Clinical trial NCT03969420
Conditions: Acute Myeloid Leukemia (AML)
Keywords: Tolero, Phase 2, AML, Relapsed, Refractory, Alvocidib, Venetoclax
Sponsor: Sumitomo Pharma America, Inc.
Start date: 2020-01-15; Completion date: 2021-05-14
Enrollment: 11 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This study will evaluate the safety and efficacy of alvocidib in patients with AML who have either relapsed from or are refractory to venetoclax in combination with azacytidine or decitabine.

Detailed description:

Arms: arm 1: Refractory (i.e., failed to achieve a CR/CRi or achieved a CR/CRi with duration \<90 days) arm 2: Relapsed (i.e., reoccurrence of disease following a CR/CRi with duration ≥90 days). arm 3: Refractory (i.e., failed to achieve a CR/CRi or achieved a CR/CRi with duration \<90 days) arm 4: Relapsed (i.e., reoccurrence of disease following a CR/CRi with duration ≥90 days).
Interventions: intervention 1: Alvocidib (flavopiridol) and cytarabine (Ara-C) intervention 2: Alvocidib (flavopiridol)
Intervention descriptions: intervention 1: Alvocidib (flavopiridol), administered intravenously, + cytarabine (Ara-C), administered by subcutaneous injection intervention 2: Administered intravenously

Protocol documents:
Prot_000.pdf: 


Protocol No. TPI-ALV-202 Amendment 2 
 
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PROTOCOL SIGNATURE PAGE
SPONSOR SIGNATURE
I have carefully read the protocol, TPI-ALV-202, titled “A Phase 2, Open-label, 
Randomized, 
Two-stage 
Clinical 
Study 
of 
Alvocidib 
in 
Patients 
with 
Relapsed/Refractory Acute Myeloid Leukemia Following Treatment with Venetoclax 
Combination Therapy” and confirm this is the approved current version.  
ate (DD/MMM/YYYY) 
INVESTIGATOR’S SIGNATURE
I have carefully read this protocol, TPI-ALV-202, 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 
 
PROTOCOL SIGNATURE PAGE ............................................................................. 2 
TABLE OF CONTENTS ............................................................................................ 3 
LIST OF TABLES ...................................................................................................... 7 
LIST OF FIGURES .................................................................................................... 7 
ABBREVIATIONS ..................................................................................................... 8 
SYNOPSIS ............................................................................................................... 11 
1. INTRODUCTION ............................................................................................... 28 
1.1 Acute Myeloid Leukemia ................................................................................. 28 
1.1.1 
Role of MCL-1 in AML ........................................................................................28 
1.1.2 
Relapsed and/or Refractory AML .......................................................................29 
1.2 Rationale ........................................................................................................ 29 
2. DRUG INFORMATION – ALVOCIDIB .............................................................. 30 
2.1 Background..................................................................................................... 30 
2.2 Chemistry........................................................................................................ 30 
2.3 Drug Description ............................................................................................. 30 
2.4 Mechanism of Action ...................................................................................... 31 
2.5 Preclinical Studies .......................................................................................... 31 
2.5.1 
In Vitro/In Vivo Studies .......................................................................................31 
2.5.2 
Safety Pharmacology .........................................................................................33 
2.5.3 
Nonclinical Absorption, Distribution, Metabolism and Excretion .........................33 
2.5.4 
Animal Toxicology ..............................................................................................33 
2.5.5 
Genotoxicity .......................................................................................................34 
2.5.6 
Reproductive and Developmental Toxicity .........................................................34 
2.5.7 
Other Toxicity Studies ........................................................................................34 
2.6 Clinical Studies ............................................................................................... 35 
2.6.1 
Phase 1 and 2 Clinical Studies of Bolus and Hybrid FLAM Regimens in 
Patients with AML ..............................................................................................35 
2.6.2 
Phase 2 Studies in Patients with Newly Diagnosed and Previously Untreated 
AML ...................................................................................................................38 
2.6.2.1 Summary of Safety in NCI-3170 (J-0254) FLAM in Adults with Refractory 
or Relapsed Acute Leukemias (Phase 1) .....................................................39 
2.6.2.2 Summary of Safety in NCI-3170 (J-0254) FLAM Extension in Adults with 
Refractory or Relapsed Poor-risk Acute Leukemias (Phase 2) .....................39 
2.6.2.3 Summary of Safety in NCI-6947 (OSU-0479) Alvocidib Monotherapy in 
Relapsed/Refractory AML (Phase 1) ............................................................39 
2.6.2.4 Summary of Safety in NCI-7889 (J-06133) FLAM in Relapsed/Refractory 
AML (Phase 1) .............................................................................................39 
2.6.2.5 Summary of Safety in ECOG-1906 FLAM in Relapsed/Refractory AML 
(Phase 2) .....................................................................................................40 
2.7 Justification for Study Treatment Plan ............................................................ 40 
2.8 Summary of Risk and Benefits ........................................................................ 41 


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3. STUDY OBJECTIVES ....................................................................................... 43 
4. INVESTIGATIONAL PLAN ............................................................................... 45 
4.1 Overall Study Design ...................................................................................... 45 
4.2 Randomization Criteria ................................................................................... 46 
4.3 Patient Population ........................................................................................... 46 
4.3.1 
Number of Patients ............................................................................................46 
4.3.2 
Inclusion Criteria ................................................................................................46 
4.3.3 
Exclusion Criteria ...............................................................................................47 
4.4 Study Treatments ........................................................................................... 48 
4.4.1 
Calculation of Dose ............................................................................................48 
4.4.2 
Study Drug Administration ..................................................................................48 
4.5 Management of Toxicities and Dosage Modifications ..................................... 52 
4.5.1 
Management of Nonhematologic Toxicities ........................................................52 
4.5.1.1 Hyperkalemia and Tumor Lysis Syndrome ...................................................52 
4.5.1.2 Diarrhea .......................................................................................................55 
4.5.1.3 Nausea/Vomiting ..........................................................................................55 
4.5.1.4 Infection Prevention ......................................................................................55 
4.5.2 
Management of Hematologic Toxicities ..............................................................55 
4.6 Concomitant Medications and Therapies ........................................................ 56 
4.6.1 
Previous Therapies ............................................................................................56 
4.6.2 
Concomitant Therapies ......................................................................................56 
4.6.2.1 Mandated / Permitted Therapies ..................................................................57 
4.6.2.2 Prohibited Therapies ....................................................................................57 
4.6.3 
Birth Control Requirements for Fertile Patients ..................................................58 
4.7 Protocol Deviations ......................................................................................... 58 
4.8 Other Precautions ........................................................................................... 58 
5. ON-STUDY CLINICAL AND LABORATORY EVALUATIONS......................... 59 
5.1 Screening........................................................................................................ 59 
5.1.1 
Within 2 Weeks Prior to First Dose of Alvocidib ..................................................59 
5.1.2 
Within 72 Hours Prior to First Dose of Alvocidib .................................................60 
5.2 Cycle 1 ............................................................................................................ 60 
5.2.1 
Cycle 1: At Least 2 Hours Prior to First Dose .....................................................60 
5.2.2 
Cycle 1: Day 1 Just Prior to First Dose ...............................................................61 
5.2.3 
Cycle 1: Dosing Days: Arm 1: Days 1, 3–12, 15; Arm 2: Days 1, 8, 15 ...............61 
5.2.4 
&\FOH'D\V௅ ..............................................................................................62 
5.2.5 
Cycle 1: Day 22 (±3 days) ..................................................................................62 
5.2.6 
Cycle 1: Day 28 (±3 days) ..................................................................................62 
5.3 Cycles 2+ ........................................................................................................ 63 
5.3.1 
Cycles 2+: At Least 2 Hours Prior to First Dose (±3 days) ..................................63 
5.3.2 
Cycles 2+: Day 1 Just Prior to First Dose ...........................................................64 
5.3.3 
Cycles 2+: Dosing Days:  Arm 1: Days 1, 3–12, 15; Arm 2: Days 1, 8, 15 ..........64 
5.3.4 
Cycles 2+: Day 22 (±3 days) ..............................................................................65 
5.3.5 
Cycles 2+: Day 28 (±3 days) ..............................................................................66 
5.4 End of Treatment Assessments ...................................................................... 66 
5.5 Follow-up Assessments .................................................................................. 67 


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6. OFF-STUDY CRITERIA .................................................................................... 68 
6.1 Withdrawal of Patients from Study Treatment................................................. 68 
6.2 Reasons for Withdrawal from Study Treatment .............................................. 68 
6.3 Follow-up for Patients Withdrawn from Study Treatment ................................ 69 
7. CRITERIA FOR EVALUATION AND ENDPOINT DEFINITIONS ..................... 70 
7.1 Safety Endpoints ............................................................................................. 70 
7.2 Efficacy Endpoints .......................................................................................... 70 
7.3 Pharmacodynamic Endpoints ......................................................................... 72 
8. ADVERSE EVENTS .......................................................................................... 73 
8.1 Definitions ....................................................................................................... 73 
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 .................................................................................... 82 
10.4 Study Center File Management .................................................................... 82 
11. STATISTICAL ANALYSIS ................................................................................ 84 
11.1 Statistical Methods ....................................................................................... 84 
11.2 Sample Size ................................................................................................. 84 
11.3 Analysis Populations .................................................................................... 84 
11.4 Data Analyses .............................................................................................. 85 
11.4.1 Demographics and Baseline Characteristics ......................................................85 
11.4.2 Efficacy Analyses ...............................................................................................85 
11.4.3 Safety Analyses .................................................................................................86 
11.4.4 Biomarker Prediction Endpoint Analyses ............................................................87 
12. PROTOCOL AMENDMENTS ............................................................................ 88 
13. MONITORING ................................................................................................... 89 


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14. AUDITING ......................................................................................................... 90 
15. ETHICS AND RESPONSIBILITY ...................................................................... 91 
15.1 Principal Investigator’s Responsibilities ........................................................ 91 
15.2 Informed Consent ......................................................................................... 91 
15.3 Institutional Review Board/Independent Ethics Committee .......................... 92 
16. CONFIDENTIALITY .......................................................................................... 93 
17. NONPROTOCOL RELATED RESEARCH ....................................................... 94 
18. PUBLICATIONS ................................................................................................ 95 
19. REFERENCES .................................................................................................. 96 
APPENDIX A – SCHEDULES OF ACTIVITIES .................................................... 101 
APPENDIX B – ECOG PERFORMANCE STATUS SCALE ................................. 105 
APPENDIX C – NCI COMMON TERMINOLOGY CRITERIA FOR ADVERSE 
EVENTS ............................................................................................... 106 
APPENDIX D – LABORATORY TESTS ............................................................... 107 
APPENDIX E – RESPONSE CRITERIA (2017 EUROPEAN LEUKEMIANET 
RECOMMENDATIONS) ....................................................................... 108 
APPENDIX F – DOSE DE-ESCALATION PLAN .................................................. 111 
APPENDIX G – ADDITIONAL STATISTICAL INFORMATION ............................ 113 
 
 
 


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LIST OF TABLES 
Table 1: 
Overview of Alvocidib Phase 1 & 2 Clinical Studies in AML (In 
Chronologic Order) ............................................................................. 36 
Table 2: 
Alvocidib/FLAM in Newly Diagnosed Poor-Risk AML ......................... 38 
Table 3: 
Recommended Dose Modifications .................................................... 52 
 
LIST OF FIGURES 
Figure 1: 
Treatment Schema for Lead-in Cohort and Stage 1 ........................... 51 
 


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ABBREVIATIONS 
7+3 
Refers to the regimen of Ara-c: Days 5-11 and Daunorubicin: Days 5, 6, 7 
5-HT3 
5-hydroxytryptamine 
ACD 
Alvocidib/Ara-c/daunorubicin (alvocidib plus 7+3) 
ACM 
Alvocidib/Ara-c/mitoxantrone (historically known as “FLAM”) 
AE(s) 
Adverse event(s) 
ALP 
Alkaline phosphatase 
ALV 
Alvocidib 
ALT 
Alanine aminotransferase 
AML 
Acute myeloid leukemia 
ANC 
Absolute neutrophil count 
APL-M3 
Acute promyelocytic leukemia 
Ara-c 
Cytarabine 
ARDS 
Acute respiratory distress syndrome 
AST 
Aspartate aminotransferase 
AUC 
Area under the curve 
ȕ-hCG 
Beta human chorionic gonadotropin 
BCL-2 
B-cell lymphoma 2 
B-CLL 
B-cell chronic lymphocytic leukemia 
BH3 
BCL-2 homology domain 3 
BID 
Every 12 hours 
BM 
Bone marrow 
BSA 
Body surface area 
BUN 
Blood urea nitrogen 
CBC 
Complete blood count 
CDK 
Cyclin-dependent kinase 
CFR 
Code of Federal Regulations 
CHR 
Complete hematologic remission 
CIV 
Continuous intravenous 
Cl 
Confidence intervals 
CLIA 
Clinical Laboratory Improvement Amendments 
CNS 
Central nervous system 
COV 
Close out visit 
CR 
Complete remission 
CRA 
Clinical research associate 
CRh 
Meets all CR criteria but with only partial recovery of both peripheral blood 
FHOOW\SHVLH$1&/DQGSODWHOHWFRXQW/) 
CRi 
Meets all CR criteria but with only full recovery of one peripheral blood cell 
W\SHLH$1&/RUSODWHOHWFRXQW/ 
CRF 
Case report form 
CRMRD– 
CR without MRD 
CTCAE 
Common Terminology Criteria for Adverse Events 
DCF 
Data clarification form 
DLT 
Dose-limiting toxicity 
DNA 
Deoxyribonucleic acid 
DSMB 
Data Safety Monitoring Board 
ECG 
Electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
Electronic case report form 
EOT 
End of Treatment 


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FISH 
Fluorescence in situ hybridization 
FLAM 
Alvocidib (Flavopiridol)/Ara-c/Mitoxantrone (termed “ACM” in this study) 
GCP(s) 
Good Clinical Practice(s) 
GFR 
Glomerular filtration rate 
hERG 
Human ether-à-go-go-related gene 
HMA 
Hypomethylating agent 
IC50 
Inhibitory concentration in 50% of animals 
ICF 
Informed consent  
ICH 
International Council on Harmonization 
IEC 
Independent Ethics Committee 
IND 
Investigational New Drug Application 
IRB 
Institutional Review Board 
IT 
Intrathecal 
IV 
Intravenous 
LDAC 
Low dose cytarabine 
LDH 
Lactate dehydrogenase 
LP 
Lumber puncture 
LVEF 
Left ventricular ejection fraction 
MCL-1 
Myeloid leukemia cell-1 
MedDRA 
Medical Dictionary for Regulatory Activities 
MPFC 
Multiparametric flow cytometry 
MLFS 
Morphologic leukemia-free state 
MRD 
Minimal residual disease 
MTD 
Maximum tolerated dose 
NCI 
National Cancer Institute 
NCI CTCAE 
NCI’s Common Terminology Criteria for Adverse Events 
NGS 
Next generation sequencing 
OS 
Overall survival 
PD 
Progressive disease 
PFS 
Progression-free survival 
PLT 
Platelets 
PR 
Partial remission/response 
PS 
Performance status 
PT 
Preferred term 
RBC(s) 
Red blood cell(s) 
RNA 
Ribonucleic acid 
SAE(s) 
Serious adverse event(s) 
SAS 
Statistical Analysis System (software) 
SC 
Subcutaneous 
SIV 
Study initiation visit 
SMQ 
Standardized MedDRA query 
SOC 
System organ class 
SOP(s) 
Standard operating procedure(s) 
T1/2 
Half-life 
TEAE 
Treatment-emergent adverse event 
TGI 
Tumor growth inhibition 
TI 
Transfusion independence 
TLS 
Tumor lysis syndrome 
TRM 
Treatment-related mortality 
TST 
Timed sequential therapy 
XIAP 
X-linked inhibitor of apoptosis 
ULN 
Upper limit of normal 


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WBC(s) 
White blood cell(s) 
WHO 
World Health Organization 


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SYNOPSIS  
Title of Study 
A Phase 2, Open-label, Randomized, Two-stage Clinical Study of 
Alvocidib in Patients with Relapsed/Refractory Acute Myeloid 
Leukemia Following Treatment with Venetoclax Combination 
Therapy 
Study Indication 
Acute Myeloid Leukemia (AML) that has progressed after, or is 
refractory to, initial induction therapy with venetoclax combined with  
azacytidine or decitabine 
Clinical Phase 
2 
Patient 
Population 
Adult patients must have refractory or relapsed AML after initial 
induction therapy with venetoclax in combination with azacytidine or 
decitabine 
Study 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). Existing standard-of-care AML therapies do 
not adequately attain sufficiently high rates of CR, duration of CR, or 
satisfactory survival rates in the majority of AML patients who are 
unfit or considered elderly.  
Venetoclax, a BCL-2 inhibitor, has been approved for front-line use 
in combination with DNA hypomethylating agents (HMAs) or low-
dose cytarabine (LDAC) for the treatment of AML in patient 
populations considered unfit for aggressive induction therapy. 
Despite this recent advance in the treatment armament, the majority 
of patients will still require treatment in the relapsed/refractory 
setting. The anti-apoptotic protein MCL-1 has been cited as a 
possible mechanism of resistance to venetoclax and the ensuing 
failure to keep AML in remission.  
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.  
MCL-1 expression is known to confer chemotherapy resistance and 
seems to be enhanced after exposure to prior chemotherapy. Clinical 
trials with alvocidib (both as monotherapy and in combination with 
cytarabine/mitoxantrone) have shown promising activity to date in 
both newly diagnosed high-risk patients with AML as well as in the 
relapsed/refractory setting. Clinically, it is felt that patients who have 
been treated with venetoclax will switch the dependency of apoptosis 
in leukemic blasts from BCL-2 to MCL-1. At that point, treatment with 
alvocidib could potentially aid in overcoming MCL-1-dependent 
venetoclax resistance by inhibiting CDK9/MCL-1 signaling. In vitro 
work has shown that AML cell lines can be re-sensitized to 
venetoclax, or other BCL-2 inhibitors, by downregulating MCL-1 via 
alvocidib treatment. Mechanistically, leukemic stem cells are 
dependent on MCL-1 which may allow alvocidib to convey a deeper 
and more durable response. 
Given that MCL-1 expression and upregulation are associated with 
resistance to venetoclax, it is thought that CDK9 inhibitors may offer 


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a viable path of action for patients previously treated with venetoclax 
combinations. This trial will address the continued unmet medical 
need in patients with AML who have either progressed on, or are 
refractory to, venetoclax in combination with azacytidine or 
decitabine but are still eligible for further disease-directed treatments. 
Planned 
Enrollment 
The study is expected to enroll approximately 134 evaluable 
patients in both stages of the study. 
Study Sites 
Patients will be enrolled at approximately 30 sites in the United 
States (US) and other countries 
Study Duration 
The study is expected to take 18 months to enroll approximately 134 
evaluable patients and an additional 2 years for follow up.  
Objectives 
Primary  
x 
To estimate the rate of combined complete remission (ie, CR + 
CR with incomplete hematological recovery [CRi]) in patients with 
AML whose disease is either refractory to initial induction therapy 
with venetoclax in combination with azacytidine or decitabine (ie, 
failed to achieve a CR/CRi or achieved a CR/CRi with duration 
<90 days) or who have relapsed (reoccurrence of disease 
following a CR/CRi dXUDWLRQGD\V 
Secondary 
To evaluate the following: 
x 
Median Overall Survival (OS) = Time from treatment (Day 1) until 
death from any cause  
x 
CRMRD– = Percentage of patients achieving complete response 
(CR) whose bone marrow is determined to be negative for 
minimal residual disease (MRD) using standardized techniques 
(ie, multiparametric flow cytometry [MPFC] and molecular testing 
including next generation sequencing [NGS]) 
x 
CR Rate = Percentage of patients achieving: 
o CR = Bone marrow blasts <5%; absence of blasts with Auer 
rods; absence of extramedullary disease; hematologic 
UHFRYHU\ DEVROXWH QHXWURSKLO FRXQW >$1&@ / DQG
SODWHOHWFRXQW/ 
x 
Composite CR rate = Combined percentage of patients 
achieving one of the following: 
o CR 
o CRi = Meets all CR criteria but with only full recovery of one 
peripheral blood cell type LH$1&/or platelet count 
/ 
o CRh = Meets all CR criteria but with only partial recovery of 
both SHULSKHUDO EORRG FHOO W\SHV LH $1& / and 
SODWHOHWFRXQW/ 


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x 
Combined Response rate = Combined percentage of patients 
achieving one of the following: 
o CR 
o CRi 
o CRh 
o Morphologic leukemia-free state (MLFS) = Bone marrow 
blasts <5%; absence of blasts with Auer rods; absence of 
extramedullary disease; no hematologic recovery required 
o Partial Response (PR) = Meets all hematologic values 
required for CR but with a decrease of at least 50% in the 
SHUFHQWDJHRIEODVWVWRWRLQERQHPDUURZ 
x 
Event-free Survival (EFS) = Time from first treatment (Day 1) 
until (a) treatment failure, (b) relapse after CR/CRi/CRh, or 
(c) death from any cause, whichever occurs first, censored at 
2 years  
x 
Duration of Composite CR = Time from first documented 
response of CR, CRi, or CRh to relapse or death from any cause. 
x 
Rates of 28- and 56-day Transfusion Independence (TI) = 
Percentages of patients who do not receive red blood cell (RBC) 
transfusions, platelet (PLT) transfusions, and neither RBC nor 
PLT transfusions for 28 and 56 days; comprised of 6 secondary 
endpoints: 
o 28-day RBC TI 
o 28-day PLT TI 
o 28-day TI (both RBC and PLT) 
o 56-day RBC TI 
o 56-day PLT TI 
o 56-day TI (both RBC and PLT) 
28- and 56-day TI will be summarized in 2×2 shift tables showing 
the percentages of patients who are transfusion independent at 
baseline according to review of medical charts versus the 
percentages of patients who achieve transfusion independence 
at any time during the study. Effort will be made to collect 
transfusion information for 56 days following withdrawal from the 
study to properly classify a patient’s post-treatment TI status. 
Patients not already classified as transfusion independent and 
who cannot be followed will be classified as ‘status unknown’ for 
the required time to establish TI.  
Exploratory 
x 
To evaluate potential biomarkers including but not limited to 
MCL-1 dependence, genetic mutations, and other biomarkers 
associated with AML.  
x 
Additional exploratory analyses may be performed if useful in the 
interpretation of the data. 


