAM in AML (Safety Data in Relapsed/Refractory Patients)


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2.6.3 
Newly Diagnosed High-Risk AML
Multiple phase II studies have been conducted using ACM (FLAM) in patients 
with newly diagnosed high-risk AML.  In most studies high-risk AML was defined 
as disease that was treatment related, had secondary AML, or had adverse-risk 
cytogenetics. A key study was NCI-8972 (Table 1) where 165 newly diagnosed 
poor-risk patients were randomized to ACM versus 7&3. The primary endpoint 
of CR following one induction cycle was found to be statistically significant 
(p=0.08) and in favor of ACM-treated patients (70% CR) versus 7&3-treated 
patients (46% CR). ACM produced CR in 31/52 (60%) of patients with secondary 
AML compared to 9/26 (35%) treated with 7&3. In this study comparing ACM 
with 7&3 in poor-risk newly diagnosed patients the adverse events were similar 
in both arms. Comparative adverse events Grade 3 included (ACM:7&3): febrile 
neutropenia (48%, 45%), infection (35%, 38%), hepatic dysfunction (21%, 23%)
and GI events (11%, 9%). Treatment related mortality was also similar between 
the arms at 30-days: ACM 5% versus 7&3 2% or at 60-days ACM 10% versus 
7&3 4%. The majority of early deaths (8/11 patients) on ACM were >60 years.  
2.7 Justification for Study Treatment Plan
Based on the initial data from single-arm Phase 1 and 2 studies as well as 
randomized Phase 2 studies, Tolero is pursuing regulatory approval for alvocidib 
as part of the alvocidib, cytarabine (ara-c) and mitoxantrone hydrochloride 
regimen or “ACM regimen” in patients with relapsed or refractory AML. As 
previously noted, because there is no standard care for patients with 
relapsed/refractory AML, the 2014 NCCN guidelines recommend that these 
patients enroll in a clinical study testing new drugs or new combinations of drugs. 
The combination of cytarabine and mitoxantrone (CM) is one of the regimens 
that can be considered for these patients. 
NOXA binds and deactivates MCL-1. Early studies have shown that MCL-1
dependence can predict the clinical activity of alvocidib in AML patient samples 
and suggests an important role for MCL-1 activity in predicting alvocidib activity. 
As such, Tolero is conducting this Phase 2 study to test the ability of MCL-1
activity to predict which patients will response favorably to alvocidib treatment 
when administered as a bolus along with cytarabine and mitoxantrone.
While both the bolus as well as hybrid dosing regimens of FLAM have shown 
substantial activity in patients with AML, the hybrid regimen will be used in this 
study. Clinical data from a randomized study that compared the two dosing 
regimens suggest that the hybrid schedule tends to produce a higher remission 
rate (62% versus 74%) in poor-risk, newly diagnosed AML patients [17].


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We have also observed a high CR rate (39%) with the hybrid regimen in relapsed 
and refractory AML patients (and 92% CR among relapsed-only patients) [10]. 
In addition, the safety profile of the two regimens appears similar, though there 
may be a trend to lower early mortality with the hybrid regimen. In these two 
studies, the incidence of Tumor Lysis Syndrome (TLS) was 9%, and treatment-
related mortality was 8% and 9%, respectively. 
Dosing for the TPI-ALV-201 study is based on the first Phase 1 AML, dose-
escalation study of alvocidib and ara-C + mitoxantrone conducted at the 
University of Maryland and Johns Hopkins University (Study JHOC J0254/NCI-
3170 [12]). This initial study administered alvocidib by 1-hour bolus infusion 
daily × 3 at doses of 40, 50 or 60 mg/m2/d, followed by 2 gm/m2/72h ara-C over 
Days 6-8 and 40 mg/m2 mitoxantrone bolus on Day 9, in 34 adults with poor-risk, 
acute leukemia (including 22 with relapsed/refractory AML and 4 first-line AML 
patients). Additional studies utilizing a pharmacologically modeled ‘hybrid’ 
schedule of alvocidib—a shorter, 30-minute IV bolus of approximately one-third 
to one-half the total dose followed by a 4-hour continuous infusion of the 
remainder of the dose [19]—have been shown to be effective with acceptable 
safety mitigated by aggressive prophylactic treatments [10, 14, 17]. As such, the 
alvocidib dosing regimen has been revised in subsequent studies to a hybrid 
schedule of a 30-minute IV infusion followed by a 4-hour infusion which is the 
regimen chosen for this Phase 2 study.
The primary change being implemented in Amendment 11 is modifying the 
lower limit of MCL-1 dependency required for inclusion in the study from 
WRAt the time that this biomarker-driven study was conceived, 
the study design with hypothesis being tested was highly innovative with 
the use of an MCL-1 dependence assay to try and identify which patients 
ZRXOG EH PRVW OLNHO\ WR UHVSRQG WR DOYRFLGLE WKHUDS\ $V WKH WULDO
progressed, a second generation assay was developed which has shown 
more consistency and reliability than the first generation assa\ 0RUH
recent results indicate that an MCL-1 dependence score of 30 is the 
appropriate clinical cutoff for the assay versus an MCL-1 dependence 
VFRUH RI  WKDW ZDV XVHG SUHYLRXVO\ 8SRQ UHYLHZ RI GDWD IURP WKH
Exploratory Arm that included patients with MCL-1 dependence scores of 
30- LW EHFDPH DSSDUHQW WKDW ERWK WKH UHVSRQVH DQG -year survival 
UDWHVZHUHVLPLODUWRSDWLHQWVLQWKH!0&/-1 dependence group, ie, 
YVDQGYVUHVSHFWLYHO\,QDGGLWLRQWKHLQFOXVLRQRI
patients with MCL-GHSHQGHQFHVFRUHVRI-FRXOGLQFUHDVHDFFUXDO
by 25-WKHUHE\DOORZLQJIRUPRUHUDSLGFRPSOHWLRQRIWKHFXUUHQWVWXG\
and more timely development of the next generation of trials leading to 
UHJLVWUDWLRQ0RUHRYHULQFOXVLRQRIWKH-39 MCL-1 dependence group 
may be more accurate in terms of serving the subpopulation of patients 
with relapsed/refractory AML who are potentially responsive to, and likely 
WREHQHILWIURPWKH$&0UHJLPHQ


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2.8 Summary of Risk and Benefits
The safety profile for ACM (FLAM) has been well-described in the eight clinical 
studies in patients with AML, and appears to be acceptable for these poor-risk 
and pretreated patient populations. The early observation of tumor lysis and the 
potential for renal failure has resulted in an aggressive prophylaxis approach to 
manage the dramatic lysis of leukemic blasts caused by FLAM. Treatment-
related mortality (TRM) for patients treated with alvocidib/FLAM is approximately 
8-10%, with a range up to 28% in Study 6 of relapsed/refractory AML patients 
(particularly among patients over 60 years old). Overall, TRM of alvocidib/FLAM 
appears to be comparable to other therapeutic options including 7&3 and 
intermediate- and high-dose cytarabine.


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3.
STUDY OBJECTIVES
Stage 1: Primary Objective
x
To determine the CR rate in patients with relapsed or refractory AML with 
MCL-1 dependence of 30% 
Stage 2: Primary Objective
x
To compare CR rates between patients with relapsed or refractory AML with 
MCL-1 dependence of 30% receiving 1 cycle of ACM treatment and those 
receiving 1 cycle of CM. 
Exploratory Objective (Stage 2): To determine if treatment with ACM can induce 
CR in patients with relapsed or refractory AML with MCL-1 dependence of 30%
who failed to achieve CR following 1 cycle of CM. 


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4.
INVESTIGATIONAL PLAN
“FLAM” (alvocidib, cytarabine, mitoxantrone hydrochloride) will now be referred 
to as “ACM”.
“AM” (cytarabine, mitoxantrone hydrochloride) will now be referred to as “CM”.
4.1
Overall Study Design
This is a Phase 2, open-label, randomized, multicenter, two-stage study to 
determine if MCL-1 dependence demonstrated by mitochondrial profiling in bone 
marrow samples will increase the Complete Remission (CR) rate after ACM
treatment. 
Stage 1 of the study will be single arm (ACM), conducted similarly to the first 
stage of a Simon 2-stage design. Patients with relapsed or refractory AML with 
demonstrated MCL-1 dependence RI30% by mitochondrial profiling in bone 
marrow will be screened according to study inclusion and exclusion criteria up 
to 14 days before the initiation of ACM study treatment. 2QFH  SDWLHQWV
enrolled in Stage 1 exhibit a CR, CRi, or CRp, enrollment into Stage 1 will close 
and additional patients will be enrolled in Stage 2 of the study. 
Enrollment into Stage 1 will be limited to no more than 23 evaluable patients, 
however enrollment into Stage 2 may be initiated at any point after confirming 
CR, CRi or CRp responses in 13 Stage-1 patients.
In Stage 2, patients with relapsed or refractory AML with demonstrated MCL-1
dependence of 30% by mitochondrial profiling in bone marrow will be 
randomized 1:1 to receive either ACM or CM. Patients will be screened for study 
inclusion and exclusion criteria up to 14 days before the initiation of study 
treatment. 
Response assessments in Stage 1 are defined by the International Working 
Group Criteria [20] and 2010 European LeukemiaNet (ELN) [21]. The 2017 ELN 
criteria will be used to determine patient responses during Stage 2. Response 
assessments (Appendix E) will include:
x
CR rate = Percentage of patients achieving CR 
x
Combined CR Rate = Percentage of patients achieving:
o
CR = Bone marrow blasts <5%; absence of blasts with Auer rods; 
absence of extramedullary disease; hematologic recovery (absolute 
neutrophil count [ANC] >1000 μL and platelet count >100,000 μL); 
independence of red cell transfusions; plus
o
CRi = Meets all CR criteria except for residual neutropenia (ANC 
<1000 μL) or lack of recovery of any other hematopoietic cell; plus
o
CRp = Meets all CR criteria except for residual thrombocytopenia 
(platelet count <100,000 μL) †


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x
Combined Response Rate = Percentage of patients achieving:
o
CR
o
CRi
o CRp †
o
PR = Meets all hematologic values required for CR but with a decrease 
of at least 50% in thHSHUFHQWDJHRIEODVWVWRWRLQERQH
marrow
x
Overall Survival (OS) = Time from randomization (Day 1) until death from 
any cause
x
Event-free Survival (EFS) = Time from randomization (Day 1) until (a) 
treatment failure, (b) relapse after CR, or (c) death from any cause, 
whichever occurs first, censored at 2 years
x
Rate of Stem Cell Transplantation = Percentage of patients proceeding 
directly to stem cell transplantation
†Note that CRp has been retained in definitions for Combined CR Rate and 
Combined Remission Rate because Stage-1 patients were assessed using 
the IWG criteria. CRp will not be used for assessing response in Stage-2
patients and, therefore, will not be included in the definitions of Combined CR 
Rate and Combined Remission Rate in Stage 2. 
The CR rate in patients failing 1 cycle of CM and crossing over to receive 
ACM will also be determined.
Safety assessments will include:
x
Mortality from any cause at 30 and 60 days
x
Adverse events graded according to National Cancer Institute’s Common 
Terminology Criteria for Adverse Events (NCI CTCAE), version 4.03 in 
Stage 1 and version 5.0 in Stage 2
o The multivariate analysis and risk score prediction model by 
Montesinos and colleagues [22] will be used to assess the potential 
for development of TLS (Appendix F)
Treatment assessments will include: 
x
Bone marrow biopsies and/or aspirates will be performed at hematologic 
recovery (ie, absolute neutrophil count (ANC) >1000 μL and platelet count 
>100,000 μL) or Day 45, whichever occurs first. Slides from bone marrow 
will also be collected.
x
Complete blood counts and chemistries assessed daily while hospitalized 
for chemotherapy administration and weekly thereafter


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x
Overall survival (OS) monitored monthly during year 1, every 2 months 
during year 2  
x
Intensive monitoring of renal function, electrolytes and uric acid levels
Pharmacodynamic assessments will include: 
x
Determination of MCL-1 dependence at prescreening using bone marrow
aspirate  
Patients who achieve CR, CRi, CRp, or PR after the first cycle (completion of all 
doses) may receive up to 3 additional optional cycles of treatment. 
x
After completing the first cycle of treatment, continued use of 
mitoxantrone is optional. 
x
Mitoxantrone must be omitted from subsequent cycles if the patient’s 
lifetime daunorubicin equivalent exceeds 460 mg/m2 (see Appendix G for 
conversion table) or the LVEF drops below 45%.
Patients not demonstrating evidence of CR, CRi, CRp, or PR after the first cycle 
of treatment will be considered for removal from the study, although with 
permission of the Medical Monitor, induction treatment may continue, if clinically 
indicated, and proYLGHGWKHUHLVQRHYLGHQFHRIWR[LFLW\1&, CTCAE grade 4
(v4.03 in Stage 1, v5.0 in Stage 2; see Appendix C). This study also includes a 
crossover option for those randomized to CM (see below). 
x Crossover: Patients randomized to CM with progressive disease or no 
response after 1 cycle of CM may cross over to receive ACM. In addition, 
patients randomized to CM with the best response of a PR after 2 cycles of 
CM may also cross over to receive ACM. Patients who cross over to ACM
may receive up to a combined total (CM + ACM) of 4 cycles. Patients crossing 
over who meet the above criteria (lifetime daunorubicin equivalent exceeds 
460 mg/m2 or the LVEF drops below 45%) will receive only AC (alvocidib and 
cytarabine) for all cycles instead of ACM.
Complete remission rates will be compared across treatment groups using the 
Cochran-Mantel-Haenszel general association test stratified by response to 
most recent induction therapy. The same test will be applied to assess the 
statistical significance of the secondary response rate endpoints. 
Incidence rates of treatment-emergent adverse events (TEAEs) will be 
summarized within treatment group at the Medical Dictionary for Regulatory 
Activities (MedDRA) preferred term and primary system organ class levels. 
Similar summaries will be made for subsets of adverse events (AEs) such as 
(1) those judged by the Investigator to be related to study treatment, and 
(2) serious adverse events (SAEs).


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Other routine safety assessments (eg, clinical laboratory parameters and vital 
signs) will be summarized by treatment group using mean, standard deviation, 
median, minimum and maximum changes from baseline values.
The study is expected to take 20-24 months to enroll up to 137 patients:
25 patients in Stage 1; 56 patients in the 4 Exploratory Arms (closed after 
Amendment 8); and 56 patients (28 patients in each of two treatment arms) in 
Stage 2.  
4.2
Randomization Criteria
This study follows a randomized, two-stage design. During Stage 1, patients will 
receive ACM:  
x
ACM – Alvocidib, Cytarabine (ara-c), and Mitoxantrone). 
Once a minimum response threshold has been met in Stage 1 as defined in the 
Statistical Analysis Plan (SAP), Stage 1 will be closed to enrollment and new 
patients will be enrolled into Stage 2 and randomized 1:1 to receive either ACM
or CM: 
x
CM – Cytarabine (ara-c) and Mitoxantrone
Randomization to treatment arm will be stratified by: 
x
Response to first-line therapy:
o
Refractory: persistent disease or complete remission [CR] duration 
<90 days
o
Early relapse: CR duration 90 days to 1 year
o
Late relapse: CR duration >1 year but <24 months
4.3
Controls
An active comparator will be used (treatment with cytarabine and mitoxantrone 
[CM regimen]).
4.4
Patient Population
4.4.1
Number of Patients
A sufficient number of patients with demonstrated MCL-1 dependence by 
mitochondrial profiling in bone marrow will be screened in order to obtain up to 
137 eligible and evaluable patients. This includes 25 patients with MCL-1
GHSHQGHQFH 30% evaluated for response in Stage 1; 56 patients in the 
4 Exploratory Arms (closed after Amendment 8); and 56 patients with MCL-1
GHSHQGHQFH30% (28 patients in each of the two treatment arms) in Stage 2. 


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Patients who drop out prior to dosing will be replaced, but will still be included in 
the Intent-to-treat (ITT) analysis population. Patients who drop out of Stage 1 
prior to being assessed for response will be replaced, but will still be included in 
the ITT analysis population and in the Safety analysis population according to 
the analysis populations defined in Section 11.3. 
4.4.2
Inclusion Criteria
To be eligible for participation in the study, patients must meet all of the following 
inclusion criteria:
During Prescreening:
1. %HEHWZHHQWKHDJHVRIDQG\HDUV  
2. Have an established, pathologically confirmed diagnoses of AML by World 
Health Organization (WHO) criteria excluding acute promyelocytic leukemia 
(APL-M3) with a bone marrow of >5% blasts based on histology or flow 
cytometry
3. Be in first relapse (within 24 months of CR) or have failed induction therapy*
(no CR or CRi after
treatment with an intensive regimen [eg,
anthracycline/cytarabine 
± 
etoposide,
gemtuzumab 
ozogamicin,
or 
cladribine])  
*Induction therapy may involve 1 or 2 cycles of the same regimen. Efficacy 
assessment of induction therapy must be >21 days from the start of the 
previous induction cycle.
4. Demonstrate MCL-1 dependence of 30% by mitochondrial profiling in bone 
marrow
During Screening:
5. Have an Eastern Cooperative Oncology Group (ECOG) performance status 
36
6. Have a serum creatinine level 1.8 mg/dL  
7. Have an alanine aminotransferase (ALT)/aspartate aminotransferase (AST) 
OHYHOWLPHVXSSHUOLPLWRIQRUPDO8/1
8. +DYHDWRWDOELOLUXELQOHYHOPJG/XQOHVVVHFRQGDU\WRGilbert syndrome, 
hemolysis, or leukemia)
9. Have a left ventricular ejection fraction (LVEF) >45% by echocardiogram 
(ECHO) or multigated acquisition (MUGA) scan
10. Be nonfertile or agree to use an adequate method of contraception. Sexually 
active patients and their partners must use an effective method of 
contraception associated with a low failure rate during and for at least
6 months after completion of study therapy (see Section 4.7.3). 


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11. Be able to comply with the requirements of the entire study.
12. Provide written informed consent prior to any study related procedure. (In the 
event that the patient is re-screened for study participation or a protocol 
amendment alters the care of an ongoing patient, a new informed consent 
form must be signed.)
4.4.3
Exclusion Criteria
Patients meeting any one of these exclusion criteria will be prohibited from 
participating in this study.
1. Received more than 2 cycles of induction therapy for AML. Investigational 
agents as part of front-line therapy for AML may by acceptable following 
discussion with the Medical Monitor. Hydroxyurea is permitted (see #5 
below).
2. Received any previous treatment with alvocidib or any other CDK inhibitor
3. Received a hematopoietic stem cell transplant within the previous 2 months
4. Have clinically significant graft versus host disease (GVHD), or GVHD 
requiring initiation or escalation of treatment within the last 21 days
5. Require concomitant chemotherapy, radiation therapy, or immunotherapy. 
Hydroxyurea is allowed up to the evening before starting (but not within 
12 hours) of starting treatment on either arm.
6. Received >360 mg/m2 equivalents of daunorubicin (see Appendix G for 
conversion table)
7. Have a peripheral blast count of >30,000/mm3 (may use hydroxyurea as in 
#5 above)
8. Received antileukemic therapy within the last 3 weeks (with the exception of 
hydroxyurea or if the patient has definite refractory disease).  Refractory 
patients who received therapy within the last 3 weeks may be eligible with 
prior approval of the Medical Monitor.
9. Diagnosed with acute promyelocytic leukemia (APL, M3)
10. Have active central nervous system (CNS) leukemia
11. Have evidence of uncontrolled disseminated intravascular coagulation
12. Have an active, uncontrolled infection
13. Have other life-threatening illness 
14. Have other active malignancies or diagnosed with other malignancies within 
the last 6 months, except nonmelanoma skin cancer or cervical intraepithelial 
neoplasia


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15. Have mental deficits and/or psychiatric history that may compromise the 
ability to give written informed consent or to comply with the study protocol.
16. Are pregnant and/or nursing
17. Have received any live vaccine within 14 days prior to first study drug 
administration
4.5
Study Treatments
4.5.1
Calculation of Dose
The dosage of study drugs will be recalculated at the beginning of each new 
treatment cycle to reflect changes in the body surface area (BSA) that may have 
occurred but will remain the same for all treatments within a treatment cycle.
4.5.2
Treatment Plan
This is an open-label, randomized, multicenter, two-stage study in patients with 
AML with demonstrated MCL-1 dependence of 30% by mitochondrial profiling 
in bone marrow who are either in first relapse or have primary refractory AML.   
Stage 1 of the study will be single arm and all enrolled in this arm will receive 
treatment with ACM. Stage 2 will be two-arm; patients enrolled in this stage will 
be randomized to receive treatment with either ACM or CM.  
4.5.3 
Treatment Schema
 Stage 1:  Treatment with ACM over Days 1-9
Patients enrolled in Stage 1 will receive treatment with ACM as outlined below: 
x
Days 1, 2 and 3: alvocidib (A) - Administer Daily
30 mg/m2 as a 30-minute (±10 minutes) intravenous (IV) bolus 
followed by  
60 mg/m2 over 4 hours (±15 minutes) as an IV infusion 
x
Days 4 and 5:  Rest (no chemotherapy treatment)  
x
Days 6, 7, and 8: cytarabine (C) - Continuous over 72 hours
2 gm/m2 by continuous IV infusion over 72 hours (±2.5 hours)
(ie, 667 mg/m2 daily for total of 2 gm/m2)
x
Day 9: mitoxantrone hydrochloride (M) is administered 12 hours 
after completion of cytarabine treatment
40 mg/m2 by IV infusion over 1-2 hours (±10 minutes)


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 Stage 2:  Treatment with ACM or CM 
Patients enrolled in Stage 2 will be randomized to either ACM or CM and will 
receive treatment as outlined below:  
Stage 2: Randomized to ACM: Treatment with ACM over Days 1-9 
Follow the Stage 1 treatment schema above
Stage 2: Randomized to CM: Treatment with CM over Days 1-4 
x
Days 1, 2, and 3: cytarabine (C) - Continuous over 72 hours
2 gm/m2 by continuous IV infusion over 72 hours (±2.5 hours)
(ie, 667 mg/m2 daily for total of 2 gm/m2)
x
Day 4: mitoxantrone hydrochloride (M) is administered 12 hours 
after completion of cytarabine treatment 
40 mg/m2 by IV infusion over 1-2 hours (±10 minutes) 
 Evaluation After Cycle 1 
x
Patients who achieve CR, CRi, CRp, or PR after the first cycle (completion 
of all doses) may receive up to 3 additional optional cycles of treatment.
o
After completing the first cycle of treatment, continued use of 
mitoxantrone is optional.
o
Mitoxantrone must be omitted from subsequent cycles if the patient’s 
lifetime daunorubicin equivalent exceeds 460 mg/m2 (see Appendix G
for conversion table) or the left ventricular ejection fraction (LVEF) 
drops below 45%.
x
Patients not demonstrating evidence of CR, CRi, CRp, or PR after the first 
cycle of treatment will be considered for removal from the study, although 
with permission of the Medical Monitor, induction treatment may continue if 
FOLQLFDOO\LQGLFDWHGDQGSURYLGHGWKHUHLVQRHYLGHQFHRIWR[LFLW\1&,&7&$(
grade 4. 
x
Perform the End of Study Assessments for those patients who do not 
continue on study to receive at least one additional cycle of treatment (see
Section 5.5). 
 Crossover (Stage 2)
x Patients randomized to CM with progressive disease or no response after 
one cycle of CM may cross over to receive ACM.
x Patients randomized to CM with a best response of PR after 2 cycles of CM
may also cross over to receive ACM.


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x
Continued use of mitoxantrone is optional after completion of one cycle of 
ACM 
x
Mitoxantrone must be omitted from subsequent cycles if the patient’s lifetime 
daunorubicin equivalent exceeds 460 mg/m2 (see Appendix G for conversion 
table) or the left ventricular ejection fraction (LVEF) drops below 45%.  
Patients crossing over who meet the above criteria will receive only AC 
(alvocidib and cytarabine) for all cycles instead of ACM. 
x
Patients who cross over to ACM may receive up to a combined total (CM +
ACM) of 4 cycles.
4.6
Management of Toxicities and Dosage Modifications
Suggested doses of supportive care therapies are provided; however, 
adjustment of the dosages based on the patient’s clinical condition or each 
institution’s standard of care is permitted.
4.6.1
Management of Nonhematologic Toxicities
Adverse events may be treated with concomitant medications, as deemed 
clinically indicated by the Principal Investigator (PI). All concomitant medications 
must be recorded in the source and on the appropriate case report form (CRF). 
Adverse events that are moderate to severe in intensity (see Section 8.1 and
Appendix C for toxicity grading) and considered possibly or probably related to 
study drug treatments may result in the delay or termination of study treatment 
in affected patients.
 Hyperkalemia and Tumor Lysis Syndrome
Tumor lysis may occur as part of initial cytoreductive therapy. The most extreme 
form, known as Tumor Lysis Syndrome (TLS), is characterized by hyperkalemia, 
hyperuricemia, hyperphosphatemia, increased lactate dehydrogenase (LDH), 
coagulopathy, and a potential cytokine release syndrome. 
Mandatory IV hydration with 0.45% NaCl (or similar hydration fluid per 
institutional standard) sterile solution at 100 cc/hour for at least 10 hours prior to 
initiation of the first dose of chemotherapy during Cycle 1 (optional for 
subsequent cycles) in all treatment arms. If, by Day 4, there is no evidence of
tumor lysis syndrome, the hydration rate can be reduced to a maintenance level.  
Diligent monitoring of urine output frequently to ensure that fluid output equals 
fluid input. If input is greater than output by 10%, administration of diuretics is 
encouraged. Replacement of excessive fluid losses, including from 
diarrhea, should be done unless otherwise clinically indicated.
x
Mandatory allopurinol orally each day of dosing for first cycle to be started 
at same time as initiation of IV hydration in all treatment arms.


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x
Mandatory oral phosphate binder to be started at the same time as 
initiation of IV hydration in all treatment arms, unless contraindicated. 
x
Evaluation of laboratory indicators of tumor lysis syndrome (TLS) 
o
Tumor lysis laboratory evaluations (‘tumor lysis labs’) include 
electrolytes (sodium, potassium, chloride, and carbon dioxide) as 
well as creatinine, calcium, lactate dehydrogenase (LDH), uric 
acid, and phosphorus levels. 
o
For patients at high risk for TLS including those with risk scores 
RIDFFRUGLQJWRWKHWDEOHLQAppendix F, those with monocytic 
leukemia phenotype, or those with a history of FLT3 positive AML:

Patients randomized to ACM (or who cross over to ACM
after failure of CM):
x
Obtain a STAT serum potassium at end of alvocidib 
infusion
x
Strongly recommend serum potassium at 2 hours 
post end of alvocidib infusion as best practice
x
Obtain full TLS panel at 4 hours post end of alvocidib 
infusion
x
If evidence of clinically meaningful TLS, obtain TLS 
panel every 2 hours during the first 24 hours post end 
of alvocidib infusion (LDH levels are recommended 
to be assessed at least once every 24 hours). 
x
If no evidence of clinically meaningful TLS, obtain 
TLS panel every 4 hours during the first 24 hours 
post end of alvocidib infusion (LDH levels are 
recommended to be assessed at least once every 
24 hours). 
x
If, after the first 24 hours post end of alvocidib
infusion, there is no evidence of TLS, obtain TLS 
panel approximately every 6 hours for the remainder 
of alvocidib treatment and then every 12 hours after 
completion of alvocidib and during cytarabine and 
mitoxantrone (LDH levels are recommended to be 
assessed at least once every 24 hours). 
x
Monitor fibrinogen levels at baseline and then as 
clinically indicated. 
x
Patients who are determined to be at intermediate- 
or high-risk for TLS should be considered for 
rasburicase prophylaxis according to institutional 
standards


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
Patients randomized to CM: 
x
During the first 24 hours - Monitor tumor lysis labs at 
the start of cytarabine and approximately every 
6 hours. Laboratory studies during this period should
be run as a “STAT” to ensure the results are 
available in a timely manner.
x
If no evidence of TLS during the first 24 hours, then 
monitor tumor lysis labs every 12 hours until 
completion of mitoxantrone.
x
Monitor fibrinogen levels at baseline and then as 
clinically indicated. 
o
For patients NOT at high risk for TLS:

Patients randomized to ACM (or who cross over to ACM 
after failure of CM):
x
During the first 24 hours - Monitor tumor lysis labs at 
the start of alvocidib and approximately every 
4 hours. Laboratory studies during this period should 
be run as a “STAT” to ensure the results are 
available in a timely manner (LDH levels are 
recommended to be assessed at least once every 
24 hours). 
x
If no evidence of TLS during first 24 hours, then 
monitor tumor lysis labs approximately every 6 hours 
for the remainder of alvocidib treatment and then 
every 12 hours after the completion of alvocidib and 
during cytarabine and mitoxantrone (LDH levels are
recommended to be assessed at least once every 
24 hours). 
x
Monitor fibrinogen levels at baseline and then as 
clinically indicated.

