A Phase 1b/2, Open-label Clinical Study to Determine Preliminary Safety and Efficacy of Alvocidib When Administered in Sequence After Decitabine or Azacitidine in Patients With MDS
Phase: PHASE1
Conditions: Myelodysplastic Syndromes (MDS)
Sponsor: Sumitomo Pharma America, Inc.



Protocol No. TPI-ALV-102 Amendment 4 
 
Final 
IND No. 057729 
 
19 August 2020 
 
 
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TABLE OF CONTENTS 
PROTOCOL SIGNATURE PAGE ............................................................................... 2 
ABBREVIATIONS ........................................................................................................ 8 
SYNOPSIS  ................................................................................................................. 10 
1. 
INTRODUCTION ................................................................................................. 27 
1.1 
Background ..................................................................................................27 
1.2 
Rationale ......................................................................................................27 
2. 
DRUG INFORMATION – ALVOCIDIB ............................................................... 29 
2.1 
Background ..................................................................................................29 
2.2 
Chemistry .....................................................................................................29 
2.3 
Mechanism of Action ....................................................................................29 
2.4 
Preclinical Studies ........................................................................................30 
2.4.1 In Vitro/In Vivo Studies ...................................................................................... 30 
2.4.2 Safety Pharmacology ........................................................................................ 31 
2.4.3 Nonclinical Absorption, Distribution, Metabolism and Excretion Studies .......... 31 
2.4.4 Animal Toxicology ............................................................................................. 32 
2.4.5 Genotoxicity ....................................................................................................... 32 
2.4.6 Reproductive and Developmental Toxicity ........................................................ 33 
2.4.7 Other Toxicity Studies ....................................................................................... 33 
2.5 
Clinical Studies .............................................................................................33 
2.5.1 Phase 1 and 2 Clinical Studies of Bolus and Hybrid FLAM Regimens in 
Patients with AML ......................................................................................................... 33 
2.5.2 Data Summaries from Phase 1 and 2 Clinical Studies in Patients with 
Relapsed/Refractory AML ............................................................................................ 37 
2.6 
Justification for Study Treatment Plan ..........................................................41 
2.7 
Summary of Risk and Benefits .....................................................................42 
3. 
STUDY OBJECTIVES ........................................................................................ 43 
3.1 
Phase 1b Objectives ....................................................................................43 
3.2 
Phase 2 Objectives ......................................................................................44 
4. 
INVESTIGATIONAL PLAN ................................................................................. 45 
4.1 
Overall Study Design ....................................................................................45 
4.2 
Assignment to Treatment .............................................................................47 
4.3 
Patient Population ........................................................................................47 
4.3.1 Number of Patients............................................................................................ 48 
4.3.2 Inclusion Criteria................................................................................................ 48 
4.3.3 Exclusion Criteria .............................................................................................. 49 
4.4 
Study Treatment ...........................................................................................50 

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4.4.1 Calculation of Doses ......................................................................................... 50 
4.4.2 Study Drug Administration ................................................................................ 50 
4.5 
Management of Toxicities and Dose Modifications .......................................54 
4.5.1 Management of Nonhematologic Toxicities ...................................................... 54 
4.5.2 Management of Hematologic Toxicities ............................................................ 58 
4.5.3 Dose-limiting Toxicities ..................................................................................... 58 
4.5.4 Dose Modifications ............................................................................................ 59 
4.6 
Concomitant Medications and Therapies ......................................................60 
4.6.1 Previous Therapies ........................................................................................... 60 
4.6.2 Concomitant Therapies ..................................................................................... 60 
4.6.3 Birth Control Requirements for Fertile Patients ................................................ 62 
4.7 
Protocol Deviations ......................................................................................62 
5. 
ON-STUDY CLINICAL AND LABORATORY EVALUATIONS ....................... 63 
5.1 
Predose Assessments (Phase 1b, Expansion at MTD, and Phase 2) ...........63 
5.1.1 Within 28 Days Prior to First Dose of Cycle 1 ................................................... 63 
5.1.2 Within 72 Hours Prior to First Dose of Cycle 1 ................................................. 64 
5.2 
Treatment Assessments during Phase 1b and Phase 2 ...............................65 
5.2.1 Cycle 1 .............................................................................................................. 65 
5.2.2 Cycles 2+........................................................................................................... 69 
5.3 
End of Study Assessments ...........................................................................72 
5.4 
Follow-up Assessments................................................................................73 
5.4.1 Follow Up for Safety .......................................................................................... 73 
5.4.2 Follow Up for Overall Survival ........................................................................... 73 
6. 
OFF-STUDY CRITERIA ...................................................................................... 74 
6.1 
Withdrawal of Patients ..................................................................................74 
6.2 
Reasons for Withdrawal ...............................................................................74 
6.3 
Follow-up for Patients Withdrawn from Study ...............................................75 
6.4 
Termination or Suspension of Study .............................................................75 
7. 
CRITERIA FOR EVALUATION .......................................................................... 76 
7.1 
Safety Endpoints ..........................................................................................76 
7.2 
Efficacy Endpoints ........................................................................................76 
7.3 
Pharmacokinetic Endpoints ..........................................................................77 
7.4 
Pharmacodynamic Endpoints .......................................................................78 
8. 
ADVERSE EVENTS ............................................................................................ 81 
8.1 
Definitions ....................................................................................................81 
8.2 
Causality ......................................................................................................82 
8.3 
Serious Adverse Events ...............................................................................82 
8.4 
Eliciting and Reporting Adverse Events ........................................................83 

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8.5 
Serious Adverse Events and/or Adverse Events Requiring Discontinuation 
of Study Drug ...............................................................................................83 
8.6 
Follow-up of Adverse Events ........................................................................84 
8.7 
Patient Deaths ..............................................................................................85 
8.8 
Reporting Adverse Events to the Regulatory Authorities ..............................85 
9. 
STUDY DRUG MANAGEMENT ......................................................................... 86 
9.1 
Study Drugs .................................................................................................86 
9.2 
Study Drug Dispensing and Accountability ...................................................86 
9.3 
Preparation and Administration ....................................................................87 
9.4 
Storage at Study Center ...............................................................................87 
9.5 
Compliance ..................................................................................................88 
10. RECORD MANAGEMENT ................................................................................. 89 
10.1 Data Collection .............................................................................................89 
10.2 Source Document Maintenance ...................................................................89 
10.3 Record Maintenance ....................................................................................91 
10.4 Study Center File Management ....................................................................91 
11. STATISTICAL CONSIDERATIONS ................................................................... 93 
11.1 General Considerations ................................................................................93 
11.2 Sample Size Considerations ........................................................................93 
11.3 Randomization and Blinding .........................................................................95 
11.4 Analysis Population Sets ..............................................................................95 
11.5 Patient Disposition ........................................................................................96 
11.6 Demographic and Baseline Characteristics ..................................................96 
11.7 Concomitant Medications .............................................................................96 
11.8 Treatment Administration / Compliance ........................................................96 
11.9 Efficacy Analysis ..........................................................................................97 
11.10 Safety Analysis .............................................................................................98 
11.10.1 
Adverse Events ............................................................................................ 98 
11.10.2 
Laboratory Tests .......................................................................................... 98 
11.10.3 
Vital Signs and Physical Examination Findings ........................................... 99 
11.11 Interim Analysis ............................................................................................99 
11.12 Pharmacokinetic Analysis .............................................................................99 
11.13 Pharmacodynamic Analysis ....................................................................... 100 

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12. PROTOCOL AMENDMENTS ........................................................................... 101 
13. MONITORING .................................................................................................... 102 
14. AUDITING .......................................................................................................... 103 
15. ETHICS AND RESPONSIBILITY ..................................................................... 104 
15.1 Principal Investigator’s Responsibilities ...................................................... 104 
15.2 Informed Consent ....................................................................................... 104 
15.3 Institutional Review Board .......................................................................... 105 
16. CONFIDENTIALITY .......................................................................................... 106 
17. NONPROTOCOL RELATED RESEARCH ..................................................... 107 
18. PUBLICATIONS ................................................................................................ 108 
19. REFERENCES .................................................................................................. 109 
APPENDIX A-1 – SCHEDULE OF ACTIVITIES (Patients Receiving DEC and 
Alvocidib) ............................................................................................. 112 
APPENDIX A-2 – SCHEDULE OF ACTIVITIES (Patients Receiving AZA and 
Alvocidib) ............................................................................................. 115 
APPENDIX A-3 – SCHEDULE FOR TLS EVALUATIONS (Patients Receiving 
AZA and Alvocidib) ............................................................................ 118 
APPENDIX B – ECOG PERFORMANCE STATUS SCALE ................................. 120 
APPENDIX C – NEW YORK HEART ASSOCIATION CLASSIFICATION OF 
HEART FAILURE ................................................................................. 121 
APPENDIX D – NCI COMMON TERMINOLOGY CRITERIA FOR ADVERSE 
EVENTS ................................................................................................ 122 
APPENDIX E – LABORATORY TESTS ................................................................. 123 
APPENDIX F – REVISED INTERNATIONAL WORKING GROUP (IWG) 
RESPONSE CRITERIA (2006) ........................................................... 124 
 
 

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LIST OF TABLES AND FIGURES 
Table 1:  Overview of Alvocidib Phase 1 & 2 Clinical Studies in AML  (In 
Chronologic Order) ............................................................................ 35 
Table 2: 
Alvocidib/FLAM in AML (Demographics and Dosing in 
Relapsed/Refractory Patients) ........................................................... 38 
Table 3: 
Alvocidib/FLAM in AML (Efficacy Parameters in 
Relapsed/Refractory Patients) ........................................................... 39 
Table 4: 
Alvocidib/FLAM in AML (Safety Data in Relapsed/Refractory 
Patients) ............................................................................................. 40 
Table 5: 
Proposed Dose Escalation Schema (DEC + Alvocidib) ..................... 52 
Table 6: 
Proposed Dose Schema (AZA + Alvocidib) ....................................... 52 
Table 7: 
Guide to Alvocidib Dose Adjustments Based on Toxicities ................ 59 
Table 8: 
Timing of PK Sampling during Cycle 1 of Phase 1b Study ................ 78 
Table 9: 
Timing of PD Sampling during Phase 1b and Phase 2 (Patients 
Receiving DEC + ALV) ...................................................................... 79 
Table 10: Timing of PD Sampling during Phase 1b and Phase 2 (Patients 
Receiving AZA + ALV) ....................................................................... 79 
 
 

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ABBREVIATIONS 
AE 
Adverse event 
ACM 
Cytarabine and mitoxantrone 
ALL 
Acute lymphocytic leukemia 
ALP 
Alkaline phosphatase 
ALT 
Alanine aminotransferase 
AML 
Acute myeloid leukemia 
aPTT 
Activated partial thromboplastin time 
AST 
Aspartate aminotransferase 
AUC 
Area under the concentration time curve 
AUC0-24 
AUC from 0 to 24 hours 
AUC0--inf 
AUC from 0 to infinity 
AUCt 
AUC from 0 to time t 
AZA 
Azacitidine 
B-CLL 
B-cell chronic lymphocytic leukemia 
β-HCG 
Beta human chorionic gonadotropin 
AUC 
Area under the curve 
BM 
Bone marrow 
BSA 
BUN 
Body surface area 
Blood urea nitrogen 
CBC 
Complete blood count 
CDK9 
Cyclin dependent kinase 9 
CFR 
Code of Federal Regulations 
CI 
Confidence interval 
CIV 
Continuous intravenous 
CL 
Clearance using noncompartmental methods 
Cmax 
Maximum concentration 
CR 
Complete response 
CRA 
Clinical research associate 
CRF 
Case report form 
CRi 
Complete Response with incomplete blood count recovery 
CRO 
Contract Research Organization 
CRR 
Complete Response Rate (CR/CRi/CRmarrow/PR/HI) 
CSR 
Clinical Study Report 
CTCAE 
Common Terminology Criteria for Adverse Events 
DCF 
Data clarification form 
DEC 
Decitabine 
DLT 
Dose-limiting toxicity 
DSMB 
Data Safety Monitoring Board 
ECOG 
Eastern Cooperative Oncology Group 
ECG 
Electrocardiogram 
eCRF 
Electronic case report form 
ESA 
Erythropoietin-stimulating agent 
FAB 
French-American-British (classification system) 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
hERG 
Human Ether­à­go­go­Related Gene 
Hgb 
Hemoglobin 
HI 
Hematologic Improvement 

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HMA 
Hypomethylating agent 
IC50 
Inhibitory concentration in 50% of test subjects 
IEC 
Independent Ethics Committee 
IHC 
Immunohistochemistry 
IND 
Investigational New Drug (application) 
IPSS-R 
Revised International Prognostic Scoring System 
IRB 
Institutional Review Board 
ITT 
Intent-to-treat 
IV 
Intravenous(ly) 
IVI 
Intravenous infusion 
IWG 
International Working Group 
LDH 
Lactate dehydrogenase 
LVEF 
Left ventricular ejection fraction 
MCL-1 
Myeloid cell leukemia 1 
MDS 
Myelodysplastic syndrome 
MedDRA 
Medical Dictionary for Regulatory Activities 
MTD 
Maximum tolerated dose 
NCI 
National Cancer Institute 
NYHA 
New York Heart Association 
OS 
Overall survival 
PD 
Progressive disease 
PD 
Pharmacodynamic 
PK 
Pharmacokinetic 
PR 
Partial response 
PRN 
As needed 
PS 
Performance status 
PT 
Prothrombin time 
QTc 
QT interval (corrected) 
RBC 
Red blood cell 
RP2D 
Recommended Phase 2 Dose 
RT-aPCR 
Quantitative reverse transcription-polymerase chain reaction 
SAE 
Serious adverse event 
SAS 
Statistical Analysis System (software) 
SD 
Stable disease 
SGOT (AST) 
Serum glutamic-oxaloacetic transaminase 
SGPT (ALT) 
Serum glutamic-pyruvic transaminase 
SIV 
SOP 
Study initiation visit 
Standard operating procedure(s) 
SPRT 
Sequential Probability Ratio Test 
T1/2 
Half-life 
TEAE 
Treatment-emergent adverse event 
TLS 
Tumor lysis syndrome 
Tmax 
Time to maximum concentration 
ULN 
Upper limit of normal 
WHO 
World Health Organization 
XIAP 
X-linked inhibitor of apoptosis 
 

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SYNOPSIS 
Title of Study: 
A Phase 1b/2, Open-label Clinical Study to Determine Preliminary 
Safety and Efficacy of Alvocidib When Administered in Sequence 
After Decitabine or Azacitidine in Patients with Myelodysplastic 
Syndromes (MDS) 
Clinical Phase: 
Phase 1b/2 
Study 
Center(s): 
Phase 1b:  US: Up to approximately 15 sites 
Phase 2:  US: Up to approximately 25 sites 
Study 
Indication: 
Myelodysplastic Syndromes 
Patient 
Population: 
• 
Patients with previously untreated MDS 
• 
Patients with MDS who have received <6 cycles of treatment 
with hypomethylating agents (HMAs) 
• 
Patients with de novo (cause unknown) or secondary MDS 
(treatment-related) who are not eligible for intensive induction 
chemotherapy or stem cell transplant  
o All French-American-British (FAB) subtypes (refractory 
anemia, refractory 
anemia 
with 
ringed 
sideroblasts, 
refractory anemia with excess blasts, refractory anemia with 
excess blasts in transformation, and chronic myelomonocytic 
leukemia) 
o Intermediate and above per the Revised International 
Prognostic Scoring System (IPSS-R) groups 
Planned 
Enrollment and 
Study 
Duration: 
Phase 1b:  Approximately 12–18 months to enroll up to 24 patients 
in dose escalation portion up to determination of the Maximum 
Tolerated Dose (MTD) and Recommended Phase 2 Dose (RP2D) 
Expansion at MTD:  Approximately 6-8 months to enroll up to 
25 patients in an Expansion cohort at MTD. Data collected from 
these patients will be used to confirm safety, explore potential 
biomarkers, and evaluate potential signals of alvocidib activity.  
Phase 2:  Approximately 18 months to enroll up to 25 patients to 
confirm efficacy   
Total study time (Phase 1b, Expansion at MTD, and Phase 2) will be 
approximately 36 to 44 months. 
Objectives: 
Phase 1b 
Primary: 
• 
To determine the MTD and RP2D of alvocidib administered in 
sequence after decitabine (DEC) or azacitidine (AZA) in patients 
with previously untreated MDS and patients with MDS who have 
received <6 cycles of treatment with HMAs 

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Secondary: 
• 
To determine the Complete Response Rate ([CRR]: Complete 
response [CR] / Complete Response with Incomplete blood 
count recovery [CRi] / CR in marrow / Partial Response [PR] / 
Hematologic Improvement [HI]) 
• 
To determine if treatment with alvocidib administered in 
sequence after DEC (during dose escalation) or AZA results in 
improvements in transfusion dependence (defined as an 
average transfusion requirement of ≥2 units/28 days of RBCs 
without any consecutive 28-day gaps between transfusions for a 
minimum of 56 days immediately preceding first dose) and/or 
hemoglobin level (transfusion data to include the hemoglobin 
value for which the transfusion was administered and must have 
been ≤10.0 g/dL within 7 days prior to transfusion administration 
to be counted toward the RBC transfusion-dependent status): 
o Hemoglobin increase of ≥1.5 g/dL without 
erythropoietin-stimulating agents (ESAs) 
OR 
o Reduction 
of 
≥4 
RBC 
transfusions/8 
weeks 
in 
comparison to pre-treatment values and lasting at least 
8 weeks 
Exploratory: 
• 
To evaluate MCL-1 dependence in untreated MDS patients via 
BH3 profiling 
• 
To determine whether DEC (during dose escalation) or AZA 
treatment modulates MCL-1 dependence in peripheral blood 
Phase 2 
Primary: 
• 
To determine preliminary efficacy and anti-MDS activity of 
alvocidib administered in sequence after AZA in untreated 
patients with de novo or secondary MDS  
Secondary: 
• 
To assess the CRR per the revised International Working Group 
(IWG) Criteria 
• 
To evaluate the tolerability of alvocidib when administered in 
sequence following AZA in this patient population 
• 
To determine whether a defined BH3 profile predicts response to 
alvocidib administered in sequence after AZA in untreated MDS 
population 
• 
To determine if treatment with alvocidib administered in 
sequence after AZA results in improvements in transfusion 
dependence (defined as an average transfusion requirement of 
≥2 units/28 days of RBCs without any consecutive 28-day gaps 
between transfusions for a minimum of 56 days immediately 

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preceding first dose) and/or hemoglobin level (transfusion data 
to include the hemoglobin value for which the transfusion was 
administered and must have been ≤10.0 g/dL within 7 days prior 
to transfusion administration to be counted toward the RBC 
transfusion-dependent status): 
o Hemoglobin increase of ≥1.5 g/dL without ESAs 
OR 
o Reduction 
of 
≥4 
RBC 
transfusions/8 
weeks 
in 
comparison to pre-treatment values and lasting at least 
8 weeks 
Exploratory Objectives: 
• 
To assess the pharmacokinetics (PK) of alvocidib when 
administered in sequence after AZA 
• 
To evaluate correlative biomarkers of therapy including, but not 
limited to, BH3 profiling with an emphasis on MCL-1 
dependence, 
genetic 
mutations, 
and 
other 
biomarkers 
associated with MDS  
• 
To document the percentage of patients transplanted 
post-treatment and outcomes post-transplant 
Additional exploratory analyses may be performed if useful in the 
interpretation of the data. 
Study Design: 
Phase 1b:  3+3 dose-escalation design 
Expansion at MTD:  using MTD determined in Phase 1b study, up to 
25 patients will be enrolled in an Expansion cohort to receive 
alvocidib following AZA to confirm safety, explore potential 
biomarkers, and evaluate potential signals of alvocidib activity 
Phase 2:  using optimal dose from the Phase 1b study, initiate 
fixed-dose study of approximately 25 patients in Simon 2-stage 
minimax design. 
Inclusion 
Criteria: 
To be eligible for participation in the study, patients must meet all of 
the following inclusion criteria: 
1. Aged ≥18 years 
2. Phase 1b Dose Escalation: Patients with previously untreated 
MDS and patients with MDS who received fewer than six (6) 
cycles of previous HMAs  
Phase 1b Expansion: Untreated patients with de novo or 
secondary MDS  
Phase 2: Untreated patients with de novo or secondary MDS 
3. Patients with an Eastern Cooperative Oncology Group (ECOG) 
Performance Status (PS) score ≤2 at enrollment 
4. Provide written informed consent prior to any study-related 
procedure. (In the event that the patient is re-screened for study 

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participation or a protocol amendment alters the care of an 
ongoing patient, a new informed consent form must be signed.) 
5. Patients with a life expectancy of ≥3 months (90 days) 
6. Patients with adequate major organ functions meeting the 
following criteria on the basis of laboratory data within 4 weeks 
(28 days) before enrollment (if multiple data are available, most 
recent data during the period): 
a. Serum creatinine: ≤1.8× the upper limit of the normal (ULN) 
range  
b. Total bilirubin: ≤2× the ULN  
c. Aspartate transaminase (AST) and alanine transaminase 
(ALT): ≤3× the ULN 
7. Be able to comply with the requirements of the entire study. 
8. Patients with Revised International Prognostic Scoring 
System (IPSS-R) intermediate-, high-, and very high-risk 
MDS  
Exclusion 
Criteria: 
Patients meeting any one of these exclusion criteria will be 
prohibited from participating in the study.  
1. Presence of concomitant severe cardiovascular disease:  
a. Patients who had myocardial infarction within 6 months 
(180 days) before enrollment 
b. Patients with significant diseases at enrollment that may 
affect study treatment, such as New York Heart Association 
(NYHA) Functional Class III or IV heart disease, National 
Cancer Institute (NCI) Common Terminology Criteria for 
Adverse Events (CTCAE) v5.0 grade ≥3 arrhythmia, angina 
pectoris, abnormal electrocardiogram findings, interstitial 
pneumonia or pulmonary fibrosis 
2. Presence of concomitant malignancy requiring chemotherapy or 
any malignancy (except basal and squamous cell carcinoma of 
the skin) for which the patient received chemotherapy within 
6 months prior to enrollment. NOTE: Diagnosis of any previous 
or concomitant malignancy is thus not an exclusion criterion. 
3. Presence of uncontrolled or uncontrollable infection(s); or 
≥Grade 3 infection according to NCI CTCAE v5.0 
4. Presence of any psychological, familial, sociological, or 
geographical condition that, in the opinion of the investigator, 
could potentially hinder compliance with the study protocol and 
follow-up schedule 
5. Patients with a dry tap on bone marrow aspiration before 
enrollment 

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6. Patients with concurrent autoimmune disease or a history of 
chronic or recurrent autoimmune disease, or patients who 
require long-term systemic steroid therapy greater than the 
equivalent of 20 mg of prednisone daily (excluding therapy given 
on an ‘as needed’ [PRN] basis) 
7. Patients with other documented malignancies within past year 
aside from synchronous or metachronous multiple cancers with 
a disease-free period of ≤5 years (excluding carcinoma in situ, 
mucosal carcinoma, or other such carcinomas curatively treated 
with local therapy) 
8. Patients with ≥Grade 2 hemorrhage according to NCI CTCAE 
v5.0 
9. Patients who have previously received alvocidib or another 
cyclin-dependent kinase 9 (CDK9) inhibitor  
10. Patients who are pregnant or breastfeeding 
11. Female patients of childbearing potential who are sexually active 
and unwilling to use a medically acceptable method of 
contraception associated with a low failure rate during and for at 
least 6 months after the last dose of study drug (Patients will be 
considered to be of childbearing potential unless surgically 
sterilized by hysterectomy, or bilateral tubal ligation / 
salpingectomy, or postmenopausal for at least 2 years.)  
12. Male patients with partners of childbearing potential who are 
unwilling to use condoms in combination with a second effective 
method of contraception during the trial and for at least 6 months 
after the last administration of study treatment. 
13. Patients who are inappropriate for participation in the study for 
other reasons in the opinion of the investigator or sub-
investigator(s) 
14. Patients with a known hypersensitivity to DEC (those patients 
enrolled in dose escalation), AZA, or mannitol 
15. Patients who have received erythropoietin-stimulating 
agents (ESAs) within 2 weeks (14 days) prior to 
Cycle 1/Day 1 
Study 
Treatment: 
Phase 1b  
Patients will receive alvocidib administered in sequence after DEC 
(during dose escalation) or AZA. 
Decitabine is administered as a 1-hour intravenous (IV) infusion (IVI) 
daily for 5 days at a dose of 20 mg/m2 followed on Day 8 by alvocidib 
as a loading dose over 30-minutes followed by a 4-hour IVI 
according to the following schedule.  
 