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Study Design 
This is an open-label, randomized, two-stage clinical study. During 
Stage 1, 26 patients will be randomized into each of the 2 treatment 
arms (52 patients total) stratified by prior response to venetoclax in 
combination with azacytidine or decitabine:  
x 
Refractory (ie, failed to achieve a CR/CRi or achieved a 
CR/CRi with duration <90 days 
x 
Relapsed (ie, reoccurrence of disease following a CR/CRi 
with duration 90 days).  
 
Lead-in Cohort 
As an additional safety measure given the unique patient population 
and outpatient treatment administration, a separate lead-in cohort of 
approximately six patients (at least three patients in each treatment 
arm) will be enrolled, treated, and evaluated for dose-limiting 
toxicities (DLTs). If a DLT is observed, dose de-escalation will occur 
as outlined in Appendix F. Should no additional DLTs be observed 
during Cycle 1, Amendment 2 be approved, and the Data Safety 
Monitoring Board (DSMB) confirm safety, randomization into 
Stage 1 will commence as outlined in the protocol. However, should 
an additional DLT be observed at Dose Level 1, a clinical meeting 
would be scheduled to discuss the utility/futility of continuing the 
study as currently designed.  
If patients treated in the lead-in cohort are still on study when 
Amendment 2 is approved and the DSMB has confirmed safety, 
they may be permitted to shift to the higher alvocidib (ALV) dose 
regimen, ie, ALV 50 mg/m2 IV bolus, per investigator discretion. 
 
Stage 1 
A futility analysis will be conducted at the end of Stage 1 to determine 
if the combined CR rate meets the threshold for continuing the study. 
Using an alpha spending function to control the overall level of 
significance, the threshold is that the one-sided p-value be <0.60525 
in order to initiate Stage 2; which is achieved if there are more than 
4 combined CRs among the 52 Stage 1 patients. No additional 
patients will be enrolled if the number of patients with combined CR 
at the end of Stage 1 fails to meet this criterion. 
 
Stage 2 
Determination of the recommended alvocidib-based treatment arm 
for Stage 2 will be subjective, comparing the response rates, relative 
safety, and the risk-benefit ratio of the two Stage 1 treatment arms. 
An additional 76 patients will be enrolled into the treatment arm 
selected for Stage 2 for a total of 102 patients (26 and 76 from 
Stages 1 and 2, respectively). The combined CR rate (primary 


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endpoint) will be tested at the end of Stage 2, with statistical 
significance declared if the one-sided p-value is <0.02407. 
Any patient who withdraws from the study for treatment-related 
toxicity prior to being evaluated for response will be considered a 
non-responder. Patients who drop out of the study for other reasons 
prior to being assessed for response will be considered non-
evaluable and may be replaced. 
Inclusion Criteria 
To be eligible for participation in the study, patients must meet all of the 
following inclusion criteria: 
1. %H years of age 
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. Have received initial induction therapy with venetoclax in 
combination with azacytidine or decitabine (with or without other 
investigational agents as part of a clinical trial; requires 
Medical Monitor review) and were either refractory (failed to 
achieve a CR/CRi or achieved a CR/CRi with duration <90 days) or 
have relapsed (reoccurrence of disease following a CR/CRi with 
duration 90 days) 
4. Have an Eastern Cooperative Oncology Group (ECOG) 
SHUIRUPDQFHVWDWXV36 
5. Have a glomerular filtration rate (GFR) 30 mL/min using the 
Cockcroft-Gault equation 
6. Have 
an 
alanine 
aminotransferase 
(ALT)/aspartate 
DPLQRWUDQVIHUDVH$67OHYHOWLPHVXSSHUOLPLWRIQRUPDO8/1 
7. +DYHDWRWDOELOLUXELQOHYHO mg/dL (unless secondary to Gilbert 
syndrome, hemolysis, or leukemia) 
8. Be infertile 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 prior to 
study entry, for the duration of study participation, and for at least 
3 months (males) and 6 months (females) after the last dose of 
study drug  
9. Be able to comply with the requirements of the entire study 
10. 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 any previous treatment with alvocidib or any other CDK 
inhibitor or received prior anti-leukemic therapy other than first-
line venetoclax in combination with azacytidine or decitabine 


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2. 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 
3. Received an allogeneic stem cell transplant within 60 days of 
treatment. Patients who received an allogeneic stem cell 
transplant must be off all immunosuppressants at the time of 
study treatment 
4. Receiving systemic therapy for graft-versus-host disease 
5. Have a peripheral blast count of >30,000/mm3 (may use 
hydroxyurea as in #2 above) 
6. Received antileukemic therapy within the last 2 weeks or 3-5 
half-lives of the prior therapy (with the exception of 
hydroxyurea or if the patient has definite refractory disease), 
whichever is less. Refractory patients who received therapy 
within the last 2 weeks may be eligible with prior approval of the 
Medical Monitor 
7. Diagnosed with acute promyelocytic leukemia (APL-M3) 
8. Have active central nervous system (CNS) leukemia 
9. Have evidence of uncontrolled disseminated intravascular 
coagulation 
10. Have an active, uncontrolled infection 
11. Have other life-threatening illness 
12. Have other active malignancies requiring treatment or diagnosed 
with other malignancies within the last 6 months, except 
nonmelanoma skin cancer or cervical intraepithelial neoplasia 
13. Have mental deficits and/or psychiatric history that may 
compromise the ability to give written informed consent or to 
comply with the study protocol 
14. Are pregnant and/or nursing 
15. Have received any live vaccine within 14 days prior to first study 
drug administration 
Study Treatment 
Study Drug Administration 
Lead-in Cohort, Two Arms (at least 3 patients per arm) 
x 
Lead-in ARM 1: Alvocidib + Low-dose cytarabine (ALDAC); 
treatment will be given every 28 days 
o Cycle 1, Day 1: alvocidib 25 mg/m2 as a 30-60 minute 
intravenous (IV) bolus  
o Cycle 1, Day 2: no treatment 
o Cycle 1, Days 3 through 12 (10 days): LDAC (low-dose 
cytarabine), 20 mg/m2 by subcutaneous (SC) injection  


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o Cycle 1, Day 15: alvocidib 50 mg/m2 as a 30-60 minute 
IV bolus  
x 
Lead-in Arm 2: Alvocidib (ALV); treatment will be given every 
28 days 
o Cycle 1, Day 1: alvocidib 25 mg/m2 as a 30-60 minute 
IV bolus 
o Cycle 1, Days 8 and 15: alvocidib 50 mg/m2 as a 
30-60 minute IV bolus 
Should no DLTs be observed during Cycle 1, Amendment 2 has 
been approved, and the DSMB confirm safety, randomization 
into Stage 1 will commence as outlined below. If patients treated 
in the lead-in cohort are still on study when Amendment 2 is 
approved, they may shift to the higher alvocidib dose regimen, 
ie, ALV as 50 mg/m2 IV bolus, per investigator discretion. 
 
Stage 1 Randomized, Two Arms (26 patients per arm) 
x 
ARM 1: Alvocidib + Low-dose cytarabine (ALDAC); treatment will 
be given every 28 days 
o Cycle 1, Day 1: alvocidib 25 mg/m2 as a 30-60 minute 
intravenous (IV) bolus  
Cycles 2+, Day 1: alvocidib 50 mg/m2 as a 30-60 minute 
IV bolus  
o Day 2: no treatment 
o Days 3 through 12 (10 days): LDAC (low dose 
cytarabine), 20 mg/m2 by subcutaneous (SC) injection  
o Day 15: alvocidib 50 mg/m2 as a 30-60 minute IV bolus  
x 
ARM 2: Alvocidib (ALV); treatment will be given every 28 days 
o Cycle 1, Day 1: alvocidib 25 mg/m2 as a 30-60 minute IV 
bolus 
Cycles 2+, Day 1: alvocidib 50 mg/m2 as a 30-60 minute 
IV bolus  
o Days 8 and 15: alvocidib 50 mg/m2 as a 30-60 minute IV 
bolus 
 
Stage 2 Single Arm (76 patients) 
Regimen to be selected based on Stage 1 performance.  
 
Additional Cycles of Treatment in Stage 1 and Stage 2 
Patients who achieve CR, CRi, MLFS, PR, or clinical benefit after the 
first cycle (completion of all doses) may receive additional optional 
cycles of treatment until disease progression (in the event of toxicities 
see the recommendations in Table 3, if applicable).  


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Those who achieve a CR, CRi, CRh, or MLFS (ie, <5% blasts in 
bone marrow) should not be given subsequent cycles until ANC 
>0.5 and platelets >50. If treatment is delayed >2 weeks for 
cytopenias, a bone marrow biopsy should be performed to 
reassess disease status. 
Patients not demonstrating evidence of CR, CRi, MLFS, PR, or 
clinical benefit after 4 cycles of treatment will be considered for 
removal from the study, although with permission of the Medical 
Monitor, treatment may continue if clinically indicated (in the event of 
toxicities see the recommendations in Table 3, if applicable).  
 
Supportive Care (Stage 1 and Stage 2)  
Supportive care will be provided including: 
x 
Tumor Lysis Prevention and Treatment 
o Due to an increased likelihood of TLS, hospitalization 
of patients with monocytic differentiation and/or a 
peripheral blast count of >10,000/mm3 is strongly 
recommended for the first dose of alvocidib (ie, 
Cycle 1 / Day 1). 
o Mandatory IV hydration with 0.45% NaCl (or similar 
hydration fluid per institutional standard) sterile solution at 
250-500 cc for 1-2 hours prior to alvocidib, then an 
additional 250-500 cc for 1-2 hours after alvocidib during 
Cycle 1 (optional for subsequent cycles for patients who 
have achieved a CR).  
x 
Replacement of excessive fluid losses, including from diarrhea, 
should be done unless otherwise clinically indicated. 
o Alvocidib is known to induce mild diarrhea during 
treatment days. Over-the-counter measures are typically 
effective in this setting if initiated early. Persistent diarrhea 
despite optimal outpatient management would trigger 
medical consultation. Early consideration should be given 
for possible Clostridioides difficile infection in this patient 
population and identifying/treating as expeditiously as 
possible should be top of mind. 
x 
Mandatory oral allopurinol to be started at least 72 hours prior to 
Day 1 of Cycle 1 and continued until completion of the first cycle 
(ie, 28 days). This may be discontinued for subsequent treatment 
cycles if uric acid levels are within normal limits and there is no 
evidence of tumor lysis syndrome. 
x 
Mandatory oral phosphate binder to be started at the same time 
as initiation of IV hydration on Day 1 of Cycle 1 and continued for 
the first week (ie, 7 days).  
o If serum phosphorus levels are <3 after the first treatment 
with alvocidib and there is no evidence of TLS, phosphate 
binders may be discontinued. Patients should continue to 


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be monitored for TLS as outlined for subsequent 
treatment cycles. Caution is warranted for patients who 
still have a high blast count as they remain at risk for TLS 
with subsequent treatments.  
x 
Evaluation of laboratory indicators of 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  
o During Cycle 1, monitor tumor lysis labs prior to alvocidib 
infusion and 2 hours (±30 minutes) after completion of IV 
hydration post alvocidib. Labs will also be drawn daily for 
the first three days following the first alvocidib dose (ie, 
Days 2-4) and at least weekly for the remainder of Cycle 
1.  
o 
During Cycles 2+, tumor lysis labs will be assessed prior 
to each dose of alvocidib 
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 azole antifungals 
(ie, 
fluconazole, 
posaconazole, 
voriconazole, 
isavuconazole) should be administered to patients in all 
treatment arms if ANC <500/L. These can be 
discontinued when the ANC /L per institutional 
standards and physician discretion. Valacyclovir (or 
equivalent) to be administered once daily (QD) or twice 
daily (BID) to all patients throughout the study based on 
institutional standards unless there are contraindications. 
Other similar antiviral agents may be administered 
per institutional standards with dosing according to 
each medication’s full prescribing information. 
o Routine 
growth 
factor 
support 
is 
not 
allowed. 
Granulocyte colony-stimulating factor (G-CSF) may 
be administered for Grade 4 neutropenia (with or 
without fever or infection) if the event occurs after the 
patient has achieved remission of at least 7 days’ 
duration and following consultation with the Medical 
Monitor. Once the toxicity has resolved to a clinically 
acceptable situation, study treatment should resume 
at the same dose and schedule. No dose reductions 
are permitted after completion of the lead-in safety 
cohort. 
o 
Donor lymphocyte infusions are not allowed at any time 
during the study 


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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. 
Study 
Assessments 
Screening 
Within 2 weeks prior to first dose 
x 
Obtain written informed consent 
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 
Collect information about any transfusions that have occurred 
within 56 days prior to Cycle 1 Day 1 
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, respiratory rate) 
x 
Collect bone marrow and peripheral blood 
o Collect bone marrow and peripheral blood samples for 
confirmation 
of 
diagnosis, 
cytogenetic 
profiling, 
and 
pharmacodynamic (PD) tests 
o Collect bone marrow sample to be sent to a central laboratory 
for MRD assessment using standardized techniques (ie, 
MPFC and molecular testing including NGS)  
o If patient is enrolled, 6 to 8 bone marrow slides will be 
prepared and sent to the Sponsor 
x 
Perform 12-lead electrocardiogram (ECG) 
x 
Record all concomitant medications including all prescription 
drugs, nonprescription drugs, and nutritional supplements taken 
within the past 2 weeks  
x Collect urine or serum sample for beta-human chorionic 
gonadotropin (ȕ-hCG) pregnancy test for females of 
childbearing potential  
x Collect blood for evaluation of laboratory parameters 
(Appendix D):  
o Hematology: complete blood count with differential and 
platelet count  
o Full serum chemistry panel. 
x Perform lumber puncture (LP) in patients with suspected CNS 
involvement 
 


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Within 72 hours prior to first dose of alvocidib 
x 
Record all concomitant medications including all prescription 
drugs, nonprescription drugs, and nutritional supplements 
x 
Collect urine or serum sample for ȕ-hCG pregnancy test for 
females of childbearing potential 
x 
Collect 
blood 
for 
evaluation 
of 
laboratory 
parameters 
(Appendix D): hematology and full serum chemistry panel 
x 
Collect urine sample for full urinalysis 
x 
Review all Inclusion/Exclusion criteria and determine if patient 
has met all eligibility criteria for inclusion into the study 
x 
Start administration of allopurinol orally daily at least 72 hours 
prior to study treatment 
x 
Provide patient with study diary and instruct them on daily 
completion. Remind patient to bring diary back at every clinic visit 
 
Cycle 1  
At least 2 hours prior to first dose 
x 
Abbreviated physical examination including weight (kg) for 
calculation of body surface area (BSA)  
x 
ECOG PS (Appendix B)  
x 
Record all concomitant medications including all prescription 
drugs, nonprescription drugs, and nutritional supplements taken 
since screening  
x 
Initiate supportive care measures 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 4.5.1)  
o Replacement of excessive fluid losses, including from 
diarrhea, should be done unless otherwise clinically indicated. 
 
Just prior to first dose 
x 
Record vital signs measured 15-30 minutes prior to the initiation 
of infusion following a 5-minute rest 
x 
Collect blood for baseline laboratory parameters (Appendix D). 
Results are not required to be reviewed prior to treatment 
o Tumor lysis labs: sodium, potassium, chloride, carbon 
dioxide, creatinine, calcium, lactate dehydrogenase, uric acid, 
and phosphorous 
o Coagulation labs: fibrinogen level 
x 
&ROOHFW XULQH RU VHUXP VDPSOH IRU ȕ-hCG pregnancy test for 
females of child-bearing potential if screening pregnancy test is 


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greater than 72 hours prior to first dose. Results must be reviewed 
prior to treatment. 
 
Stage 1 Dosing Days: Arm 1: Days 1, 3–12, 15; Arm 2: Days 1, 8, 15 
A ±2-day window will be allowed for Day 15 of both treatment 
arms. A ±1-day window will be allowed for Day 8 (Arm 2 only). 
x 
Abbreviated physical examination (Arm 1: Days 8 and 15; 
Arm 2: Days 8 and 15)  
x 
Assess ECOG PS (Arm 1: Days 8 and 15; Arm 2: Days 8 and 
15) (Appendix B)  
x 
Record vital signs on Days 1, 8, and 15 (both arms)  
x 
Record only those medications (prescription, nonprescription, 
nutritional supplements) administered in conjunction with an AE 
x 
Assess patient for adequate hydration at all study visits and 
replace excessive fluid losses, including from diarrhea, unless 
otherwise clinically indicated 
x 
Collect 
blood 
for 
evaluation 
of 
laboratory 
parameters 
(Appendix D): hematology and full serum chemistry panel on 
each day of alvocidib administration and twice weekly (minimum 
of 72 hours between collections) during the LDAC treatment 
(Days 3-12 of Arm 1) 
x 
Monitor tumor lysis labs (Section 4.5.1.1 and Appendix D)  
o During Cycle 1, monitor tumor lysis labs prior to alvocidib 
infusion and 2 hours (±30 minutes) after completion of IV 
hydration post alvocidib. Labs will also be drawn daily for the 
first three days following the first alvocidib dose (ie, Days 2-4) 
and at least weekly for the remainder of Cycle 1.  
o During Cycles 2+, tumor lysis labs will be assessed prior to 
each dose of alvocidib 
x 
Monitor fibrinogen levels as clinically indicated. 
x 
Administer prophylactic antibiotics and antivirals, and antifungals 
according to Section 4.5.1.4 
x 
Assess for AEs 
x 
Administer 
alvocidib 
and/or 
cytarabine 
according 
to  
Section 4.4.2 
x 
Review study diary and remind patient to bring diary back at next 
visit 
 
The Stage 2 dosing regimen will be selected based on results from 
Stage 1 arms in terms of response rates, relative safety, and risk-
benefit ratio.    


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Cycle 1 Day 22 (±3 days):  
x 
Abbreviated physical examination (AE- or symptom-directed 
exam) 
x 
ECOG PS (Appendix B) 
x 
Vital signs (temperature, heart rate, systolic and diastolic 
blood pressures, and respiratory rate) 
x 
Record only those medications (prescription, nonprescription, 
nutritional supplements) administered in conjunction with an AE 
x 
Collect 
blood 
for 
evaluation 
of 
laboratory 
parameters 
(Appendix D): hematology, tumor lysis labs (to be drawn at least 
weekly for the remainder of Cycle 1), fibrinogen level (as clinically 
indicated) 
x 
Assess for AEs 
x 
Review study diary and remind patient to bring diary back at next 
clinic visit 
 
Cycle 1 Day 28 (±3 days) 
x 
Collect bone marrow and peripheral blood for response 
assessment and PD tests. Collect bone marrow sample to be sent 
to a central laboratory for MRD assessment using standardized 
techniques (ie, MPFC and molecular testing including NGS). If 
the procedure is nonproductive or not diagnostic, it must be 
repeated within 7-10 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 
Laboratory Manual. 
x 
Record only those medications (prescription, nonprescription, 
nutritional supplements) administered in conjunction with an AE  
x 
Assess for AEs 
x 
Review study diary and remind patient to bring diary back at the 
next clinic visit 
 
Cycles 2+  
Patients who achieve CR, CRi, CRh, MLFS, PR, or clinical benefit 
after the first cycle (completion of all doses) may receive additional 
optional cycles of treatment until disease progression (in the event of 
toxicities see the recommendations in Table 3).  
Those who achieve a CR, CRi, CRh, or MLFS (ie, <5% blasts in 
bone marrow) should not be given subsequent cycles until ANC 
>0.5 and platelets >50. If treatment is delayed >2 weeks for 
cytopenias, a bone marrow biopsy should be performed to 
reassess disease status. 


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Patients not demonstrating evidence of CR, CRi, CRh, MLFS, PR, or 
clinical benefit after the first 4 cycles of treatment will be considered 
for removal from the study, although with permission of the Medical 
Monitor, treatment may continue if clinically indicated (in the event of 
toxicities see the recommendations in Table 3, if applicable). 
Please see Section 5.3 for details. 
 
End of Treatment 
x 
Abbreviated physical examination (AE- or symptom directed 
exam) including weight (kg) and other measures of disease and 
disease symptoms, eg, extramedullary disease 
x 
Vital signs  
x 
ECOG PS (Appendix B)  
x 
12-lead ECG only if clinically indicated 
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 
Record only those medications (prescription, nonprescription, 
nutritional supplements) administered in conjunction with an AE 
x 
Urinalysis 
x 
Collect bone marrow and peripheral blood (if not done within the 
previous 30 days): 
o Collect bone marrow and peripheral blood for response 
assessment, PD tests, and treatment guidance.  
o Collect bone marrow sample to be sent to a central laboratory 
for MRD assessment using standardized techniques (ie, 
MPFC and molecular testing including NGS).  
o If the bone marrow procedure is nonproductive or not 
diagnostic, it must be repeated within 7-10 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 Laboratory Manual.  
x 
Assess for AEs 
x 
Collect study diary 
 
Follow Up 
Patients will be contacted by telephone to record data on PBRC 
and/or platelet transfusions occurring within 56 days after the last 
dose of study drug. Patients will also be contacted by telephone to 
assess for date of death, date of stem cell transplant, date of relapse, 
or continued remission for 2 years.  


