Phase II Study of the Combination of CPX-351 and Glasdegib in Previously Untreated Patients With Acute Myelogenous Leukemia With MDS Related Changes or Therapy-related Acute Myeloid Leukemia
Phase: PHASE2
Conditions: Acute Myelogenous Leukemia (AML) Due to Therapy, Acute Myeloid Leukemia With Myelodysplasia-Related Changes
Sponsor: University of California, Irvine

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Phase II study of the combination of CPX-351 and Glasdegib in previously untreated 
patients with Acute Myelogenous Leukemia with MDS related changes or therapy-related 
Acute myeloid leukemia: A University of California Hematologic Malignancies Consortium 
Protocol (UCHMC1913/UCI 18-105) 
 
 
 
Principal Investigator 
Deepa Jeyakumar, MD 
Assistant Clinical Professor of Medicine 
Division of Hematology/Oncology 
University of California, Irvine 
Chao Family Comprehensive Cancer Center 
200 S. Manchester Ave. 
Suite 400 
Orange, CA 92868 
Phone: 714-456-5153 
Fax: 714-456-2242 
E-mail: djeyakum@hs.uci.edu 
 
Research Coordinating Center 
UCI Chao Family Comprehensive Cancer Center 
101 The City Dr. South 
Orange, CA 92868 
uci18105@hs.uci.edu  
 
 
 
Study Agent:  
Daunorubicin and Cytarabine liposomal CPX-351 (CPX-351®) 
 
 
 
Glasdegib (DaurismoTM) 
 
 
Current Protocol 
Date 
v 8.0 
March 29, 2022 
 
 
Previous Versions 
Date 
(v7.0) 
August 4, 2021 
(v 6.0)  
October 23, 2020 
(v 5.0)  
(v 4.0) 
May 20, 2020 
February 19, 2020 
(v 3.0) 
(v 2.0) 
January 17, 2020 
December 17, 2019 

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(v 1.0) 
October 17, 2019 
 
 
LIST OF INVESTIGATORS 
 
 
PRINCIPAL INVESTIGATOR 
Deepa Jeyakumar, MD 
Associate Professor of Medicine, Division of Hematology/Oncology 
UC Irvine Chao Family Comprehensive Cancer Center 
200 S. Manchester Ave., Suite 400 
Orange, CA 92868 
Phone: 714-456-5153 
Fax: 714-456-2242 
Email: djeyakum@hs.uci.edu 
 
CO-INVESTIGATOR(S) 
 
University of California, Los Angeles 
Gary Schiller, MD  
Hematological Malignancies/Stem Cell Transplantation Unit  
David Geffen School of Medicine at UCLA  
200 UCLA Medical Plaza Suite 120  
Los Angeles, CA 90095  
Phone: 310-206-6909  
Email: gschiller@mednet.ucla.edu 
 
University of California, San Francisco 
Lloyd Damon, MD 
University of California, San Francisco 
Helen Diller Family Comprehensive Cancer Center 
400 Parnassus Ave, UC Clinics, A446 
San Francisco, CA 94143 
Phone: 415-353-2749 
Email:  lloyd.damon@ucsf.edu 
 
University of California, Davis 
Brian Jonas, MD, PhD 
University of California, Davis 
UC Davis Comprehensive Cancer Center 
2279 45th Street 
Sacramento, CA 95817 
 
 
SUB-INVESTIGATOR(S) 
 
Local: University of California, Irvine 
Susan O’Brien, MD 
Associate Director for Clinical Sciences, UC Irvine Chao Family Comprehensive Cancer Center 
Division of Hematology/Oncology 
Email: obrien@uci.edu 

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Richard Van Etten, MD, PhD 
Director, UC Irvine Chao Family Comprehensive Cancer Center 
Division of Hematology/Oncology 
Email: vanetten@uci.edu 
 
Edward Nelson, MD 
Chief, Division of Hematology/Oncology 
Email: enelson@uci.edu 
 
Angela Fleischman, MD, PhD 
Division of Hematology/Oncology 
agf@uci.edu 
 
Elizabeth Brem, MD 
Division of Hematology/Oncology 
Email: ebrem@uci.edu 
 
Lisa X. Lee, MD 
Division of Hematology/Oncology 
Email: lisaxl@uci.edu 
 
Piyanuch Kongtim, MD, PhD 
Division of Hematology/Oncology 
Email: pkongtim@hs.uci.edu  
 
Stefan Ciurea, MD 
Division of Hematology/Oncology 
Email: sciurea@uci.edu 
 
Chinsuk Kim, NP 
Division of Hematology/Oncology 
Email: chinsukk@uci.edu 
 
Sara Cooper, NP 
Division of Hematology/Oncology 
Email: skcooper@hs.uci.edu  
 
BIOSTATISTICIAN 
Thomas Taylor 
Department of Epidemiology 
thtaylor@uci.edu 
 
 
 
 

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Signature Page 
 
 
The signature below constitutes the approval of this protocol and the attachments, and provides 
the necessary assurances that this trial will be conducted according to all stipulations of the 
protocol, including all statements regarding confidentiality, and according to local legal and 
regulatory requirements and applicable U.S. federal regulations and ICH guidelines. 
 
 
 
UCI Principal Investigator / Study Chair 
 
 
_____________________________ 
Printed Name 
 
 
_____________________________  
____________________ 
Signature 
 
 
 
 
Date 
 
 
 
 
 
Participating Site Principal Investigator 
 
 
_____________________________  
_____________________________ 
Printed Name  
 
 
 
Institution 
 
 
_____________________________  
____________________ 
Signature 
 
 
 
 
Date 
 
 
 
 

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TABLE OF CONTENTS 
STUDY SCHEMA ...................................................................................................................................................................... 9 
STUDY SUMMARY ............................................................................................................................................................... 10 
SCHEDULE OF EVENTS ...................................................................................................................................................... 16 
1.0 BACKGROUND AND RATIONALE ......................................................................................................................... 19 
1.1 
DISEASE BACKGROUND .............................................................................................................................................................. 19 
1.2 
AML WITH MYELODYSPLASTIC CHANGES ............................................................................................................................... 19 
1.3 
MINIMAL/MEASURABLE RESIDUAL DISEASE (MRD) IN AML .......................................................................................... 19 
1.4 
GLASDEGIB ................................................................................................................................................................................... 20 
1.5 
CPX-351 ...................................................................................................................................................................................... 21 
1.6 
RATIONALE FOR THE COMBINATION OF GLASDEGIB AND CPX-351 .................................................................................. 23 
1.7 
CORRELATIVE STUDIES .............................................................................................................................................................. 23 
2.0 STUDY OBJECTIVES ................................................................................................................................................. 23 
2.1 
PRIMARY OBJECTIVE/ PRIMARY ENDPOINT .......................................................................................................................... 23 
2.2 
SECONDARY OBJECTIVES/ SECONDARY ENDPOINTS............................................................................................................. 24 
2.3 
EXPLORATORY OBJECTIVES/ EXPLORATORY ENDPOINTS ................................................................................................... 24 
3.0 PATIENT ELIGIBILITY ............................................................................................................................................. 24 
3.1 
INCLUSION CRITERIA .................................................................................................................................................................. 24 
3.2 
EXCLUSION CRITERIA ................................................................................................................................................................. 26 
4.0 REGISTRATION PROCEDURES .............................................................................................................................. 27 
4.1 
PATIENT REGISTRATION PROCEDURES ................................................................................................................................... 27 
4.2 
PATIENT ELIGIBILITY ................................................................................................................................................................. 27 
5.0 TREATMENT PLAN ................................................................................................................................................... 27 
5.1 
TREATMENT DOSAGE AND ADMINISTRATION ........................................................................................................................ 28 
5.2 
INDUCTION ................................................................................................................................................................................... 28 
5.3 
REINDUCTION .............................................................................................................................................................................. 28 
5.4 
CONSOLIDATION .......................................................................................................................................................................... 28 
5.6 
ALLOGENIC STEM CELL TRANSPLANTATION ........................................................................................................................... 29 
5.7 
MAINTENANCE ............................................................................................................................................................................ 29 
5.8 
DURATION OF THERAPY ............................................................................................................................................................. 29 
5.9 
DURATION OF FOLLOW UP ........................................................................................................................................................ 30 
5.10 
OTHER THERAPEUTIC AGENTS ................................................................................................................................................. 30 
5.11 
PRE-MEDICATIONS ..................................................................................................................................................................... 30 
5.12 
INFECTION PROPHYLAXIS ........................................................................................................................................................... 30 
5.13 
PERMITTED CONCOMITANT THERAPY ..................................................................................................................................... 30 
5.14 
PROHIBITED CONCOMITANT THERAPY .................................................................................................................................... 31 
6.0 TOXICITIES AND DOSING DELAYS/DOSE MODIFICATIONS ........................................................................ 31 
6.1 
CPX-351 DOSE MODIFICATION ................................................................................................................................................ 31 
6.2 
GLASDEGIB DOSE MODIFICATION FOR NON-HEMATOLOGIC TOXICITIES ............................................................................. 31 
6.3 
GLASDEGIB DOSE MODIFICATION FOR HEMATOLOGIC TOXICITIES ...................................................................................... 31 
6.4 
GLASDEGIB DOSE MODIFICATION FOR QTC PROLONGATION ................................................................................................ 31 
7.0 STUDY PROCEDURES .............................................................................................................................................. 32 
7.1 
SCREENING/BASELINE PROCEDURES ...................................................................................................................................... 32 
7.2 
PROCEDURES DURING TREATMENT ......................................................................................................................................... 34 
7.3 
END OF TREATMENT VISIT ........................................................................................................................................................ 36 
7.4 
FOLLOW-UP PROCEDURES ......................................................................................................................................................... 37 

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7.5 
CORRELATIVE STUDIES .............................................................................................................................................................. 37 
8.0 REMOVAL OF SUBJECTS FROM STUDY TREATMENT AND STUDY ............................................................ 37 
9.0 DATA AND SPECIMEN SUBMISSION GUIDELINES ........................................................................................... 38 
9.1 
LABELING SAMPLES .................................................................................................................................................................... 38 
9.2 
SAMPLE COLLECTION GUIDELINES ........................................................................................................................................... 38 
10.0 MEASUREMENT OF EFFECT .................................................................................................................................. 38 
10.1 
ANTITUMOR EFFECT- HEMATOLOGIC TUMORS ..................................................................................................................... 38 
10.2 
COMPLETE REMISSION ................................................................................................................................................................ 39 
10.3 
PROGRESSIVE DISEASE ............................................................................................................................................................... 39 
10.4 
EVENT-FREE SURVIVAL .............................................................................................................................................................. 39 
10.5 
FINAL RESPONSE ASSESSMENT ................................................................................................................................................ 39 
11.0 ADVERSE EVENTS ..................................................................................................................................................... 39 
11.1 
EVENT DEFINITIONS ................................................................................................................................................................... 40 
11.2 
ADVERSE EVENT MONITORING ................................................................................................................................................ 41 
11.3 
REPORTING REQUIREMENTS FOR ADVERSE EVENTS ............................................................................................................ 43 
11.4 
ADDITIONAL REPORTING OF EVENTS FROM INVESTIGATORS AT PARTICIPATING SITES TO THE SPONSOR 
INVESTIGATOR ............................................................................................................................................................................................... 46 
12.0 AGENT INFORMATION ............................................................................................................................................ 48 
12.1 
GLASDEGIB ................................................................................................................................................................................... 48 
12.2 
CPX-351 ...................................................................................................................................................................................... 48 
13.0 STATISTICAL CONSIDERATIONS ......................................................................................................................... 49 
13.1 
STUDY DESIGN ............................................................................................................................................................................. 49 
13.2 
DATA ANALYSES PLANS ............................................................................................................................................................. 49 
13.3 
SAMPLE SIZE AND ACCRUAL GOAL ........................................................................................................................................... 50 
13.4 
OTHER ANALYSES ....................................................................................................................................................................... 50 
14.0 STUDY MANAGEMENT ............................................................................................................................................ 51 
14.1 
CONFLICT OF INTEREST.............................................................................................................................................................. 51 
14.2 
REGULATORY ISSUES .................................................................................................................................................................. 51 
14.3 
SCIENTIFIC REVIEW COMMITTEES ........................................................................................................................................... 52 
14.4 
INSTITUTIONAL REVIEW BOARDS ............................................................................................................................................ 52 
14.5 
SMART IRB PROCESS ............................................................................................................................................................... 52 
15.0 UCHMC PUBLICATION POLICY ............................................................................................................................. 60 
15.1 
OVERVIEW .................................................................................................................................................................................... 60 
15.2 
PUBLICATION PREPARATION AND REVIEW ............................................................................................................................ 60 
15.3 
PUBLICATION ACKNOWLEDGEMENTS ...................................................................................................................................... 60 
15.4 
AUTHORSHIP ................................................................................................................................................................................ 60 
16.0 REFERENCES .............................................................................................................................................................. 62 
17.0 APPENDICES .............................................................................................................................................................. 65 
APPENDIX A. CYTOGENETIC ABNORMALITIES .......................................................................................................................................... 65 
APPENDIX B. PERFORMANCE STATUS ....................................................................................................................................................... 66 
APPENDIX C. CYP35A INHIBITORS/INDUCERS ...................................................................................................................................... 67 
APPENDIX D. DRUGS KNOWN TO PROLONG QTC ..................................................................................................................................... 70 
APPENDIX E. IWG RESPONSE CRITERIA .................................................................................................................................................. 72 
APPENDIX F. PILL DIARY ............................................................................................................................................................................. 74 
APPENDIX G. ELIGIBILITY CHECKLIST ....................................................................................................................................................... 76 
APPENDIX H: ANTHRACYCLINES EQUIVALENT GUIDELINESA ............................................................................................................... 80 

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LIST OF ABBREVIATIONS 
AE 
Adverse event 
ALT 
Alanine aminotransferase 
AML 
Acute Myeloid Leukemia 
ANC 
Absolute neutrophil count 
aPTT 
Activated partial thromboplastin time 
AST 
Aspartate aminotransferase 
CBC 
Complete blood count 
CML 
Chronic Myelogenous Leukemia 
CMML 
Chronic Myelomonocytic Leukemia 
CMP 
Comprehensive metabolic panel 
CNS 
Central Nervous System 
CR 
Complete Remission 
CrCl 
Creatinine clearance 
CRF 
Case Report Form 
CRi 
Complete Remission with incomplete recovery 
CTCAE 
Common Terminology Criteria for Adverse Events 
DLT 
Dose limiting toxicity 
DSMB 
Data and Safety Monitoring Board 
ECG 
Electrocardiogram 
ECHO 
Echocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
EFS 
Event-free survival  
ET 
Essential Thrombocythemia 
FDA 
Food and Drug Administration 
FISH 
Fluorescence in situ hybridization 
GCP 
Good Clinical Practice 
GFR 
Glomerulus filtration rate 
GI 
Gastrointestinal  
HCG 
Human chorionic gonadotropin 
Hgb  
Hemoglobin  
HIPAA 
Health Insurance Portability and Accountability Act 
HIV 
Human Immunodeficiency virus 
HSCT 
Hematopoietic Stem Cell Transplantation 
ICF 
Informed consent form 
INR 
International normalized ratio 
IRB 
Institutional Review Board 
LAIP 
Leukemia-associated immunophenotypes 
LDAC 
Low dose cytarabine 