 

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Additional cycles may be considered following discussions between 
the investigators and the Medical Monitor.  
Supportive care measures for all patients to include: 
• 
Infection 
prevention 
(antibiotics, 
antifungals, 
antivirals) 
according to institutional standards 
• 
Routine growth factor support is not allowed. Growth factor 
support can be given at the discretion of the Investigator and with 
the Medical Monitor’s approval in the presence of life threatening 
infection with ongoing neutropenia. 
TLS Prophylaxis (DEC + ALV) 
• 
All patients receiving DEC (during dose escalation) will receive 
TLS prophylaxis as per each institution’s standard of care 
TLS Prophylaxis (AZA + ALV)  
All patients receiving alvocidib in sequence following AZA will 
receive TLS prophylaxis as detailed below: 
• 
IV Hydration 
o Prior to AZA 
 
IV hydration according to each institution’s standard of care 
o Prior to Alvocidib 
 
Mandatory IV hydration with 0.45% NaCl (or similar 
hydration fluid per institutional standard) sterile solution at 
500 cc for 1-2 hours prior to alvocidib, then an additional 
500 cc for 1-2 hours after alvocidib during Cycle 1 (volume 
may be reduced to between 250 cc-500 cc, if clinically 
indicated). Hydration is optional for subsequent cycles.  
• 
Diarrhea Prophylaxis 
o During AZA and Alvocidib Dosing 
 
Replace excessive fluid losses, including from diarrhea, 
unless otherwise clinically indicated. 
o Alvocidib-specific Measures 
 
Alvocidib can induce diarrhea when given over a short 
period of time. Over-the-counter measures are typically 
effective in this setting if initiated early.  
 
It is strongly suggested that patients take 2 tablets of 
loperamide, 2 mg each (or equivalent), prior to the 
alvocidib IVI and then take 1 tablet (2 mg) for every loose 
stool up to a maximum of 8 tablets (16 mg) in a 24-hour 
period. 
 
Persistent 
diarrhea 
despite 
optimal 
outpatient 
management would trigger medical consultation. Early 
consideration should be given for possible Clostridioides 

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difficile (C. difficile) infection in this patient population and 
identifying/treating as expeditiously as possible should be 
top of mind. 
• 
Oral Allopurinol 
o Mandatory oral allopurinol to be started on Day 1 of Cycle 1 
and continued daily for the first 2 weeks (ie, 14 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. 
• 
Oral Phosphate Binder 
o Mandatory oral phosphate binder to be started on Day 1 of 
Cycle 1 and continued daily for the first 2 weeks (ie, 14 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.  
• 
Laboratory Evaluations for Tumor Lysis Syndrome (‘tumor lysis 
labs’): 
o 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 first AZA and 2 hours 
(±30 minutes) after completion of first AZA dose 
 
Monitor tumor lysis labs prior to alvocidib IVI and 2 hours 
(±30 minutes) after completion of IV hydration post 
alvocidib.  
 
All tumor lysis labs should be drawn; however, the 
potassium level obtained at 2 hours post first AZA dose 
and 2 hours post hydration following alvocidib IVI should 
be reviewed immediately to determine if additional 
treatment is warranted (see Section 4.5.1.2).  
 
Labs will also be drawn daily for the first 2 days following 
first AZA dose (ie, Days 2-3) and alvocidib (ie, Days 11-12) 
and at least weekly for the remainder of Cycle 1.  
o 
During Cycle 2, tumor lysis labs will be assessed: 
 
Prior to C2D1 first AZA dose and at 2 hours post C2D1 
AZA dose  

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 
Prior to C2D10 alvocidib IVI and 2 hours (±30 minutes) 
after completion of alvocidib IVI. 
o 
During Cycles 3+, tumor lysis labs will be assessed at the 
discretion of the investigator in relation to patient blast counts 
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. 
Treatment 
Plan: 
Phase 1b 
Patients will be enrolled in cohorts of 3-6 patients. Escalation of the 
alvocidib dose will follow a standard 3+3 design with sequential 
cohorts of 3 patients treated with incrementally higher doses of 
alvocidib until a dose-limiting toxicity (DLT) is observed and the MTD 
is established. The first 2 patients at a dose level may be enrolled 
simultaneously and third patient will be enrolled after 14 days so long 
as the 2 initial patients have not experienced any unacceptable 
toxicity.  
Dose-limiting toxicities will be defined as: 
• 
Any Grade 5 toxicity that is not clearly and incontrovertibly 
related to the underlying disease or extraneous causes 
• 
Any Grade 4 nonhematologic toxicity considered at least 
possibly drug related 
• 
Grade 4 neutropenia lasting ≥42 days from the start of a cycle in 
the absence of evidence of active disease 
• 
Any AST or ALT elevation ≥3x ULN accompanied by serum 
bilirubin levels >2x ULN 
• 
Any Grade 3 nonhematologic toxicity considered at least 
possibly drug related and that does not resolve to ≤Grade 2 
within 48 hours, with the following exceptions: 
o Grade 3 bilirubin, AST, ALT or alkaline phosphatase will be 
considered dose-limiting only if resolution to ≤Grade 2 
requires more than 7 days  
o Grade 3 diarrhea, mucositis, nausea, or vomiting will be 
considered dose limiting only if resolution to ≤Grade 2 
(including use of supportive care) requires more than 7 days 
o ≥Grade 3 creatinine elevation that does not resolve to 
≤Grade 2 within 7 days 
o Anorexia, fever, neutropenic fever, and infections of any 
grade  
• 
Bone marrow hypoplasia that occurs for >42 days with bone 
marrow (BM) cellularity ≤5% and no evidence of MDS/leukemia. 
Bone marrow disease assessments conducted per protocol on 

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Day 28 (±3 days) of every even cycle may be used to guide this 
decision. 
If 1 of 3 patients in a cohort experiences a DLT, up to 3 additional 
patients will be treated at that dose level. If no additional DLTs are 
observed in the expanded 3- to 6-patient cohort within 28 days after 
the last patient was first dosed, the dose will be escalated in a new 
cohort of 3 patients. If 2 or more of 3-6 patients at a given dose level 
experience a DLT during the first cycle, then the MTD will have been 
exceeded and up to a total of 6 patients will be treated at the 
previous lower dose level. If 0 or 1 of 6 patients experiences a DLT 
at this previous lower dose level, this dose will be declared the MTD. 
The MTD is defined as the dose at which ≤1 of 6 patients experience 
a DLT during Cycle 1 with the next higher dose having at least 2 of 
3 to 6 patients experiencing a DLT during Cycle 1. Adverse events 
meeting the definition of DLT during Cycles 2+ will be taken into 
consideration when evaluating dose escalation.   
Once the MTD of ALV has been determined using the hybrid dosing 
schedule (ie, 30-minute IV bolus + 4-hour IVI), 2 cohorts of at least 
3 patients each will receive AZA followed in sequence by alvocidib 
administered as a 30- to 60-minute IVI. 
Expansion at MTD 
Once the MTD or preliminary RP2D of alvocidib administered by 30- 
to 60-minute IVI is identified, up to 25 patients will be enrolled in an 
Expansion cohort to receive alvocidib following AZA to confirm 
safety, explore potential biomarkers, and evaluate potential signals 
of alvocidib activity. Once this Expansion cohort is completed, the 
study will progress to Phase 2. 
Phase 2  
Stopping Rules based on Efficacy 
The Phase 2 design is based on the Simon 2-stage minimax design 
(Simon 1989). 
• 
Stage 1: Up to 15 evaluable patients will be enrolled and treated 
at the RP2D identified in the Phase 1b study. Stage 2 may be 
initiated 
at 
any 
point 
after 
confirming 
a 
response 
(CR/CRi/CRmarrow/PR/HI) in two Stage 1 patients. If there is ≤1 
responder among 15 evaluable Stage-1 patients, the study will 
be stopped after Stage 1. 
• 
Stage 2: Ten patients will be enrolled to bring the total enrollment 
in Phase 2 (including Stage-1 patients) to 25 evaluable patients. 
Stage-2 patients will also receive the RP2D dose of alvocidib 
administered by 30- to 60-minute IVI identified in the Phase 1b 
study. If 6 or more responses are observed in 25 patients, the 
conclusion will be that the combination regimen is worthy of 
further investigation. When the true response rate of 30% 
(alternative hypothesis) is tested against the null hypothesis 

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response rate of 10%; this design yields a Type I error rate of 
0.05 and power of 80%. 
Any patient who withdraws from Stage 1 or 2 for treatment-related 
toxicity or disease progression, or dies prior to being evaluated for 
response will be considered a nonresponder. Patients who drop out 
for other reasons prior to being assessed for response will be 
considered unevaluable and may be replaced. Enrollment into 
Phase 2 may be stopped at any point once ≥6 patients have had a 
response to treatment, but the maximum enrollment in Phase 2 will 
be 25 evaluable patients.  
Stopping Rules based on Safety 
Early stopping rules for safety are based on a Sequential Probability 
Ratio Test (SPRT) with a baseline toxicity rate of 5%; an upper 
ceiling of unacceptable toxicity of 20% (ie, toxicities meeting one or 
more DLT criteria as stated in Section 4.5.3); and alpha=0.05 with 
power=80%. 
The study will be stopped if unacceptable toxicities are observed in: 
• 
2 of the first 2 patients 
• 
3 of the first 11 patients  
• 
4 of the first 20 patients 
• 
5 of the first 29 patients (Ph 2 study to enroll maximum of 
25 patients, but considering possible replacement patients)  
Study 
Assessments: 
These assessments apply to both phases of the study.  
Predose 
• 
Screening Period (Within 28 Days Prior to First Dose of Cycle 1) 
o Informed Consent 
o Complete medical and disease history 
o Complete physical examination (all body systems) and 
including height (cm) and weight (kg) 
o Vital signs (body temperature, heart rate, systolic and 
diastolic blood pressures) 
o ECOG performance status  
o Hematology panel: complete blood cell count (CBC) with 
manual differential and platelet count 
 
Record all transfusions (hemoglobin and platelet) 
for the 8 weeks/56 days prior to screening (including 
the transfusion date and number of units with each 
transfusion) 
 
Record all CBC data for the 8 weeks/56 days prior to 
screening including each CBC that prompted a 
transfusion 
o Full serum chemistry panel  
o Coagulation parameters: prothrombin time (PT) and 
activated partial thromboplastin time (aPTT) 

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o Serum or urine pregnancy test in females of childbearing 
potential  
o Perform a 12-lead electrocardiogram (ECG) including 
assessment of corrected QT interval (QTc) 
o Chest radiograph (‘x-ray’) (if not done within previous 
28 days) 
o Perform bone marrow biopsy and/or aspiration and collect 
peripheral blood for disease status, standard cytogenetics, 
and pharmacodynamic (PD) analyses. If the initial bone 
marrow aspirate is nonproductive or not diagnostic, the 
procedure must be repeated. 
o Record 
all 
concomitant 
medications 
including 
all 
prescription drugs, nonprescription drugs, and nutritional 
supplements within the previous 28 days 
• 
Baseline Period (Within 72 Hour Prior to First Dose of Cycle 1) 
o Complete physical examination including weight (kg) and 
calculation of body surface area (BSA) 
o Vital signs 
o ECOG performance status  
o Hematology panel 
o Full serum chemistry panel  
o Serum or urine pregnancy test in females of childbearing 
potential 
o Administer prophylactic antibiotics, antivirals, antifungals, 
antiemetics, antidiarrheals according to standard practices 
at each investigational site (Day 1) 
o Administer TLS prophylaxis prior to first DEC dose 
according to standard practices at each investigational site  
o Administer TLS prophylaxis prior to first AZA and alvocidib 
doses per the guidelines provided in Section 4.5.1.1.2  
o Concomitant medications taken since previous predose 
assessment visit 
Treatment Period  
• 
Administer TLS prophylaxis prior to first DEC dose (during dose 
escalation) 
according 
to 
standard 
practices 
at 
each 
investigational site  
• 
Administer TLS prophylaxis prior to first AZA and alvocidib doses  
o AZA-specific TLS prophylaxis 
 
Administer pretreatment IV hydration per institutional 
standards 
 
Begin oral allopurinol daily from Days 1-14 of Cycle 1 
 
Begin oral phosphate binder treatment daily from 
Days 1-14 of Cycle 1  

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 
Replace excessive fluid losses, including from diarrhea, 
unless 
otherwise 
clinically 
indicated 
(see 
Section 4.5.1.2 and Section 4.5.1.3) 
o Alvocidib-specific TLS prophylaxis 
 
Administer pretreatment IV hydration at least 2 hours 
prior to first dose of alvocidib 
 
Continue oral allopurinol daily from Days 1-14 of 
Cycle 1  
 
Continue oral phosphate binder treatment daily from 
Days 1-14 of Cycle 1 (see Section 4.5.1.1.2) 
 
Replace excessive fluid losses, including from diarrhea, 
unless otherwise clinically indicated (Section 4.5.1.2 
and Section 4.5.1.3) 
• 
Just Prior to First Dose of DEC, AZA, and Alvocidib 
o Record vital signs measured 5-15 minutes prior to the 
initiation of infusion following a 5-minute rest 
o Collect blood for evaluation of laboratory parameters 
(Appendix E):  
 
Tumor lysis labs 
o Collect urine or serum sample for β-hCG pregnancy test for 
females of child-bearing potential if screening pregnancy 
test is greater than 72 hours prior to first dose. 
• 
At 2 hours post initial AZA dose or post IV hydration (alvocidib), 
draw tumor lysis labs and immediately assess potassium level 
for indications of tumor lysis 
• 
Each Cycle: Weekly Unless Otherwise Stated 
o Abbreviated physical examination (AE- or symptom-directed 
exam) 
o Vital signs 
o ECOG performance status 
o CBC with differential and platelet count 
o Full serum chemistry panel  
o Response assessments and standard cytogenetics at end 
of Cycles 2, 4, 6, and then every 4 cycles, thereafter, or as 
clinically indicated 
o Assessment of BH3 profiling and other potential biomarkers 
in peripheral blood (as indicated) and bone marrow 
aspirates (whenever samples are collected for response 
assessments)  
o Assessment of AEs 
o Concomitant medications associated with an AE 
o Record all transfusions (hemoglobin and platelet) 
including the transfusion date and number of units with 
each transfusion  

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Pharmaco-
kinetic 
Assessments: 
PK parameters assessed using noncompartmental methods to 
include:  
• 
Cmax = maximum observed plasma concentration 
• 
Tmax = time to Cmax (peak time) 
• 
AUC0-24 = area under the plasma concentration curve from time 
0 to 24 hours 
• 
AUC0-inf = AUC from time 0 to infinity 
• 
AUCt = area under the plasma concentration curve from time 0 
to time t 
• 
t1/2 = half life 
• 
CL = clearance using noncompartmental methods 
Pharmaco-
dynamic 
Assessments: 
Peripheral blood and bone marrow samples will be collected at 
protocol-specific time points to assess the effects of alvocidib when 
administered in sequence after DEC (during dose escalation) or 
AZA. Analyses may include, but are not limited to, assessment of 
BH3 profiling by flow cytometry with an emphasis on MCL-1 
dependence, evaluating genetic mutations, and other biomarkers 
associated with MDS. 
The samples may be retained for no longer than 20 years after study 
completion or per local requirements. 
Safety 
Endpoints: 
Phase 1b 
Safety and tolerability of alvocidib when administered in sequence 
after DEC (during dose escalation) or AZA will be assessed by 
analyzing DLTs, MTD, and incidence rates of treatment-emergent 
adverse events (TEAEs) summarized within treatment group(s) 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). Adverse events will be graded 
according to NCI CTCAE v5.0. 
Other routine safety assessments (eg, physical examinations, vital 
sign measurements, and clinical laboratory testing (hematology and 
chemistry) will be evaluated as measures of safety and tolerability 
for the entire study duration. These assessments will be summarized 
by shift tables and treatment group using mean, standard deviation, 
median, minimum and maximum changes from baseline values.  
Mortality (all causes) will be calculated. 
Phase 2 
During the Phase 2 study, tolerance and toxicity will be assessed 
through evaluation of physical examinations, vital signs, laboratory 
studies, solicited and unsolicited adverse events, and all causes of 
mortality at 30 and 60 days. 
Routine safety assessments will be summarized by shift tables using 
mean, standard deviation, median, minimum and maximum changes 
from baseline values. 
Mortality (all causes) will be calculated. 

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Efficacy 
Endpoints: 
Phase 2  
Primary Efficacy Endpoints 
• 
Assess preliminary efficacy, as determined by response rate, 
duration of response, hematological improvement, rate of 
transfusion independence, time to acute myeloid leukemia 
(AML), and overall survival (OS). 
Efficacy endpoints will be any objective response to study drug 
therapy using assessments defined by the 2006 revised 
International Working Group (IWG) and European MDS Working 
Group. 
Secondary Efficacy Endpoints 
• 
The proportion of MDS patients in the overall population 
achieving RBC transfusion independence with duration ≥84 days 
(12 weeks) during treatment. Baseline RBC transfusion 
dependency is defined as an average transfusion requirement of 
≥2 units/28 days of RBCs without any consecutive 28-day gaps 
between transfusions for a minimum of 56 days immediately 
preceding first dose. Transfusion data include the hemoglobin 
value for which the transfusion was administered and must have 
been ≤10.0 g/dL within 7 days prior to transfusion administration 
to be counted toward the RBC transfusion-dependent status. 
• 
Platelet transfusion independence with duration ≥84 days 
(12 weeks) will be assessed in the proportion of patients who 
were platelet transfusion-dependent at baseline. Baseline 
platelet transfusion requirements are established by the number 
of platelet transfusions administered during the 56 days 
immediately preceding and including the date of first dose. 
• 
Erythroid hematologic improvement and platelet hematologic 
improvement will be assessed according to the 2006 revised 
IWG criteria.  
• 
Correlation of complete response rates with BH3 profiling results 
including MCL-1 dependency 
• 
Overall survival compared to historical survival 
Complete details of the planned analysis will be documented in a full 
Statistical Analysis Plan (SAP), which will be finalized before locking 
the study database.  
PK Endpoints: 
Plasma concentrations of alvocidib will be summarized by 
descriptive statistics, including mean, n, standard deviation, 
coefficient of variation, minimum, maximum, and median. Prior to 
analysis of study samples, the assay sensitivity, specificity, linearity, 
and reproducibility will be documented.  
Plasma PK analyses for alvocidib and known metabolites, if any, and 
dose proportionality will be determined on Days 8 and 9 (for patients 
receiving alvocidib following DEC during dose escalation) or 
Days 10 and 11 (for patients receiving alvocidib following AZA) of 

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1. 
INTRODUCTION 
1.1 BACKGROUND 
Myelodysplastic syndromes (MDS) are a heterogeneous group of 
hematopoietic stem cell disorders. They are characterized by dysplasia in the 
myeloid, megakaryocytic and/or erythroid lineages. The abnormal cells 
belong to a malignant clone, which represses the remaining normal cells in 
the bone marrow. Patients suffer from peripheral blood cytopenias (anemia, 
leukopenia and/or thrombocytopenia).  
The overall incidence of MDS is estimated to be 3 to 4 cases per 100,000 
persons per year. Greater than 85% of these patients are older than 60 years 
at the time of the diagnosis. It is generally assumed that the incidence is 
underestimated due to the complexity of diagnosing MDS. Indolent forms of 
MDS, when blast counts are normal or only slightly elevated are difficult to 
diagnose. However, there are a number of other conditions, such as infections 
or medication that can result in transient cytopenias and dysplastic cells, 
without clonal aberrations. In approximately 50% of patients, chromosomal 
abnormalities are found using conventional cytogenetics, which can facilitate 
the diagnosis of MDS. 
The natural course of MDS ranges from an indolent disease without impaired 
survival that can be controlled with supportive care, to a more acute 
manifestation with severe bone marrow failure resulting in life-threatening 
complications. About 30% of the patients diagnosed with MDS progress to 
develop acute myeloid leukemia (AML). The primary cause of mortality in 
MDS patients is from complications of bone marrow failure. 
1.2 RATIONALE 
Treatment options for patients with MDS include supportive care, high 
intensity and/or low intensity drug therapy and, in a small proportion of 
patients, stem cell transplantation.  
Supportive care is typically targeted at addressing anemia as well as 
infections or other comorbidities related to ineffective bone marrow function. 
Supportive care may include transfusion therapy, erythropoiesis-stimulating 
agents and antibiotic therapy. 
Drug therapy includes: 
• Lenalidomide for those with myelodysplastic syndrome associated with 
an isolated del(5q) chromosome abnormality who need frequent red 
blood cell transfusions 
• Immunosuppressive therapy to decrease erythrocyte turnover and 
therefore lessen the need for red blood cell transfusions. 