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Efficacy 
Endpoints 
Primary Endpoint 
The primary endpoint is the rate of combined complete remission (CR 
+ CRi) as defined by the International Working Group Criteria and 
2017 European LeukemiaNet. 
Secondary Endpoints 
x 
Median OS  
x 
CRMRD–  
x 
CR Rate  
x 
Composite CR rate (CR + CRi + CRh) 
x 
Combined Response Rate (CR + CRi + CRh + MLFS + PR)  
x 
EFS  
x 
Duration of composite CR = Time from first documented 
response of CR, CRi, CRh to relapse or death from any cause 
x 
Rates of 28- and 56-day Transfusion Independence (TI) = 
Percentages of patients who do not receive red blood cell (RBC) 
transfusions, platelet (PLT) transfusions, and neither RBC nor 
PLT transfusions for 28 and 56 days (ie, 6 secondary endpoints) 
Safety Endpoints 
Safety and tolerability of the regimen will be assessed by analyzing 
the incidence rates of treatment-emergent adverse events (TEAEs) 
summarized at the 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).  
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 following last treatment will 
also be calculated. Adverse events will be graded according to 
National Cancer Institute’s Common Terminology Criteria for 
Adverse Events (NCI CTCAE), version 5.0. 
A Data Safety Monitoring Board (DSMB) will monitor key outcomes 
from the study. 
Pharmacodynamic
Endpoints 
Pharmacodynamic (PD) endpoints include:  
x 
BH3 profiling, including determination of MCL-1 dependence, at 
Baseline and End of Treatment using bone marrow.  
x 
Analysis of MRD to be performed at a central Clinical Laboratory 
Improvement Amendments (CLIA)-accredited laboratory on bone 
marrow samples collected at baseline and at time of response 
assessments using standardized techniques (ie, MPFC and 
molecular testing including NGS).  


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x 
Peripheral blood and bone marrow samples will be collected at 
protocol-specific time points to evaluate other potential 
biomarkers including but not limited to MCL-1 dependence.  
These assessments may be explored in the context of AML or 
related conditions or drugs of similar class. 
The samples may be retained for no longer than 20 years after study 
completion or per local requirements. 
Statistical 
Analysis 
Sample Size 
This study follows a 2-stage adaptive design that allows for 
continuing patient recruitment into the recommended alvocidib-
based treatment arm used in Stage 1. It is designed to test the null 
hypothesis that the combined CR rate is 10% against the 
alternative that the combined CR rate is >10%. Up to 128 eligible 
patients from Stage 1 and Stage 2 will be evaluated for efficacy. 
Patients enrolled in the lead-in safety cohort will not be 
included in the efficacy analyses since they will receive a 
lower dose of alvocidib than the patients enrolled in Stage 1 
and Stage 2. Assuming the actual combined CR rate is 20%, the 
study has 80% power at the one-sided 2.5% level of significance. 
The underlying statistical properties of this design are based on a 
2-stage sequential design where the overall one-sided 2.5% level 
of significance is protected using error spending. Forty percent of 
total information will be accumulated prior to the interim analysis at 
the end of Stage 1, where 10% of the overall alpha will be used. All 
data from Stages 1 and 2 will be used for the statistical test of 
combined CR rate at the end of the study, hence the adaptive 
component of this design (dropping 1 of the 2 treatment arms at 
the end of Stage 1) does not affect the overall type-1 and type-2 
error probabilities (see Appendix G). 
Efficacy Analyses 
Descriptive statistics will be calculated within and across treatment 
arms for all efficacy endpoints. 
Combined complete remissions (patients with a best response of 
CR or CRi), complete remissions, composite complete remissions 
(patients with a best response of CR, CRi or CRh), and combined 
responses (patients with a best response of CR, CRi, CRh, MLFS 
or PR) will be summarized by observed response rates and 
estimated 95% CIs. 
Kaplan-Meier time-to-event analyses will be conducted on overall 
survival, progression-free survival, and duration of composite CR. 
Mortality (all causes) at 30 and 60 days after the last treatment will 
also be calculated. 
Safety Analyses 
Reported adverse event (AE) terms will be mapped to MedDRA 
preferred terminology. Adverse events suggestive of TLS will be 
flagged based in the standardized MedDRA query (SMQ) for TLS. 
All reported events will appear in AE listings; however only 


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treatment-emergent (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 is rated by the 
Investigator according to CTCAE version 5.  
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 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 study treatment 
x 
TEAEs leading to death. 
The base summary of TEAEs will show within– and between–
treatment-arm incidence rates for each MedDRA primary System 
Organ Class (SOC) and/or Preferred Term (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. 
 
PD Analyses 
Summary of baseline biomarker values will include within– and 
between–treatment-arm descriptive statistics. If there are sufficient 
numbers of patients achieving remissions for an analysis to be 
informative, a logistic regression model will be fit to examine the 
relationship between potential biomarkers and the independent 
binary variables complete remissions, combined complete 
remissions, and combined remissions during the study. 


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1. INTRODUCTION 
1.1 Acute Myeloid Leukemia 
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 likely, 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. 
Until recently, the best treatment for unfit patients with AML was ill defined; 
however, results from clinical trials of venetoclax in combination with 
hypomethylating agents (HMAs) demonstrated an impressive complete 
response rate of 54% (CR/CRi) with a median time to first response of 
1.4 months and median duration of response 8.1 months providing a new option 
for patients previously considered ‘unfit’ for intensive induction regimens [1]. For 
patients who relapse after venetoclax/HMA therapy, second-line therapy is not 
defined. There remains an unmet medical need to identify safe and effective 
outpatient treatment options for this patient population while preserving their 
quality of life. 
1.1.1 
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 [2,3]. The BCL-2 family of polypeptides 
has been widely studied as regulators of cell death [4]. 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 [5,6]. 
Other studies have indicated that MCL-1 expression can be induced rapidly in 
response to a number of DNA-damaging agents [7,8]. 
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 [9,10] and acts synergistically with other chemotherapeutic 
agents like daunorubicin and cytarabine. Through use of mitochondrial (BH3) 
profiling, the mechanism by which apoptosis is suppressed in a population of 


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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 [11]. TMS1 is a NOXA mimetic that is used 
to measure MCL-1 dependency in addition to other potential molecular (genetic) 
targets [12]. 
1.1.2 
Relapsed and/or Refractory AML 
A significant number of patients receiving initial induction chemotherapy for AML 
either do not achieve remission or relapse after induction of remission. 
According to the venetoclax package insert, 58% of patients treated with 
venetoclax plus low-dose cytarabine (LDAC), 39% of patients treated with 
venetoclax plus azacytidine, and 38.3% of patients treated with venetoclax plus 
decitabine did not achieve CR or CRh. Although venetoclax, a BCL-2 inhibitor, 
is transforming the treatment landscape for AML and other hematologic 
malignancies, existing standard-of-care AML therapies do not adequately attain 
sufficiently high rates of CR, duration of CR, or satisfactory survival rates in the 
majority of AML patients who are unfit or considered elderly.  
1.2 Rationale 
Acute myeloid leukemia (AML) continues to be one of the highest unmet medical 
needs, due to very short survival from time of diagnosis (median <1 to 2 years). 
Shorter survival of AML patients is directly correlated with the presence of 
unfavorable cytogenetics and multiple adverse clinical features including 
advanced age and reduced performance status. Initial complete remission still 
remains elusive in approximately 40-60% of AML patients resulting in 
progression and shortened survival. The targeting of anti-apoptotic proteins, 
such as BCL-2 and MCL-1, in AML is thought to be a prime therapeutic strategy 
moving forward with novel and/or potent compounds [13]. 
Clinical trials with alvocidib (both as monotherapy and in combination with 
cytarabine/mitoxantrone) have shown promising activity to date. These trials 
have spanned the front-line setting for newly diagnosed high-risk population to 
the relapsed refractory setting. Recently presented at the American Society of 
Hematology (ASH) 2018 Annual Meeting were the Stage 1 results of the Zella 
201 trial demonstrating a 77% response (CR/CRi) in evaluable refractory AML 
patients receiving alvocidib/cytarabine/mitoxantrone combination therapy. The 
median MCL-1 dependence score (flow cytometry-based assay) was 53% in 
that patient population [14].  
Interestingly, there appears to be an opportunity to overcome MCL-1 dependent 
venetoclax resistance by inhibiting MCL-1 signaling with alvocidib. In vitro work 
has shown that AML cell lines can be re-sensitized to venetoclax, or other BCL-
2 inhibitors, by downregulating MCL-1 via alvocidib [15,16]. Mechanistically, 
leukemic stems cells are dependent on MCL-1 which may allow alvocidib to 
help deepen a response [17]. Clinically, it is thought that patients who have been 
treated with venetoclax will switch the dependency of apoptosis in leukemic 
blasts from BCL-2 to MCL-1. 


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2. DRUG INFORMATION – ALVOCIDIB 
A comprehensive review of alvocidib is contained in the Investigator’s 
Brochure provided by the Sponsor. This document should be reviewed 
prior to initiating the study. 
2.1 Background 
Alvocidib (formerly flavopiridol) was discovered and synthesized from an 
alkaloid isolated from the stems and leaves of Dysoxylum binectariferum (India). 
Dr. Edward Sausville and colleagues at the National Cancer Institute (NCI) first 
determined alvocidib cell cycle arrest/growth inhibition properties in 1992. 
2.2 Chemistry 
 
2.3 Drug Description 
Alvocidib hydrochloride is supplied as a sterile, intravenous, nonpyrogenic, 
yellow-colored aqueous solution. Each vial contains 50 mg of alvocidib base 
(10 mg/mL). Alvocidib is to be diluted with either 0.9% Sodium Chloride 
Injection, USP, or 5% Dextrose Injection, USP, prior to infusion, providing 
solutions between 0.09 to 1.0 mg/mL alvocidib. 


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2.4 Mechanism of Action 
Alvocidib is a potent cyclin-dependent kinase (CDK) inhibitor with selectivity for 
CDKs 9, 1, 2, 4 and 7 [18,19,20]. The greatest inhibition (Ki of 3 nM) was 
observed with CDK 9 [21]. Alvocidib-induced apoptosis results at least in part 
from inhibition of multiple serine-threonine CDKs leading to changes in gene 
expression of critical survival and proliferative genes including BCL-2, myeloid 
cell leukemia-1 (MCL-1) and c-myc [22,23,24]. Whereas inhibition of CDK 2 and 
CDK 4 contributes to cell cycle arrest in G1 and G2, alvocidib-triggered 
inactivation of the CDK 9/cyclin T complex (also known as PTEF-b) inhibits the 
activating phosphorylation of RNA polymerase 2 and diminishes mRNA 
synthesis [25,26]. Consequently, alvocidib-treated cells are unable to 
synthesize transcripts encoding polypeptides, such as cyclin D1 and c-myc, 
which are expressed in a cell cycle-dependent manner [27]. 
Inhibition of CDK 9, which is involved in the regulation of transcription by RNA 
polymerase 2, is postulated to be a key event in the inhibition of transcription 
observed following alvocidib treatment. Effects on CDK 9 may be particularly 
relevant to inducing apoptosis in malignant hematopoietic cells [28]. 
These observations, coupled with the ability of alvocidib to kill non-cycling cells, 
suggested that alvocidib might be particularly effective when administered first 
and then followed several days later by cytarabine. Therapeutically achievable 
alvocidib concentrations induced apoptotic cell death in bone marrow leukemic 
blasts in vitro and that alvocidib-treated blast cultures exhibited increased 
sensitivity to the subsequent pro-apoptotic effects of cytarabine relative to either 
agent alone [29]. 
2.5 Preclinical Studies 
2.5.1 
In Vitro/In Vivo Studies 
Alvocidib (2 to 430 nM) demonstrated cyclin-dependent kinase (CDK) selective 
inhibition when tested on a panel of recombinant kinases [18,19,20]. In 
particular, CDK 9 is involved in the regulation of transcription by phosphorylating 
ribonucleic acid polymerase II (RNA pol II) and is inhibited to the greatest extent 
(3 nM) [21]. Consistent with the CDK 9 inhibition, alvocidib (50 to 200 nM) 
significantly inhibited the uptake (up to 80%) of [3H]-uridine incorporation into 
total ribonucleic acid (RNA) compatible with inhibition of RNA transcription as a 
primary mechanism of action [30]. 
Alvocidib inhibited the proliferation of cell lines from a large panel of 
histologically distinct hematological and solid tumors at submicromolar 
concentrations ranging from 7 nM (PC3 human prostate) to 182 nM 
(K562 human chronic myelogenous leukemia). Alvocidib also induced dose 
dependent apoptosis in B-cell chronic lymphocytic leukemia (B-CLL) cells at 
drug concentrations ranging from 10 to 100 nM [31,32]. The induction of 
apoptosis correlated best with depletion of the antiapoptotic proteins myeloid 
cell leukemia-1 (MCL-1) and X-linked inhibitor of apoptosis (XIAP) [22,24]. 


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Chronic lymphocytic leukemia cells are nonproliferating and dependent on the 
continuous expression of antiapoptotic proteins. As a result, reduction of 
antiapoptotic proteins by alvocidib may in part account for the drug-induced 
apoptotic response. 
Significant antitumor activity was observed in 6 human leukemia xenograft 
models in mice (EOL-1 and ML-2 acute myeloid leukemia [AML], Ramos 
nonHodgkin’s lymphoma, SUDHL-4 follicular lymphoma, HL-60 promyelocytic 
leukemia, and L363 multiple myeloma). In the SUDHL-4 and HL-60 studies, 
optimal activity was observed with daily × 5 bolus intravenous (IV) or 
intraperitoneal administration of 7.5 mg/kg alvocidib that gave peak plasma 
OHYHOVRIȝ0IROORZHd by a progressive decline to approximately 100 nM in 
8 hours [33]. In contrast, continuous infusion of alvocidib for 3 days 
demonstrated only modest activity. This infusion resulted in plasma levels of 
approximately 420 nM; these levels exceeded the in vitro 50% inhibitory 
concentration (IC50), 20 to 200 nM, for most cell lines. This observation is 
consistent with the finding that alvocidib binds strongly to plasma proteins. 
These data also indicate that protein binding can be overcome with higher doses 
of alvocidib that achieve micromolar concentrations for short duration. 
Alvocidib has enhanced antitumor activity when combined with standard of care 
agents in nonclinical models of AML. Due to its MCL-1-targeting activity, cells 
treated with alvocidib are in a primed state to undergo apoptosis which can be 
further exploited when followed by an agent known to induce apoptosis. Indeed, 
nonclinical data in AML strongly suggest that cytarabine and mitoxantrone are 
highly synergistic when preceded by alvocidib treatment. These data support 
the clinical regimen combining alvocidib, cytarabine, and mitoxantrone (ACM) 
[34]. 
Another study was designed to model the ‘7+3’ clinical regimen in an animal 
model to determine if alvocidib could enhance the efficacy of cytarabine and 
daunorubicin in the MV-4-11 model for AML. Mice were given two ‘cycles’ of 
alvocidib, cytarabine, and daunorubicin (ACD), in which they were dosed for two 
days with alvocidib, one day with cytarabine and daunorubicin, followed by two 
additional days with cytarabine alone. Following these two treatment cycles, 
tumor volumes and body weights were observed until volumes neared 
1500 mm3. The ACD regimen modeled in this xenograft study demonstrated 
superior efficacy when compared to either cytarabine, daunorubicin, or the 
combination of the two drugs. The full drug combination (ACD) was tolerated 
well at the lower alvocidib dose level (1.25 mg/kg) and tolerated moderately at 
the higher dose level (2.5 mg/kg) with minor body weight loss observed. In the 
ACD regimen, alvocidib significantly enhanced tumor growth inhibition [35]. 
Alvocidib demonstrated only minor activity when evaluated in vivo in various 
solid tumor models. 














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2.6.2.1 Summary of Safety in NCI-3170 (J-0254) FLAM in Adults with Refractory or 
Relapsed Acute Leukemias (Phase 1)  
In the Phase 1 dose-escalating study [37], dose-limiting toxicity of alvocidib in 
bolus ACM occurred at 60 mg/m2/d with profound neutropenia >40 days 
duration, with the maximal tolerated dose (MTD) of 50 mg/m2/d. Mild TLS was 
observed in 9/34 (26%) of patients, with no relapsed or refractory AML patients 
requiring dialysis. Induction-related mortality was observed in 4/34 (12%) of 
patients; 2 with fungal sepsis and 2 cardiac-related deaths. Adverse events 
*UDGH  LQFOXGHG  GLDUUKHD  RUDO PXFRVLWLV DQG  JDVWURLQWHVWLQDO
mucositis and 6% neutropenic fever/infection (with 1 Grade 5 fungal infection). 
2.6.2.2 Summary of Safety in NCI-3170 (J-0254) FLAM Extension in Adults with 
Refractory or Relapsed Poor-risk Acute Leukemias (Phase 2)  
In the J0254 Phase 2 “Extension Study” [38], all-grade TLS was observed in 
15/47 (32%) of the relapsed/refractory AML patients, with one patient requiring 
dialysis, and all-grade TLS was noted in 9/15 (60%) patients with newly 
diagnosed secondary AML. Treatment-related induction mortality was observed 
in 3/62 (5%) of patients, due to fungal infection and multi-organ failure. Other 
$(V*UDGHLQFOXGHGDUUK\WKPLDDQGGHFUHDVHGOHIWYHQWULFXODUHMHFWLRQ
fraction, 2% GI mucositis, and 5% fungal infection/multi-organ failure. 
2.6.2.3 Summary of Safety in NCI-6947 (OSU-0479) Alvocidib Monotherapy in 
Relapsed/Refractory AML (Phase 1)  
Alvocidib was given as a hybrid regimen: 30-minute IV bolus followed by a 
4-hour continuous IV infusion, daily for 3 days. A second cycle of treatment was 
permitted, based on a 21-day cycle, depending on cytoreduction. Dosing began 
at 20 mg/m2 IV bolus and 30 mg/m2 continuous IV infusion (ie, ‘20/30’) with 
escalation by approximately 25% increments following a classic 3+3 phase I 
design schema to determine the MTD of the schedule. Clinical TLS occurred in 
a single AML patient (1/19, 5%) who required dialysis [39]. This patient was the 
only treatment-related death, due to a subsequent fungal infection. Among all 
19 AML patients and 5 ALL patients treated with monotherapy alvocidib, AEs 
Grade >3 included: 58% neutropenic fever/infection, 42% fatigue, 29% diarrhea, 
13% decreased ejection fraction, 4% hypotension at the 40/60 mg/m2 dose 
level, 4% prolonged QT at the 30/35 mg/m2 dose level, and 4% mucositis. 
2.6.2.4 Summary of Safety in NCI-7889 (J-06133) FLAM in Relapsed/Refractory 
AML (Phase 1)  
Clinical TLS was observed in 5/55 (9%), with 1 patient requiring dialysis [41]. 
Treatment-related mortality at 60 days was observed in 5/55 (9%) of patients, 
due to infeFWLRQDQGPXOWLRUJDQIDLOXUH$GYHUVHHYHQWV*UDGHLQFOXGHG
hyperbilirubinemia, 7% oral mucositis, 7% infection, 5% decreased ejection 
fraction or atrial fibrillation or pericarditis and 4% GI mucositis.   


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2.6.2.5 Summary of Safety in ECOG-1906 FLAM in Relapsed/Refractory AML 
(Phase 2)  
$GYHUVH HYHQWV *UDGH  LQFOXGHG  GLDUUKHD  IHEULOH QHXWURSHQLD
22% lung infection, 19% sepsis, 19% anorexia, 19% hyperglycemia and 15% 
hypotension [42]. 
During this study, the eligibility criteria were amended to lower the upper age 
limit from 70 to 65 years, as 6 treatment-related deaths occurred in the initial 
27 patients accrued to the ACM regimen. All of these patients died of septic 
shock or multiorgan failure and 5 of the 6 died within one month of the start of 
therapy. Most of these patients were over age 65 (53, 62, 67, 68, 69 and 
69 years).  
Among the 36 patients treated with ACM on Arm B, there were 10 Grade 5 
events within 30 days of the end of therapy. The vast majority of these deaths 
were attributed to infection and multiorgan failure except two, which were 
secondary to disease. 
2.7 Justification for Study Treatment Plan 
As stated earlier, existing standard-of-care AML therapies do not adequately 
attain sufficiently high rates of CR, duration of CR, or satisfactory survival rates 
in the majority of AML patients who are unfit or considered elderly. Venetoclax, 
is transforming the treatment landscape for AML and other hematologic 
malignancies. Unfortunately, most patients attain suboptimal benefit from 
venetoclax alone and the majority of patients will still require treatment in the 
relapse/refractory setting. Thus, the combination of BCL-2 inhibitors and DNA 
hypomethylating agents (HMA) was investigated. This study led to the approval 
of venetoclax in combination with HMAs or LDAC for the unfit AML population 
as new standard of care front-line therapy. The anti-apoptotic protein MCL-1 
has been cited as a possible mechanism of resistance for venetoclax and the 
ensuing failure to keep AML in remission [46].  
Alvocidib, a potent cyclin-dependent kinase (CDK) inhibitor, downregulates the 
expression of MCL-1 through inhibition of CDK 9. It is known that MCL-1 
expression is associated with chemotherapy resistance and seems to be 
acquired after exposure to prior chemotherapy [4].  
A 
large 
pool 
of 
data 
shows 
promising 
activity 
for 
alvocidib/cytarabine/mitoxantrone combination therapy. Furthermore, alvocidib 
monotherapy has shown acceptable safety in this patient population, but the 
monotherapy hasn’t been evaluated for efficacy. Given that MCL-1 expression 
is associated with chemotherapy resistance observed in this patient population 
[4] and alvocidib can downregulate MCL-1 expression through the inhibition of 
CDK 9, SDP Oncology is pursuing the development of alvocidib monotherapy 
or in combination with low-dose cytarabine in patients with AML who are 
refractory to, or progress following a short-lived response to treatment with 
venetoclax in combination therapy with azacytidine or decitabine. 