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LDH 
Lactate dehydrogenase 
LSC 
Leukemic stem cells 
LVEF 
Left Ventricular Ejection Fraction 
MDS 
Myelodysplastic Syndrome 
MFC 
Multiparameter flow cytometry 
MPN 
Myeloproliferative Neoplasm 
MRD 
Minimal/Measurable Residual Disease 
NCI 
National Cancer Institute 
NGS 
Next Generation Sequencing 
NYHA 
New York Heart Association 
ORR 
Overall response rate 
OS 
Overall survival 
PI 
Principal investigator 
Plt 
Platelet 
PO 
per os/by mouth/orally 
PT 
Prothrombin time 
PV 
Polycythemia Vera 
RFS 
Relapse-free survival 
RSC 
Radiation Safety Committee 
RT-PCR 
Reverse transcription polymerase chain reaction 
SAE 
Serious adverse event 
SGOT 
Serum Glutamic Oxaloacetic Transaminase 
SMO 
Smoothened 
SPGT 
Serum Glutamic Pyruvic Transaminase 
Sub-I 
Sub-investigator  
ULN 
Upper limit of normal 
UPR 
Unanticipated problem 
WBC 
White blood cell 
WHO 
World Health Organization 
 
 

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STUDY SCHEMA 
 
 
 

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STUDY SUMMARY 
Title 
Phase II study of the combination of CPX-351 and Glasdegib in 
previously untreated patients with Acute Myelogenous Leukemia 
with MDS related changes or therapy-related Acute myeloid 
leukemia: A University of California Hematologic Malignancies 
Consortium Protocol (UCHMC1913/UCI 18-105) 
Short Title 
CPX-351 and Glasdegib for newly diagnosed acute myelogenous 
leukemia with MDS related changes or therapy-related Acute 
myeloid leukemia 
Phase 
Phase 2 
Sponsor 
University of California Hematologic Malignancies Consortium 
Methodology 
Single-arm, open-label trial 
Study Duration 
2-3 years 
Study Center(s) 
The University of California Hematologic Malignancies Consortium: 
University of California, Irvine 
University of California, Los Angeles 
University of California, San Diego 
University of California, San Francisco  
University of California, Davis 
 
Objectives 
Primary objective:  
• 
Determine the efficacy of the combination of CPX-351 and 
Glasdegib for newly diagnosed AML with MDS related 
changes and therapy-related AML   
Secondary objectives:  
• 
Determine the toxicity of the combination of CPX-351 and 
Glasdegib in adults with newly diagnosed AML with MDS 
related changes  
• 
Determine the rate of response by measuring overall 
remission rate (ORR) of the combination. The overall 
remission rate includes complete remission (CR) and 
complete remission with incomplete recovery (CRi) 
• 
Determine the durability of response by measuring relapse 
free survival (RFS) 
• 
Determine the survival and length of survival by measuring 
Overall Survival (OS) 
• 
Determine the time to return of normal hematopoiesis, 
duration of response 
• 
Determine the proportion of patients who go on to receive 
allogeneic HSCT 
 
Exploratory objectives:  
• 
Determine if MRD status based on multiparameter flow 
cytometry from University of Washington can be used as a 
surrogate marker for survival  
• 
To determine if gene expression profiling can be 
biomarkers of response   
Number of Subjects 
30 evaluable subjects 
Diagnosis and Main 
Inclusion Criteria 
1. Previously untreated therapy-related AML or AML with 
myelodysplastic related changes as described by WHO 

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2016 
a. AML arising in MDS (including CMML) or MDS/MPN 
syndrome 
b. AML with MDS-related cytogenetic abnormalities 
(Appendix A, metaphase FISH allowable as 
surrogate for cytogenetics) 
c. AML with multilineage dysplasia involving the 
presence of 50% or more dysplastic cells in at least 
two cell lines and in the absence of mutation in 
NPM1 or biallelic CEBPA (as per WHO 2016) 
2. Adults 18 years of age or older 
 
3. ECOG performance status 0 to 2 
 
4. Adequate organ function as defined as: 
a. Left Ventricular Ejection Fraction (LVEF) > 50% 
b. Serum total bilirubin < 2.0 mg/dL, unless considered 
due to Gilbert's disease or leukemic involvement 
c. AST, ALT and alkaline phosphatase < 3 times the 
upper limit of normal, unless considered due to 
leukemic involvement 
d. Serum creatinine < 2.0 mg/dL, or creatinine 
clearance > 40 mL/min based on Cockcroft-Gault 
GFR 
 
5. Absence of unstable cardiac disease defined as myocardial 
infarction within 6 months, uncontrolled heart failure, or 
uncontrolled cardiac arrhythmia 
 
6. Ability to understand and the willingness to sign a written 
informed consent or subject’s legally authorized 
representative (LAR) has provided informed consent prior 
to any study-specific activities/procedures being initiated 
when the subject has any kind of condition that, in the 
opinion of the investigator, may compromise the ability of 
the subject to give written informed consent 
 
7. Women of child-bearing potential and men with partners of 
child-bearing potential must agree to use 2 methods of birth 
control or be surgically sterile, or abstain from heterosexual 
activity for the course of the study through 120 days after 
the last dose of study medication 
 
A woman of child-bearing potential is any female 
(regardless of sexual orientation, having undergone a tubal 
ligation, or remaining celibate by choice) who meets the 
following criteria: 
• Has not undergone a hysterectomy or bilateral 
oophorectomy; or  
• Has not been naturally postmenopausal for at least 12 
consecutive months (i.e., has had menses at any time in 

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the preceding 12 consecutive months) 
 
Women of child-bearing potential has negative pregnancy 
test within 72 hours of initiating study drug dosing 
 
Male subjects must agree to use a latex condom during 
sexual contact with females of childbearing potential even if 
they have had a successful vasectomy starting with the first 
dose of study therapy through 120 days after the last dose 
of study therapy 
 
8. Leukapheresis, corticosteroid and hydroxyurea are 
permitted as initial management of hyperleukocytosis at the 
investigator’s discretion for up to 7 days after starting study 
therapy. Hyperleukocytosis is defined as greater than 30k 
WBC. When possible, a bone marrow biopsy for screening 
should be performed prior to the initiation hyperleukocytosis 
management 
 
Exclusion Criteria 
1. Prior treatment with Glasdegib or CPX-351 
 
2. Previously treated AML except for initial management of 
hyperleukocytosis. Treatment with hypomethylating therapy 
for MDS is allowable but not since their diagnosis of AML. 
No prior treatment with cytarabine or daunorubicin are 
allowed 
 
3. Concurrent FLT3 mutation that the treating physician 
deems necessary to treat with midostaurin, whereas 
patients with FLT3-mutated AML not treated with 
midostaurin can be enrolled. Patients with known Core 
Binding Factor –t(8;21), inv(16), t(16;16) are allowed for 
study participation at the treating investigator's discretion 
 
4. Active CNS or testicular involvement by leukemia; 
diagnostic lumbar puncture is not required 
 
5. History of neurologic disorder including but not limited to: 
prior seizure, epilepsy, structural brain abnormality, benign 
brain tumor, stroke, brain injuries, dementia, movement 
disorder or other significant CNS abnormalities 
 
6. Baseline QT corrected interval based on Fridericia’s 
formula (QTcF) interval > 450 ms 
 
7. Acute coronary syndrome in the past 12 months, NYHA 
class III or VI 
 
8. Known history of Wilson’s disease or other copper handling 
disorder 
 

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9. History of GI malabsorptive disease 
 
10. Has a known additional malignancy that is progressing or 
requires active treatment. Exceptions include basal cell 
carcinoma of the skin, squamous cell carcinoma of the skin, 
or in situ cervical cancer that has undergone potentially 
curative therapy 
 
11. Known HIV infection 
 
12. Active hepatitis B or hepatitis C infection (patients who 
successfully completed curative hepatitis C therapy can be 
enrolled) 
 
13. Any uncontrolled infection, active bacterial or viral infection 
manifesting as fevers or hemodynamic instability within the 
past 72 hours 
 
14. Proven active invasive fungal infection 
 
15. Is pregnant or breastfeeding, or expecting to conceive or 
father children within the projected duration of the trial, 
starting with the pre-screening or screening visit through 
120 days after the last dose of trial treatment 
 
16. Severe or uncontrolled medical disorder that would, in the 
investigator’s opinion, impair ability to receive study 
treatment (i.e., uncontrolled diabetes, chronic renal 
disease, chronic pulmonary disease or active, uncontrolled 
infection, psychiatric illness/social situations that would limit 
compliance with study requirements 
 
17. Current or anticipated use of other investigational agents 
 
18. For patients with prior anthracycline exposure, the 
cumulative life-time dose should not exceed 386mg/m2 at 
the time of study entry (to convert different anthracycline to 
daunorubicin-equivalent, see Appendix H for conversion 
factors) 
 
Study Product(s)  
CPX-351 and Glasdegib 
Duration of 
administration 
• 
CPX-351 will be administer during Induction on days 1, 3 
and 5. Glasdegib will be given starting on day 6 and 
continuing until beginning of consolidation 
• 
Consolidation can be either 1 or 2 cycles. CPX-351 will be 
administered during days 1 and 3. Glasdegib will begin on 
day 4 and continue daily 
• 
If the patient is a candidate for HSCT and moves forward 
with HSCT, then Glasdegib will be discontinued at least 7 
days prior 

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• 
During Maintenance, Glasdegib will be taken daily for up to 
1 year 
 
Reference therapy 
Lancet Phase II CPX-351 versus 7+3. Blood 2014 
Study Outcome 
Measures 
Safety 
• 
Common Terminology Criteria for Adverse Events (CTCAE) 
version 5.0 
• 
Adverse events  
• 
Serious adverse events  
• 
Adverse events leading to discontinuation of study therapy  
Efficacy 
• 
Event-free survival  
• 
Objective response rate  complete remission (CR) plus 
complete remission with incomplete hematologic recovery 
(CRi) 
• 
Relapse free survival 
• 
Duration of response  
• 
Time to return of normal hematopoiesis  
• 
Overall survival  
• 
Proportion of patients who go on to receive allogeneic 
HSCT  
Exploratory outcome measures 
• 
Determine if MRD status can be used as a surrogate 
marker for survival  
• 
Determine if using gene expression profiling can identify 
subset of patients who are more likely to respond   
 
Rationale  
In the phase III trial of CPX-351 versus 7+3 chemotherapy for first 
line treatment of secondary AML in patients 60-75 years of age, 
309 patients were treated with either of the two regimen. There 
was a statistically significant improvement in overall survival as 
well as overall remission rate in the CPX-351 arm.  
 
Glasdegib in combination with LDAC has been shown to have 
tolerable side effect profile while improving survival outcomes in 
some patients with elderly AML who are unfit for chemotherapy.  
In the phase II trial of Glasdegib with cytarabine and daunorubicin, 
69 patients with newly diagnosed AML were treated with the 
combination. The overall survival of the combination was improved 
to historical controls.  
 
We hypothesize that the combination of CPX-351 with Glasdegib 
will demonstrate improvements in event-free survival as well as 
being well tolerated. 
 

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Study Title: Phase II study of the combination of Glasdegib and CPX-351 in previously 
untreated patients with Acute Myelogenous Leukemia with MDS related changes or 
therapy-related Acute myeloid leukemia: A University of California Hematologic Malignancies 
Consortium Protocol (UCHMC1913/UCI 18-105) 
 
PI: Deepa Jeyakumar, MD, Assistant Clinical Professor of Medicine 
Institution: Chao Comprehensive Cancer Center, University of California Irvine, Orange, CA 

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SCHEDULE OF EVENTS 
 
 
Screening 
Induction/ Re-inductionE 
(Days 1-75)  
ConsolidationJ 
(Days 1-55) 
MaintenanceK 
(Days 1-28) 
EOT 
Follow-
up 
Protocol 
Activity 
< 28 days 
prior to 
D1 
D1 D3 D5 
D6 
Weekly 
(+/- 2 
days) 
Induction 
response 
D20 
(+1 day) 
Remission 
evaluation 
D28 to D60 
D1 D3 D4 
Weekly 
(+/- 2 
days) 
D1  
(+/- 7 days) 
Within 
7 days 
of last 
dose 
Every 3 
month 
(+/- 14 
days) 
Informed 
ConsentA 
X 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
Clinical Evaluation and Procedures 
Eligibility 
Review 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Disease 
Classification 
X 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
Medical 
History 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Concomitant 
Medication 
Review 
X 
For the entire duration of study participation 
 
AE/ SAE 
Review 
 
From when participant start study therapy on induction day 1 up until 28 days after the last dose of study therapy/ and until 
resolution of any treatment-related AE/ SAE 
Physical 
Exam 
X 
X 
 
 
 
X 
 
 
X 
 
 
X 
X 
X 
X 
ECOG 
Performance 
X 
X 
 
 
 
X 
 
 
X 
 
 
X 
X 
X 
X 
12-lead ECG 
X 
 
 
 
XG 
XG,H 
 
 
 
 
XG 
 
 
X 
 
ECHO 
X  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
BMA/BMBX  
XC 
 
 
 
 
 
X 
X 
 
 
 
XN 
 
XL 
 
MRD  
(send to UW) 
 
 
 
 
 
 
X 
X 
  
 
 
 
 
XL 
 
Cytogenetics 
/Molecular 
profiling  
XC 
 
 
 
 
 
X 
X 
  
 
 
 
 
XL 
 

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Research 
sample for 
gene 
expression 
correlatives  
XC, D 
 
 
 
 
 
XD 
XD 
 
 
 
 
 
XD,L 
 
HSCT 
information/ 
Survival 
Status 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
XM 
Laboratory Assessments 
Hematology 
X 
X 
 
 
 
X 
X 
X 
X 
 
 
X 
X 
X 
X 
Chemistry 
X 
X 
 
 
 
X 
 
 
X 
 
 
X 
X 
X 
 
Urinalysis 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Coagulation 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy 
TestB 
X 
 
 
 
 
 
 
 
X 
 
 
 
X 
 
 
Study treatment 
CPX-351 
Infusion 
 
X 
X 
XF 
 
 
 
 
X 
X 
 
 
 
 
 
Glasdegib 
 
 
 
 
XI 
 
 
 
 
 
XI 
 
X 
 
 
Abbreviations:  
AE=Adverse Event, SAE=Serious Adverse Event, ECOG=Eastern Cooperative Oncology Group, ECG=Electrocardiogram, 
ECHO=Echocardiogram, BMA=Bone Marrow Aspirate, BMBX=Bone Marrow Biopsy, MRD=Minimal/Measurable Residual Disease, 
UW=University of Washington, HSCT=Hematopoietic Stem Cell Transplant, D=Day, EOT=End of Treatment 
 
Footnotes:  
A Must be obtained before undergoing any protocol-specific study procedures, unless as part of standard of care 
B Serum beta-HCG should be done for any female of child-bearing potential 
C Bone marrow collections do not need to be repeated if a diagnostic bone marrow procedure was done prior to informed consent and 
is done within 28 days of starting day 1 of induction 
D Collect bone marrow aspirate for research sample for gene expression correlatives; if patient has any circulating blasts, then 
peripheral blood can be collected instead of aspirate; if bone marrow is a “dry tap,” then this sample does not need to be collected 
E Re-induction is based on response evaluation bone marrow done on day 20 of induction. If there is greater than 5% blast count, re-
induction is recommended. The final decision for re-induction is based on investigator’s discretion. For patients who will be treated 
with re-induction, an ECHO and pregnancy test (for female patients of child-bearing potentials) will be done before starting re-
induction 
F Omit CPX-351 on day 5 for participants receiving re-induction 

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G ECG is done pre-dose and can be done up to 24 hours before planned glasdegib dosing 
H During induction, repeat an ECG a week after starting glasdegib (around day 13-15). If clinically significant abnormal ECG or 
clinically significant changes in QTc, then refer to section 6.4 for further guidance. If normal or non-clinically significant abnormalities 
and/or changes in QTc, additional ECG monitoring is not required and is done per the treating investigator’s discretion 
I Glasdegib should continue until day 1 of the next cycle of CPX-351 
J Up to two cycles of consolidation is allowed. These are 28 day cycles, unless delays are necessary. In the case of a delay, 
glasdegib will continue daily until the start of CPX-351 infusion in the next cycle. If the patient will proceed to allogenic SCT, then 
consolidation can be skipped or shorten. Glasdegib will be stopped at least 7 days before transplant.  
K These are 28 days cycle. Patients who are not receiving HSCT will be allowed to proceed to glasdegib maintenance for up to 1 year 
of study start 
L At the time of suspected relapse, a bone marrow aspirate/ biopsy will be done and samples will be collected. Patients will 
discontinue glasdegib in anticipation of start of treatment for relapsed disease 
M Patients who undergo HSCT will have their HSCT information collected and will only require survival follow up. No other procedures 
or requirements will be collected 
NAt the end of consolidation, a bone marrow biopsy is recommended but is not required by the protocol. If it is done, it is suggested to 
send for cytogenetics, molecular studies, and MRD.    
 