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• Hypomethylating agents (HMAs), ie, azacitidine (AZA) and decitabine 
(DEC) 
• Chemotherapy with stem cell transplant 
Alvocidib in time-sequential therapy demonstrated significant clinical activity 
in secondary AML patients with prior MDS. Alvocidib, a cyclin-dependent 
kinase 9 (CDK 9) inhibitor is being developed for the treatment of AML; is 
involved in regulating of transcription through activation of RNA polymerase 2.  
In cancer biology, CDK 9 is particularly relevant as a key enzyme regulating 
levels of myeloid cell leukemia (MCL-1), an important survival factor that is 
controlled by RNA polymerase. Alvocidib has been evaluated in patients with 
solid tumors and hematologic malignancies. Eight Phase I or II clinical trials 
have been completed in patients with AML, totaling more than 400 patients 
with both relapsed/refractory or newly diagnosed AML. In these trials, 
alvocidib was evaluated as a single agent as well as in time-sequential 
therapy with cytarabine and mitoxantrone (ACM). 
Patients with IPSS-R intermediate and above MDS have an increased risk of 
developing AML and may be treated with the same chemotherapy regimens 
used in patients with AML.    
Preclinical studies have demonstrated that decitabine exposure increased the 
expression of NOXA, which is a specific antagonist of the survival factor 
MCL-1. Pharmacologic downregulation of MCL-1 via CDK 9 inhibition, as well 
as upregulation of the MCL-1 antagonist, NOXA, following decitabine 
exposure may result in enhanced antileukemic activity in MCL-1-dependent 
malignancies. In addition, MV411 cells pretreated with alvocidib were shown 
to be more sensitive to subsequent treatment with another HMA, azacitidine. 

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synthesis [8, 9]. 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 [10]. 
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 [11]. 
Patients with IPSS-R intermediate and above MDS have an increased risk of 
developing AML and may be treated with the same chemotherapy regimens 
used in patients with AML.    
Preclinical studies have demonstrated that decitabine exposure increased the 
expression of NOXA, which is a specific antagonist of the survival factor 
MCL-1. Pharmacologic downregulation of MCL-1 via CDK 9 inhibition, as well 
as upregulation of the MCL-1 antagonist, NOXA, following decitabine 
exposure may result in enhanced antileukemic activity in MCL-1 dependent 
malignancies. 
2.4 PRECLINICAL STUDIES 
2.4.1 
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 [1, 2, 3]. 
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) [4].  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 [12]. 
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 B­cell chronic lymphocytic leukemia (B­CLL) cells at 
drug concentrations ranging from 10 to 100 nM [13, 14]. The induction of 
apoptosis correlated best with depletion of the antiapoptotic proteins myeloid 
cell leukemia­1 (MCL­1) and X­linked inhibitor of apoptosis (XIAP) [5, 7]. 
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. 

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Significant antitumor activity was observed in 6 human leukemia xenograft 
models in mice (EOL­1 and ML­2 acute myeloid leukemia [AML], Ramos Non-
Hodgkin’s lymphoma, SUDHL­4 follicular lymphoma, HL­60 promyelocytic 
leukemia, and L363 multiple myeloma). In the SUDHL­4 and HL­60 studies, 
optimal activity was observed with daily × 5 bolus intravenous (IV) or 
intraperitoneal administration of 7.5 mg/kg alvocidib that gave peak plasma 
levels of 7 μM, followed by a progressive decline to approximately 100 nM in 
8 hours [15]. 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 demonstrated only minor activity when evaluated in vivo in various 
solid tumor models. 
2.4.2 
Safety Pharmacology 
Alvocidib produced no significant effects on the central nervous, respiratory, 
or hematological systems, however, alvocidib at 1 μM produced a slightly 
increased contractile force (+24%) and a decreased rate of contractions 
(­26%) in isolated guinea pig atria. Alvocidib slightly blocked in vitro Human 
Ether­à­go­go­Related Gene (hERG) currents, with an average IC50 value of 
3.2 μmol/L (1286 ng/mL). Alvocidib produced no physiologically relevant 
modifications of hemodynamic parameters or electrocardiogram in 
anesthetized dogs when given intravenously at 0.8 mg/kg (16 mg/m2) during 
a 1­hour infusion. 
2.4.3 
Nonclinical Absorption, Distribution, Metabolism and Excretion 
Studies 
Nonclinical pharmacokinetic studies in intravenously treated mice, rats, and 
dogs showed that plasma clearance was high (3.5 L/h/kg in rats and 
1.4 L/h/kg in dogs) and elimination half-lives (t1/2) were short (1.9 hours in rats 
and 1.1 hours in dogs). In vitro protein binding of the drug was concentration 
independent. Binding was highest in human plasma (>90%) and slightly lower 
in rat (~88%) and dog (~80%) plasma. In rats, alvocidib and/or its metabolites 
were distributed throughout the body within 5 minutes and disappeared from 
organs and tissues within 72 hours.  
In pigmented rats, binding of alvocidib and/or its metabolites was associated 
with the melaniferous tissue of the eye. 

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2.4.4 
Animal Toxicology  
Single-dose intravenous (IV) toxicity studies were conducted in rats 
(30­minute infusion) and dogs (30­minute or 24­hour infusion). The maximum 
tolerated dose (MTD) in the rat was 10 mg/kg (60 mg/m2), whereas in the dog 
(30­minute infusion), the MTD was 0.75 mg/kg (15 mg/m2). Clinical 
observations included vomiting (dogs), diarrhea (rats and dogs), and 
gastrointestinal bleeding (dogs). Deaths were attributed to gastrointestinal 
toxicity. Administration of alvocidib at 2.6 mg/kg (52 mg/m2) by 24­hour 
continuous intravenous (CIV) infusion was nonlethal in the dog, whereas 
1.5 mg/kg (30 mg/m2) was lethal when administered as a 30­minute IV 
infusion. 
Repeated-dose toxicity studies were conducted in rats and dogs by multiple 
30­minute IV infusions and multiple 72­hour infusions. Four-week studies with 
daily 30­minute infusions caused mortality in rats at 3 mg/kg/day 
(18 mg/m2/day) and in dogs at 0.5 mg/kg/day (10 mg/m2/day). The 
dose-limiting toxicity (DLT) related to the exaggerated pharmacological 
properties of the compound occurred in the gastrointestinal tract, in the bone 
marrow, and in the lymphoid tissues. Liver enzymes were elevated in some 
of the studies. Toxicity was generally dose proportional and independent of 
gender. Most effects were partially or completely reversible within 4 weeks. In 
general, target organ toxicity seen with continuous infusion was comparable 
to that produced by daily dosing. Multiple-cycle toxicity studies (72­hour IV 
infusions every 2 weeks) in rats (over 3 and 6­month periods) and dogs (over 
a 6­month period) were associated with thrombosis, necrosis, inflammation, 
and fibrosis at the infusion site (vena cava) in many animals.  This local toxicity 
was not predicted by single-dose local tolerance studies in dogs and rabbits 
conducted by IV, perivenous, intra-arterial, and intramuscular administration. 
2.4.5 
Genotoxicity 
Alvocidib was found to be negative in the bacterial reverse mutation test 
(Ames test) (Study 98.0059, Study C350.501017) and in the hypoxanthine-
guanine phosphoribosyltransferase gene mutation tests in Chinese hamster 
V79 cells (Study 98.0057, Study 98.0058). It was found to be positive in the 
mouse lymphoma assay only in the presence of metabolic activation (study 
C350.703). These results suggested that alvocidib could lack mutagenic 
activity. Alvocidib was found to be positive in the in vivo mouse bone marrow 
micronucleus test (study 98.0056), but negative in the in vitro chromosome 
aberration test in Chinese hamster V79 cells under the experimental 
conditions of the test (study 98.0058), suggesting that alvocidib was able to 
induce chromosome damage in vivo. Based on this battery of genetic toxicity 
studies, alvocidib was considered to be potentially genotoxic. 

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2.4.6 
Reproductive and Developmental Toxicity 
Alvocidib did not affect fertility and reproduction in mice or rats, although 
degeneration/necrosis of seminiferous tubular germ cells was observed in 
mice at 4 mg/kg/day (12 mg/m2/day). Potential embryo-fetal toxicity has been 
evaluated in rats and rabbits. Alvocidib caused embryo-fetal toxicity at IV 
doses ≥0.32 mg/kg/day (1.9 mg/m2/day) in Sprague-Dawley rats and 
≥0.1 mg/kg/day (1.2 mg/m2/day) in rabbits. Toxic effects included intrauterine 
deaths, decreased intrauterine fetal growth, and skeletal changes (ie, 
decreased ossification and malformations). In a peri- and postnatal toxicity 
study in rats, toxicities were limited to bilateral microphthalmia in one 
0.1 mg/kg/day (0.6 mg/m2/day) F1 pup and unilateral eye microphthalmia in 
one 0.75 mg/kg/day (4.5 mg/m2/day) F1 pup. These malformations were 
considered to be test-article related based on historical control data in this 
strain of rats. 
2.4.7 
Other Toxicity Studies 
In the in vitro hemolytic potential assay, alvocidib formulations at final 
concentrations of >1 mg/mL induced slight to severe hemolysis of human 
whole 
blood. 
Alvocidib 
formulations 
caused 
precipitates 
at 
final 
concentrations of ≥2.5 mg/mL and cloudiness at a final concentration of 
1 mg/mL when mixed with human plasma in vitro. Final alvocidib 
concentrations of ≤0.5 mg/mL and the vehicle did not cause hemolysis in 
human whole blood and were fully compatible with human plasma in vitro. 
Alvocidib did not produce in vitro phototoxicity in 3T3 cells when tested up to 
200 μg/mL (limit of solubility in the culture media) in the presence of ultraviolet 
A irradiation. 
2.5 CLINICAL STUDIES 
Alvocidib has now been evaluated in solid tumors and hematologic 
malignancies. Eight Phase 1 and 2 clinical trials have been completed in 
patients with intermediate and poor-risk AML, including more than 
400 patients with both relapsed/refractory and newly diagnosed AML. In these 
trials, alvocidib has been evaluated as a single agent as well as in combination 
with cytarabine and mitoxantrone. 
2.5.1 
Phase 1 and 2 Clinical Studies of Bolus and Hybrid FLAM Regimens 
in Patients with AML 
Initially, Phase 1 clinical trials in AML patients incorporated alvocidib into the 
“Timed Sequential Therapy” (TST) AML induction therapy approach from the 
1990s, which had utilized cytarabine and later added mitoxantrone (AM) [16]. 
Investigators at the University of Maryland, and then at Johns Hopkins, added 
alvocidib to AM for the dual purpose of initial cytoreduction and enhancing the 
cell cycle progression of the remaining leukemic cell cohort, followed by the 

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cycle-dependent agents cytarabine and mitoxantrone (FLAM regimen). Two 
alvocidib dosing schedules have been evaluated: by 1-hour bolus infusion, 
and by a hybrid dosing schedule consisting of a 30-minute short IV bolus dose 
followed by a 4-hour IV infusion. A listing of all eight (8) clinical studies of 
FLAM in relapsed/refractory patients and newly diagnosed patients is 
provided in Table 1. 
 
 

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Table 1:  
Overview of Alvocidib Phase 1 & 2 Clinical Studies in AML  
(In Chronologic Order) 
Study (Reference) 
N 
Treatment Regimen 
Patient Population 
Study 1:  
JHOC J0254/ 
NCI-3170  
Phase 1 FLAM [17] 
Total: 
34 
 
AML: 
26 
 
Alvocidib Bolus 1 hr IV: 
40, 50, 60 mg/m2/d on Days 1-3 
Ara-c: 2 gm/m2/72h by CIV given 
Days 6-8 
Mitoxantrone: 40 mg/m2 given by  
60-120 min IV on day 9 
Adults median age 54, 
primary refractory, multi-
refractory or relapsed 
AML (26) ALL (7) CML 
(1)  
Study 2: 
JHOC J0254/ 
NCI-3170  
Phase 2 FLAM [18] 
62 
AML 
Alvocidib Bolus 1 hr IV:  
50 mg/m2/d on Days 1-3 
Ara-c: 2 gm/m2/72h by CIV given 
Days 6-8 
Mitoxantrone: 40 mg/m2 given by  
60-120 min IV on day 9 
Adults median age 58, 
primary refractory (13), 
multirefractory (10), 
relapsed (24), newly 
diagnosed secondary 
AML 
(15) 
Study 3: 
OSU-0479/ 
NCI-6947  
Phase 1 Alvocidib  
Monotherapy [19] 
Total: 
24 
 
AML: 
19 
Alvocidib monotherapy  
dose-escalation, Hybrid regimen: 
20 mg/m2 & 30 mg/m2  
30 mg/m2 & 35 mg/m2 
30 mg/m2 & 50 mg/m2 
40 mg/m2 & 60 mg/m2 
50 mg/m2 & 75 mg/m2 
30 min bolus followed by 4-hr 
infusion/day on Days 1,2,3 
Adults median age 62, 
relapsed or refractory  
non-M3 AML (19), ALL 
(5) 
Study 4: 
JHOC J0669/ 
NCI-7845  
Phase 2 FLAM [20] 
45 
AML 
Alvocidib Bolus 1hr IV: 50 mg/m2/d 
Days 1-3 
Ara-c: 2 gm/m2/72h by CIV given 
Days 6-8 
Mitoxantrone: 40 mg/m2 given by  
60-120 min IV on day 9 
Adults median age 61, 
newly diagnosed, 
pathologically confirmed, 
previously untreated 
intermediate/poor risk 
AML 
Study 5: 
JHOC J06133/ 
NCI-7889  
Phase 1 FLAM [21] 
Total: 
55 
 
AML: 
49 
Alvocidib dose-escalation in Hybrid 
regimen 
20 mg/m2 & 30 mg/m2  
25 mg/m2 & 35 mg/m2 
30 mg/m2 & 40 mg/m2 
30 mg/m2 & 50 mg/m2 
30 mg/m2 & 60 mg/m2 
30 mg/m2 & 70 mg/m2 
given as:  
30-min bolus followed by 4-hr 
infusion/d on Days 1,2,3  
Ara-c: 2 gm/m2/72h by CIV given 
Days 6-8 
Mitoxantrone: 40 mg/m2 given by  
60-120 min IV on day 9 
Adults median age 54, 
pathologically confirmed 
relapsed and refractory 
AML (49), ALL (3), ABL 
(3) 
 
 
 

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Table 1:  
Overview of Alvocidib Phase 1 & 2 Clinical Studies in AML  
(In Chronologic Order) (cont) 
Study (Reference) 
N 
Treatment Regimen 
Patient Population 
Study 6: 
ECOG 1906  
Phase 2 Randomized 
Trial  
of Carboplatin and 
Topotecan; Alvocidib, 
Mitoxantrone and 
Cytosine Arabinoside; 
and Sirolimus, 
Mitoxantrone, 
Etoposide and Cytosine 
Arabinoside for the 
Treatment of Adults 
With Primary Refractory 
or Initial Relapse of 
AML [22] 
Ongoing follow-up 
AML 
 
Total: 
111  
 
Arm B 
FLAM:
36 
Arm A:  CT 
carboplatin and topotecan IV 
continuously over 24 hours on 
days 1-5 
Arm B:  Hybrid FLAM 
Alvocidib: 30 mg/m2 by 30-min 
bolus followed by & 60 mg/m2  
by 4-hr CIV/day on Days 1,2,3 
Ara-c: 2 gm/m2/72h by CIV given 
Days 6-8 
Mitoxantrone: 40 mg/m2 given by  
60-120 min IV on day 9 
Arm C:  Sirolimus-MEC 
sirolimus PO QD on days 2-9, 
mitoxantrone hydrochloride IV 
over 15 minutes QD, etoposide IV 
over 1 hour QD, and Ara-c IV over 
3 hours QD on days 4-8 or 5-9 
Adults 18-70 years,  
relapsed or refractory 
AML (36 on FLAM 
arm);  
median age 58 
Study 7: 
JHOC J0856/ 
NCI-8237 
Phase 2 FLAM [23] 
AML 
78 
Arm A:  Bolus FLAM 
Alvocidib Bolus 1 hr IV:  
50 mg/m2/d on Days 1-3 
Ara-c: 2 gm/m2/72h by CIV given 
Days 6-8 
Mitoxantrone: 40 mg/m2 given by  
60-120 min IV on day 9 
Arm B: Hybrid FLAM 
Alvocidib: 30 mg/m2 by 30-min 
bolus followed by 40 mg/m2  
by 4-hr CIV/day on Days 1,2,3 
Ara-c: 2 gm/m2/72h by CIV given 
Days 6-8 
Mitoxantrone: 40 mg/m2 given by  
60-120 min IV on day 9 
Adults median age 
61, newly diagnosed, 
pathophysiologically 
confirmed, previously 
untreated 
intermediate/poor risk 
AML 
Study 8: 
JHOC J1101/  
NCI-8972  
Randomized  
Phase 2  
FLAM vs 7&3 [24] 
Ongoing follow-up 
AML 
Total: 
165 
 
FLAM: 
109 
 
 
7&3: 
56 
Arm A: Bolus FLAM 
Alvocidib Bolus 1-hr IV:  
50 mg/m2/d on Days 1-3 
Ara-c: 2 gm/m2/72h by CIV given 
Days 6-8 
Mitoxantrone: 40 mg/m2 given by  
60-120 min IV on day 9 
 
Arm B:  7&3 
Ara-c: 100 mg/m2/day IV infusion 
Days 1-7 
Daunorubicin 90 mg/m2 /day IV 
over 30-60 minutes Days 1, 2, 3 
Adults median age 60 
(FLAM), newly 
diagnosed, 
pathologically 
confirmed, previously 
untreated 
intermediate/poor risk 
AML 
(including Secondary 
AML) 
 

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2.5.2 
Data Summaries from Phase 1 and 2 Clinical Studies in Patients 
with Relapsed/Refractory AML 
Table 2, Table 3, and Table 4 provide details regarding the demographics, 
efficacy, and safety data, respectively, summarized from the five trials of 
FLAM in relapsed/refractory AML patients (ie, Studies 1, 2, 3, 5, and 6). 