Patients randomized to CM: 
x
During the first 24 hours - Monitor tumor lysis labs at 
the start of cytarabine and approximately every 
6 hours. Laboratory studies during this period should
be run as a “STAT” to ensure the results are 
available in a timely manner. 


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x
If no evidence of TLS during first 24 hours, then 
monitor tumor lysis labs every 12 hours until 
completion of mitoxantrone.
x
Monitor fibrinogen levels at baseline and then as 
clinically indicated.
Risk of TLS and Guidelines for Management of High Risk Patients
TLS management during treatment with alvocidib was implemented in previous 
studies, which included medical prophylaxis for hyperuricemia, as well as 
aggressive monitoring and management of hyperkalemia and other biochemical 
laboratory abnormalities. Rapid development of hyperkalemia has been of 
particular concern in earlier studies. While these guidelines are not necessarily 
consistent with specific standard recommendations for the treatment of TLS, 
they are recommended based on previous experience with the treatment of 
patients with alvocidib. These measures resulted in a lower incidence of TLS 
without adverse outcomes. 
For this reason, you are encouraged to follow the recommended guidelines
below but may follow your own institution’s protocols in determining the best 
treatment for your patients.
x
If potassium levels are increasing to >4.0 mEq/L, patients should receive 
a 30-gm dose of sodium polystyrene sulfonate, unless there are other 
likely causes of hyperkalemia other than TLS or contraindication to its 
use.  
x
If potassium levels rise to >5.0 mEq/L, in addition to the 30-gm dose of 
sodium polystyrene sulfonate, patients should also receive 10 units of 
IV rapid-acting insulin and 25 gm (one ampule) of IV dextrose 50%,
unless there are other likely causes of hyperkalemia other than TLS or 
contraindication to its use. 
x
If potassium levels rise to >5.5 mEq/L, patients should be considered for 
emergent intermittent or continuous dialysis.
x
Calcium supplementation should only be given for symptomatic 
hypocalcemia in this setting to avoid renal precipitation of calcium 
phosphate crystals.
x
Patients who develop clinical evidence of cytokine release syndrome or 
who have hyperkalemia requiring dialysis will receive immediate steroid
therapy with an equivalent of at least 20 mg of IV dexamethasone.


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 Diarrhea
If diarrhea occurs during therapy, patients should initiate loperamide (or 
equivalent) 2 mg by mouth every 2 hours during the waking hours. The rapid 
introduction of loperamide (or equivalent) at the first signs of diarrhea is strongly 
encouraged. Testing for Clostridioides difficile (C. difficile) should start with first 
episode of diarrhea. Should testing indicate the presence of C. difficile,
appropriate antibiotics targeting this infection should be initiated. Should testing 
exclude the presence of C. difficile, loperamide should be continued. Once the 
diarrhea is controlled, the time interval of loperamide may be titrated to a 
frequency that adequately controls the diarrhea. The diarrhea observed with 
alvocidib almost always resolves following completion of therapy, so treatment 
with loperamide following completion of therapy will not be required in most 
patients. If loperamide (or equivalent) does not control diarrhea, cholestyramine 
(or equivalent) 5 gm orally four (4) times daily may be added. For patients 
developing diarrhea during alvocidib administration, subsequent treatments 
should include a similar diarrhea prophylaxis. If diarrhea is not controlled with 
the above prophylactic regimen and is grade 2 or greater, therapy should be held 
until diarrhea has resolved. Replacement of excessive fluid losses should be 
done unless otherwise clinically indicated.
 Nausea/Vomiting
Antiemetics (ie, 5-hydroxytryptamine [5-HT3] receptor inhibitor or other 
antiemetic medications) are permitted according to standard practices at each 
investigational site. 
 Infection Prevention
Prophylactic antibiotics including levofloxacin (or equivalent) 500 mg orally once
daily and valacyclovir (or equivalent) 500 mg orally BID each day should be 
administered to patients in all treatment arms at the start of chemotherapy.
Alternative prophylactic antibiotic or antiviral therapy is left to the discretion of 
the treating physician and according to institutional standards. For guidance on 
possible C. difficile infections, refer to Section 4.6.1.2.
Antifungal prophylaxis to be administered according to each institution’s 
standard of care.
To prevent cytarabine-related conjunctivitis, corticosteroid eye drops per 
institutional formulary (eg, prednisolone 0.1%) must begin 1 day prior to 
institution of cytarabine infusion (ie, Day 6 for ACM; Day 1 for CM) and continue 
for at least 7 days.  
Routine growth factor support LVQRWDOORZHG'D\RIWKHUDS\*URZWKIDFWRU
support can be given at the discretion of the Investigator >Day 35 of therapy in 
the presence of life-threatening infection with ongoing neutropenia.  


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Donor lymphocyte infusions are not allowed unless discussed and approved by 
the medical monitor.
4.6.2
Management of Hematologic Toxicities
Adverse events that are moderate to severe in intensity (see Section 8.1 and 
Appendix C for toxicity grading) and considered possibly or probably related to 
study drug treatments may result in the termination of study treatment in the 
affected study patient. Such termination should be reviewed with the Sponsor’s 
Medical Monitor at the earliest possible time (see Section 8.5). Following review 
with the Sponsor’s Medical Monitor, the study patient may be permanently 
withdrawn from the study depending upon the nature and severity of the event.
Adverse events may be treated with concomitant medications, as deemed 
clinically indicated by the PI. All concomitant medications must be recorded on 
the appropriate CRF. 
4.6.3
Dose Modifications
There will be no dose reductions for alvocidib or cytarabine. The dose of 
mitoxantrone must be reduced by 50% if the patient’s total bilirubin value is 
>3 mg/dL and <5 mg/dL, and must be omitted if the patient’s total bilirubin value 
is 5 mg/dL on the day of planned mitoxantrone administration. After completing 
the first cycle of treatment, continued use of mitoxantrone is optional. 
Mitoxantrone must be omitted from subsequent cycles if the patient’s lifetime 
daunorubicin equivalent exceeds 460 mg/m2 (see Appendix G for conversion 
table) or the left ventricular ejection fraction (LVEF) drops below 45%.
4.7
Concomitant Medications and Therapies
4.7.1
Previous Therapies
During Screening, patients will be asked about all previous therapies and all 
medications used during the previous 30 days from anticipated first dose. This 
information will be recorded in the source documentation and appropriate CRF 
along with the diagnosis or reason for use. If a branded product is being taken, 
the generic name should be reported, if known.  
Subjects will not be enrolled into the study if they have had any previous 
treatment with alvocidib or other CDK inhibitor, or have received >360 mg/m2
equivalents of daunorubicin (see Appendix G for conversion table). 


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4.7.2
Concomitant Therapies
Concomitant therapies are any new or existing medications or therapy taken by 
the patient including:
x
Drugs, including but not limited to, prescription, over-the-counter, birth 
control pills/patches/hormonal devices, and homeopathic preparations
x
Nondrug therapies, including but not limited to, thermal/laser/radiation 
procedures, vitamins, herbal medicines/supplements.
During the Screening process (up to two weeks prior to anticipated first dose of 
study drug), information on all concomitant therapies, medications, and 
procedures will be recorded in the source documents and appropriate CRF along 
with the diagnosis or reason for use. 
Once the patient receives the first dose of study drug, recording of concomitant 
therapies will be limited to any new medication or modification of an existing 
medication taken for treatment of an adverse event (AE). These therapies will 
be recorded in the source documents and appropriate CRF along with the 
diagnosis or reason for use. Those therapies used for the treatment of an 
adverse event are to be linked to an AE and documentation of the AE must also 
be completed (refer to Section 8).  
If a branded product is being taken, the generic name should be reported, if 
known.  
 Mandated / Permitted Therapies
Concomitant medications necessary for the health and well-being of the patient 
and that do not interfere with study assessments are permitted during the study 
at the Investigator’s discretion. This includes the use of appropriate medications 
for the treatment of AEs and/or concurrent illnesses under the direction of the 
Principal Investigator. All such therapies must be recorded in the source and on 
the appropriate CRF.  
In patients with rapidly proliferating disease, hydroxyurea may be administered 
up to the evening before starting treatment in either Stage, but not within 
12 hours prior to dosing.
Patients may be allowed on study if they have undergone a diagnostic lumbar 
puncture (LP) for suspected CNS leukemic involvement. If, at the time of the LP, 
they received a single dose of intrathecal (IT) chemotherapy, that patient would 
still be considered eligible for this study so long as the LP was negative for CNS 
disease. Should the LP indicate positive cytology necessitating continued IT
therapy, the patient would be ineligible for study inclusion.
Medications and procedures that are mandatory or permitted during the study
are listed in Section 4.6.1. 


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 Prohibited Therapies
The following medications are excluded from concomitant use: 
x
Antileukemic therapy (chemotherapy, radiation therapy, immunotherapy) 
within the last 3 weeks prior to the first study drug administration and 
during the cycle of study treatment (see Section 4.7.2.1 for permitting prior 
hydroxyurea and IT chemotherapy)
x
Live vaccines within 14 days prior to first study drug administration, during 
the study, and for approximately 3 months after the last dose of study 
drug.
x
Donor lymphocyte infusions are not allowed unless discussed and 
approved by the medical monitor.
4.7.3
Birth Control Requirements for Fertile Patients
Sexually active patients and their partners must use an effective method of 
contraception associated with a low failure rate during and for at least 6 months 
after completion of study therapy. The following are considered effective 
contraceptives: (1) oral contraceptive pill; (2) condom plus spermicide;
(3) diaphragm plus spermicide; (4) true abstinence when this is in line with the 
preferred and usual lifestyle of the subject (periodic abstinence [eg, calendar, 
ovulation, symptothermal, post-ovulation methods, etc], declaration of 
abstinence for the duration of exposure to study drugs, and withdrawal are not 
acceptable methods of contraception); (5) patient or partner surgically sterile; (6) 
patient or partner more than 2 years post-menopausal; or (7) injectable or 
implantable agent/device. Male patients enrolled in the study must use a condom 
to avoid exposing partners to semen, which may contain toxic drugs.
4.8
Protocol Deviations
It is expected that this study will be conducted as described in this protocol, 
except for an emergency situation in which the protection, safety and well-being 
of the patient requires immediate intervention, based on the judgment of the 
Principal Investigator (or a responsible, appropriately trained and credentialed 
professional[s] designated by the PI). In the event of a significant deviation from 
the protocol due to an emergency, accident or error, the PI or Designee must 
contact the Sponsor at the earliest possible time by telephone. This will allow an 
early joint decision to be made as to whether or not the patient should continue 
in the study. This decision will be documented in writing by both the PI and the 
Sponsor.
4.9
Other Precautions
Dose adjustments for nonhematologic and hematologic toxicities and laboratory 
abnormalities will be made according to Section 4.6.1 and Section 4.6.2,
respectively. 


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5.
ON-STUDY CLINICAL AND LABORATORY EVALUATIONS
See Appendix A - Schedule of Activities
5.1
Prescreening (Stage 1, Stage 2)
x
Obtain written informed consent (must be obtained prior to prescreening 
evaluations)
x
Perform bone marrow aspiration for mitochondrial profiling to determine
MCL-1 dependence. If the initial bone marrow aspirate is nonproductive 
or not diagnostic, the procedure must be repeated. (An aspirate must be 
obtained for mitochondrial profiling to determine MCL-1 dependence).
x
Collect a disease history including pathological confirmed diagnosis of 
AML by WHO criteria and confirmation of either relapsed/refractory 
disease or newly diagnosed high-risk disease. 
5.2
Screening (Stage 1, Stage 2)
5.2.1
Within 2 Weeks Prior to First Dose 
If the MCL-1 dependence scores are 30%, perform the following activities and 
evaluations within 2 weeks prior to administration of the first dose of 
chemotherapy to determine if a patient meets the eligibility criteria:
x
Collect and document a complete medical history including pathological 
confirmed diagnosis of AML by WHO criteria and all other measures of 
disease and disease symptoms (eg, extramedullary disease)
x
Perform a complete physical examination including height (cm) and 
weight (kg)
x Assess ECOG PS (Appendix B) 
x
Record vital signs (temperature, heart rate, systolic and diastolic blood 
pressures)
x
Perform bone marrow biopsy and/or aspiration for diagnosis and 
cytogenetic profiling. If the initial bone marrow biopsy and/or aspirate is 
nonproductive or not diagnostic, the procedure must be repeated.  
o
If an aspirate with cytogenetics was performed as part of the 
mitochondrial profiling to determine MCL-1 dependence and it was 
done within 2 weeks of the first dose, then it does not need to be 
repeated. 


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o
In addition, 6 to 8 bone marrow slides will be prepared at screening 
(in addition to the fresh bone marrow samples required for 
mitochondrial profiling to determine MCL-1 dependence) and sent 
to the Sponsor. Details regarding the collection and shipping of 
these slides is provided in the Study Manual.
x
Perform 12-lead electrocardiogram (ECG)
x
Perform echocardiogram (ECHO) or multigated acquisition (MUGA) scan 
x
Perform chest radiograph (may omit, if performed within 30 days prior to 
anticipated first dose)
x
Record all concomitant medications including all prescription drugs, 
nonprescription drugs, and nutritional supplements within the past 
2 weeks
5.2.2
Within 72 Hours Prior to First Dose (Stage 1, Stage 2) 
Perform the following activities and evaluations within 72 hours prior to
administration of the first dose of study drug:
x
Collect blood for evaluation of laboratory parameters (Appendix D): 
o
Hematology
o
Full serum chemistry panel
x
Collect urine sample for full urinalysis
x
&ROOHFWXULQHRUVHUXPVDPSOHIRUȕ-hCG pregnancy test (urine or serum) 
for females of child-bearing potential
x
Record all concomitant medications including all prescription drugs, 
nonprescription drugs, and nutritional supplements
Review all Inclusion/Exclusion criteria and determine if patient has met all 
eligibility criteria for inclusion into the study.  
Refer to the Study Manual of Procedures for detailed instructions on 
enrollment (and randomization for Stage 2). 
5.3 Stage 1 Assessments
Sections 5.3.1 – 5.3.5.6 applies for all patients enrolled in Stage 1.
5.3.1
Assessments Required Prior to First Dose
Within 24 hours prior to first dose, patients will be hospitalized to receive 
supportive care measures and should remain hospitalized at least through 
Day 9. Patients will be discharged after Day 9 once deemed clinically stable by 
the investigator.  


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31 Cycle 1 – At Least 10 Hours Prior to First Dose
Perform the following procedures at least 10 hours prior to dosing on Day 1:
x
Physical examination including weight (kg) for calculation of body surface 
area (BSA)
x
Assess ECOG PS (Appendix B) 
x
Initiate supportive care measures at least 10 hours prior to first dose in all 
patients to minimize the likelihood of tumor lysis syndrome:
o
Administer pretreatment IV hydration, oral allopurinol, and oral 
phosphate binder (see Section 4.6.1) 
o
Diligent monitoring of urine output frequently to ensure that it 
equals fluid input. If input is greater than output by 10%, 
administration of diuretics is encouraged. Replacement of 
excessive fluid losses, including from diarrhea, should be done 
unless otherwise clinically indicated.
x
Record all concomitant medications including all prescription drugs, 
nonprescription drugs, and nutritional supplements taken since 
screening. 
312 Cycle 1, Day 1 – Just Prior to First Dose
Perform the following procedures just prior to dosing on Day 1:
x
Record vital signs (body temperature, heart rate, systolic and diastolic 
blood pressures) measured 5-15 minutes prior to the initiation of infusion 
following a 5-minute rest
x Collect blood for evaluation of laboratory parameters (Appendix D): 
o
Tumor lysis labs to include electrolytes (sodium, potassium, 
chloride, and carbon dioxide) as well as creatinine, calcium, lactate 
dehydrogenase (LDH), uric acid, and phosphorus levels
o
Coagulation: fibrinogen level
x
&ROOHFWXULQHRUVHUXPVDPSOHIRUȕ-hCG pregnancy test for females of 
child-bearing potential if screening pregnancy test is greater than 
72 hours prior to first dose
x
Record all concomitant medications including all nonprescription drugs 
and nutritional supplements


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5.3.2 
Cycle 1, Day 1 – Dosing
All Patients (regardless of risk of TLS): 
x
Monitor tumor lysis labs at the start of alvocidib and throughout the 
treatment cycle according to the schedule outlined in Section 4.6.1.1.
[Note: there are different blood collection schedules for monitoring of TLS 
labs for patients at high risk of TLS and for those NOT at high risk for 
TLS.] 
x
Monitor fibrinogen levels as clinically indicated.
x
Monitor urine output frequently to ensure that it equals fluid input. If input 
is greater than output by 10%, administration of diuretics is encouraged. 
Replacement of excessive fluid losses, including from diarrhea, should be 
done unless otherwise clinically indicated.
x
Test for presence of C. difficile infection at first instance of diarrhea (refer 
to Section 4.6.1.2 for additional guidance)
x
Administer prophylactic antibiotics and antivirals, corticosteroid eye 
drops, and antifungals according to Section 4.6.1.4
x
Assess for AEs
x
Record only those medications (prescription, nonprescription, nutritional 
supplements) administered in conjunction with an AE.
321 Cycle 1 – Daily during Hospitalization for Chemotherapy
Perform the following procedures daily (or more frequently if clinically indicated) 
while patients are hospitalized for chemotherapy administration (ie, Days 2-9): 
x
Collect blood for evaluation of laboratory parameters (Appendix D):
o
Hematology
o
Tumor lysis labs as outlined in Section 4.6.1.1 (or more frequently 
if clinically indicated) 
o
Fibrinogen level (as clinically indicated)
x
Monitor urine output frequently to ensure that it equals fluid input. If input 
is greater than output by 10%, administration of diuretics is encouraged. 
Replacement of excessive fluid losses, including from diarrhea, should be 
done unless otherwise clinically indicated.
x
Test for presence of C. difficile infection at first instance of diarrhea (refer 
to Section 4.6.1.2 for additional guidance)
x
Assess for AEs
x
Record only those medications (prescription, nonprescription, nutritional 
supplements) administered in conjunction with an AE.


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5.3.3 
Cycle 1 – Weekly after Completion of Chemotherapy Regimen
Perform the following procedures weekly (or more frequently if clinically 
indicated) after patients have completed their chemotherapy regimen:
x
Abbreviated physical examination (AE- or symptom-directed exam) 
including weight (kg)
x
Vital signs (temperature, heart rate, systolic and diastolic blood 
pressures)
x
Collect blood for evaluation of laboratory parameters (Appendix D):
o
Hematology
o
Tumor lysis labs
o
Fibrinogen level (as clinically indicated)
x
Assess ECOG PS (Appendix B) 
x
Assess for AEs
x
Record only those medications (prescription, nonprescription, nutritional 
supplements) administered in conjunction with an AE.
5.3.4 
Cycle 1 – At Hematologic Recovery
x
Assess response by bone marrow biopsy and/or aspiration at time of 
hematologic recovery (ie, absolute neutrophil count (ANC) >1000 μL and 
platelet count >100,000 μL) or Day 45 (±2), whichever occurs first. If the 
bone marrow biopsy and/or aspirate is nonproductive or not diagnostic, 
the procedure must be repeated within 7 days.  
o
At time of response assessment, 6 to 8 bone marrow slides will be 
prepared and sent to the Sponsor. Details regarding the collection 
and shipping of these slides is provided in the Study Manual.
x
Assess for AEs, including tumor lysis clinical symptoms
x
Record only those medications (prescription, nonprescription, nutritional 
supplements) administered in conjunction with an AE.
5.3.5 
Cycles 2 - 4 
Patients who achieve CR, CRi, CRp, or PR after the first cycle (completion of all 
doses) may receive up to 3 additional optional cycles of treatment. After 
completing the first cycle of treatment, continued use of mitoxantrone is optional. 
Mitoxantrone must be omitted from subsequent cycles if the patient’s lifetime 
daunorubicin equivalent exceeds 460 mg/m2 (see Appendix G for conversion 
table) or the LVEF drops below 45%.


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Patients not demonstrating evidence of CR, CRi, CRp, or PR after the first cycle 
of treatment will be considered for removal from the study, although with 
permission of the Medical Monitor, induction treatment may continue if clinically
LQGLFDWHGDQGSURYLGHGWKHUHLVQRHYLGHQFHRIWR[LFLW\1&, CTCAE grade 4
(v4.03 in Stage 1, v5.0 in Stage 2; see Appendix C). 
There is a maximum limit of 90 days between the start of cycles unless otherwise 
discussed with the medical monitor. 
35 Cycles 2 - 4, Day 1 – At Least 10 Hours Prior to First Dose
Perform the following assessments in patients receiving subsequent cycles of 
chemotherapy:
x
If clinically indicated, administer pretreatment IV hydration, oral 
allopurinol, and oral phosphate binder (see Section 4.6.1) 
x
If supportive care measures for prevention of tumor lysis are initiated, 
monitor urine output frequently to ensure that it equals fluid input. If input 
is greater than output by 10%, administration of diuretics is encouraged. 
Replacement of excessive fluid losses, including from diarrhea, should be 
done unless otherwise clinically indicated.
x
ECHO or MUGA scan to be performed before each dose of mitoxantrone. 
If mitoxantrone is omitted after Cycle 1, the ECHO or MUGA scan can 
also be omitted.
35 Cycles 2 - 4, Day 1 – Just Prior to First Dose
Perform the following procedures just prior to dosing on Day 1:
x
Physical examination including weight (kg) for recalculation of BSA
x
Record vital signs measured 5-15 minutes prior to the initiation of infusion 
following a 5-minute rest
x
Assess ECOG PS (Appendix B) 
x
Collect blood for evaluation of laboratory parameters (Appendix D):
o
Hematology
o
Tumor lysis labs
o
Fibrinogen level (as clinically indicated)
x
If supportive care measures for prevention of tumor lysis were initiated, 
monitor urine output frequently to ensure that it equals fluid input. If input 
is greater than output by 10%, administration of diuretics is encouraged. 
Replacement of excessive fluid losses, including from diarrhea, should be 
done unless clinically indicated.
x
&ROOHFWXULQHRUVHUXPVDPSOHIRUȕ-hCG pregnancy test for females of 
child-bearing potential. 


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x
Record only those medications (prescription, nonprescription, nutritional 
supplements) administered in conjunction with an AE. 
35 Cycles 2 - 4, Day 1 – Dosing
x
Collect blood for evaluation of laboratory parameters (Appendix D):
o
Hematology
o
Tumor lysis labs
o
Fibrinogen level (as clinically indicated)
x
If supportive care measures for prevention of tumor lysis were initiated, 
monitor urine output frequently to ensure that it equals fluid input. If input 
is greater than output by 10%, administration of diuretics is encouraged. 
Replacement of excessive fluid losses, including from diarrhea, should be 
done unless otherwise clinically indicated.
x
Test for presence of C. difficile infection at first instance of diarrhea (refer 
to Section 4.6.1.2 for additional guidance)
x
Administer prophylactic antibiotics and antivirals, corticosteroid eye 
drops, and antifungals according to Section 4.6.1.4.
x Assess for AEs
x
Record only those medications (prescription, nonprescription, nutritional 
supplements) administered in conjunction with an AE. 
354 Cycles 2 - 4 – Daily during Hospitalization for Chemotherapy
Perform the following procedures daily (or more frequently if clinically indicated) 
while patients are hospitalized for chemotherapy administration (ie, Days 2-9): 
x
Collect blood for evaluation of laboratory parameters (Appendix D):
o
Hematology
o
Tumor lysis labs
o
Fibrinogen level (only required if clinically indicated)
x
If supportive care measures to prevent/treat tumor lysis were initiated, 
must monitor urine output frequently to ensure that it equals fluid input. 
If input is greater than output by 10%, administration of diuretics is 
encouraged. Replacement of excessive fluid losses, including from 
diarrhea, should be done unless otherwise clinically indicated.
x
Test for presence of C. difficile infection at first instance of diarrhea (refer 
to Section 4.6.1.2 for additional guidance)
x
Assess for AEs
x
Record only those medications (prescription, nonprescription, nutritional 
supplements) administered in conjunction with an AE.


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355 Cycles 2 - 4 – Weekly after Completion of Chemotherapy Regimen
Perform the following procedures weekly (or more frequently if clinically 
indicated) after patients have completed their chemotherapy regimen:
x
Abbreviated physical examination including weight (kg)
x
Vital signs (temperature, heart rate, systolic and diastolic blood 
pressures)
x
Assess ECOG PS (Appendix B) 
x
Collect blood for evaluation of laboratory parameters (Appendix D):
o
Hematology
o
Tumor lysis labs
o
Fibrinogen level (only required if clinically indicated)
x
Assess for AEs
x
Record only those medications (prescription, nonprescription, nutritional 
supplements) administered in conjunction with an AE.
356 Cycles 2 - 4 – At Hematologic Recovery 
x
Assess response by bone marrow biopsy and/or aspiration at time of 
hematologic recovery (ie, absolute neutrophil count (ANC) >1000 μL and 
platelet count >100,000 μL) or Day 45 (±2), whichever occurs first. If the 
bone marrow biopsy and/or aspirate is nonproductive or not diagnostic, 
the procedure must be repeated within 7 days.  
o
At time of response assessment, 6 to 8 bone marrow slides will be 
prepared and sent to the Sponsor. Details regarding the collection 
and shipping of these slides is provided in the Study Manual.
x
Assess for AEs, including tumor lysis clinical symptoms
x
Record only those medications (prescription, nonprescription, nutritional 
supplements) administered in conjunction with an AE. 


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5.4 Stage 2 Assessments
Sections 5.4.1 – 5.4.5.6 applies for all patients enrolled in Stage 2.
5.4.1 
Assessments Required Prior to First Dose
411 Cycle 1, Day 1 – At Least 10 Hours Prior to First Dose
Perform the following procedures at least 10 hours prior to dosing on Day 1:
x
Physical examination including weight (kg) for calculation of body surface 
area (BSA)
x
Assess ECOG PS (Appendix B) 
x
Initiate supportive care measures at least 10 hours prior to first dose in all
patients to minimize the likelihood of tumor lysis syndrome:
o
Administer pretreatment IV hydration, oral allopurinol, and oral 
phosphate binder (see Section 4.6.1) 
o
Diligent monitoring of urine output frequently to ensure that it 
equals fluid input. If input is greater than output by 10%, 
administration of diuretics is encouraged. Replacement of 
excessive fluid losses, including from diarrhea, should be done 
unless otherwise clinically indicated.
x
Record all concomitant medications including all prescription drugs, 
nonprescription drugs, and nutritional supplements taken since 
screening. 
412 Cycle 1, Day 1 – Just Prior to First Dose
Perform the following procedures just prior to dosing on Day 1:
x
Record vital signs (body temperature, heart rate, systolic and diastolic 
blood pressures) measured 5-15 minutes prior to the initiation of infusion 
following a 5-minute rest
x
Collect blood for evaluation of laboratory parameters (Appendix D): 
o
Tumor lysis labs to include electrolytes (sodium, potassium, 
chloride, and carbon dioxide) as well as creatinine, calcium, lactate 
dehydrogenase (LDH), uric acid, and phosphorus levels. 
o
Coagulation: fibrinogen level
x
&ROOHFWXULQHRUVHUXPVDPSOHIRUȕ-hCG pregnancy test for females of 
child-bearing potential if screening pregnancy test is greater than 
72 hours prior to first dose. 
x
Record all concomitant medications including all nonprescription drugs 
and nutritional supplements. 


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5.4.2 
Cycle 1, Day 1 – Dosing
All Patients (regardless of risk of TLS): 
x
Monitor tumor lysis labs at the start of treatment (alvocidib for ACM,
cytarabine for CM) and throughout the treatment cycle according to the 
schedule outlined in Section 4.6.1.1. [Note: there are different blood 
collection schedules for monitoring of TLS labs for patients at high risk of 
TLS and for those NOT at high risk for TLS.] 
x
Monitor fibrinogen levels as clinically indicated.
x
Monitor urine output frequently to ensure that it equals fluid input. If input 
is greater than output by 10%, administration of diuretics is encouraged.
Replacement of excessive fluid losses, including from diarrhea, should be 
done unless otherwise clinically indicated.
x
Test for presence of C. difficile infection at first instance of diarrhea (refer 
to Section 4.6.1.2 for additional guidance)
x
Administer prophylactic antibiotics and antivirals, corticosteroid eye 
drops, and antifungals according to Section 4.6.1.4.
x
Assess for AEs
x
Record only those medications (prescription, nonprescription, nutritional 
supplements) administered in conjunction with an AE.
42 Cycle 1 – Daily during Hospitalization for Chemotherapy
Perform the following procedures daily (or more frequently if clinically indicated) 
while patients are hospitalized for chemotherapy administration (ie, Days 2-9 for 
patients receiving ACM: Days 1-3 for patients receiving CM): 
x
Collect blood for evaluation of laboratory parameters (Appendix D):
o
Hematology
o
Tumor lysis labs daily (or more frequently if clinically indicated) 
o
Fibrinogen level (only required if clinically indicated) 
x
Monitor urine output frequently to ensure that it equals fluid input. If input 
is greater than output by 10%, administration of diuretics is encouraged.
Replacement of excessive fluid losses, including from diarrhea, should be 
done unless otherwise clinically indicated.
x
Test for presence of C. difficile infection at first instance of diarrhea (refer 
to Section 4.6.1.2 for additional guidance)
x
Assess for AEs
x
Record only those medications (prescription, nonprescription, nutritional 
supplements) administered in conjunction with an AE.