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In clinical trials, 67% of patients achieved CR/CRi following venetoclax in 
combination with HMA in the frontline setting of treatment-naïve AML [4]. 
Median duration of CR/CRi was 12.5 months. Therefore, patients are now 
achieving high CR/CRi rates with reasonable duration of response, but then 
ultimately do relapse. In this setting, post venetoclax combination therapy, there 
are poorly defined good therapeutic options. Given that MCL-1 expression and 
upregulation is associated with resistance to venetoclax, it is thought that CDK9 
inhibitors may offer a viable path of action for patients previously treated with 
venetoclax or venetoclax combinations with HMA or LDAC [4]. This trial will 
address the unmet need in patients who are refractory to or have relapsed after 
short-lived responses to venetoclax in combination with azacytidine or 
decitabine and meet the criteria for further treatment. 
2.8 Summary of Risk and Benefits 
There have been no clinical studies conducted using alvocidib post-venetoclax 
induction failure; however, the safety profile for alvocidib has been well-
described in several clinical studies in patients with AML and appears to be 
acceptable in patients with nonfavorable disease characteristics. The early 
observation of tumor lysis and the potential for renal failure has resulted in an 
aggressive prophylaxis approach to manage the possible dramatic lysis of 
leukemic blasts caused by alvocidib. This approach in the most recent studies 
in patients with AML has resulted in an overall incidence of any grade TLS <30% 
and of any grade TLS as a serious adverse event <5% with no deaths due to 
TLS on study or within 30 days of the last dose of study drug. Treatment-related 
mortality for patients treated with alvocidib/FLAM is approximately 8-10%, with 
a range up to 28% in Study 6 in relapsed/refractory AML patients. Overall, TRM 
of alvocidib/FLAM appears to be comparable to other therapeutic options 
including 7+3 and intermediate- and high-dose cytarabine.  
Alvocidib 
monotherapy 
(Study 3) 
showed 
acceptable 
safety 
in 
the 
relapsed/refractory AML setting with diarrhea being the dose-limiting toxicity. A 
single patient experienced hyperacute TLS requiring dialysis following alvocidib 
administration on Day 1, and subsequently died of fungal sepsis. Prophylaxis 
for TLS was not mandated in this study. Following this instance of hyperacute 
TLS, the protocol was amended to allow treatment with hydroxyurea up until the 
evening before alvocidib was administered (but not within 8 hours) for patients 
with highly proliferative disease.  
The study drugs are being administered in an outpatient setting with mandatory 
prophylaxis with IV fluids before and after alvocidib doses along with oral 
allopurinol and oral phosphate binders to mitigate the risk of TLS. In addition, 
patients will return to the clinic daily for the first three days (72 hours) to receive 
each dose of alvocidib, be monitored for hydration status and clinical symptoms, 
and have TLS labs drawn. The starting alvocidib dose in this study is 
approximately one quarter of the typical starting dose used in previous clinical 
studies with alvocidib and patients with high circulating peripheral blast counts 
(ie, >30,000) are excluded from participation in hopes of mitigating the 


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propensity for development of TLS. A lead-in cohort has been included in the 
study design to test the starting doses and provide guidance for de-escalation 
of the alvocidib doses should dose-limiting toxicities (DLTs) be observed at 
Dose Level 1. Symptoms indicative of TLS are usually observed during the first 
72 hours after hybrid alvocidib dosing (ie, IV bolus followed by continuous IV 
infusion); therefore, during Cycle 1, tumor lysis labs will be monitored prior to 
the alvocidib infusion and 2 hours (±30 minutes) after completion of the required 
IV hydration post alvocidib dosing. Labs will also be drawn daily for the first three 
days (72 hours) following the first alvocidib dose (ie, Days 2௅4) and at least 
weekly for the remainder of Cycle 1. During Cycles 2+, tumor lysis labs will be 
assessed prior to each dose of alvocidib. Prophylactic antibiotics, antivirals and 
antifungals are encouraged to stay abreast of potential infections and 
investigators are made aware of the need for testing for possible Clostridioides 
difficile infection in patients with diarrhea that continues despite optimal medical 
management. These aggressive measures, combined with a much lower 
starting dose, should balance the safety risk with the potential clinical benefit of 
alvocidib’s activity post-venetoclax induction failure.   
 
 


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3. STUDY OBJECTIVES 
Primary Objective 
x To estimate the rate of combined complete remission (CR + CR with 
incomplete hematological recovery [CRi]) in patients with AML whose 
disease is either refractory to initial induction therapy with venetoclax in 
combination with azacytidine or decitabine (ie, failed to achieve a CR/CRi or 
achieved a CR/CRi with duration <90 days) or who have relapsed 
(reoccurrence of disease following a CR/CRi duration 90 days). 
Secondary Objectives 
To evaluate the following: 
x Median Overall Survival (OS) = Time from treatment (Day 1) until death from 
any cause  
x CRMRD– = Percentage of patients achieving complete response (CR) whose 
bone marrow is determined to be negative for MRD using standardized 
techniques (ie, multiparametric flow cytometry [MPFC] and molecular testing 
including next generation sequencing [NGS]) 
x 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 
QHXWURSKLOFRXQW>$1&@/DQGSODWHOHWFRXQW/ 
x Composite CR rate = Combined percentage of patients achieving one of the 
following: 
o CR 
o CRi = Meets all CR criteria but with only full recovery of one peripheral 
blood cell type LH$1&/or SODWHOHWFRXQW/ 
o CRh = Meets all CR criteria but with only partial recovery of both 
SHULSKHUDO EORRG FHOO W\SHV LH $1& / and platelet count 
/ 
x Combined Response rate = Combined percentage of patients achieving one 
of the following: 
o CR 
o CRi 
o CRh 
o Morphologic leukemia-free state (MLFS) = Bone marrow blasts <5%; 
absence of blasts with Auer rods; absence of extramedullary disease; 
no hematologic recovery required 


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o Partial Response (PR) = Meets all hematologic values required for CR 
EXWZLWKDGHFUHDVHRIDWOHDVWLQWKHSHUFHQWDJHRIEODVWVWR
to LQERQHPDUURZ 
x Event-free Survival (EFS) = Time from first treatment (Day 1) until 
(a) treatment failure, (b) relapse after CR/CRi/CRh, or (c) death from any 
cause, whichever occurs first, censored at 2 years  
x Duration of Composite CR = Time from first documented response of CR, 
CRi, or CRh to relapse or death from any cause 
x Rates of 28- and 56-day Transfusion Independence (TI) = Percentages of 
patients who do not receive red blood cell (RBC) transfusions, platelet (PLT) 
transfusions, and neither RBC nor PLT transfusions for 28 and 56 days; 
comprised of 6 secondary endpoints: 
o 28-day RBC TI 
o 28-day PLT TI 
o 28-day TI (both RBC and PLT) 
o 56-day RBC TI 
o 56-day PLT TI 
o 56-day TI (both RBC and PLT) 
28- and 56-day TI will be summarized in 2×2 shift tables showing the 
percentages of patients who are transfusion independent at baseline 
according to review of medical charts versus the percentages of patients 
who achieve transfusion independence at any time during the study. Effort 
will be made to collect transfusion information for 56 days following 
withdrawal from the study to properly classify a patient’s post-treatment TI 
status. Patients not already classified as transfusion independent and who 
cannot be followed will be classified as ‘status unknown’ for the required 
time to establish TI.  
Exploratory Objective(s) 
x Additional exploratory analyses may be performed if useful in the 
interpretation of the data. 
x To evaluate potential biomarkers including but not limited to MCL-1 
dependence, genetic mutations, and other biomarkers associated with AML.   


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4. INVESTIGATIONAL PLAN 
4.1 Overall Study Design 
This is an open-label, randomized, two-stage, Phase 2 study to evaluate 
alvocidib in adult patients with AML who are either refractory to, or have 
relapsed following, initial induction therapy with venetoclax in combination with 
azacytidine or decitabine. A separate safety lead-in cohort comprised of 
approximately six patients (at least 3 patients in each treatment arm) will 
be treated prior to enrolling patients in Stage 1.  
During Stage 1, 26 patients will be randomized into each of the 2 treatment 
arms (52 patients total). The randomization schedule will be stratified by prior 
response to initial induction therapy with venetoclax in combination with 
azacytidine or decitabine (refractory [ie, failed to achieve a CR/CRi or achieved 
a CR/CRi with duration <90 days] or relapsed [reoccurrence of disease following 
a CR/CRi duration 90 days]). 
As an additional safety measure given the unique patient population and 
outpatient treatment administration, a lead-in cohort of approximately six 
patients (at least three patients in each treatment arm) will be enrolled, treated, 
and evaluated for dose-limiting toxicities (DLTs). If a DLT is observed, dose de-
escalation will occur as outlined in Appendix F. Should no additional DLTs be 
observed during Cycle 1, Amendment 2 be approved, and the Data Safety 
Monitoring Board (DSMB) has confirmed safety, randomization into Stage 1 
will commence as outlined in the protocol. However, should an additional DLT 
be observed at Dose Level 1, a clinical meeting would be scheduled to discuss 
the utility/futility of continuing the study as currently designed. 
If patients treated in the lead-in cohort are still on study when Amendment 
2 is approved and the DSMB has confirmed safety, they may be permitted 
to shift to the higher alvocidib dose regimen, ie, ALV 50 mg/m2 IV bolus, 
per investigator discretion. 
Determination of the recommended alvocidib-based treatment arm for Stage 2 
will be subjective, comparing the response rates, relative safety, and the risk-
benefit ratio of the two Stage 1 treatment arms. An additional 76 patients will 
be enrolled into the treatment arm selected for Stage 2 for a total of 
102 patients treated with the recommended alvocidib-based treatment 
regimen (26 and 76 from Stage 1 and Stage 2, respectively). 
Any patient who withdraws from the study for treatment related toxicity prior to 
being evaluated for response will be considered a nonresponder. Patients who 
drop out of the study for other reasons prior to being assessed for response will 
be considered non-evaluable and may be replaced.  


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4.2 Randomization Criteria 
This study follows a randomized, two-stage design. During Stage 1, patients will 
be randomized 1:1 to receive either ALDAC or ALV:  
x ALDAC – Alvocidib plus Low Dose Ara-C (cytarabine) 
x ALV – ALVocidib 
Randomization to treatment arm will be stratified by response to initial induction 
therapy with venetoclax in combination with azacytidine or decitabine: 
x Refractory: failed to achieve a CR/CRi or achieved a CR/CRi with 
duration <90 days 
x Relapsed: reoccurrence of disease following a CR/CRi with duration 
90 days 
The sponsor may elect to close enrollment in Stage 1 once the minimum 
response threshold has been met in Stage 1 (as defined in the Study Design), 
and the sponsor has sufficient information to select the recommended 
alvocidib-based treatment arm for Stage 2. The recommended alvocidib-based 
treatment will be determined subjectively by comparing the response rates, 
relative safety, and the risk-benefit ratio of the two Stage 1 treatment arms.  
4.3 Patient Population 
Patients enrolled in this study must have refractory or relapsed AML after initial 
induction therapy with venetoclax in combination with azacytidine or decitabine.  
4.3.1 
Number of Patients 
A sufficient number of patients will be screened in order to obtain up to 
128 eligible and evaluable patients for dosing.  
4.3.2 
Inclusion Criteria 
To be eligible for participation in the study, patients must meet all of the following 
inclusion criteria: 
1. %H years of age 
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 


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3. Are refractory (ie, failed to achieve a CR/CRi or achieved a CR/CRi with 
duration <90 days) or have relapsed (reoccurrence of disease following a 
CR/CRi duration 90 days) after initial induction therapy with venetoclax in 
combination with azacytidine or decitabine (with or without other 
investigational agents as part of a clinical trial; requires Medical Monitor 
review) 
4. Have an Eastern Cooperative Oncology Group (ECOG) performance status 
36 
5. Have a *)5 mL/min using the Cockcroft-Gault equation 
6. Have an alanine aminotransferase (ALT)/aspartate aminotransferase (AST) 
OHYHOWLPHVXSSHUOLPLWRIQRUPDO8/1 
7. +DYH D WRWDO ELOLUXELQ OHYHO  mg/dL (unless secondary to Gilbert 
syndrome, hemolysis, or leukemia) 
8. Be infertile 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 prior to study entry, for the duration of study 
participation, and for at least 3 months (males) and 6 months (females) after 
the last dose of study drug  
9. Be able to comply with the requirements of the entire study 
10. 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.) 
4.3.3 
Exclusion Criteria 
Patients meeting any one of these exclusion criteria will be prohibited from 
participating in this study. 
1. Received any previous treatment with alvocidib or any other CDK inhibitor 
or received prior anti-leukemic therapy other than first-line venetoclax in 
combination with azacytidine or decitabine 
2. 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 
3. Received an allogeneic stem cell transplant within 60 days of treatment. 
Subjects who received an allogeneic stem cell transplant must be off all 
immunosuppressants at the time of study treatment 
4. Receiving systemic therapy for graft-versus-host disease 


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5. Have a peripheral blast count of >30,000/mm3 (may use hydroxyurea as in 
#2 above) 
6. Received antileukemic therapy within the last 2 weeks or 3-5 half lives of 
the prior therapy (with the exception of hydroxyurea or if the patient has 
definite refractory disease), whichever is less. Refractory patients who 
received therapy within the last 2 weeks may be eligible with prior approval 
of the Medical Monitor. 
7. Diagnosed with acute promyelocytic leukemia (APL-M3) 
8. Have active central nervous system (CNS) leukemia 
9. Have evidence of uncontrolled disseminated intravascular coagulation 
10. Have an active, uncontrolled infection 
11. Have other life-threatening illness 
12. Have other active malignancies requiring treatment or diagnosed with other 
malignancies within the last 6 months, except nonmelanoma skin cancer or 
cervical intraepithelial neoplasia 
13. Have mental deficits and/or psychiatric history that may compromise the 
ability to give written informed consent or to comply with the study protocol 
14. Are pregnant and/or nursing 
15. Have received any live vaccine within 14 days prior to first study drug 
administration 
4.4 Study Treatments 
4.4.1 
Calculation of Dose 
The patient’s weight will be taken at the beginning of each new treatment cycle 
to determine whether a > 10% change in body weight occurred.  The dose of 
ALV or LDAC will remain the same as Cycle 1 for all subsequent treatments 
unless there has been a > 10% change in body weight.  If there has been a 
> 10% change in body weight, the BSA should be recalculated and the dose 
adjusted accordingly. 
4.4.2 
Study Drug Administration 
Lead-in Cohort, Two Arms (at least 3 patients per arm) 
As an additional safety measure given the unique patient population and novel 
outpatient treatment administration, a lead-in cohort of approximately six 
patients (at least three patients in each treatment arm) will be enrolled, treated, 
and evaluated for DLTs. If a DLT is observed, dose de-escalation will occur as 


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outlined in Appendix F. Should no additional DLTs be observed during Cycle 1, 
Amendment 2 has been approved, and the DSMB has confirmed safety, 
randomization into Stage 1 will commence as outlined in the protocol. 
However, should an additional DLT be observed at Dose Level 1, a clinical 
meeting would be scheduled to discuss the utility/futility of continuing the study 
as currently designed. 
If patients treated in the lead-in cohort are still on study when Amendment 
2 is approved and the DSMB has confirmed safety, they may be permitted 
to shift to the higher alvocidib dose regimen, ie, ALV 50 mg/m2 IV bolus, 
per investigator discretion. 
Stage 1 Randomized, Two Arms (26 patients per Arm) 
Stage 1 of the study is comprised of two arms with study drug administration 
schedules as follows:  
x ARM 1: Alvocidib plus low-dose cytarabine (ALDAC); treatment will 
be given every 28 days 
o Cycle 1 Day 1: alvocidib 25 mg/m2 as a 30-60 minute 
intravenous (IV) bolus  
Cycles 2+ Day 1: alvocidib 50 mg/m2 as a 30-60 minute IV 
bolus  
o Day 2: no treatment 
o Days 3 through 12 (10 days): LDAC, 20 mg/m2 by subcutaneous 
(SC) injection  
o Day 15: alvocidib 50 mg/m2 as a 30-60 minute IV bolus 
x ARM 2: Alvocidib (ALV);  treatment will be given every 28 days 
o Cycle 1 Day 1: alvocidib 25 mg/m2 as a 30-60 minute IV bolus  
Cycles 2+ Day 1: alvocidib 50 mg/m2 as a 30-60 minute IV 
bolus  
o Days 8 and 15: alvocidib 50 mg/m2 as a 30-60 minute IV bolus  
The treatment schema is outlined in Figure 1. 
Stage 2, Single Arm (76 patients) 
Regimen to be selected based on Stage 1 performance. 
Additional Cycles of Treatment in Stage 1 and Stage 2 
Patients who achieve CR, CRi, CRh, MLFS, PR, or clinical benefit after the first 
cycle (completion of all doses) may receive additional optional cycles of 
treatment until disease progression (in the event of toxicities see the 
recommendations in Table 3, if applicable).  


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Those who achieve a CR, CRi, CRh, or MLFS (i.e. <5% blasts in bone marrow) 
should not be given subsequent cycles until ANC >0.5 and platelets >50. If 
treatment is delayed >2 weeks for cytopenias, a bone marrow biopsy should be 
performed to reassess disease status. 
Patients not demonstrating evidence of CR, CRi, MLFS, PR, or clinical benefit 
after 4 cycles of treatment will be considered for removal from the study, 
although with permission of the Medical Monitor, treatment may continue if 
clinically indicated (in the event of toxicities see the recommendations in 
Table 3, if applicable). 






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syndrome. Due to an increased likelihood of TLS, hospitalization of 
patients with monocytic differentiation and/or a peripheral blast count of 
>10,000/mm3 is strongly recommended for the first dose of alvocidib (ie, 
Cycle 1 / Day 1). 
x Mandatory IV hydration with 0.45% NaCl (or similar hydration fluid per 
institutional standard) sterile solution at 250-500 cc for 1-2 hours prior to 
alvocidib, then an additional 250-500 cc for 1-2 hours after alvocidib 
during Cycle 1 (optional for subsequent cycles for patients who have 
achieved a CR).  
x Replacement of excessive fluid losses, including from diarrhea, should 
be done unless otherwise clinically indicated. 
o Alvocidib is known to induce mild diarrhea during treatment days. 
Over-the-counter measures are typically effective in this setting if 
initiated early. Persistent diarrhea despite optimal outpatient 
management would trigger medical consultation. Early consideration 
should be given for possible Clostridioides difficile (C. difficile) 
infection in this patient population and identifying/treating as 
expeditiously as possible should be top of mind (see Section 4.5.1.2). 
x Mandatory oral allopurinol to be started at least 72 hours prior to Day 1 
of Cycle 1 and continued until completion of the first cycle (ie, 28 days). 
This may be discontinued for subsequent treatment cycles if uric acid 
levels are within normal limits and there is no evidence of TLS. 
x Mandatory oral phosphate binder to be started at the same time as 
initiation of IV hydration on Day 1 of Cycle 1 and continued for the first 
week (ie, 7 days).  
o If serum phosphorus levels are <3 after the first treatment with 
alvocidib and there is no evidence of TLS, phosphate binders may be 
discontinued. Patients should continue to be monitored for TLS as 
outlined for subsequent treatment cycles. Caution is warranted for 
patients who still have a high blast count as they remain at risk for 
TLS with subsequent treatments.  
x Evaluation of laboratory indicators of TLS during initial therapy (may be 
adjusted for subsequent cycles based on extent of tumor burden): 
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 During Cycle 1, monitor tumor lysis labs prior to alvocidib infusion 
and 2 hours (±30 minutes) after completion of IV hydration post 
alvocidib. Labs will also be drawn daily for the first three days 


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following the first alvocidib dose (ie, Days 2-4) and at least weekly 
for the remainder of Cycle 1.  
o During Cycles 2+, tumor lysis labs will be assessed prior to each 
dose of alvocidib 
Risk of TLS and Guidelines for Management  
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 with the hybrid dosing regimen of alvocidib. 
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 the hybrid dosing 
regimen of alvocidib. These measures resulted in a lower incidence of TLS 
without adverse outcomes.  
For this reason, Investigators 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 (1 ampule) of IV dextrose 50%, unless 
there are other likely causes of hyperkalemia other than TLS or 
contraindication to its use. Investigators are strongly encouraged to 
consider patient hospitalization for inpatient monitoring and follow up.  
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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4.5.1.2 Diarrhea 
Alvocidib is known to induce mild diarrhea during the days of treatment. Over-
the-counter measures are typically effective in this setting if initiated early. At 
the first signs of diarrhea, patients should initiate loperamide (or equivalent) 
2 mg by mouth every 2 hours during the waking hours (not to exceed 
16 mg/day). 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 for 4 times daily may be added. If 
diarrhea is not controlled with the above prophylactic regimen and is Grade 2 or 
greater, patients should contact the clinic and study drug treatment should be 
held until diarrhea has resolved. Should diarrhea persist beyond Cycle 1, 
patients should undergo testing for C. difficile. Should testing indicate the 
presence of C. difficile, appropriate antibiotics targeting this infection should be 
initiated. Should testing exclude the presence of C. difficile, diarrhea prophylaxis 
similar to Cycle 1 should be continued in subsequent cycles. Replacement of 
excessive fluid losses should be done unless otherwise clinically indicated. 
4.5.1.3 Nausea/Vomiting 
Antiemetics (ie, 5-hydroxytryptamine [5-HT3] receptor inhibitor or other 
antiemetic medications) are permitted according to standard practices at each 
investigational site.  
4.5.1.4 Infection Prevention 
Prophylactic antibiotics including levofloxacin (or equivalent) 500 mg orally once 
daily and azole antifungals (ie, fluconazole, posaconazole, voriconazole, 
isavuconazole) should be administered to patients in all treatment arms if ANC 
<500/L. These can be discontinued when the ANC 500/L per institutional 
standards and physician discretion. Valacyclovir (or equivalent) to be 
administered once daily (QD) or twice daily (BID) to all patients throughout the 
study based on institutional standard unless there are contraindications. Other 
similar antiviral agents may be administered per institutional standards 
with dosing according to each medication’s full prescribing information. 
Donor lymphocyte infusions are not allowed at any time during the study.  
4.5.2 
Management of Hematologic Toxicities 
Adverse events that are moderate to severe in intensity (see 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. 


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Adverse events may be treated with concomitant medications, as deemed 
clinically indicated by the Principal Investigator. All concomitant medications 
must be recorded on the appropriate CRF.  
4.6 Concomitant Medications and Therapies 
4.6.1 
Previous Therapies 
During Screening, patients will be asked about 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.   
Patients will not be enrolled into the study if they received any previous 
treatment with alvocidib or any other CDK inhibitor or receive other antileukemic 
therapy within the past 2 weeks or 3-5 half lives of the prior therapy, 
whichever is less. 
4.6.2 
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 2 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.   