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

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

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

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2.6 JUSTIFICATION FOR STUDY TREATMENT PLAN 
About 30% of patients diagnosed with MDS will progress to AML. Patients with 
IPSS-R intermediate and above MDS have an increased risk of developing 
AML and may be treated with the same chemotherapy regimens used in 
patients with AML.  
Two alvocidib dosing schedules (ie, bolus and hybrid dosing) have been 
evaluated in eight clinical trials in patients with AML (Table 1). While both 
regimens of ACM have shown substantial activity in patients with AML, the 
hybrid regimen will be used in this study. Clinical data from a randomized study 
that compared the two dosing regimens suggest that the hybrid schedule tends 
to produce a higher remission rate (62% versus 74%) in poor-risk, newly 
diagnosed AML patients [23]. A high CR rate (39%) has also been documented 
with the hybrid regimen in relapsed and refractory AML patients (and 92% CR 
among relapsed-only patients) [21]. In addition, the safety profile of the two 
regimens appears similar, though there may be a trend to lower early mortality 
with the hybrid regimen. In these two studies, the incidence of Tumor Lysis 
Syndrome (TLS) was 9%, and treatment-related mortality was 8% and 9%, 
respectively. 
Alvocidib is a potent inhibitor of CDK9 and downregulates CDK9-driven 
transcription of super enhancer-regulated genes, such as c-Myc and MCL-1. 
Primary pharmacology of alvocidib is related to potent inhibition of CDK9 which 
disrupt super enhancer-driven expression of MCL-1 as this plays a central role 
in the super enhancer complex. The ability of alvocidib to alter the expression 
of MCL-1 may provide a novel approach to targeting MCL-1-dependent 
malignancies such as MDS or multiple myeloma. Apoptosis following alvocidib 
is rapid and not linked to cell cycle arrest [25].  
In the clinic, three-day dosing of alvocidib resulted in an average reduction of 
circulating blasts of greater than 75% [19]. A functional assay has been 
developed to identify patients with a malignancy dependent on MCL-1 which 
involves adding NOXA peptide or a NOXA mimetic peptide (eg, T-MS1) to 
patient samples and measuring induction of apoptosis. The readout is 
percentage of cells entering apoptosis. In MDS patients, the assay is being 
planned to be run on peripheral blood as well as standard bone marrow 
aspirates on diagnostic bone marrow samples. This functional assay is 
scalable and has a quick turnaround (24-48 hours). 
Enrollment in this study to date has not been optimal and seems to be driven, 
in part, by the availability of slots for patient participation. Timing for initiation 
of treatment is critical in these patients and sometimes these patients are 
hesitant to wait 14 or more days to begin therapy. A modified enrollment 
strategy implemented in Amendment 2 permits the first two patients in a dose 
cohort to be enrolled simultaneously with the third patient permitted after 
Day 14 if no unacceptable toxicities are observed in the first two patients. This 

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change will not compromise patient safety and will permit more efficient 
escalation to planned Dose Cohort 4 which was the established MTD in prior 
AML studies with alvocidib. 
The hypomethylating agents azacitidine and decitabine are used for the 
treatment of patients with MDS in the US. On a global basis, azacitidine is 
approved and used. It is now the intent to have a global experience with the 
combination of azacitidine and alvocidib in patients with MDS. In efforts to 
reduce the amount of time patients are required to be at the clinic, alvocidib 
administration in this amendment will change from hybrid dosing (ie, 30-minute 
IV bolus followed 30 minutes later by a 4-hour IV infusion [IVI]) to a 30- to 
60-minute  IVI which has been tested before. Once the MTD of alvocidib 
administered using hybrid dosing is determined, 2 cohorts of patients (at least 
3 patients each) will receive the standard dose of azacitidine (75 mg/m2) 
followed by alvocidib at a starting dose of 75 mg/m2/day administered by 30- 
to 60-minute IVI with escalation to 90 mg/m2/day in the absence of dose-
limiting toxicities. Alvocidib has previously been administered as a 30- to 
60-minute IVI at a dosage of 78 mg/m2/day to patients with solid tumors who 
had been previously treated (some heavily) [31]. Observed Grades 3 and 4 
adverse events (AEs) included lymphocytopenia, neutropenia (dose-limiting), 
diarrhea, hypophosphatemia, and reversible hyperglycemia. Since patients in 
the current study will likely be treated prophylactically with antibiotics, 
antivirals, and antifungal therapies (depending on each institution’s standards 
of care) and will receive aggressive antidiarrheal treatment, similar AEs should 
be manageable. Once the MTD of alvocidib administered as a 30- to 
60-minute IVI has been determined in those 2 cohorts, up to 25 patients will 
be enrolled in an Expansion cohort to receive either HMA followed by alvocidib 
to further characterize the safety of the combinations and evaluate potential 
signals of alvocidib activity. 
2.7 SUMMARY OF RISK AND BENEFITS 
While there have been no clinical studies conducted using alvocidib in 
sequence with decitabine (DEC) or azacitidine (AZA) in this patient population, 
the safety profile for alvocidib—either as a single agent or in combination with 
cytarabine and mitoxantrone—has been well described in several clinical 
studies in patients with AML and appears to be acceptable. Alvocidib has been 
administered in combination with vorinostat in patients with relapsed, 
refractory, or poor prognosis acute leukemia or refractory anemia with excess 
blasts-2 [26]. Side effects were tolerable and manageable with 50% of patients 
experiencing stable disease. Since the outcome in patients with high-risk MDS 
is poor, we hope to evaluate whether treatment with alvocidib in sequence 
after DEC (during dose escalation) or AZA enacts any enhanced 
antileukemic and/or pharmacokinetic effects in this elderly patient population. 

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3. 
STUDY OBJECTIVES 
3.1 PHASE 1B OBJECTIVES 
Primary: 
• To determine the maximum tolerated dose (MTD) and recommended 
Phase 2 dose (RP2D) of alvocidib when administered in sequence after 
DEC (during dose escalation) or AZA in patients with previously 
untreated MDS and patients with MDS who have received <6 cycles of 
treatment with previous hypomethylating agents (HMAs)  
Secondary: 
• To determine the Complete Response Rate ([CRR]: complete response 
[CR] / complete response with incomplete blood count recovery [CRi] / 
CRmarrow / partial response [PR] / hematologic improvement [HI])  
• To determine if treatment with alvocidib administered in sequence after 
DEC (during dose escalation) or AZA results in improvements in 
transfusion 
dependence 
(defined 
as 
an 
average 
transfusion 
requirement of ≥2 units/28 days of RBCs without any consecutive 
28-day gaps between transfusions for a minimum of 56 days 
immediately preceding first dose) and/or hemoglobin level (transfusion 
data to include the hemoglobin value for which the transfusion was 
administered and must have been ≤10.0 g/dL within 7 days prior to 
transfusion administration to be counted toward the RBC transfusion-
dependent status): 
o Hemoglobin increase of ≥1.5 g/dL without erythropoietin-
stimulating agents (ESAs) 
 
OR 
o Reduction of ≥4 RBC transfusions/8 weeks in comparison to pre-
treatment values and lasting at least 8 weeks 
Exploratory: 
• To evaluate MCL-1 dependence in untreated MDS patients via BH3 
profiling 
• To determine whether DEC (during dose escalation) or AZA 
treatment modulates MCL-1 dependence in peripheral blood 

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3.2 PHASE 2 OBJECTIVES 
Primary: 
• To determine preliminary efficacy and anti-MDS activity of alvocidib 
administered in sequence after AZA in untreated patients with de novo 
or secondary MDS  
Secondary: 
• To assess the CRR (per 2006 revised International Working Group 
[IWG] criteria [28]) 
• To evaluate the tolerability of alvocidib when administered in sequence 
following AZA in this patient population 
• To determine whether a defined BH3 profile predicts response to 
alvocidib administered in sequence after AZA in untreated MDS 
population 
• To determine if treatment with alvocidib administered in sequence after 
AZA results in improvements in transfusion dependence (defined as an 
average transfusion requirement of ≥2 units/28 days of RBCs without 
any consecutive 28-day gaps between transfusions for a minimum of 
56 days immediately preceding first dose) and/or hemoglobin level 
(transfusion data to include the hemoglobin value for which the 
transfusion was administered and must have been ≤10.0 g/dL within 
7 days prior to transfusion administration to be counted toward the RBC 
transfusion-dependent status): 
o Hemoglobin increase of ≥1.5 g/dL without ESAs 
 
OR 
o Reduction of ≥4 RBC transfusions/8 weeks in comparison to pre-
treatment values and lasting at least 8 weeks 
Exploratory Objectives 
• To assess the pharmacokinetics (PK) of alvocidib when administered in 
sequence after AZA 
• To evaluate correlative biomarkers of therapy including, but not limited 
to, BH3 profiling with an emphasis on MCL-1 dependence, genetic 
mutations, and other biomarkers associated with MDS 
• To document the percentage of patients transplanted post-treatment 
and outcomes post-transplant  
Additional exploratory analyses may be performed, if useful, in the 
interpretation of the data. 

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4. 
INVESTIGATIONAL PLAN 
4.1 OVERALL STUDY DESIGN 
This is a Phase 1b/2, open-label, safety, efficacy, PK, and pharmacodynamic 
(PD) study.  
Phase 1b 
Patients will be enrolled in cohorts of 3-6 patients. Escalation of the alvocidib 
dose will follow a standard 3+3 design with sequential cohorts of 3 patients 
treated with incrementally higher doses of alvocidib administered in sequence 
after DEC (during dose escalation) or AZA until a DLT is observed and the 
MTD is established (Section 4.5.3). The first 2 patients at a dose level may be 
enrolled simultaneously and the third patient will be enrolled after 14 days so 
long as the 2 initial patients have not experienced any unacceptable toxicity.  
If 1 of 3 patients in a cohort experiences a DLT, up to 3 additional patients will 
be treated at that dose level. If no additional DLTs are observed in the 
expanded 3- to 6-patient cohort within 28 days after the last patient was first 
dosed, the dose will be escalated in a new cohort of 3 patients. If 2 or more of 
3-6 patients at a given dose level experience a DLT during the first cycle, then 
the MTD will have been exceeded and up to a total of 6 patients will be treated 
at the previous lower dose level. If 0 or 1 of 6 patients experiences a DLT at 
this previous lower dose level, this dose will be declared the MTD. 
The MTD is defined as the dose at which ≤1 of 6 patients experience a DLT 
during Cycle 1 with the next higher dose having at least 2 of 3 to 6 patients 
experiencing a DLT during Cycle 1. Adverse events meeting the definition of 
DLT during Cycles 2+ will be taken into consideration when evaluating dose 
escalation.   
Once the MTD or preliminary RP2D of alvocidib administered via hybrid dosing 
(ie, IV bolus followed by IVI) is identified, 2 cohorts of at least 3 patients each 
will receive AZA followed by alvocidib administered as a 30- to 60-minute IVI.  
Expansion at MTD 
Once the MTD or preliminary RP2D of alvocidib administered as a 30- to 
60-minute IVI is determined, up to 25 patients will be enrolled in an Expansion 
cohort to receive alvocidib following AZA to confirm safety, explore potential 
biomarkers, and evaluate potential signals of alvocidib activity. Once this 
Expansion cohort is completed, the study will progress to Phase 2. 

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Phase 2  
The Phase 2 design is based on the Simon 2-stage minimax design [27]. 
• Stage 1: Up to 15 evaluable patients will be enrolled and treated at the 
RP2D identified in the Phase 1b study. Stage 2 may be initiated at any 
point after confirming a response (CR/CRi/CRmarrow/PR/HI) in two 
Stage 1 patients. If there is ≤1 responder among 15 evaluable Stage-1 
patients, the study will be stopped after Stage 1. 
• Stage 2: Ten patients will be enrolled to bring the total enrollment in 
Phase 2 (including Stage-1 patients) to 25 evaluable patients. Stage-2 
patients will also receive the RP2D dose of alvocidib administered by 
30- to 60-minute IVI identified in the Phase 1b study. If 6 or more 
responses are observed in 25 patients, the conclusion will be that the 
combination regimen is worthy of further investigation. When the true 
response rate of 30% (alternative hypothesis) is tested against the null 
hypothesis response rate of 10%; this design yields a Type I error rate 
of 0.05 and power of 80%. 
Any patient who withdraws from Stage 1 or 2 for treatment-related toxicity or 
disease progression, or dies prior to being evaluated for response will be 
considered a nonresponder. Patients who drop out for other reasons prior to 
being assessed for response will be considered unevaluable and may be 
replaced. Enrollment into Phase 2 may be stopped at any point once 
≥6 patients have had a response to treatment, but the maximum enrollment in 
Phase 2 will be 25 evaluable patients. 
The study may be stopped early during Phase 2 in the event of unacceptable 
toxicities. Early stopping rules for safety are based on a Sequential Probability 
Ratio Test (SPRT) with a baseline toxicity rate of 5%; an upper ceiling of 
unacceptable toxicity of 20% (ie, toxicities meeting one or more DLT criteria 
as stated in Section 4.5.3); and alpha=0.05 with power=80%. 
The study will be stopped if unacceptable toxicities are observed in: 
• 2 of the first 2 patients 
• 3 of the first 11 patients  
• 4 of the first 20 patients 
• 5 of the first 29 patients (Ph 2 study to enroll maximum of 25 patients, 
but considering possible replacement patients) 
Safety Assessments 
Incidence rates of treatment-emergent adverse events (TEAEs) will be 
summarized within treatment group at the Medical Dictionary for Regulatory 
Activities (MedDRA) preferred term and primary system organ class levels. 

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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 treatment group using mean, standard deviation, 
median, minimum and maximum changes from baseline values. 
Response Assessments 
Response to treatment will be assessed according to the revised IWG Criteria 
[28]. 
4.2 ASSIGNMENT TO TREATMENT 
This is an open-label study. All patients will receive alvocidib and DEC (during 
dose escalation) or AZA according to the dose cohort in which they are 
enrolled. The MTD will be assessed during the first cycle of treatment though 
toxicities observed during Cycle 2 and later cycles will be considered when 
determining the RP2D and the dose escalation scheme.  
Patients will be enrolled into open dosing cohorts from all participating centers. 
The study will be managed by the Sponsor and/or its designee and all sites 
must receive authorization from the Medical Monitor for enrollment of any 
eligible patient. 
4.3 PATIENT POPULATION 
The targeted patient population will generally fall into one of these categories: 
• Patients with previously untreated MDS 
• Patients with MDS who have received <6 cycles of treatment with 
hypomethylating agents (HMAs) 
• Patients with de novo (cause unknown) or secondary MDS (treatment-
related) who are not eligible for intensive induction chemotherapy or 
stem cell transplant  
o All French-American-British (FAB) subtypes (refractory anemia, 
refractory anemia with ringed sideroblasts, refractory anemia 
with excess blasts, refractory anemia with excess blasts in 
transformation, and chronic myelomonocytic leukemia) 
o Intermediate and above per the revised International Prognostic 
Scoring System (IPSS-R) groups 

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4.3.1 
Number of Patients 
It is planned to enroll up to 24 patients in the Phase 1b, dose-escalation part 
of this study to determine the MTD/RP2D. Once the MTD or preliminary RP2D 
of alvocidib administered via hybrid dosing (ie, IV bolus followed by IVI) is 
identified, 2 cohorts of patients (minimum of 6 patients; 3 per cohort) will 
receive AZA followed by alvocidib administered as a 30- to 60-minute IVI.  
Once the MTD or preliminary RP2D of alvocidib administered as a 30- to 
60-minute IVI is determined, up to 25 patients will be enrolled into an 
Expansion cohort to receive alvocidib following AZA to further characterize the 
safety, explore potential biomarkers, and evaluate potential signals of alvocidib 
activity. Once this Expansion cohort is completed, the study will progress to 
Phase 2 with planned enrollment of up to 25 patients (Stage 1 and Stage 2) to 
confirm the efficacy of alvocidib when administered with AZA. Total study time 
(Phase 1b and Phase 2) will be approximately 36 to 44 months. 
4.3.2 
Inclusion Criteria 
To be eligible for participation in the study, patients must meet all of the 
following inclusion criteria: 
1. Aged ≥18 years 
2. Phase 1b Dose Escalation: Patients with previously untreated MDS and 
patients with MDS who received fewer than six (6) cycles of previous HMAs 
 
Phase 1b Expansion: Untreated patients with de novo or secondary 
MDS 
Phase 2: Untreated patients with de novo or secondary MDS 
3. Patients with an Eastern Cooperative Oncology Group (ECOG) 
Performance Status (PS) score ≤2 at enrollment 
4. 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.) 
5. Patients with a life expectancy of ≥3 months (90 days) 
6. Patients with adequate major organ functions meeting the following criteria 
on the basis of laboratory data within 4 weeks (28 days) before enrollment 
(if multiple data are available, most recent data during the period): 
a. Serum creatinine: ≤1.8× the upper limit of the normal (ULN) range  
b. Total bilirubin: ≤2× the ULN  
c. Aspartate transaminase (AST) and alanine transaminase (ALT): 
≤3× the ULN 

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7. Be able to comply with the requirements of the entire study. 
8. Patients with Revised International Prognostic Scoring System 
(IPSS R) intermediate-, high-, and very high-risk MDS 
4.3.3 
Exclusion Criteria 
Patients meeting any one of these exclusion criteria will be prohibited from 
participating in this study: 
1. Presence of concomitant severe cardiovascular disease:  
a. Patients who had myocardial infarction within 6 months (180 days) 
before enrollment 
b. Patients with significant diseases at enrollment that may affect study 
treatment, such as New York Heart Association (NYHA) Functional 
Class III or IV heart disease, National Cancer Institute (NCI) 
Common Toxicity Criteria for Adverse Events (CTCAE) v5.0 grade 
≥3 arrhythmia, angina pectoris, abnormal electrocardiogram 
findings, interstitial pneumonia or pulmonary fibrosis 
2. Presence of concomitant malignancy requiring chemotherapy or any 
malignancy (except basal and squamous cell carcinoma of the skin) for 
which the patient received chemotherapy within 6 months prior to 
enrollment. NOTE: Diagnosis of any previous or concomitant malignancy 
is, thus, not an exclusion criterion. 
3. Presence of uncontrolled or uncontrollable infection(s); or ≥Grade 3 
infection according to NCI CTCAE v5.0 
4. Presence of any psychological, familial, sociological or geographical 
condition that, in the opinion of the investigator, could potentially hinder 
compliance with the study protocol and follow-up schedule 
5. Patients with a dry tap on bone marrow aspiration before enrollment 
6. Patients with concurrent autoimmune disease or a history of chronic or 
recurrent autoimmune disease, or patients who require long-term systemic 
steroid therapy greater than the equivalent of 20 mg of prednisone daily 
(excluding therapy given on an ‘as needed’ (PRN) basis) 
7. Patients with other documented malignancies within the past year aside 
from synchronous or metachronous multiple cancers with a disease-free 
period of ≤5 years (excluding carcinoma in situ, mucosal carcinoma, or 
other such carcinomas curatively treated with local therapy) 
8. Patients with ≥Grade 2 hemorrhage according to NCI CTCAE v5.0 

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9. Patients who have previously received alvocidib or another cyclin-
dependent kinase 9 (CDK9) inhibitor  
10. Patients who are pregnant or breastfeeding 
11. Female patients of childbearing potential who are sexually active and 
unwilling to use a medically acceptable method of contraception associated 
with a low failure rate during and for at least 6 months after the last dose of 
study drug. (Patients will be considered to be of childbearing potential 
unless surgically sterilized by hysterectomy, or bilateral tubal ligation/ 
salpingectomy, or postmenopausal for at least 2 years.) 
12. Male patients with partners of childbearing potential who are unwilling to 
use condoms in combination with a second effective method of 
contraception during the trial and for at least 6 months after the last 
administration of study treatment. 
13. Patients who are inappropriate for participation in the study for other 
reasons in the opinion of the investigator or sub-investigator(s) 
14. Patients with a known hypersensitivity to DEC (those patients enrolled in 
dose escalation), AZA, or mannitol 
15. Patients who have received erythropoietin-stimulating agents (ESAs) 
within 2 weeks (14 days) prior to Cycle 1/Day 1 
4.4 STUDY TREATMENT 
4.4.1 
Calculation of Doses 
The dosage of study drugs will be recalculated at the beginning of each new 
treatment cycle to reflect changes in the body surface area (BSA) that may 
have occurred but will remain the same for all treatments within a treatment 
cycle. Doses can be adjusted for changes in body weight of ±10% used in the 
calculation of the current dose. 
4.4.2 
Study Drug Administration 
Evaluation of the safety and efficacy of alvocidib when administered in 
sequence after DEC (during dose escalation) or AZA will occur in three 
phases:  
• Phase 1b Escalation: 3+3 dose escalation design 
• Phase 1b Expansion at MTD: once the MTD of alvocidib administered 
by 30- to 60-minute IVI is determined in Phase 1b, up to 25 patients will 
be enrolled in an Expansion cohort to receive alvocidib following AZA to 
confirm safety, explore potential biomarkers, and evaluate potential 
signals of alvocidib activity 
• Phase 2: using the RP2D from Phase 1b, initiate Simon 2-stage 
minimax design  

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Decitabine and Alvocidib 
• Days 1-5: Decitabine to be administered at as a 1-hour IVI (ie, starting 
dose for Cohort 1; see Table 5 for assigned decitabine doses per 
treatment cohort). 
• Day 6 and 7: Drug-free days 
• Day 8: Alvocidib to be administered as a 30-minute (±10 minutes) IV 
bolus followed up to 30 minutes later by a 4-hour (±15 minutes) IVI (see 
Table 5 for assigned alvocidib doses per treatment cohort).  
Azacitidine and Alvocidib 
Once the MTD of alvocidib administered via hybrid dosing (ie, 30-minute bolus 
followed by a 4-hour IVI) has been determined, 2 cohorts of patients (minimum 
of 6 patients; 3 per cohort) will receive AZA followed by alvocidib administered 
as a 30- to 60-minute IVI. Azacitidine may be administered as either an IVI 
over 10 to 40 minutes or as a subcutaneous (SC) injection on either a 7-day 
or 5-2-2 schedule (see below). Regardless of which AZA schedule or route of 
administration is used, alvocidib will be given on Day 10 as a 30- to 60-minute 
IVI. Choice of schedule and route of administration of AZA will be at the 
discretion of the investigator. 
• AZA 7-day Schedule 
o Days 1-7: AZA to be administered as a 75 mg/m2 IVI over 10 to 
40 minutes or SC injection daily for 7 consecutive days  
o Days 8-9: Drug-free days 
o Day 10: Alvocidib to be administered as a 30- to 60-minute IVI  
• AZA 5-2-2 Schedule 
o Days 1-5: AZA to be administered as a 75 mg/m2 IVI over 10 to 
40 minutes or SC injection daily for 5 consecutive days  
o Days 6-7: Drug-free days 
o Days 8-9: AZA to be administered as a 75 mg/m2 IVI over 10 to 
40 minutes or SC injection daily for 2 consecutive days  
o Day 10: Alvocidib to be administered as a 30- to 60-minute IVI  
4.4.2.1 Phase 1b: Dose-escalation 
Patients will receive alvocidib administered in sequence after fixed doses of 
either DEC or AZA using a standard 3+3 design according to the dose cohorts 
in Table 5 and Table 6.  