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5.4.3 
Cycle 1 – Weekly after Completion of Chemotherapy Regimen
Perform the following procedures weekly (or more frequently if clinically 
indicated) after patients have completed their chemotherapy regimen:
x
Abbreviated physical examination including weight (kg)
x
Vital signs (temperature, heart rate, systolic and diastolic blood
pressures)
x
Collect blood for evaluation of laboratory parameters (Appendix D):
o
Hematology
o
Tumor lysis labs
o
Fibrinogen level (only required if clinically indicated)
x
Assess for AEs
x
Record only those medications (prescription, nonprescription, nutritional
supplements) administered in conjunction with an AE.
5.4.4 
Cycle 1 – At Hematologic Recovery
x
Assess response by bone marrow biopsy and/or aspiration at time of
hematologic recovery (ie, absolute neutrophil count (ANC) >1000 μL and
platelet count >100,000 μL) or Day 45 (±2), whichever occurs first. If the
bone marrow biopsy and/or aspirate is nonproductive or not diagnostic,
the procedure must be repeated within 7 days.
o
At time of response assessment, 6 to 8 bone marrow slides will be
prepared and sent to the Sponsor. Details regarding the collection
and shipping of these slides is provided in the Study Manual.
x
Assess for AEs, including tumor lysis clinical symptoms
x
Record only those medications (prescription, nonprescription, nutritional
supplements) administered in conjunction with an AE.
5.4.5 
Cycles 2 - 4
Patients who achieve CR, CRi, CRp, or PR after the first cycle (completion of all 
doses) may receive up to 3 additional optional cycles of treatment. After 
completing the first cycle of treatment, continued use of mitoxantrone is optional. 
Mitoxantrone must be omitted from subsequent cycles if the patient’s lifetime 
daunorubicin equivalent exceeds 460 mg/m2 (see Appendix G for conversion 
table) or the LVEF drops below 45%.
Patients not demonstrating evidence of CR, CRi, CRp, or PR after the first cycle 
of treatment will be considered for removal from the study, although with 
permission of the Medical Monitor, induction treatment may continue if clinically 
LQGLFDWHGDQGSURYLGHGWKHUHLVQRHYLGHQFHRIWR[LFLW\1&, CTCAE grade 4.


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However, patients randomized to CM with progressive disease or no response 
after 1 cycle of CM may cross over to receive ACM. In addition, patients 
randomized to CM with the best response of a PR after 2 cycles of CM may also 
cross over to receive ACM. Patients who cross over to ACM may receive up to 
a combined total (CM + ACM) of 4 cycles. 
There is a maximum limit of 90 days between the start of cycles unless otherwise 
discussed with the medical monitor. 
451 Cycles 2 - 4, Day 1 – Within 10 Hours Prior to First Dose
Perform the following assessments in patients receiving subsequent cycles of 
chemotherapy:
x
If clinically indicated, administer pretreatment IV hydration, oral 
allopurinol, and oral phosphate binder (see Section 4.6.1) 
x
If supportive care measures for prevention of tumor lysis are initiated, 
monitor urine output frequently to ensure that it equals fluid input. If input 
is greater than output by 10%, administration of diuretics is encouraged.
Replacement of excessive fluid losses, including from diarrhea, should be 
done unless otherwise clinically indicated.
x
ECHO or MUGA scan to be performed before each dose of mitoxantrone. 
If mitoxantrone is omitted after Cycle 1, the ECHO or MUGA scan can 
also be omitted.  
45 Cycles 2 - 4, Day 1 – Just Prior to First Dose
Perform the following procedures just prior to dosing on Day 1:
x
Physical examination including weight (kg) for recalculation of BSA
x
Record vital signs measured 5-15 minutes prior to the initiation of infusion 
following a 5-minute rest
x
Assess ECOG PS (Appendix B) 
x
Collect blood for evaluation of laboratory parameters (Appendix D):
o
Hematology
o
Tumor lysis labs
o
Fibrinogen level (only required if clinically indicated)
x
If supportive care measures for prevention of tumor lysis were initiated, 
monitor urine output frequently to ensure that it equals fluid input. If input 
is greater than output by 10%, administration of diuretics is encouraged.
Replacement of excessive fluid losses, including from diarrhea, should be 
done unless otherwise clinically indicated.


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x
&ROOHFWXULQHRUVHUXPVDPSOHIRUȕ-hCG pregnancy test for females of 
child-bearing potential 
x
Record only those medications (prescription, nonprescription, nutritional 
supplements) administered in conjunction with an AE.
45 Cycles 2 - 4, Day 1 – Dosing
x
Treatment with ACM or CM. 
After completing the first cycle of treatment, continued use of 
mitoxantrone is optional.
x
Collect blood for evaluation of laboratory parameters (Appendix D):
o
Hematology
o
Tumor lysis labs
o
Fibrinogen level (only required if clinically indicated)
x
If supportive care measures for prevention of tumor lysis were initiated, 
monitor urine output frequently to ensure that it equals fluid input. If input 
is greater than output by 10%, administration of diuretics is encouraged.
Replacement of excessive fluid losses, including from diarrhea, should be 
done unless otherwise clinically indicated.
x
Test for presence of C. difficile infection at first instance of diarrhea (refer 
to Section 4.6.1.2 for additional guidance)
x
Administer prophylactic antibiotics and antivirals, corticosteroid eye 
drops, and antifungals according to Section 4.6.1.4. 
x
Assess for AEs
x
Record only those medications (prescription, nonprescription, nutritional 
supplements) administered in conjunction with an AE.
45
Cycles 2 - 4 – Daily during Hospitalization for Chemotherapy
Perform the following procedures daily (or more frequently if clinically 
indicated) 
while 
patients 
are 
hospitalized 
for 
chemotherapy 
administration:
x
Collect blood for evaluation of laboratory parameters (Appendix D):
o
Hematology
o
Tumor lysis labs
o
Fibrinogen level (only required if clinically indicated)


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x
If supportive care measures to prevent/treat tumor lysis were initiated, 
must monitor urine output frequently to ensure that it equals fluid input. 
If input is greater than output by 10%, administration of diuretics is 
encouraged. Replacement of excessive fluid losses, including from 
diarrhea, should be done unless otherwise clinically indicated.
x
Test for presence of C. difficile infection at first instance of diarrhea (refer 
to Section 4.6.1.2 for additional guidance)
x
Assess for AEs
x
Record only those medications (prescription, nonprescription, nutritional 
supplements) administered in conjunction with an AE.
45 Cycles 2 - 4 – Weekly after Completion of Chemotherapy Regimen
Perform the following procedures weekly (or more frequently if clinically 
indicated) after patients have completed their chemotherapy regimen:
x
Abbreviated physical examination including weight (kg)
x
Vital signs (temperature, heart rate, systolic and diastolic blood 
pressures)
x
Assess ECOG PS (Appendix B) 
x
Collect blood for evaluation of laboratory parameters (Appendix D):
o
Hematology
o
Tumor lysis labs
o
Fibrinogen level (only required if clinically indicated)
x
Assess for AEs
x
Record only those medications (prescription, nonprescription, nutritional 
supplements) administered in conjunction with an AE.
45 Cycles 2 - 4 – At Hematologic Recovery
x
Assess response by bone marrow biopsy and/or aspiration at time of 
hematologic recovery (ie, absolute neutrophil count (ANC) >1000 μL and 
platelet count >100,000 μL) or Day 45 (±2), whichever occurs first. If the 
bone marrow biopsy and/or aspirate is nonproductive or not diagnostic, 
the procedure must be repeated within 7 days. 
o
At time of response assessment, 6 to 8 bone marrow slides will be 
prepared and sent to the Sponsor. Details regarding the collection 
and shipping of these slides is provided in the Study Manual.
x
Assess for AEs, including tumor lysis clinical symptoms


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x
Record only those medications (prescription, nonprescription, nutritional 
supplements) administered in conjunction with an AE. 
5.5 End of Study Assessments (Stage 1, Stage 2)
To be completed at time patient is withdrawn from the study.
x
Abbreviated physical examination including weight (kg) and other 
measures of disease and disease symptoms, eg, extramedullary disease
x
Vital signs (temperature, heart rate, systolic and diastolic blood 
pressures)
x
ECOG PS (Appendix B) 
x
Collect blood for evaluation of laboratory studies (Appendix D):
o
Hematology
o
Full serum chemistry panel
o
Fibrinogen level (only required if clinically indicated)
x
Urinalysis
x
Perform bone marrow biopsy and/or aspiration (if not done in the 
preceding 30 days). If the bone marrow biopsy and/or aspirate is 
nonproductive or not diagnostic, the procedure must be repeated.  
o
At end of study, 6 to 8 bone marrow slides will be prepared and 
sent to the Sponsor (if not done in the preceding 30 days). Details 
regarding the collection and shipping of these slides is provided in 
the Study Manual.
x
Perform 12-lead ECG (as clinically indicated)
x
Perform ECHO or MUGA scan (as clinically indicated)
x
Assess for AEs
x
Record only those medications (prescription, nonprescription, nutritional 
supplements) administered in conjunction with an AE
5.6
Follow-up Assessments (Stage 1, Stage 2 and Exploratory Arms) 
All study patients will be contacted by telephone to assess for date of death, date 
of stem cell transplant, date of relapse, or continued remission for two years:
x
Year 1: Phone calls monthly beginning the month after the patient 
completes the end-of-study assessments to 12 months after Day of 
Randomization regardless of how many cycles a patient receives 
(Year 1 = Day of Randomization plus 12 months) 
x
Year 2: Phone calls every other month during Year 2 (months 14 to 
24 after Day of Randomization). 


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6.
OFF-STUDY CRITERIA 
6.1
Withdrawal of Patients
All patients have the right to withdraw at any time during treatment without 
prejudice. Circumstances may occur under which a patient may be permanently 
removed from the study. The criteria used to justify withdrawal of a study patient 
are described below.
In the event of a premature withdrawal, the assessments for the End of Study
visit, as detailed in the Schedule of Activities (See Appendix A), should be 
completed at the time of the withdrawal, wherever possible, including dates of 
remission and death. If the study patient is prematurely withdrawn due to an 
adverse event(s), attempts should also be made to clinically follow the study 
patient until the event is resolved, stable or permanent as determined by the PI
and Sponsor.   
6.2
Reasons for Withdrawal
A patient may be permanently removed from the study for any of the following 
reasons:
x
Failure to achieve a CR or PR. Patients not demonstrating evidence of 
CR, CRi, CRp, or PR after the first cycle of treatment will be considered 
for removal from the study, although with permission of the Medical 
Monitor, induction treatment may continue if clinically indicated and 
provided there is no HYLGHQFHRIWR[LFLW\1&,&7&$(JUDGH (v4.03 in 
Stage 1, v5.0 in Stage 2). See Section 4.5.3 for criteria for patients 
randomized to CM that may cross over to ACM.
x
An excessive grade 3-4 toxicity without a response to treatment or 
occurrence of any other adverse event, concurrent illness or laboratory 
abnormality which, in the opinion of the PI, warrants the patient’s 
permanent withdrawal 
x
Patient noncompliance, defined as refusal or inability to adhere to the 
study schedule;
x
At the request of the patient, PI, the Sponsor, or regulatory authority; 
x
Patient is lost to follow-up; or
x
Patient death
x
Patient becomes pregnant while on study


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6.3
Follow-up for Patients Withdrawn from Study
Patients withdrawn from the study with an ongoing adverse event must be 
followed clinically until the event is resolved, deemed stable or permanent by the 
PI, or the patient begins a new treatment for their disease. A stable adverse 
event is defined as an event that is not expected to change in nature, severity or 
frequency. See Sections 8.4 – 8.8 for reporting of adverse events. Patients 
withdrawn from the study for pregnancy will be followed according to Section 5.6
Follow-up Assessments. The pregnancy of any patient, or patient’s partner, will 
be followed to term to record any birth defects/abnormalities at time of birth.


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7.
CRITERIA FOR EVALUATION AND ENDPOINT DEFINITIONS 
7.1
Efficacy Endpoints
Response assessments in Stage 1 are defined by the International Working 
Group Criteria and 2010 European LeukemiaNet (ELN) [20, 21]. The 2017 ELN 
criteria will be used to determine patient responses during Stage 2 [23]. These 
criteria are summarized in Section 11.4.2 and provided in Appendix E.
7.1.1
Primary Efficacy Endpoint
x
CR rate 
7.1.2
Secondary Efficacy Endpoints
x
Combined CR rate 
x
Combined Response Rate
x
Overall Survival (OS) 
x
Event-free Survival (EFS)
x
Rate of Stem Cell Transplantation
7.2
Safety Endpoints
Tolerance and toxicity of the ACM versus CM regimens will be assessed through 
evaluation of physical examinations, vital signs, laboratory studies, solicited and 
unsolicited adverse events, and all causes of mortality at 30 and 60 days.
x
30- and 60-day Mortality
x
Adverse Events 
x
Clinical Laboratory Assessments
A Data Safety Monitoring Board (DSMB) will monitor key outcomes from the 
study. 


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8.
ADVERSE EVENTS
8.1
Definitions
An adverse event (AE) is defined as any untoward medical occurrence 
associated with the use of a drug in humans, whether or not considered drug 
related. 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 drug, whether or not related to the drug product.)
Suspected adverse reaction means any adverse event for which there is a 
reasonable possibility that the drug caused the adverse event. For the purposes 
of IND safety reporting, ‘reasonable possibility’ means there is evidence to 
suggest a causal relationship between the drug and the adverse event.
Unexpected adverse event or unexpected suspected adverse reaction: An 
adverse event or suspected adverse reaction is considered unexpected if it is 
not listed in the current Investigator’s Brochure or is not listed at the specificity 
or severity that has been observed; or, is not consistent with the risk information 
described in the general investigational plan (clinical study protocol).
Toxicities will be assessed according to the NCI CTCAE, version 4.03 during 
Stage 1 and v5.0 during Stage 2 (see Appendix C). When the NCI CTCAE grade 
is not available, the investigator will use the following toxicity grading: mild, 
moderate, severe, life-threatening or fatal.   




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8.2
Causality
Relationship of the adverse event (AE) to the study drug should be defined as 
follows: 
Unrelated:
AE is clearly not related to the investigational agent(s)
Unlikely:
AE is doubtfully related to the investigational agent(s)
Possible:
AE may be related to the investigational agent(s)
Probable:
AE is likely related to the investigational agent(s)
Definite:
AE is clearly related to the investigational agent(s)
8.3
Serious Adverse Events
A serious adverse event (SAE) is defined as any experience that suggests a 
significant hazard, contraindication, side effect, or precaution.  An SAE includes:
x
Any death, or 
x
Any life-threatening event (ie, the patient is at immediate risk of death 
from the event as it occurred), or
x
Any event that is persistently, significantly, severely or permanently 
disabling, or requires intervention to prevent such disability, or
x
Any event which requires inpatient hospitalization or prolongs 
hospitalization, or
x
Any congenital abnormality/birth defect, or
x
Any medically significant event that may jeopardize the patient or may 
require intervention to prevent one of the other outcomes listed above.
In addition, any adverse event which results in termination of the patient from 
study will be considered a potentially serious adverse event and must be 
reported to the Sponsor as described in Section 8.4 below.


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Bone marrow suppression and associated complications are expected events 
during leukemia therapy and are part of the treatment process (marrow emptying 
of leukemic cells). Therefore, myelosuppression and associated complications 
directly related to the myelosuppression, such as fever, infections and bleeding, 
will not be reported as serious adverse events (SAEs), but will be reported as 
adverse events on the adverse event CRF and will be summarized in the 
updated and final reports. Anemia and thrombocytopenia will not be reported as 
an SAE. Prolonged bone marrow suppression (as defined by the NCI toxicity 
criteria specific for leukemia, ie, bone marrow cellularity <5% on day 42 or later 
(6 weeks) from start of therapy without evidence of leukemia) or the unexpected 
nature, 
severity 
or 
frequency 
of 
myelosuppression, 
anemia, 
and 
thrombocytopenia or an associated complication will be reported as an SAE.  
8.4
Eliciting and Reporting Adverse Events
All adverse events, regardless of severity, which occur during the study, will be 
documented in the study progress notes, and the “AE” CRF will be completed. 
This includes both serious and non-serious events. Adverse events occurring 
from the time of the first dose will be captured.
All adverse events noted by study staff or volunteered by study patients at any 
time will be recorded. $Q\XQH[SHFWHG$(1&,&7&$(*UDGHWKDWRFFXUV
during this study and up to 30 days after discontinuation of study drug (alvocidib 
in Stage 1; alvocidib, cytarabine or mitoxantrone in Stage 2) or alternate cancer 
therapy, whichever occurs first, regardless of relationship, should be reported to 
the Medical Monitor at the next investigator call. The Investigator or a qualified 
designated staff physician will conduct clinical assessments of all patients at 
each scheduled clinic visit. In addition, patients will be queried about any adverse 
symptoms they have experienced since the previous study visit. In order to avoid 
bias in eliciting events, suggestive questioning of the patients shall not occur. 
For Stage 1 (CTCAE v4.03) and Stage 2 (CTCAE v5.0) patients, record a 
laboratory abnormality as an AE if it is associated with clinical sequelae or 
requires a therapeutic intervention. For both non-laboratory and laboratory 
abnormalities capture only the highest grade of an event using Start/Stop dates 
of the longest duration of the AE not the longest duration of the highest grade. If 
worst grade is captured on a lab drawn between visits, enter the lab under 
Unscheduled Evaluations. Additional details are provided in the electronic case 
report form (eCRF) Completion Guidelines.
Adverse events will be reported and described in terms of intensity, seriousness 
and causality, based on the Investigator’s judgment using protocol-defined 
definitions. Necessary counter measures will also be reported on the appropriate 
CRF used to collect concomitant medications.


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8.5
Serious Adverse Events and/or Adverse Events Requiring Discontinuation 
of Study Drug
Any serious adverse event (SAE) that occurs during this study and up to 30 days 
after discontinuation of study drug (alvocidib in Stage 1; alvocidib, cytarabine or 
mitoxantrone in Stage 2) or initiation of alternate cancer therapy, whichever 
occurs first, must be reported to the Study Medical Monitor within 24 hours of the 
Investigator’s awareness of the event, whether or not this reaction is considered 
to be associated with use of the investigational drug. 
In addition, the occurrence of any AE leading to permanent discontinuation of 
study drug must also be reported to the Sponsor within 24 hours of the 
Investigator’s awareness of the event.   
Serious adverse events must be scanned and emailed to the Sponsor/Study 
Medical Monitor. 
Email: 
It is expected that the Investigator will provide or arrange appropriate supportive 
care for the study patient. A patient experiencing an SAE(s) should be followed 
clinically until the event is resolved, deemed stable or permanent by the PI, or 
the patient begins a new treatment for their disease. All telephone and 
scanned/emailed reports must be followed with a written SAE report form within 
24 hours of the Investigator’s awareness of serious adverse events and 
nonserious events which required discontinuation of study drug. 
The SAE report form should be completed and signed by the Investigator, 
scanned, and sent by email to the Sponsor as described above. The SAE Report 
Form is distinct and separate from the adverse event form included in the CRF. 
Grades for all SAEs and AEs, regardless of whether they trigger expedited 
reporting or not, must still be captured by the CRF.
8.6
Follow-up of Adverse Events
Adverse events, which are identified on the last scheduled visit, must be 
recorded on the AE CRF page and reported to the Sponsor according to the 
procedures outlined in Section 8.4.
Patients with unresolved previously reported adverse events or new adverse 
events identified on the last scheduled visit should be followed by the 
Investigator until the events resolve, are deemed stable or permanent, or the 
patient begins another treatment for their disease. Resolution means the patient 
has returned to his/her baseline state of health or the Investigator does not 
expect any further improvement or worsening of the adverse event. The 
Investigator should continue to report any significant follow-up information to the 
Sponsor up to the point the event has resolved. Any adverse events reported by 
the patient to the Investigator which occur after the last scheduled visit, and are 
determined by the Investigator to be reasonably associated with the use of the 


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study drug or meet the criteria of a reportable adverse event as described above, 
should be reported to the Sponsor.
Patients withdrawn from the study with an ongoing adverse event must be 
followed clinically until the event is resolved, deemed stable or permanent as 
determined by the Investigator and Sponsor, or the patient begins another 
treatment for their disease. A stable adverse event is defined as an event, which 
is not expected to change in nature, severity, or frequency. The Investigator
should continue to report any significant follow-up information to the Sponsor.
8.7
Patient Deaths
Every effort will be made in the case of patients who die to determine the cause 
of death. Information regarding a patient who dies more than 30 days after
receiving study drug may be recorded on a Death Report Form (no SAE report 
is required). An SAE report is recorded only if the death occurs within 30 days of 
the last administration of study drug (alvocidib in Stage 1; alvocidib, cytarabine 
or mitoxantrone in Stage 2). 
The Death Report Form is distinct and separate from the adverse event form 
included in the CRF. 
8.8
Reporting Adverse Events to the Regulatory Authorities
The Sponsor will be responsible for reporting adverse events to the Food and 
Drug Administration (FDA) as described in 21 Code of Federal Regulations 
(CFR) Section 312.32 (IND Safety Reports) and to other Regulatory Authorities 
according to local regulations.
In addition, the Investigator is required by FDA regulations to notify the 
Institutional Review Board (IRB) promptly of all unexpected SAEs occurring at 
the investigator’s study site. The Investigator is also required by FDA regulations 
to forward the IRB all IND Safety Reports received from the sponsor.
The Sponsor will also report SAEs in compliance with local regulatory 
requirements.


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9.
STUDY DRUG MANAGEMENT
9.1
Study Drug
The investigational study drug, alvocidib, will be provided to the PI by the 
Sponsor or designee. 
Alvocidib is supplied for parenteral administration as a sterile, nonpyrogenic, 
injectable, clear pale yellow to yellow-colored, 10 mg/mL solution, which is 
packaged in glass vials fitted with coated rubber closures crimped with an 
aluminum seal and light blue plastic cap. Each vial contains 50 mg of alvocidib 
(calculated with reference to the active moiety). The fill volume has been 
established to ensure removal of 5 mL. The pH of the solution ranges between 
2.7 and 3.3. The solution contains the following excipients: water for injection, 
glacial acetic acid, and sodium hydroxide (as needed to reach the targeted pH). 
Alvocidib is to be diluted with either 0.9% sodium chloride injection or 5% 
dextrose injection prior to infusion, providing solutions of 0.09 to 1.0 mg/mL 
alvocidib.  
Cytarabine and mitoxantrone, approved pharmaceutical products, will be 
provided by commercially available sources.
9.2
Study Drug Dispensing and Accountability
Alvocidib will be provided by the Sponsor to study centers as an investigational 
drug. The label and package for the drug product will be prepared in accordance 
with current regulatory requirements. The Investigator or designee will inventory 
and acknowledge receipt of all shipments of study drugs. The study drugs must 
be kept in a locked area with access restricted to designated study personnel.  
An accurate and current accounting of the dispensing of the study drugs for each 
patient will be maintained on an ongoing basis by a member of the study site 
staff in a drug accountability log or equivalent document and will be verified by
the sponsor's study monitor. All drug supplies, including unused study drug, must 
be accounted for. A final inventory of the total amount of drug received at each 
study site against the amount used and returned must be recorded in the study 
drug accountability log or an equivalent document. Inventory and dispense 
records must be readily available for inspection by the study monitor and/or 
auditor, and open to government inspection at any time. Study drug destruction 
will be handled by the sites of open/used vials. Unopened study drug vials should 
be returned to the Sponsor or the Contract Research Organization (ie, Courante)
at the end of the study only after full drug accountability has been completed by 
the study monitor.


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9.3
Preparation and Administration
Alvocidib is to be diluted with either 0.9% Sodium Chloride Injection or 5% 
Dextrose Injection prior to infusion, providing solutions of 0.09 to 1.0 mg/mL 
alvocidib. The diluted solution should be administered according to treatment 
schedule provided in Section 4.5.  
Cytarabine (Ara-c), using the 2-gm vial, may be reconstituted with 20 mL of 
Bacteriostatic Water for Injection with Benzyl Alcohol 0.945% w/v added as 
preservative. The resulting solution contains 100 mg of cytarabine per mL. 
Administer according to treatment schedule in Section 4.5. 
Mitoxantrone is supplied as a concentrate that MUST BE DILUTED PRIOR TO 
INJECTION. The dose of mitoxantrone should be diluted to at least 50 mL with 
either 0.9% Sodium Chloride Injection or 5% Dextrose Injection. Mitoxantrone 
may be further diluted into Dextrose 5% in Water, Normal Saline or Dextrose 5% 
with Normal Saline and used immediately. Mitoxantrone should not be mixed in 
the same infusion as heparin since a precipitate may form. Because specific 
compatibility data are not available, it is recommended that mitoxantrone not be 
mixed in the same infusion with other drugs.  Administer according to treatment 
schedule in Section 4.5. 
Both cytarabine and mitoxantrone are approved pharmaceutical products. 
Complete instructions and training on the proper preparation and administration 
of all study drugs will be provided to study sites in the Pharmacy Manual.
9.4
Storage at Study Center
x
Alvocidib should be stored between 2° to 30°C (36° to 86°F).
x
Cytarabine (Ara-c) should be stored between 15° to 30°C (59° to 86°F). 
x
Mitoxantrone (mitoxantrone hydrochloride) should be stored between 20° to 
25°C (68° to 77°F). DO NOT FREEZE. 
9.5
Compliance
Study drugs will be administered by trained staff at the treatment site(s). 


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10.
RECORD MANAGEMENT 
10.1 Data Collection
The Investigator must maintain required records for all study subjects. Case 
report forms are used to record clinical study data and are an integral part of the 
study and subsequent reports. Data for this study will be recorded in the subject's 
source document and into an eCRF system that must be kept current to reflect 
patient status during each part of the study. Patients are not to be identified by 
name on the eCRF. Appropriately coded identification (site number, patient 
identification number, and patient initials) should be used.
Electronic CRFs are not to be used as source documents. Investigators must 
keep accurate separate records (other than the CRFs) of all subjects' visits, 
being sure to include all pertinent study related information. A statement should 
be made indicating that the subjects have been enrolled in this clinical study and 
have provided written Informed Consent. Any adverse events must be 
thoroughly documented. Results of any diagnostic tests conducted during the 
study should also be included in the source documentation.  
All data should be recorded completely and promptly in the eCRFs as soon after 
the visit as possible, but no later than 5 days. All queries are to be answered 
within 3 days of query date.  
The Principal Investigator will allow the Sponsor or its representative, or an 
appropriate representative of the regulatory authorities to inspect study 
documents (eg, consent forms, drug distribution forms, IRB approval) and 
pertinent hospital or clinic records for confirmation of data throughout the study 
period.
10.2 Source Document Maintenance
Source documents are defined as the results of original observations and 
activities of a clinical investigation. Source documents may include, but are not 
limited to, hospital medical records, study progress notes, consent forms, 
computer printouts, laboratory data and recorded data from automated 
instruments. All source documents produced in this study will be maintained by 
the PI and made available for inspection by representatives of the Sponsor or 
the Regulatory Authorities. The original signed informed consent form for each 
participating patient shall be filed with the records kept by the PI with a copy filed 
in the patient’s medical records, and a copy given to the patient. 
A source document is an original record of information, also known as source 
data, which is necessary for the reconstruction and evaluation of a clinical trial. 
The purpose of source documents is to provide proof of a participant’s existence, 
confirm that protocol-related procedures were completed and conducted per 
protocol and to verify that data reported in the study CRFs are accurate. 


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Source documents at a clinical trial site may be maintained in paper or electronic 
format and typically contain the types of information below.  If electronic source 
documents are used, sponsor and study monitors will be given access to verify 
study data. 
Source documents can include, but are not limited to:
x
Notes from clinic physicians, nurses, and other study staff
x
Reports of procedures and tests
x
Flow sheets, checklists, and worksheets
x
Subject diaries, study calendars
x
Pharmacy records, accountability logs, shipping receipts
x
Study notes or memos to file
x
Documented telephone calls, emails, faxes
x
Hospital admission forms and discharge summaries
x
Sponsor/site-generated study source document templates
Source documents must meet five fundamental principles of data quality 
(“ALCOA”).  They must be:
x
Attributable – The data originator is identified. If data needs to be amended, 
the amender is identified.
x
Legible – The source document must be readable.  If handwritten, black or 
blue ink must be used, never pencil.
x
Contemporaneous – The document must be signed and dated when the 
information is first recorded, with any updates or corrections noted in real 
time as well.
x
Original – The document must be the first place the information is recorded.
x
Accurate – The information must be error-free, and any conflicts with data 
recorded elsewhere must be reconciled.
10.3 Record Maintenance
The Investigator must retain a comprehensive and centralized filing system of all 
clinical study-related documentation that is suitable for inspection by the 
Sponsor and representatives of regulatory authorities. 
The Investigator must retain essential study documents (as specified in 
Section 8 of ICH-GCP and as required by the applicable regulatory 
requirements) until at least 2 years after the last approval of a marketing 
application. Patient files and other source data (including copies of protocols, 
CRFs, original reports of test results, agent-dispensing logs, correspondence, 
records of informed consent, and other documents pertaining to the conduct of 
the trial) must be kept for the maximum period of time permitted by the institution.