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4.6.2.1 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. After the first dose, hydroxyurea may continue to 
be used per investigator discretion. 
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. 
Investigators are permitted to administer IT chemotherapy per institutional 
protocols. The administration of prophylactic dose of IT chemotherapy during a 
diagnostic LP is permitted once only.   
Routine growth factor support is not allowed. Granulocyte colony-
stimulating factor (G-CSF) may be administered for Grade 4 neutropenia 
(with or without fever or infection) if the event occurs after the patient has 
achieved remission of at least 7 days’ duration (Table 3) and following 
consultation with the Medical Monitor. Once the toxicity has resolved to a 
clinically acceptable situation, study treatment should resume at the same 
dose and schedule. No dose reductions are permitted after completion of 
the lead-in safety cohort. 
Medications and procedures that are mandatory or permitted during the study 
are listed in Section 4.6. 
4.6.2.2 Prohibited Therapies 
The following medications are excluded from concomitant use:  
x Antileukemic 
therapy 
(chemotherapy, 
radiation 
therapy, 
immunotherapy) within the last 2 weeks or 3-5 half lives of the prior 
therapy, whichever is less, prior to the first study drug 
administration and during the cycle of study treatment. 


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4.6.3 
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 prior to study entry, for the 
duration of study participation, and for at least 3 months (males) and 6 months 
(females) after the last dose of study drug. The following are considered 
effective contraceptives: (1) oral contraceptive pill; (2) condom plus spermicide; 
(3) diaphragm plus spermicide; (4) abstinence; (5) patient or partner surgically 
sterile; (6) patient or partner more than 2 years post-menopausal; or 
(7) injectable or implantable agent/device. 
4.7 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 Principal Investigator). In the event of a 
significant deviation from the protocol due to an emergency, accident or error, 
the Principal Investigator 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 Principal Investigator and the Sponsor. 
4.8 Other Precautions 
Based on observed nonhematologic and hematologic toxicities and laboratory 
abnormalities, dose adjustments for patients enrolled only in the lead-in 
cohort will be made according to the dose de-escalation plan outlined in 
Appendix F.  


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5. ON-STUDY CLINICAL AND LABORATORY EVALUATIONS 
See Appendix A - Schedule of Activities.  
5.1 Screening 
5.1.1 
Within 2 Weeks Prior to First Dose of Alvocidib 
x Obtain written informed consent 
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 Collect information about any transfusions that have occurred within 
56 days prior to Cycle 1 Day 1 
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, and respiratory rate) 
x Collect bone marrow and peripheral blood  
o Collect bone marrow and peripheral blood samples for 
confirmation of diagnosis, cytogenetic profiling, and PD tests 
(Section 7.3).  
o Collect bone marrow sample to be sent to a central laboratory for 
MRD assessment using standardized techniques (ie, MPFC and 
molecular testing including NGS) (Appendix D) 
o If patient is enrolled, 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 Laboratory Manual.  
x Perform 12-lead electrocardiogram (ECG) 
x Record all concomitant medications including all prescription drugs, 
nonprescription drugs, and nutritional supplements taken within the past 
2 weeks  
x Collect urine or serum sample for beta-human chorionic gonadotropin 
ȕ-hCG) pregnancy test for females of childbearing potential  


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x Collect blood for evaluation of laboratory parameters (Appendix D): 
o Hematology: complete blood count (CBC) with differential and 
platelet count 
o Full serum chemistry panel. 
x Perform lumber puncture (LP) in patients with suspected CNS 
involvement 
5.1.2 
Within 72 Hours Prior to First Dose of Alvocidib 
Perform the following activities and evaluations within 72 hours prior to 
administration of the first dose of alvocidib: 
x Record all concomitant medications including all prescription drugs, 
nonprescription drugs, and nutritional supplements 
x &ROOHFWXULQHRUVHUXPVDPSOHIRUȕ-hCG pregnancy test for females of 
childbearing potential 
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 Review all Inclusion/Exclusion criteria and determine if patient has met 
all eligibility criteria for inclusion into the study 
x Start administration of allopurinol orally daily at least 72 hours prior to 
study treatment.  
x Provide patient with study diary and instruct them on daily completion. 
Remind patient to bring diary back at every clinic visit.  
5.2 Cycle 1  
5.2.1 
Cycle 1: At Least 2 Hours Prior to First Dose 
Perform the following procedures at least 2 hours prior to starting therapy on 
Day 1 (unless otherwise stated): 
x Abbreviated physical examination including weight (kg) for calculation of 
body surface area (BSA)  
x Assess ECOG PS (Appendix B)  
x Record all concomitant medications including all prescription drugs, 
nonprescription drugs, and nutritional supplements taken since 
screening  


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x Initiate supportive care measures 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 4.5.1.1)  
o Replacement of excessive fluid losses, including from diarrhea, 
should 
be 
done 
unless 
otherwise 
clinically 
indicated 
(Section 4.5.1.2 and Section 4.5.1.3) 
5.2.2 
Cycle 1: Day 1 Just Prior to First Dose 
Perform the following procedures just prior to dosing on Day 1: 
x Record vital signs measured 15-30 minutes prior to the initiation of 
infusion following a 5-minute rest 
x Collect blood for baseline laboratory parameters (Appendix D): Results 
are not required to be reviewed prior to treatment. 
o Tumor lysis labs: sodium, potassium, chloride, carbon dioxide, 
creatinine, calcium, lactate dehydrogenase (LDH), uric acid, and 
phosphorus  
o Coagulation labs: 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. Results must be reviewed prior to treatment. 
5.2.3 
Cycle 1: Dosing Days: Arm 1: Days 1, 3–12, 15; Arm 2: Days 1, 8, 15 
A ±2-day window will be allowed for Day 15 of both treatment arms. A ±1-day 
window will be allowed for Day 8 (Arm 2 only). 
x Abbreviated physical examination (Arm 1: Days 8 and 15; Arm 2: Days 8 
and 15)  
x Assess ECOG PS (Arm 1: Days 8 and 15; Arm 2: Days 8 and 15) 
(Appendix B)  
x Record vital signs on Days 1, 8, and 15 of both arms 
x Record only those medications (prescription, nonprescription, nutritional 
supplements) administered in conjunction with an AE 
x Assess patient for adequate hydration at all study visits and replace 
excessive fluid losses, including from diarrhea, unless otherwise clinically 
indicated (Section 4.5.1.2 and Section 4.5.1.3) 
x 
Collect blood for evaluation of laboratory parameters (Appendix D): 
hematology and full serum chemistry panel on each day of alvocidib 
administration and twice weekly (minimum of 72 hours between 
collections) during LDAC treatment (ie, Days 3-12 of Arm 1) 
x Monitor tumor lysis labs according to Section 4.5.1.1  


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x Monitor fibrinogen levels as clinically indicated 
x Administer prophylactic antibiotics, antivirals, and antifungals according 
to Section 4.5.1.4 
x Assess for AEs 
x Administer alvocidib and/or cytarabine according to Section 4.4.2 
x Review study diary and remind patient to bring diary back at next clinic 
visit 
Stage 2 dosing regimen will be selected based on results from Stage 1 arms 
in terms of response rates, relative safety, and risk-benefit ratio. 
5.2.4 
Cycle 1: Days 2௅ 
Tumor lysis labs will be drawn daily for the first three days (72 hours) following 
the first alvocidib dose (ie, Days 2௅4). 
5.2.5 
Cycle 1: Day 22 (±3 days)  
In the event that there is a delay in starting the next cycle, the below procedures 
should be done weekly (approximately every 7 days, or more frequently if 
clinically indicated) and recorded as unscheduled visit: 
x Abbreviated physical examination (AE- or symptom-directed exam) 
x Assess ECOG PS (Appendix B) 
x Vital signs (temperature, heart rate, systolic and diastolic blood 
pressures, and respiratory rate) 
x Record only those medications (prescription, nonprescription, nutritional 
supplements) administered in conjunction with an AE 
x Collect blood for evaluation of laboratory parameters (Appendix D): 
o Hematology 
o Tumor lysis labs to be drawn at least weekly for the remainder of 
Cycle 1 
o Fibrinogen level (as clinically indicated) 
x Assess for AEs 
x Review study diary and remind patient to bring diary back at next clinic 
visit 
5.2.6 
Cycle 1: Day 28 (±3 days) 
x Collect bone marrow and peripheral blood for response assessment and 
PD tests (Section 7.3). Collect bone marrow sample to be sent to a 
central laboratory for MRD assessment using standardized techniques 
(ie, MPFC and molecular testing including NGS) (Appendix D). If the 


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procedure is nonproductive or not diagnostic, it must be repeated within 
7-10 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 Laboratory Manual. 
x 
Record only those medications (prescription, nonprescription, nutritional 
supplements) administered in conjunction with an AE  
x 
Assess for AEs 
x 
Review study diary and remind patient to bring diary back at next clinic 
visit 
5.3 Cycles 2+ 
Patients who achieve CR, CRi, CRh, MLFS, PR, or clinical benefit after the first 
cycle (completion of all doses) may receive additional optional cycles of 
treatment until disease progression (in the event of toxicities see the 
recommendations in Table 3, if applicable).  
Those who achieve a CR, CRi, CRh, or MLFS (ie, <5% blasts in bone marrow) 
should not be given subsequent cycles until ANC >0.5 and platelets >50. If 
treatment is delayed >2 weeks for cytopenias, a bone marrow biopsy should be 
performed to reassess disease status. 
Patients not demonstrating evidence of CR, CRi, CRh, MLFS, PR, or clinical 
benefit after 4 cycles of treatment will be considered for removal from the study, 
although with permission of the Medical Monitor, treatment may continue if 
clinically indicated (in the event of toxicities see the recommendations in 
Table 3, if applicable). 
There is a maximum limit of 6 weeks between the start of cycles unless 
otherwise discussed with the medical monitor. 
5.3.1 
Cycles 2+: At Least 2 Hours Prior to First Dose (±3 days) 
During Cycles 2+, pretreatment IV hydration, oral allopurinol, and oral 
phosphate binder may be discontinued if serum uric acid and phosphorus levels 
are within normal limits and there is no evidence of TLS.  
Should TLS be suspected during subsequent cycles, perform the following 
procedures at least 2 hours prior to starting therapy on Day 1 (unless otherwise 
stated): 
x Initiate supportive care measures prior to first dose in all patients to 
minimize the likelihood of TLS: 
o Administer pretreatment IV hydration and determine if oral 
allopurinol and oral phosphate binder are still clinically indicated 
(see Section 4.5.1) 


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o Assess patient for adequate hydration at all study visits and 
replace excessive fluid losses, including from diarrhea, unless 
otherwise clinically indicated (Section 4.5.1.2 and Section 4.5.1.3) 
x Review study diary and remind patient to bring diary back at next clinic 
visit 
5.3.2 
Cycles 2+: Day 1 Just Prior to First Dose 
Perform the following procedures just prior to dosing on Day 1: 
x Perform a complete physical examination including height (cm) and 
weight (kg) for calculation of body surface area (BSA) (Note: Dose is only 
adjusted at the beginning of each cycle after Cycle 1 if there has been a 
> 10% change in weight compared to the weight used to calculate the 
current dose.) 
x Record vital signs measured 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 Full serum chemistry panel 
o Coagulation: fibrinogen level as clinically indicated 
x &ROOHFWXULQHRUVHUXPVDPSOHIRUȕ-hCG pregnancy test for females of 
child-bearing potential 
x Record all concomitant medications, including all prescription drugs, 
nonprescription drugs, and nutritional supplements, administered in 
conjunction with an AE.  
x Record all transfusions (PRBC and platelets) that have occurred while 
on study. 
x Review study diary and remind patient to bring diary back at next clinic 
visit 
5.3.3 
Cycles 2+: Dosing Days:  Arm 1: Days 1, 3–12, 15; Arm 2: Days 1, 8, 15 
A ±2-day window will be allowed for Day 15 of both treatment arms. A ±1-day 
window will be allowed for Day 8 (Arm 2 only). 
x Abbreviated physical examination (Arm 1: Day 15; Arm 2: Days 8 and 
15)  
x Assess ECOG PS (Arm 1: Day 15; Arm 2: Days 8 and 15) (Appendix B)  
x Record vital signs on Days 1, 8, and 15 in both arms 


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x Assess patients for adequate hydration at all study visits and replace 
excessive fluid losses, including from diarrhea, unless otherwise clinically 
indicated (Section 4.5.1.2 and Section 4.5.1.3) 
x Collect blood for evaluation of laboratory parameters (Appendix D):  
o Hematology and full serum chemistry panel on each day of 
alvocidib administration (Arm 2) and twice weekly (minimum of 
72 hours between collections) during LDAC treatment (ie, 
Days 3-12 of Arm 1) 
o Tumor lysis labs as indicated in Section 4.5.1.1 
o Coagulation: fibrinogen level as clinically indicated 
x Record all concomitant medications, including all prescription drugs, 
nonprescription drugs, and nutritional supplements, administered in 
conjunction with an AE 
x Administer prophylactic antibiotics and antivirals, and antifungals 
according to Section 4.5.1.4 
x Assess for AEs 
x Administer alvocidib or cytarabine according to Section 4.4.2  
x Review study diary and remind patient to bring diary back at next clinic 
visit 
Stage 2 dosing regimen will be selected based on results from Stage 1 arms in 
terms of response rates, relative safety, and risk-benefit ratio. 
5.3.4 
Cycles 2+: Day 22 (±3 days) 
In the event that there is a delay in starting the next cycle, the below procedures 
should be done weekly (approximately every 7 days, or more frequently if 
clinically indicated) and recorded as unscheduled visit: 
x Vital signs (temperature, heart rate, systolic and diastolic blood 
pressures, and respiratory rate) 
x Collect blood for evaluation of laboratory parameters (Appendix D): 
o Hematology 
o Tumor lysis labs 
o Fibrinogen level (as clinically indicated) 
x Record only those medications (prescription, nonprescription, nutritional 
supplements) administered in conjunction with an AE 
x Assess for AEs. 
x Review study diary and remind patient to bring diary back at next clinic 
visit 


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5.3.5 
Cycles 2+: Day 28 (±3 days) 
x Collect bone marrow (even-numbered cycles only) and peripheral blood 
for response assessment, PD tests (Section 7.3), and treatment 
guidance.  
x Collect bone marrow sample to be sent to a central laboratory for MRD 
assessment using standardized techniques (ie, MPFC and molecular 
testing including NGS) (even-numbered cycles only) (Appendix D) 
x Additionally, patients who experience cytopenias lasting for 42 days from 
prior cycles or suspected of relapse or disease progression will have 
bone marrow collected on Day 28 [±3 days]. If the bone marrow 
procedure is nonproductive or not diagnostic, it must be repeated within 
7-10 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 are provided in the Laboratory Manual.  
x 
Record only those medications (prescription, nonprescription, nutritional 
supplements) administered in conjunction with an AE 
x 
Assess for AEs  
x Review study diary and remind patient to bring diary back at next clinic 
visit 
5.4 End of Treatment Assessments 
If, at any time, a patient discontinues study treatment, a visit should be 
scheduled as soon as possible and within 14 days of the last dose of study drug 
or within 14 days of the decision to discontinue study treatment. If the decision 
to withdraw the patient occurs at a regularly scheduled visit, that visit may 
become the End of Treatment visit rather than having the patient return for an 
additional visit. 
x Abbreviated physical examination (AE- or symptom-directed exam) 
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 12-lead ECG only if clinically indicated 
x Collect blood for evaluation of laboratory studies (Appendix D): 
o Hematology 
o Full serum chemistry panel 


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o Fibrinogen level (only required if clinically indicated) 
x Record only those medications (prescription, nonprescription, nutritional 
supplements) administered in conjunction with an AE 
x Urinalysis 
x Collect bone marrow and peripheral blood samples (if not done within 
the previous 30 days): 
o Collect bone marrow and peripheral blood for response 
assessment, PD tests (Section 7.3), and treatment guidance. 
o Collect bone marrow sample to be sent to a central laboratory for 
MRD assessment using standardized techniques (ie, MPFC and 
molecular testing including NGS) (Appendix D)  
o If the bone marrow procedure is nonproductive or not diagnostic, 
it must be repeated within 7-10 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 Laboratory Manual.   
x Assess for AEs 
x Collect study diary 
5.5 Follow-up Assessments 
Patients will be contacted by telephone to record data on PBRC and/or platelet 
transfusions occurring within 56 days after the last dose of study drug. Patients 
will also be contacted by telephone to assess for date of death, date of stem cell 
transplant, date of relapse, or continued remission for 2 years:  
x Year 1: Phone calls monthly (±5 days) beginning the month after the 
patient completes the end-of-study assessments to 12 months after End 
of Treatment visit regardless of how many cycles a patient receives 
(Year 1=Day of First Treatment plus 12 months).  
x Year 2: Phone calls every other month (±5 days) during Year 2 
(Months 14 to 24 after End of Treatment visit). 


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6. OFF-STUDY CRITERIA 
6.1 Withdrawal of Patients from Study Treatment 
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 
Treatment 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 Principal Investigator and Sponsor. 
6.2 Reasons for Withdrawal from Study Treatment 
A patient may be permanently removed from study treatment for any of the 
following reasons: 
x Failure to achieve a CR, CRi, CRh, PR, or clinical benefit. Patients not 
demonstrating evidence of CR, CRi, CRh, PR, or clinical benefit after the 
first cycle of treatment will be considered for removal from the study, 
although with permission of the Medical Monitor, treatment may continue 
if clinically indicated and provided there is no evidence of *rade 3 
toxicity considered at least possibly related to alvocidib.  
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 Principal Investigator, 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, Principal Investigator, the Sponsor, or 
regulatory authority;  
x Patient is lost to follow-up;  
x Patient becomes pregnant while on study;  
x Patient begins another treatment for their disease; or 
x Patient death. 


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6.3 Follow-up for Patients Withdrawn from Study Treatment 
Patients withdrawn from study treatment with an ongoing adverse event must 
be followed clinically until the event is resolved, deemed stable or permanent 
by the PI, or the patient starts another 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 Section 8.4 through Section 8.8 for reporting of 
adverse events. The pregnancy of any patient, or patient’s partner, will be 
followed via monthly telephone calls until the birth of the child to term to record 
any birth defects/abnormalities. 


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7. CRITERIA FOR EVALUATION AND ENDPOINT DEFINITIONS 
7.1 Safety Endpoints 
Safety and tolerability of the regimen will be assessed by analyzing the 
incidence rates of treatment-emergent adverse events summarized 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).  
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 following last treatment will also be 
calculated. Adverse events will be graded according to National Cancer 
Institute’s Common Terminology Criteria for Adverse Events (NCI CTCAE), 
version 5.0. 
A Data Safety Monitoring Board (DSMB) will monitor key outcomes from the 
study. 
7.2 Efficacy Endpoints 
Primary Endpoint 
x Combined Complete Remission Rate = CR + CRi as defined by the 
International Working Group Criteria and 2017 European LeukemiaNet 
Secondary Endpoints 
x Median Overall Survival (OS) = Time from treatment (Day 1) until death 
from any cause  
x CRMRD– = Percentage of patients achieving complete response (CR) 
whose bone marrow is determined to be negative for MRD using 
standardized techniques (ie, MPFC and molecular testing including 
NGS)  
x 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 
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x Composite CR rate = Combined percentage of patients achieving one of 
the following: 
o CR 
o CRi = Meets all CR criteria but with only full recovery of one 
SHULSKHUDO EORRG FHOO W\SH LH $1& / or platelet count 
/ 
o CRh = Meets all CR criteria but with only partial recovery of both 
SHULSKHUDO EORRG FHOO W\SHV LH $1& / and platelet count 
/ 
x Combined Response rate = Combined percentage of patients achieving 
one of the following: 
o CR 
o CRi 
o CRh 
o Morphologic leukemia-free state (MLFS) = Bone marrow blasts <5%; 
absence of blasts with Auer rods; absence of extramedullary 
disease; no hematologic recovery required 
o Partial Response (PR) = Meets all hematologic values required for 
CR but with a decrease of at least 50% in the percentage of blasts 
WRWRLQERQHPDUURZ 
x Event-free Survival (EFS) = Time from first treatment (Day 1) until 
(a) treatment failure, (b) relapse after CR/CRi/CRh, or (c) death from any 
cause, whichever occurs first, censored at 2 years  
x Duration of Composite CR = Time from first documented response of CR, 
CRi, or CRh to relapse or death from any cause 
x Rates of 28- and 56-day Transfusion Independence (TI) = Percentages 
of patients who do not receive red blood cell (RBC) transfusions, platelet 
(PLT) transfusions, and neither RBC nor PLT transfusions for 28 and 
56 days; comprised of 6 secondary endpoints: 
o 28-day RBC TI 
o 28-day PLT TI 
o 28-day TI (both RBC and PLT) 
o 56-day RBC TI 
o 56-day PLT TI 
o 56-day TI (both RBC and PLT) 
28- and 56-day TI will be summarized in 2×2 shift tables showing the 
percentages of patients who are transfusion independent at baseline 
according to review of medical charts versus the percentages of patients 
who achieve transfusion independence at any time during the study. 


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Effort will be made to collect transfusion information for 56 days following 
withdrawal from the study to properly classify a patient’s post-treatment 
TI status. Patients not already classified as transfusion independent and 
who cannot be followed will be classified as ‘status unknown’ for the 
required time to establish TI.  
Exploratory Endpoints 
x To evaluate potential biomarkers including but not limited to MCL-1 
dependence, genetic mutations, and other biomarkers associated with 
AML.  
x Additional exploratory analyses may be performed if useful in the 
interpretation of the data. 
7.3 Pharmacodynamic Endpoints 
Pharmacodynamic endpoints include:  
x BH3 profiling, including determination of MCL-1 dependence, at Baseline 
and End of Treatment using bone marrow.  
x Minimal residual disease (MRD) to be determined by central CLIA 
accredited laboratory evaluation of bone marrow samples collected at 
baseline and at time of response assessments using standardized 
techniques (ie, MPFC and molecular testing including NGS).  
x Peripheral blood and bone marrow samples will be collected at protocol-
specific time points to evaluate other potential biomarkers including but 
not limited to MCL-1 dependence. These assessments may be explored 
in the context of AML or related conditions or drugs of similar class. 