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4.4.2.2 Expansion at MTD/RP2D 
Once the MTD or preliminary RP2D of alvocidib administered as a 30- to 
60-minute IVI is identified, up to 25 patients will be enrolled in an Expansion 
cohort to receive alvocidib following AZA to confirm safety, explore potential 
biomarkers, and evaluate potential signals of alvocidib activity.  
Once this Expansion cohort is completed, the study will progress to Phase 2. 
4.4.2.3 Phase 2 
The Phase 2 study will then commence in a Simon 2-stage minimax design 
[27] using the RP2D of alvocidib administered as a 30- to 60-minute IVI 
determined from the Phase 1b study to explore the efficacy of alvocidib when 
administered in sequence after AZA.  
• Stage 1: Up to 15 evaluable patients will be enrolled and treated at the 
RP2D identified in the Phase 1b study. Stage 2 may be initiated at any 
point after confirming a response (CR/CRi/CRmarrow/PR/HI) in two 
Stage 1 patients. If there is ≤1 responder among 15 evaluable Stage-1 
patients, the study will be stopped after Stage 1. 
• Stage 2: Ten patients will be enrolled to bring the total enrollment in 
Phase 2 (including Stage-1 patients) to 25 evaluable patients. Stage-2 
patients will also receive the RP2D dose of alvocidib administered as a 
30- to 60-minute IVI identified in the Phase 1b study. 
Enrollment into Phase 2 may be stopped at any point once ≥6 patients have 
had a response to treatment, but the maximum enrollment in Phase 2 will be 
25 evaluable patients. 
The study may be stopped early during Phase 2 in the event of unacceptable 
toxicities. Early stopping rules for safety are based on a Sequential Probability 
Ratio Test (SPRT) with a baseline toxicity rate of 5%; an upper ceiling of 
unacceptable toxicity of 20% (ie, toxicities meeting one or more DLT criteria 
as stated in Section 4.5.3); and alpha=0.05 with power=80%. 
The study will be stopped if unacceptable toxicities are observed in: 
• 2 of the first 2 patients 
• 3 of the first 11 patients  
• 4 of the first 20 patients 
• 5 of the first 29 patients (Ph 2 study to enroll maximum of 25 patients, 
but considering possible replacement patients) 

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4.5 MANAGEMENT OF TOXICITIES AND DOSE MODIFICATIONS 
Suggested doses of supportive care therapies are provided; however, 
adjustment of the dosages based on the patient’s clinical condition or each 
institution’s standard of care is permitted. 
Adverse events may be treated with concomitant medications, as deemed 
clinically indicated by the Principal Investigator (PI). All concomitant 
medications must be recorded in the source and on the appropriate case report 
form (CRF). 
Adverse events that are moderate to severe in intensity (see Section 8.1 for 
intensity assessment when NCI CTCAE grade [Appendix D] is not 
available) and considered possibly or probably related to study drug 
treatments may result in the delay or termination of study treatment in affected 
patients. 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. 
4.5.1 
Management of Nonhematologic Toxicities 
4.5.1.1 Hyperkalemia and Tumor Lysis Syndrome 
Tumor lysis may occur as part of initial cytoreductive therapy. The most 
extreme form, known as Tumor Lysis Syndrome (TLS), is characterized by 
hyperkalemia, 
hyperuricemia, 
hyperphosphatemia, 
increased 
lactate 
dehydrogenase (LDH), coagulopathy, and a potential cytokine release 
syndrome. Preventative measures to reduce the likelihood of developing TLS 
include ensuring adequate hydration of patients prior to administration of 
alvocidib as well as careful monitoring of laboratory parameters before and 
after infusion. Investigators should follow their own institutional protocols in 
determining the best treatment for patients with symptoms of TLS.  
4.5.1.1.1 TLS Prophylaxis for DEC + Alvocidib 
Tumor lysis syndrome prophylaxis for patients receiving alvocidib in sequence 
following DEC should follow each institution’s standard of care. 
4.5.1.1.2 TLS Prophylaxis for AZA + Alvocidib 
All patients receiving alvocidib in sequence following AZA will receive TLS 
prophylaxis as detailed below: 
• IV Hydration 
o Prior to AZA 
 IV hydration according to each institution’s standard of care 

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o Prior to Alvocidib 
 Mandatory IV hydration with 0.45% NaCl (or similar hydration 
fluid per institutional standard) sterile solution at 500 cc for 
1-2 hours prior to alvocidib, then an additional 500 cc for 
1-2 hours after alvocidib during Cycle 1 (volume may be reduced 
to between 250 cc-500 cc, if clinically indicated). Hydration is 
optional for subsequent cycles.  
• Diarrhea Prophylaxis 
o During AZA and Alvocidib Dosing 
 Replace excessive fluid losses, including from diarrhea, unless 
otherwise clinically indicated. 
o Alvocidib-specific Measures  
 Alvocidib can induce diarrhea when given over a short period of 
time. Over-the-counter measures are typically effective in this 
setting if initiated early (see Section 4.5.1.2).  
 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 is imperative (see Section 4.5.1.2). 
• Oral Allopurinol 
o Mandatory oral allopurinol to be started on Day 1 of Cycle 1 and 
continued daily for first 2 weeks (ie, 14 days). This may be 
discontinued for subsequent treatment cycles if uric acid levels are 
within normal limits and there is no evidence of TLS. 
• Oral Phosphate Binder 
o Mandatory oral phosphate binder to be started on Day 1 of Cycle 1 
and continued daily for the first 2 weeks (ie, 14 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. 

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• Laboratory Evaluations for Tumor Lysis Syndrome (‘tumor lysis labs’) 
o 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 AZA and 2 hours 
(±30 minutes) after completion of AZA dosing 
 Monitor tumor lysis labs prior to alvocidib IVI and 2 hours 
(±30 minutes) after completion of IV hydration post alvocidib.  
 All tumor lysis labs should be drawn, however the potassium 
level obtained at 2 hours post dose (AZA) and 2 hours post 
hydration (alvocidib) should be reviewed immediately to 
determine if additional treatment is warranted.  
 Labs will also be drawn daily for the first 2 days following 
alvocidib (ie, Days 11-12) and at least weekly for the 
remainder of Cycle 1  
o During Cycle 2, tumor lysis labs will be assessed: 
 
Prior to C2D1 first AZA dose and at 2 hours post C2D1 AZA 
dose  
 
Prior to C2D10 alvocidib IVI and 2 hours (±30 minutes) after 
completion of alvocidib IVI. 
o During Cycles 3+, tumor lysis labs will be checked at the 
discretion of the investigator in relation to patient blast counts 
4.5.1.1.3 Risk of TLS with Alvocidib 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. 

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• 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.  
• 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.  
• If potassium levels rise to >5.5 mEq/L, patients should be considered for 
emergent intermittent or continuous dialysis. 
• Calcium supplementation should only be given for symptomatic 
hypocalcemia in this setting to avoid renal precipitation of calcium 
phosphate crystals. 
• 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. 
4.5.1.2 Diarrhea 
Alvocidib can induce diarrhea when given over a short period of time. 
Dehydration from diarrhea can exacerbate the morbidity associated with tumor 
lysis syndrome (ie, acute renal failure). Over-the-counter measures are 
typically effective in this setting if initiated early. It is strongly suggested that 
patients take 2 tablets of loperamide, 2 mg each (or equivalent), prior to the 
alvocidib IVI and then take 1 tablet (2 mg) for every loose stool up to a 
maximum of 8 tablets (16 mg) in a 24-hour period. 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, diphenoxylate 
hydrochloride with atropine sulfate (or equivalent) 5 mg orally four (4) times 
daily may be added. If diarrhea is not controlled with the above prophylactic 
regimens 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. 

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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 antibiotic, antiviral, and/or antifungal therapy is left to the 
discretion of the treating physician and according to institutional standards.  
Routine growth factor support is not allowed before achieving a leukemia-free 
bone marrow state.  Support with growth factors (eg, filgrastim) is discouraged. 
If a patient has Grade 4 sepsis with life-threatening infection with ongoing 
neutropenia, then this may be considered at the discretion of the Investigator. 
4.5.2 
Management of Hematologic Toxicities 
Bone marrow suppression and associated complications are expected events 
during MDS therapy and are part of the treatment process (marrow emptying 
of abnormal cells). Therefore, hospitalization or prolongation of hospitalization 
for myelosuppression and associated complications directly related to the 
myelosuppression, such as fever, infections and bleeding, will not be reported 
as serious adverse events (SAEs), but will be reported as adverse events on 
the adverse event case report form and will be summarized in the updated and 
final reports.   
4.5.3 
Dose-limiting Toxicities 
Dose-limiting toxicities (DLTs) will be determined during Cycle 1 and defined 
as follows based on the NCI CTCAE v5.0: 
• Any Grade 5 toxicity that is not clearly and incontrovertibly related to 
the underlying disease or extraneous causes 
• Any Grade 4 nonhematologic toxicity considered at least possibly drug 
related 
• Grade 4 neutropenia lasting ≥42 days from the start of a cycle in the 
absence of evidence of active disease 
• Any AST or ALT elevation ≥3x ULN accompanied by serum bilirubin 
levels >2x ULN 
• Any Grade 3 nonhematologic toxicity considered at least possibly drug 
related and that does not resolve to ≤Grade 2 within 48 hours, with the 
following exceptions: 
o Grade 3 bilirubin, AST, ALT or alkaline phosphatase will be 
considered dose-limiting only if resolution to ≤Grade 2 requires 
more than 7 days  

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Patients who experience a DLT will be required to discontinue study 
participation, unless the Investigators and Medical Monitor determine that it is 
in the best interest of the patient to continue with the dose reduction and only 
upon recovery of the toxicity to Grade 2 or better. 
Dose reduction will be required for patients who have a delay in treatment 
greater than 6 weeks due to a lack of recovery of any hematologic or 
nonhematologic toxicity, even if DLT criteria are not met. Subsequent 
retreatment of patients who are not able to be treated after a 6-week delay and 
who eventually recover will be discussed between Investigators and Medical 
Monitor considering the potential benefit/risk for the individual patient. In 
addition, dose reductions may be permitted for patients who have toxicities 
that do not meet the criteria of a DLT. These toxicities will be discussed by the 
Investigators and Medical Monitor to determine if it would be in the best interest 
of the patient to continue to receive decitabine or azacitidine and a reduced 
dose of alvocidib. 
4.6 CONCOMITANT MEDICATIONS AND THERAPIES 
4.6.1 
Previous Therapies 
During Screening, patients will be asked about all previous therapies and all 
medications used during the previous 28 days from anticipated first dose. This 
information will be recorded in the source documentation and appropriate CRF 
along with the diagnosis or reason for use. If a branded product is being taken, 
the generic name should be reported, if known.   
Subjects will not be enrolled into the study if they have had any previous 
treatment with alvocidib or other CDK inhibitor. 
4.6.2 
Concomitant Therapies 
Concomitant therapies are any new or existing medications or therapy taken 
by the patient including: 
• Drugs, including but not limited to, prescription, over-the-counter, birth 
control pills/patches/hormonal devices, and homeopathic preparations 
• Nondrug therapies, including but not limited to, thermal/laser/radiation 
procedures, vitamins, herbal medicines/supplements. 
During the Screening process (up to 28 days 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.  

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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.   
4.6.2.1 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 PI. 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 Phase, but not within 
12 hours prior to dosing. 
4.6.2.2 Prohibited Therapies 
The following medications are excluded from concomitant use:  
• Antileukemic 
therapy 
(chemotherapy, 
radiation 
therapy, 
immunotherapy) within the last 3 weeks prior to the first study drug 
administration and during the cycle of study treatment. 
• Live vaccines within 14 days prior to first study drug administration, 
during the study, and for approximately 3 months after the last dose of 
study drug. 
• Routine growth factor support is not allowed. Growth factor 
support can be given at the discretion of the Investigator and with 
the Medical Monitor’s approval in the presence of life-threatening 
infection with ongoing neutropenia. 

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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 during and for at least 
6 months 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) true abstinence when this is in 
line with the preferred and usual lifestyle of the subject (periodic abstinence 
[eg, calendar, ovulation, symptothermal, post-ovulation methods, etc], 
declaration of abstinence for the duration of exposure to study drugs, and 
withdrawal are not acceptable methods of contraception); (5) patient or partner 
surgically sterile; (6) patient or partner more than 2 years post-menopausal; or 
(7) injectable or implantable agent/device. Male patients enrolled in the study 
must use a condom to avoid exposing partners to semen, which may contain 
toxic drugs. 
4.7 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 PI (or a responsible, appropriately trained and credentialed professional[s] 
designated by the PI). In the event of a significant deviation from the protocol 
due to an emergency, accident or error, the PI or Designee must contact the 
Sponsor at the earliest possible time by telephone. This will allow an early joint 
decision to be made as to whether or not the patient should continue in the 
study. This decision will be documented in writing by both the PI and the 
Sponsor. 

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5. 
ON-STUDY CLINICAL AND LABORATORY EVALUATIONS 
See Appendix A-1 – Schedule of Activities (Patients Receiving DEC and 
Alvocidib), Phase 1b, Expansion, and Phase 2; Appendix A-2 – Schedule of 
Activities (Patients Receiving AZA and Alvocidib), Phase 1b, Expansion, and 
Phase 2; and Appendix A-3 – Schedule of TLS Evaluations (Patients 
Receiving AZA and Alvocidib). 
During each cycle, it is critical to record all laboratory values for hematology 
and serum chemistry parameters collected during the time the patient is on 
study to facilitate change-from-baseline analyses. Any laboratory parameters 
assessed outside the per-protocol visits (ie, interim labs) will be recorded as 
‘Unscheduled Laboratory Assessments’ in the database. 
5.1 PREDOSE ASSESSMENTS (PHASE 1B, EXPANSION AT MTD, AND 
PHASE 2) 
5.1.1 
Within 28 Days Prior to First Dose of Cycle 1 
Perform the following activities and evaluations within 28 days prior to 
administration of the first dose of study drug: 
• Obtain written informed consent (must be obtained prior to study-
related screening evaluations. Evaluations performed as standard-of-
care prior to obtaining consent may be utilized for screening) 
• Collect and document a complete medical and disease history including 
histologically confirmed diagnosis of MDS  
• Collect and document transfusion dependency, ie, transfusion 
requirement 
without 
any 
consecutive 
28-day 
gaps 
between 
transfusions for a minimum of 56 days immediately preceding first dose 
and/or hemoglobin level  
o Record all transfusions (hemoglobin and platelet) for the 
8 weeks/56 
days prior 
to 
screening 
(including 
the 
transfusion date and number of units with each transfusion) 
o Record all CBC data for the 8 weeks/56 days prior to 
screening including each CBC that prompted a transfusion 
• Perform a complete physical examination of all body systems and 
including height (cm) and weight (kg) 
• Record vital signs (temperature, heart rate, systolic and diastolic blood 
pressures) 
• Assess Eastern Cooperative Oncology Group (ECOG) Performance 
Status (PS) (Appendix B) 
• Perform a 12-lead electrocardiogram (ECG) including assessment of 
corrected QT interval 
• Perform chest radiograph (‘x-ray’) (may omit, if performed within 
28 days prior to anticipated first dose) 

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• Collect blood for evaluation of laboratory parameters (Appendix E): 
o Hematology 
o Full serum chemistry panel 
o Coagulation panel 
• Collect urine or serum sample for beta-human chorionic gonadotropin 
(β-hCG) pregnancy test for females of child-bearing potential 
• Perform bone marrow biopsy and/or aspiration and collect peripheral 
blood for disease status, standard cytogenetics, and pharmacodynamic 
(PD) analyses (Section 7.4, Table 9 and Table 10; Appendix E).  
o If the initial bone marrow aspirate is nonproductive or not 
diagnostic, the procedure must be repeated. 
o Six to 8 bone marrow slides will be prepared (in addition to fresh 
bone marrow samples) and sent to the Sponsor. 
• Record all concomitant medications including all prescription drugs, 
nonprescription drugs, and nutritional supplements within the past 
28 days 
5.1.2 
Within 72 Hours Prior to First Dose of Cycle 1 
Perform the following activities and evaluations anytime within 72 hours prior 
to administration of the first dose (on Day 1) of study drug: 
• Perform a complete physical examination including weight (kg), 
calculation of BSA, and baseline signs and symptoms 
• Record vital signs (temperature, heart rate, systolic and diastolic blood 
pressures) 
• Assess ECOG PS (Appendix B) 
• Collect blood for evaluation of laboratory parameters (Appendix E): 
o Hematology panel 
o Full serum chemistry panel 
• TLS prophylaxis for patients receiving DEC (during dose escalation) 
followed by alvocidib should follow each institution’s standard of care. 
• Collect urine or serum sample for β-hCG pregnancy test for females of 
child-bearing potential 
• Record all concomitant medications including all prescription drugs, 
nonprescription drugs, and nutritional supplements taken since 
previous predose assessment 
Review all Inclusion/Exclusion criteria and determine if patient has met all 
eligibility criteria for inclusion into the study.  

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As early as possible during the screening process, the Medical Monitor (or 
designee) should be provided the required information for review and approval 
to enroll patient with updates provided, if applicable, up to the point of enrolling 
the patient. See Study Manual for detailed instructions on procedures on 
enrollment. 
5.2 TREATMENT ASSESSMENTS DURING PHASE 1B AND PHASE 2 
5.2.1 
Cycle 1 
5.2.1.1 Cycle 1 – Day 1 (and as otherwise indicated) 
• Patients receiving DEC (during dose escalation) and Alvocidib  
o Initiate TLS prophylaxis and supportive care measures 
according to each institution’s standard of care 
• Patients receiving AZA and Alvocidib 
o Administer pretreatment IV hydration prior to first AZA dose per 
institutional standards  
o Begin oral allopurinol daily from Days 1-14 of Cycle 1 
o Begin oral phosphate binder daily from Days 1-14 of Cycle 1 
(see Section 4.5.1.1.2) 
o Replace excessive fluid losses, including from diarrhea, unless 
otherwise clinically indicated (see Section 4.5.1.2 and 
Section 4.5.1.3) 
• Record vital signs (temperature, heart rate, systolic and diastolic blood 
pressures) prior to first dose 
• Obtain baseline signs and symptoms prior to first dose 
• Collect blood for evaluation of laboratory parameters (Appendix E):  
o Hematology panel 
o Full serum chemistry panel 
o Tumor lysis labs required just prior to AZA dose in patients 
receiving AZA + alvocidib and 2 hours post AZA dose 
(Appendix A-3) 
 Immediately assess potassium level at 2 hours post dosing 
for indications of tumor lysis syndrome 
 Tumor lysis labs to also be drawn on Days 2 and 3 prior to 
AZA doses during Cycle 1 
• Collect peripheral blood for PD analyses on Days 1, 3 and 5 in patients 
receiving DEC or on Days 1, 3, 5, and 7 in patients receiving AZA 
(Section 7.4, Table 9 and Table 10, respectively) 

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• Collect urine or serum sample for β-hCG pregnancy test for females of 
child-bearing potential if screening pregnancy test is greater than 
72 hours prior to first dose  
• Administer prophylactic antibiotics, antivirals, antifungals, antiemetics, 
antidiarrheals according to standard practices at each investigational 
site 
• Administer DEC on Days 1-5 (during dose escalation) or AZA on 
7-day or 5-2-2 schedule according to Section 4.4.2.1 
• Assess for AEs 
• Record 
only 
those 
medications 
(prescription, 
nonprescription, 
nutritional supplements) administered in conjunction with an AE. 
5.2.1.2 Cycle 1 – Day 8 (Patients receiving DEC + Alvocidib)   
Cycle 1 – Day 10 (Patients receiving AZA + Alvocidib) 
• Perform an abbreviated physical examination (AE- or symptom-directed 
exam)  
• Record vital signs (temperature, heart rate, systolic and diastolic blood 
pressures) 5-15 minutes prior to initiation of alvocidib following a 
5-minute rest  
• Assess ECOG PS (Appendix B) 
• Alvocidib-specific TLS Prophylaxis 
o Administer pretreatment IV hydration at least 2 hours prior to first 
dose of alvocidib 
o Continue oral allopurinol daily from Days 1-14 of Cycle 1 
o Continue oral phosphate binder daily from Days 1-14 of Cycle 1 
(see Section 4.5.1.1.2) 
o Replace excessive fluid losses, including from diarrhea, unless 
otherwise 
clinically 
indicated 
(Section 
4.5.1.2 
and 
Section 4.5.1.3) 
• Administer prophylactic antibiotics, antivirals, antifungals, antiemetics, 
antidiarrheals according to standard practices at each investigational 
site 
• Administer alvocidib according to Section 4.4.2.1 

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• Collect blood for evaluation of laboratory parameters just prior to the 
start of the infusion and again approximately 4 hours post end of IVI 
(Appendix E): 
o Hematology panel 
o Full serum chemistry panel 
o Tumor lysis labs required just prior to alvocidib dosing and 2 hours 
after end of IV hydration post alvocidib IVI in patients receiving 
AZA + alvocidib (Appendix A-3) 
 All tumor lysis labs should be drawn; however, the 
potassium level obtained at 2 hours post IV hydration 
should be reviewed immediately to determine if additional 
treatment is warranted (Section 4.5.1.1.3). 
• Phase 1b only – Collect blood for evaluation of PK parameters 
(Section 7.3, Table 8) 
• Collect peripheral blood for PD analyses (Section 7.4, Table 9 and 
Table 10) 
• Assess for AEs 
• Record 
only 
those 
medications 
(prescription, 
nonprescription, 
nutritional supplements) administered in conjunction with an AE. 
5.2.1.3 Cycle 1 – Day 9 (Patients receiving DEC + Alvocidib)   
Cycle 1 – Day 11 (Patients receiving AZA + Alvocidib) 
• Perform an abbreviated physical examination (AE- or symptom-directed 
exam)  
• Record vital signs (temperature, heart rate, systolic and diastolic blood 
pressures) 
• Collect blood for follow-up evaluation of laboratory parameters 
(Appendix E): 
o Hematology panel 
o Full serum chemistry panel 
 Full panel required with specific attention to tumor lysis 
labs in patients receiving AZA + alvocidib on Day 11 
(Appendix A-3) 
• Patients receiving AZA and alvocidib 
o Continue oral allopurinol daily on Days 1-14 of Cycle 1 
o Continue oral phosphate binder daily from Days 1-14 of Cycle 1 
(see Section 4.5.1.1.2) 