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No trial document will be destroyed without prior written agreement between the 
Sponsor and the Investigator. Should the Investigator wish to assign the trial 
records to another party or move them to another location, written agreement 
must be obtained from the Sponsor. 
The Principal Investigator shall take responsibility for maintaining adequate and 
accurate hard-copy source documents of all observations and data generated 
during this study, including any data clarification forms (DCF’s) received from the 
Sponsor. Such documentation is subject to inspection by the Sponsor and the 
FDA or other Regulatory Authorities.
10.4 Study Center File Management
It will be the responsibility of the Principal Investigator to assure that the study 
file at the center is maintained.  The study file for this protocol will contain, but 
will not be limited to, the information listed below:
x
Investigator’s Brochure (all versions provided during the study period.) 
x
Final study protocol.
x
Protocol amendments (if applicable).
x
Original informed consent form (blank).
x
Revised informed consent forms and/or all addenda (if applicable).
x
Copy of signed FDA Form(s) 1572
x
Curricula Vitae and medical licenses of Principal
Investigator and 
Subinvestigators.
x
Financial Disclosure Form of Principal Investigator and Subinvestigators (if 
applicable).
x
DHHS Number for IRB, or other documentation of IRB compliance with FDA 
regulation (US sites).
x
Documentation of IRB/IEC approval of protocol, consent form, any protocol 
amendments and any consent form revisions.
x
Annual IRB/IEC updates and approvals.
x
All correspondence between the Principal Investigator, IRB/IEC and Sponsor 
or Sponsor’s representative relating to study conduct.
x
Copies of all 7-day and 15-day Safety Reports submitted to the Regulatory
Authorities 
(provided 
by 
Sponsor) 
and 
IRB/IEC
correspondence 
documenting their submission.
x
Laboratory certifications.
x
Normal laboratory value ranges for tests required by the protocol for all 
laboratories that are utilized.
x
CRA monitoring log.
x
List of signatures and Delegation of Authority for all study personnel
x
Drug invoices for both receipt and return of study drug, as well as drug 
inventory/accountability records.


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11.
STATISTICAL ANALYSIS
A brief overview of the statistical analysis plan is presented below. Complete 
details of the planned analysis will be documented in a full Statistical Analysis 
Plan, which will be finalized before locking the study database.
11.1 Statistical Methods
Statistical analyses will be performed using Statistical Analysis System (SAS)
software. Default estimation methods in version 9.4 of SAS are always used 
unless an alternative is specified below. In general, data summaries will include 
the mean, standard deviation, median, minimum and maximum values for 
continuous data; the median, 25th and 75th percentiles, minimum and maximum 
values for time-to-event endpoints; and the number and percentage of patients 
in each category for categorical data. Pointwise 95% confidence intervals (CI) 
will also be estimated for the mean (continuous data), median (time-to-event 
endpoints) or percentage of patients (categorical data).
Durations of time expressed in months (eg, times-to-event endpoints) will be 
reported in proportional “months” according to the formula
݉݋݊ݐ݄ݏ= 12
365 ×  ݀ܽݕݏ
Baseline value of a characteristic is defined as the last measured value prior to 
the first dose of study drug.
Statistical p-values will be truncated for display at the third digit following the 
decimal point. P-values less than 0.001 will be displayed as “<0.001.” 
11.2 Sample Size
11.2.1
Sample Size in Stage 1
The sample size of 23 eligible patients for Stage 1 was selected because it 
allows estimation of the remission rate by means of a 90% confidence interval 
with maximum width of ±17%. Although this study does not follow a Simon 
2-stage design, 23 patients is consistent with the sample size for Stage 1 of the 
Simon 2-stage minimax design with 80% power for testing the null hypothesis 
that the remission rate is 50% against a one-sided alternative at the 5% level of 
significance when the actual remission rate is 70%. In the Simon 2-stage design 
described, the study would continue to Stage 2 only if 13 patients achieve 
remission out of a maximum of 23 eligible patients. Therefore, this was selected 
as the requirement to proceed to Stage 2 of this study. However, the study may 
proceed to Stage 2 as soon as 13 patients achieve remission.  


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The primary objective of Stage 1 is to determine the CR rate in patients with 
relapsed or refractory AML with MCL-1 dependence of 30%. Thus a patient 
who leaves the study prior to providing a bone marrow sample adequate for
assessing response to treatment will be replaced by another eligible patient.
11.2.2
Sample Size in Stage 2
The planned sample size of 56 patients (28 per treatment arm) in Stage 2 of this 
study provides 90% power to reject the null hypothesis of equal CR rates across 
treatment arms under the following conditions:
x
CR rates of 70% and 30% for patients receiving ACM and CM,
respectively
x
One-sided 2.5% significance level
x
Randomization based on a 1:1 patient allocation ratio (ACM to CM) 
The primary objective of Stage 2 is to compare CR rates between patients with 
relapsed or refractory AML with MCL-1 dependence of 30% receiving 1 cycle 
of ACM treatment and those receiving 1 cycle of CM. Thus a patient who leaves 
the study prior to receiving one course of study treatment will be replaced by 
another eligible patient.
11.3 Analysis Populations
x
Intent-to-treat (ITT) patient population: includes all patients enrolled 
into Stage 1; the exploratory arms; or randomized to receive study drug 
in Stage 2 regardless of whether they actually received study drug and 
regardless of whether evidence is found indicating they failed to meet 
study inclusion/exclusion criteria or had other protocol violations. When 
the ITT patient population is analyzed, Stage 2 patients are grouped 
according to their randomized treatment regardless of actual treatment 
received. The ITT patient population is the analysis population for all 
primary statistical inference and tests of hypotheses related to efficacy 
endpoints.
x
Safety patient population: a subset of ITT patients who received at least 
one dose of study drug. When the safety patient population is analyzed, 
patients are grouped according to actual treatment received. ACM is 
considered a patient’s “treatment received” in the safety patient 
population if alvocidib is administered at any time during the study. The 
safety patient population is the analysis population for all analyses of 
safety data.
x
Per-protocol patient population: a subset of the safety patient 
population who either (a) have at least one response evaluation on study, 
or (b) die prior to their first scheduled response evaluation. However, 
patients are excluded from the per-protocol patient population if they have 


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an important protocol deviation, such as when evidence is found 
indicating they failed to meet any study inclusion/exclusion criterion. 
When the per-protocol patient population is analyzed, patients are 
grouped according to actual treatment received. ACM is considered a 
patient’s “treatment received” in the per-protocol patient population if 
alvocidib is administered at any time prior to CR (or at any time during the 
study for patients never achieving CR). The per-protocol population is 
used for sensitivity (secondary, supportive) analyses of efficacy 
endpoints.
x
Response-assessment population: a subset of the safety population 
who have at least one response evaluation on study. When the response-
assessment patient population is analyzed, patients are grouped 
according to actual treatment received. ACM is considered a patient’s 
“treatment received” in the response assessment patient population if 
alvocidib is administered at any time prior to CR (or at any time during the 
study for patients never achieving CR). The response-assessment 
population is the primary population for assessing the correlation between 
MCL-1 dependency and response to ACM and is used for sensitivity 
(secondary, supportive) analyses of efficacy endpoints.
11.4 Data Analyses
The overall significance level for this study will be 2.5% using one-sided 
hypothesis tests. Results from Stage 1 will be reported using descriptive 
statistics and confidence intervals. Primary statistical comparisons of efficacy 
results will use only data from Stage 2; however, data from Stage 1 patients will 
be combined with data from patients receiving ACM in Stage 2 for secondary
efficacy analyses. Details of the analyses planned for this study are provided in 
the Statistical Analysis Plan under separate cover. 
Stage 2 complete remission (CR) rates will be compared across treatment 
groups using the Cochran-Mantel-Haenszel general association test stratified by 
response to most recent induction therapy (refractory [persistent disease or CR 
duration <90 days], early relapse [CR duration 90 days to 1 calendar year], or 
late relapse [CR duration >1 calendar year but <24 months]). The same test will 
be applied to assess statistical significance of secondary response rate 
endpoints. Control of the overall 2.5% type-1 error rate for multiple comparisons 
will be achieved using the hierarchical closed test procedure. 
Treatment-group distributions of time-to-event endpoints will be compared using 
the log-rank test stratified by response to most recent induction therapy.
Incidence rates of TEAEs will be summarized within treatment group at the 
MedDRA preferred term and primary system organ class levels. Similar 
summaries will be made for subsets of AEs such as (1) those judged by the 
Investigator to be related to study treatment, and (2) SAEs.


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Other routine safety assessments (eg, clinical laboratory parameters and vital
signs) will be summarized by treatment group using mean, standard deviation, 
median, minimum and maximum changes from baseline values.
A DSMB will monitor key outcomes from the study.
11.4.1
Demographics and Baseline Characteristics
Demographics and baseline characteristics will be summarized.
11.4.2 
Efficacy Analyses
Response assessments in Stage 1 are defined by the International Working 
Group and 2010 ELN Criteria [20, 21]. The 2017 ELN criteria will be used to 
determine patient responses during Stage 2 [23] (Appendix E). The primary 
analysis for these response rates will be performed using data from all enrolled 
patients (intent-to-treat, ITT). In the ITT analysis, patients withdrawing from the 
study for any reason prior to a response assessment will be classified as a 
nonresponder. A secondary analysis of per protocol patients will also be 
performed.  
Primary Efficacy Endpoint
x
Complete Remission (CR) rate = Percentage of patients achieving CR
Secondary Efficacy Endpoints
x
Combined CR Rate = Percentage of patients achieving a CR, CRi or CRp†
x
Combined Response Rate = Percentage of patients achieving a CR, CRi, 
CRp†, or PR  
x
Overall Survival (OS) = Time from randomization (Day 1) until death from 
any cause
x
Event-free Survival (EFS) = Time from randomization (Day 1) until (a) 
treatment failure, (b) relapse after CR, or (c) death from any cause, 
whichever occurs first, censored at 2 years
x
Rate of Stem Cell Transplantation = Percentage of patients proceeding 
directly to stem cell transplantation
†Note that CRp has been retained in definitions for Combined CR Rate and 
Combined Remission Rate because Stage-1 patients were assessed using the 
IWG criteria. CRp will not be used for assessing response in Stage-2 patients 
and, therefore, will not be included in the definitions of Combined CR Rate and 
Combined Remission Rate in Stage 2.
The CR rate in patients failing CM and crossing over to receive ACM will also be 
determined. 


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Secondary endpoints described for Stage 1/Stage 2 will also be assessed. 
Additional exploratory analyses may be performed to assist the sponsor in 
planning future studies.
Without taking appropriate measures, testing multiple efficacy parameters 
inflates the overall significance level since the probability of making a type-1 error 
in at least one from a set of hypothesis tests is greater than the probability of 
making a type-1 error in any single test. The hierarchical closed test procedure 
will be used to maintain the overall 2.5% significance level.
The order of efficacy endpoints for the hierarchical closed test procedure is:
1. CR rate
2. Combined CR rate
3. Combined Response Rate
4. OS
5. EFS
6. Stem cell transplant rate
Each efficacy endpoint will be tested at a one-sided 2.5% significance level using 
the statistical procedures described above. CR rate, the primary efficacy 
endpoint, will be declared statistically significant if its test p-YDOXH  $
secondary efficacy endpoint will be declared statistically significant only if its test 
p-YDOXH  DQG DOO HIILFDF\ HQGSRLQWV SUHFHGLQJ LW LQ WKH KLHUDUchy are 
statistically significant. In other words, declaration of statistical significance for 
efficacy endpoints will advance in order down the hierarchy only until a p-value 
>0.025 is found.
In addition, although there will be primary and supportive analytical methods for 
each endpoint in the hierarchy (supportive methods will be documented in the 
formal Statistical Analysis Plan), only the p-value from the primary analysis will 
be used for deciding statistical significance. Supportive (sensitivity) analyses are 
to demonstrate the robustness of primary results to slight modifications to how 
endpoints are defined and/or analyzed.
Declarations of statistical significance will not be advanced for endpoints not 
included in the hierarchy of the closed test procedure.
11.4.3
Pharmacodynamic Endpoint Analyses
Summary of baseline biomarker values will include within– and between–
treatment-arm descriptive statistics. A logistic regression model will be fit to 
examine the relationship between baseline MCL-1 dependence and the 
independent binary variable achievement of CR during the study. The full model 
will include effects for baseline MCL-1 dependence, treatment arm, and the two-
way interaction between baseline MCL-1 dependence and treatment arm. In 
addition, area under the curve (AUC) and 95% CI will be calculated (by treatment 


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arm) for the trapezoidal receiver operating characteristic curve. This value will 
quantify the ability of MCL-1 dependence to predict CR. 
11.4.4 
Safety Analyses
The following safety analyses will be performed on all patients who receive at 
least one dose of study drug.
x
30- and 60-day Mortality = Estimates of 30- and 60-day mortality and 
their pointwise 95% CIs will be derived from Kaplan-Meier curves for OS 
by treatment arm
x
Adverse Events = Reported AE terms will be mapped to MedDRA 
preferred terminology. All reported events will appear in AE listings, 
however only TEAEs will be summarized. A TEAE is an AE that starts or 
increases in severity any time after the first administration of any study 
drug up to 30 days following the last administration of any study drug. AE 
severity will be rated by the investigator according to NCI CTCAE version 
4.03 in Stage 1 and version 5.0 in Stage 2 (see Appendix C).  
x
Clinical Laboratory Assessments = Laboratory test results measured 
on a continuous scale and changes from baseline values will be 
summarized by visit and within treatment arm using mean, standard 
deviation, median, minimum and maximum values. Categorical test 
results will be summarized within treatment arm using shift tables. 
Additionally, for tests where NCI CTCAE, version 4.03 in Stage 1 and 
version 5.0 in Stage 2 (see Appendix C), severity criteria are specified, 
NCI CTCAE severity grades will be summarized in shift tables.
x
Vital Signs = Vital signs and changes from baseline values will be 
summarized by visit and within treatment arm using mean, standard 
deviation, median, minimum and maximum values.


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12.
PROTOCOL AMENDMENTS
Any permanent change to the protocol must be handled as a protocol 
amendment.  Protocol amendments will be written by the Sponsor. All protocol 
amendments must be submitted in writing to the Institutional Review Board 
(IRB)/Independent Ethics Committee (IEC), and the Principal Investigator must
await IRB/IEC approval of the amendments before implementing the changes. 
However, a protocol change that is intended to eliminate an apparent immediate 
hazard to patients may be implemented immediately and the IRB/IEC is to be
notified within five (5) days. The Sponsor should also be notified by telephone 
as soon as possible, ideally before the amendment is implemented and definitely 
within 5 days. The Sponsor will submit protocol amendments to the Regulatory
Authorities.
When an amendment to the protocol substantially alters the study design and/or 
increases the potential risk to the patient, the currently approved written informed 
consent form will require similar modification and IRB/IEC approval. In such 
cases, repeat written informed consent will be obtained from patients currently 
enrolled in the study before expecting continued participation.


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13.
MONITORING
Prior to enrolling any participants, a study initiation visit, including protocol 
training, will be conducted for the study center. A Study Manual of Procedures 
will be provided to each clinical site. A record of site personnel training will be 
maintained by the site onsite training logs.
Clinical Research Associates (CRAs) and other applicable personnel will receive 
training prior to study initiation about the disease, applicable Standard Operating 
Procedures (SOPs), the protocol and other study-specific items. Team 
organization, communication, and operational issues will also be discussed.
The conduct of the study will be closely monitored by representatives (Clinical 
Research Associates "CRAs” or study monitors) of the Sponsor or designee, to 
verify adherence to the Protocol, ICH GCP guidelines, and applicable 
regulations. The CRA will verify electronic CRF (eCRF) entries by comparing 
them with Sponsor/site-generated source documents, hospital, clinic, office 
and/or study records which will be made available for this purpose. CRAs will 
monitor the study as outlined in the Monitoring Plan prepared for the study.
During the study, CRAs will visit the clinical sites to assess and assure 
satisfactory enrollment rate, data recording, and maintenance of required 
regulatory documentation, drug accountability, and compliance with the protocol.  
CRAs will also be able to monitor the data remotely. The Investigator will ensure 
that all requested materials, including subject charts, eCRFs, source documents, 
laboratory records, and drug inventory records, will be available to the CRA. At 
the end of the study, a closeout visit will be performed.  
The Investigator will allow Sponsor’s representatives, designee and/or and any 
regulatory agency to have direct access to all study records, eCRFs, 
corresponding subject medical records, test product dispensing records and test 
product storage area, and any other documents considered source 
documentation. The Investigator also agrees to assist the representative, if 
required.


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14.
AUDITING
The study is conducted under the sponsorship of Tolero Pharmaceuticals, Inc, 
in compliance with the applicable international and local regulatory requirements 
as well as applicable ICH guidelines, Declarations of Helsinki (1964, 1975, 1983, 
1989, 1996, 2000, 2002, 2004, 2008, 2013) and in respect of the Sponsor or 
designee’s SOPs for study conduct and monitoring.
Audits may be carried out by Sponsor representatives, and inspection may be 
performed by regulatory authorities’ inspectorate or IRBs/IECs before, during, or 
after the study. The Investigator will allow and assist Sponsor’s representatives 
and any regulatory agency to have direct access to all study records, eCRFs, 
subject medical records, study product dispensing records and study product 
storage area, study facilities, and any other documents considered source 
documentation.
For the Audit(s) performed by, or on behalf of, Sponsor’s auditors, audit 
certificate(s) will be provided by Quality Assurance.


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15.
ETHICS AND RESPONSIBILITY
15.1 Principal Investigator’s Responsibilities
The PI shall ensure that all work and services described herein, or incidental to 
those described herein, shall be conducted in accordance with the highest 
standards of GCP. The PI shall administer the investigational drug only to 
patients under his/her personal supervision, or under the supervision of any Sub-
Investigator(s) responsible to him/her, who are identified on the Form FDA 
1572/Regulatory Authorities approval form. The PI will provide copies of the 
study protocol, amendments, and investigational brochure to all Sub-
Investigators, Pharmacists, or other staff responsible for study conduct.
With the exception of eliminating an immediate hazard to a subject, the 
Investigator should not deviate from the protocol or implement any changes 
without written prior approval from Sponsor and prior review and documented 
approval/favorable opinion from the IRB/IEC of an amendment.
Change(s) which involve(s) only logistical or administrative changes are 
authorized. The Investigator should document and explain any deviation from 
the protocol.
The Investigator is responsible for adequate and safe medical care of subjects 
during the trial and for ensuring that appropriate medical care and relevant 
follow-up procedures are maintained after the trial. Any additional data from 
these follow-up procedures must be documented and available to Sponsor who 
will determine whether or not the data need to be documented in the CRFs. 
15.2 Informed Consent
It is the ethical and legal responsibility of the PI to ensure that each patient 
considered for inclusion in this study is given a full explanation of the protocol, in 
a language in which the patient is fluent, and in which the patient will clearly 
understand. This shall be documented on a written informed consent form, which
shall be approved by the same IRB/IEC responsible for approval of this protocol. 
Each informed consent form shall include the elements required by local 
regulations. The Sponsor will draft this document in consultation with the PI. The 
PI agrees to obtain written approval of the consent form from the Sponsor prior
to submission to the IRB/IEC. 
Once the appropriate essential information has been provided to the patient and 
fully explained by the PI (or his/her qualified Designee) and it is felt that the 
patient understands the implications of participating in the study, the IRB/IEC-
approved consent form shall be signed by the patient, a witness (when 
appropriate) and the PI. Written informed consent will be obtained from each 
patient prior to any study-related procedures (including any pre-treatment 
procedures) that are performed. The patient shall be given a copy of the informed 
consent form when signed; the original shall be kept on file by the PI and a 
second copy shall be placed in the patient’s medical chart. 


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15.3 Institutional Review Board/Independent Ethics Committee
This protocol and all amendments will be reviewed and approved by the 
Institutional or Independent Review Board(s) or Independent Ethics 
Committee(s) charged with this responsibility at the study center. Notification in 
writing of approval must come from the Chairman or the Secretary of the IRB/IEC
meeting minutes where this protocol and associated informed consent form were 
discussed. The PI shall not participate in the decision, and, if an IRB/EC
member, the written approval must indicate such non-participation. The PI shall 
submit status reports to the IRB/IEC no less frequently than annually (when 
applicable). 
The IRB/IEC must be notified by the PI in writing of the interruption and/or 
completion of the study; the PI must promptly report to the IRB/IEC all changes 
in research (protocol amendments) and will not make such changes without 
IRB/IEC approval, except where necessary to eliminate apparent immediate 
hazards to human patients. In these cases, the IRB/IEC must be notified within 
five days of the change. The PI will promptly report to the IRB/IEC all 
unanticipated problems involving risk to patients or others. The PI is required to 
maintain an accurate and complete record of all written correspondence to, and 
received from the IRB/IEC, and must agree to share all such documents and 
reports with the Sponsor.


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16.
CONFIDENTIALITY
The existence of this clinical study is confidential and should not be discussed 
with persons outside of the study. The Investigator shall hold confidential, and 
not disclose directly or indirectly to any third party other than those persons 
involved in the study who have a need to know, the protocol, the data arising out 
of the study, and any other information related to the study or to Tolero’s 
products or research programs that is provided by Tolero to you (the 
“Confidential Information”).  All such persons must be instructed not to further 
disseminate this information to others.  Investigator shall not use the Confidential 
Information for any purpose other than the study.  The foregoing obligations of 
confidence and non-use assumed by you shall not apply to: (a) information which 
at the time of disclosure is in the public domain; (b) information which thereafter 
lawfully becomes part of the public domain other than through disclosure by or 
through you; (c) information which, as evidenced by your written records, was 
known by you prior to Tolero’s disclosure; (d) information which is lawfully 
disclosed to you by a third party not under any obligation of confidence to Tolero; 
or (e) information which is required to be disclosed by law or government 
regulatory agency, provided reasonable advance notice of such disclosure is 
given to Tolero. 
All information generated in this study must be considered highly confidential 
and must not be disclosed to any persons not directly concerned with the study, 
without written permission from the Sponsor. However, authorized drug 
regulatory officials and the Sponsor’s representatives will be allowed full access 
to the records.  
Patients will be identified only by initials and assigned a patient number. Their 
full names may, however, be made known to a drug regulatory agency or other 
authorized official if necessary. 
All data and discoveries arising out of the study, patentable or non-patentable, 
shall be the sole property of Tolero, Inc.
In signing this protocol, Investigator agrees to the release of the data from this 
study and acknowledges the above confidentiality and publication policy.  The 
provisions of this Statement shall survive the completion of the study. 
Clinical information will not be released without the written permission of the 
patient, except as necessary for monitoring by the Sponsor or the Regulatory
Authorities, or as required by law.


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17.
NONPROTOCOL RELATED RESEARCH
The Sponsor has a legal responsibility to report fully to regulatory authorities all 
the results of administration of investigational drugs. No investigative procedures 
other than those in this protocol shall be undertaken on the enrolled patients 
without the agreement of the IRB/IEC and the Sponsor’s medical monitor.


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18. 
PUBLICATIONS
The publication policy for the study will be described in the clinical study 
agreement. To avoid disclosures that could jeopardize proprietary rights, the 
investigator agrees to give Tolero Pharmaceuticals, Inc, the right to review all 
manuscripts, abstracts, and presentations related to this study prior to their 
submission for publication or presentation. Tolero may use these data now and 
in the future for presentation or publication at Tolero’s discretion or for 
submission to government regulatory agencies. 
Authorship among Investigators generally will be based on the extent of 
significant contribution, including scientific and clinical, to the publication.


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19.
REFERENCES
1.
Hanahan D, Weinberg RA. The hallmarks of cancer. Cell 2000;100:57–70.
2.
National 
Cancer 
Institute, 
What 
is 
Cancer? 
Available 
at: 
http://www.cancer.gov/about-cancer/what-is-cancer Accessed on: 30 June 2015.
3.
Kaufmann SH, Karp JE, Svingen PA, et al. Elevated Expression of the Apoptotic 
Regulator Mcl-1 at the Time of Leukemic Relapse. Blood 1998;91(3):991–1000.
4.
Reynolds JE, Yang T, Qian L, et al. Mcl-1, a member of the Bcl-2 family, delays 
apoptosis induced by c-Myc overexpression in Chinese hamster ovary cells. 
Cancer Res 1994;54:6348–6352.
5.
Zhou P, Qian L, Kozopas KM, et al. Mcl-1, a Bcl-2 family member, delays the death 
of hematopoietic cells under a variety of apoptosis-inducing conditions. Blood 
1997;89:630–643.
6.
Yang T, Buchan HL, Townsend KJ, Craig RW. MCL-1, a member of the BCL-2
family, is induced rapidly in response to signals for cell differentiation or death, but 
not to signals for cell proliferation. J Cell Physiol 1996;166:523–536.
7.
Zhan Q, Bieszczaed CK, Bae I, et al. Induction of Bcl-2 family member Mcl-1 as 
an early response to DNA damage. Oncogene 1997;14:1031–1039.
8.
Bose P, Perkins EB, Honeycut C, et al. Phase I trial of the combination of 
flavopiridol and imatinib mesylate in patients with Bcr-Abl+ hematological 
malignancies. Cancer Chemother Pharmacol 2012;69:1657–1667. 
9.
Ma Y, Cress WD, Haura EB. Flavopiridol-induced apoptosis is mediated through 
up-regulation of E2F1 and repression of Mcl-1. Mol Cancer Ther 2003;2:73–81.
10.
Karp JE, Smith BD, Resar LS, et al. Phase 1 and pharmacokinetic study of bolus-
infusion flavopiridol followed by cytosine arabinoside and mitoxantrone for acute 
leukemias. Blood 2011;117:3302–3310 (Phase 1 Study No. J06133 / NCI7889).
11.
Geller RB, Burke PJ, Karp JE, et al. A two-step timed sequential treatment for
acute myelocytic leukemia. Blood 1989;74:1499–1506.
12.
Karp JE, Passaniti A, Gojo I, et al. Phase I and pharmacokinetic study of 
flavopiridol followed by 1-beta-D-arabinofuranosylcytosine and mitoxantrone in 
relapsed and refractory adult acute leukemias. Clin Cancer Res 2005;11:8403–
8412. (Phase 1 Study No. J0254/NCI3170)
13.
Karp JE, Smith BD, Levis MJ, et al. Sequential flavopiridol, cytosine arabinoside, 
and mitoxantrone: a phase II trial in adults with poor-risk acute myelogenous 
leukemia. Clin Cancer Res 2007;13:4467–4473. (Phase 2 Extension Study No. 
J0254 / NCI3170)


Protocol No. TPI-ALV-201 Amendment 11 
 
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14.
Blum W, Phelps MA, Klisovic RB, et al. Phase I clinical and pharmacokinetic study 
of a novel schedule of flavopiridol in relapsed or refractory acute leukemias. 
Haematologica 2010;95:1098–1105. (Phase 1 Study No. OSU-0479/NCI-6947)
15.
Karp JE, Blackford A, Smith BD, et al. Clinical activity of sequential flavopiridol, 
cytosine arabinoside, and mitoxantrone for adults with newly diagnosed, poor-risk 
acute myelogenous leukemia. Leuk Res 2010;34:877–882. (Study No. J0669 / 
NCI7845).
16.
Litzow MR, Wang XV, Carroll MP, et al. Randomized Phase II Trial of Three Novel 
Regimens for Relapsed/ Refractory Acute Myeloid Leukemia (AML) Demonstrates 
Encouraging Results with a Flavopiridol-Based Regimen: Results of Eastern 
Cooperative Oncology Group (ECOG) Trial E1906. Proc ASH: Blood 2014 #3742.
17.
Karp JE, Garrett-Mayer E, Estey EH, et al. Randomized phase II study of two 
schedules of flavopiridol given as timed sequential therapy with cytosine 
arabinoside and mitoxantrone for adults with newly diagnosed, poor-risk acute 
myelogenous leukemia. Haematologica 2012;97:1736–1742.
18.
Zeidner JF, Foster MC, Blackford AL, et al. Randomized multicenter phase 2 study 
of flavopiridol (alvocidib), cytarabine, and mitoxantrone (FLAM) versus 
cytarabine/daunorubicin (7+3) in newly diagnosed acute myeloid leukemia 
Haematologica January 2015: doi:10.3324/haematol.2015.125849 (Phase 2 
Study No. J1101/NCI-8972).
19.
Byrd JC, Lin TS, Dalton JT, et al. Flavopiridol administered using a 
pharmacologically derived schedule is associated with marked clinical efficacy in 
refractory, 
genetically 
high-risk 
chronic 
lymphocytic 
leukemia. 
Blood 
2007;109(2):399–404.
20.
Cheson BD, Bennett JM, Kopecky KJ, et al. Revised recommendations of the 
International Working Group for Diagnosis, Standardization of Response Criteria, 
Treatment Outcomes, and Reporting Standards for Therapeutic Trials in Acute 
Myeloid Leukemia. J Clin Oncol 2003;21:4642–4649.
21.
Döhner H, Estey EH, Amadori S, et al. Diagnosis and management of acute
myeloid leukemia in adults: recommendations from an international expert panel, 
on behalf of the European LeukemiaNet. Blood 2010;115(3):453–474.  
22.
Montesinos P, Lorenzo I, Martín G, et al. Tumor lysis syndrome in patients with 
acute myeloid leukemia: identification of risk factors and development of a 
predictive model. Haematologica 2008;93(1):67–74. 
23.
Döhner H, Estey EH, Grimwade D, et al. Diagnosis and management of AML in 
adults: 2017 ELN recommendations from an international expert panel. Blood 
2017;129(4):424–447. 