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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 5.0 (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. 
GRADE 1 – Mild: 
Transient or mild discomfort; no limitation in 
activity; no medical intervention/therapy 
required. 
GRADE 2 – Moderate: 
Mild to moderate limitation in activity – 
some assistance may be needed; no or 
minimal medical intervention/therapy 
required. 
GRADE 3 – Severe: 
Marked limitation in activity, some 
assistance usually required; medical 
intervention/therapy required, 
hospitalizations possible. 
GRADE 4 – Life Threatening: 
Extreme limitation in activity, significant 
assistance required; life threatening 
(immediate risk of death); significant 
medical intervention/therapy required, 
hospitalization or hospice care probable. 
GRADE 5 – Fatal: 
Results in death. 


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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. 
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, hospitalization or prolongation of 
hospitalization for myelosuppression and associated complications directly 


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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 case report form 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 “Adverse Event” case report 
form 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. The Principal 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.  
A laboratory abnormality must be reported on the “Adverse Event” case report 
form only if it is the main causative factor of an SAE, requires a therapeutic 
intervention, or is the reason the patient is coming off treatment. For laboratory 
abnormalities that require reporting on an Adverse Event case report form, 
clinical sites should enter only the highest CTCAE severity grade of the test 
result and document the start and end dates at the highest grade.  However, all 
laboratory assessments, whether required according to the protocol’s schedule 
of events or an unscheduled assessment performed according the site’s Good 
Medical Practices, should be entered into the clinical database on the 
appropriate laboratory test results case report form (e.g., Hematology or Serum 
Chemistry). 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 Principal Investigator’s judgment using protocol-
defined definitions. Necessary counter measures will also be reported on the 
appropriate case report form 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) or unexpected AE NCI CTCAE Grade 3 that 
occurs during this study and up to 30 days after discontinuation of study drug 
must be reported to the Study Medical Monitor within 24 hours of the Principal 
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 Principal 
Investigator’s awareness of the event.   
Serious adverse events must be scanned and emailed to the Sponsor/Study 
Medical Monitor. 
Email to:
  
It is expected that the Principal Investigator will provide or arrange appropriate 
supportive care for the study patient. A patient experiencing a serious adverse 
event(s) should be followed clinically until the event is resolved, deemed stable 
or permanent, or the patient starts another treatment for their disease. All 
telephone and scanned/emailed reports must be followed with a written Serious 
Adverse Event (SAE) report form within 24 hours of the Principal 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 Principal 
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 case report form. 
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 Principal 
Investigator until the events resolve, are deemed stable or permanent, or the 
patient starts another treatment for their disease. Resolution means the patient 
has returned to his/her baseline state of health or the Principal Investigator does 
not expect any further improvement or worsening of the adverse event. The 
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information to the Sponsor up to the point the event has resolved. Any adverse 
events reported by the patient to the Principal Investigator which occur after the 
last scheduled visit, and are determined by the Principal Investigator to be 
reasonably associated with the use of the 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, or 
the patient starts 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 Principal 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 event leading up to the 
patient’s death began within 30 days of the last administration of study drug. 
The Death Report Form is distinct and separate from the adverse event form 
included in the case report form. 
8.8 Reporting Adverse Events to the Regulatory Authorities 
The Sponsor will be responsible for reporting adverse events to the FDA as 
described in 21 CRF Section 312.32 (IND Safety Reports) and to other 
Regulatory Authorities according to local regulations. 
In addition, the Principal Investigator is required by FDA regulations to notify the 
IRB promptly of all unexpected SAEs occurring at the Investigator’s study site. 
The Principal 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 Principal 
Investigator 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, USP, or 
5% Dextrose Injection, USP, prior to infusion, providing solutions of 0.09 to 
1.0 mg/mL alvocidib.  
Cytarabine, an approved pharmaceutical product, 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. Destruction of 
open/used vials of study drug will be handled by the sites. Unopened study drug 
vials should be returned to Patwell Pharmaceutical Solutions, LLC, at the end 
of the study but 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, USP, or 
5% Dextrose Injection, USP, 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 4.4.2.  
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 4.4.2. 
Cytarabine is an approved pharmaceutical product. 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 at USP controlled room temperature (ie, 20°C to 
25°C [68°F to 77°F]) with excursions between 2°C to 30°C (36°F to 86°F) 
permitted. 
x Cytarabine (Ara-c) should be stored between 15°C to 30°C (59°F to 86°F).  
9.5 Compliance 
Study drugs will be administered by trained staff. 


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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 electronic Case Report Form (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 Case Report Forms) 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 Principal Investigator 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 Principal Investigator with a copy filed in the patient’s medical records, 
and a copy given to the patient. 


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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.  
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. 


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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. 
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) 


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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 SAS software version 9.4 or higher. 
Data summaries will be compiled by treatment arm and overall and 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). 
Baseline value of a characteristic is defined as the last measured value prior to 
the first dose of alvocidib. 
11.2 Sample Size 
This study follows a 2-stage adaptive design that allows for continuing patient 
recruitment into the recommended alvocidib-based treatment arm used in 
Stage 1. It is designed to test the null hypothesis that the combined CR rate is 
10% against the alternative that the combined CR rate is >10%. Up to 
128 eligible patients from Stage 1 and Stage 2 will be evaluated for efficacy. 
Patients enrolled in the safety lead-in cohort will not be included in the 
efficacy analyses since they will receive a lower dose of alvocidib than the 
patients enrolled in Stage 1 and Stage 2. Assuming the actual combined CR 
rate is 20%, the study has 80% power at the one-sided 2.5% level of 
significance. The underlying statistical properties of this design are based on a 
2-stage sequential design where the overall one-sided 2.5% level of significance 
is protected using error spending. Forty percent of total information will be 
accumulated prior to the interim analysis at the end of Stage 1, where 10% of 
the overall alpha will be used. All data from Stages 1 and 2 will be used for the 
statistical test of combined CR rate at the end of the study, hence the adaptive 
component of this design (dropping 1 of the 2 treatment arms at the end of 
Stage 1) does not affect the overall type-1 and type-2 error probabilities (see 
Appendix G). 
11.3 Analysis Populations 
The 
intent-to-treat 
(ITT) 
patient 
population 
includes 
all 
patients 
randomized/enrolled 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. 


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When the ITT patient population is analyzed, patients are grouped according to 
their randomized/assigned treatment regardless of actual treatment received. 
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. 
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. 
11.4 Data Analyses 
11.4.1 
Demographics and Baseline Characteristics 
Demographics and baseline characteristics will be summarized by alvocidib 
dose level and overall using descriptive statistics and confidence intervals. 
11.4.2 
Efficacy Analyses 
Efficacy analyses will be conducted on data collected from patients 
enrolled in Stage 1 and Stage 2. Patients enrolled in the safety lead-in 
cohort will not be included in the efficacy analyses since they will receive 
a lower dose of alvocidib than the patients enrolled in Stage 1 and Stage 2. 
Response to treatment will be determined using the remission definitions 
detailed in the 2017 European LeukemiaNet Recommendations in AML [47] 
(see Appendix E). 
Descriptive statistics will be calculated within and across treatment arms for all 
efficacy endpoints (see in Section 7.2 for a description of the primary and 
secondary efficacy endpoints). 
The numbers of Combined complete remissions (ie, patients with a best 
response of CR or CRi), Complete remissions, Composite complete remissions 
(patients with a best response of CR, CRi, or CRh), and Combined responses 
(patients with a best response of CR, CRi, CRh, MLFS, or PR) will be 
summarized by observed response rates and estimated 95% CIs. 
Kaplan-Meier time-to-event analyses will be conducted on overall survival, 
progression-free survival and duration of composite CR. Mortality (all causes) 
at 30 and 60 days after the last treatment will also be calculated.  
Additional exploratory analyses may be performed to assist the sponsor in 
planning future studies. 


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11.4.3 
Safety Analyses 
The following safety analyses will be performed on all patients who receive at 
least one dose of study drug (including patients in the safety lead-in cohort). 
Adverse Events 
Reported AE terms will be mapped to MedDRA preferred terminology. Adverse 
events suggestive of 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 (TEAEs) will be summarized. A 
treatment-emergent adverse event 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. Adverse event severity is rated by the 
Investigator according to Common Terminology Criteria for Adverse Events 
(CTCAE) version 5 criteria.  
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 study treatment 
x TEAEs leading to death. 
The base summary of TEAEs will show within– and between–treatment-arm 
incidence rates for each MedDRA primary System Organ Class (SOC) and/or 
Preferred Term (PT) by highest reported CTCAE severity grade and overall. A 
separate summary will be produced for 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. 


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Clinical Laboratory Assessments 
Laboratory test results measured on a continuous scale and changes from 
baseline values will be summarized by visit and within alvocidib dose level using 
mean, standard deviation, median, minimum and maximum values. Categorical 
test results will be summarized within alvocidib dose level using shift tables. 
Additionally, for tests where NCI CTCAE, version 5.0, severity criteria are 
specified, NCI CTCAE severity grades will be summarized in shift tables. 
Vital Signs 
Vital signs and changes from baseline values will be summarized by visit and 
within alvocidib dose level using mean, standard deviation, median, minimum 
and maximum values. 
11.4.4 
Biomarker Prediction Endpoint Analyses 
Summary of baseline biomarker values will include within– and between–
treatment-arm descriptive statistics. If there are sufficient numbers of patients 
achieving remissions for an analysis to be informative, a logistic regression 
model will be fit to examine the relationship between potential biomarkers and 
the independent binary variables complete remissions and combined 
remissions during the study.  
 


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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 (SIV), 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 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 (COV) 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 SDP Oncology, Inc, in 
compliance with the applicable international and local regulatory requirements 
as well as applicable ICH guidelines, 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 the Sponsor’s Quality Assurance group. 


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15. ETHICS AND RESPONSIBILITY 
15.1 Principal Investigator’s Responsibilities 
The Principal Investigator 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 Good Clinical Practice (GCP). The 
Principal Investigator 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 Principal Investigator 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 prior written 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 case report 
forms. 
15.2 Informed Consent 
It is the ethical and legal responsibility of the Principal Investigator 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 Principal Investigator. The Principal Investigator 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 Principal Investigator (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 Principal Investigator. Written informed consent will 


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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 Principal Investigator and a second copy shall be placed in the patient’s 
medical chart.  
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 and must be described in meeting minutes where this protocol and 
associated informed consent form were discussed. The Principal Investigator 
shall not participate in the decision, and, if an IRB/EC member, the written 
approval must indicate such non-participation. The Principal Investigator shall 
submit status reports to the IRB/IEC no less frequently than annually (when 
applicable).  
The IRB/IEC must be notified by the Principal Investigator in writing of the 
interruption and/or completion of the study; the Principal Investigator 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 Principal 
Investigator will promptly report to the IRB/IEC all unanticipated problems 
involving risk to patients or others. The Principal Investigator 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. 


Protocol No. TPI-ALV-202 Amendment 2 
 
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SDP ONCOLOGY, INC 
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 SDP 
Oncology’s products or research programs that is provided by SDP Oncology 
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 SDP Oncology’s disclosure; 
(d) information which is lawfully disclosed to you by a third party not under any 
obligation of confidence to SDP Oncology; 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 SDP Oncology.  
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 SDP Oncology, 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. 


Protocol No. TPI-ALV-202 Amendment 2 
 
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11 August 2020 
 
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SDP ONCOLOGY, INC 
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. 


Protocol No. TPI-ALV-202 Amendment 2 
 
Final 
IND No. 057729 
 
11 August 2020 
 
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SDP ONCOLOGY, INC 
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 SDP Oncology, Inc, the right to review all 
manuscripts, abstracts, and presentations related to this study prior to their 
submission for publication or presentation. SDP Oncology may use these data 
now and in the future for presentation or publication at SDP Oncology’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. 
 
 


Protocol No. TPI-ALV-202 Amendment 2 
 
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IND No. 057729 
 
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SDP ONCOLOGY, INC 
19. REFERENCES 
1. Wei AH, Strickland SA Jr, Hou JZ, Fiedler W, Lin TL, Walter RB, et al. 
Venetoclax Combined with Low-Dose Cytarabine for Previously Untreated 
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Clin Oncol 2019;37(15):1277–1284.  
2. Hanahan D, Weinberg RA. The hallmarks of cancer. Cell 2000;100:57–70. 
3. National 
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4. 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. 
5. 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. 
6. 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. 
7. Yang T, Buchan HL, Townsend KJ, et al. 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. 
8. 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. 
9. 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.  
10. 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. 
11. Kim W, Whatcott CJ, Siddiqui-Jain A, et al. The CDK9 Inhibitor, Alvocidib, 
Potentiates the Non-clinical Activity of Azacytidine or Decitabine in an 
MCL-1-dependent Fashion, Supporting Clinical Exploration of a Decitabine 
and Alvocidib Combination. American Society of Hematology Association 
Annual Meeting, 1-4 Dec 2018; San Diego, CA, USA. 
12. Foight GW, Ryan JA, Gullá SV, et al. Designed BH3 peptides with high 
affinity and specificity for targeting Mcl-1 in cells. ACS Chem Biol 
2014;9(9):1962–1968.  


Protocol No. TPI-ALV-202 Amendment 2 
 
Final 
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11 August 2020 
 
PROPRIETARY/CONFIDENTIAL  
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SDP ONCOLOGY, INC 
13. Ramsey HE, Fischer MA, Lee T, et al. A Novel MCL1 Inhibitor Combined 
with Venetoclax Rescues Venetoclax-Resistant Acute Myelogenous 
Leukemia. Cancer Discov 2018;8(12):1566-1581. 
14. Zeidner JF, Lin TL, Vigil CE, et al. Zella 201: A Biomarker-Guided Phase II 
Study of Alvocidib Followed by Cytarabine and Mitoxantrone in MCL-1 
Dependent Relapsed/Refractory Acute Myeloid Leukemia (AML). Blood 
2018;132:30. 
15. Lin KH, Winter PS, Xie A, et al. Targeting MCL-1/BCL-XL Forestalls the 
Acquisition of Resistance to ABT-199 in Acute Myeloid Leukemia. Sci Rep 
2016;6:27696. 
16. Luedtke DA, Niu X, Pan Y, et al. Inhibition of Mcl-1 enhances cell death 
induced by the Bcl-2-selective inhibitor ABT-199 in acute myeloid leukemia 
cells. Signal Transduct Target Ther 2017;2:17012. 
17. Glaser SP, Lee EF, Trounson E, et al. Anti-apoptotic Mcl-1 is essential for 
the development and sustained growth of acute myeloid leukemia. Genes 
Dev 2012; 26(2):120–125. 
18. Carlson BA, Dubay MM, Sausville EA, et al. Flavopiridol induces G1 arrest 
with inhibition of cyclin-dependent kinase (CDK) 2 and CDK4 in human 
breast carcinoma cells. Cancer Res 1996;56(13):2973–2978.  
19. Losiewicz MD, Carlson BA, Kaur G, et al. Potent inhibition of CDC2 kinase 
activity by the flavonoid L86-8275. Biochem Biophys Res Commun 
1994;201(2):589–595.  
20. Kaur G, Stetler-Stevenson M, Sebers S, et al. Growth inhibition with 
reversible cell cycle arrest of carcinoma cells by flavone L86-8275. J Natl 
Cancer Inst 1992;84(22):1736–1740.  
21. Baumli S, Lolli G, Lowe ED, et al. The structure of P-TEFb (CDK9/cyclin T1), 
its complex with flavopiridol and regulation by phosphorylation. EMBO J 
2008;27(13):1907–918.  
22. Kitada S, Zapata JM, Andreeff M, et al. Protein kinase inhibitors flavopiridol 
and 7-hydroxy-staurosporine down-regulate antiapoptosis proteins in B-cell 
chronic lymphocytic leukemia. Blood 2000;96(2):393–397.  
23. Wittmann S, Bali P, Donapaty S, et al. Flavopiridol down-regulates 
antiapoptotic proteins and sensitizes human breast cancer cells to 
epothilone B-induced apoptosis. Cancer Res 2003;63(1):93–99.  
24. Gojo I, Zhang B, Fenton RG. The cyclin-dependent kinase inhibitor 
flavopiridol induces apoptosis in multiple myeloma cells through 
transcriptional repression and down-regulation of MCL-1. Clin Cancer Res 
2002;8(11):3527–3538.  


Protocol No. TPI-ALV-202 Amendment 2 
 
Final 
IND No. 057729 
 
11 August 2020 
 
PROPRIETARY/CONFIDENTIAL  
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SDP ONCOLOGY, INC 
25. Chao SH, Price DH. Flavopiridol inactivates P-TEFb and blocks most RNA 
polymerase II transcription in vivo. J Biol Chem 2001;276(34):31793–31799.  
26. Lam LT, Pickeral OK, Peng AC, et al. Genomic-scale measurement of mRNA 
turnover and the mechanisms of action of the anti-cancer drug flavopiridol. 
Genome Biol 2001;2(10):RESEARCH0041.  
27. Carlson B, Lahusen T, Singh S, et al. Down-regulation of cyclin D1 by 
transcriptional repression in MCF-7 human breast carcinoma cells induced 
by flavopiridol. Cancer Res 1999;59(18):4634–4641.  
28. Romano G, Giordano A. Role of the cyclin-dependent kinase 9-related 
pathway in mammalian gene expression and human diseases. Review 
Article. Cell Cycle 2008;7(23):3664–3668.  
29. Karp JE, Ross DD, Yang W, et al. Timed sequential therapy of acute 
leukemia with flavopiridol: in vitro model for a phase I clinical trial. Clin 
Cancer Res 2003;9(1):307–315.  
30. Chen R, Keating MJ, Gandhi V, et al. Transcription inhibition by flavopiridol: 
mechanism 
of 
chronic 
lymphocytic 
leukemia 
cell 
death. 
Blood 
2005;106(7):2513–2519.  
31. König A, Schwartz GK, Mohammad RM, et al. The novel cyclin-dependent 
kinase inhibitor flavopiridol downregulates bcl-2 and induces growth arrest 
and apoptosis in chronic B-cell leukemia lines. Blood 1997;90(11):4307–
4312.  
32. Byrd JC, Shinn C, Waselenko JK, et al. Flavopiridol induces apoptosis in 
chronic lymphocytic leukemia cells via activation of caspase-3 without 
evidence of bcl-2 modulation or dependence on functional p53. Blood 
1998;92(10):3804–3816.  
33. Arguello F, Alexander M, Sterry JA, et al. Flavopiridol induces apoptosis of 
normal lymphoid cells, causes immunosuppression, and has potent 
antitumor activity In vivo against human leukemia and lymphoma xenografts. 
Blood 1998;91(7):2482–2490.  
34. Haws H, Livingston M, Kim W, et al. By an MCL-1-dependent mechanism, 
Alvocidib potentiates the activity of cytarabine and mitoxantrone when 
administered in a time sequential regimen in AML. EHA Learning Center. 
2017;Eposter Abstract E881. (Abstract release date: May 18, 2017;180657). 
Available 
at: 
https://learningcenter.ehaweb.org/eha/2017/22nd/180657/ 
steven.warner.by.an.mcl-1-dependent.mechanism.alvocidib.potentiates. 
the.html?f=m3s57748. Accessed on 27 August 2017. 


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11 August 2020 
 
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SDP ONCOLOGY, INC 
35. Kim W, Haws H, Mangelson R, et al. Alvocidib synergizes with cytarabine 
and daunorubicin (7+3) in preclinical models of acute myeloid leukemia. EHA 
Learning Center. 2017;Eposter Abstract E902. (Abstract release date: May 
18, 2017;180678). Available at: https://learningcenter.ehaweb.org/eha/2017/ 
22nd/180678/steven.warner.alvocidib.synergizes.with.cytarabine.and.daun
orubicin.2872B329.in.html?f=m3s57748. Accessed on 27 August 2017. 
36. Geller RB, Burke PJ, Karp JE, et al. A two-step timed sequential treatment 
for acute myelocytic leukemia. Blood 1989;74:1499–1506. 
37. 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). 
38. 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). 
39. 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). 
40. 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). 
41. 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). 
42. 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. 
43. 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. 


Protocol No. TPI-ALV-202 Amendment 2 
 
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44. 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 2015;100(9):1172–1179. (Phase 2 Study No. 
J1101/NCI-8972). 
45. Zeidner JF, Foster MC, Blackford AL, et al. Final results of a randomized 
multicenter phase II study of alvocidib, cytarabine, and mitoxantrone versus 
cytarabine and GDXQRUXELFLQ ௗௗ LQ QHZO\ GLDJQRVHG KLJK-risk acute 
myeloid leukemia (AML). Leuk Res. 2018;72:92-95. 
46. DiNardo CD, Pratz K, Pullarkat V, et al. Venetoclax combined with decitabine 
or azacytidine in treatment-naive, elderly patients with acute myeloid 
leukemia. Blood 2019;133:7-17. 
47. 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. 
 










Protocol No. TPI-ALV-202 Amendment 2 
 
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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 housework, 
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 
*Source: 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. 
 
 


Protocol No. TPI-ALV-202 Amendment 2 
 
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APPENDIX C – NCI COMMON TERMINOLOGY CRITERIA FOR ADVERSE EVENTS  
View the National Cancer Institute Common Terminology Criteria for Adverse Events 
v5.0 (NCI CTCAE) criteria electronically at the following Web site:  
https://evs.nci.nih.gov/ftp1/CTCAE/CTCAE 5.0/ 
The Study Manual includes a copy of the NCI CTCAE.  
 