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• Phase 1b only – Collect blood for evaluation of PK parameters 
(Section 7.3, Table 8) 
• Collect peripheral blood for PD analyses (Section 7.4, Table 9 and 
Table 10) 
• 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) 
• Assess for AEs 
• Record 
only 
those 
medications 
(prescription, 
nonprescription, 
nutritional supplements) administered in conjunction with an AE. 
5.2.1.4 Cycle 1 – Day 12 (Patients receiving AZA + Alvocidib) 
• Collect blood for follow-up evaluation of laboratory parameters 
(Appendix E): 
o Tumor lysis labs  
• Continue oral allopurinol daily on Days 1-14 of Cycle 1 
• Continue oral phosphate binder daily on Days 1-14 of Cycle 1 
• 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) 
5.2.1.5 Cycle 1 – Days 15, 22 (±3 Days) 
Perform the following activities and evaluations on Days 15 and 22 of Cycle 1: 
• Perform an abbreviated physical examination (AE- or symptom-directed 
exam)  
• Record vital signs (temperature, heart rate, systolic and diastolic blood 
pressures) 
• Assess ECOG PS (Appendix B) 
• Collect blood for follow-up evaluation of laboratory parameters 
(Appendix E): 
o Hematology panel 
o Full serum chemistry panel 
o Tumor lysis labs (Day 22 in patients receiving AZA + alvocidib) 
• Collect peripheral blood for PD analyses (Section 7.4, Table 9 and 
Table 10) 

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• 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) 
• Assess for AEs 
• Record 
only 
those 
medications 
(prescription, 
nonprescription, 
nutritional supplements) administered in conjunction with an AE. 
5.2.2 
Cycles 2+ 
5.2.2.1 Cycles 2+: At Least 2 Hours Prior to First Dose of Alvocidib in 
Patients Receiving AZA + Alvocidib 
During Cycles 2+, pretreatment IV hydration, oral allopurinol, and oral 
phosphate binder may be discontinued in patients receiving AZA and alvocidib 
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 alvocidib dosing on Day 10 (unless 
otherwise stated): 
• Initiate supportive care measures prior to first dose of alvocidib in 
patients receiving AZA + alvocidib 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 4.5.1.1.2 and Appendix A-3) 
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) 
5.2.2.2 Cycles 2+ – Day 1 
Perform the following activities and evaluations on Day 1 of Cycles 2+: 
• Perform an abbreviated physical examination including weight (kg) and 
calculation of BSA  
• Assess ECOG PS (Appendix B) 
• Record vital signs (temperature, heart rate, systolic and diastolic blood 
pressures) prior to first dose 
• Collect blood for evaluation of laboratory parameters (Appendix E): 
o Hematology panel 
o Full serum chemistry panel 
o Tumor lysis labs required just prior to C2D1 AZA dose and 
2 hours post C2D1 AZA dose (Appendix A-3) 

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•
Collect peripheral blood for PD analyses (Section 7.4, Table 9 and 
Table 10)
•
Collect urine or serum sample for β-hCG pregnancy test for females of 
child-bearing potential
•
Administer prophylactic antibiotics, antivirals, antifungals, antiemetics, 
antidiarrheals according to standard practices at each investigational 
site
•
Administer DEC on Days 1-5 (during dose escalation) or AZA on
7-day or 5-2-2 schedule according to Section 4.4.2.1
•
Assess for AEs
•
Record 
only 
those 
medications 
(prescription, 
nonprescription, 
nutritional supplements) administered in conjunction with an AE.
5.2.2.3 Cycles 2+ – Day 8 (Patients receiving DEC + Alvocidib) 
Cycles 2+ – Day 10 (Patients receiving AZA + Alvocidib) 
•
Abbreviated physical examination (AE- or symptom-directed exam)
•
Record vital signs (temperature, heart rate, systolic and diastolic blood
pressures)
•
Assess ECOG PS (Appendix B)
•
Administer prophylactic antibiotics, antivirals, antifungals, antiemetics,
antidiarrheals according to standard practices at each investigational
site
•
Administer alvocidib according to Section 4.4.2.1
•
Collect blood for evaluation of laboratory parameters just prior to the
start of the infusion and again approximately 4 hours post end of IVI
(Appendix E):
o
Hematology panel
o
Full serum chemistry panel
o
Tumor lysis labs required just prior to C2D10 alvocidib IVI and
2 hours after end of alvocidib IVI in patients receiving AZA +
alvocidib (Appendix A-3)
•
Collect peripheral blood for PD analyses (Section 7.4, Table 9 and
Table 10)
•
Assess for AEs
•
Record 
only 
those 
medications 
(prescription, 
nonprescription,
nutritional supplements) administered in conjunction with an AE.

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5.2.2.4- Cycles 2+ – Day 9 (Patients receiving DEC + Alvocidib)  
Cycles 2+ – Day 11 (Patients receiving AZA + Alvocidib) 
• Record vital signs (temperature, heart rate, systolic and diastolic blood 
pressures) 
• Collect blood for follow-up evaluation of laboratory parameters 
(Appendix E): 
o Hematology panel 
o Full serum chemistry panel 
After Cycle 3, frequency of labs may be performed as per 
standard of care starting after Day 9 for patients on DEC (during 
dose escalation) and after Day 11 for patients on AZA. 
• Assess for AEs 
• Record 
only 
those 
medications 
(prescription, 
nonprescription, 
nutritional supplements) administered in conjunction with an AE. 
5.2.2.5 Cycles 2+ – Days 15, 22 (±3 Days) 
Perform the following activities and evaluations on Days 15 and 22 of 
Cycles 2+: 
• Record vital signs (temperature, heart rate, systolic and diastolic blood 
pressures) 
• Collect blood for follow-up evaluation of laboratory parameters 
(Appendix E): 
o Hematology panel 
o Full serum chemistry panel 
• Collect peripheral blood on Day 15 for PD analyses (Section 7.4, 
Table 9 and Table 10) 
• Assess for AEs 
• Record 
only 
those 
medications 
(prescription, 
nonprescription, 
nutritional supplements) administered in conjunction with an AE. 
5.2.2.6 Cycles 2+ – Day 28 (+1/-3 Days) 
Perform the following evaluations on Day 28 of every EVEN cycle (ie, Cycle 2, 
Cycle 4, etc): 
• Perform bone marrow biopsy and aspiration and collect peripheral 
blood sample for assessment of response (Appendix F), standard 
cytogenetics, and PD analyses (Section 7.4, Table 9 and Table 10; 

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Appendix E). [Note with a +1/-3 day window, these may be performed 
on Days 25-28 or Day 1 of the next cycle. If performed on Day 1 of the 
next cycle, please collect bone marrow and aspiration as well as 
peripheral blood samples prior to administering first dose of DEC or 
AZA] 
o If the bone marrow biopsy and/or aspirate is nonproductive or 
not diagnostic, at the EVEN 2+ cycle visits, there should be no 
delay in dosing and the procedure should be repeated within 
7 days. 
o Six to 8 bone marrow slides will be prepared (in addition to 
fresh bone marrow samples) and sent to the Sponsor. 
• Response assessments with standard cytogenetics and blood sample 
collection for PD analyses should be repeated on Day 28 (+1/-3 days) 
of Cycles 2, 4, and 6, and then every 4 cycles, thereafter, or as clinically 
indicated. If medically appropriate, response assessments should be 
repeated at the time of disease progression.  
• Assess for AEs 
• Record 
only 
those 
medications 
(prescription, 
nonprescription, 
nutritional supplements) administered in conjunction with an AE. 
5.3 END OF STUDY 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 Study visit rather than having the patient return for an 
additional visit. 
Perform the following assessments whenever a patient discontinues study 
treatment/is withdrawn: 
• Perform a full physical examination including weight (kg) and other 
measures of disease and disease symptoms, eg, extramedullary 
disease 
• Record vital signs (temperature, heart rate, systolic and diastolic blood 
pressures) 
• Assess ECOG PS (Appendix B) 
• Collect blood for follow-up evaluation of laboratory parameters 
(Appendix E): 
o Hematology panel 
o Full serum chemistry panel 
o Coagulation panel (as clinically indicated) 

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• If ≥8 weeks since last response assessment, perform bone marrow 
biopsy and aspiration and collect peripheral blood sample for 
assessment of response (Appendix F), and PD analyses (Section 7.4, 
Table 9 and Table 10; Appendix E) 
o If the bone marrow biopsy and/or aspirate is nonproductive or not 
diagnostic, the procedure must be repeated within 7 days. 
o Six to 8 bone marrow slides will be prepared (in addition to fresh 
bone marrow samples) and sent to the Sponsor. 
• Collect urine or serum sample for β-hCG pregnancy test for females of 
child-bearing potential 
• Assess for AEs 
• Record 
only 
those 
medications 
(prescription, 
nonprescription, 
nutritional supplements) administered in conjunction with an AE 
5.4 FOLLOW-UP ASSESSMENTS 
5.4.1 
Follow Up for Safety 
Patients must have a safety evaluation 30-45 days after the last dose of study 
drug (ie, 30 days +15-day window). This evaluation can be done by phone. 
The following assessments will be performed: 
• Assess for AEs 
o Ongoing AEs must be followed clinically until they resolve, are 
deemed permanent or no longer clinically significant, or the 
patient begins an alternative treatment regimen  
• Record only those medications (prescription, nonprescription, and 
nutritional supplements) administered in conjunction with an AE, as well 
as any antineoplastic therapies initiated since discontinuation of study 
drug.  
5.4.2 
Follow Up for Overall Survival 
All patients enrolled and treated in the Phase 2 study will be contacted by 
telephone to assess for date of death, date of stem cell transplant, date of 
relapse, or continued remission for three years: 
• Year 1: Phone calls monthly beginning the month after the patient 
completes the end-of-study assessments to 12 months after Date of 
First Dose regardless of how many cycles a patient receives 
(Year 1 = Date of First Dose plus 12 months)  
• Year 2: Phone calls every other month during Year 2 (months 14 to 
24 months after Date of First Dose).  
• Year 3: Phone calls every three months during Year 3 (months 25 to 
36 months after Date of First Dose). 

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6. 
OFF-STUDY CRITERIA 
6.1 WITHDRAWAL OF PATIENTS 
All patients have the right to withdraw at any time during treatment without 
prejudice. Circumstances may occur under which a patient may be 
permanently removed from the study. The criteria used to justify withdrawal of 
a study patient are described below. 
In the event of a premature withdrawal, the assessments for the End of Study 
visit, as detailed in the Schedule of Activities (Appendix A), should be 
completed at the time of the withdrawal, wherever possible, including dates of 
response and death. If the study patient is prematurely withdrawn due to an 
AE, attempts should also be made to clinically follow the study patient until the 
event is resolved, stable or permanent as determined by the PI and Sponsor.    
6.2 REASONS FOR WITHDRAWAL 
A patient may be permanently removed from the study for any of the following 
reasons: 
• Failure to achieve a response. Patients not demonstrating evidence of 
CR/CRi/CRmarrow/PR/HI after the second cycle of treatment will be 
considered for removal from the study, although with permission of the 
Medical Monitor, induction treatment may continue if clinically indicated 
and provided there is no evidence of toxicity ≥NCI CTCAE grade 4; 
• An excessive Grade 3-4 toxicity without a response to treatment or 
occurrence of any other AE, concurrent illness or laboratory abnormality 
which, in the opinion of the PI, warrants the patient’s permanent 
withdrawal; 
• Patient noncompliance, defined as refusal or inability to adhere to the 
study schedule; 
• At the request of the patient, PI, the Sponsor, or regulatory authority; 
• Patient is lost to follow-up; 
• Patient becomes pregnant while on study; 
• Patient begins another treatment for their disease; or 
• Patient death. 
 

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6.3 FOLLOW-UP FOR PATIENTS WITHDRAWN FROM STUDY 
Patients withdrawn from the study with an ongoing AE must be followed 
clinically until the event is resolved, deemed stable or permanent, or the patient 
begins an alternative treatment regimen. A stable adverse event is defined as 
an event that is not expected to change in nature, severity or frequency. See 
Sections 8.4 – 8.8 for reporting of adverse events. Patients withdrawn from the 
study for pregnancy will be followed according to Section 5.4. The pregnancy 
of any patient, or patient’s partner, will be followed to term to record any birth 
defects/abnormalities at time of birth. 
6.4 TERMINATION OR SUSPENSION OF STUDY 
Should the Sponsor or their representatives, Investigators, or appropriate 
regulatory officials discover conditions during the study that indicate that the 
study or site involvement should be put ‘On Hold’ or ‘Terminated’, this action 
may be taken after appropriate consultation with the Sponsor, Investigators 
and Study Monitors.  
Conditions that may warrant termination of the study or involvement of a study 
site include, but are not limited to: 
• If the Data Safety Monitoring Board (DSMB)* recommends stopping the 
study due to safety concerns (*if applicable, as DSMBs may not be 
utilized in every study);  
• The decision on the part of the Sponsor to suspend or discontinue 
testing, evaluation, or development of the study drug  
• The discovery of an unexpected, serious, unacceptable risk to patients 
enrolled in the study; 
• Failure of the Investigator(s) to comply with pertinent clinical trial 
regulations; or 
• Submission of knowingly false information from the research facility 
to the Sponsor, study monitor, or regulatory agencies. 
• Insufficient adherence to protocol requirements. 
Study termination and follow-up will be performed in compliance with the 
conditions set forth in the International Council on Harmonisation (ICH) sixth 
efficacy publication (E6) on Good Clinical Practice (GCP), Section 4.12, ICH 
E6 4.13, ICH E6 5.20, and ICH E6 5.21, with appropriate notification of the 
Food and Drug Administration (FDA) and all IRBs having approved the study 
protocol and ICF. 
 

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7. 
CRITERIA FOR EVALUATION 
7.1 SAFETY ENDPOINTS 
Safety and tolerability of alvocidib when administered in sequence after DEC 
(during dose escalation) or AZA will be assessed by analyzing the DLTs, 
MTD, and incidence rates of treatment-emergent adverse events (TEAEs) 
summarized within treatment group(s) 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, physical examinations, vital sign 
measurements, and clinical laboratory testing [hematology, serum chemistry, 
and coagulation]) will be analyzed as additional measures of safety and 
tolerability for the entire study duration. These assessments will be 
summarized by shift tables and treatment group using mean, standard 
deviation, median, minimum and maximum changes from baseline values.  
Mortality (all causes) will be calculated. 
7.2 EFFICACY ENDPOINTS 
Primary Efficacy Endpoints 
• Assess preliminary efficacy, as determined by response rate, duration 
of response, hematological improvement, rate of transfusion 
dependence, time to AML, and overall survival. 
Efficacy endpoints will be any objective response to study drug therapy using 
assessments defined by the 2006 revised International Working Group (IWG) 
criteria [28] and European MDS Working Group. 
Secondary Efficacy Endpoints 
• The proportion of MDS patients in the overall population achieving RBC 
transfusion independence with duration ≥84 days (12 weeks) during 
treatment. Baseline RBC transfusion dependence is defined as an 
average transfusion requirement of ≥2 units/28 days of RBCs without 
any consecutive 28-day gaps between transfusions for a minimum of 
56 days immediately preceding first dose. Transfusion data include the 
hemoglobin value for which the transfusion was administered and must 
have been ≤10.0 g/dL within 7 days prior to transfusion administration 
to be counted toward the RBC transfusion-dependent status. 

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• Platelet transfusion independence with duration ≥84 days (12 weeks) 
will be assessed in the proportion of patients who were platelet 
transfusion dependent at baseline. Baseline platelet transfusion 
requirements are established by the number of platelet transfusions 
administered during the 56 days immediately preceding and including 
the date of first dose. 
• Erythroid 
hematologic 
improvement 
and 
platelet 
hematologic 
improvement will be assessed according to International Working 
Group 2006 criteria.  
• Correlation of complete response rates with BH3 profiling results 
including MCL-1 dependency 
• Overall survival compared to historical data 
Complete details of the planned analysis will be documented in a full Statistical 
Analysis Plan (SAP), which will be finalized before locking the study database.  
7.3 PHARMACOKINETIC ENDPOINTS 
Plasma concentrations of alvocidib will be summarized by descriptive 
statistics, including mean, n, standard deviation, coefficient of variation, 
minimum, maximum, and median. Prior to analysis of study samples, the 
assay sensitivity, specificity, linearity, and reproducibility will be documented.  
Parameters to be assessed include the time to Cmax (Peak time, Tmax) and the 
area under the plasma concentration versus time curve (AUC) from time 0 to 
24 hours post-dose (AUC0-24), the maximum observed plasma concentration 
(Cmax), half life (t1/2), AUC from 0 to time t (AUCt), AUC from time 0 to infinity 
(AUC0-inf), and clearance (CL). 
Plasma PK analyses for alvocidib and known metabolites, if any, and dose 
proportionality will be determined during Cycle 1 on Days 8 and 9 (in patients 
receiving alvocidib following DEC) or Days 10 and 11 (in patients receiving 
alvocidib following AZA) (Table 8).   

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The samples may be retained for no longer than 20 years after study 
completion or per local requirements. 

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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 Investigational New Drug (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 v5.0 (see 
Appendix D). 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) 
• Possibly: 
• AE may be related to the investigational 
agent(s) 
• Probably: 
• AE is likely related to the investigational 
agent(s) 
• Definitely: 
• 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: 
• Any death, or  
• Any life-threatening event (ie, the patient is at immediate risk of death 
from the event as it occurred), or 
• Any event that is persistently, significantly, severely or permanently 
disabling, or requires intervention to prevent such disability, or 
• Any event which requires inpatient hospitalization or prolongs 
hospitalization, or 
• Any congenital abnormality/birth defect, or 
• 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 seen as part of 
the spectrum of underlying MDS and are expected events during MDS therapy. 
Therefore, myelosuppression and associated complications directly related to 
the myelosuppression, such as fever, febrile neutropenia, infections, anemia, 
thrombocytopenia, and bleeding, will not be reported as serious adverse 
events (SAEs) but will be reported as AEs on the AE CRF and will be 
summarized in the updated and final reports. 

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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 PI 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 will be reported on the “Adverse Event” case report 
form only if it is the main causative factor of an SAE, requires a therapeutic 
intervention, is the reason for a patient coming off study, or meets DLT criteria. 
Record the highest grade of the laboratory abnormality with start and stop 
dates associated with that grade. Laboratory values for hematology and serum 
chemistry parameters will be collected during the time the patient is on study 
to facilitate duration of worst CTCAE grade per cycle change-from-baseline 
analyses and overall worst CTCAE grade during the study. Any laboratory 
parameters assessed outside the per-protocol visits (ie, interim labs) will be 
recorded as ‘Unscheduled Laboratory Assessments’ in the database. 
Adverse events will be reported and described in terms of intensity, 
seriousness and causality, based on the PI’s judgment using protocol-defined 
definitions. Necessary counter measures will also be reported on the 
appropriate case report form used to collect concomitant medications. 
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 PI’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 PI’s awareness of the event.   
Serious adverse events must be scanned and emailed to the Sponsor/Study 
Medical Monitor. 
Email: CRF@couranteoncology.com 

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It is expected that the PI will provide or arrange appropriate supportive care 
for the study patient. A patient experiencing a SAE should be followed clinically 
until the event resolves, is deemed permanent or no longer clinically 
significant, or the patient begins an alternative treatment regimen. All 
telephone and scanned/emailed reports must be followed with a written 
Serious Adverse Event (SAE) report form within 24 hours of the PI’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 PI, 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 AEs or new AEs identified on the 
last scheduled visit should be followed by the PI until the AEs resolve, are 
deemed permanent or no longer clinically significant, or the patient begins an 
alternative treatment regimen. Resolution means the patient has returned to 
his/her baseline state of health or the PI does not expect any further 
improvement or worsening of the adverse event. The PI should continue to 
report any significant follow-up information to the Sponsor up to the point the 
event has resolved. Any adverse events reported by the patient to the PI which 
occur after the last scheduled visit, and are determined by the PI 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 AE or SAE must be 
followed clinically until the event is resolved, deemed permanent or no longer 
clinically significant, or the patient begins an alternative treatment regimen. A 
stable adverse event is defined as an event, which is not expected to change 
in nature, severity, or frequency. The PI should continue to report any 
significant follow-up information to the Sponsor. 