 

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1.0 BACKGROUND AND RATIONALE 
1.1 Disease Background 
According to the SEER database in 2018, there are an estimated 19,250 cases of AML 
diagnosed [1]. Unfortunately, there are 10,670 estimated deaths attributed to AML that same 
year [1]. The prognosis of patients with acute myelogenous leukemia with MDS related changes 
and secondary AML is poor [2]. The long term survival of these patients with the standard of 
care “7+3” chemotherapy is low. This is related to lower rates of complete remission as well as 
relapse after obtaining complete remission related to residual disease. 
 
1.2 AML with myelodysplastic changes 
The presence of multilineage dysplasia alone does not classify a case as AML with 
myelodysplastic-related changes when a mutation of NPM1 or biallelic mutation of CEBPA is 
present [3]. The outcome of 318 cases of NPM1 mutated AML were examined retrospectively 
[4]. Multilineage dysplasia was present in 23% of them. The outcomes of the NPM1 mutated 
AML were equivalent independent of the status of multilineage dysplasia. These results were 
confirmed in another retrospective analysis of 130 patients [5]. NPM1 mutations were present in 
68 patients. There were 19 cases of multilineage dysplasia in AML with NPM1 mutation and 13 
cases of multilineage dysplasia in AML without NPM1 mutation. The outcomes of the patients 
with AML with NPM1 mutation were similar whether multilineage dysplasia was present or not. 
The outcome of 108 cases of CEPBA mutated AML were examined retrospectively [6]. The 
cases with multilineage dysplasia had lower white blood cell counts. However, the biologic 
characteristics, cytogenetic and mutational analysis were similar. There was no difference in the 
2 year overall survival or event free survivals in patients with multilineage dysplasia or without 
multilineage dysplasia.  
 
In cases lacking these mutations, the morphologic detection of multilineage dysplasia (defined 
as the presence of 50% of more dysplastic cells in at least 2 cell lines) remains a poor 
prognostic indicator and is sufficient to make a diagnosis of AML with myelodysplastic changes 
[3]. The outcome of 177 cases of AML with multilineage dysplasia without NPM1 were analyzed 
retrospectively [7]. There were 43 cases of AML with WHO criteria of multilineage dysplasia. 
There were 16 cases of AML with significant dysplasia but not sufficient for WHO criteria for 
multilineage dysplasia. There were 80 cases of AML without evidence of multilineage dysplasia. 
The presence of multilineage dysplasia was associated with lower complete remission rates 
after initial frontline chemotherapy. Furthermore, if patients were censored for going to 
transplant, cases of AML with multilineage dysplasia were associated with a shorter survival.  
These results were confirmed in another series of cases of AML without NPM1 mutation, there 
was an inferior response to induction chemotherapy at 53% versus 85% [5]. Furthermore, in 
these cases, multilineage dysplasia was an unfavorable prognostic value for response rate and 
survival in multivariable analysis. 
 
1.3 Minimal/Measurable Residual Disease (MRD) in AML 
While assessment of “measurable” residual disease in AML has been standardized in ALL, the 
assessment of measurable residual disease (MRD) in AML is still evolving. There are three 
different methods of assessing MRD which are multiparameter flow cytometry (MFC), NGS or 
RT-PCR based [8]. In the US, MFC has been more widely tested while in Europe, RT-PCR 
based assays are more common. MFC based assays will measure for leukemia-associated 

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immunophenotypes (LAIP) with CD2, CD4, CD7, CD13, CD15, CD19, CD33, CD34, CD45, 
CD56, CD123, CD117 and HLA-DR. RT-PCR will measure for mutations in CBFB-MYH11, 
FTL3-ITD, IDH1 and IDH2, NPM1, RUNX1/RUNXITI, t(10,11)-KMT2A-MLLT10, t(11,19)- 
KMT2A-ELL, t(6,11)- KMT2A-MLLT4, t(9,11)- KMT2A-MLLT3 and WT1. 
 
Recently, NGS based assays are being present for certain mutations including NPM1, RUNX1, 
FLT3-IRD, IDH1 and IDH2. However, particular attention was made to the sensitivities of the 
various assays. Furthermore, it is important to separate out age-related clonal hematopoiesis 
from leukemia-specific signature. Specific examples of mutations that are more likely to be 
clonal hematopoiesis including DNMT3A, TET2 and ASXL1. In the recent study that utilized 
NGS testing, when mutations related to clonal hematopoiesis is separated, then the difference 
in relapse rate was clearly different between the MRD positive and MRD negative group [9]. 
 
Assessment of MRD by MFC has been tested in various trials. Recently, in patients with biallelic 
CEPBA mutated AML, the assessment of MRD by MFC at the end of consolidation was able to 
distinguish a high and low risk group of patients [10]. Patients that were MRD positive at the end 
of consolidation had lower relapse-free survival than patients who were MRD negative at the 
end of consolidation.  
 
Similarly, there are been several trials using MRD by MFC to determine if we can determine 
higher risk patient population for relapse in patients with AML undergoing induction 
chemotherapy [11,12].  
 
1.4 Glasdegib 
Aberrant signaling in the hedgehog pathway has been identified in leukemia and specifically in 
leukemia stem cells. Upregulation of these pathways has been shown in resistant AML cell 
lines. Therefore, inhibition of this pathway with an inhibitor is an attractive target for anti-
leukemia therapy. Glasdegib is a small molecule inhibitor of smoothened (SMO) in the Sonic 
Hedgehog pathway [13].  
 
1.4.1 Preclinical work with Glasdegib 
Glasdegib inhibits SMO in vitro and induces significant antitumor activity in vivo [14-15]. 
Furthermore, SMO inhibition has been shown to reduce leukemia stem cells (LSC) population in 
xenograft models by inhibition of the Hedgehog (Hh) signaling and reduction in cell populations 
expressing LSC markers [16]. 
 
1.4.2 Early clinical work with Glasdegib  
In the phase 1 dose-escalation study in patients with advanced myeloid malignancies, 
Glasdegib was well tolerated as a single agent [17]. The most common treatment related 
adverse effects were dysgeusia, decreased appetite and alopecia. Based on these results, 
subsequent phase II trial were focused on patients with acute myeloid leukemia, 
myelodysplastic syndrome and myelofibrosis. In a separate Phase 1 trial in Japanese patients 
with hematologic malignancies, patients received Glasdegib as a single agent as a once a daily 
for each 28 days cycle after they had received a single dose five days prior to starting the first 
cycle. There were similar treatment related adverse events noted in patients who received 
Glasdegib as a single agent [18]. Furthermore, the GLI1 was downregulated in the skin of these 
patients by 80%. Downregulation of GLI1 is associated with inhibition of tumor growth. While 
there is no direct evidence that GLI1 suppression in skin correlates with suppression in 

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hematologic malignancies, this pathway has been shown to be part of the pathogenesis of the 
basal cell carcinoma [19, 20]. 
 
1.4.3 Early clinical trials with Glasdegib in combination  
In the phase 1b study, Glasdegib was studied in combination with other anti-leukemic therapies 
in patients with newly diagnosed AML or high risk MDS [21]. There were three arms. Arms A 
and B for patients who were unfit for standard chemotherapy. Arm A was Glasdegib with low 
dose cytarabine. Arm B was Glasdegib with decitabine. Arm C was Glasdegib with standard 
cytarabine and daunorubicin for patients who were fit for standard induction chemotherapy. The 
study was following the standard 3+3 dose escalation design. The primary endpoint was dose 
limiting toxicity (DLT). There were 10 additional patients in the expansion cohorts of arms A and 
C. There were no DLT’s observed in arms A and B. In Arm C, there was one patient with grade 
4 neuropathy. The most common treatment related adverse events were mostly grade 1 or 2. 
There were some cases of dysgeusia, muscle spasms and alopecia. Overall, thirty one percent 
of patients had complete remission (CR) or complete remission with incomplete recovery (CRi). 
In the phase 2 portion of this trial, Glasdegib with low dose cytarabine was found to improve 
overall survival compared to low dose cytarabine alone [22]. Based on the results of this trial, 
FDA approved Glasdegib in combination with low dose cytarabine with patients with newly 
diagnosed AML who are over the age of 75 or who have chronic health problems that preclude 
intensive chemotherapy on November 21, 2018 [23]. These results have been updated and 
published [24]. Of note, Glasdegib has not been studied in patients with severe renal or 
moderate-to-severe hepatic impairment. 
 
Based on the results of the phase I trial of the combination of Glasdegib with standard 
chemotherapy, a phase II open-label study of Glasdegib in combination with cytarabine and 
daunorubicin with patients with newly diagnosed AML or high-risk MDS was initiated [25]. 
Patients received Glasdegib started on day -3 at 100mg orally daily in continuous 28 days 
cycles. They also received cytarabine at 100mg/m2 on day 1-7 and daunorubicin at 60mg/m2 
on day 1-3. Once in remission, they received cytarabine consolidation at 1gm/m2 twice daily on 
days 1, 3, 5 of each cycle for 2-4 cycles total. This was followed by maintenance Glasdegib for 
up to 6 cycles. The complete remission rate was 46%. Among patients older than 55, the 
complete remission rate was 40%. Among all 69 patients, the median overall survival was 14.9 
months. The most common treatment related adverse reactions were diarrhea and nausea. The 
combination was well tolerated.  
 
In the non-intensive arm of the phase II trial with LDAC with Glasdegib, there were several 
genes that correlated with improved OS [26]. Lower levels of expression of FOXM1 and MSI2 
and higher expression levels of BCL2 and CCND2 correlated with improved overall survival. In 
the intensive treatment arm with Glasdegib and cytarabine/daunorubicin, higher PTCH1 
expression correlated with improved overall survival. Furthermore, in the intensive arm, 
mutations in FLT3, TP53, CEP170, NPM1 and ANKRD26 correlated with overall survival. 
Interesting to note, that patients with AML with mutated FLT3 (which is generally a poor risk 
group) did better than AML with wild type FLT3. Therefore, we will be measuring some of these 
genes to see if this observation of their correlation with improved overall survival is confirmed. 
 
1.5 CPX-351 
CPX-351 was designed as a fixed 5:1 molar ratio of cytarabine to daunorubicin within a 
liposomal carrier.  
 

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1.5.1 Preclinical work with CPX-351 
There is strong supporting pre-clinical evidence that CPX-351 may be more effective than 7+3. 
Based on in vitro work, the highest proportion of synergy occurs at 5:1 molar ratio [27]. There is 
relatively high accumulation and persistence of the liposomal drug within the marrow [28]. 
 
Finally, there is selective uptake within the leukemic cells [29]. 
 
1.5.2 Early clinical work with CPX-351 
In the first-in-man of CPX-351 in relapsed and refractory AML, CPX-351 was found to be safe 
and producing complete remissions in eight out of 33 patients with refractory leukemia [30]. 
There was a dose-limiting toxicity (DLT) noticed in 3 out of 6 patients in the phase 1 trial at dose 
level 134 units/m2 that led to dose reduction. The DLT was congestive heart failure, 
hypertensive crisis and cytopenias beyond day 56. This led to using a lower dose level of 101 
units/m2 in the next cohort which was well tolerated without DLTs. Subsequent trials have used 
the dose to 100units/m2.  
 
In the phase II trial, CPX-351 was compared to investigator’s choice of first salvage 
chemotherapy in 125 patients with AML in first relapse [31]. In this study, CPX-351 did not meet 
the 1 year survival improvement in the overall population. However, there were higher response 
rates in the poor-risk group as well as event-free survival and overall survival.  Also, the 60-day 
mortality rate was lower than with salvage chemotherapy in the poor-risk group. 
 
1.5.3 Further development of CPX-351 
In the phase II trial, the outcomes were compared of CPX-351 versus traditional 
cytarabine/daunorubicin (7+3) chemotherapy in 126 patients with newly diagnosed AML [32]. 
CPX-351 had higher response rates than traditional cytarabine/daunorubicin (7+3) 
chemotherapy at 66.7% versus 51.2% with p=0.07 which met the predefined criteria of p<0.1. 
There was a prolongation of event-free survival as well as overall survival but this was not 
significant. The recovery after cytopenias were more prolonged after CPX-351 with more grade 
3-4 infections but without increased deaths due to infection. Aside for risk of infection, patients 
did have diarrhea, nausea, edema, constipation, rash, febrile neutropenia. However, these side 
effects were also seen with the cytarabine/daunorubicin arm. Furthermore, the 60-day mortality 
was not increased in the CPX-351 arm. This provided the rationale for a phase III trial.  
 
In the phase 3 clinical trial, CPX-351 has improved overall survival rates, event-free survival and 
response rate (complete response and complete responses with incomplete recovery) to 
traditional 7+3 chemotherapy in the patients with previously untreated AML with MDS related 
changes as well as AML evolving out of MDS [33]. There was a prolongation in recovery of 
cytopenias seen again. There were similar rates of grade 3-5 infections between CPX-351 and 
standard cytarabine/daunorubicin induction chemotherapy. At median follow-up of 21 months, 
the median overall survival was 9.5 months in CPX-351 arm versus 5.9 months in the standard 
7+3 arm. The complete remission/complete remission with incomplete recovery (CR/CRi) rate 
were 47% with CPX-351 versus 33% in 7+3 arm (p=0.008). The duration of remission was 
similar between the two groups at 6.9 months versus 6.1 months in CPX-351 and 7+3 arm, 
respectively.  As a result of improved response rates, more patients receiving CPX-351 were 
also able to go to transplant than 7+3 arm at 34% versus 25% p=0.049 [34]. Furthermore, as an 
exploratory endpoint, there was improved post-transplant survival in patients who received 
CPX-351 versus 7+3 chemotherapy [35]. 