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24.
NCCN Clinical Practice Guidelines in Oncology. Acute Myeloid Leukemia. 
National 
Comprehensive 
Cancer 
Network. 
Available 
at
https://www.nccn.org/professionals/physician_gls/pdf/aml.pdf. Version 1.2018 — 
07 February 2018; Accessed: 18 April 2018.




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Notes:
a 
Collect and document a complete medical history including pathological confirmed diagnosis of AML by WHO criteria and documentation of all other 
measures of disease and disease symptoms (eg, extramedullary disease)
b 
Vital signs to include: body temperature, heart rate, systolic and diastolic blood pressure
c 
Required if not performed/obtained within 30 days prior to anticipated first dose. 
d 
&ROOHFWXULQHRUVHUXPVDPSOHIRUȕ-hCG pregnancy test from females of child-bearing potential
e 
See Appendix D – Laboratory Tests, Hematology  
f
See Appendix D – Laboratory Tests, Full Serum Chemistry 
g 
See Appendix D – Laboratory Tests, Urinalysis
h 
Diligent monitoring of urine output frequently to ensure that it equals fluid input. If input is greater than output by 10%, administration of diuretics is 
encouraged. Replacement of excessive fluid losses, including from diarrhea, should be done unless otherwise clinically indicated. Test for presence of 
C. difficile infection at first instance of diarrhea (refer to Section 4.6.1.2 for additional guidance).
i 
See Appendix D – Laboratory Tests, Tumor Lysis Labs  
j 
Toxicities will be assessed according to the NCI CTCAE, version 4.03 in Stage 1 (see Appendix C).  When the NCI CTCAE grade is not available, the 
investigator will use the following toxicity grading: mild, moderate, severe, life-threatening or fatal
k 
Bone marrow biopsy and/or aspirate required for diagnosis, cytogenetic profiling, and BH3 profiling. If the initial bone marrow biopsy and/or aspirate is 
nonproductive or not diagnostic, the procedure must be repeated. (If an aspirate with cytogenetics was performed as part of the BH3 profiling and it 
was done within 2 weeks of the first dose, then it does not need to be repeated.)  At screening, 6 to 8 bone marrow slides will be prepared and sent to 
the Sponsor if the patient is enrolled. Details regarding the collection and shipping of these slides is provided in the Study Manual.
l 
Including all nonprescription medications and nutritional supplements taken within the past 2 weeks
m Including all prescription and nonprescription medications and nutritional supplements
n 
Review all inclusion and exclusion criteria to determine if patient has met all eligibility criteria for enrollment into the study. 
o 
Including all nonprescription medications and nutritional supplements taken since screening
p 
Mandatory IV hydration with 0.45% NaCl (or similar hydration fluid per institutional standard) sterile solution at 100 cc/hour for at least 10 hours prior 
to initiation of first dose during Cycle 1 (optional for subsequent cycles). If, by Day 4, there is no evidence of tumor lysis syndrome, the hydration rate 
can be reduced to a maintenance level.
q 
Mandatory allopurinol orally each day of dosing for first cycle to be started at same time as initiation of IV hydration.
r 
Mandatory oral phosphate binder to be started at the same time as initiation of IV hydration, unless contraindicated.
s 
Measured 5-15 minutes prior to the initiation of infusion following a 5-minute rest
t
Required if screening pregnancy test was performed greater than 72 hrs prior
u 
To include only those medications (prescription, nonprescription, nutritional supplements) administered in conjunction with an AE. 
v 
For patients at high risk for TLS: See Section 4.6.1.1 for TLS labs collection schedule.
w
For patients NOT at high risk for TLS: See Section 4.6.1.1 for TLS labs collection schedule.
x 
Only required if clinically indicated
y 
Abbreviated physical examination (AE- or symptom-directed exam).
z 
Bone marrow biopsies and/or aspirates will be performed at hematologic recovery (ie, absolute neutrophil count (ANC) >1000 μL and platelet count 
>100,000 μL) or on Day 45 (±2), whichever occurs first. If the bone marrow biopsy and/or aspirate is nonproductive or not diagnostic, the procedure
must be repeated within 7 days. In addition, 6 to 8 bone marrow slides will be prepared and sent to the Sponsor. Details regarding the collection and 
shipping of these slides is provided in the Study Manual.
aa Including tumor lysis clinical symptoms
bb  An End of Study visit is to be performed at time of patient withdrawal [See SCHEDULE OF ACTIVITIES – STAGE 1, Cycles 2 - 4 (ACM only) for 
details of required assessments]




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demonstrating evidence of CR, CRi, CRp, or PR after the first cycle of treatment will be considered for removal from the study, although with permission 
of the Medical Monitor, induction treatment may continue if clinically indicated and provided there is no evideQFHRIWR[LFLW\1&,&7&$(JUDGH
b 
If pretreatment to manage/treat tumor lysis syndrome is clinically indicated in subsequent cycles, must monitor urine output frequently to ensure that it 
equals fluid input. If input is greater than output by 10%, administration of diuretics is encouraged. Replacement of excessive fluid losses, including from 
diarrhea, should be done unless otherwise clinically indicated. Test for presence of C. difficile infection at first instance of diarrhea (refer to 
Section 4.6.1.2 for additional guidance).
c 
Vital signs to include: body temperature, heart rate, systolic and diastolic blood pressure
d 
See Appendix D – Laboratory Tests, Hematology  
e 
See Appendix D – Laboratory Tests, Tumor Lysis Labs
f
See Appendix D – Laboratory Tests, Urinalysis
g 
To include only those medications (prescription, nonprescription, nutritional supplements) administered in conjunction with an AE.
h 
Toxicities will be assessed according to the NCI CTCAE, version 4.03 in Stage 1 (see Appendix C). When the NCI CTCAE grade is not available, the 
investigator will use the following toxicity grading: mild, moderate, severe, life-threatening or fatal
i 
See Appendix D – Laboratory Tests, Full Serum Chemistry 
j 
Urinalysis to include: color, specific gravity, pH, bilirubin, ketones, glucose, hemoglobin, blood, protein, urobilinogen, nitrites, WBCs, RBCs, casts, 
crystals, bacteria
k 
If clinically indicated, begin IV hydration with 0.45% NaCl (or similar hydration fluid per institutional standard) sterile solution at 100 cc/hour at least 
10 hours prior to initiation of first dose. If, by Day 4, there is no evidence of tumor lysis syndrome, the hydration rate can be reduced to a maintenance
level.
l 
If clinically indicated, begin allopurinol orally each day of dosing at same time as initiation of IV hydration.
m If clinically indicated, begin oral phosphate binder at the same time as initiation of IV hydration, unless contraindicated.
n 
ECHO or MUGA scan to be performed before each dose of mitoxantrone. If mitoxantrone is omitted after Cycle 1, the ECHO or MUGA scan can also 
be omitted.
o 
Measured 5-15 minutes prior to the initiation of infusion following a 5-minute rest
p 
Only required if clinically indicated
q 
Continued use of mitoxantrone is optional. Mitoxantrone must be omitted from subsequent cycles if the patient’s lifetime daunorubicin equivalent 
exceeds 460 mg/m2 (see Appendix G for conversion table) or the LVEF drops below 45%.
r 
Abbreviated physical examination (AE- or symptom-directed exam).
s 
Bone marrow biopsies and/or aspirates will be performed at hematologic recovery (ie, absolute neutrophil count (ANC) >1000 μL and platelet count 
>100,000 μL) or on Day 45 (±2), whichever occurs first. If the bone marrow biopsy and/or aspirate is nonproductive or not diagnostic, the procedure 
must be repeated within 7 days. At time of response assessment and end-of-study visit, 6 to 8 bone marrow slides will be prepared and sent to the 
Sponsor. Details regarding the collection and shipping of these slides is provided in the Study Manual. 
t
Including other measures of disease and disease symptoms, eg, extramedullary disease
u 
If not done in preceding 30 days
v
Patients will be contacted by telephone to assess for date of death, date of stem cell transplant, date of relapse, or continued remission for two years:  
Year 1: Phone calls monthly beginning the month after the patient completes the end-of-study assessments to 12 months after Day of Randomization 
regardless of how many cycles a patient receives (Year 1 = Day of Randomization plus 12 months); Year 2: Phone calls every other month during 
Year 2 (months 14 to 24 months after Day of Randomization).




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Notes:
a 
Collect and document a complete medical history including pathological confirmed diagnosis of AML by WHO criteria and documentation of all other 
measures of disease and disease symptoms (eg, extramedullary disease)
b 
Vital signs to include: body temperature, heart rate, systolic and diastolic blood pressure
c 
Required if not performed/obtained within 30 days prior to anticipated first dose. 
d 
&ROOHFWXULQHRUVHUXPVDPSOHIRUȕ-hCG pregnancy test from females of child-bearing potential
e 
See Appendix D – Laboratory Tests, Hematology
f
See Appendix D – Laboratory Tests, Full Serum Chemistry 
g 
See Appendix D – Laboratory Tests, Urinalysis 
h 
Diligent monitoring of urine output frequently to ensure that it equals fluid input. If input is greater than output by 10%, administration of diuretics is 
encouraged. Replacement of excessive fluid losses, including from diarrhea, should be done unless otherwise clinically indicated.
i 
See Appendix D – Laboratory Tests, Tumor Lysis Labs
j 
Toxicities will be assessed according to the NCI CTCAE, version 5.0 in Stage 2 (see Appendix C). When the NCI CTCAE grade is not available, the 
investigator will use the following toxicity grading: mild, moderate, severe, life-threatening or fatal.
k 
Bone marrow biopsy and/or aspirate required for diagnosis, cytogenetic profiling, and BH3 profiling. If the initial bone marrow biopsy and/or aspirate is 
nonproductive or not diagnostic, the procedure must be repeated. (If an aspirate with cytogenetics was performed as part of the BH3 profiling and it 
was done within 2 weeks of the first dose, then it does not need to be repeated). At screening, 6 to 8 bone marrow slides will be prepared and sent to 
the Sponsor if the patient is enrolled. Details regarding the collection and shipping of these slides is provided in the Study Manual.
l 
Including all nonprescription medications and nutritional supplements taken within the past 2 weeks
m Review all inclusion and exclusion criteria to determine if patient has met all eligibility criteria for enrollment into the study. 
n 
Including all nonprescription medications and nutritional supplements taken since screening
o 
Mandatory IV hydration with 0.45% NaCl (or similar hydration fluid per institutional standard) sterile solution at 100 cc/hour for at least 10 hours prior to 
initiation of first dose during Cycle 1 (optional for subsequent cycles) in both treatment arms. If, by Day 4, there is no evidence of tumor lysis syndrome, 
the hydration rate can be reduced to a maintenance level.
p 
Mandatory allopurinol orally each day of dosing for first cycle to be started at same time as initiation of IV hydration in both treatment arms.
q 
Mandatory oral phosphate binder to be started at the same time as initiation of IV hydration in both treatment arms, unless contraindicated.
r 
Measured 5-15 minutes prior to the initiation of infusion following a 5-minute rest
s 
Required if screening pregnancy test was performed greater than 72 hrs prior
t
Including all nonprescription medications and nutritional supplements
u 
To include only those medications (prescription, nonprescription, nutritional supplements) administered in conjunction with an AE. 
v 
For patients at high risk for TLS: See Section 4.6.1.1 for TLS labs collection schedule.
w
For patients NOT at high risk for TLS: See Section 4.6.1.1 for TLS labs collection schedule.
x 
Only required if clinically indicated
y 
Abbreviated physical examination (AE- or symptom-directed exam).
z 
Bone marrow biopsies and/or aspirates will be performed at hematologic recovery or on Day 45 (±2), whichever occurs first. If the bone marrow biopsy 
and/or aspirate is nonproductive or not diagnostic, the procedure must be repeated within 7 days. At time of response assessment, 6 to 8 bone marrow 
slides will be prepared and sent to the Sponsor. Details regarding the collection and shipping of these slides is provided in the Study Manual.
aa Including tumor lysis clinical symptoms  
bb An End of Study visit is to be performed at time of patient withdrawal [See SCHEDULE OF ACTIVITIES – STAGE 2, Cycles 2 - 4 (ACM vs CM) for 
details of required assessments]




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1 cycle of CM may cross over to receive ACM. In addition, patients randomized to CM with the best response of a PR after 2 cycles of CM may also 
cross over to receive ACM. Patients who cross over to ACM may receive up to a combined total (CM + ACM) of 4 cycles (See Section 4.5.3.4)
b 
If pretreatment to manage/treat tumor lysis syndrome is clinically indicated in subsequent cycles, must monitor urine output frequently to ensure that it 
equals fluid input. If input is greater than output by 10%, administration of diuretics is encouraged. Replacement of excessive fluid losses, including from 
diarrhea, should be done unless otherwise clinically indicated.
c 
Vital signs to include: body temperature, heart rate, systolic and diastolic blood pressure
d 
See Appendix D – Laboratory Tests, Hematology
e 
See Appendix D – Laboratory Tests, Tumor Lysis Labs
f
&ROOHFWXULQHRUVHUXPVDPSOHIRUȕ-hCG pregnancy test from females of child-bearing potential
g 
To include only those medications (prescription, nonprescription, nutritional supplements) administered in conjunction with an AE.
h 
Toxicities will be assessed according to the NCI CTCAE, version 5.0 in Stage 2 (see Appendix C). When the NCI CTCAE grade is not available, the 
investigator will use the following toxicity grading: mild, moderate, severe, life-threatening or fatal
i 
See Appendix D – Laboratory Tests, Full Serum Chemistry 
j 
See Appendix D – Laboratory Tests, Urinalysis 
k 
If clinically indicated, begin IV hydration with 0.45% NaCl (or similar hydration fluid per institutional standard) sterile solution at 100 cc/hour at least 
10 hours prior to initiation of first dose in both treatment arms. If, by Day 4, there is no evidence of tumor lysis syndrome, the hydration rate can be 
reduced to a maintenance level.
l 
If clinically indicated, begin allopurinol orally each day of dosing at same time as initiation of IV hydration in both treatment arms.
m If clinically indicated, begin oral phosphate binder at the same time as initiation of IV hydration in both treatment arms, unless contraindicated. 
n 
ECHO or MUGA scan to be performed before each dose of mitoxantrone. If mitoxantrone is omitted after Cycle 1, the ECHO or MUGA scan can also 
be omitted.
o 
Measured 5-15 minutes prior to the initiation of infusion following a 5-minute rest
p 
Only required if clinically indicated
q 
Continued use of mitoxantrone is optional. Mitoxantrone must be omitted from subsequent cycles if the patient’s lifetime daunorubicin equivalent 
exceeds 460 mg/m2 (see Appendix G for conversion table) or the LVEF drops below 45%.
r  
Abbreviated physical examination (AE- or symptom-directed exam).
s  
Bone marrow biopsies and/or aspirates will be performed at hematologic recovery (ie, absolute neutrophil count (ANC) >1000 μL and platelet count 
>100,000 μL) or on Day 45 (±2), whichever occurs first. If the bone marrow biopsy and/or aspirate is nonproductive or not diagnostic, the procedure 
must be repeated within 7 days. At time of response assessment and end-of-study visit, 6 to 8 bone marrow slides will be prepared and sent to the 
Sponsor. Details regarding the collection and shipping of these slides is provided in the Study Manual. 
t
Including other measures of disease and disease symptoms, eg, extramedullary disease
u  If not done in preceding 30 days
v
Patients will be contacted by telephone to assess for date of death, date of stem cell transplant, date of relapse, or continued remission for two years:  
Year 1: Phone calls monthly beginning the month after the patient completes the end-of-study assessments to 12 months after Day of Randomization 
regardless of how many cycles a patient receives (Year 1 = Day of Randomization plus 12 months); Year 2: Phone calls every other month during 
Year 2 (months 14 to 24 months after Day of Randomization).


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APPENDIX B – ECOG PERFORMANCE STATUS SCALE
ECOG PERFORMANCE STATUS*
Grade
ECOG
0 
Fully active, able to carry on all pre-disease performance without restriction
1 
Restricted in physically strenuous activity but ambulatory and able to carry out 
work of a light or sedentary nature, e.g., light house work, office work
2 
Ambulatory and capable of all selfcare but unable to carry out any work 
activities. Up and about more than 50% of waking hours
3 
Capable of only limited selfcare, confined to bed or chair more than 50% of 
waking hours
4 
Completely disabled. Cannot carry on any selfcare. Totally confined to bed or 
chair
5 
Dead
Oken MM, Creech RH, Tormey DC, et al. Toxicity And Response Criteria Of The Eastern Cooperative 
Oncology Group. Am J Clin Oncol 1982;5:649-655.
Available at: http://www.ecog.org/general/perf stat.html
*The ECOG Performance Status is in the public domain therefore available for public use. To duplicate 
the scale, please cite the reference above and credit the Eastern Cooperative Oncology Group, Robert 
Comis, MD, Group Chair.


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APPENDIX C – NCI COMMON TERMINOLOGY CRITERIA FOR ADVERSE EVENTS 
View the National Cancer Institute Common Terminology Criteria for Adverse Events 
(NCI CTCAE) v4.03 (for Stage 1) and v5.0 (for Stage 2) electronically at the following 
Web sites:
https://evs.nci.nih.gov/ftp1/CTCAE/CTCAE 4.03/CTCAE 4.03 2010-06-
14 QuickReference 8.5x11.pdf
https://ctep.cancer.gov/protocoldevelopment/electronic applications/docs/CTCAE
v5 Quick Reference 8.5x11.pdf
The Study Manual includes copies of both versions of the NCI CTCAE.


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APPENDIX D – LABORATORY TESTS
Hematology
x
CBC with manual differential
x
Platelet Count
Note:  A manual differential is the preferred method and is
required on each day that the assessment is done.
Automated differentials may be used for subsequent 
differentials performed on the same day.
Full Serum Chemistry
x
Blood urea nitrogen (BUN)
x
Phosphorus
x
Magnesium
x
Lactate dehydrogenase 
(LDH)
x
Creatinine
x
Uric acid
x
Total protein
x
Albumin
x
Calcium
x
Glucose
x
Total bilirubin
x
Alkaline phosphatase 
(ALP) Aspartate 
aminotransferase (AST)
x
Alanine 
aminotransferase (ALT)
x
Electrolytes 
o Sodium
o Potassium
o Chloride 
o Carbon dioxide
(bicarbonate)
Tumor Lysis Labs
x
Phosphorus
x
Uric acid
x
Electrolytes (sodium, 
potassium, chloride, and 
carbon dioxide)
x
LDH*
x
Creatinine
x
Calcium
Coagulation
x
Fibrinogen
Urinalysis
x
Color
x
Specific gravity
x
pH
x
Bilirubin
x
Ketones
x
Glucose
x 
Occult Blood (Hemoglobin) 
x
Leukocyte esterase
x
Protein
x
Urobilinogen
x
Nitrites
Microscopic
x
White blood cells 
(WBCs)
x
Red blood cells (RBCs)
x
Casts, crystals, bacteria
Cardiac Tests
x
12-lead Electrocardiogram 
(ECG)
x
Echocardiogram 
(ECHO) or Multigated 
Acquisition (MUGA) 
scan
Pharmacodynamic 
Tests
x
MCL-1 dependence by mitochondrial profiling in bone 
marrow
Other Tests
x
Pregnancy test (urine or 
serum determination of 
ȕ-hCG in females of 
childbearing potential)
x
Chest radiograph
*Recommended every 24 hours in patients receiving alvocidib. 


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APPENDIX E – RESPONSE CRITERIA
Response to treatment will be evaluated according to different criteria depending on the 
stage of the study. 
During Stage 1, responses will be defined by the International Working Group and 2010 
European LeukemiaNet Criteria. 
During Stage 2, responses will be defined by the 2017 European LeukemiaNet Criteria. 


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INTERNATIONAL WORKING GROUP CRITERIA
Response Criteria in AML
Definition of Treatment Outcomes
Source: Cheson BD, et al. J Clin Oncol 2003;21:4642-4649.


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2010 EUROPEAN LEUKEMIANET CRITERIA
Response Criteria in AML
Source: Döhner H, et al. Blood 2010;115:453-474.


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2017 EUROPEAN LEUKEMIANET CRITERIA
Source:
Döhner H, Estey EH, Grimwade D, et al. Blood 2017;129(4):424–447.


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APPENDIX F – MULTIVARIATE ANALYSIS AND RISK SCORE PREDICTION MODEL 
FOR DEVELOPMENT OF TUMOR LYSIS SYNDROME IN AML
CTLS = clinical tumor lysis syndrome; LDH = lactate dehydrogenase; 
ULN = upper limit of normal; WBC = white blood cells
*Patients with an overall score of 2 will be considered at high risk for 
development of TLS in this study. 
Source: Montesinos P, Lorenzo I, Martín G, et al. Haematologica 2008;93(1):67–74.
*


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APPENDIX G –ASSESSMENT OF PRIOR AND CUMULATIVE 
ANTHRACYCLINE/ANTHRACENEDIONE EXPOSURE*

SAP_001.pdf: 
STATISTICAL ANALYSIS PLAN
Study Title:
A Phase 2, Randomized, Biomarker-Driven, Clinical 
Study in Patients with Relapsed or Refractory Acute 
Myeloid Leukemia (AML) with an Exploratory Arm in 
Patients with Newly Diagnosed High-Risk AML and 
Exploratory Arms with Varying Levels of MCL-1
Dependence
Protocol Number:
TPI-ALV-201
IND Number:
057729
Study Drug:
Alvocidib (test agent; formerly flavopiridol) in
combination with Ara-C (cytarabine) and 
mitoxantrone
Phase of Development:
Phase 2
Sponsor:
Tolero Pharmaceuticals, Inc.
Date of SAP:
13-JUN-2018 (Version 1.0)


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Table of Contents
1. 
Synopsis .................................................................................................................. 4 
2. 
Abbreviations ........................................................................................................... 6 
3. 
Definitions ................................................................................................................ 7 
4. 
Introduction .............................................................................................................. 8 
4.1. Study Endpoints................................................................................................. 8 
4.2. Statistical Objectives........................................................................................ 10 
5. 
Sample Size........................................................................................................... 10 
5.1. Primary Study................................................................................................... 10 
5.1.1. 
Stage 1 ...................................................................................................... 10 
5.1.2. 
Stage 2 ...................................................................................................... 11 
5.2. Exploratory Study Arms ................................................................................... 12 
6. 
Treatment Randomization...................................................................................... 12 
7. 
Statistical Methods................................................................................................. 12 
7.1. Analysis Populations........................................................................................ 13 
7.2. Missing Values................................................................................................. 14 
7.3. Visit Windows................................................................................................... 15 
7.4. Interim Analysis................................................................................................ 15 
7.4.1. 
Outcomes and Study Continuation............................................................ 15 
7.5. Overall Type-1 Error Rate ................................................................................ 15 
7.5.1. 
Type-1 Error Rate Control for Interim Analysis.......................................... 16 
7.5.2. 
Type-1 Error Rate Control for Multiple Comparisons................................. 16 
7.6. Patient Disposition ........................................................................................... 17 
7.7. Baseline Characteristics................................................................................... 17 
7.8. Study Drug Exposure....................................................................................... 18 
7.9. Efficacy Endpoints............................................................................................ 18 
7.9.1. 
Remission Rates ....................................................................................... 18 
7.9.2. 
Progression-Free Survival ......................................................................... 20 
7.9.3. 
Stem Cell Transplant Rate......................................................................... 22 
7.9.4. 
Overall Survival ......................................................................................... 22 
7.9.5. 
Relapse-Free Survival Following CR......................................................... 23 
7.9.6. 
Complete Remission Duration................................................................... 24 


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7.9.7. 
ECOG Performance Status ....................................................................... 25 
7.10. Biomarker......................................................................................................... 25 
7.11. Safety Endpoints.............................................................................................. 26 
7.11.1. 30- and 60-Day Mortality ........................................................................... 26 
7.11.2. Adverse Events ......................................................................................... 26 
7.11.3. Classification of Tumor Lysis Syndrome.................................................... 27 
7.11.4. Clinical Laboratory Parameters ................................................................. 27 
7.11.5. Vital Signs.................................................................................................. 28 
7.11.6. Concomitant Medication Use..................................................................... 28 
7.12. Subgroup Analyses.......................................................................................... 28 
8. 
Adverse Event and Medication Coding Dictionaries............................................... 29 
9. 
Summary Tables.................................................................................................... 29 
10. References............................................................................................................. 32 
List of Tables
Table 1. 
Study Endpoints............................................................................................. 9 
Table 2. 
SAS Programming Statements for Sample Size Calculation ....................... 11 
Table 3. 
SAS PROC SEQDESIGN Output: Boundary Information ............................ 11 
Table 4. 
SAS PROC SEQDESIGN Output: Sample Sizes......................................... 11 
Table 5. 
Statistical Analyses of Cycle-1 CR Rates..................................................... 19 
Table 6. 
Statistical Analyses of PFS, OS, RFS and CR Duration .............................. 21 
Table 7. 
Statistical Analyses of Stem Cell Transplant Rate ....................................... 22 
Table 8. 
Cairo-Bishop Definition of Laboratory Tumor Lysis Syndrome..................... 27 
Table 9. 
Planned Summary Tables............................................................................ 29 
List of Appendices
Appendix 1. 
Criteria for Grading Severity of Clinical Tumor Lysis Syndrome............. 33 
Appendix 2. 
Sample Summary Table Templates ....................................................... 34 


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1. Synopsis
Protocol Title:
A Phase 2, Randomized, Biomarker-Driven, Clinical Study in Patients with Relapsed or 
Refractory Acute Myeloid Leukemia (AML) with an Exploratory Arm in Patients with 
Newly Diagnosed High-Risk AML and Exploratory Arms with Varying Levels of MCL-1
Dependence
Study Design:
There is a primary study component and four exploratory study arms
x
Primary Study: single-arm, Simon two-stage lead in to confirm efficacy 
assumptions followed by a randomized, two-arm parallel design
x
Exploratory Study Arms: single-arm observational
Study Populations:
x
Primary Study: Relapsed and refractory AML patients with MCL-1 dependence
≥40%
x
Exploratory Study Arms:
x
Patients with newly diagnosed, high-risk AML and MCL-1 dependence ≥40%
x
Relapsed and refractory AML patients with MCL-1 dependence between 0%
and <15%
x
Relapsed and refractory AML patients with MCL-1 dependence between 15%
and <30%
x
Relapsed and refractory AML patients with MCL-1 dependence between 30%
and <40%
Treatment Arms:
x
ACM (alvocidib, Ara-C [cytarabine] and mitoxantrone)
x
CM (Ara-C [cytarabine] and mitoxantrone)
Biomarker:
x
MCL-1 dependence measured by mitochondrial sensitivity to NOXA BH3 
peptides (hereafter referred to as MCL-1 dependence)
Sample Size:
x
Primary Study, Stage 1: up to 23 patients
x
Primary Study, Stage 2: 106 patients (53 patients per treatment arm)
x
Exploratory Study Arms: 20 patients in each of four exploratory patient 
populations
Randomization:
x
Primary Study, Stage 1: Not randomized, all patients receive ACM


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x
Primary Study, Stage 2: Randomized 1:1 to ACM or CM stratified by response to
frontline AML therapy
x
Exploratory Study Arms: Not randomized, all patients receive ACM
Analysis Populations:
Intent-to-treat (primary for efficacy), safety, response-available, per-protocol, crossover
Response Assessments:
Central review performed by a panel of independent, expert hematologists according to 
an approved charter under change control (primary response assessment); local review 
of bone marrow and blood test results by the investigator at the study center where 
patient is enrolled (secondary assessment); “sponsor review” by employees and/or 
agents of Tolero Pharmaceuticals
Missing Values:
Missing values will not be replaced by imputed values. Patients who do not supply bone 
marrow for response assessment are counted among those not achieving remission. 
Missing time-to-event endpoints will be censored using standard rules detailed below.
Interim Analysis:
Single interim analysis after cycle-1 responder status is established for 28 patients per 
treatment arm; O’Brien-Fleming boundaries to control type-1 error rate
Significance Level:
One-sided, 2.5% including control for interim analysis and multiple comparisons
Procedure for Multiple Comparisons:
Hierarchical closed test procedure
Efficacy Endpoints:
Cycle-1 CR rate (primary endpoint), cycle-1 combined CR rate, cycle-1 combined 
remission rate, stem cell transplant rate, overall survival, progression-free survival, 
relapse-free survival, CR duration
Safety Endpoints:
30- and 60-day survival, adverse events, time to neutrophil recovery, time to platelet 
recovery, prevalence of tumor lysis syndrome, clinical laboratory parameters, vital signs
Statistical Methods:
Treatment-arm comparisons of cycle-1 complete remission rates (primary efficacy 
endpoint) and stem cell transplant rates by stratified CMH general association test
(primary analysis) and logistic regression (supportive analyses); comparisons of time-to-
event endpoints (progression-free survival, overall survival, relapse-free survival, and 
complete remission duration) by stratified log rank test (primary analysis) and Cox PH 
models (supportive analyses)


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2. Abbreviations
Standard abbreviations (e.g., AML = acute myeloid leukemia and mg = milligrams) are 
omitted intentionally.
ACM
Alvocidib, Ara-C (Cytarabine) and Mitoxantrone
AE
Adverse Event
ANC
Absolute Neutrophil Count
ATC
Anatomical and Therapeutic Class
AUC
Area Under Curve
BM
Bone Marrow
BSA
Body Surface Area
CI
Confidence Interval
CM
Ara-C (Cytarabine) and Mitoxantrone
CMH
Cochran-Mantel-Haenszel (test)
CR
Complete Remission
CRi
Complete Remission with Incomplete Blood Count Recovery
CRp*
Complete Remission with Incomplete Platelet Recovery
CTCAE
Common Terminology Criteria for Adverse Events
DDE
Drug Dictionary Enhanced
DSMB
(Independent) Data Safety Monitoring Board
ECOG
Eastern Cooperative Oncology Group (performance status)
HR
Hazards Ratio
ITT
Intent-to-Treat (patient population)
IWG
International Working Group
KM
Kaplan-Meier (survivor function estimate)
LR
Logistic Regression
MedDRA
Medical Dictionary for Regulatory Activities
OS
Overall Survival
PBSC
Peripheral Blood Stem Cells
PFS
Progression-Free Survival
PH
Proportional Hazards (model)
* The term CRp appears in this document to maintain compatibility with the study’s case report forms, 
however CRp will not be used by the hematologists performing the central review of patients’ responses 
and it is not expected to be used by the investigators.