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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 Food and 
Drug Administration (FDA) as described in 21 CRF Section 312.32 (IND Safety 
Reports) and to other Regulatory Authorities according to local regulations. 
In addition, the PI is required by FDA regulations to notify the Institutional 
Review Board (IRB) promptly of all unexpected SAEs occurring at the 
investigator’s study site. The PI 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 DRUGS 
The investigational study drug, alvocidib, will be provided to the PI by the 
Sponsor or designee. 
Alvocidib is supplied for parenteral administration as a sterile, nonpyrogenic, 
injectable, clear pale yellow to yellow-colored, 10 mg/mL solution, which is 
packaged in glass vials fitted with coated rubber closures crimped with an 
aluminum seal and 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).  
Decitabine and azacitidine are approved pharmaceutical products and will be 
provided by commercially available sources. 
Decitabine for Injection is a white to almost-white sterile, lyophilized powder 
supplied in a clear colorless glass vial. Each 20-mL, single-dose, glass vial 
contains 50 mg decitabine, 68 mg monobasic potassium phosphate 
(potassium dihydrogen phosphate) and 11.6 mg sodium hydroxide sterile [29].  
Azacitidine for injection is a white to off-white solid. Each 100-mg, single-dose 
vial contains 100 mg of azacitidine and 100 mg mannitol as a sterile lyophilized 
powder [30].  
9.2 STUDY DRUG DISPENSING AND ACCOUNTABILITY 
Alvocidib will be provided by the Sponsor to study centers as an investigational 
drug. The label and package for the drug product will be prepared in 
accordance with current regulatory requirements. The Investigator or designee 
will inventory and acknowledge receipt of all shipments of study drugs. The 
study drugs must be kept in a locked area with access restricted to designated 
study personnel.   
An accurate and current accounting of the dispensing of the study drugs for 
each patient will be maintained on an ongoing basis by a member of the study 
site staff in a drug accountability log or equivalent document and will be verified 
by the sponsor's study monitor. All drug supplies, including unused study drug, 
must be accounted for. A final inventory of the total amount of drug received 
at each study site against the amount used and returned must be recorded in 
the study drug accountability log or an equivalent document. Inventory and 
dispense records must be readily available for inspection by the study monitor 
and/or auditor, and open to government inspection at any time. Study drug 
destruction will be handled by the sites of open/used vials.  Unopened study 

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drug vials should be returned to the Sponsor or the Contract Research 
Organization (CRO) and/or drug may be authorized for destruction onsite 
at the end of the study only after full drug accountability has been completed 
by the study monitor. 
9.3 PREPARATION AND ADMINISTRATION 
Alvocidib is to be diluted with either 0.9% Sodium Chloride Injection, United 
States Pharmacopeia (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 4.4.2.1.  
Decitabine should be aseptically reconstituted with 10 mL of Sterile Water for 
Injection, USP; upon reconstitution, each mL contains approximately 5.0 mg 
of decitabine at pH 6.7-7.3 [29]. Immediately after reconstitution, the solution 
should be further diluted with 0.9% Sodium Chloride Injection or 5% Dextrose 
Injection to a final drug concentration of 0.1-1.0 mg/mL. Unless used within 
15 minutes of reconstitution, the diluted solution must be prepared using cold 
(2°C to 8°C) infusion fluids and stored at 2°C to 8°C (36°F to 46°F) for up to a 
maximum of 4 hours until administration. The diluted solution should be 
administered according to treatment schedule provided in Section 4.4.2.1. 
Azacitidine should be aseptically reconstituted with Sterile Water for Injection, 
USP, per the US prescribing information and based on intended route of 
administration [30]. (Azacitidine is incompatible with 5% Dextrose solutions, 
Hespan, or solutions that contain bicarbonate. These solutions have the 
potential to increase the rate of degradation of azacitidine and should therefore 
be avoided). The total dose should be administered according to treatment 
schedule provided in Section 4.4.2.1. Administration must be completed within 
1 hour of reconstitution of the vial(s). 
Decitabine and azacitidine are approved pharmaceutical products. Complete 
instructions and training on the proper preparation and administration of all 
study drugs will be provided to study sites in the Pharmacy Manual. 
9.4 STORAGE AT STUDY CENTER 
• Alvocidib should be stored at USP controlled room temperature (ie, 20°C to 
25°C [68°F to 77°F]) with permitted excursions between between 2°C to 
30°C (36°F to 86°F) 
• Decitabine should be stored at 25°C (77°F); excursions permitted to 15°C 
to 30°C (59°F to 86°F) 
• Azacitidine unreconstituted vials should be stored at 25°C (77°F); 
excursions permitted to 15°C to 30°C (59°F to 86°F) 

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9.5 COMPLIANCE 
Study drugs will be administered by trained staff at the treatment site(s). 

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10. 
RECORD MANAGEMENT 
10.1 DATA COLLECTION 
The Investigator must maintain required records for all study subjects. Case 
report forms are used to record clinical study data and are an integral part of 
the study and subsequent reports. Data for this study will be recorded in the 
subject's source document and into an 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 CRFs) of all subjects' visits, 
being sure to include all pertinent study related information. A statement 
should be made indicating that the subjects have been enrolled in this clinical 
study and have provided written Informed Consent. Any adverse events must 
be thoroughly documented. Results of any diagnostic tests conducted during 
the study should also be included in the source documentation.   
All data should be recorded completely and promptly in the eCRFs as soon 
after the visit as possible, but no later than 5 days. All queries are to be 
answered within 3 days of query date.   
The PI 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, institutional review board/independent 
ethics committee [IRB/IEC] approval) and pertinent hospital or clinic records 
for confirmation of data throughout the study period. 
10.2 SOURCE DOCUMENT MAINTENANCE 
Source documents are defined as the results of original observations and 
activities of a clinical investigation. Source documents may include, but are not 
limited to, hospital medical records, study progress notes, consent forms, 
computer printouts, laboratory data and recorded data from automated 
instruments. All source documents produced in this study will be maintained 
by the PI and made available for inspection by representatives of the Sponsor 
or the Regulatory Authorities. The original signed informed consent form for 
each participating patient shall be filed with the records kept by the PI with a 
copy filed in the patient’s medical records, and a copy given to the patient. 

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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: 
• Notes from clinic physicians, nurses, and other study staff 
• Reports of procedures and tests 
• Flow sheets, checklists, and worksheets 
• Subject diaries, study calendars 
• Pharmacy records, accountability logs, shipping receipts 
• Study notes or memos to file 
• Documented telephone calls, emails, faxes 
• Hospital admission forms and discharge summaries 
• Sponsor/site-generated study source document templates 
Source documents must meet five fundamental principles of data quality 
(“ALCOA”).  They must be: 
• Attributable – The data originator is identified. If data needs to be 
amended, the amender is identified. 
• Legible – The source document must be readable.  If handwritten, black 
or blue ink must be used, never pencil. 
• 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. 
• Original – The document must be the first place the information is 
recorded. 
• 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 PI 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 (DCFs) 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 PI 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: 
• Investigator’s Brochure, current version, and all versions provided 
during the study period. 
• Final study protocol. 
• Protocol amendments (if applicable). 
• Original informed consent form (blank). 
• Revised informed consent forms and/or all addenda (if applicable). 
• Copy of signed FDA Form(s) 1572 
• Curricula Vitae and medical licenses of PI and Subinvestigators. 
• Financial Disclosure Form of PI and Subinvestigators (if applicable). 

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• Department of Health and Human Services Number for IRB, or other 
documentation of IRB compliance with FDA regulation (United States 
sites). 
• Documentation of IRB/IEC approval of protocol, consent form, any 
protocol amendments and any consent form revisions. 
• Annual IRB/IEC updates and approvals. 
• All correspondence between the PI, IRB/IEC and Sponsor or Sponsor’s 
representative relating to study conduct. 
• 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. 
• Laboratory certifications. 
• Normal laboratory value ranges for tests required by the protocol for all 
laboratories that are utilized. 
• Clinical Research Associate (CRA) monitoring log. 
• List of signatures and Delegation of Authority for all study personnel 
• Drug invoices for both receipt and return of study drug, as well as drug 
inventory/accountability records. 

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11. 
STATISTICAL CONSIDERATIONS 
11.1 GENERAL CONSIDERATIONS 
Protocol TPI-AVL-102 is a Phase 1b / 2, multicenter, open-label study in which 
Phase 1b will employ the 3+3 dose-escalation design, dose expansion at 
MTD/RP2D, and Phase 2 utilizing the Simon 2-stage minimax design [27].  
Results of statistical analyses, descriptive statistics, and supporting listings will 
be presented by study phase (Phase 1b and Phase 2) and within alvocidib 
dose level. In addition, overall statistics will be calculated for Phase 1b patients 
across all alvocidib dose levels and for the total study population (ie, 
regardless of study phase). 
Statistical analysis for all safety and efficacy parameters will be primarily 
descriptive in nature. Categorical variables will be summarized by frequency 
distributions (number and percentages of patients), continuous variables will 
be summarized by mean, standard deviation, median, minimum, maximum, 
and time-to-event variables will be summarized using Kaplan-Meier methods 
and figures for the estimated median time. No formal statistical hypothesis 
testing is planned; however, if exploratory analyses are conducted and 
confidence intervals (CIs) are provided for estimates, the 95% confidence 
intervals are consistent with a 2-sided 5% significance level. All analyses, 
summaries, and listings will be performed using SAS software (version 9.4 or 
higher) 
A detailed methodology for summary and statistical analysis of the data 
collected in this study will be documented in a Statistical Analysis Plan (SAP) 
that will be finalized prior to database lock. The SAP may modify the data 
analysis plans outlined in the protocol; and if so, will be clearly documented in 
the SAP. Any major modifications of the study design or study endpoints 
and/or its analysis will also be reflected in a protocol amendment. 
11.2 SAMPLE SIZE CONSIDERATIONS 
Phase 1b  
Patients will be enrolled in cohorts of 3-6 patients. Escalation of the alvocidib 
dose will follow a standard 3+3 design with sequential cohorts of 3 patients 
treated with incrementally higher doses of alvocidib until a DLT is observed 
and the MTD is established (Section 4.5.3). Per the standard oncology 3+3 
Phase 1 dose escalation design, the total number of patients to be enrolled 
cannot be precisely determined as the sample size is dependent upon the 
observed safety profile, which will determine the number of patients per dose 
cohort, as well as the number of dose escalations required to achieve the MTD. 
It is anticipated that a maximum of 24 patients will be required to reach MTD 
and determine the RP2D. 

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The MTD is defined as the dose at which ≤1 of 6 patients experience a DLT 
during Cycle 1 with the next higher dose having at least 2 of 3 to 6 patients 
experiencing a DLT during Cycle 1. Adverse events meeting the definition of 
DLT during Cycles 2+ will be taken into consideration when evaluating dose 
escalation.   
Once the MTD or preliminary RP2D of alvocidib administered via hybrid dosing 
(ie, IV bolus followed by IVI) is identified, 2 cohorts of at least 3 patients each 
will receive AZA followed in sequence by alvocidib with the total dose of 
alvocidib administered by 30- to 60-minute IVI.  
Expansion at MTD 
Once the MTD or preliminary RP2D of alvocidib administered by 30- to 
60-minute IVI is determined, up to 25 patients will be enrolled in an Expansion 
cohort to receive alvocidib following either DEC or AZA to confirm safety, 
explore potential biomarkers, and evaluate potential signals of alvocidib 
activity. Once this Expansion cohort is completed, the study will progress to 
Phase 2. 
Phase 2 
Stopping Rules based on Efficacy 
The statistical power calculations for Phase 2 are based on the Simon 2-stage 
minimax design [27]. 
• Stage 1: Up to 15 evaluable patients will be enrolled and treated at the 
RP2D identified in the Phase 1b study. Stage 2 may be initiated at any 
point after confirming a response (CR/CRi/CRmarrow/PR/HI) in two 
Stage 1 patients. If there is ≤1 responder among 15 evaluable Stage-1 
patients, the study will be stopped after Stage 1. 
• Stage 2: Ten patients will be enrolled to bring the total enrollment in 
Phase 2 (including Stage-1 patients) to 25 evaluable patients. Stage-2 
patients will also receive the RP2D dose of alvocidib administered by 
30- to 60-minute IVI identified in the Phase 1b study. If 6 or more 
responses are observed in 25 patients, the conclusion will be that the 
combination regimen is worthy of further investigation. When the true 
response rate of 30% (alternative hypothesis) is tested against the null 
hypothesis response rate of 10%; this design yields a Type I error rate 
of 0.05 and power of 80%. 
Any patient who withdraws from Stage 1 or 2 for treatment-related toxicity or 
disease progression or dies prior to being evaluated for response, they will be 
considered a non-responder. Patients who drop out for other reasons prior to 
being assessed for response will be considered unevaluable and may be 

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replaced. Enrollment into Phase 2 may be stopped at any point once 
≥6 patients have had a response to treatment, but the maximum enrollment in 
Phase 2 will be 25 evaluable patients. 
Stopping Rules based on Safety 
The study may be stopped early during Phase 2 in the event of unacceptable 
toxicities. Early stopping rules for safety are based on a Sequential Probability 
Ratio Test (SPRT) with a baseline toxicity rate of 5%; an upper ceiling of 
unacceptable toxicity of 20% (ie, toxicities meeting one or more DLT criteria 
as stated in Section 4.5.3); and alpha=0.05 with power=80%. 
The study will be stopped if unacceptable toxicities are observed in: 
• 2 of the first 2 patients 
• 3 of the first 11 patients  
• 4 of the first 20 patients 
• 5 of the first 29 patients (Ph 2 study to enroll maximum of 25 patients, 
but considering possible replacement patients) 
11.3 RANDOMIZATION AND BLINDING 
This is an open-label, single arm, Phase 1b / 2 study; thus, randomization and 
blinding are not part of the study design. 
11.4 ANALYSIS POPULATION SETS 
This study will have three analysis populations: 
• Intent-to-Treat (ITT) analysis set includes all patients who were 
enrolled into the study. 
• Safety Analysis Set consists of all patients who received study 
treatment (alvocidib). 
• Response Evaluable Set consists of patients who have at least one 
post-baseline efficacy assessment; patients without a post-baseline 
efficacy assessment will not be considered evaluable for the primary 
efficacy analysis. Patients who discontinue due to disease progression 
or die or treatment-related toxicity prior to having a disease assessment 
will be included in the Response Evaluable population. 

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11.5 PATIENT DISPOSITION 
A detailed description of patient disposition will be provided. It will include: 
• The number of patients who were enrolled, included in the ITT, safety, 
and response evaluable analysis sets. 
• A summary of patient dose cohorts. 
• A summary of patients who complete the protocol. 
• A summary of reasons for withdrawal from study. 
• A summary of reasons for patients with treatment failure. 
• An account of all identified protocol violations. 
• All patients enrolled in the study will be accounted for in the summation.  
11.6 DEMOGRAPHIC AND BASELINE CHARACTERISTICS 
Demographic characteristics including age, gender, race, and ethnicity will be 
presented in the form of tabular summary statistics. Other subject baseline 
characteristics including but not limited to: weight, height, body surface area, 
initial stage of disease, prior therapies, and ECOG performance status will be 
presented similarly. 
11.7 CONCOMITANT MEDICATIONS 
The number and proportion of patients using different concomitant 
medications will be tabulated and summarized by WHODrug anatomical 
therapeutic chemical (ATC) and preferred term. 
11.8 TREATMENT ADMINISTRATION / COMPLIANCE 
Study drug administration will be described in terms of the total number of 
cycles administered, the median (range) of cycles administered, dose 
intensity, and reasons for the deviations from planned therapy. 

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11.9 EFFICACY ANALYSIS 
The efficacy endpoints include the following: 
• Complete Response Rate (CRR) is the percentage of patients 
achieving a CR, CRi, CRmarrow, PR, or HI. Patients who, for any 
reason, do not supply bone marrow for response assessment are 
counted among those not achieving CR/CRi/CRmarrow/PR/HI. CRR 
will be summarized by number and percentage of patients meeting the 
definition of CRR along with the corresponding exact 95% confidence 
intervals. 
• Duration of response and time to AML will be summarized by Kaplan-
Meier methods (median, 95% CI, number of events, number censored, 
and Kaplan-Meier figures), 
• Hematological improvement and rate of transfusion independence will 
be summarized using the appropriate descriptive statistics and 95% 
confidence intervals.  
• Overall survival (OS), defined as the time from first dose to death from 
any cause. OS will be summarized by Kaplan-Meier methods (median, 
95% CI, number of events, number censored, and Kaplan-Meier 
figures). 
Descriptive statistics will also be calculated for each secondary measure of 
efficacy. 
• The proportion of MDS patients in the overall population achieving RBC 
transfusion independence with duration ≥84 days (12 weeks) during 
treatment. Baseline RBC transfusion dependency is defined as an 
average transfusion requirement of ≥2 units/28 days of RBCs without 
any consecutive 28-day gaps between transfusions for a minimum of 
56 days immediately preceding first dose. Transfusion data include the 
hemoglobin value for which the transfusion was administered and must 
have been ≤10.0 g/dL within 7 days prior to transfusion administration 
to be counted toward the RBC transfusion-dependent status.  
• Platelet transfusion independence with duration ≥84 days (12 weeks) 
will be assessed in the proportion of patients who were platelet 
transfusion-dependent at baseline. Baseline platelet transfusion 
requirements are established by the number of platelet transfusions 
administered during the 56 days immediately preceding and including 
the date of first dose. 

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• Erythroid 
hematologic 
improvement 
and 
platelet 
hematologic 
improvement will be assessed according to the 2006 revised IWG 
criteria [28]. 
Additional analyses may be performed to assist the sponsor in planning future 
studies.  
11.10 SAFETY ANALYSIS 
Safety will be monitored during the period starting after receipt of the first dose 
of study drug and ending 30 days after the final administration of alvocidib. 
During Phase 1, the safety endpoints will be evaluated after Cycle 1. The dose 
escalation committee will have access to complete safety profiles of all patients 
receiving alvocidib and will be able to take decisions accordingly. 
All patients who receive any dose (any amount) of alvocidib will be included in 
the summaries and listings of safety data. Overall safety profile will be 
characterized by type, frequency, severity, timing, duration and relationship of 
study drug of adverse events and laboratory abnormalities. 
11.10.1 Adverse Events 
Adverse events will be classified using the MedDRA classification system 
version 20.0 or higher. The severity of the toxicities will be graded according 
to the NCI CTCAE v5.0. 
In all summaries, emphasis will be placed on TEAEs, namely, those with initial 
onset or that worsen in severity after the first dose of alvocidib. Adverse events 
will be summarized by the frequency of patients experiencing TEAEs 
corresponding to body systems and MedDRA preferred term and by worst NCI 
CTCAE (v5.0) grade. Summaries will also be provided of treatment-related 
TEAEs, namely, those judged by the investigator to be related or likely related 
to alvocidib and/or combination regimens.  
Adverse events resulting in discontinuation of alvocidib treatment or 
withdrawal from the study, Grade 3 or higher, serious adverse events, and 
deaths on-study will be tabulated. 
All DLTs will be reported and the MTD and RP2D identified. 
11.10.2 Laboratory Tests 
Laboratory data will be summarized for the observed values at each scheduled 
assessment, together with the corresponding changes from baseline (the 
value obtained prior to dosing on Day 1 of Cycle 1) using descriptive statistics.  
For those analytes with NCI CTCAE v5.0 severity criteria are specified, 
abnormal laboratory values will be summarized by shift tables displaying 
numerical values and percentages classified by Baseline grade (ie, grade prior 

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to dosing on Day 1 of Cycle 1) and maximum grade on treatment. All laboratory 
data will be presented in listings. 
11.10.3 Vital Signs and Physical Examination Findings 
Vital signs data will be summarized by the observed valued at each scheduled 
assessment, together with the corresponding changes from baseline using 
descriptive statistics. 
Physical examination findings will be presented in data listings.  
11.11 INTERIM ANALYSIS 
For Phase 1b, safety data will be monitored continuously per standard Phase 1 
oncology study practices. 
For Phase 2, because the Simon 2-stage minimax design will be employed, 
response rate data will be assessed after Stage 1 and Stage 2. 
11.12 PHARMACOKINETIC ANALYSIS 
Pharmacokinetic 
parameters 
will 
be 
estimated 
using 
standard 
noncompartmental methods and according to FDA guidance. PK parameters 
include:  
• Cmax = maximum observed plasma concentration 
• Tmax = time to Cmax (peak time) 
• AUC0-24 = area under the plasma concentration curve from time 0 to 
24 hours 
• AUC0-inf = AUC from time 0 to infinity 
• AUCt = area under the plasma concentration curve from time 0 to time t 
• t1/2 = half life 
• CL = clearance using noncompartmental methods 
Actual sample collection times will be used rather than scheduled collection 
times. Plasma concentrations below the limit of quantification will be treated 
as 0. Imbedded missing plasma concentrations (ie, missing values between 
two observed values) will be estimated using linear extrapolation. This is 
consistent with using the trapezoidal rule to calculate AUC. Other missing 
plasma concentrations will be excluded from calculations to estimate PK 
parameters. 

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11.13 PHARMACODYNAMIC ANALYSIS 
Peripheral blood and bone marrow samples will be collected at protocol-
specific time points to assess the effects of alvocidib when administered in 
sequence after DEC (during dose escalation) or AZA. Analyses may include, 
but are not limited to: correlation of complete response rates with BH3 profiling 
by flow cytometry with an emphasis on MCL-1 dependence, evaluating 
recurrent genetic mutations, and other biomarkers associated with MDS. 

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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 PI must await IRB/IEC 
approval of the amendments before implementing the changes. However, a 
protocol change which is intended to eliminate an apparent immediate hazard 
to patients may be implemented immediately, provided the IRB/IEC is 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 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 Sumitomo Dainippon 
Pharma Oncology, Inc (SDP Oncology), in compliance with the applicable 
international and local regulatory requirements as well as applicable ICH 
guidelines, Declarations of Helsinki (1964, 1975, 1983, 1989, 1996, 2000, 
2002, 2004, 2008, 2013) and in respect of the Sponsor or designee’s standard 
operating procedures (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 
findings will be provided by Quality Assurance, in writing. 

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15. 
ETHICS AND RESPONSIBILITY 
15.1 PRINCIPAL INVESTIGATOR’S RESPONSIBILITIES 
The PI shall ensure that all work and services described herein, or incidental 
to those described herein, shall be conducted in accordance with the highest 
standards of GCP. The PI shall administer the investigational drug only to 
patients under his/her personal supervision, or under the supervision of any 
Sub-Investigator(s) responsible to him/her, who are identified on the Form 
FDA 1572/Regulatory Authorities approval form. The PI will provide copies of 
the study protocol, amendments, and investigational brochure to all Sub-
Investigators, Pharmacists, or other staff responsible for study conduct. 
With the exception of eliminating an immediate hazard to a subject, the 
Investigator should not deviate from the protocol or implement any changes 
without written prior approval from Sponsor and prior review and documented 
approval/favorable opinion from the IRB/IEC of an amendment. 
Change(s) which involve(s) only logistical or administrative changes are 
authorized. The Investigator should document and explain any deviation from 
the protocol. 
The Investigator is responsible for adequate and safe medical care of subjects 
during the trial and for ensuring that appropriate medical care and relevant 
follow-up procedures are maintained after the trial. Any additional data from 
these follow-up procedures must be documented and available to Sponsor 
who will determine whether or not the data need to be documented in the case 
report forms. 
15.2 INFORMED CONSENT 
It is the ethical and legal responsibility of the PI to ensure that each patient 
considered for inclusion in this study is given a full explanation of the protocol, 
in a language in which the patient is fluent, and in which the patient will clearly 
understand. This shall be documented on a written informed consent form, 
which shall be approved by the same IRB/IEC responsible for approval of this 
protocol. Each informed consent form shall include the elements required by 
local regulations. The Sponsor will draft this document in consultation with the 
PI. The PI agrees to obtain written approval of the consent form from the 
Sponsor prior to submission to the IRB/IEC. 