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1.6 Rationale for the combination of Glasdegib and CPX-351 
While either of these drugs separately has proven to improve the outcome of this patient 
population, it remains clear that effective treatment options for this patient population still is an 
unmet medical need. CPX-351 has been shown to have better response rates and survival 
rates compared to 7+3 chemotherapy. Glasdegib has been shown to improve upon survival 
outcomes when added to 7+3 chemotherapy. Given the increased cytoreduction from CPX-351 
which can lead to higher rates of complete remission and the improvement in survival outcomes 
seen with Glasdegib in combination with cytotoxic chemotherapy like cytarabine/daunorubicin, it 
is reasonable that the combination may prove to have improvements in outcomes for patients. 
  
1.7 Correlative Studies 
In the non-intensive arm of the phase II trial with LDAC with Glasdegib, there were several 
genes that correlated with improved OS [26]. Lower levels of expression of FOXM1 and MSI2 
and higher expression levels of BCL2 and CCND2 correlated with improved overall survival. In 
the intensive treatment arm with Glasdegib and cytarabine/daunorubicin, higher PTCH1 
expression correlated with improved overall survival. Furthermore, in the intensive arm, 
mutations in FLT3, TP53, CEP170, NPM1 and ANKRD26 correlated with overall survival. 
Interesting to note, that patients with AML with mutated FLT3 (which is generally a poor risk 
group) did better than AML with wild type FLT3. Therefore, we will be measuring some of these 
genes to see if this observation of their correlation with improved overall survival is confirmed. 
 
Furthermore, we will be measuring MRD at the end of induction by MFC at University of 
Washington. We would like to determine if MRD negative status at the end of induction 
correlated with survival outcomes in this patient population.  
 
 
2.0 STUDY OBJECTIVES 
 
The purpose of this trial is to examine the combination of Glasdegib and liposomal 
daunorubicin/cytarabine CPX-351 in previously untreated patients with AML with MDS related 
changes or therapy-related AML.  
 
2.1 Primary Objective/ Primary Endpoint 
 
2.1.1 Primary Objective 
2.1.2 Primary Endpoint 
• 
To determine the efficacy when using 
the combination of CPX-351 and 
Glasdegib to treat patients with newly 
diagnosed AML with MDS-related 
changes or treatment related AML 
• 
Efficacy will be measured by following 
the 6 month event-free survival (EFS). 
EFS is defined as the as the time 
from screening biopsy to the date of 
confirmed disease progression, 
relapse from CR/CRi, treatment 
failure, or death, whichever comes 
first. Of interest, a 6 month EFS will 
be important to follow 

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2.2 Secondary Objectives/ Secondary Endpoints 
 
2.2.1 Secondary Objectives 
2.2.2 Secondary Endpoints 
• 
To evaluate any toxicities associated 
with the combination 
• 
Adverse events are to be captured 
and characterized by type, frequency, 
severity (as graded by NCI CTCAE 
v.5.0), timing, seriousness and 
relationship to study drugs 
• 
To evaluate the rate of response 
• 
The overall response rate (ORR) 
includes the rate of complete 
remission (CR) and complete 
remission with incomplete count 
recovery (CRi) 
• 
To evaluate the durability of response 
• 
Durability of response will be 
measured by relapse-free survival 
(RFS), defined as the amount of time 
a patient remains in remission after 
having achieve a CR or CRi  
• 
To evaluate survival and the length of 
survival 
• 
Survival follow up information will be 
collected to determine overall survival 
(OS) 
• 
To evaluate the time to return of 
normal hematopoiesis 
• 
Laboratory studies including complete 
blood counts (CBCs) will be collected 
to evaluate the recovery of bone 
marrow hematopoiesis 
• 
To evaluate the proportion of subjects 
who go on to receive allogenic HSCT   
• 
HSCT information will be collected for 
patients who proceed to allogenic 
HSCT 
 
2.3 Exploratory Objectives/ Exploratory Endpoints  
 
2.3.1 Exploratory Objectives 
2.3.2 Exploratory Endpoints 
• 
To determine if minimal residual 
disease (MRD) status can be used as 
a surrogate marker for survival 
• 
MRD status based on multiparameter 
flow cytometry from University of 
Washington will be collected at each 
response assessment time points 
• 
To determine if gene expression 
profiling can be biomarkers of 
response 
• 
Molecular, cellular and soluble 
biomarkers in peripheral blood and 
bone marrow samples will be 
collected 
 
 
3.0 PATIENT ELIGIBILITY 
3.1 Inclusion Criteria 
Subjects must meet all of the inclusion criteria to participate in this study. 

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1. Previously untreated therapy-related AML or AML with myelodysplastic related changes 
as described by WHO 2016 
a. AML arising in MDS (including CMML) or MDS/MPN syndrome 
b. AML with MDS-related cytogenetic abnormalities (Appendix A, metaphase FISH 
allowable as surrogate for cytogenetics) 
c. AML with multi-lineage dysplasia involving the presence of 50% or more 
dysplastic cells in at least two cell lines and in the absence of mutation in NPM1 
or biallelic CEBPA (as per WHO 2016) 
 
2. Adults 18 years of age or older 
 
3. ECOG performance status 0 to 2 
 
4. Adequate organ function as defined as: 
a. Left Ventricular Ejection Fraction (LVEF) > 50% 
b. Serum total bilirubin < 2.0 mg/dL, unless considered due to Gilbert's disease or 
leukemic involvement 
c. AST, ALT and alkaline phosphatase < 3 times the upper limit of normal, unless 
considered due to leukemic involvement 
d. Serum creatinine < 2.0 mg/dL, or creatinine clearance > 40 mL/min based on 
Cockcroft-Gault GFR 
 
5. Absence of unstable cardiac disease defined as myocardial infarction within 6 months, 
uncontrolled heart failure, or uncontrolled cardiac arrhythmia 
 
6. Ability to understand and the willingness to sign a written informed consent or subject’s 
legally authorized representative (LAR) has provided informed consent prior to any 
study-specific activities/procedures being initiated when the subject has any kind of 
condition that, in the opinion of the investigator, may compromise the ability of the 
subject to give written informed consent 
 
7. Women of child-bearing potential and men with partners of child-bearing potential must 
agree to use 2 methods of birth control or be surgically sterile, or abstain from 
heterosexual activity for the course of the study through 120 days after the last dose of 
study medication 
 
A woman of child-bearing potential is any female (regardless of sexual orientation, 
having undergone a tubal ligation, or remaining celibate by choice) who meets the 
following criteria: 
• 
Has not undergone a hysterectomy or bilateral oophorectomy; or  
• 
Has not been naturally postmenopausal for at least 12 consecutive months 
(i.e., has had menses at any time in the preceding 12 consecutive months) 
 
Women of child-bearing potential has negative pregnancy test within 72 hours of 
initiating study drug dosing 
 
Male subjects must agree to use a latex condom during sexual contact with females of 
childbearing potential even if they have had a successful vasectomy starting with the first 
dose of study therapy through 120 days after the last dose of study therapy 
 

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8. Leukapheresis, corticosteroid and hydroxyurea are permitted as initial management of 
hyperleukocytosis at the investigator’s discretion for up to 7 days after starting study 
therapy. Hyperleukocytosis is defined as greater than 30k WBC. When possible, a bone 
marrow biopsy for screening should be performed prior to the initiation hyperleukocytosis  
3.2 Exclusion Criteria 
Subjects meeting any of the exclusion criteria at baseline will be excluded from study 
participation. 
 
1. Prior treatment with Glasdegib or CPX-351 
 
2. Previously treated AML except for initial management of hyperleukocytosis. Treatment 
with hypomethylating therapy for MDS is allowable but not since their diagnosis of AML. 
No prior treatment with cytarabine or daunorubicin are allowed 
 
3. Concurrent FLT3 mutation that the treating physician deems necessary to treat with 
midostaurin, whereas patients with FLT3-mutated AML not treated with midostaurin can 
be enrolled. Patients with known Core Binding Factor –t(8;21), inv(16), t(16;16) are 
allowed for study participation at the treating investigator's discretion 
 
4. Active CNS or testicular involvement by leukemia; diagnostic lumbar puncture is not 
required 
 
5. History of neurologic disorder including but not limited to: prior seizure, epilepsy, 
structural brain abnormality, benign brain tumor, stroke, brain injuries, dementia, 
movement disorder or other significant CNS abnormalities 
 
6. Baseline QT corrected interval based on Fridericia’s formula (QTcF) interval > 450 ms 
 
7. Acute coronary syndrome in the past 12 months, NYHA class III or VI 
 
8. Known history of Wilson’s disease or other copper handling disorder 
 
9. History of GI malabsorptive disease 
 
10. Has a known additional malignancy that is progressing or requires active treatment. 
Exceptions include basal cell carcinoma of the skin, squamous cell carcinoma of the 
skin, or in situ cervical cancer that has undergone potentially curative therapy 
 
11. Known HIV infection 
 
12. Active hepatitis B or hepatitis C infection (patients who successfully completed curative 
hepatitis C therapy can be enrolled) 
 
13. Any uncontrolled infection, active bacterial or viral infection manifesting as fevers or 
hemodynamic instability within the past 72 hours 
 
14. Proven active invasive fungal infection 
 
15. Is pregnant or breastfeeding, or expecting to conceive or father children within the 
projected duration of the trial, starting with the pre-screening or screening visit through 

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120 days after the last dose of trial treatment 
 
16. Severe or uncontrolled medical disorder that would, in the investigator’s opinion, impair 
ability to receive study treatment (i.e., uncontrolled diabetes, chronic renal disease, 
chronic pulmonary disease or active, uncontrolled infection, psychiatric illness/social 
situations that would limit compliance with study requirements 
 
17. Current or anticipated use of other investigational agents 
 
18. For patients with prior anthracycline exposure, the cumulative life-time dose should not 
exceed 386mg/m2 at the time of study entry (to convert different anthracycline to 
daunorubicin-equivalent, see Appendix H for conversion factors) 
 
 
4.0 REGISTRATION PROCEDURES 
Subjects will be evaluated for eligibility by the site principal investigator to ensure that the 
inclusion and exclusion criteria have been met. 
 
4.1 Patient Registration Procedures  
Patients that have signed informed consent to participate in a UCHMC protocol must be 
registered with the initiating site and enrolled on the protocol.   
 
Patients must be entered into the OnCore system the same day the informed consent is signed.   
 
All patients will be assigned a specific study ID which will correlate with the study number, site 
number and patient enrollment numbers.  Patient ID’s will be assigned by the lead site and 
formatted as follows:  UCHMC1913-XX-XX. 
 
Study specific ID will be provided by the initiating site once eligibility is confirmed by the initiating 
center.  
 
All patients must obtain a study ID number from the initiating center before initiation of 
treatment.  
 
4.2 Patient Eligibility  
Eligibility of the patient is determined by the clinical protocol and confirmed prior to registration.  
Participating sites need to send a redacted copy of the eligibility checklist signed by the treating 
investigator and accompanying redacted source which may include but is not limited to, 
pathology report, physical exam including ECOG, medical and oncology history and screening 
labs, must be provided to the initiating site for the specific study. Approval by initiating site PI 
and the initiating site clinical research manager is required prior to initiating treatment. 
Participating sites should send the requested redacted information above to 
uci18105@hs.uci.edu for confirmation of eligibility at least 3 business days prior to the planned 
start date of treatment.     
  
 
5.0 TREATMENT PLAN 

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5.1 Treatment Dosage and Administration 
 
5.2 Induction 
During induction, patients will receive the combination of Glasdegib and CPX-351. The dose of 
Glasdegib is 100mg orally daily on days 6 to 28. CPX-351 will be given at a dose of 
daunorubicin 44mg/m2-cytarabine100mg/m2 via 90 minute infusion on days 1, 3, 5. Induction 
can last longer than 28 days and up to 60 days. If induction last more than 28 days, patient 
should continue to take glasdegib daily and as prescribed until day 1 of next cycle of CPX-351. 
Patient will be instructed to hold glasdegib on the day they receive CPX-351 infusion.. 
 
5.3 Reinduction 
Patients who are responding to the initial induction but not yet less than 5% blasts can receive a 
second induction. Patients who have not had any reduction in blasts count should be 
considered as refractory and should be considered for other treatment options off protocol. 
However, if there is a greater than 50% reduction in blast count but greater than 5% blasts 
present on marrow, re-induction is strongly recommended. The use of re-induction will be at the 
treating physician’s discretion based on bone marrow biopsy performed on day 20 (+1 day). The 
regimen for re-induction will be CPX-351 at a dose of daunorubicin 44mg/m2–cytarabine 
100mg/m2 on days 1 and 3. Glasdegib will be administered at 100mg daily on days 4-28. 
Reinduction can last longer than 28 days and up to 60 days. If reinduction last more than 28 
days, patient should continue to take glasdegib daily and as prescribed until day 1 of next cycle 
of CPX-351. Patient will be instructed to hold glasdegib on the day they receive CPX-351 
infusion. 
 
5.4 Consolidation 
Patients who achieve CR or CRi, can be continued on consolidation therapy for up to two 
cycles. In general, patients who have achieve CRi, consolidation should be initiated once the 
platelet count ≥ 50,000/uL and ANC ≥ 500/uL. The first consolidation cycle should start between 
28 to 75 days after initiation of the last induction therapy. Each subsequent cycle of 
consolidation should be initiated between 28 to 55 days after the start of previous cycle of 
Agent 
Dose 
Route 
Schedule 
CPX-351 for Induction 
Daunorubicin 
44mg/m2-cytarabine 
100mg/m2 
IV infusion for 
90 minutes 
Days 1, 3 and 5 
CPX-351 for Reinduction 
Daunorubicin 
44mg/m2 -cytarabine 
100mg/m2 
IV infusion for 
90 minutes 
Days 1 and 3 
CPX-351 for Consolidation 
Daunorubicin  
29mg/m2-cytarabine 
65mg/m2 
IV infusion for 
90 minutes 
Days 1 and 3 
Glasdegib 
100 mg 
PO daily in 
the a.m. 
Begins day after 
completion of CPX-351 
infusion and continues 
daily until Day 1 of 
subsequent cycle of 
CPX-351 

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consolidation. The exact day is at the treating physician’s discretion. The number of 
consolidation cycles will depend on the time required for identification and availability of a 
suitable stem cell donor for patients going to stem cell transplantation.  
 
The dose of CPX-351 will be at a dose of daunorubicin 29 mg/m2–cytarabine 65 mg/m2 on days 
1 and 3. Glasdegib will be administered at 100mg daily for days 4-28. Consolidation cycles can 
last longer than 28 days. If cycles last more than 28 days, patient should continue to take 
glasdegib daily and as prescribed until day 1 of next cycle of CPX-351. Patient will be instructed 
to hold glasdegib on the day they receive CPX-351 infusion. 
 
 
5.6 Allogenic stem cell transplantation 
The decision to go to allogeneic transplant once the patient is in remission is based on the 
treating’s physician discretion as well as the desire of the patient. Patients who are considered 
candidates for allogeneic transplant and have a donor stem cell source available can proceed to 
allogeneic transplant. Alternatively, patients can receive up to two cycles of consolidation 
chemotherapy prior to allogeneic transplant.  
 
For patients going to transplant, Glasdegib will be discontinued within 7 days prior to start of 
conditioning for their transplant. 
 