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PR
Partial Remission
PT
(MedDRA) Preferred Term
RFS
Relapse-Free Survival
ROC
Receiver Operating Characteristic (curve)
SAE
Serious Adverse Event
SAP
Statistical Analysis Plan
SCT
Stem Cell Transplant/Transplantation
SMQ
Standardized MedDRA Query
SOC
(MedDRA) System Organ Class
TEAE
Treatment Emergent Adverse Event
TLS
Tumor Lysis Syndrome
WHO
World Health Organization
3. Definitions
Standard statistical terminology (e.g., type-1 error rate and significance level) is omitted 
intentionally. Efficacy endpoints are defined in Section 4.1 below (see Table 1).
Baseline Value: last measured value prior to the first dose of study drug (or prior to 
randomization for patients not treated)
Combined CR: response assessment of CR, CRi or CRp
Combined Remission: response assessment of CR, CRi, CRp or PR
Crossover Patient: a patient randomized to CM who, following 1-2 cycles of CM, 
receives ACM as stipulated in the study protocol
Cycle 1: period of time from the first dose of study drug until the start of study drug in 
cycle 2 or the start of alternative AML therapy other than supportive measures such as 
blood product transfusions (hence a patient whose first response assessment in cycle 1 
is a CRi or CRp is considered to have achieved CR if neutrophils and platelets recover 
prior to initiation of cycle 2 or alternative AML therapy)
Cycle-1 Combined CR Rate: percentage of patients who achieve a combined CR (CR, 
CRi or CRp) after one cycle of treatment
Cycle-1 Combined Remission Rate: percentage of patients who achieve a combined 
remission (CR, CRi, CRp or PR) after one cycle of treatment
Cycle-1 CR Rate: percentage of patients who achieve a CR after one cycle of treatment
(see section 7.9.1)
Intent-to-Treat Population: all patients randomized to receive study drug regardless of 
whether they actually received study drug and regardless of whether evidence is found 
indicating they failed to meet study inclusion/exclusion criteria or had other protocol 
violations (see section 7.1)


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Neutrophil Recovery: Absolute neutrophil count ≥1x109/L following the administration of 
study drug
Per-Protocol Population: The subset of safety patients who either (a) have at least one 
response assessment on study, or (b) die prior to their first scheduled response 
assessment; however, patients are excluded from the per-protocol population if they 
have an important protocol deviation, such as when evidence is found indicating they 
failed to meet any study inclusion/exclusion criterion (see section 7.1)
Platelet Recovery: Platelet count ≥100x109/L following the administration of study drug
Pointwise: without controlling for multiple comparisons
Prestudy: Occurrence prior to randomization
Response-Available Population: The subset of safety patients who have at least one 
response assessment on study (see section 7.1)
Safety Population: The subset of intent-to-treat patients who received at least one dose 
of study drug (see section 7.1)
Sensitivity Analysis: study of how statistical methodology and assumptions affect results 
of the primary analysis
Shift Table: two-way frequency table pairing baseline value with the most extreme post-
baseline result
Study Drug: alvocidib, Ara-C (cytarabine) and mitoxantrone
Supportive Analysis: synonymous with Sensitivity Analysis
Treatment Failure: failing to achieve a CR, CRi, CRp or PR following induction therapy 
(see section 7.9.2)
4. Introduction
This Statistical Analysis Plan (SAP) details the planned methodology for summarizing 
data collected in the clinical study conducted under Tolero, Inc. protocol TPI-ALV-201
and for comparing outcomes between the two treatment arms, ACM (alvocidib, Ara-C
[cytarabine] and mitoxantrone) and CM (Ara-C [cytarabine] and mitoxantrone). The 
current version of the study protocol is Amendment 7 dated 30-MAY-2018. Future 
protocol amendments (if any) will be reviewed to assess whether the changes 
necessitate modification of this SAP.
Since the study protocol is a companion document to this SAP, aspects in the protocol 
unrelated to statistical issues (e.g., patient eligibility criteria, descriptions of clinical 
materials, and criteria for defining treatment failure, response to treatment and disease 
relapse) are not repeated here.
4.1. Study Endpoints
Statistical analysis and/or summarization is planned for the following study endpoints.
Complete details on how endpoints are calculated and compared across treatment arms 
are presented in the subsections below. A key to abbreviated terms appears in Section 
2.


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Table 1.
Study Endpoints
Primary Efficacy Endpoint
x
Cycle-1 CR Rate: percentage of patients who achieve a CR after one cycle of 
treatment
Secondary Efficacy Endpoints (not listed in order of importance)
x
Cycle-1 Combined CR Rate: percentage of patients achieving a combined CR 
(CR, CRi or CRp) after one cycle of treatment
x
Cycle-1 Combined Remission Rate: percentage of patients achieving a 
combined remission (CR, CRi, CRp or PR) after one cycle of treatment
x
Overall Survival: time from the date of randomization (Day 1) until death from 
any cause
x
Progression-Free Survival: time from the date of randomization (Day 1) until (a) 
treatment failure, (b) relapse after combined remission (CR, CRi, CRp or PR), 
or (c) death from any cause, whichever occurs first
x
Relapse-Free Survival Following CR (defined only for patients who achieve a 
CR during the study): time from the date of CR (Day 1) until (a) relapse after 
CR, or (b) death from any cause, whichever occurs first
x
Relapse-Free Survival Following Combined CR (defined only for patients who 
achieve a combined CR during the study): time from the earliest date of 
combined CR (Day 1) until (a) relapse after combined CR, or (b) death from 
any cause, whichever occurs first
x
Relapse-Free Survival Following Combined Remission (defined only for 
patients who achieve a combined remission during the study): time from the 
earliest date of combined remission (Day 1) until (a) relapse after combined 
remission, or (b) death from any cause, whichever occurs first
x
CR Duration (defined only for patients who achieve a CR during the study): 
time from the date of CR (Day 1) until relapse after CR
x
Combined CR Duration (defined only for patients who achieve a combined CR 
during the study): time from the earliest date of combined CR (Day 1) until 
relapse after combined CR
x
Combined Remission Duration (defined only for patients who achieve a 
combined remission during the study): time from the earliest date of combined 
remission (Day 1) until relapse after combined remission
x
Stem Cell Transplant Rate: percentage of patients proceeding directly to stem 
cell transplantation within 90 days after their last dose of study drug


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Table 1.
Study Endpoints
Safety Endpoints (not listed in order of importance)
x
30- and 60-Day Mortality
x
Adverse Event Incidence Rates
x
Time to neutrophil recovery ≥1x109/L
x
Time to platelet recovery ≥100x109/L
x
Presence and Severity of Tumor Lysis Syndrome
x
Clinical Laboratory Parameters
x
Vital Signs
Other Endpoints
x
Concomitant Medication Usage Rates
4.2. Statistical Objectives
The statistical objectives are fourfold:
1. To establish the statistical significance at a controlled, one-sided 2.5% 
significance level, the superiority of the ACM cycle-1 CR rate in 
relapsed/refractory AML patients with baseline MCL-1 dependence ≥40% 
compared to that for CM treatment
2. To demonstrate the statistical significance of the superiority of ACM treatment 
compared to CM with respect to secondary measures of efficacy while controlling 
for the inflationary effects of multiple comparisons on the overall significance
level
3. To model the relationship between baseline MCL-1 dependence and response to 
treatment with ACM
4. To describe the safety of ACM treatment in relapsed/refractory and newly 
diagnosed, high-risk AML patients (safety in relapsed/refractory AML patients will 
be judged relative treatment with CM)
5. Sample Size
5.1. Primary Study
5.1.1. Stage 1
The sample size of 23 eligible patients for stage 1 was selected because it allows 
estimation of the CR rate by means of a 90% confidence interval with maximum width of 
±17%. Although this study does not follow a Simon 2-stage design, 23 patients is 
consistent with the sample size for stage 1 of the Simon 2-stage minimax design with 
80% power for testing the null hypothesis that the CR rate is 50% against a one-sided 
alternative at the 5% level of significance when the actual CR rate is 70%. In the Simon 


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2-stage design described, the study would continue to stage 2 only if 13 patients 
achieve remission out of a maximum of 23 eligible patients. Therefore, this was selected 
as the requirement to proceed to stage 2 of this study.
5.1.2. Stage 2
The total planned sample size of 106 patients (53 per treatment arm) in stage 2 of the 
primary study provides 90% power to reject the null hypothesis of equal cycle-1 CR
rates across treatment arms under the following conditions:
x
Cycle-1 CR rates of 70% and 40% for patients receiving ACM and CM,
respectively
x
One-sided 2.5% significance level
x
A single interim analysis of cycle-1 CR rates using O’Brien-Fleming boundaries1
(see section 7.5.1) after responder status has been defined for 56 patients (28 
per treatment arm)
x
Randomization based on a 1:1 patient allocation ratio (ACM to CM)
Table 2 lists the programming statements used in SAS (version 9.4) to compute the 
sample size. Relevant SAS output is shown in Table 3 and Table 4.
Table 2.
SAS Programming Statements for Sample Size Calculation
proc seqdesign boundaryscale=pvalue;
design alpha=0.025 alt=upper beta=0.1 info=cum(56 106) method=obf nstages=2;
samplesize model=twosamplefreq(nullprop=0.40 prop=0.70 test=prop weight=1);
run;
Table 3.
SAS PROC SEQDESIGN Output: Boundary Information
_Stage_
Alternative
Boundary Values
Information Level
Reference
Upper
Proportion
Actual
N
Upper
Alpha
1
0.5283
62.2073
55.98657
2.36615
0.00321
2
1.0000 117.7495
105.9746
3.25537
0.02378
Table 4.
SAS PROC SEQDESIGN Output: Sample Sizes
_Stage_
Fractional N
Ceiling N
N N(Grp 1) N(Grp 2) Information
N N(Grp 1) N(Grp 2) Information
1
55.99
27.99
27.99
62.2073
56
28
28
62.2222


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Table 4.
SAS PROC SEQDESIGN Output: Sample Sizes
_Stage_
Fractional N
Ceiling N
N N(Grp 1) N(Grp 2) Information
N N(Grp 1) N(Grp 2) Information
2 105.97
52.99
52.99
117.7 106
53
53
117.8
5.2. Exploratory Study Arms
The sample size of 20 eligible patients in each of the four exploratory arms was 
selected because it allows estimation of the CR rate by means of a 90% confidence 
interval with maximum width of ±18%.
6. Treatment Randomization
All patients participating in stage 1 of the primary study or an exploratory study arm will 
be assigned treatment with ACM. Randomization is not used in these parts of the study.
The remainder of this section refers only to patient participating in stage 2 of the primary 
study.
Stage 2 of the primary study follows a randomized, two-arm parallel design. The two 
treatment arms are ACM and CM. Dosages and infusion times are detailed in the study 
protocol.
Enrolled patients are randomized to receive ACM or CM in a 1:1 ratio and stratified by a
three-category classification of response to first-line therapy:
x
Refractory – defined as persistent disease or a CR duration less than 90 days
x
Early Relapse – defined as a CR duration between 90 days and 1 year
x
Late Relapse – defined as a CR duration greater than 1 year but less than 24 
months
7. Statistical Methods
Statistical inference (hypothesis testing) to address the first and second objectives 
shown in section 4.2 will be addressed using data from stage 2 of the primary study 
only. Data from stage 1 of the primary study and the exploratory study arms will not be 
used for statistical inference.
Analyses will be performed using SAS statistical software. Default estimation methods
in version 9.4 of SAS are always used unless an alternative is specified below. Data 
summaries will include the mean, standard deviation, median, minimum and maximum
values for continuous data; the median, 25th and 75th percentiles, minimum and 
maximum values for time-to-event endpoints; and the number and percentage of 
patients in each category for categorical data. Pointwise 95% confidence intervals (CI) 
will also be estimated for the mean (continuous data), median (time-to-event endpoints) 
or percentage of patients (categorical data).


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In general, data values will be obtained directly from the clinical database (e.g., birth 
date, treatment dates, AML relapse date and death date). Derivations for certain values 
not collected explicitly in the database are explained in relevant sections below (e.g., 
age and treatment failure date, sections 7.7 and 7.9.2, respectively). In some instances,
it is beyond the scope of this SAP to explain schemes for patient classifications and 
data derivations (e.g., classifying patients in cytogenetic risk group according to 
published criteria). These details will be expounded in the clinical study report.
Durations of time expressed in months (e.g., times-to-event endpoints) will be reported 
in proportional “months” according to the formula
months =
12
365.25 × days
Baseline value of a characteristic is defined as the last measured value prior to the first 
dose of study drug (or prior to randomization for patients not treated).
Statistical p-values will be truncated for display at the third digit following the decimal 
point. P-values less than 0.001 will be displayed as “<0.001.”
7.1. Analysis Populations
The intent-to-treat (ITT) patient population includes all patients randomized to receive
study drug regardless of whether they actually received study drug and regardless of 
whether evidence is found indicating they failed to meet study inclusion/exclusion 
criteria or had other protocol violations. When the ITT patient population is analyzed, 
patients are grouped according to their randomized treatment regardless of actual 
treatment received. The ITT patient population is the analysis population for the primary 
analyses of efficacy endpoints (i.e., all statistical inference and tests of hypotheses
related to efficacy endpoints in stage 2 and univariate summaries of efficacy endpoints 
in stage 1 and the exploratory study arms).
The safety patient population is the subset of ITT patients who received at least one 
dose of study drug. When the safety patient population is analyzed, patients are 
grouped according to actual treatment received. ACM is considered a patient’s 
“treatment received” in the safety patient population if alvocidib is administered at any 
time during the study (except for ACM administered to a “crossover” patient). The safety 
patient population is the analysis population for all analyses of safety data.
The response-available patient population is the subset of safety patients who have at 
least one response assessment on study. However, patients are excluded from the
response-available patient population if they have an important protocol deviation, such 
as when evidence is found indicating they failed to meet any study inclusion/exclusion 
criterion. When the response-available patient population is analyzed, patients are 
grouped according to actual treatment received. ACM is considered a patient’s 
“treatment received” in the response-available patient population if alvocidib is
administered at any time prior to a combined remission or at any time during the study 
for patients never achieving combined remission (except for ACM administered to a 
“crossover” patient). The response-available population is used for biomarker analyses 
and sensitivity (secondary, supportive) analyses of efficacy endpoints.


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The per-protocol patient population is the subset of safety patients who either (a) have 
at least one response assessment on study, or (b) die prior to their first scheduled 
response assessment. However, patients are excluded from the per-protocol patient 
population if they have an important protocol deviation, such as when evidence is found 
indicating they failed to meet any study inclusion/exclusion criterion. When the per-
protocol patient population is analyzed, patients are grouped according to actual 
treatment received. ACM is considered a patient’s “treatment received” in the per-
protocol patient population if alvocidib is administered at any time prior to a combined 
remission or at any time during the study for patients never achieving combined 
remission (except for ACM administered to a “crossover” patient). The per-protocol 
population is used for sensitivity (secondary, supportive) analyses of efficacy endpoints.
The crossover patient population includes all patients randomized to CM who, following 
1-2 cycles of CM, receive ACM as stipulated in the study protocol.
Each of the patient populations listed above may be further subdivided for certain 
analyses. For example, data from ITT patients with relapsed/refractory AML who 
received ACM (i.e., the ITT population excluding relapsed/refractory patients receiving 
CM in cycle 1 and patients with newly diagnosed, high-risk AML) will be analyzed to 
quantify the relationship between baseline MCL-1 dependence and the independent 
binary variable cycle-1 CR (see section Error! Reference source not found.).
7.2. Missing Values
In general, missing values will not be replaced by imputed values.
x
Although the central hematologists’ assessment of response is the primary 
evaluation, the local assessment (i.e., the one recorded at the study center 
where the patient is enrolled) will be used for patients who are missing an 
evaluation from the central hematologists (see section 7.9.1)
x
Patients who, for any reason, do not supply bone marrow for response 
assessment are counted among those not achieving remission
x
Patients missing a time-to-event endpoint will have their value censored 
according to the rules set forth below (see sections 7.9.2 to 7.9.6)
Exceptions to the general rule of not replacing missing values are planned for the 
following items.
x
The first day of the month will be used for a missing day component of a partial 
birthdate, and January will be substituted for a missing birth month (these 
substitutions are relevant only for calculating a patient’s age)
x
Partial start and end dates for adverse events will be replaced by calendar dates 
that maximize the duration of the adverse event (see section 7.11.2)
x
Missing clinical laboratory parameters and vital signs will be replaced using the 
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7.3. Visit Windows
Visit windows are not relevant for analyzing efficacy endpoints since these endpoints
are either binary outcomes over the entire study period (e.g., CR rate) or measured on a 
continuous time scale (e.g., OS and PFS). Some safety assessments (clinical laboratory 
parameters and vital signs) are summarized over time and visit windows will be used 
(see sections 7.11.4 and 7.11.5, respectively).
7.4. Interim Analysis
A single interim analysis is planned when cycle-1 response has been defined for 28 
patients per treatment arm. Cycle-1 response may be available for more than 28 
patients in one treatment arm when the alternate treatment arm reaches 28 because the 
enrollment ratio may not be precisely 1:1 over time. The additional patients in the faster-
enrolling treatment arm will be included in the interim analysis. Therefore, the interim 
analysis sample size may be slightly more than 56 patients.
Cycle-1 CR rate (the primary efficacy endpoint) will be tested using the statistical 
procedures described below. As shown in Table 3, a p-value ≤0.00321 is required to 
reject the null hypothesis of equal cycle-1 CR rates across treatment arms.
Measures taken to counter the effect of the interim analysis and maintain an overall 
2.5% significance level are presented in section 7.5.1.
7.4.1. Outcomes and Study Continuation
Two outcomes are possible from the interim analysis: statistical significance or 
nonsignificance. In the event of a nonsignificant difference between ACM and CM 
Cycle-1 CR rates (p-value >0.00321), the study will continue to accrue and randomize 
patients.
If the interim analysis result for the primary analysis of Cycle-1 CR rate (see section 
7.9.1) is statistically significant (p-value ≤0.00321), then randomization will be stopped. 
Additional eligible stage-2 patients will be enrolled into the study to receive open-label 
ACM until the planned enrollment of 53 ACM patients is complete. No additional 
patients will be enrolled into the CM treatment arm. Terminating randomization after the 
interim analysis will have a negative effect on the power to declare treatment 
differences in secondary endpoints as statistically significant, however it is understood 
from polling investigators that they would be unwilling to enroll patients into the study 
once ACM has been established as superior to CM with respect to Cycle-1 CR rate.
7.5. Overall Type-1 Error Rate
A type-1 error in statistics is rejecting the null hypothesis as false when it is actually 
true. In this study, this corresponds to concluding the population’s efficacy response 
following ACM is superior to that from CM when in fact it is not. The probability of 
committing a type-1 error is commonly referred to as the significance level or α (alpha) 
level. The overall significance level for this study will be 2.5% using one-sided 
hypothesis tests.


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7.5.1. Type-1 Error Rate Control for Interim Analysis
An O’Brien-Fleming sequential design1 is employed to maintain the overall 2.5% 
significance level of the study following the single interim analysis described in section 
7.4. Although the interim analysis will include several safety endpoints, cycle-1 CR rate 
will be the only efficacy endpoint considered when determining whether O’Brien-
Fleming boundaries have been crossed. Programming statements in Table 2 were run 
in SAS software (version 9.4) giving output in Table 3 and Table 4. Thus, according to 
the O’Brien-Fleming boundaries, the final analysis will use a one-sided significance level 
of 2.378% to determine statistical significance (see Table 4).
7.5.2. Type-1 Error Rate Control for Multiple Comparisons
Without taking appropriate measures, testing multiple efficacy parameters inflates the 
overall significance level since the probability of making a type-1 error in at least one 
from a set of hypothesis tests is greater than the probability of making a type-1 error in 
any single test. The hierarchical closed test procedure3,4 will be used to maintain the 
overall 2.5% significance level.
The order of efficacy endpoints for the hierarchical closed test procedure is:
1. Cycle-1 CR rate
2. Progression-Free Survival
3. Stem Cell Transplant Rate
4. Cycle-1 Combined CR Rate
5. Cycle-1 Combined Remission Rate
6. Overall Survival
7. Combined Remission Duration
8. Combined CR Duration
9. CR Duration
The final analysis will be conducted at a one-sided 2.378% significance level using the 
statistical procedures described below. Cycle-1 CR rate, the primary efficacy endpoint, 
will be declared statistically significant if its test p-value ≤0.02378. A secondary efficacy 
endpoint will be declared statistically significant only if its test p-value ≤0.02378 and all 
efficacy endpoints preceding it in the hierarchy are statistically significant. In other 
words, declaration of statistical significance for efficacy endpoints will advance in order 
down the hierarchy only until a p-value >0.02378 is found.
In addition, although primary and supportive analytical methods are specified for each 
endpoint in the hierarchy, only the p-value from the primary analysis will be used for 
deciding statistical significance. Supportive (sensitivity) analyses are to demonstrate the 
robustness of primary results to slight modifications to how endpoints are defined and/or 
analyzed.
Declarations of statistical significance will not be advanced for endpoints not included in 
the hierarchy of the closed test procedure (e.g., ECOG performance status).




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medical history (e.g., baseline ECOG performance status, hemoglobin, leukocyte and 
platelet counts, and blood chemistry parameters assessing liver and kidney function). 
Reported medical history terms will be mapped to Medical Dictionary for Regulatory 
Activities (MedDRA) preferred terminology and then summarized within and between
treatment-arms by incidence rates for each MedDRA primary system organ class (SOC) 
and preferred term (PT). Optionally, depending on the perceived relevance, prestudy 
medications will mapped to terminology in the World Health Organization (WHO) Drug 
Dictionary Enhanced (DDE) and then summarized within treatment arm by usage rates 
for each WHO DDE anatomical and therapeutic class (ATC) and preferred (i.e., 
standardized) drug name. Relevant data supporting these summaries will be listed by 
patient within treatment arm.
7.8. Study Drug Exposure
Patients’ total exposures to study drugs and average exposures per treatment cycle will 
be calculated and summarized within treatment arm by the mean, standard deviation, 
median, minimum and maximum values. Numbers of treatment cycles received will be 
summarized within treatment arm as a continuous variable (by the mean, standard 
deviation, median, minimum and maximum values) and as a categorical variable (by the 
number and percentage of patients in each category). Reasons for noncompliance with 
protocol-specified dosing schedules will be summarized within treatment arm as a 
categorical variable. Relevant data supporting these summaries (including actual 
infusion durations and expected doses based on BSA calculated from a patient’s latest 
reported height and weight) will be listed by patient within treatment arm.
7.9. Efficacy Endpoints
Relevant data supporting efficacy analyses will be listed by patient within treatment arm.
7.9.1. Remission Rates
The primary efficacy endpoint is cycle-1 CR rate (i.e., the percentage of patients who
achieve a CR after one cycle of treatment). Cycle 1 does not end until the patient starts 
cycle 2 or alternative AML therapy other than supportive measures (e.g., blood product 
transfusions). Therefore, a patient whose first response assessment in cycle 1 is a CRi 
or CRp* is considered to have achieved CR if neutrophils and platelets recover prior to 
initiation of cycle 2 or alternative AML therapy including bone marrow or stem cell 
transplant. Patients who, for any reason, do not supply bone marrow for response 
assessment are counted among those not achieving remission. Best response during 
the study (i.e., best response following one or more cycles of treatment) was not 
selected as the primary efficacy endpoint due to the anticipated confounding effects of 
patients who are randomized to CM but crossover after one or two cycles to receive 
treatment with ACM.
Three response assessments are planned for each postbaseline bone marrow sample:
1. The “central review” performed by a panel of independent, expert hematologists
according to an approved charter under change control
* See footnote on page 6.