 


Protocol No. TPI-ALV-202 Amendment 2 
 
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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 
12-lead Electrocardiogram (ECG) 
Biomarker 
Prediction Tests 
Minimal residual disease (MRD) to be determined by central laboratory 
evaluation of bone marrow samples using standardized techniques (ie, 
multiparametric flow cytometry [MPFC] and molecular testing including 
next generation sequencing [NGS] and cytogenetics/fluorescence in 
situ hybridization [FISH]); other potential biomarkers including but not 
limited to MCL-1 dependency to also be assessed. 
Other Tests 
x 
Pregnancy test XULQHRUVHUXPGHWHUPLQDWLRQRIȕ-hCG in females 
of childbearing potential) 
 
 


Protocol No. TPI-ALV-202 Amendment 2 
 
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SDP ONCOLOGY, INC 
APPENDIX E – RESPONSE CRITERIA 
(2017 EUROPEAN LEUKEMIANET RECOMMENDATIONS) 
 
*Including patients with morphologic CR who are MRD+ and cytogenetic and/or molecular marker positive.
 
*








Protocol No. TPI-ALV-202 Amendment 2 
 
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x Grade 3 tumor lysis syndrome or related electrolyte disturbances (hyperkalemia, 
K\SRSKRVSKDWHPLDK\SHUXULFHPLDWKDWGRQRWUHVROYHWR*UDGHZLWKLQGD\V 
x Grade HOHYDWLRQVLQFUHDWLQLQHWKDWGRQRWUHVROYHWR*UDGHZLWKLQGD\V 
x Any AST and/or ALT elevation 3 × ULN accompanied by serum bilirubin levels 
>2 × ULN is suggestive of possible drug-induced liver injury (ie, liver function test 
abnormalities meeting Hy’s Law criteria) and should be considered a DLT 
regardless of duration unless an alternative etiology is more likely 
x Grade 3 or 4 nonhematologic AEs will be considered dose limiting, regardless of 
duration, with the exception of Grade 3 – 4 nausea, vomiting, diarrhea, and 
electrolyte imbalances unless persisting for more than 48 hours despite optimal 
medical management (in which case they will be considered DLTs) 
x Dosing delays >1 week due to treatment-emergent adverse events (TEAEs) or 
related severe laboratory test values. 
 
 





SAP_001.pdf: 
Sumitomo Dainippon Pharma Oncology, Inc
Statistical Analysis Plan
Protocol: TPI-ALV-202
Version: 1.2 (Dated 03JUN2021)
Confidential/Proprietary Property of Sumitomo Dainippon Pharma Oncology, Inc
Page 1 of 30
STATISTICAL ANALYSIS PLAN
Study Title:
A Phase 2, Open-label, Randomized, Two-stage Clinical 
Study of Alvocidib in Patients with Relapsed/Refractory 
Acute Myeloid Leukemia Following Treatment with 
Venetoclax Combination Therapy
Sponsor
Protocol Number
TPI-ALV-202
IND Number
057729
Investigational Product
Alvocidib (formerly flavopiridol)
Phase of Development
Phase 2
Analysis Plan Version
Version 1.2
Analysis Plan Date
June 3, 2021
The information in this document is confidential and proprietary to Vantage Data Designs (VDD) and its Clients. The 
information may only be used by the entities to which it was disclosed. The information must not be disclosed to any third 
parties without the prior written consent of VDD.


Sumitomo Dainippon Pharma Oncology, Inc
Statistical Analysis Plan
Protocol: TPI-ALV-202
Version: 1.2 (Dated 03JUN2021)
Confidential/Proprietary Property of Sumitomo Dainippon Pharma Oncology, Inc
Page 2 of 30
STATISTICAL ANALYSIS PLAN APPROVAL 
AUTHOR:
Signature                                                                  Date
APPROVED BY:
Signature                      
Date
Signature                                             
Date


Sumitomo Dainippon Pharma Oncology, Inc
Statistical Analysis Plan
Protocol: TPI-ALV-202
Version: 1.2 (Dated 03JUN2021)
Confidential/Proprietary Property of Sumitomo Dainippon Pharma Oncology, Inc
Page 3 of 30
TABLE OF CONTENTS
Section
Page
1. INTRODUCTION ...............................................................................................................6 
2. OVERVIEW OF STUDY DESIGN ....................................................................................7 
3. STUDY OBJECTIVES AND ENDPOINTS.......................................................................9 
3.1 Study Objectives..........................................................................................................9 
3.1.1 Primary Objective ...............................................................................................9 
3.1.2 Secondary Objectives..........................................................................................9 
3.1.3 Exploratory Objectives......................................................................................11 
3.2 Study Endpoints.........................................................................................................11 
3.2.1 Primary Endpoint ..............................................................................................11 
3.2.2 Secondary Endpoints.........................................................................................11 
3.2.3 Safety Endpoints ...............................................................................................12 
3.2.4 Pharmacodynamic (PD) Endpoints...................................................................12 
4. SAMPLE SIZE JUSTIFICATION ....................................................................................13 
5. RANDOMIZATION, BLINDING, AND REPLACEMENT OF 
PATIENTS.........................................................................................................................13 
6. DEFINITIONS OF PATIENT POPULATIONS TO BE 
ANALYZED......................................................................................................................14 
7. PLANNED ANALYSES...................................................................................................14 
7.1 Interim Analysis ........................................................................................................14 
7.2 Final Analysis............................................................................................................14 
8. DATA PRESENTATION AND HANDLING..................................................................15 
8.1 General Summary Table and Individual Patient Data Listing Considerations..........15 
8.2 General Summary Table and Patient Data Listing Format Considerations ..............15 
8.3 Data Management......................................................................................................16 
8.4 Data Presentation Conventions..................................................................................16 
8.5 Treatment Comparisons.............................................................................................17 
8.6 Definitions, Computations, Derived Data .................................................................18 
9. GENERAL CONSIDERATIONS FOR DATA ANALYSES ..........................................18 
9.1 Multicenter Studies....................................................................................................18 
9.2 Other Strata and Covariates.......................................................................................19 
9.3 Examination of Subgroups ........................................................................................19 
9.4 Multiple Comparisons and Multiplicity ....................................................................19 
9.5 Missing Data and Dropouts.......................................................................................19 
9.5.1 Adverse Events..................................................................................................19 


Sumitomo Dainippon Pharma Oncology, Inc
Statistical Analysis Plan
Protocol: TPI-ALV-202
Version: 1.2 (Dated 03JUN2021)
Confidential/Proprietary Property of Sumitomo Dainippon Pharma Oncology, Inc
Page 4 of 30
9.5.2 Concomitant Medications .................................................................................19 
9.5.3 Other Situations.................................................................................................19 
10. STUDY POPULATION ....................................................................................................19 
10.1 Patient Disposition.....................................................................................................19 
10.2 Protocol Violations or Deviations .............................................................................20 
10.3 Demographics............................................................................................................20 
10.4 AML History .............................................................................................................20 
10.5 Medical History.........................................................................................................20 
10.6 Concomitant Medications..........................................................................................21 
10.7 Study Drug Administration and Exposure ................................................................21 
11. EFFICACY ANALYSIS ...................................................................................................21 
12. SAFETY ANALYSIS........................................................................................................21 
12.1 Treatment Emergent Adverse Events........................................................................21 
12.2 Serious Adverse Events.............................................................................................23 
12.3 Clinical Laboratory Tests ..........................................................................................23 
12.4 Vital Signs .................................................................................................................23 
12.5 12-Lead Electrocardiogram (ECG) ...........................................................................23 
12.6 ECOG Performance Status........................................................................................23 
12.7 Physical Examination and Pregnancy Test................................................................24 
13. PHARMACOKINETIC (PK) ANALYSIS .......................................................................24 
14. PHARMACODYNAMIC (PD) ANALYSIS ....................................................................24 
15. COMMITMENT TO GOOD STATISTICAL PRACTICE ..............................................24 
15.1 Definition of Good Statistical Practice......................................................................24 
15.2 Data Management and Use of CDISC Standards......................................................25 
15.3 Testing/Validation Plan and Software System..........................................................25 
16. STATISTICAL ANALYSIS CHANGES FROM THE 
PROTOCOL ......................................................................................................................25 
17. REFERENCES ..................................................................................................................25 
18. SCHEDULE OF ASSESSMENTS....................................................................................27 


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ABBREVIATIONS AND DEFINITIONS
ADaM
analysis data model
AE
adverse event
ALDAC
Alvocidib + Low-dose cytarabine
ALV
Alvocidib
ATC
anatomical therapeutic chemical
BMI
body mass index
bpm
beats per minute
CR
complete response
CRF
case report form
CS
clinically significant
CTCAE
Common Terminology Criteria for Adverse Events
ECG
electrocardiogram
ECOG
Eastern Cooperative Oncology Group
eCRF
electronic case report form 
EDC
electronic data capture
EOS
end-of-study
FDA
Food and Drug Administration
GCP
Good Clinical Practices
ICH
International Committee for Harmonization
IP
Investigational Product
ITT
intent to treat
MedDRA
Medical Dictionary for Regulatory Activities
NCI
National Cancer Institute 
NCS
not clinically significant
PD
progressive disease
PK
pharmacokinetic
PR
partial response
PT
preferred term
SAE
serious adverse event
SAP
statistical analysis plan
SAS
Statistical Analysis Software
SD
stable disease
SOC
system organ class
SDPO
Sumitomo Dainippon Pharma Oncology, Inc
TEAE
treatment-emergent adverse event


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1.
INTRODUCTION
The Statistical Analysis Plan (SAP) describes the data analysis specifications for Sumitomo 
Dainippon Pharma Oncology, Inc (SDPO) protocol TPI-ALV-202 titled: “A Phase 2, Open-
label, Randomized, Two-stage Clinical Study of Alvocidib in Patients with 
Relapsed/Refractory Acute Myeloid Leukemia Following Treatment with Venetoclax 
Combination Therapy”. It details the planned statistical methodologies to be used in
analyzing study data and outlines the statistical programming specifications, tables, figures, 
and listings. It describes the variables and populations, anticipated data transformations and 
manipulations, and other details of the analyses typically not provided in the clinical study
protocol.
This version of the SAP was prepared in accordance with the protocol TPI-ALV-202
Amendment 2 dated August 11, 2020. Other related documents are the annotated patient case
report forms (version 6 dated October 16, 2020) and the corresponding InForm electronic
data capture (EDC) data dictionary.
The SAP will be finalized prior to database lock and describes the statistical analysis as it is 
foreseen when the study is being planned. If circumstances should arise during the study
rendering this analysis inappropriate, or if in the meantime improved methods of analysis 
should come to light, different analyses may be made. Any deviations from the SAP after 
database lock, reasons for such deviations, and all alternatives or additional statistical 
analyses that may be performed will be described in a SAP Addendum and in the clinical
study report. This SAP supersedes the statistical considerations identified in the protocol.
NOTE: On November 17, 2020, the investigative sites were notified of the decision by 
SDPO to close TPI-ALV-202 following a review of the company portfolio. This SAP will 
reflect the latest protocol (Amendment 2) along with the current study status where 
appropriate.
Enrollment status as of November 17, 2020:
x
Lead-In Safety Cohort: n=7 patients enrolled.

Arm 1: ALDAC (Alvocidib + Low-dose cytarabine): n=3

Arm 2: ALV (Alvocidib): n=4
x
Stage 1: n=4 patients enrolled.

Arm 1: ALDAC (Alvocidib + Low-dose cytarabine): n=2

Arm 2: ALV (Alvocidib): n=2


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Efficacy endpoints will not be analyzed via inferential statistical methods due to low 
enrollment (sample size). Summary tables as described in this SAP and full patient 
listings will be provided to enable a synoptic clinical study report to be written for this
study. 
2.
OVERVIEW OF STUDY DESIGN
Experimental Design:
This is an open-label, randomized, two-stage clinical study. During Stage 1, patients will be 
randomized in a 1:1 treatment allocation into one of two treatment arms:
x
Arm 1: ALDAC (Alvocidib + Low-dose cytarabine
x
Arm 2: ALV (Alvocidib)
stratified by prior response to venetoclax in combination with azacytidine or decitabine:
x
Refractory (i.e., failed to achieve a CR/CRi or achieved a CR/CRi with duration <90 
days. OR
x
Relapsed (i.e., reoccurrence of disease following a CR/CRi with duration ≥90 days).
This study will be divided into three main parts: 
1. Lead-in Cohort
Current Status: Based on a review of data (n=7 patients) from the safety lead-in 
cohort, the Data Safety Monitoring Board (DSMB) granted unconditional approval 
to continue enrollment (reference DSMB Recommendation Form dated 11 Sep
2020) into the TPI-ALV-202 clinical trial.
Planned: As an additional safety measure given the unique patient population and 
outpatient treatment administration, a separate lead-in cohort of approximately six
patients (at least three patients in each treatment arm) will be enrolled, treated, and 
evaluated for dose-limiting toxicities (DLTs). If a DLT is observed, dose de-escalation 
will occur. Should no additional DLTs be observed during Cycle 1 and the Data Safety 
Monitoring Board (DSMB) confirm safety, randomization into Stage 1 will commence as 
outlined in the protocol. However, should an additional DLT be observed at Dose Level 
1, a clinical meeting would be scheduled to discuss the utility/futility of continuing the 
study as currently designed.


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If the DSMB has confirmed safety, patients may be permitted to shift to the higher 
alvocidib (ALV) dose regimen, i.e., ALV 50 mg/m2 IV bolus, per investigator discretion.
Stage 1
Current Status: As of November 17, 2020, 4 patients were enrolled in Stage 1. 
Planned: A futility analysis will be conducted at the end of Stage 1 to determine if the 
combined CR rate meets the threshold for continuing the study. Using an alpha spending
function to control the overall level of significance, the threshold is that the one-sided p-
value be <0.60525 in order to initiate Stage 2, which is achieved if there are more than 4 
combined CRs among the 52 Stage 1 patients. No additional patients will be enrolled if 
the number of patients with combined CR at the end of Stage 1 fails to meet this criterion.
The sponsor may elect to close enrollment in Stage 1 once the minimum response 
threshold has been met in Stage 1 (as defined in the Study Design), and the sponsor has
sufficient information to select the recommended alvocidib-based treatment arm for Stage 
2. The recommended alvocidib-based treatment will be determined subjectively by 
comparing the response rates, relative safety, and the risk-benefit ratio of the two Stage 1
treatment arms.
2. Stage 2
Current Status: As of November 17, 2020, zero patients were enrolled in Stage 2.


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Planned: Determination of the recommended alvocidib-based treatment arm for Stage 2 
will be subjective, comparing the response rates, relative safety, and the risk-benefit ratio 
of the two Stage 1 treatment arms. An additional 76 patients will be enrolled into the 
treatment arm selected for Stage 2 for a total of 102 patients (26 and 76 from Stages 1  
and  2,  respectively).  The  combined  CR rate (primary endpoint) will be tested at the 
end of Stage 2, with statistical significance declared if the one-sided p-value is <0.02407.
Any patient who withdraws from the study for treatment-related toxicity prior to being 
evaluated for response will be considered a non-responder. Patients who drop out of the 
study for other reasons prior to being assessed for response will be considered non-
evaluable and may be replaced.
Study treatments:
Alvocidib + Low-dose cytarabine treatment will be given every 28 days.
Alvocidib treatment will be given every 28 days
Number of patients planned: It was planned that up to 6 evaluable patients will be enrolled
into the Safety Lead-In Cohort, 52 evaluable patients in Stage 1, and 76 patients into Stage 2.
Thus, up to 134 evaluable patients may be enrolled in the study.
Study Duration: The study was expected to take 18 months to enroll approximately 134
evaluable patients and an additional 2 years for follow up.
As of the study termination date of November 17, 2020; 11 patients have enrolled into this 
study.
3.
STUDY OBJECTIVES AND ENDPOINTS
3.1
Study Objectives
3.1.1
Primary Objective
To estimate the rate of combined complete remission (i.e., CR + CR with incomplete 
hematological recovery [CRi]) in patients with AML whose disease is either refractory to 
initial induction therapy with venetoclax in combination with azacytidine or decitabine (i.e.,
failed to achieve a CR/CRi or achieved a CR/CRi with duration <90 days) or who have 
relapsed (reoccurrence of disease following a CR/CRi duration ≥90 days).
3.1.2
Secondary Objectives
The secondary objectives are: 


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x
Median Overall Survival (OS) = Time from treatment (Day 1) until death from any 
cause
x
CRMRD– = Percentage of patients achieving complete response (CR) whose bone
marrow is determined to be negative for minimal residual disease (MRD) using 
standardized techniques (i.e., multiparametric flow cytometry [MPFC] and molecular 
testing including next generation sequencing [NGS])
x
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)
x
Composite CR rate = Combined percentage of patients achieving one of the 
following:
o
CR
o
CRi = Meets all CR criteria but with only full recovery of one peripheral 
blood cell type (i.e., ANC ≥1000/μL or platelet count ≥100,000/μL)
o
CRh = Meets all CR criteria but with only partial recovery of both peripheral 
blood cell types (i.e., ANC ≥500/μL and platelet count ≥50,000/μL
x
Combined Response rate = Combined percentage of patients achieving one of the
following:
o
CR
o
CRi
o
CRh
o
Morphologic leukemia-free state (MLFS) = Bone marrow blasts <5%; 
absence of blasts with Auer rods; absence of extramedullary disease; no 
hematologic recovery required
o
Partial Response (PR) = Meets all hematologic values required for CR but
with a decrease of at least 50% in the percentage of blasts to ≥5% to ≤25% in 
bone marrow
x
Event-free Survival (EFS) = Time from first treatment (Day 1) until (a) treatment 
failure, (b) relapse after CR/CRi/CRh, or (c) death from any cause, whichever occurs 
first, censored at  2 years.


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x
Duration of Composite CR = Time from first documented response of CR, CRi, or 
CRh to relapse or death from any cause.
x
Rates of 28- and 56-day Transfusion Independence (TI) = Percentages of patients 
who do not receive red blood cell (RBC) transfusions, platelet (PLT) transfusions, 
and neither RBC nor PLT transfusions for 28 and 56 days; comprised of 6 secondary 
endpoints:
o
28-day RBC TI
o
28-day PLT TI
o
28-day TI (both RBC and PLT)
o
56-day RBC TI
o
56-day PLT TI
o
56-day TI (both RBC and PLT)
3.1.3
Exploratory Objectives
x
To evaluate potential biomarkers including but not limited to MCL-1 dependence, 
genetic mutations, and other biomarkers associated with AML.
x
Additional exploratory analyses may be performed if useful in the interpretation of
the data.
3.2
Study Endpoints
3.2.1
Primary Endpoint
The primary endpoint is the rate of combined complete remission (CR+ CRi) as defined by 
the International Working Group Criteria and 2017 European LeukemiaNet.
3.2.2
Secondary Endpoints
x
Median OS
x
CRMRD
x
CR Rate
x
Composite CR rate (CR + CRi + CRh)
x
Combined Response Rate (CR + CRi + CRh + MLFS + PR)
x
EFS


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x
Duration of composite CR = Time from first documented response of CR, CRi, CRh
to relapse or death from any cause
x
Rates of 28- and 56-day Transfusion Independence (TI) = Percentages of patients 
who do not receive red blood cell (RBC) transfusions, platelet (PLT) transfusions, 
and neither RBC nor PLT transfusions for 28 and 56 days (i.e., 6 secondary 
endpoints)
3.2.3
Safety Endpoints
Safety and tolerability of the regimen will be assessed by analyzing the incidence rates of 
treatment-emergent adverse events (TEAEs) summarized at the 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).
Other routine safety assessments (i.e., 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 following last treatment will also be calculated.
Adverse events will be graded according to National Cancer Institute’s Common 
Terminology Criteria for Adverse Events (NCI CTCAE), version 5.0.
A Data Safety Monitoring Board (DSMB) will monitor key outcomes from the study.
3.2.4
Pharmacodynamic (PD) Endpoints
x
BH3 profiling, including determination of MCL-1 dependence, at Baseline and End 
of Treatment using bone marrow.
x
Analysis of MRD to be performed at a central Clinical Laboratory Improvement 
Amendments (CLIA)-accredited laboratory on bone marrow samples collected at 
baseline and at time of response assessments using standardized techniques (i.e.,
MPFC and molecular testing including NGS).
x
Peripheral blood and bone marrow samples will be collected at protocol-specific time 
points to evaluate other potential biomarkers including but not limited to MCL-1
dependence. These assessments may be explored in the context of AML or related 
conditions or drugs of similar class.
The samples may be retained for no longer than 20 years after study completion or per local 
requirements.


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4.
SAMPLE SIZE JUSTIFICATION
This study follows a 2-stage adaptive design that allows for continuing patient recruitment 
into the recommended alvocidib-based treatment arm used in Stage 1. It is designed to test 
the null hypothesis that the combined CR rate is 10% against the alternative that the  
combined  CR  rate  is  >10%. Up to 128 eligible patients from Stage 1 and Stage 2 will be 
evaluated for efficacy. Patients enrolled in the safety lead-in cohort will not be included in 
the efficacy analyses since they will receive a lower dose of alvocidib than the patients 
enrolled in Stage 1 and Stage 2. Assuming the actual combined CR rate is 20%, the study has 
80% power at the one-sided 2.5% level of significance. The underlying statistical properties 
of this design are based on a 2-stage sequential design where the overall one-sided 2.5% level
of significance is protected using error spending. Forty percent of total information will be 
accumulated prior to the interim analysis at the end of Stage 1, where 10% of the overall 
alpha will be used. All data from Stages 1 and 2 will be used for the statistical test of
combined CR rate at the end of the study, hence the adaptive component of this design 
(dropping 1 of the 2 treatment arms at the end of Stage 1) does not affect the overall type-1
and type-2 error probabilities.
Note: As of the study termination date of November 17, 2020; 11 patients have enrolled into 
this study.
5.
RANDOMIZATION, BLINDING, AND REPLACEMENT OF PATIENTS
This study follows a randomized, two-stage design. During the Lead-in Cohort and Stage 1, 
patients will be randomized 1:1 to receive either ALDAC or ALV:
x
ALDAC – Alvocidib plus Low Dose Ara-C (cytarabine)
x
ALV – ALVocidib
Randomization to treatment arm will be stratified by response to initial induction therapy 
with venetoclax in combination with azacytidine or decitabine:
x
Refractory: failed to achieve a CR/CRi or achieved a CR/CRi with duration <90 days
x
Relapsed: reoccurrence of disease following a CR/CRi with duration ≥90 days
Although this study is randomized, it is unblinded. IQVIA (data management vendor) was
responsible for the randomization schedule and implementation into the EDC system.
Patients who are lost to follow-up or withdraw consent for study participation prior to
administration of study drug may be replaced, at sponsor’s discretion.