5.7 Maintenance 
For patients who complete consolidation chemotherapy and not proceeding to allogeneic 
transplant, they will proceed to maintenance therapy. Glasdegib oral daily will be continued for 
up to one year. The patients will proceed with monthly assessments of disease status if they are 
on Glasdegib maintenance. If they are adults of child-bearing age and potential, they will need 
to be reminded of contraception. If they are a woman of child-bearing age and potential, they 
will need to have pregnancy test.  
 
5.8 Duration of Therapy 
In the absence of treatment delays due to adverse events, treatment may continue until 
completion or protocol-defined therapy or until: 
• 
Disease progression 
• 
Inter-current illness that prevents further administration of therapy 
• 
Unacceptable adverse events 
• 
Patient decided to withdraw from the study 
• 
General or specific examples in the patient’s condition render the patient unacceptable 
for further treatment in the judgement of the investigator 
 
Subjects who become medically incapacitated or cognitively impaired after enrollment into this 
trial may continue with protocol therapy as long as they are benefiting from treatment in the 
judgement of the investigator. In the event that this occurs, a surrogate or legally authorized 
representative (LAR) must sign the ICF. The surrogate/LAR will assist the subject in completion 
of study procedures and diary. If a subject regains ability to regains the cognitive ability to 
consent, they must be re-consented using standard consenting procedure    
 

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5.9 Duration of Follow Up 
Patients will be followed every 3 months for one year after removal from or completion of 
treatment or death, whichever comes first. Patients removed from treatment for unacceptable 
adverse events will be followed until resolution or stabilization of the adverse event then for 
relapse and survival afterwards. Patients who undergo allogeneic stem cell transplant will only 
be followed for survival.  
 
5.10 
Other therapeutic Agents 
The use of therapeutic agents or approaches for malignancy outside of what is expressly stated 
in this protocol is strictly forbidden. This includes any study undefined use of the study specific 
therapeutic agents, the same class of agents, or agents not expressly defined in the protocol 
with potential or known anti-leukemic activity. Institutional standard of care supportive 
medications are allowed as long as they do not have known or predicted anti-leukemic activity 
or are in conflict with study dictated supportive care. 
 
If hyperleukocytosis is present (when greater than 30k), cytoreduction is allowed with 
leukapheresis, corticosteroids or hydroxyurea for up to 7 days at the investigator’s discretion.  
 
5.11 
Pre-Medications 
Anti-emetics should be given prior to CPX-351. The exact antiemetic should be used per the 
institutional protocol or treating physician discretion. One common regimen is ondansetron 8mg 
IV on days 1, 3 and 5 given 30 minutes prior to CPX-351 administration. Monitor for infusion 
reactions during and at least 1 hour after the end of the infusion.  
 
5.12 
Infection prophylaxis 
5.12.1 Prophylaxis during neutropenia 
Prophylaxis during neutropenia including antibacterial and antifungal therapies is to be 
administered per local standard of care. For antibacterial prophylaxis, levofloxacin 500mg daily 
is recommended.  Cefpodoxime is an allowable alternative to avoid QTc prolongation. Acyclovir 
is strongly recommended for viral prophylaxis.  
 
5.12.2 Fungal prophylaxis during neutropenia 
During periods of neutropenia patients should receive fungal prophylaxis. Recommended 
treatment is: isavuconazole due to drug interactions with glasdegib for absolute neutrophil count 
<500/mcl. Alternate prophylactic regimens are up to individual investigator’s discretion.  
 
5.13 
Permitted concomitant therapy 
Growth factors including granulocyte colony-stimulating factors and granulocyte-macrophage 
colony-stimulating factors are permitted and should be used based on American Society of 
Clinical Oncology guidelines. 
 

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5.14 
Prohibited concomitant therapy 
Antineoplastic agents other than CPX-351, Glasdegib and hydroxyurea prior to the start of the 
study are not allowed.  
 
Glasdegib can lead to QTc prolongation. Therefore, drugs that can prolong QTc should be 
avoided. Please refer to list of drugs in Appendix D.  
 
Caution must be taken with moderate/strong CYP3A4/5 inhibitor in conjunction with Glasdegib. 
If possible, it is best to avoid the combination. If this is not possible, then QTc monitoring is 
recommended.  
 
When there is an urgent need to start a moderate/strong CYP3A4/5 inhibitor or TdP drug, 
administration of these medications should not be delayed, the Investigator should consider 
temporarily interrupting Glasdegib dosing and should implement these additional monitoring 
procedures as soon as it is reasonably possible. 
 
6.0 Toxicities and Dosing Delays/Dose Modifications 
Any patient who receives treatment on this protocol will be evaluable for toxicity. Each patient 
will be assessed for the development of toxicity according to the NCI Common Toxicity Criteria 
for Adverse Events (CTCAE), version 5.0. Dose adjustments should be made according to the 
system showing the greatest degree of toxicity. 
 
6.1 CPX-351 dose modification 
The dose of CPX-351 should not be modified. The dose can be delayed due to prolonged 
cytopenias or due to infections at any time. 
 
CPX-351 should remain the same dose for entire cycle. For subsequent cycles, if body surface 
area (BSA) change is >10%, then the dose should be recalculated using the new BSA. If BSA 
remains <10% of baseline BSA (at time of screening), then dose of CPX-351 should not change 
and is calculated using baseline BSA 
6.2 Glasdegib dose modification for non-hematologic toxicities 
If a grade 3 non-hematologic toxicity occurs, interrupt the treatment until symptoms reduce or 
return to baseline. Resume Glasdegib at the same dose level if the event is not attributable to 
the study drug as determined by the Investigator. If the investigator deems the event as being 
possibly related to the study drug, then reduce the dose in increments of 25 mg. If a dose 
reduction is necessary after 50 mg, then the study treatment should be discontinued. 
 
6.3 Glasdegib dose modification for hematologic toxicities 
The dose of Glasdegib should not be modified for any hematologic toxicities.  
 
6.4 Glasdegib dose modification for QTc prolongation 
The dose of Glasdegib should be modified if there is evidence of QTc prolongation.  
 
If the QTc is found to be between 480 to 500 ms, the recommendations are as follows:  

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• 
Correct any electrolyte abnormalities 
• 
Review and adjust any medications that may be contributing to QTc prolongation. Refer 
to Appendix D for medications that are associated with QTc prolongation. 
• 
Monitor ECG at least weekly for two weeks following resolution of the QTc prolongation 
to less than 480 ms 
• 
If the QTc is found to be greater than 500, the recommendations are as follows:  
o 
Correct any electrolyte abnormalities 
o 
Review and adjust any medications that may be contributing to QTc prolongation 
o 
Interrupt Glasdegib 
o 
Resume Glasdegib at a reduced dose of 50 mg once daily when QTc is less than 
480 ms or if the QTc returns to within 30 ms of baseline 
o 
Monitor ECG at least weekly for two weeks following resolution of the QTc 
prolongation to less than 480 ms 
o 
Consider re-escalating the dose to 100 mg daily if an alternative etiology for QTc 
prolongation is identified 
• 
If QTc interval prolongation is associated with life-threatening arrhythmia, then 
Glasdegib should be discontinued permanently.  
 
 
 
7.0 STUDY PROCEDURES 
7.1 Screening/Baseline Procedures 
Assessments performed exclusively to determine eligibility for this study will be done only after 
obtaining informed consent. Assessments performed for clinical indications (not exclusively to 
determine study eligibility) may be used for baseline values even if the studies were done before 
informed consent was obtained. 
 
All screening procedures must be performed within 28 days prior to registration unless 
otherwise stated. The screening procedures include: 
 
7.1.1 Informed Consent 
A complete description of the study is to be presented and discussed with each potential subject 
or the subject’s legally authorized representative, if applicable, and a signed and dated informed 
consent form is to be obtained before any study specific procedure is performed. A copy of the 
signed and dated consent form should be given to the subject before participation in the study. 
 
The initial informed consent form, any subsequent reviewed written informed consent form and 
any written information provided to the subject must receive the IRB approval in advance of use. 
The subject should be informed in a timely manner if new information become available that 
may be relevant to the subject’s willingness to continue participation in the trial. The 
communication of the information will be provided and documented via a revised consent form 
that captures the subject’s dated signature. The informed consent will adhere to IRB 
requirements, applicable laws and regulations and sponsor requirements. 
 
7.1.2 Medical history 
Complete medical, surgical and oncology history as well as history of infections are obtained at 
screening. Any changes from Screening (e.g. worsening severity or abnormal findings) are 
considered to be adverse events (AEs). 

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7.1.3 Demographics 
 Demographic profile will include date of birth, gender, race, and ethnicity. 
 
7.1.4 Review subject eligibility criteria 
At the initiating site, the information below must be reviewed with the initiating site PI and 
research manager prior to the assignment of the subject study ID and initiation of treatment. For 
participating sites, the following information must be redacted of any patient identifiers and sent 
at least 3 business days prior to the planned start date of treatment for eligibility confirmation 
and subject ID assignment to uci18105@hs.uci.edu via secure email:  
• 
Signed informed consent 
• 
Signed eligibility checklist 
• 
Bone marrow biopsy report 
• 
Physical exam including ECOG and medical history 
• 
All screening labs 
• 
Baseline ECG 
 
Review of eligibility criteria, as described in Section 3, is required to ensure subject qualification 
for study entry. 
 
The signed eligibility checklist, redacted source documentation as mentioned above and signed 
informed consent for each enrolled patient must be emailed to uci18105@hs.uci.edu per section 
4.1. 
 
7.1.5 Review previous and concomitant medications 
All concomitant medications taken by the subject during the study are to be recorded up until 28 
days after last study dose. If a reportable adverse event occurs within 28 days after last study 
dose, recording of concomitant medications should continue until resolution of adverse event. 
 
7.1.6 Physical exam including vital signs, height and weight 
Vital signs (temperature, pulse, respirations, blood pressure), height, weight will be collected at 
screenings and during each physical exam. Subjects will be examined by an investigator during 
study visits. (Note: height is only required at screening.)  
 
7.1.7 Performance status 
The Eastern Cooperative Oncology Group (ECOG) Performance status will be evaluated prior 
to study entry, on day 1 of induction and day 28 of induction, on day 1 and day 28 of each 
subsequent consolidation cycles, and on day 1 of each cycle of maintenance. (See appendix A) 
 
7.1.8 Hematology 
Hematology to include hemoglobin (Hgb), platelets, total white blood cell count (WBC), and 
differential. 
 
7.1.9 Serum chemistries 

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Comprehensive metabolic panel (CMP) to include: albumin, alkaline phosphatase, ALT/SGPT, 
AST/SGOT, BUN, creatinine, electrolytes (sodium, potassium, calcium, chloride, bicarbonate), 
glucose, and total bilirubin. Additional chemistries: lactate dehydrogenase (LDH), phosphate, 
magnesium, and uric acid.  
 
7.1.10 Coagulation 
Coagulation profile includes International Normalized Ratio (INR), prothrombin time (PT) and 
activated partial thromboplastin time (PTT). 
 
7.1.11 ECG 
Resting 12-lead ECG will be taken at screening. 
 
7.1.12 Echocardiogram 
An ECHO should be performed during screening before starting treatment with CPX-351. 
 
7.1.13 Urinalysis 
Standard urinalysis dipstick assessment (pH, protein, glucose, blood, ketones, and leukocytes) 
should be performed.   
 
7.1.14 Pregnancy test (for females of child bearing potential) 
Serum or urine beta HCG test are acceptable and should be done prior to starting treatment. 
Sites should follow local institutional guidelines.  
 
7.1.15 Bone marrow procedures 
Bone marrow aspirate and biopsy should be done during screening. It should be completed 
within 28 days. Cytogenetic and molecular profiling will be analyzed with these samples. 
 
7.1.16 Research samples  
Additional bone marrow aspirate or peripheral blood will be collected for gene 
expression testing. 
7.2 Procedures during Treatment 
7.2.1 Induction 
• 
Physical exam will be done weekly 
• 
Review previous and concomitant medications  
• 
ECOG Performance Status Review 
• 
Blood draws for laboratory studies will be done weekly 
• 
ECGs will be done on day 6 before starting Glasdegib and approximately one week after 
day 6 (on day 13-15) 
• 
Review of concomitant medications  
• 
Adverse event assessment 
• 
Assessment of minimal residual disease assessed by multi-parameter flow cytometry. 
This should be done according to local institutional guidelines. 

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• 
Bone marrow aspiration and biopsy 
o Day 20 
o Upon recovery of cytopenias typically around day 28 to 60, at the discretion of 
treating physician. If counts has not recovered by day 60, then complete on day 60.  
• 
Additional BMA or PB will be collected for gene expression testing  
 
7.2.2 Rationale for the timeline of bone marrow assessments 
During the phase II and III trials with CPX-351, there was evidence of relatively delayed 
clearance of bone marrow blasts compared to standard induction chemotherapy. Therefore, 
bone marrow assessments should be performed on day 20, in order to avoid labeling a patient 
as requiring re-induction if the bone marrow biopsy is done on day 14 inadvertently.  
 
Similarly, the subsequent bone marrow should be delayed until there is 
evidence of normal hematopoiesis between days 28-60. The exact day to 
perform the bone marrow assessment is at the discretion of the treating 
physician. It is strongly encouraged to avoid performing the bone marrow 
biopsy prematurely. If peripheral counts do not recover by day 60, bone 
marrow should be performed to assess the status of the disease. 
7.2.3 Adequacy of bone marrow specimen 
An adequate bone marrow specimen is required to evaluate for remission (during induction days 
28-60). An adequate bone marrow specimen is defined as having nucleated cells in the aspirate 
with spicules. The nucleated cell count is determined by the pathologist and the presence of 
spicules can be determined by the provider performing the bone marrow biopsy at the time of 
obtaining the aspirate. If the sample is inadequate, the bone marrow should be repeated within 
one week. In case of a dry tap without any aspirate, two cores are preferred; however, local 
institutional guidelines should be followed. 
 
7.2.4 Bone marrow blasts of 5-10% 
In the case of the bone marrow specimen has 5-10% blasts on bone marrow obtained prior to 
induction day 46, it is encouraged to reassess the marrow in 1-2 weeks (no later than day 60), 
instead of labeling the patient as not in remission. This will allow more time for the relatively 
delayed effects of CPX-351. The final decision is at the discretion of the treating physician.  
 
7.2.5 Assessment of remission status 
The date of CR and CRi or relapse is based on the date of the bone marrow biopsy that was 
performed. The exact date of achievement of CR is based on the date when the bone marrow 
biopsy demonstrates less than 5% blasts with the peripheral ANC ≥ 1,000/uL and the platelet 
count ≥ 100,000/uL. If the bone marrow biopsy shows less than 5% blasts prior the day the 
peripheral counts recover, then the date of CR is based on the date when the peripheral counts 
recover.  
 