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2. The “local review” of bone marrow and blood test results by the investigator at the 
study center where patient is enrolled
3. The “sponsor review” by employees and/or agents of Tolero Pharmaceuticals
It is beyond the scope of this SAP to restate or summarize the written charter detailing 
the methods and criteria the panel of hematologists use to grade response, but both 
central and local assessments are made according to criteria specified in the study 
protocol. The primary assessments of remission for comparing efficacy across 
treatment arms is the central review of bone marrow; however, in cases where the 
central hematologists are unable to rate response, the investigator’s response 
assessment will be used in place of the missing central assessment. Supportive efficacy 
analyses will be conducted using assessments from the local and sponsor reviews.
Hypothesis testing will be based on the stratified Cochran-Mantel-Haenszel (CMH) 
general association test statistic6,7 (see Table 5). Stratification levels will be the same as 
those used for the randomization scheme (see section 6). Although the alternative 
hypothesis for the CMH general association test statistic is that cycle-1 CR is correlated
with treatment arm in at least one stratum, the statistic has low power for detecting an 
association in which the patterns of association for some of the strata are in the 
opposite direction of the patterns displayed by other strata.8 Therefore, a statistically 
significant CMH general association statistic will validate the positive contribution of 
alvocidib (added to CM) to induce CR (over CM alone).
Within–treatment-arm statistics will include the number and percentage of patients rated 
as not achieving CR due to not providing a bone marrow biopsy/aspirate, proportion of 
patients who achieve a cycle-1 CR and exact 95% CI estimated without stratification. 
Between–treatment-arm statistics will include the Mantel-Haenszel odds ratio and 95% 
CI estimated with stratification.
A standard logistic regression (LR) model will be estimated relating the probability of a 
cycle-1 CR as a function of baseline MCL-1 dependence, treatment arm, and the two-
way interaction between baseline MCL-1 dependence and treatment arm. If the p-value 
for the Wald chi-square statistic for two-way interaction is >0.10, then the Wald chi-
square statistic for treatment arm will be interpreted as testing the equality of cycle-1 CR
rates controlling for the effect of baseline MCL-1 dependence. Results will be presented 
graphically as follows. Patients will be divided into groups according to which range of 
values their baseline MCL-1 dependence falls:
(0%-≤d1), (d1-≤d2), (d2-≤d3), …, (d8-≤d9), (d9-100%)
where d1,…,d9 are deciles for baseline MCL-1 dependence regardless of treatment arm. 
Empirical within–treatment-arm cycle-1 CR rates will be calculated for patients within
each range and plotted alongside cycle-1 CR probabilities estimated from the LR model.
Table 5.
Statistical Analyses of Cycle-1 CR Rates
Analysis 
Population
Analytical Method
Response 
Assessment
Role of Analysis
Intent-to-Treat
Stratified CMH
Central
Primary
Intent-to-Treat
Stratified CMH
Local and Sponsor
Supportive


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Table 5.
Statistical Analyses of Cycle-1 CR Rates
Analysis 
Population
Analytical Method
Response 
Assessment
Role of Analysis
Intent-to-Treat
Logistic regression
Central
Supportive
Intent-to-Treat
Logistic regression
Local and Sponsor
Supportive
Per-Protocol
Stratified CMH
Central
Supportive
Per-Protocol
Stratified CMH
Local and Sponsor
Supportive
Per-Protocol
Logistic regression
Central
Supportive
Per-Protocol
Logistic regression
Local and Sponsor
Supportive
Response-Available
Logistic regression
Central
Supportive
Response-Available
Logistic regression
Local and Sponsor
Supportive
Subgroups based on 
patient 
characteristics
Logistic regression
Central, Local and 
Sponsor
Exploratory
If the test for between–treatment-arm homogeneity of any baseline characteristic gives 
two-sided p-value <0.10, then the effect that baseline characteristic has on cycle-1 CR
rate will be quantified using LR. Two LR models will be fit. One model will include the 
baseline characteristic in question as the only independent variable, and the second 
model will include the baseline characteristic and the stratification factors used for 
randomization.
Other remission rates (e.g., cycle-1 combined CR rate and cycle-1 combined remission 
rate) will be summarized similar to cycle-1 CR rate.
Correlation between central and local review will be assessed descriptively in 2-way
frequency tables, both as a bivariate response (CR yes or no) and on the full scale (CR, 
CRi, CRp, PR, resistance/relapse). The simple kappa coefficient8,9 will be calculated as 
a measure of agreement between the central and local reviews. Since the two response 
variables are two independent ratings of the same tissue sample, the kappa coefficient 
equals 1 when there is complete agreement of the raters. When the observed 
agreement exceeds chance agreement, kappa is positive, with its magnitude reflecting 
the strength of agreement. Although this is unusual in practice, kappa is negative when 
the observed agreement is less than chance agreement.8
7.9.2. Progression-Free Survival
PFS time is defined for all patients and is measured from the date of randomization 
(Day 1) until (a) treatment failure, (b) relapse after combined remission, or (c) death 
from any cause, whichever occurs first.
Treatment failure is defined as failing to achieve a combined remission following 
induction therapy. The date of treatment failure is the protocol-specified date for bone 
marrow collection following the first induction attempt (i.e., at neutrophil and platelet 
recovery or Day 45 of the treatment cycle, whichever occurs first), regardless of whether 
the patient received a second induction attempt (unless the second induction resulted in 
a combined remission in which case “treatment failure” does not apply).
Additional rules for defining PFS time are:


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x
A patient found to have relapsed after missing one or more scheduled response 
assessments will have his PFS time end on the scheduled date for the first 
missed response assessment following the last confirmation of combined 
remission
x
A patient who misses the first scheduled response assessment and who never 
achieves combined remission will have his PFS time end on the scheduled date 
for the first response assessment (unless the patient died before this date)
Rules for censoring PFS time are:
x
A patient with PFS continuing as of the date he is lost to follow-up will have his 
PFS time censored on the date of his last response assessment
x
A patient with PFS continuing as of the database lock will have his PFS time 
censored on the date of his last response assessment
Hypothesis testing for PFS will be based on the stratified log rank test statistic (see 
Table 6). Stratification levels will be the same as those used for the randomization 
scheme (see section 6). Two Cox proportional hazards (PH) models will be fit to provide 
estimates of the hazards ratio (HR). One model will include treatment arm as the only 
independent variable, and the second model will include treatment arm and the 
stratification factors used for randomization. Kaplan-Meier (KM) “survival” curves10 will
be graphed for visual inspection of differences in PFS between the treatment arms. 
Within–treatment-arm statistics will include the number and percentage of censored 
PFS times, quartile PFS times, 95% CIs for the quartile PFS times, and KM “survival” 
percentages with 95% CIs at select milestone times (e.g., 6, 12 and 18 months).
Between–treatment-arm statistics will include HRs from the Cox PH models and their
95% CIs.
Sensitivity analyses will be run with PFS time censored on the date of stem cell 
transplantation (bone marrow [BM] or peripheral blood stem cells [PBSC]).
Table 6.
Statistical Analyses of PFS, OS, RFS and CR Duration
Analysis 
Population
Analytical Method
Censor for 
Transplant
Role of Analysis
Intent-to-Treat
Stratified log rank
No
Primary
Intent-to-Treat
Stratified log rank
Yes
Supportive
Intent-to-Treat
Cox PH Model
No
Supportive
Intent-to-Treat
Cox PH Model
Yes
Supportive
Per-Protocol
Stratified log rank
No
Supportive
Per-Protocol
Stratified log rank
Yes
Supportive
Per-Protocol
Cox PH Model
No
Supportive
Per-Protocol
Cox PH Model
Yes
Supportive
Subgroups based 
on patient 
characteristics
Cox PH model
No
Exploratory


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If the test for between–treatment-arm homogeneity of any baseline characteristic gives 
two-sided p-value <0.10, then the effect that baseline characteristic has on PFS time will 
be quantified using Cox PH modeling. Two PH models will be fit. One model will include 
the baseline characteristic in question as the only independent variable, and the second 
model will include the baseline characteristic and the stratification factors used for 
randomization.
7.9.3. Stem Cell Transplant Rate
Stem cell transplant (SCT) rate is the percentage of patients proceeding to SCT within 
90 days after their last dose of study drug regardless of whether the patient remains 
enrolled in this study. Unless documentation of SCT is provided, patients who are lost to 
follow-up within the 90 days following their last dose of study drug are counted among 
those not receiving SCT.
Hypothesis testing will be based on the stratified CMH general association test statistic 
(see Table 7). Stratification levels will be the same as those used for the randomization 
scheme (see section 6).
Within–treatment-arm statistics will include the number and percentage of patients 
counted as not receiving SCT due to being lost to follow-up; proportion of patients 
receiving SCT within 90 days after their last dose of study drug; and exact 95% CI 
estimated without stratification. Between–treatment-arm statistics will include the 
Mantel-Haenszel odds ratio and 95% CI estimated with stratification.
Table 7.
Statistical Analyses of Stem Cell Transplant Rate
Analysis Population
Analytical Method
Role of Analysis
Intent-to-Treat
Stratified CMH
Primary
Per-Protocol
Stratified CMH
Supportive
Subgroups based on 
patient characteristics
Logistic regression
Exploratory
If the test for between–treatment-arm homogeneity of any baseline characteristic gives 
two-sided p-value <0.10, then the effect that baseline characteristic has on SCT rate will 
be quantified using LR. Two LR models will be fit. One model will include the baseline 
characteristic in question as the only independent variable, and the second model will 
include the baseline characteristic and the stratification factors used for randomization.
7.9.4. Overall Survival
OS time is defined for all patients and is measured from the date of randomization (Day 
1) until death from any cause.
Rules for censoring OS time are:
x
A patient with OS continuing as of the date he is lost to follow-up will have his OS
time censored on the date of his last assessment of any type
x
A patient with OS continuing as of the database lock will have his OS time 
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Hypothesis testing for OS will be based on the stratified log rank test statistic (see Table 
6). Stratification levels will be the same as those used for the randomization scheme 
(see section 6). Two Cox PH models will be fit to provide estimates of the HR. One
model will include treatment arm as the only independent variable, and the second 
model will include treatment arm and the stratification factors used for randomization. 
KM survival curves will be graphed for visual inspection of differences in OS between
the treatment arms. Within–treatment-arm statistics will include the number and 
percentage of censored OS times, quartile OS times, 95% CIs for the quartile OS times, 
and KM survival percentages with 95% CIs at select milestone times (e.g., 6, 12 and 18
months). Between–treatment-arm statistics will include HRs from the Cox PH models 
and their 95% CIs.
Sensitivity analyses will be run with OS time censored on the date of BM or PBSC
transplant.
If the test for between–treatment-arm homogeneity of any baseline characteristic gives 
two-sided p-value <0.10, then the effect that baseline characteristic has on OS time will
be quantified using Cox PH modeling. Two PH models will be fit. One model will include 
the baseline characteristic in question as the only independent variable, and the second 
model will include the baseline characteristic and the stratification factors used for 
randomization.
7.9.5. Relapse-Free Survival Following CR
RFS time is defined only for patients who achieve a CR during the study and is 
measured from the date of CR (Day 1) until (a) relapse after CR, or (b) death from any 
cause, whichever occurs first.
An additional rule for defining RFS time is:
x
A patient found to have relapsed after missing one or more scheduled response 
assessments will have his RFS time end on the scheduled date for the first 
missed response assessment following the last confirmation of CR
Rules for censoring RFS time are:
x
A patient with RFS continuing as of the date he is lost to follow-up will have his
RFS time censored on the date of his last response assessment
x
A patient with RFS continuing as of the database lock will have his RFS time 
censored on the date of his last response assessment
Hypothesis testing for RFS will be based on the stratified log rank test statistic (see 
Table 6). Stratification levels will be the same as those used for the randomization 
scheme (see section 6). Two Cox PH models will be fit to provide estimates of the HR.
One model will include treatment arm as the only independent variable, and the second 
model will include treatment arm and the stratification factors used for randomization. 
KM “survival” curves will be graphed for visual inspection of differences in RFS between 
the treatment arms. Within–treatment-arm statistics will include the number and 
percentage of patients who achieve a CR, the number and percentage of censored RFS 
times, quartile RFS times, 95% CIs for the quartile RFS times, and KM “survival” 
percentages with 95% CIs at select milestone times (e.g., 6, 12 and 18 months).


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Between–treatment-arm statistics will include HRs from the Cox PH models and their 
95% CIs.
Sensitivity analyses will be run with RFS time censored on the date of BM or PBSC 
transplant.
If the test for between–treatment-arm homogeneity of any baseline characteristic gives 
two-sided p-value <0.10, then the effect that baseline characteristic has on RFS time 
will be quantified using Cox PH modeling. Two PH models will be fit. One model will 
include the baseline characteristic in question as the only independent variable, and the 
second model will include the baseline characteristic and the stratification factors used 
for randomization.
Two endpoints analogous to relapse-free survival following CR will be analyzed using 
similar methods.
x
Relapse-Free Survival Following Combined CR (defined only for patients who 
achieve a combined CR during the study): time from the earliest date of 
combined CR (Day 1) until (a) relapse after combined CR, or (b) death from any 
cause, whichever occurs first
x
Relapse-Free Survival Following Combined Remission (defined only for patients 
who achieve combined remission during the study): time from the earliest date of 
combined remission (Day 1) until (a) relapse after combined remission, or (b) 
death from any cause, whichever occurs first
Response categories included in “combined CR” and “combined remission” are 
delineated in Section 3.
7.9.6. Complete Remission Duration
CR duration is defined only for patients who achieve a CR during the study and is 
measured from the date of CR (Day 1) until relapse.
An additional rule for defining CR duration is:
x
A patient found to have relapsed after missing one or more scheduled response
assessments will have his CR duration end on the scheduled date for the first 
missed response assessment following the last confirmation of CR
Rules for censoring CR duration are:
x
A patient who dies while in remission will have his CR duration censored on the 
date of death
x
A patient in remission on the date he is lost to follow-up will have his CR duration 
censored on the date of his last response assessment
x
A patient in remission on the database lock will have his CR duration censored 
on the date of his last response assessment
Hypothesis testing for CR duration will be based on the stratified log rank test statistic 
(see Table 6). Stratification levels will be the same as those used for the randomization 
scheme (see section 6). Two Cox PH models will be fit to provide estimates of the HR.
One model will include treatment arm as the only independent variable, and the second 


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model will include treatment arm and the stratification factors used for randomization. 
KM “survival” curves will be graphed for visual inspection of differences in CR duration 
between the treatment arms. Within–treatment-arm statistics will include the number 
and percentage of patients who achieve a CR, the number and percentage of censored 
CR durations, quartile CR durations, 95% CIs for the quartile CR durations, and KM 
“survival” percentages with 95% CIs at select milestone times (e.g., 6, 12 and 18 
months). Between–treatment-arm statistics will include HRs from the Cox PH models 
and their 95% CIs.
Sensitivity analyses will be run with CR duration censored on the date of BM or PBSC 
transplant.
If the test for between–treatment-arm homogeneity of any baseline characteristic gives 
two-sided p-value <0.10, then the effect that baseline characteristic has on CR duration 
will be quantified using Cox PH modeling. Two PH models will be fit. One model will 
include the baseline characteristic in question as the only independent variable, and the 
second model will include the baseline characteristic and the stratification factors used 
for randomization.
Two endpoints analogous to CR duration will be analyzed using similar methods.
x
Combined CR Duration (defined only for patients who achieve a combined CR
during the study): time from the earliest date of combined CR (Day 1) until 
relapse after combined CR
x
Combined Remission Duration (defined only for patients who achieve combined 
remission during the study): time from the earliest date of combined remission 
(Day 1) until relapse after combined remission
Response categories included in “combined CR” and “combined remission” are 
delineated in Section 3.
7.9.7. ECOG Performance Status
ECOG performance status will be summarized within treatment arm using shift tables.
7.10.
Biomarker
The biomarker in this study is MCL-1 dependence measured by mitochondrial sensitivity 
to NOXA BH3 peptides. Relevant data supporting analyses of MCL-1 dependence will
be listed by patient within treatment arm. Summary of baseline biomarker values will 
include within– and between–treatment-arm descriptive statistics appropriate for 
continuous variables (see section 7.7). An LR model will be fit to examine the 
relationship between baseline MCL-1 dependence and the independent binary variable
cycle-1 CR for relapsed and refractory AML patients receiving ACM. In addition, area
under the curve (AUC) will be calculated (by treatment arm) for the trapezoidal receiver 
operating characteristic (ROC) curve. This value will quantify the ability of MCL-1
dependence to predict cycle-1 CR.11 Ninety-five percent CIs will be calculated by 
assuming estimated AUC follows a normal distribution.
AUC
෣± zଵିఈଶ
⁄  SEAUC


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where the standard error SEAUC is calculated by the jackknife method.12 Data from 
relapsed/refractory patients receiving CM in cycle 1 and patients with newly diagnosed, 
high-risk AML will not be used in these analyses. Similar analyses will be conducted for
(1) cycle-1 combined CR and (2) cycle-1 combined remission.
Quantifying the effect of MCL-1 dependence on response rates will not infer a safety 
and/or efficacy benefit (or detriment) of treatment with ACM over CM. Therefore, no
statistical analyses of MCL-1 dependence across treatment arms are planned other 
than comparing baseline values to confirm randomization created homogeneous groups 
with respect to prestudy values.
7.11.
Safety Endpoints
Summaries of safety endpoints will include data collected from the safety patient 
population. Relevant data supporting safety analyses will be listed by patient within 
treatment arm.
7.11.1.
30- and 60-Day Mortality
Estimates of 30- and 60-day mortality and their pointwise 95% CIs will be derived from 
KM curves for OS by treatment arm (see section 7.9.4).
7.11.2. Adverse Events
Reported adverse event (AE) terms will be mapped to MedDRA preferred terminology.
AEs suggestive of tumor lysis syndrome (TLS) will be flagged based in the standardized 
MedDRA query (SMQ) for TLS. All reported events will appear in AE listings, however 
only treatment-emergent adverse events will be summarized. A treatment-emergent 
adverse event (TEAE) is an AE that starts or increases in severity any time after the first 
administration of any study drug up to 30 days following the last administration of any 
study drug. AE severity was rated by the investigator according to Common 
Terminology Criteria for Adverse Events (CTCAE) version 4.03 criteria.13
A high-level safety summary will display the numbers of patients within each treatment 
arm and overall who experience one or more AEs in each of the following categories:
x
All TEAEs regardless of severity or presumed relationship to study drug
x
TEAEs judged related to study drug
x
All TLS SMQ TEAEs
x
TLS SMQ TEAEs judged related to study drug
x
Treatment-emergent serious adverse events (SAEs)
x
TEAEs leading to a delay in the administration of study drug
x
TEAEs leading to a reduction in the protocol-specified dose of study drug
x
TEAEs leading to discontinuation of study drug
x
TEAEs leading to withdrawal from the study
x
TEAEs leading to death


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The base summary of TEAEs will show within– and between–treatment-arm incidence 
rates for each MedDRA primary SOC and/or PT by highest reported CTCAE severity 
grade and overall. A separate summary will be produced each of the AE subsets listed 
above. Additional AE summaries may be produced using safety data from subsets of 
patients and/or characterized using additional SMQs.
Partial start and end dates for adverse events will be replaced by calendar dates that 
maximize the duration of the adverse event. The following steps will be followed.
For a partial start date:
1. Replace a missing month with January
2. Replace a missing calendar day with the first of the month
3. If the replacement date is prior to the first dose of study drug, then set the 
adverse event start date equal to the date of the first dose
For a partial end date:
1. Replace a missing month with December
2. Replace a missing calendar day with the last day of the month
The replacement date for a missing end date may exceed end of the adverse event 
reporting period specified in the study protocol.
An end date will not be estimated for adverse events marked continuing at the end of 
the study.
7.11.3. Classification of Tumor Lysis Syndrome
Cairo-Bishop definitions for laboratory TLS and clinical TLS will be used to diagnose
and grade TLS.14 Patients are classified as experiencing laboratory TLS if they have 
any two or more serum values of uric acid, potassium, phosphorus and/or calcium 
shown in Table 8 within 3 days before or 7 days after the initiation of study drug.
Table 8.
Cairo-Bishop Definition of Laboratory Tumor Lysis Syndrome
Laboratory Parameter
Criteria
Uric Acid
≥476 μmol/L or 25% increase from baseline
Potassium
≥6.0 mmol/L or 25% increase from baseline
Phosphorus
≥1.45 mmol/L or 25% increase from baseline
Calcium
≤1.75 mmol/L or 25% decrease from baseline
Diagnosis of clinical TLS requires the presence of laboratory TLS and elevated serum 
creatinine levels, cardiac arrhythmia and/or seizures. Criteria for grading the severity of 
clinical TLS are presented in Appendix 1.
The numbers of patients experiencing laboratory TLS and the various severities of 
clinical TLS will be summarized within and between treatment arms.
7.11.4. Clinical Laboratory Parameters
Typical comparisons of results summarized by visit may have limited interpretability in 
this study because (1) study drugs from the two treatment arms are administered on 


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different cycle days (Days 1-9 for ACM versus Days 1-4 for CM), (2) the schedule for
clinical laboratory evaluations (cycle day and frequency) is different between the 
treatment arms, and (3) additional cycles of treatment start according to patients’ 
response to treatment rather than based on a predetermined schedule. Therefore, four 
groups of laboratory data will be summarized separately:
x
Cycle 1 results (from all patients in the safety population) up to the day a patient 
starts Cycle 2 or 10 weeks after starting Cycle 1, whichever comes first
x
Cycle 2 results (from patients in the safety population who receive at least 2 
cycles of study drug) up to the day a patient starts Cycle 3 or 10 weeks after 
starting Cycle 2, whichever comes first
x
Cycle 3 results (from patients in the safety population who receive at least 3 
cycles of study drug) up to the day a patient starts Cycle 4 or 10 weeks after 
starting Cycle 3, whichever comes first
x
Cycle 4 results (from patients in the safety population who receive 4 cycles of 
study drug) up to 10 weeks after starting Cycle 4
Laboratory test results measured on a continuous scale and changes from baseline 
values will be summarized within treatment arm using mean, standard deviation, 
median, minimum and maximum values. Results will be summarized at baseline, on 
Days 1-9, and every 7 days starting with Day 15 for patients receiving ACM, and at 
baseline, on Days 1-4, and every 7 days starting with Day 8 for patients receiving CM.
Up to the point of starting a new treatment cycle or withdrawing from the study, a 
patient’s most recent test result will be carried forward and included in analyses on days 
when clinical laboratory testing was not performed.
Ordinal categorical test results will be summarized within treatment arm using shift 
tables. Additionally, for tests where CTCAE [version 4.03] severity criteria are specified, 
CTCAE severity grades will be summarized in shift tables.
7.11.5. Vital Signs
Vital signs and changes from baseline values will be summarized by visit and within 
treatment arm using mean, standard deviation, median, minimum and maximum values.
Results will be summarized at baseline, on Day 1 of each dosing cycle, and every 7 
days thereafter. A patient’s most recent test result will be carried forward and included 
in analyses on days when vital signs were not assessed. Typical comparisons of results 
summarized by visit may have limited interpretability for the same reasons outlined in 
section 7.11.4. Therefore, vital signs will be analyzed separately for the four groups 
identified there.
7.11.6. Concomitant Medication Use
Optionally, depending on the perceived relevance, concomitant medications will
mapped to terminology in the WHO DDE and then summarized within treatment arm by 
usage rates for each level-1 ATC term and preferred (i.e., standardized) drug name.
7.12.
Subgroup Analyses


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8. Adverse Event and Medication Coding Dictionaries
The MedDRA and WHO DD versions (editions) that will be used to standardize medical 
terminology are not known at this time, but both will be recent editions published within 
2 years before the date the first patient is randomized into the study and the versions 
used will be documented in the clinical study report.
9. Summary Tables
Suggested titles for summary tables to be included in the clinical study report are shown 
in Table 9 and blueprints for the format and content of these tables are presented in 
Appendix 2.
Table 9.
Planned Summary Tables
Summary Table [comments]
Patient Population
ITT
Safety
Per-
Protocol
Patient Disposition
X 
 
 
Demography
X 
 X  
 X  
AML History
X 
 X  
 X  
Medical History
 X  
 X  
 X  
Pre-Existing Medical Conditions
 X  
 X  
 X  
Relevant Prestudy Medications
 X  
 X  
 X  
Study Drug Exposure
 X  
 X  
 X  
Complete Remission Rates – Independent
Hematologists Review [repeat as needed for 
subgroup analyses]
X 
 
 X  
Complete Remission Rates – Local Investigator
Review [repeat as needed for subgroup analyses]
X 
 
 X  
Combined CR and Combined Remission Rates –
Independent Hematologists Review [repeat as needed 
for subgroup analyses]
 X  
 
 X  
Combined CR and Combined Remission Rates –
Local Investigator Review [repeat as needed for 
subgroup analyses]
 X  
 
 X  
Correlation Between Independent Hematologists and 
Local Investigator Reviews – Complete Remission
 X  
 
 X  
Correlation Between Independent Hematologists and 
Local Investigator Reviews – All Levels of Remission
 X  
 
 X  
Progression-Free Survival [repeat as needed for 
subgroup analyses]
 X  
 
 X  
Progression-Free Survival Censoring at Transplant 
[repeat as needed for subgroup analyses]
 X  
 
 X  
Overall Survival [repeat as needed for subgroup 
analyses]
X 
 
 X  
Overall Survival Censoring at Transplant [repeat as 
needed for subgroup analyses]
 X  
 
 X  


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Summary Table [comments]
Patient Population
ITT
Safety
Per-
Protocol
Relapse-Free Survival Following CR [repeat as 
needed for subgroup analyses]
 X  
 
 X  
Relapse-Free Survival Following CR Censoring at 
Transplant [repeat as needed for subgroup analyses]
 X  
 
 X  
Relapse-Free Survival Following Combined CR 
[repeat as needed for subgroup analyses]
 X  
 
 X  
Relapse-Free Survival Following Combined CR
Censoring at Transplant [repeat as needed for 
subgroup analyses]
 X  
 
 X  
Relapse-Free Survival Following Combined 
Remission [repeat as needed for subgroup analyses]
 X  
 
 X  
Relapse-Free Survival Following Combined 
Remission Censoring at Transplant [repeat as needed 
for subgroup analyses]
 X  
 
 X  
Complete Remission Duration [repeat as needed for 
subgroup analyses]
 X  
 
 X  
Complete Remission Duration Censoring at 
Transplant [repeat as needed for subgroup analyses]
 X  
 
 X  
Combined Complete Remission Duration [repeat as 
needed for subgroup analyses]
 X  
 
 X  
Combined Complete Remission Duration Censoring at 
Transplant [repeat as needed for subgroup analyses]
 X  
 
 X  
Combined Remission Duration [repeat as needed for 
subgroup analyses]
 X  
 
 X  
Combined Remission Duration Censoring at 
Transplant [repeat as needed for subgroup analyses]
 X  
 
 X  
Stem Cell Transplant Rates
 X  
 
 X  
ECOG Performance Status Shift Table
 X  
 
 X  
30- and 60-Day Mortality
 
X 
 
Numbers of Patients with Adverse Events
 
X 
 
Treatment-Emergent Adverse Events: Incidence 
Rates by MedDRA System Organ Class
 
X 
 
Treatment-Emergent Adverse Events: Incidence 
Rates by MedDRA Preferred Term
 
X 
 
Treatment-Emergent Adverse Events Judged Related 
to Study Drug: Incidence Rates by MedDRA System 
Organ Class
 
 X  
 
Treatment-Emergent Adverse Events Judged Related 
to Study Drug: Incidence Rates by MedDRA Preferred 
Term
 
X 
 


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Summary Table [comments]
Patient Population
ITT
Safety
Per-
Protocol
Treatment-Emergent Adverse Events in the 
Standardized MedDRA Query for Tumor Lysis 
Syndrome: Incidence Rates by MedDRA Preferred 
Term
 
 X  
 
Treatment-Emergent Adverse Events in the 
Standardized MedDRA Query for Tumor Lysis 
Syndrome Judged Related to Study Drug: Incidence 
Rates by MedDRA Preferred Term
 
 X  
 
Serious Adverse Events: Incidence Rates by MedDRA 
System Organ Class
 
 X  
 
Serious Adverse Events: Incidence Rates by MedDRA 
Preferred Term
 
X 
 
Serious Adverse Events Judged Related to Study 
Drug: Incidence Rates by MedDRA System Organ 
Class
 
 X  
 
Serious Adverse Events Judged Related to Study 
Drug: Incidence Rates by MedDRA Preferred Term
 
 X  
 
Treatment-Emergent Adverse Events Leading to a 
Delay in the Administration of Study Drug: Incidence 
Rates by MedDRA Preferred Term
 
 X  
 
Treatment-Emergent Adverse Events Leading to a 
Reduction in the Protocol-Specified Dose of Study 
Drug: Incidence Rates by MedDRA Preferred Term
 
 X  
 
Treatment-Emergent Adverse Events Leading to 
Discontinuation of Study Drug: Incidence Rates by 
MedDRA Preferred Term
 
 X  
 
Treatment-Emergent Adverse Events Leading to 
Withdrawal from the Study: Incidence Rates by 
MedDRA Preferred Term
 
 X  
 
Fatal Adverse Events: Incidence Rates by MedDRA 
Preferred Term
 
X 
 
Tumor Lysis Syndrome Incidence Rates During Cycle 
1 by Maximum Cairo-Bishop Severity Grade
 
X 
 
Tumor Lysis Syndrome Incidence Rates During Study 
by Maximum Cairo-Bishop Severity Grade
 
 X  
 
Clinical Laboratory Test Results and Changes from 
Baseline
 
 X  
 
Clinical Laboratory Test Result Shift Tables
 
 X  
 
Vital Signs and Changes from Baseline
 
 X  
 
Concomitant Medications
 
 X  
 


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10.References
1. O’Brien PC, Fleming TR. A Multiple Testing Procedure for Clinical Trials.
Biometrics. 1979;35:549-556.
2. Grimwade D, Walker H, Oliver F, et al. The Importance of Diagnostic 
Cytogenetics on Outcome in AML: Analysis of 1,612 Patients Entered Into the 
MRC AML 10 Trial. Blood. Oct 1 1998;92:2322-2333.
3. Yue L. Testing Multiple Secondary Endpoints in Confirmatory Comparative 
Studies – A Regulatory Perspective. Presented at: 2nd Annual AdvaMed 
Statistical Issues for Medical Devices and Diagnostics; April 29, 2009; Bethesda, 
MD. Available at: http://www.advamedmtli.org/download/File/
Statistics_April_2009/Yue_lilly_pres.pdf. Accessed February 5, 2015.
4. Koch GG, Gansky SA. Statistical Considerations for Multiplicity in Confirmatory 
Protocols. Drug Information J. 1996;30:523-533. Available at: http://
ferran.torres.name/download/shared/general/Multiplicity%20dj302612.pdf.
Accessed February 5, 2015.
5. Mosteller RD. Simplified Calculation of Body-Surface Area. N Engl J Med.
1987;317:1098
6. Mantel N, Haenszel W. Statistical Aspects of Analysis of Data from Retrospective 
Studies of Disease. J Natl Cancer Inst. 1959;22:719-748.
7. Mantel N. Chi-Square Tests with One Degree of Freedom: Extensions of the 
Mantel-Haenszel Procedure. J Am Stat Assoc. 1963;58:690-700.
8. SAS Institute Inc. 2010. Base SAS® 9.2 Procedures Guide: Statistical 
Procedures, Third Edition. Cary, NC: SAS Institute Inc.
9. Cohen J. A Coefficient of Agreement for Nominal Scales. Educ Psychol Meas.
1960;20:37-46.
10.Kaplan EL, Meier P. Nonparametric Estimation from Incomplete Observations. J
Am Stat Assoc. 1958;53:457-481.
11.Pierceall WE, Lena R, Medeiros BC, et al. Mcl-1 Dependence Predicts Response
to Vorinostat and Gemtuzumab Ozogamicin in Acute Myeloid Leukemia. Leuk 
Res. 2014;38:564-568.
12.Efron B, Stein C. The Jackknife Estimate of Variance. Annals Stat. 1981;9:586-
596.
13.Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0. U.S. 
Dept of Health and Human Services, National Institutes of Health, National 
Cancer Institute; May 28, 2009 (v4.03 June 14, 2010). Available at: http://evs.nci.
nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-14_QuickReference_5x7.pdf.
Accessed February 16, 2015.
14.Cairo MS, Bishop M. Tumor Lysis Syndrome: New Therapeutic Strategies and 
Classification. Br J Haematol. 2004;127:3-11.