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6.
DEFINITIONS OF PATIENT POPULATIONS TO BE ANALYZED
This study will have three analysis populations:
x
Intent-to-Treat (ITT) analysis set includes all patients randomized/enrolled 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/assigned treatment regardless of 
actual treatment received.
x
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.
x
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.
NOTE: due to the study status, the safety population will be used for all summary tables. 
7.
PLANNED ANALYSES
7.1
Interim Analysis
There are no formal efficacy interim analyses planned for this study. The safety data was 
planned to be monitored every 3 months by the Data Safety Monitoring Board (DSMB).
The DSMB reviewed safety data from the safety lead-in cohort (n=7 patients). The DSMB
granted unconditional approval to continue enrollment (reference DSMB Recommendation 
Form dated 11 Sep 2020) into the TPI-ALV-202 clinical trial. As noted earlier, this study 
was terminated November 17, 2020 prior to the next scheduled DSMB meeting. 
7.2
Final Analysis
The final tables, listings, graphs, and data analysis will be conducted once all participants have 
completed the study and the clinical database has been locked.


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NOTE: For this study, the database will be locked with 11 patients enrolled.
8.
DATA PRESENTATION AND HANDLING
8.1
General Summary Table and Individual Patient Data Listing Considerations
Summary tables and listings will be prepared according to (ICH) Guideline E3 (as 
appropriate for a Phase I study).
In general, summary tables will be organized with respect to dose cohort and presented as:
Lead-In Cohort
Stage 1
Arm 1: ALDAC
(N=3)
Arm 2: ALV
(N=4)
Total
(N=7)
Arm 1: ALDAC
(N=2)
Arm 2: ALV
(N=2)
Total
(N=4)
Overall
(N=11)
x
Lead-In Cohort: Arm 1 (ALDAC), Arm 2 (ALV), Total. 
x
Stage 1: Arm 1 (ALDAC), Arm 2 (ALV) , Total
x
Overall study total. 
Row entries in post text tables are made only if data exists for at least one patient (e.g., a row 
with all zeros will not appear). The only exception to this rule will apply to tables that 
summarize the study termination status of patients (e.g., reasons for not completing the
study). In this case, zeros will appear for study termination reasons that no patient satisfied.
The summary tables will clearly indicate the number of patients to which the data apply and 
unknown or not performed are distinguished from missing data.
Adverse event preferred terms and body/organ systems and medical history conditions will 
be coded using the Medical Dictionary for Regulatory Activities (MedDRA®) dictionary 
Version 21.0 (or later). 
Listings will also be sorted by lead-in cohort, Stage 1 (where applicable), and patient
number. Listings will also include visit number, visit date/time.
In general, missing data will not be imputed unless otherwise specified. Any imputed or 
derived data will be flagged in the individual patient data listings. Imputed data will not be 
incorporated into any raw or primary datasets. These data will be retained in derived analysis 
datasets.
8.2
General Summary Table and Patient Data Listing Format Considerations
The tables and listings will be numbered as closely as possible to the ALV-202 abbreviated 
clinical study report tables/listings. Each table and listing title will be complete, accurate and 
concise. The last line of the title will provide the analysis group being summarized (e.g., 


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Safety Population). Variables being summarized, and statistics reported will appear in the left 
most column(s) of a table. The next columns to the right should report the treatment arm data 
for the lead-in cohort and stage 1.
8.3
Data Management
All data will be recorded by the site in individual source documents. An eCRF will be 
created by the data management group for recording of the required data in the study 
database. All eCRF information is to be filled in by site staff. If an item is not available or is 
not applicable, this fact should be indicated. Blank spaces should not be present unless
otherwise directed.
The study monitor will perform source data verification of data entered into the eCRF and 
raise queries for correction by the site. The data entered into the eCRF will be patient to data
validation checks for consistency and completeness by the data management group. Data 
queries will then be generated and sent to the investigational site for response before the
database is locked and released for statistical analysis.
Database build, AE coding, and data cleaning will be conducted according to the IQVIA
Data Management Plan for this specific study.
Derived datasets will be created using SAS® software. Data analyses and summary tables
will be generated using the currently supported version at the time of data analysis (currently 
version 9.4).
8.4
Data Presentation Conventions
Continuous safety variables (e.g., clinical laboratory values and vital signs) will be listed to
the same precision as the source data. Derived variables will be calculated and listed using
the same precision as the value(s) from which they were derived. 
For the tabular reporting of descriptive statistics:
x
Continuous variables: the same number of decimal places as in the raw data will be 
presented when reporting minimum and maximum, 1 more decimal place than in the 
raw data will be presented when reporting mean and median, and 2 more decimal 
places than in the raw data will be presented when reporting SD.
x
Categorical/discrete variables: the frequency count and the percentage (of available
data) for each class of the variable will be presented and will be displayed in the form
XX (XX.X%) where the percentage is in the parentheses. All percentages will be
presented to 1 decimal place, unless otherwise specified. Percentages equal to 100 


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will be reported as 100% and percentages will not be presented for zero frequencies.
Unless otherwise specified, percentages will be calculated based on the number of 
patients specified by the appropriate population definition. 
x
Date variables: formatted as DDMMMYYYY for presentation. Time will be 
formatted in military time as HH:MM for presentation.
Extra measurements (such as unscheduled or repeat assessments) will not be included in 
summary tables but will be included in patient listings. They will be used in summary tables
which are not ‘time specific’, for example, summaries of maximum post dose values.
All tables, listings, figures will be produced in landscape orientation using Times New 
Roman 9-point font. Output files will be created in rich text file (RTF) format.
Missing or invalid data will be generally treated as missing, not imputed, unless otherwise 
stated (see Section 9.5).
The table, figures and listing shells and table of contents as part of this SAP provide the 
expected layout and titles of the tables, listings and figures. Any changes to format, layout,
titles, numbering, or any other minor deviation will not necessitate a revision to the SAP nor 
will it be considered a deviation from planned analyses. Only true differences in the analysis 
methods or data handling will necessitate such documentation. The appropriate listings 
supporting the tables will be included and are not specified in the individual sections
throughout the document.
Minor modifications may be necessary to the planned design of tables, listings and figures to
accommodate data collected during the actual study conduct. Any major deviations from the 
final approved SAP (e.g., change in the population used, change from statistical 
method/assumption listed, transformation of data type [e.g., continuous data transformed to 
categorical], exclusion of planned analysis, etc.) or additional unplanned analyses will be 
documented (with justification) in the CSR.
8.5
Treatment Comparisons
The following labels for dose level will be used on all tabulations, in the following order: 
Lead-In Cohort
Stage 1
Arm 1: ALDAC
(N=3)
Arm 2: ALV
(N=4)
Total
(N=7)
Arm 1: ALDAC
(N=2)
Arm 2: ALV
(N=2)
Total
(N=4)
Overall
(N=11)


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8.6
Definitions, Computations, Derived Data
x
Screening: Screening is defined as ≤14 days prior to Cycle 1 Day 1 prior to the first
study drug administration. 
x
Baseline: Measurements taken at Screening or prior to receiving the first dose of 
study drug; whichever is latest. 
x
1 year = 365.25 days. Year is calculated as (days / 365.25) and will be rounded to 1
digit after the decimal point (tenths) for presentation purposes.
x
1 month = 30.4375 days. Month is calculated as (days / 30.4375) and will be rounded 
to 1 digit after the decimal point (tenths) for presentation purposes.
x
1 pound = 0.454 kg and 1 kg = 2.2 pounds.
x
1 inch = 2.54 cm and 1 cm = 0.3937 inches.
x
Body mass index (BMI) calculated as [weight (lbs) / height (in)2] x 703.
x
Age will be calculated in years relative to the date of study consent based on the 
following SAS statement: Age = ([Consent Date - Date of Birth] / 365.25) and will be 
rounded to 1 digit after the decimal point (tenths) for presentation purposes.
9.
GENERAL CONSIDERATIONS FOR DATA ANALYSES
The listings, figures and summary tables for the disposition and safety, and efficacy data will 
be the responsibility of the study Biostatistician at Vantage Data Designs.
The currently supported version of SAS software (9.4 or later) will be used to perform all 
data analyses. The actual SAS version used will be presented in the Clinical Study Report.
All data in the database will be presented in the data listings. Unless otherwise stated, all
listings will be sorted by cohort (lead-in, stage 1), patient number and assessment date/time.
Unless otherwise stated, continuous variables will be summarized using descriptive statistics 
including number of non-missing observations, mean, standard deviation, median, minimum 
and maximum values. Categorical variables will be summarized with frequency counts and 
percentages. The population size (N for sample size and n for available data) and the 
percentage (of available data) for each class of the variable will be presented. 
9.1
Multicenter Studies
Data from all participating sites will be pooled for the analysis.


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9.2
Other Strata and Covariates
Not applicable for this study.
9.3
Examination of Subgroups
Not applicable for this study.
9.4
Multiple Comparisons and Multiplicity
Not applicable for this study.
9.5
Missing Data and Dropouts
The issue of how to handle missing data caused by dropouts in clinical studies is a research 
topic that is still under development in the statistical literature. As has been noted in the ICH-
E9 guideline, “no universally applicable method of handling missing values can be 
recommended”. The best approach is to minimize the chance of dropouts at the design stage 
of the clinical study and during study monitoring. 
In general, data will be analyzed as received from the clinical database. Hence, missing 
values will not be replaced by imputed values.
9.5.1
Adverse Events
Adverse events with missing or partial dates will be handled such that in the absence of 
contradictory information an AE is classified as “treatment emergent”.
9.5.2
Concomitant Medications
Medications with missing or partial dates will not have dates imputed and will presented as 
collected in the patient listings.
9.5.3
Other Situations
For patients who are withdrawn from the study prior to study completion, all data compiled 
up to the point of discontinuation will be used for analysis. All withdrawals will be included 
in all analyses up to the time of withdrawal.
10.
STUDY POPULATION
All disposition, baseline and demographic analyses will be conducted on the Safety 
population.
10.1
Patient Disposition
The patient disposition summary will include:


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x
The number of patients who were enrolled at each study center.
x
Number of patients in Lead-In Cohort and Stage 1. 
x
A summary of primary reason for treatment discontinuation from study.
x
A summary of primary reason for discontinuation from study. 
A listing of patient enrollment and disposition will be provided. A listing of whether or not 
all inclusion and exclusion criteria were met and if not, which criteria were not met, by 
patient, will also be presented.
10.2
Protocol Violations or Deviations
Protocol deviations were not collected per the eCRFs. 
10.3
Demographics
Demographic characteristics will include age, age category (18-25, 26-35, 36-45, 46-55, 56-
65, >65 years), sex, race, ethnicity, and ECOG Performance Status.
The categorical (discrete) variables will be summarized using counts and percentages. The 
continuous variables will be summarized using mean, median, standard deviation, and range 
(maximum, minimum). All demographic data will be listed by patient.
10.4
AML History
AML History variables include French-American-British (FAB) AML Type, MDS prior to 
AML, Primary or Secondary AML, Extramedullary Disease, central nervous system (CNS) 
involvement, FLT3 Mutations, CEBPA (C/EBP-Alpha) Mutations, NPM1 Mutations,
ASXL1 Mutations, and RUNX1 Mutations.
The categorical (discrete) variables will be summarized using counts and percentages. The 
continuous variables will be summarized using mean, median, standard deviation, and range 
(maximum, minimum). All AML history data will be listed by patient.
10.5
Medical History
The incidence of Medical history will be summarized by system organ class (SOC) and 
preferred term (PT) using MedDRA version 21.1. In the summary tables, patients may be 
counted under multiple system organ class (SOC) and preferred terms (PT), but for each 
SOC and PT category, patients will be counted only once. All medical history data will be 
presented in patient listings. 


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10.6
Concomitant Medications
All prior medication and concomitant medications will be presented in patient listings.
10.7
Study Drug Administration and Exposure
Study drug administration and exposure will be summarized by number of treatment cycles 
completed and the number of weeks on study. The categorical (discrete) variables will be 
summarized using counts and percentages. The continuous variables will be summarized 
using mean, median, standard deviation, and range (maximum, minimum). All study drug
administration data will be listed by patient.
11.
EFFICACY ANALYSIS
The response criteria for this study are from the 2017 European Leukemianet 
recommendations from an international expert panel (Blood 2017;129(4):424–447).
Response categories include CR, CRi, CRh, CRMRD, MLFS, PR, SD, PD, Not Evaluated /
Missing. The best objective response for each patient will be summarized by number and 
percentage.
In addition, response rates will be categorized and summarized by number and percentage of 
patients meeting these definitions:
x
Combined Complete Remissions (CR, CRi).
x
Composite Complete Remission Rate (CR, CRi, CRh).
x
Combined Response Rate (CR, CRi, CRh, MLFS, and PR).
In addition to the summary tables, efficacy data will also be presented in the individual
patient listings.
12.
SAFETY ANALYSIS
The Safety Population is defined as all enrolled patients who received any amount of study 
treatment will be utilized for all safety analyses. 
In addition to the summary tables, safety data will also be presented in the individual patient 
listings.
12.1
Treatment Emergent Adverse Events
Treatment-emergent adverse events (TEAEs) are defined as all AEs that begin on or after the
date of the first administration of study drug. Related AEs are those reported as possibly
related, probably related, or related to study drug (ALDAC or ALV). The verbatim terms of 


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the Treatment Emergent Adverse Events (TEAE) will be coded to preferred terms (PT) and 
system organ classes (SOC) per MedDRA® (Medical Dictionary for Regulatory Activities)
Version 21.1 (or later).
All reported AEs (including non-TEAEs) will be listed, documenting all information 
collected on the eCRF including verbatim term, MedDRA preferred term, MedDRA system
organ class, start date, stop date, severity and relationship to study drug action taken, and 
outcome.
The TEAEs will be graded by the Investigator in terms of:
x
Severity graded 1-5 according to CTCAE v5.0:
o
1=Mild, 2=Moderate, 3=Severe, 4= Life Threatening, 5=Fatal.
x
Relation to study drug (ALDAC or ALV):
o
‘Related’ includes events where the causality was reported as ‘Possibly Related’, 
or ‘Probably Related’, or ‘Definitely Related’, or where the relationship was not 
reported on the eCRF.
o
‘Not Related’ includes events where the study drug causality was reported as 
‘Unrelated ‘or ‘Unlikely Related’ on the eCRF.
All TEAE summary tables will be presented with the number and percentages of patients in 
the Safety population. An overall summary of TEAEs will be tabulated by treatment
regimen, relation to study treatment, and grade. In addition, TEAEs will be summarized by
system organ class (SOC) and preferred term (PT).
Planned TEAE summary tables include: 
x
Overall Summary of Treatment-Emergent Adverse Events (Safety Population)
x
Incidence of Treatment-Emergent Adverse Events by MedDRA System Organ Class
and Preferred Term (Safety Population)
x
Incidence of Treatment-Emergent Adverse Events by MedDRA System Organ Class,
Preferred Term, and CTCAE Severity Grade  (Safety Population)
x
Incidence of Treatment-Emergent Grade 3, Grade 4, and Grade 5 Adverse Events by
MedDRA System Organ Class and Preferred Term (Safety Population)
x
Incidence of Treatment-Emergent Grade 3, Grade 4, and Grade 5 Adverse Events by 
MedDRA System Organ Class and Preferred Term and CTCAE Severity Grade 
(Safety Population)


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x
Incidence of Treatment-Emergent Adverse Events Judged Possibly, Probably or 
Definitely Related to the Study Drug Regimen by MedDRA System Organ Class and
Preferred Term  (Safety Population)
x
Incidence of Treatment-Emergent Grade 3, Grade 4, and Grade 5 Adverse Events 
Judged Possibly, Probably or Definitely Related to the Study Drug Regimen by 
MedDRA System Organ Class and Preferred Term  (Safety Population)
In the summary tables, patients may be counted under multiple system organ class (SOC) and 
preferred terms (PT), but for each SOC and PT category, patients are only counted once. If a
patient has the same AE on multiple occasions, the highest severity grade (fatal > life 
threatening > severe > moderate > mild) or drug relationship (related > possibly related > not
related) recorded for the event will be summarized.
12.2
Serious Adverse Events
Planned Serious TEAE summary tables include: 
x
Incidence of Serious Treatment-Emergent Adverse Events by MedDRA System 
Organ Class and Preferred Term (Safety Population)
x
Incidence of  Serious Treatment-Emergent Adverse Events Judged Possibly, Probably 
or Definitely Related to the Study Drug Regimen by MedDRA System Organ Class
and Preferred Term  (Safety Population)
x
Treatment-Emergent Adverse Events in the Standardized MedDRA Query for Tumor 
Lysis Syndrome Judged Possibly, Probably or Definitely Related to the Study Drug 
Regimen by MedDRA Preferred Term (Safety Population)
12.3
Clinical Laboratory Tests
Safety laboratory assessments will be presented in patient listings. 
12.4
Vital Signs
Vital signs data will be presented in patient listings. 
12.5
12-Lead Electrocardiogram (ECG)
ECG data will be presented in patient listings.
12.6
ECOG Performance Status
ECOG assessments will be presented in patient listings.


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12.7
Physical Examination and Pregnancy Test
The physical examination data and pregnancy test results will be presented in patient listings.
13.
PHARMACOKINETIC (PK) ANALYSIS
Not applicable. 
14.
PHARMACODYNAMIC (PD) ANALYSIS
Pharmacodynamic endpoints include:
x
BH3 profiling, including determination of MCL-1 dependence, at Baseline and End of
Treatment using bone marrow.
x
Minimal residual disease (MRD) to be determined by central CLIA accredited 
laboratory evaluation of bone marrow samples collected at baseline and at time of 
response assessments using standardized techniques (i.e., MPFC and molecular 
testing including NGS).
x
Peripheral blood and bone marrow samples will be collected at protocol- specific time 
points to evaluate other potential biomarkers including but not limited to MCL-1
dependence. These assessments may be explored in the context of AML or related 
conditions or drugs of similarclass.
Any PD data analysis will be performed by SDPO R&D group and/or sponsor PD consultant.
15.
COMMITMENT TO GOOD STATISTICAL PRACTICE
15.1
Definition of Good Statistical Practice
International Conference on Harmonization (ICH) Guidance on Statistical Principles for 
Clinical Trials (ICH E9) implicitly defines good statistical practice. Good statistical practice
includes both appropriate statistical designs to minimize bias and to maximize precision of
analysis plus operational excellence to assure credibility of results. The scientific design 
associated with any clinical trial is found in the protocol and in a more detailed pre-specified 
statistical analysis plan such as this one.
Due to the early termination of this study and low sample size, efficacy and safety endpoints 
will not be analyzed via inferential statistical methods. Descriptive statistics will be presented 
in the summary tables as described in this SAP, and full patient listings will be provided to
enable a synoptic clinical study report to be written for this study.


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15.2
Data Management and Use of CDISC Standards
Data standards for clinical development of drugs have been defined and are maturing under
various initiatives through the Clinical Data Interchange Standards Consortium (CDISC).
SDPO used third party vendors for clinical data collection and data analysis. Clinical data 
will be managed by IQVIA (US based CRO). and will be captured in electronic case report
form (eCRF) by the InForm EDC platform. The “raw” data contained in the eCRF clinical 
database will then be converted into Study Data Tabulation Model (SDTM) datasets per 
CDISC standards. The SDTM datasets will be utilized to create Analysis Data Model 
(ADaM) datasets. These CDISC data conversions will be conducted by Vantage Data 
Designs. These CDISC data conversions and data analysis will be conducted by Vantage 
Data Designs.
Other applicable standards include regulatory guidance’s from the Food and Drug
Administration (FDA), ICH Guidance on the Structure and Content of Clinical Study Reports 
(ICH E3), and ICH Guidance for Good Clinical Practice (ICH E6).
15.3
Testing/Validation Plan and Software System
Statistical Analysis Software (SAS) version 9.4 or later will be used to analyze the data, 
create summary tables, patient data listings, and graphical representation of the data. All SAS 
computer programs will be validated using industry standard validation procedures including 
independent quality control programming.
16.
STATISTICAL ANALYSIS CHANGES FROM THE PROTOCOL
The analyses described are based on the final clinical study protocol TPI-ALV-202
Amendment Version 2.0 dated August 11, 2020. This SAP supersedes the statistical 
considerations identified in the protocol.
17.
REFERENCES
1. 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.
2. FDA Draft Guidance for Industry: Clinical Trial Imaging Endpoint Process Standards. 
March 2015.


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3. International Conference on Harmonisation of Technical Requirements for Registration 
of Pharmaceuticals for Human Use, ICH Harmonised Tripartite Guideline, Structure and 
Content of Clinical Study Reports (E3), 30 November 1995.
4. International Conference on Harmonisation of Technical Requirements for Registration 
of Pharmaceuticals for Human Use, ICH Harmonised Tripartite Guideline, Good Clinical 
Practice Integrated Addendum: ICH E6 (R2, March 2018.
5. International Conference on Harmonisation of Technical Requirements for Registration
of Pharmaceuticals for Human Use, ICH Harmonised Tripartite Guideline, Statistical 
Principles for Clinical Trials (E9), 5 February 1998.
6. International Federation of Pharmaceutical Manufacturers and Associations. Medical 
Dictionary for Regulatory Activities (MedDRA). Version 21.0. Reston, Virginia, USA;
2008.
7. Protocol TPI-ALV-202: “A Phase 2, Open-label, Randomized, Two-stage Clinical Study 
of Alvocidib in Patients with Relapsed/Refractory Acute Myeloid Leukemia Following 
Treatment with Venetoclax Combination Therapy”. Amendment 2 dated August 11, 
2020.
8. SAS Institute Inc. SAS Version 9.4. Cary, NC, USA; 2002-2003.