7.2.6 Reinduction 
• 
Prior to reinduction, an ECHO should be completed 
• 
Review of concomitant medications  
• 
Adverse event assessment 
• 
ECOG performance status 

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• 
Physical exam will be done weekly 
• 
Blood draws for laboratory studies will be done weekly 
• 
ECGs will be done within 24 hours of day 4 before starting Glasdegib  
• 
For females with childbearing potential, a pregnancy test will be done 
• 
Assessment of minimal residual disease assessed by multi-parameter flow cytometry. 
This should be done according to local institutional guidelines. 
• 
Bone marrow aspiration and biopsy 
o Day 20  
o Upon recovery of cytopenias typically around day 28 to 60, at the discretion of the 
physician. If counts has not recovered by day 60, then complete on day 60. 
• 
Additional BMA or PB will be collected for gene expression testing 
 
7.2.7 Consolidation 
• 
Physical exam will be done weekly 
• 
Review of concomitant medications  
• 
Adverse event assessment 
• 
Blood draws for laboratory studies will be done weekly 
• 
For females with childbearing potential, a pregnancy test will be done 
• 
ECOG performance status  
• 
ECGs will be done on within 24 hours of day 4 of every cycle 
• 
Adverse event assessment 
• 
Bone marrow at the end of consolidation is recommended but is not required by the 
study.  
 
7.2.8 Maintenance 
• 
Physical exam will be done on day 1 of every cycle 
• 
Review of concomitant medications  
• 
Adverse event assessment 
• 
ECOG performance status 
• 
Blood draws for laboratory studies will be done on day 1 of every cycle 
• 
For females with childbearing potential, a pregnancy test will be done 
7.3 End of Treatment Visit 
All subjects will undergo an end of treatment evaluation. End of study is defined as at least 12 
months after the final subject is enrolled, or sooner if all subjects have died, discontinued the 
study, are lost to follow-up, or withdrew consent prior to the two years after the last subject is 
enrolled. 
 
• 
Physical exam  
• 
Review of concomitant medications  
• 
Adverse event assessment 
• 
ECOG Performance Status Review 
• 
ECG will be done  
• 
Blood draws for laboratory studies  
• 
Assessment of minimal residual disease assessed by multi-parameter flow cytometry. 
This should be done according to local institutional guidelines. 
• 
Bone marrow aspiration and biopsy 

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o At any time of suspected relapsed disease, at the discretion of treating physician 
• 
Additional BMA or PB will be collected for gene expression testing 
7.4 Follow-up Procedures 
Patients will be followed every 3 months for a minimum of one year after removal from or 
completion of treatment or death, whichever comes first. Patients who undergo allogeneic stem 
cell transplant will only be followed up for survival status. Patients removed from treatment for 
unacceptable adverse events will be followed until resolution or stabilization of the adverse 
event then for relapse and survival afterwards.    
• 
Survival status (either in clinic during standard visit or by phone)  
• 
Physical Exam 
• 
ECOG Performance Status Review 
• 
Blood draws for laboratory studies 
• 
Bone marrow aspiration and biopsy 
o At any time of suspected relapsed disease, at the discretion of treating physician 
• 
Assessment of minimal residual disease assessed by multi-parameter flow cytometry. 
This should be done according to local institutional guidelines. 
 
 
7.5 Correlative Studies 
In the non-intensive arm of the phase II trial with LDAC with Glasdegib, there were several 
genes that correlated with improved OS [11]. Lower levels of expression of FOXM1 and MSI2 
and higher expression levels of BCL2 and CCND2 correlated with improved overall survival. In 
the intensive treatment arm with Glasdegib and cytarabine/daunorubicin, higher PTCH1 
expression correlated with improved overall survival. Furthermore, in the intensive arm, 
mutations in FLT3, TP53, CEP170, NPM1 and ANKRD26 correlated with overall survival. 
Interesting to note, that patients with AML with mutated FLT3 (which is generally a poor risk 
group) did better than AML with wild type FLT3. Therefore, we will be measuring some of gene 
expression to see if this observation of their correlation with improved overall survival is 
confirmed. 
 
Furthermore, we will be measuring MRD by MFC at the end of induction. University of 
Washington is the preferred facility who will receive the samples and assess MRD. If samples 
cannot be sent to University of Washington, sites should send their samples for MRD 
assessment according to their local institutional guidelines. We will determine if the status of 
MRD by MFC at the end of induction correlates with survival. 
 
8.0 Removal of Subjects from Study Treatment and Study 
Patients can be taken off the study treatment and/or study at any time at their own request, or 
they may be withdrawn at the discretion of the investigator for safety, behavioral or 
administrative reasons. The reason(s) for discontinuation will be documented and may include: 
1. Patient completed study treatment; 
2. Patient voluntarily withdraws from treatment (follow-up permitted);  
3. Patient withdraws consent (termination of treatment and follow-up); 
4. Patient/LAR is unable to comply with protocol requirements; 
5. Patient demonstrates disease progression (unless continued treatment with study drug 
is deemed appropriate at the discretion of the investigator); 
6. Patient experiences toxicity that makes continuation in the protocol unsafe; 

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7. Treating physician judges continuation on the study would not be in the patient’s best 
interest; 
8. Patient becomes pregnant (pregnancy to be reported along same timelines as a serious 
adverse event); 
9. Development of second malignancy (except for basal cell carcinoma or squamous cell 
carcinoma of the skin) that requires treatment, which would interfere with this study; 
10. Lost to follow-up.  
If a research subject cannot be located to document survival after a period of 2 years, 
the subject may be considered “lost to follow-up.” All attempts to contact the subject 
during the two years must be documented.  
 
 
9.0 DATA AND SPECIMEN SUBMISSION GUIDELINES  
9.1 Labeling Samples  
Each sample to be labeled with patient specific study ID, initials, visit type, date of 
collection and time of collection.  
 
9.2 Sample Collection Guidelines 
MRD Testing  
For minimal residual disease testing, a first pull aspirate sample should be collected and sent 
overnight to the University of Washington or the facility designated by your local institutional 
guidelines for analysis. The aspirate should be collected in a 1mL to 5mL EDTA vial or 
according to local institutional guidelines.   
 
Gene Expression 
For gene expression testing, 2 mL will be collected from the bone marrow biopsy sample. In the 
event that there is a dry tap, the gene expression sample will be collected using peripheral 
blood if there are any circulating blasts present. If there are no circulating blasts, the gene 
expression sample will not be collected for testing. The sample needs to be processed 
immediately and carefully handled. Sites are responsible for providing their own tubes and vials 
for collection of all research related samples. In the event that a site does not have funding for 
supplies, the sample will not be collected and will not be considered a deviation. All samples will 
be shipped to and stored at UCI Clinical Trials Biospecimen Laboratory until analysis, which will 
be done at another laboratory. Please refer to the study sample lab manual for further 
processing, storage, and shipment instructions.    
 
 
 
10.0 Measurement of Effect 
 
10.1 Antitumor Effect- Hematologic Tumors 
Response criteria for bone marrow are as per International Working Group Response Criteria in 
AML listed in Table 2. 
 

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10.2 Complete remission 
Complete remission is defined as no circulating blasts or extramedullary disease with a bone 
marrow biopsy with trilineage hematopoiesis with less than 5% blasts and ANC greater/equal 
than 1,000/uL and platelet count greater/equal than 100,000/uL. 
 
Refractory disease is the failure to achieve CR at the end of induction. 
 
Progressive disease is the increase of at least 25% in the absolute number of circulating or 
bone marrow leukemic blasts or appearance of extramedullary disease. 
 
Relapsed disease is the reappearance of blasts in the bone marrow (greater than 5%) or in the 
blood after achieving CR or CRi. 
 
MRD negative CR is the absence of detectable leukemic blasts using multiparameter flow 
cytometry at the University of Washington. 
 
10.3 Progressive disease 
Progressive disease is the evidence for an increase in bone marrow blast percentage and/or 
increase of absolute blast counts in blood by 50% or new extramedullary disease. 
 
10.4 Event-free survival 
Event-free survival is defined as the time from screening biopsy to the date of confirmed 
disease progression, relapse from CR/CRi, treatment failure, or death, whichever comes first. 
This was chosen as an endpoint for several reasons. It is known to incorporate several 
endpoints of interest including efficacy of the treatment as well as toxicity that both contribute to 
the outcome of the patient. Complete remission may not capture the full benefits of Glasdegib 
since the drug may prevent relapse through different mechanisms than enhanced cytotoxicity.    
 
10.5 Final Response Assessment 
Overall survival is measured as the time from the date of diagnostic biopsy which confirmed 
disease to the date of death from any cause. Patients not known to have died at last follow-up 
are censored on the date they were last known to be alive. Patients will be followed for a 
minimum of one year from the completion of the treatment. 
 
Patients who go on to allogeneic transplant will be censored for survival on the dates that they 
start conditioning regimen to avoid transplant as a confounding factor in analysis of overall 
survival.  
 
 
11.0 ADVERSE EVENTS 
All adverse events will be graded as toxicity using the CTCAE version 5.0 grading system. 
Graded toxicity should be recorded in the CRF.  
 
Analyses will be performed for all patients having received at least one dose of study drug.  
 

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11.1 Event Definitions 
• 
Adverse event (AE) - An adverse event is any untoward medical experience or change 
of an existing condition that occurs during or after treatment, whether or not it is 
considered to be related to the protocol intervention. An AE can therefore be any 
unfavorable and unintended sign (including a clinically significant abnormal laboratory 
finding), symptom, or disease temporally associated with the use of an experimental 
intervention, whether or not related to the intervention. 
• 
Unexpected Adverse Event [Modified from the definition of unexpected adverse drug 
experience in FDA regulations at 21 CFR 312.32 (a)] – An adverse event is unexpected 
if it is not listed in the investigator’s brochure and/or package insert; is not listed at the 
specificity or severity that has been observed; is not consistent with the risk information 
described in the protocol and/or consent; is not an expected natural progression of any 
underlying disease, disorder, condition, or predisposed risk factor of the research 
participant experiencing the adverse event. 
• 
Expected Adverse Event - Any event that does not meet the criteria for an unexpected 
event OR is an expected natural progression of any underlying disease, disorder, 
condition, or predisposed risk factor of the research participant experiencing the adverse 
event. 
• 
Serious Adverse Event (SAE) [21 CFR 312.32] - defined as any expected or 
unexpected adverse event that result in any of the following outcomes: 
o Death 
o Is life-threatening experiences (places the subject at immediate risk of death from 
the event as it occurred) 
o Unplanned hospitalization equal or greater than 24 hours)) or prolongation of 
existing hospitalization 
o A persistent or significant disability/incapacity 
o A congenital anomaly/birth defect 
o Any other adverse event that, based upon appropriate medical judgment, may 
jeopardize the subject’s health and may require medical or surgical intervention 
to prevent one of the outcomes listed above (examples of such events include 
allergic bronchospasm requiring intensive treatment in the emergency room or at 
home, blood dyscrasias of convulsions that do not result in inpatient 
hospitalization, or the development of drug dependency or drug abuse). 
• 
Unanticipated problem (UP) - Any incident, experience or outcome that meets all three 
of the following criteria: 
1. 
Unexpected (in term nature, severity, or frequency) given the following: a) the 
research procedures described in the protocol-related documents such as the 
IRB approved research protocol, informed consent document or Investigator 
Brochure (IB); and b) the characteristics of the subject population being studied; 
AND 
2. 
Related or possibly related to participation in the research (possibly related 
means there is a reasonable possibility that the incident, experience, or 
outcomes may have been caused by the drugs, devices or procedures involved 
in the research); AND 
3. 
Suggests that the research places subjects or others at greater risk of harm 
(including physical, psychological, economic, or social harm) than previously 
known or recognized. 
• 
Protocol Violation- A protocol violation is an accidental or unintentional change to or 
noncompliance with the IRB-approved protocol that increases risk or decreases benefit 
and/or affects the subject's rights, safety, welfare, and/or the integrity of the data. 

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Examples of incidents that may be considered violations include: enrolling a participant 
who does not meet the inclusion criteria; obtaining verbal consent before the initiation of 
study procedures when the IRB requires signed, written informed consent; and failure to 
collect screening labs before initiation of study procedures [Reference: Policy #57 UCI 
HRPP Policy and Procedure Glossary]. 
• 
Protocol Deviation- a protocol deviation is an accidental or unintentional change to the 
research protocol that does not increase risk or decrease benefit or have a significant 
effect on the participant’s rights, safety or welfare, or on the integrity of the data. 
Deviations may result from the action of the participant, researcher, or staff. Examples: a 
rescheduled study visit, an omitted routine safety lab for a participant with previously 
normal values; or failure to collect an ancillary self-report questionnaire data (e.g., quality 
of life) [Reference: Policy #57 UCI HRPP Policy and Procedure Glossary]. 
11.2 Adverse Event Monitoring 
All patients who have received at least one dose of CPX-351 will be considered evaluable for 
safety. After initiation of study drug, all adverse events (AEs) and serious adverse events 
(SAEs) regardless of attribution will be collected at every visit until 28 days following the last 
administration of study drug, until study discrimination/termination, or until initiation of 
subsequent anticancer therapy, whichever comes first. Subjects will be assessed at each follow-
up visit to determine if there are any new AEs. Adverse events will no longer be reported in 
patients who go on to allogeneic transplant. AEs and SAEs will be recorded on the adverse 
event report section within OnCore. Please reference section 11.3 and 11.4 for a complete list 
of all entities who require notifications of AEs and SAEs.   
 
Adverse event data collection and reporting, which are required as part of every clinical trial, are 
done to ensure the safety of subjects enrolled in the studies as well as those who will enroll in 
future studies using similar agents. Adverse events are reported in a routine manner at 
scheduled times during a trial. Additionally, certain adverse events must be reported in an 
expedited manner to allow for optimal monitoring of patient safety and care.  
 
As far as possible, each adverse event should be evaluated to determine: 
• 
duration (start and end dates) 
• 
severity (grade) 
• 
seriousness 
• 
relationship to study agent 
• 
action taken (i.e., none, study agent modification, medical intervention) 
• 
outcome (i.e., resolved without sequelae, resolved with sequelae, ongoing) 
 
Adverse events monitoring begins after initiation of study treatment and ends 28 days following 
the last administration of study treatment or study discontinuation/termination, whichever is 
earlier. 
 
All patients experiencing an adverse event, at least possibly related to the drug, will be 
monitored until:  
 the adverse event resolves or the symptoms or signs that constitute the adverse 
event return to baseline;  
 any clinically significant abnormal laboratory values have returned to baseline;  
 there is a satisfactory explanation other than the study drug for the changes 
observed; or 
 death. 

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11.2.1 Severity 
All non-hematologic adverse events will be graded according to the NCI Common Terminology 
Criteria for Adverse Events (CTCAE) version 5.0. The CTCAE v5.0 is available at 
http://ctep.cancer.gov/reporting/ctc.html 
 
If no CTCAE grading is available, the severity of an AE is graded as follows: 
Mild (grade 1): the event causes discomfort without disruption of normal daily activities. 
Moderate (grade 2): the event causes discomfort that affects normal daily activities. 
Severe (grade 3): the event makes the patient unable to perform normal daily activities 
or significantly affects his/her clinical status. 
Life-threatening (grade 4): the patient was at risk of death at the time of the event. 
Fatal (grade 5): the event caused death. 
 
11.2.2 Seriousness 
A “serious” adverse event is defined in regulatory terminology as any untoward medical 
occurrence that: 
1. Results in death. 
If death results from (progression of) the disease, the disease should be reported as 
event (SAE) itself. 
2. Is life-threatening. 
(the patient was at risk of death at the time of the event; it does not refer to an event that 
hypothetically might have caused death if it were more severe). 
3. Requires in-patient hospitalization or prolongation of existing hospitalization for ≥ 24 
hours. 
4. Results in persistent or significant disability or incapacity. 
5. Is a congenital anomaly/birth defect 
6. Is an important medical event 
Any event that does not meet the above criteria, but that in the judgment of the 
investigator jeopardizes the patient, may be considered for reporting as a serious 
adverse event. The event may require medical or surgical intervention to prevent one of 
the outcomes listed in the definition of “Serious Adverse Event“.  
For example: allergic bronchospasm requiring intensive treatment in an emergency room 
or at home; convulsions that may not result in hospitalization; development of drug 
abuse or drug dependency. 
 