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Appendix 1. Criteria for Grading Severity of Clinical Tumor Lysis Syndrome
Grade 1
Grade 2
Grade 3
Grade 4
Grade 5
Renal
Creatinine
≤1.5 x ULN
Creatinine
>1.5-3.0 x ULN
Creatinine
>3.0-6.0 x ULN
Creatinine
>6.0 x ULN
Death
Cardiac 
Arrhythmia
Intervention not 
indicated
Non-urgent medical 
intervention indicated
Symptomatic and 
incompletely controlled 
medically or controlled 
with device (e.g., 
defibrillator)
Life-threatening (e.g., 
arrhythmia associated 
with CHF, hypotension, 
syncope, shock)
Death
Seizure
—
One brief generalized 
seizure; seizure(s) well 
controlled by 
anticonvulsants or
infrequent focal motor 
seizures not interfering 
with activities of daily 
living
Seizure in which 
consciousness is 
altered; poorly 
controlled seizure 
disorder; with 
breakthrough 
generalized seizures 
despite medical 
intervention
Seizures of any kind 
which are prolonged, 
repetitive or difficult to 
control (e.g., status 
epilepticus, intractable 
epilepsy)
Death
Clinical TLS requires one or more clinical manifestations (renal, cardiac, neuro) along with criteria for laboratory TLS
Maximal clinical manifestation defines the severity grade
ULN = upper limit of normal; 114.4 and 105.6 μmol/L will be used for males and females, respectively, if ULN is not available for an institution


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Appendix 2. Sample Summary Table Templates
Blueprint for summaries of continuous data within and between treatment arms (delete p-value if summary is for safety 
data; delete fourth column if summary is only within treatment arm):
Study TPI-ALV-201
Title for Summary Table
Page x of x
(<ITT | Safety | Per-Protocol> Patient Population)
ACM
(n=xxx)
CM
(n=xxx)
All Patients
(n=xxx)
Characteristic 1
Mean (SD)
95% CI
Median
Minimum, Maximum
p-value[a]
xx.x (xx.x)
(xx.x, xx.x)
xx.x
xx.x, xx.x
0.xxx
xx.x (xx.x)
(xx.x, xx.x)
xx.x
xx.x, xx.x
xx.x (xx.x)
(xx.x, xx.x)
xx.x
xx.x, xx.x
Characteristic 2
Mean (SD)
95% CI
Median
Minimum, Maximum
p-value[a]
xx.x (xx.x)
(xx.x, xx.x)
xx.x
xx.x, xx.x
0.xxx
xx.x (xx.x)
(xx.x, xx.x)
xx.x
xx.x, xx.x
xx.x (xx.x)
(xx.x, xx.x)
xx.x
xx.x, xx.x
Characteristic 3
Mean (SD)
95% CI
Median
Minimum, Maximum
p-value[a]
xx.x (xx.x)
(xx.x, xx.x)
xx.x
xx.x, xx.x
0.xxx
xx.x (xx.x)
(xx.x, xx.x)
xx.x
xx.x, xx.x
xx.x (xx.x)
(xx.x, xx.x)
xx.x
xx.x, xx.x
[a]p-value from the Student t test
SAS v9.4 (dd-mmm-yyyy hh:mm) from ADxx, ADxx, ADxx


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Blueprint for summaries of time-to-event data within and between treatment arms (delete fourth column if summary is only 
within treatment arm):
Study TPI-ALV-201
Title for Summary Table
Page x of x
(<ITT | Safety | Per-Protocol> Patient Population)
ACM
(n=xxx)
CM
(n=xxx)
All Patients
(n=xxx)
Characteristic 1
Median
95% CI
25%, 75% Percentiles
Minimum, Maximum
p-value[a]
xx.x
(xx.x, xx.x)
xx.x, xx.x
xx.x, xx.x
0.xxx
xx.x
(xx.x, xx.x)
xx.x, xx.x
xx.x, xx.x
xx.x
(xx.x, xx.x)
xx.x, xx.x
xx.x, xx.x
Characteristic 2
Median
95% CI
25%, 75% Percentiles
Minimum, Maximum
p-value[a]
xx.x
(xx.x, xx.x)
xx.x, xx.x
xx.x, xx.x
0.xxx
xx.x
(xx.x, xx.x)
xx.x, xx.x
xx.x, xx.x
xx.x
(xx.x, xx.x)
xx.x, xx.x
xx.x, xx.x
Characteristic 3
Median
95% CI
25%, 75% Percentiles
Minimum, Maximum
p-value[a]
xx.x
(xx.x, xx.x)
xx.x, xx.x
xx.x, xx.x
0.xxx
xx.x
(xx.x, xx.x)
xx.x, xx.x
xx.x, xx.x
xx.x
(xx.x, xx.x)
xx.x, xx.x
xx.x, xx.x
[a]p-value from the log-rank test
SAS v9.4 (dd-mmm-yyyy hh:mm) from ADxx, ADxx, ADxx


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Blueprint for summaries of categorical data within and between treatment arms (delete p-value if summary is for safety 
data; delete fourth column if summary is only within treatment arm):
Study TPI-ALV-201
Title for Summary Table
Page x of x
(<ITT | Safety | Per-Protocol> Patient Population)
ACM
(n=xxx)
CM
(n=xxx)
All Patients
(n=xxx)
Characteristic 1
Category A
95% CI
Category B
95% CI
Category C
95% CI
⁞
p-value[a]
xxx (xx.x%)
(xx.x%, xx.x%)
xxx (xx.x%)
(xx.x%, xx.x%)
xxx (xx.x%)
(xx.x%, xx.x%)
⁞
0.xxx
xxx (xx.x%)
(xx.x%, xx.x%)
xxx (xx.x%) 
(xx.x%, xx.x%)
xxx (xx.x%) 
(xx.x%, xx.x%)
⁞
xxx (xx.x%)
(xx.x%, xx.x%)
xxx (xx.x%) 
(xx.x%, xx.x%)
xxx (xx.x%) 
(xx.x%, xx.x%)
⁞
Characteristic 2
Category A
95% CI
Category B 
95% CI
Category C 
95% CI
⁞
p-value[a]
xxx (xx.x%)
(xx.x%, xx.x%)
xxx (xx.x%) 
(xx.x%, xx.x%)
xxx (xx.x%) 
(xx.x%, xx.x%)
⁞
0.xxx
xxx (xx.x%)
(xx.x%, xx.x%)
xxx (xx.x%) 
(xx.x%, xx.x%)
xxx (xx.x%) 
(xx.x%, xx.x%)
⁞
xxx (xx.x%)
(xx.x%, xx.x%)
xxx (xx.x%) 
(xx.x%, xx.x%)
xxx (xx.x%) 
(xx.x%, xx.x%)
⁞
[a]p-value from the Fisher exact test
SAS v9.4 (dd-mmm-yyyy hh:mm) from ADxx, ADxx, ADxx


Statistical Analysis Plan
Draft 1.2
Protocol TPI-ALV-201
13 June 2018
CONFIDENTIAL
37 | 48
TOLERO PHARMACEUTICALS, INC
Summaries of continuous, time-to-event and categorical data may be combined similar to this blueprint for AML history
(delete fourth column if summary is only within treatment arm):
Study TPI-ALV-201
AML History
Page x of x
(<ITT | Per-Protocol> Patient Population)
ACM
(n=xxx)
CM
(n=xxx)
All Patients
(n=xxx)
Months Since AML Dx
Median
95% CI
25%, 75% Percentiles
Minimum, Maximum
p-value[a]
xx.x
(xx.x, xx.x)
xx.x, xx.x
xx.x, xx.x
0.xxx
xx.x
(xx.x, xx.x)
xx.x, xx.x
xx.x, xx.x
xx.x
(xx.x, xx.x)
xx.x, xx.x
xx.x, xx.x
Clinical Onset of AML
De Novo AML
95% CI
Prior MDS
95% CI
Prior Leukemogenic Tx
95% CI
p-value[b]
xxx (xx.x%)
(xx.x%, xx.x%)
xxx (xx.x%) 
(xx.x%, xx.x%)
xxx (xx.x%) 
(xx.x%, xx.x%)
0.xxx
xxx (xx.x%)
(xx.x%, xx.x%)
xxx (xx.x%) 
(xx.x%, xx.x%)
xxx (xx.x%) 
(xx.x%, xx.x%)
xxx (xx.x%)
(xx.x%, xx.x%)
xxx (xx.x%) 
(xx.x%, xx.x%)
xxx (xx.x%) 
(xx.x%, xx.x%)
⁞
⁞
⁞
⁞
[a]p-value from the log-rank test
[b]p-value from the Fisher exact test
SAS v9.4 (dd-mmm-yyyy hh:mm) from ADxx, ADxx, ADxx


Statistical Analysis Plan
Draft 1.2
Protocol TPI-ALV-201
13 June 2018
CONFIDENTIAL
38 | 48
TOLERO PHARMACEUTICALS, INC
Blueprint for summaries of CR rates:
Study TPI-ALV-201
Complete Remission Rates Based on <Central | Local> Hematologist’s Review
Page 1 of 1
(<ITT | Per-Protocol> Patient Population)
ACM
(n=xxx)
CM
(n=xxx)
Complete Remission Rates
Number (%) w/o Bone Marrow[a]
CR Rate (95% CI)
p-value[b]
Odds Ratio[c] (95% CI)
xx (xx.x%)
xx.x% (xx.x%, xx.x%)
0.xxx
xx.x (xx.x, xx.x)
xx (xx.x%)
xx.x% (xx.x%, xx.x%)
[a]patients rated as not achieving CR due to not providing bone marrow biopsy/aspirate
[b]p-value from CMH general association test stratified by [list stratification factors used for randomization]
[c]Mantel-Haenszel odds ratio stratified by [list stratification factors used for randomization]
SAS v9.4 (dd-mmm-yyyy hh:mm) from ADxx, ADxx, ADxx


Statistical Analysis Plan
Draft 1.2
Protocol TPI-ALV-201
13 June 2018
CONFIDENTIAL
39 | 48
TOLERO PHARMACEUTICALS, INC
Blueprint for summaries of CRi, CRp, PR, combined CR and combined remission rates:
Study TPI-ALV-201
CRi, CRp, PR, Combined CR and Combined Remission Rates
Page x of x
Based on <Central | Local> Hematologist’s Review
(<ITT | Per-Protocol> Patient Population)
ACM
(n=xxx)
CM
(n=xxx)
CRi Rates
Number (%) w/o Bone Marrow[a]
CRi Rate (95% CI)
p-value[b]
Odds Ratio[c] (95% CI)
xx (xx.x%)
xx.x% (xx.x%, xx.x%)
0.xxx
xx.x (xx.x, xx.x)
xx (xx.x%)
xx.x% (xx.x%, xx.x%)
CRp Rates
Number (%) w/o Bone Marrow[a]
CRp Rate (95% CI)
p-value[b]
Odds Ratio[c] (95% CI)
xx (xx.x%)
xx.x% (xx.x%, xx.x%)
0.xxx
xx.x (xx.x, xx.x)
xx (xx.x%)
xx.x% (xx.x%, xx.x%)
PR Rates
Number (%) w/o Bone Marrow[a]
PR Rate (95% CI)
p-value[b]
Odds Ratio[c] (95% CI)
xx (xx.x%)
xx.x% (xx.x%, xx.x%)
0.xxx
xx.x (xx.x, xx.x)
xx (xx.x%)
xx.x% (xx.x%, xx.x%)
⁞
⁞
⁞
[a]patients rated as not achieving response due to not providing bone marrow biopsy/aspirate
[b]p-value from CMH general association test stratified by [list stratification factors used for randomization]
[c]Mantel-Haenszel odds ratio stratified by [list stratification factors used for randomization]
SAS v9.4 (dd-mmm-yyyy hh:mm) from ADxx, ADxx, ADxx


Statistical Analysis Plan
Draft 1.2
Protocol TPI-ALV-201
13 June 2018
CONFIDENTIAL
40 | 48
TOLERO PHARMACEUTICALS, INC
Blueprint for summaries of correlation between central and local hematologist reviews (delete rows and columns for CRi, 
CRp and PR if summary is CR assessments only):
Study TPI-ALV-201
Correlation Between Central and Local Hematologist Reviews
Page 1 of 1
<Complete | All Levels of> Remission
(ITT Patient Population[a])
Local Review
Central Review
CR
CRi
CRp
PR
NR[b]
Total
CR
xx (xx.x%)
xx (xx.x%)
xx (xx.x%)
xx (xx.x%)
xx (xx.x%)
xx (xx.x%)
CRi
xx (xx.x%)
xx (xx.x%)
xx (xx.x%)
xx (xx.x%)
xx (xx.x%)
xx (xx.x%)
CRp
xx (xx.x%)
xx (xx.x%)
xx (xx.x%)
xx (xx.x%)
xx (xx.x%)
xx (xx.x%)
PR
xx (xx.x%)
xx (xx.x%)
xx (xx.x%)
xx (xx.x%)
xx (xx.x%)
xx (xx.x%)
NR[b]
xx (xx.x%)
xx (xx.x%)
xx (xx.x%)
xx (xx.x%)
xx (xx.x%)
xx (xx.x%)
Total
xx (xx.x%)
xx (xx.x%)
xx (xx.x%)
xx (xx.x%)
xx (xx.x%)
xx (100%)
Kappa (correlation) coefficient[c]: K=0.xxx
[a]Table summarizes all post-baseline slides from ITT population, therefore a patient may be counted more than once
[b]NR = no response
[c]x slides only reviewed by the central hematologist and x slides only reviewed by the local investigator (not tabled) are 
not included in the calculation of the kappa coefficient
SAS v9.4 (dd-mmm-yyyy hh:mm) from ADxx, ADxx, ADxx


Statistical Analysis Plan
Draft 1.2
Protocol TPI-ALV-201
13 June 2018
CONFIDENTIAL
41 | 48
TOLERO PHARMACEUTICALS, INC
Blueprint for summaries of time-to-event efficacy endpoints (delete rows for Treatment Failure and Relapse After CR as 
appropriate):
Study TPI-ALV-201
Title for Summary Table
Page 1 of 1
(<ITT | Per-Protocol> Patient Population)
ACM
(n=xxx)
CM
(n=xxx)
<PFS | OS | RFS | Resp. Duration>
Treatment Failure (%)
Relapse After CR (%)
Death (%)
Censored (%)
First Quartile (95% CI)
Median (95% CI)
Third Quartile (95% CI)
Minimum, Maximum
Survival Estimates (95% CI)
6 months
12 months
18 months
p-value[a]
Hazards Ratio[b] (95% CI)
Hazards Ratio[c] (95% CI)
xx (xx.x%)
xx (xx.x%)
xx (xx.x%)
xx (xx.x%)
xx.x (xx.x, xx.x)
xx.x (xx.x, xx.x)
xx.x (xx.x, xx.x)
xx.x, xx.x
xx.x% (xx.x%, xx.x%)
xx.x% (xx.x%, xx.x%)
xx.x% (xx.x%, xx.x%)
0.xxx
x.xx (x.xx, x.xx)
x.xx (x.xx, x.xx)
xx (xx.x%)
xx (xx.x%)
xx (xx.x%)
xx (xx.x%)
xx.x (xx.x, xx.x)
xx.x (xx.x, xx.x)
xx.x (xx.x, xx.x)
xx.x, xx.x
xx.x% (xx.x%, xx.x%)
xx.x% (xx.x%, xx.x%)
xx.x% (xx.x%, xx.x%)
[a]footnote origin of p-value
[b]based on Cox proportional hazards model with treatment arm as the only independent variable
[c]based on Cox PH model with effects for treatment arm and [list stratification factors used for randomization]
SAS v9.4 (dd-mmm-yyyy hh:mm) from ADxx, ADxx, ADxx


Statistical Analysis Plan
Draft 1.2
Protocol TPI-ALV-201
13 June 2018
CONFIDENTIAL
42 | 48
TOLERO PHARMACEUTICALS, INC
Blueprint for summaries of stem cell transplant rates:
Study TPI-ALV-201
Stem Cell Transplant Rates
Page 1 of 1
(<ITT | Per-Protocol> Patient Population)
ACM
(n=xxx)
CM
(n=xxx)
Stem Cell Transplant Within 90 Days 
Following Last Dose of Study Drug
SCT Status Unknown[a]
SCT Rate (95% CI)
p-value[b]
Odds Ratio[c] (95% CI)
xx (xx.x%)
xx.x% (xx.x%, xx.x%)
0.xxx
xx.x (xx.x, xx.x)
xx (xx.x%)
xx.x% (xx.x%, xx.x%)
[a]patients lost to follow-up (without documentation of SCT) within 90 days following last dose of study drug; these 
patients are counted as not receiving SCT
[b]p-value from CMH general association test stratified by [list stratification factors used for randomization]
[c]Mantel-Haenszel odds ratio stratified by [list stratification factors used for randomization]
SAS v9.4 (dd-mmm-yyyy hh:mm) from ADxx, ADxx, ADxx


Statistical Analysis Plan
Draft 1.2
Protocol TPI-ALV-201
13 June 2018
CONFIDENTIAL
43 | 48
TOLERO PHARMACEUTICALS, INC
Blueprint for shift tables:
Study TPI-ALV-201
Title for Summary Table
Page x of x
Treatment Arm: ACM
(<ITT | Safety | Per-Protocol> Patient Population)
Worst <Score | Grade> During Study
Baseline <Score | Grade>
0
1
2
3
4
5
Total
0
xx (xx.x%)
xx (xx.x%)
xx (xx.x%)
xx (xx.x%)
xx (xx.x%)
xx (xx.x%)
xx (xx.x%)
1
xx (xx.x%)
xx (xx.x%)
xx (xx.x%)
xx (xx.x%)
xx (xx.x%)
xx (xx.x%)
xx (xx.x%)
2
xx (xx.x%)
xx (xx.x%)
xx (xx.x%)
xx (xx.x%)
xx (xx.x%)
xx (xx.x%)
xx (xx.x%)
3
xx (xx.x%)
xx (xx.x%)
xx (xx.x%)
xx (xx.x%)
xx (xx.x%)
xx (xx.x%)
xx (xx.x%)
4
xx (xx.x%)
xx (xx.x%)
xx (xx.x%)
xx (xx.x%)
xx (xx.x%)
xx (xx.x%)
xx (xx.x%)
5
xx (xx.x%)
xx (xx.x%)
xx (xx.x%)
xx (xx.x%)
xx (xx.x%)
xx (xx.x%)
xx (xx.x%)
Total
xx (xx.x%)
xx (xx.x%)
xx (xx.x%)
xx (xx.x%)
xx (xx.x%)
xx (xx.x%)
xx (xx.x%)
Treatment Arm: CM
Worst <Score | Grade> During Study
Baseline <Score | Grade>
0
1
2
3
4
5
Total
0
xx (xx.x%)
xx (xx.x%)
xx (xx.x%)
xx (xx.x%)
xx (xx.x%)
xx (xx.x%)
xx (xx.x%)
1
xx (xx.x%)
xx (xx.x%)
xx (xx.x%)
xx (xx.x%)
xx (xx.x%)
xx (xx.x%)
xx (xx.x%)
2
xx (xx.x%)
xx (xx.x%)
xx (xx.x%)
xx (xx.x%)
xx (xx.x%)
xx (xx.x%)
xx (xx.x%)
3
xx (xx.x%)
xx (xx.x%)
xx (xx.x%)
xx (xx.x%)
xx (xx.x%)
xx (xx.x%)
xx (xx.x%)
4
xx (xx.x%)
xx (xx.x%)
xx (xx.x%)
xx (xx.x%)
xx (xx.x%)
xx (xx.x%)
xx (xx.x%)
5
xx (xx.x%)
xx (xx.x%)
xx (xx.x%)
xx (xx.x%)
xx (xx.x%)
xx (xx.x%)
xx (xx.x%)
Total
xx (xx.x%)
xx (xx.x%)
xx (xx.x%)
xx (xx.x%)
xx (xx.x%)
xx (xx.x%)
xx (xx.x%)
SAS v9.4 (dd-mmm-yyyy hh:mm) from ADxx, ADxx, ADxx


Statistical Analysis Plan
Draft 1.2
Protocol TPI-ALV-201
13 June 2018
CONFIDENTIAL
44 | 48
TOLERO PHARMACEUTICALS, INC
Blueprint for summaries of relevant prestudy and concomitant medications within and between treatment arms:
Study TPI-ALV-201
<Relevant Prestudy | Concomitant> Medications
Page x of x
(<ITT | Safety | Per-Protocol> Patient Population)
WHO Drug Dictionary 
Enhanced Anatomical and 
Therapeutic Class
ACM
(n=xxx)
CM
(n=xxx)
All Patients
(n=xxx)
ATC 1
Drug 1.1 under ATC 1 
Drug 1.2 under ATC 1
Drug 1.3 under ATC 1
Drug 1.4 under ATC 1
⁞
xxx (xx.x%)
xxx (xx.x%)
xxx (xx.x%)
xxx (xx.x%)
xxx (xx.x%)
⁞
xxx (xx.x%)
xxx (xx.x%)
xxx (xx.x%)
xxx (xx.x%)
xxx (xx.x%)
⁞
xxx (xx.x%)
xxx (xx.x%)
xxx (xx.x%)
xxx (xx.x%)
xxx (xx.x%)
⁞
ATC 2
Drug 2.1 under ATC 2 
Drug 2.2 under ATC 2
Drug 2.3 under ATC 2
Drug 2.4 under ATC 2
⁞
xxx (xx.x%)
xxx (xx.x%)
xxx (xx.x%)
xxx (xx.x%)
xxx (xx.x%)
⁞
xxx (xx.x%)
xxx (xx.x%)
xxx (xx.x%)
xxx (xx.x%)
xxx (xx.x%)
⁞
xxx (xx.x%)
xxx (xx.x%)
xxx (xx.x%)
xxx (xx.x%)
xxx (xx.x%)
⁞
A patient is counted once if he or she received any <relevant prestudy | concomitant> medications coded to the WHO 
Drug Dictionary preferred drug name.
SAS v9.4 (dd-mmm-yyyy hh:mm) from ADxx, ADxx, ADxx; WHO DDE [version]


Statistical Analysis Plan
Draft 1.2
Protocol TPI-ALV-201
13 June 2018
CONFIDENTIAL
45 | 48
TOLERO PHARMACEUTICALS, INC
Blueprint for summaries of relevant pre-existing medical conditions and adverse events within and between treatment 
arms (delete SOC for summaries sorted by preferred term):
Study TPI-ALV-201
Title for Summary Table
Page x of x
(<ITT | Safety | Per-Protocol> Patient Population)
MedDRA SOC
MedDRA Preferred Term
ACM
(n=xxx)
CM
(n=xxx)
All Patients
(n=xxx)
SOC 1
PT 1.1 under SOC 1
Any Grade
Grade 5
Grade 4
Grade 3
Grade 2
Grade 1
⁞
PT 2.1 under SOC 1
Any Grade
Grade 5
Grade 4
Grade 3
Grade 2
Grade 1
⁞
xxx (xx.x%)
xxx (xx.x%)
xxx (xx.x%)
xxx (xx.x%)
xxx (xx.x%)
xxx (xx.x%)
xxx (xx.x%)
⁞
xxx (xx.x%)
xxx (xx.x%)
xxx (xx.x%)
xxx (xx.x%)
xxx (xx.x%)
xxx (xx.x%)
⁞
xxx (xx.x%)
xxx (xx.x%)
xxx (xx.x%)
xxx (xx.x%)
xxx (xx.x%)
xxx (xx.x%)
xxx (xx.x%)
⁞
xxx (xx.x%)
xxx (xx.x%)
xxx (xx.x%)
xxx (xx.x%)
xxx (xx.x%)
xxx (xx.x%)
⁞
xxx (xx.x%)
xxx (xx.x%)
xxx (xx.x%)
xxx (xx.x%)
xxx (xx.x%)
xxx (xx.x%)
xxx (xx.x%)
⁞
xxx (xx.x%)
xxx (xx.x%)
xxx (xx.x%)
xxx (xx.x%)
xxx (xx.x%)
xxx (xx.x%)
⁞
A patient is counted once if he or she experienced any event coded to the MedDRA term. The highest reported severity 
grade is presented.
SAS v9.4 (dd-mmm-yyyy hh:mm) from ADxx, ADxx, ADxx; MedDRA v#


Statistical Analysis Plan
Draft 1.2
Protocol TPI-ALV-201
13 June 2018
CONFIDENTIAL
46 | 48
TOLERO PHARMACEUTICALS, INC
Blueprint for summary of 30- and 60-day mortality
Study TPI-ALV-201
30- and 60-Day Mortality
Page 1 of 1
(Safety Patient Population)
ACM
(n=xxx)
CM
(n=xxx)
Number of Deaths
30-Day Mortality[a]
95% CI
xx
xx.x%
(xx.x%, xx.x%)
xx
xx.x%
(xx.x%, xx.x%)
Number of Deaths
60-Day Mortality[a]
95% CI
xx
xx.x%
(xx.x%, xx.x%)
xx
xx.x%
(xx.x%, xx.x%)
[a]derived from Kaplan-Meier curves for Overall Survival
SAS v9.4 (dd-mmm-yyyy hh:mm) from ADxx, ADxx, ADxx


Statistical Analysis Plan
Draft 1.2
Protocol TPI-ALV-201
13 June 2018
CONFIDENTIAL
47 | 48
TOLERO PHARMACEUTICALS, INC
Blueprint for high-level safety summary (include additional page to show [1] TEAE leading to a reduction in the protocol-
specified dose of study drug, [2] TEAE leading to discontinuation of study drug, and [3] TEAE leading to withdrawal from 
the study)
Study TPI-ALV-201
Numbers of Patients with Adverse Events
Page 1 of 2
(Safety Patient Population)
Number of Patients with
any…
ACM
(n=xxx)
CM
(n=xxx)
All Patients
(n=xxx)
TEAE
Grade 5
Grade 4 or Higher
Grade 3 or Higher
Grade 2 or Higher
Any Grade
xxx (xx.x%)
xxx (xx.x%)
xxx (xx.x%)
xxx (xx.x%)
xxx (xx.x%)
xxx (xx.x%)
xxx (xx.x%)
xxx (xx.x%)
xxx (xx.x%)
xxx (xx.x%)
xxx (xx.x%)
xxx (xx.x%)
xxx (xx.x%)
xxx (xx.x%)
xxx (xx.x%)
Treatment-Related TEAE
Grade 5
Grade 4 or Higher
Grade 3 or Higher
Grade 2 or Higher
Any Grade
xxx (xx.x%)
xxx (xx.x%)
xxx (xx.x%)
xxx (xx.x%)
xxx (xx.x%)
xxx (xx.x%)
xxx (xx.x%)
xxx (xx.x%)
xxx (xx.x%)
xxx (xx.x%)
xxx (xx.x%)
xxx (xx.x%)
xxx (xx.x%)
xxx (xx.x%)
xxx (xx.x%)
Treatment-Emergent SAE
xxx (xx.x%)
xxx (xx.x%)
xxx (xx.x%)
TEAE Leading to a Delay in 
the Administration of Study 
Drug
xxx (xx.x%)
xxx (xx.x%)
xxx (xx.x%)
TEAE = Treatment-Emergent Adverse Event; SAE = Serious Adverse Event
SAS v9.4 (dd-mmm-yyyy hh:mm) from ADxx, ADxx, ADxx


Statistical Analysis Plan
Draft 1.2
Protocol TPI-ALV-201
13 June 2018
CONFIDENTIAL
48 | 48
TOLERO PHARMACEUTICALS, INC
Blueprint for TLS incidence rates by Cairo-Bishop severity grade
Study TPI-ALV-201
Tumor Lysis Syndrome Incidence Rates During [Cycle 1 | Study]
Page 1 of 1
by Maximum Cairo-Bishop Severity Grade
(Safety Patient Population)
Number of patients with…
ACM
(n=xxx)
CM
(n=xxx)
All Patients
(n=xxx)
No TLS
xxx (xx.x%)
xxx (xx.x%)
xxx (xx.x%)
Laboratory TLS[a]
xxx (xx.x%)
xxx (xx.x%)
xxx (xx.x%)
Clinical TLS
Grade 1
Grade 2
Grade 3
Grade 4
Grade 5
xxx (xx.x%)
xxx (xx.x%)
xxx (xx.x%)
xxx (xx.x%)
xxx (xx.x%)
xxx (xx.x%)
xxx (xx.x%)
xxx (xx.x%)
xxx (xx.x%)
xxx (xx.x%)
xxx (xx.x%)
xxx (xx.x%)
xxx (xx.x%)
xxx (xx.x%)
xxx (xx.x%)
[a]Without clinical manifestations
SAS v9.4 (dd-mmm-yyyy hh:mm) from ADxx, ADxx, ADxx