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Once the appropriate essential information has been provided to the patient 
and fully explained by the PI (or his/her qualified designee) and it is felt that 
the patient understands the implications of participating in the study, the 
IRB/IEC-approved consent form shall be signed by the patient, a witness 
(when appropriate) and the PI (or designee). Written informed consent will be 
obtained from each patient prior to any study-related procedures (including 
any pre-treatment procedures) that are performed. The patient shall be given 
a copy of the informed consent form when signed; the original shall be kept on 
file by the PI and a second copy shall be placed in the patient’s medical chart 
(or per EMR SOP).  
15.3 INSTITUTIONAL REVIEW BOARD 
This protocol and all amendments will be reviewed and approved by the 
Institutional or Independent Review Board(s) or Independent Ethics 
Committee(s) charged with this responsibility at the study center. Notification 
in writing of approval must come from the Chairman or the Secretary of the 
IRB/IEC meeting minutes where this protocol and associated informed 
consent form were discussed. The PI shall not participate in the decision, and, 
if an IRB/EC member, the written approval must indicate such non-
participation. The PI shall submit status reports to the IRB/IEC no less 
frequently than annually (when applicable). The IRB/IEC must be notified by 
the PI in writing of the interruption and/or completion of the study; the PI must 
promptly report to the IRB/IEC all changes in research (protocol amendments) 
and will not make such changes without IRB/IEC approval, except where 
necessary to eliminate apparent immediate hazards to human patients. In 
these cases, the IRB/IEC must be notified within five days of the change. The 
PI will promptly report to the IRB/IEC all unanticipated problems involving risk 
to patients or others. The PI is required to maintain an accurate and complete 
record of all written correspondence to, and received from the IRB/IEC, and 
must agree to share all such documents and reports with the Sponsor. 

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16. 
CONFIDENTIALITY 
The existence of this clinical study is confidential (with exception of listing on 
clinicaltrials.gov) 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 patient number in case 
report forms. 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 nonpatentable, 
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. 

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

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18. PUBLICATIONS 
The publication policy for the study will be described in the clinical study 
agreement. To avoid disclosures that could jeopardize proprietary rights, the 
investigator agrees to give 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. 

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19. 
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27. Simon R. Optimal two-stage designs for phase II clinical trials. Control Clin 
Trials 1989;10(1):1–10. 
28. Cheson BD, Greenberg PL, Bennett JM, et al. Clinical application and proposal 
for modification of the International Working Group (IWG) response criteria in 
myelodysplasia. Blood 2006;108:419–425. 
29. DACOGEN® (decitabine) for INJECTION. Full Prescribing Information. Otsuka 
America Pharmaceutical, Inc. Rockville, MD, USA. October 2014.  
30. VIDAZA® (azacitidine for injection). Full Prescribing Information. Celgene 
Corporation. Summit, NJ, USA. Revised September 2018.  
31. Tan AR, Headlee D, Messmann R, et al. Phase I clinical and pharmacokinetic 
study of flavopiridol administered as a daily 1-hour infusion in patients with 
advanced neoplasms. Clin Oncol 2001;20(19):4074–4082. 
 

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Notes:  
a. 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 Study visit rather than having the patient return for an additional visit. 
b. Patients must have a safety evaluation 30-45 days after the last dose of study drug (ie, 30 days +15-day window). This evaluation can be done 
by phone. 
c. Written informed consent must be obtained prior to conduct of study-related screening evaluations. Evaluations performed as standard-of-care 
prior to obtaining consent may be utilized for screening. 
d. Collect and document a complete medical and disease history including histologically confirmed diagnosis of MDS. 
e. Vital signs to include: temperature, heart rate, systolic and diastolic blood pressures. 
f. 
May omit if performed within 28 days prior to anticipated first dose. 
g. Full serum chemistry panel to include: blood urea nitrogen, phosphorus, magnesium, lactate dehydrogenase, creatinine, uric acid, total protein, 
albumin, calcium, glucose, total bilirubin, alkaline phosphatase, aspartate aminotransferase, alanine aminotransferase, and electrolytes 
(sodium, potassium, chloride, CO2) (see Appendix E). All laboratory values for hematology and serum chemistry parameters collected during 
the time the patient is on study to facilitate change-from-baseline analyses. Any laboratory parameters assessed outside the per-protocol visits 
(ie, interim labs) will be recorded as ‘Unscheduled Laboratory Assessments’ in the database. 
h. Collect urine or serum sample for β-hCG pregnancy test in females of child-bearing potential. 
i. 
Including all prescription and nonprescription medications and nutritional supplements. 
j. 
Review all inclusion and exclusion criteria to determine if patient has met all eligibility criteria for enrollment into the study. Obtain Medical 
Monitor (or designee) approval to enroll patient. 
k. Including prophylactic antibiotics, antivirals, antifungals, antiemetics, antidiarrheals according to standard practices at each site. 
l. 
Toxicities will be assessed according to the NCI CTCAE v5.0 (see Appendix D). When the NCI CTCAE grade is not available, the investigator 
will use the following toxicity grading: mild, moderate, severe, life-threatening, or fatal. 
m. AE- or symptom-directed physical examination. 
n. Perform bone marrow biopsy and/or aspiration and collect peripheral blood for disease status, standard cytogenetics, and PD analyses 
(Appendix E). If the initial bone marrow aspirate is nonproductive or not diagnostic, the procedure must be repeated. Six to 8 bone marrow 
slides will be prepared (in addition to fresh bone marrow samples) and sent to the Sponsor.  
o. Including all prescription and nonprescription medications and nutritional supplements taken over previous 28 days. 
p. Including all prescription and nonprescription medications and nutritional supplements taken since previous predose assessment visit. 
q. Conducted just prior to first dose. 
r. 
Collect peripheral blood samples for PD analyses on Days 1, 3, and 5 of Cycle 1 within 10 minutes prior to decitabine infusion (Section 7.4, 
Table 9; Appendix E) 
s. Required if screening pregnancy test was performed >72 hours prior to first dose. 
t. 
Record only those medications (prescription, nonprescription, nutritional supplements) administered in conjunction with an AE. 
u. Collect and document transfusion dependency, ie, transfusion requirement without any consecutive 28-day gaps between transfusions for a 
minimum of 56 days immediately preceding first dose and/or hemoglobin level. Record all transfusions (hemoglobin and platelet) for the 8 
weeks/56 days prior to screening (including the transfusion date and number of units with each transfusion). Record all CBC data 
for the 8 weeks/56 days prior to screening including each CBC that prompted a transfusion. 
v. Collect blood just prior to start of infusion and again approximately 4 hrs post end of IVI (Time 0 = start of alvocidib IVI). 
w. Collect peripheral blood for PD analyses (see Section 7.4, Table 9; Appendix E).  

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x. Phase 1b only - Collect blood samples for PK analyses on Day 8 just before the alvocidib IVI (Sample #1) and at the end of the alvocidib IVI 
(Sample #2). The time between the end of the 30-min bolus and beginning of the 4-hr alvocidib IVI should be up to 30 mins. Continue to collect 
blood samples for PK analyses 30 mins after end of the alvocidib IVI (Sample #3), 1 hr after end of the alvocidib IVI (Sample #4), 2 hrs after 
end of the alvocidib IVI (Sample #5), and 4 hrs after end of the alvocidib IVI (Sample #6) (Section 7.3, Table 8).  
y. Phase 1b only - Collect a blood sample for PK analysis from all patients on Day 9 at 23 hrs after the start of the alvocidib IVI administered on 
Day 8 (Sample #7) (Section 7.3, Table 8).   
z. Perform bone marrow biopsy and aspiration and collect peripheral blood sample for assessment of response (Appendix F), standard 
cytogenetics, and PD analyses (Appendix E). [Note: with a +1/-3 day window, these assessments may be performed on Days 25-28 or Day 1 
of the next cycle. If performed on Day 1 of the next cycle, collect bone marrow and aspiration as well as peripheral blood samples prior to 
administering the first dose of decitabine.] 
If the bone marrow biopsy and/or aspirate is nonproductive or not diagnostic, at the EVEN 2+ cycle visits, there should be no delay in dosing 
and the procedure should be repeated within 7 days. Six to 8 bone marrow slides will be prepared (in addition to fresh bone marrow samples) 
and sent to the Sponsor.  
Response assessments and standard cytogenetics should be repeated on Day 28 (+1/-3 days) of Cycles 2, 4, and 6, and then every 4 cycles, 
thereafter, or as clinically indicated. If medically appropriate, response assessments should be repeated at the time of disease progression.  
aa Peripheral blood samples to be collected for PD analyses on Day 28 of even cycles 2, 4 and 6 and then every 4 cycles thereafter (ie, 
Cycle 10, Cycle 14, etc) or as clinically indicated (Appendix E).  
bb As clinically indicated. 
cc If ≥8 weeks since last response assessment, perform bone marrow biopsy and aspiration and collect peripheral blood sample for assessment 
of response (Appendix F), and PD analyses (Appendix E). If the bone marrow biopsy and/or aspirate is nonproductive or not diagnostic, the 
procedure must be repeated within 7 days. Six to 8 bone marrow slides will be prepared (in addition to fresh bone marrow samples) and sent 
to the Sponsor. 
dd Including any antineoplastic therapies initiated since discontinuation of study drug. 
ee Ongoing AEs must be followed clinically until the event is resolved, deemed permanent or no longer clinically significant, or the patient begins 
an alternative treatment regimen. 
ff 
Alvocidib to be administered at the dosages noted in Table 5 first as a (30-min [±10 mins]) IV bolus followed up to 30 mins later by a 4-hr 
[±15 mins) IVI. 
gg After Cycle 3, frequency of labs may be performed as per standard of care starting after Day 9. 
 
 

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Notes:  
a 
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 Study visit rather than having the patient return for an additional visit. 
b 
Patients must have a safety evaluation 30-45 days after the last dose of study drug (ie, 30 days plus a 15-day window). This evaluation can be 
done by phone. 
c 
Written informed consent must be obtained prior to conduct of study-related screening evaluations. Evaluations performed as standard-of-care 
prior to obtaining consent may be utilized for screening. 
d 
Collect and document a complete medical and disease history including histologically confirmed diagnosis of MDS. 
e 
Collect and document transfusion dependency, ie, transfusion requirement without any consecutive 28-day gaps between transfusions for a 
minimum of 56 days immediately preceding first dose and/or hemoglobin level. Record all transfusions (hemoglobin and platelet) for the 
8 weeks/56 days prior to screening (including the transfusion date and number of units with each transfusion). Record all CBC data 
for the 8 weeks/56 days prior to screening including each CBC that prompted a transfusion. 
f 
Vital signs to include: temperature, heart rate, systolic and diastolic blood pressures. 
g 
May omit if performed within 28 days prior to anticipated first dose. 
h 
Full serum chemistry panel to include: blood urea nitrogen, phosphorus, magnesium, lactate dehydrogenase, creatinine, uric acid, total protein, 
albumin, calcium, glucose, total bilirubin, alkaline phosphatase, aspartate aminotransferase, alanine aminotransferase, and electrolytes 
(sodium, potassium, chloride, CO2) (see Appendix E). All laboratory values for hematology and serum chemistry parameters collected during 
the time the patient is on study to facilitate change-from-baseline analyses.  
i 
Any laboratory parameters assessed outside the per-protocol visits (ie, interim labs) will be recorded as ‘Unscheduled Laboratory Assessments’ 
in the database. 
j 
Collect urine or serum sample for β-hCG pregnancy test in females of child-bearing potential. 
k 
Including all prescription and nonprescription medications and nutritional supplements. 
l 
Review all inclusion and exclusion criteria to determine if patient has met all eligibility criteria for enrollment into the study. Obtain Medical 
Monitor (or designee) approval to enroll patient. 
m Including prophylactic antibiotics, antivirals, antifungals, antiemetics, antidiarrheals according to standard practices at each site. 
n 
Toxicities will be assessed according to the NCI CTCAE v5.0 (see Appendix D). When the NCI CTCAE grade is not available, the investigator 
will use the following toxicity grading: mild, moderate, severe, life-threatening, or fatal. 
o 
Azacitidine (AZA) may be administered as either an IVI over 10 to 40 minutes or a subcutaneous (SC) injection on either a 7-day schedule (ie, 
Days 1-7 of AZA) or a 5-2-2 schedule (ie, Days 1-5 of AZA, Days 6-7 drug-free days, and Days 8-9 of AZA). (Schedule and route of AZA 
administration is at discretion of investigator).  
p 
AE- or symptom-directed physical examination. 
q 
Alvocidib to be administered by 30- to 60-minute IVI according to the dose cohorts listed in Table 6. 
r 
Perform bone marrow biopsy and/or aspiration and collect peripheral blood for disease status, standard cytogenetics, and PD analyses 
(Appendix E). If the initial bone marrow aspirate is nonproductive or not diagnostic, the procedure must be repeated. Six to 8 bone marrow 
slides will be prepared (in addition to fresh bone marrow samples) and sent to the Sponsor.  
s 
Including all prescription and nonprescription medications and nutritional supplements taken over previous 28 days. 
t 
Including all prescription and nonprescription medications and nutritional supplements taken since previous predose assessment visit. 
u 
Conducted just prior to first AZA dose. 
v 
Required if screening pregnancy test was performed >72 hours prior to first dose. 

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w 
Collect peripheral blood samples for PD analyses on Days 1, 3, 5, and 7 (Day 7 only in pts receiving 7-day AZA schedule) of Cycle 1 within 
10 mins prior to AZA infusion (Section 7.4, Table 10; Appendix E) 
x 
Collect peripheral blood for PD analyses (see Section 7.4, Table 10; Appendix E).  
y 
Record only those medications (prescription, nonprescription, nutritional supplements) administered in conjunction with an AE. 
z 
Collect blood just prior to start of IVI and again approximately 4 hrs post end of IVI (Time 0 = start of 30- to 60-minute alvocidib IVI). 
aa Record vital signs (temperature, heart rate, systolic and diastolic blood pressures) 5-15 mins prior to initiation of alvocidib following a 5-min rest 
bb Collect blood samples for PK analyses on Day 10 just before the alvocidib IVI (Sample #1) and at the end of the alvocidib IVI (Sample #2). 
Continue to collect blood samples for PK analyses 30 mins after end of the alvocidib IVI (Sample #3), 1 hr after end of the alvocidib IVI 
(Sample #4), 2 hrs after end of the alvocidib IVI (Sample #5), and 4 hrs after end of alvocidib IVI (Sample #6) (Section 7.3, Table 8). 
cc Phase 1b only - Collect a blood sample for PK analysis from all patients on Day 11 at 23 hrs after start of the alvocidib IVI administered on 
Day 10 (Sample #7) (Section 7.3, Table 8).   
dd Perform bone marrow biopsy and aspiration and collect peripheral blood sample for assessment of response (Appendix F), standard 
cytogenetics, and PD analyses (Appendix E). [Note: with a +1/-3 day window, these assessments may be performed on Days 25-28 or Day 1 
of the next cycle. If performed on Day 1 of the next cycle, collect bone marrow and aspiration as well as peripheral blood samples prior to 
administering the first dose of AZA.] 
If the bone marrow biopsy and/or aspirate is nonproductive or not diagnostic, at the EVEN 2+ cycle visits, there should be no delay in dosing 
and the procedure should be repeated within 7 days. Six to 8 bone marrow slides will be prepared (in addition to fresh bone marrow samples) 
and sent to the Sponsor.  
Response assessments and standard cytogenetics should be repeated on Day 28 (+1/-3 days) of Cycles 2, 4, and 6, and then every 4 cycles, 
thereafter, or as clinically indicated. If medically appropriate, response assessments should be repeated at the time of disease progression.  
ee Peripheral blood samples to be collected for PD analyses on Day 28 of even Cycles 2, 4 and 6 and then every 4 cycles thereafter (ie, 
Cycle 10, Cycle 14, etc) or as clinically indicated (Appendix E).  
ff 
As clinically indicated. 
gg If ≥8 weeks since last response assessment, perform bone marrow biopsy and aspiration and collect peripheral blood sample for assessment 
of response (Appendix F), and PD analyses (Appendix E). If the bone marrow biopsy and/or aspirate is nonproductive or not diagnostic, the 
procedure must be repeated within 7 days. Six to 8 bone marrow slides will be prepared (in addition to fresh bone marrow samples) and sent 
to the Sponsor. 
hh Including any antineoplastic therapies initiated since discontinuation of study drug. 
ii 
Ongoing AEs must be followed clinically until the event is resolved, deemed permanent or no longer clinically significant, or the patient begins 
an alternative treatment regimen. 
jj 
After Cycle 3, frequency of labs may be performed as per standard of care starting after Day 11. 
 
 
 

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j 
Mandatory IV hydration with 0.45% NaCl (or similar hydration fluid per institutional standard) sterile solution at 500 cc for 1-2 hrs prior to alvocidib, 
then an additional 500 cc for 1-2 hrs after alvocidib during Cycle 1 (volume may be reduced to between 250 cc – 500 cc, if clinically indicated). 
Hydration is optional for subsequent cycles. 
k 
Continue oral phosphate binder daily on Days 1-14 of Cycle 1.  
l 
Assess tumor lysis labs prior to alvocidib IVI and 2 hrs (±30 mins) after completion of IV hydration post alvocidib.  
m Potassium levels obtained as part of the tumor lysis lab panel at 2 hrs after completion of IV hydration post alvocidib should be reviewed 
immediately for indications of tumor lysis syndrome as additional treatment may be warranted (footnote ‘h’). 
n 
Tumor lysis labs to be drawn daily for the first 2 days following alvocidib IVI (ie, Days 11-12) and at least weekly for the remainder of Cycle 1. 
o 
Oral allopurinol may be discontinued for subsequent treatment cycles if uric acid levels are within normal limits and there is no evidence of TLS. 
p 
Oral phosphate binder may be discontinued for subsequent treatment cycles if serum phosphorus levels are <3 after the first treatment with 
alvocidib and there is no evidence of TLS 
q 
If diarrhea persists 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. 
r 
Assess tumor lysis labs just prior to C2D1 AZA dose and 2 hours post C2D1 AZA dose  
s 
Assess tumor lysis labs just prior to C2D10 alvocidib IVI and 2 hrs (±30 mins) after completion of alvocidib IVI 
t 
During Cycles 3+, TLS labs to be checked at the discretion of the investigator in relation to patient blast counts 

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

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APPENDIX D – 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://ctep.cancer.gov/protocoldevelopment/electronic applications/docs/CTCAE
v5 Quick Reference 8.5x11.pdf 
 
 

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APPENDIX E – LABORATORY TESTS 
Hematology* 
• 
CBC with manual differential 
• 
 
• 
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 Panel* 
• 
Blood urea nitrogen (BUN) 
• 
Phosphorus 
• 
Magnesium 
• 
Lactate dehydrogenase (LDH) 
• 
Creatinine 
• 
Uric acid 
• 
Total protein 
• 
Albumin 
• 
Calcium 
• 
Glucose 
• 
Total bilirubin 
 
• 
Alkaline phosphatase (ALP) 
Aspartate aminotransferase 
(AST) 
• 
Alanine aminotransferase 
(ALT) 
• 
Electrolytes  
o Sodium 
o Potassium 
o Chloride  
o Carbon dioxide (CO2) 
Tumor Lysis Labs 
• 
Electrolytes  
o 
Sodium 
o 
Potassium 
o 
Chloride  
o 
CO2 
• 
Creatinine 
• 
Calcium 
• 
LDH 
• 
Uric acid 
• 
Phosphorus 
Coagulation Panel 
• 
Prothrombin time (PT) 
• 
Activated partial 
thromboplastin time (aPTT) 
Cardiac Tests 
• 
12-lead Electrocardiogram (ECG) with QTc 
Disease Status, 
Standard 
Cytogenetics & 
Response 
• 
Bone marrow biopsy and/or aspiration and peripheral blood 
(including peripheral blasts) 
• 
Samples to be analyzed at local laboratories 
Pharmacodynamic 
Analyses 
• 
Bone marrow biopsy and/or aspiration and peripheral blood 
• 
BH3 profiling with an emphasis on MCL-1 dependence, genetic 
mutations, and other biomarkers associated with MDS 
• 
Samples to be analyzed at a central laboratory (see Reference 
Laboratory Manual for additional information) 
Pharmacokinetic 
Analyses 
• 
Cmax, Tmax, AUC0-24, t1/2, AUCt, AUC0-inf, and CL 
Other Tests 
• 
Pregnancy test (urine or serum determination of β-hCG in females of 
childbearing potential)  
* 
During each cycle, it is critical to record all laboratory values for hematology and serum chemistry parameters 
collected during the time the patient is on study to facilitate change-from-baseline analyses. Any laboratory 
parameters assessed outside the per-protocol visits (ie, interim labs) will be recorded as ‘Unscheduled 
Laboratory Assessments’ in the database. 
.

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APPENDIX F – REVISED INTERNATIONAL WORKING GROUP (IWG) RESPONSE CRITERIA (2006) 
 
 
 

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APPENDIX F – INTERNATIONAL WORKING GROUP (IWG) RESPONSE CRITERIA (2006) (CONT) 
 
 
 
 
 
 

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APPENDIX F – INTERNATIONAL WORKING GROUP (IWG) RESPONSE CRITERIA (2006) (CONT) 
 
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