11.2.3 Relationship 
Attribution categories for adverse events in relationship to protocol therapy are as follows: 
Related – The AE is clearly related to the study treatment 
Unrelated – The AE is clearly NOT related to the study treatment. 
 
11.2.4 Prior experience 
Expected events are those that have been previously identified as resulting from administration 
of the agent. An adverse event is considered unexpected, for expedited reporting purposes 
only, when either the type of event or the severity of the event is not listed in the current known 
adverse events listed in the agent clinical experience section of this protocol or Product Label. 
 

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11.3 Reporting Requirements for Adverse Events 
 
Adverse events, serious adverse events, deviations, violations, and unanticipated problems 
must be entered into the clinical trial management system (CTMS), OnCore, and must also be 
reported to the following entities according to the timelines mentioned in the chart below. 
Serious adverse events collection will start at the time patient signs consent until 28 days after 
the end of treatment. Adverse events will be collected from the time the research patient begins 
treatment until 28 days after the end of treatment. All adverse events/serious adverse events 
should be followed until resolution or stabilization.  

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Event Type  
Coordinating 
Center/Medical 
Monitor 
UCI IRB  
Local IRB 
Jazz Pharmaceuticals 
 
Pfizer 
CFCCC DSMB 
Unanticipated 
Problem  
Within 24 hours from 
date the site is aware 
of the event, the site 
should enter this 
information into 
OnCore. An email 
notification should 
also be sent via email 
to  
djeyakum@hs.uci.edu 
and 
uci18105@hs.uci.edu.   
Within 5 
business days 
submit an 
Unanticipated 
Problem 
Report (UP) 
through Kuali 
Research 
Protocols. 
Current policy 
can be found 
here. 
According 
to local 
institutional 
policies 
and 
guidelines 
 
Within 1 business day of 
learning of the event. Submit 
all UPs to 
AEreporting@jazzpharma.com 
and submit any copies of the 
FDA submissions to 
PVcomms@jazzpharma.com 
when the FDA submission is 
made. All follow up information 
must be sent to Jazz 
Pharmaceuticals within 1 
business day of PI’s receipt of 
new information.  
Within 1 
business 
day of 
learning of 
the event. 
Submit all 
UPs via 
CIOMS form 
or a Pfizer 
approved 
SAE form.  
Within 5 days from date PI is 
aware of the event. This 
information must be reported 
into OnCore.  
AEs and 
SAEs (non-
Unanticipated 
Problem)  
Please refer to section 
11.4 for reporting 
timeframes on AEs 
and SAEs    
N/A  
 All SAEs should be reported 
in the same manner as a UP. 
All other adverse events will 
be reported to Jazz 
Pharmaceuticals in summary 
or line-item form upon Jazz 
Pharmaceuticals’ request and 
at the conclusion of the study. 
All SAEs 
should be 
reported in 
the same 
manner as a 
UP.  
Please refer to section 11.4  
for clarification on reporting 
timeframes for AEs and 
SAEs  
Non-
compliance  
N/A 
N/A 
N/A 
N/A 
Please refer to section 11.4 
for reportable 
deviations/violations  
Serious or 
continuing 
non-
compliance  
Within 24 hours via 
email to  
djeyakum@hs.uci.edu 
and 
uci18105@hs.uci.edu.   
Within 5 
business days 
submit a 
reportable 
event  through 
Kuali Research 
Protocols. 
N/A 
N/A 
Within 5 days from date PI is 
aware of the event.  
Prospective/P
lanned 
Deviations  
At least 5 business 
days prior to the event 
via email to  
djeyakum@hs.uci.edu 
At least 48 
hours prior to 
date the 
request is 
N/A  
N/A 
At the time of progress 
review as aggregate reports  

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and 
uci18105@hs.uci.edu 
for approval.    
needed by. 
Submit a  
Prospective 
Deviation 
Request form 
through Kuali 
Research 
Protocols. 

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11.4 
Additional Reporting of Events from Investigators at Participating Sites to the Sponsor Investigator  
• Investigators at participating institutions must report AE, SAE, deviations, violations, and unanticipated problems according to their 
institutional policies. 
• Investigators at participating institutions must also report AE, SAE, deviations, violations, and unanticipated problems to the PI of the 
coordinating center (or other entity such as a contract research organization) in the following timeframes: 
 
Adverse Event/ Serious Adverse Events  
Event Type  
Reporting Timeframe to 
CFCCC DSMB  
(Notification is done by 
entering this information 
into OnCore within the 
timelines below) 
Reporting Timeframe to 
Coordinating Center 
(Notification is done via 
email to  
djeyakum@hs.uci.edu and 
uci18105@hs.uci.edu 
within the timelines below) 
Serious Adverse Events (all attributions) that meet all of the 
following criteria: 
• 
Unexpected 
• 
Grades 3-5 
• 
Occurring during treatment or within 28 days of the end of 
treatment* 
5 business days from date 
the PI is aware of the event 
24 hours from date the site is 
aware of the event. 
Adverse Events that meet all of the following criteria: 
• 
Unexpected 
• 
Study related (possibly, probably, or definitely) 
• 
Grades 3-4 
• 
Occurring during treatment or within 28 days of the end of 
treatment* 
5 business days from date 
the PI is aware of the event 
24 hours from date the site is 
aware of the event. 
All other Adverse Events and Serious Adverse Events should be 
reported as noted in the ‘Reporting Requirements for Adverse 
Events’ section 
Prior to each scheduled 
progress review.  
5 business days from the 
date the site is aware of the 
event 
* Investigators are not obligated to actively seek information regarding the occurrence of new AEs or SAEs beginning after the 28-
day post-treatment period. However, if the investigator learns of such an event and that event is deemed relevant to the study, 
he/she should promptly document and report the event. 
 
 

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Deviations/Violations 
Event Type  
• Reporting Timeframe to CFCCC 
DSMB 
• (Notification is done by entering 
this information into OnCore 
within the timelines below) 
• Reporting Timeframe to 
Coordinating Center (Or other 
entity monitoring/coordinating 
the trial) 
Violations as defined above (e.g. wrong dosage of drug 
administered, safety procedures not being conducted at 
specific time points). 
5 business days from the date the 
PI is aware of the event 
24 hours from the date the site is 
aware of the event 
Deviations as defined above, including: 
• 
Planned deviations (e.g. rescheduling a visit that will 
be out of window due to a holiday) 
• 
Unplanned deviations (e.g. rescheduled visit, a missed 
routine safety laboratory test for a participant with 
previously normal values) 
Prior to each scheduled progress 
review  
5 business days from the date the 
site is aware of the event  
 
 

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12.0 AGENT INFORMATION 
12.1 Glasdegib 
Please refer to product label for more comprehensive information. 
 
Other names for the drug: Daurismo 
 
Mechanism of action (or Product description):  Hedgehog pathway inhibitor 
 
Availability: Provided by funder,  
 
How supplied: Glasdegib will be supplied in 30 count pill bottles. Initial dose will be supplied in 
100 mg tablets. If dose modifications are needed, Glasdegib will be supplied in 25 mg tablets.   
 
Storage and stability: Store at 20℃ to 25℃ (68℉ to 77℉); excursions permitted between 15℃ 
to 30℃ (59℉ to 86℉). 
 
Route of administration for this study: Oral dose, given daily in the morning with or without 
food 
 
Side effects: Anemia, fatigue, hemorrhage, febrile neutropenia, musculoskeletal pain, nausea, 
edema, thrombocytopenia, dyspnea, decreased appetite, dysguesia, mucositis, constipation, 
rash. 
 
12.1.1 Return and Retention of Study Drug 
Remaining drug is to be destroyed, according to Chao Cancer Center Investigational Drug 
Services destruction policy. Participating sites are to follow their institutional practice for 
destruction of study drug.  
 
12.1.2 Drug Accountability/Subject Compliance 
Records of study medications used, dosages administered, and intervals between visits will be 
kept during the study.  Patients will be asked to fill out a pill diary and bring with them for review 
after each cycle of study treatment. (Appendix E) 
 
Drug accountability will be noted at the completion of the trial.  Patients will be asked to return 
all unused medication at the end of the study. 
 
12.2 
CPX-351 
Please refer to product label for more comprehensive information. 
 
Other names for the drug: Vyxeos; Liposomal Cytarabine and Daunorubicin 
 
Mechanism of action (or Product description):  liposomal formulation of cytarabine and 
daunorubicin in fixed 5:1 molar ratio which was developed to treat AML.  
 
Availability: Provided by funder,  
 
How supplied: CPX-351 will be supplied as 100mg cytarabine plus 44mg daunorubicin in a 
50ml vial. 

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Storage and stability: Store unreconstituted VYXEOS vials in a refrigerator at 2°C to 8°C 
(36°F to 46°F) in an upright position. The vial should be stored in its original carton to protect 
from light. 
 
Route of administration for this study: The appropriate number of vials of CPX-351 should 
be removed from the refrigerator prior to reconstitution. Reconstitute with 19 mL of sterile water 
for injection using a 20 mL syringe. Do not heat CPX-351. After reconstitution, invert vials gently 
3-4 times and let rest for 15 minutes and repeat vial inversion prior to withdrawing drug from 
dilution. The concentration of the reconstituted dispersion is 5u/mL. CPX-351 should be diluted 
in approximately 500 mL of sodium chloride injection or dextrose injection. 
 
The IV bags and infusion sets must follow the Vyxeos package insert). Per Vyxeos package 
insert, nondi(2-ethylhexyl)phthalate (DEHP) IV bags and infusion sets are not required. Aseptic 
technique must be strictly observed throughout the handling of CPX-351 since no bacteriostatic 
agent or preservative is present. The infusion of CPX-351 must be started within 4 hours of 
dilution. Vials are for single use only. Unused material should be recorded as such and 
discarded according to institutional policies. Procedures for proper handling and disposal of 
anticancer drugs should be implemented. 
 
The infusion of CPX-351 will be performed though a central venous catheter, using an infusion 
pump to ensure that the drug is infused over the specific time period. Do not use an in-line filter. 
CPX-351 should never be given by intramuscular or subcutaneous route. Administer CPX-351 
over approximately 90 minutes vial an infusion pump. Flush the line to ensure the administration 
of the full dose. 
 
Side effects: Hemorrhagic events, febrile neutropenia, rash, edema, nausea, mucositis, 
diarrhea, constipation, musculoskeletal pain, fatigue, abdominal pain, dyspnea, headache, 
cough, decreased appetite, arrhythmia, pneumonia, bacteremia, chills, sleep disorders, and 
vomiting 
 
 
13.0 STATISTICAL CONSIDERATIONS 
13.1 
Study Design 
This is an investigator-initiated trial which will evaluate the outcome of the combination of CPX-
351 and Glasdegib in patients with newly diagnosed AML. This is a single-arm, open-label, 
Phase-IIA clinical trial to estimate the efficacy and tolerability of the combination of CPX-351 
and Glasdegib in the study population. 
 
UC Irvine will be the primary site of enrollment and additional sites within the University of 
California Hematologic Malignancies Consortium (UCHMC), including UCSF, UCLA, UCSD, 
and UCD can be added.  Total of 1-5 U.S. centers. Enrollment can occur at any site as long as 
the trial is open at that site. 
 
13.2 
Data Analyses Plans 
 
13.2.1 Primary Objectives 
For efficacy, the primary objective is to estimate proportion of evaluable participants who are 
event-free at six months (EFS6) and compare to the historical figure of 50 percent.  

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13.2.2 Primary Endpoint 
The primary endpoint for efficacy is EFS6.  The event-free interval begins with the date of 
diagnostic biopsy, and ends as described in Section 2.1.   
13.2.3 Primary Analysis 
The null hypothesis is that EFS6 is 50%.  The alternative hypothesis is that EFS6 will be 65% or 
more.  The figure of 65% is the minimum thought to indicate the treatment regimen is worthy of 
further study.  We will construct an exact (Clopper-Pearson), one-sided (lower), 90% confidence 
interval about the observed EFS6.  If that the lower limit of that confidence interval is greater 
than 0.5, the treatment regimen will be deemed worthy of further study.  
 
13.3 
Sample Size and Accrual Goal 
The accrual goal is 30 evaluable participants. The table below shows the lower bound of the 
90%, one-sided, exact confidence interval as a function of sample size and true proportion 
(precision = 0.14).  As the table shows, given the true proportion EFS6 is at least 65%, then 28 
observations from evaluable subjects have at least 90% probability to yield a lower, one-sided 
confidence bound that excludes the historical-control value of 50%.   Our goal is 30 evaluable 
subjects to allow for unanticipated loses. 
 
 
Sample 
Size 
(evaluable) 
 
True 
Proportion 
 
Lower 
Bound* 
28 
60% 
46% 
28 
65% 
51% 
28 
70% 
56% 
• 
Rounded so as to assure coverage 
 
13.4 
Other Analyses 
13.4.1 Description of Participants 
Participants will be described by sex, age, and other host or clinical factors, using means, 
medians, and percentiles for continuous variables and counts and percentages for categorical 
variables.  To the extent possible, participants will be compared to those who decline to 
participate in order to assess representativeness of the studied sample.    
 

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13.4.2 Analyses of Secondary Endpoints and Ad-Hoc Comparisons 
13.4.2.1 General Philosophy 
Consistent with the phase-ii nature of the project, we will examine the data in many ways to 
inform decisions about further research, including plots, tables, and statistical tests. Secondary 
analyses will be performed on intent-to-treat, per protocol, and ad-hoc data sets, as warranted.  
Given the total sample size of 28 to 30, probability values from statistical tests will be used as a 
guide to interpretation, which will also depend on clinical judgment.  Therefore, we will not be 
concerned with overall, study-wise, type-1 error rates for secondary and ad-hoc analyses.  As 
may be indicated, we will transform data to approach more closely analytic requirements, using 
logit transforms for percent data and log (for first choice) for continuous measures.  If 
transformations fail, we will fall back on the analysis of ranks or use non-parametric methods.   
13.4.2.2 Proportions 
Proportions, such as, overall remission rates and proportion who go to HSCT will be 
characterized by exact, binomial interval estimates and compared with Fisher’s exact test. 
13.4.2.3 Survival  
Time-to-event measures, such as, overall survival, time to normal hematopoiesis, duration of 
response, and influence of MRD status will be characterized by Kaplan-Meier methods, both 
overall and by strata of interest.  Differences in times/survival between or among groups will be 
evaluated by the log-rank test.  If assumptions are reasonably met, then Cox proportional-
hazards models will be made to examine the effects on survival of covariates adjusting for other 
covariates.  Ties in survival time will be broken by the subtracting a small, randomly generated 
amount from each tied observation (Borucka, 2014).   
13.4.2.4 Gene Expression 
We will use differential gene-expression analysis to try to identify genes or sets of genes where 
change in expression levels correlate with response to study treatment.   
13.4.2.5 Analyses of Intolerability or Toxicity 
We will examine the data to discover factors that may predict adverse reactions to the study 
treatment.  We will proceed in the same way as outlined above for secondary analyses.  
Adverse events will be classified by type, frequency, severity, timing, grade, and other factors 
that may aid interpretation, and be summarized by proportions, overall and within groups of 
subjects. 
 
 
 
14.0 STUDY MANAGEMENT 
14.1 
Conflict of Interest 
Any investigator who has a conflict of interest with this study (patent ownership, royalties, or 
financial gain greater than the minimum allowable by their institution, etc.) must have the conflict 
reviewed according to their local conflict of interest policy. If there is a positive disclosure, the 
site must communicate this information to the initiating site to determine if any revisions to the 
consent form are required with the IRB of record based on the COI outcome.  
 
14.2 
Regulatory Issues 
Regulatory requirements both at the federal level and the institutional level must be followed.  
The federal regulations for human subject protections and for clinical trials can be found in the 

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Federal Code of Regulations for the Department of Health and Human Services (DHHS) and 
the websites for federal agencies such as the National Institutes of Health (NIH) and the Food 
and Drug Administration (FDA).  
 
14.3 
Scientific Review Committees  
Each participating institution must submit the protocol to their individual scientific review 
committees per their institutional policies.  Scientific Review Committee approval is required 
prior to IRB approval through individual IRBs and reliance on the initiating site’s IRB. Site may 
rely on Scientific Review Committee approval by another NCI designated cancer center.  
 
14.4 
Institutional Review Boards  
Each clinical site must obtain approval by their local Institutional Review Board (IRB) prior to the 
initiation of any UCHMC clinical trial.  Communication between a site and the respective IRB is 
the responsibility of the site investigator.  Copies of IRB correspondence, including protocol 
approval letters, must be kept on file at the site.  A site may begin accrual upon contacting the 
Clinical Trials Operations Core by e-mail to assure any outstanding regulatory issues have been 
addressed and resolved. The UCHMC Clinical Trial Operations Core will be responsible for 
ensuring that all necessary essential documents as listed below in the trial master file are in place 
and kept up to date throughout the study.  It is not required to wait until all UCHMC sites secure 
local IRB approval to begin enrolling at an approved site. Each site is responsible for the annual 
renewal of IRB approval if not operated through UC Reliance.  Each investigator must report to 
the IRB any problems, serious adverse drug reactions or proposed changes in the protocol that 
may affect the status of the investigation and the willingness of patients to participate in the trial.  
The investigator must also report to the IRB at intervals appropriate to the degree of risk in the 
study, but no less frequently than once a year or at study closure.   
 
14.5 
SMART IRB Process  
The initiating site’s IRB will act as IRB of record through the SMART IRB reliance agreement. 
   
14.5.1 Initial Review Process 
 
1. All relying PIs agree to reliance through the SMART IRB process  
2. The initiating site PI will proceed with local IRB submission and notify the initiating site’s 
IRB about the participating sites   
3. Reviewing IRB approves the study  
4. IRB approved documents are pulled by the initiating site and distributed to the 
participating sites   
5. Each participating site will begin their local IRB submission and obtain approval and 
acceptance of the reliance  
6. Once accepted, the smart IRB agreement will be finalized and distributed to the sites  
14.5.2 Continuing Review  
Continuing Reviews (Annual Reviews) are the responsibility of the Reviewing PI. If the 
Continuing Review approval is not obtained in a timely manner, none of the relying sites will be 
allowed to continue research. The initiating site will inform the relying sites once the Continuing 
Review approval has been granted.  
 

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If the participating sites are relying on the initiating site’s IRB, participating sites are to provide 
the initiating site of all requested documents and information approximately 120 days prior to the 
expiration date of the study. Sites utilizing their local IRB must submit the continuing review 
approximately 90 days prior to expiration date of the study. Once the Continuing Review has 
been approved, the initiating site will update the expiration date in OnCore. Any sites utilizing 
their local IRB must submit their continuing review approval to the lead site upon receipt by 
sending the form to uci18105@hs.uci.edu.  
 
The Office of the President notes: "... no relying UC site on your study will be able to continue 
work if you don't obtain IRB renewal [continuing review approval] on time: it is your responsibility 
as a Reviewing Campus PI to apply for the renewal [continuing review] on time!"  
 
14.5.3 Amendments  
You are required to promptly inform the Reviewing PI/RC of the need for amendments.  
 
Protocol and ICF amendments will be submitted to the IRB of record by the initiating site.  Once 
approval is granted by the IRB of record, approved documents will be provided to the sub-sites.  
 
14.5.4 Adverse Events 
You are required to report to the Reviewing PI/RC and the IRB of record any adverse or 
unanticipated events. Each site is responsible for notifying the Reviewing Campus IRB following 
the Reviewing Campus's guidelines and notifying their local IRB, Jazz Pharmaceuticals, the 
study’s DSMB, as applicable. Any decision, change in protocol, etc. will be reported and 
uploaded to the Registry by the Reviewing Campus IRB. 
 
 
14.5.5 Protocol Amendment Procedures 
Should amendments to the protocol be required, the amendments will be originated and 
documented by the Study Chair. It should also be noted that when an amendment to the 
protocol substantially alters the study design or the potential risk to the patient, a revised 
consent form might be required.  
 
The written amendment, and if required the amended consent form, must be sent to the IRB for 
approval prior to implementation. 
 
Any substantial change should be discussed during the UCHMC Monthly Teleconference.  If the 
need for a protocol revision is agreed upon, the originator of the protocol is responsible for 
modifying the protocol, and sending the revised version electronically to the UCHMC Coordinating 
Center and sites along with the summary of the proposed changes.  The originator of the protocol 
also has responsibility for submitting the amendment to the FDA, if applicable.   
 
If the changes are solely administrative and do not alter trial conduct, UCHMC Clinical Trials 
Steering Committee approval is not required. Steering Committee Members should be made 
aware of all amendments.  Each Steering Committee member should be provided with a list of 
changes implemented in an amendment.  
 
The initiating site’s IRB will be utilized for all protocol amendment approvals. Each center must 
submit the revision to their respective IRB for approval if not relying through the SMART IRB 
reliance agreement. A copy of the IRB approval is to be sent to uci18105@hs.uci.edu.    
 

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The primary site will ensure that all sites are operating off the correct protocol and ICF version 
and will obtain training documentation from each site. Each site will follow their institutional policy 
on protocol training. A copy of each site’s institutional policy must be sent to the initiating site prior 
to the site initiation visit.   
 
14.5.6 Institutional Review Board (IRB) Approval and Consent  
The IRB should approve the consent form and protocol prior to any study-related activities.  It is 
expected that the IRB will have the proper representation and function in accordance with 
federally mandated regulations.  
 
In obtaining and documenting informed consent, the investigator should comply with the 
applicable regulatory requirement(s), and should adhere to Good Clinical Practice (GCP) and to 
ethical principles that have their origin in the Declaration of Helsinki. 
 
 
Before recruitment and enrollment onto this study, the patient will be given a full explanation of 
the study and will be given the opportunity to review the consent form. Each consent form must 
include all the relevant elements currently required by the FDA Regulations and local or state 
regulations. Once this essential information has been provided to the patient and the 
investigator is assured that the patient understands the implications of participating in the study, 
the patient will be asked to give consent to participate in the study by signing an IRB-approved 
consent form. 
 
Prior to a patient’s participation in the trial, the written informed consent form should be signed 
and personally dated by the patient and by the person who conducted the informed consent 
discussion. 
 
14.5.7 Required Documentation  
Trial Master File (TMF)  
Prior to initiating a UCHMC protocol and enrolling subjects, the initiating site must insure that all 
essential documents are in place and activate the site.   
Before the study can be initiated at any site, the following documentation must be provided to 
the UCI Clinical Trials Office:  
 
UC Irvine Health 
Chao Family Comprehensive Cancer Center 
 Clinical Trials  
200 Manchester Drive, Suite 400 
Orange, CA, 92868 
Phone: 714-456-5153 
Fax: 714-456-2242 
Email : uci18105@hs.uci.edu 
 
- 
A copy of the official IRB approval letter for the protocol and informed consent document 
OR documentation of agreement to accept UCI IRB approval of the protocol and consent 
through the UC IRB Reliance Registry by means of the SMART IRB reliance agreement 
- 
IRB membership list or FWA letter 
- 
A copy of the IRB approved consent form 
- 
CAP and CLIA Laboratory certification numbers and institution lab normal values for 
those listed on the 1572 
- 
Executed clinical research contract 

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- 
Delegation of Authority Log  
- 
1572 
- 
Financial Disclosure Forms 
o For PI and each Sub-I 
- 
CVs and Medical Licenses 
o For PI and each Sub-I 
- 
GCP Training  
o For PI, Sub-Is and study personnel   
- 
Protocol Signature Page 
- 
IATA Training Certificate for Coordinators  
- 
Site Drug Destruction SOPs 
- 
Institutional SOPs  
- 
Site contact sheet  
 
Sub-sites will receive activation notice upon receipt of all required documents by the initiating 
site.   
 
14.5.8 Protocol Initiation 
When a protocol has been submitted for IRB approval at a site, the initiating site must be 
notified.  Protocols will be tracked in OnCore.  Each clinical site must ensure that the protocol 
has been approved by a local IRB prior to the initiation of a trial.  A copy of the protocol approval 
letter must be sent to the UCI by emailing uci18105@hs.uci.edu.  If a site is not relying on the 
initiating site’s IRB, each site is responsible for annual renewal of IRB approval and should 
email a copy of the renewal letter to central study email when it is received.  If run through the 
smart IRB reliance, the initiating site will be responsible for providing documentation of annual 
renewal approval to each of the participating centers.  
 
 
Site Initiation Visits 
Prior to activation and patient enrollment on a protocol a site initiation visit must occur.  All PIs 
must be in attendance along with the coordinator, regulatory associate and pharmacy when 
appropriate. SIV’s may be conducted in person or remotely per the initiating PI’s preference.  
 
Site Activation  
Prior to enrolling the first patient, all sites must obtain notice of activation from the initiating site. 
At a minimum, sites must show documentation of IRB approval, IRB Stamped ICF, completed 
delegation of authority log, and if applicable with the site policy, SIV training documentation.  
 
14.5.9 Protocol Amendments and Continuing Renewal Approvals 
Protocol Amendments 
For all protocol amendments, each site must follow their institutional policy on protocol training. A 
copy of this policy must be sent to initiating site for review prior to the site initiation visit.   
 
Signed protocol signature pages must also be completed by each PI for each version of the 
protocol.  
 
Prior to submitting the revised ICF, the initiating site is to work with each site to ensure that 
changes to the ICF per the amendment are appropriate per their institutional requirements. The 
initiating site will provide each site with their IRB stamped version of the amended ICF if applicable 
and clearly indicate whether or not patients must be re-consented. If necessary, foreign language 

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translations of the ICF and other patient facing materials will be provided to each site by the 
initiating site.  
 
IRB approval documentation to be provided by the initiating site to each sub-site for each 
amended protocol.  
 
Continuing Renewals  
Prior to submitting the continuing renewal to the IRB, the initiating site will work with each sub-
site to obtain patient narratives and non-UPR logs (deviation log) per their IRBs operating 
procedures.  Once continuing renewal has been granted, it is the responsibility of the initiating 
site to provide each site with the IRB approval notice and stamped ICF with updated expiration 
date. If necessary, all translated materials will be provided at this time.  
 
Site Close out Visit 
A Site close out visit must be performed prior to a site closing a study with the IRB.  During the 
site close out visit, final data review will occur, review and collection of all regulatory documents 
will be performed, and final drug accountability will occur. This visit may be an on-site visit or 
can be completed remotely.  
 
14.5.10 Electronic Data Capture “OnCore EDC” 
 
Data must be entered within 10 business days of each study visit. Data progress will be 
monitored by the clinical research manager to ensure that all data is entered in a timely manner 
per the UCHMC guidelines.  
 
User Training 
Instruction concerning the use of eCRF forms is provided by the clinical research manager. 
Instruction concerning the use of the OnCore EDC Database, remote training concerning the 
proper use of the EDC system is available to sites by request, or if training appears is needed 
based on inconsistency or errors in data reported.   
 
• 
The PI at the initiating site will have access to view the data of all patients at all sites 
• 
Local PI and coordinator for individual sub-sites will have access to view only the data 
pertaining to their patients.  
 
Changes in study status must be promptly recorded in the OnCore EDC System.  Case report 
forms (CRFs) are to be entered into OnCore by clinical site personnel within 10 business days 
of the patient’s visit.   
 
Registration/Baseline Data 
The Registration/Baseline data is captured by the OnCore EDC System.  Clinical staff is 
required to check with their IRB and the initiating site for current protocol accrual before 
consenting or attempting to enroll patients in any clinical trial.  
 
If errors are made in attempting to enroll in a protocol, the data entry can only be corrected by 
contacting the study team at uci18105@hs.uci.edu.   
 
Clinical Data 
The Clinical case report forms are intended to capture laboratory values and clinical visit 
information at time intervals specified by each protocol.  These values are to be entered into the 
OnCore EDC system within 10 business days of the patient visit.   

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14.5.11 Data Forms and Submission Schedule via OnCore EDC 
Data Forms Completion 
Data forms are to be completed following Screening, and then after each study visit. 
 
 
Data Forms Submission 
Data forms are to be completed in the OnCore EDC system and corresponding source 
documentation uploaded within 2 weeks after each study visit.  Timeline for Data Form 
submission is as follows: 
 
 
 
Screening Forms:  to be completed within 24 hours following confirmation of eligibility and 
enrollment on the study. 
 
Treatment Visit Forms:  within 2 weeks of the end of each visit, to include Con Med forms. 
 
Off-Study Form/Death Form:  within 1 week of knowledge of off-study status or death of patient. 
 
AE Forms:  please refer to the reporting requirements section 11.3 and 11.4 to determine the 
appropriate timeline in which this information should be entered. All AEs should always be 
entered prior to scheduled Study Conference Calls (scheduled monthly) 
 
SAE Forms:  to be sent within 24 hours of knowledge of the event, and then as soon as a final 
report can be done. Please refer to the reporting requirements section 11.3 and 11.4 to 
determine the appropriate timeline in which this information should be entered.  
 
14.5.12 Data Monitoring  
It is the responsibility of the clinical research manager and study coordinator to review all of the 
case report forms submitted using the OnCore EDC Database.  Electronic submission of clinical 
data should be reviewed monthly, of all data entered in that month.   Any problems with the 
OnCore EDC System (e.g. system access, errors, bugs) should be reported to the lead 
institution immediately.  The OnCore team can be reached via email at 
OnCore_Admin@hs.uci.edu. You may also contact the central study email, 
uci18105@hs.uci.edu, with any OnCore issues as well.  
 
 
14.5.13 Study Monitoring Conference Calls  
During the study, we will hold bi-weekly or monthly teleconferences to be attended by the 
study investigators or their representatives, the principal investigator, data management, and 
the statistical data center to review adverse events, accrual and other issues that arise over the 
course of the study. This teleconference is only required for those sites with patients on study.  
 
14.5.14 
Subject Data Protection 
In accordance with the Health Information Portability and Accountability Act (HIPAA), subjects 
who have provided written informed consent must also sign a subject authorization to release 
medical information to the study Sponsor and allow a regulatory authority, or Institutional 
Review Board access to subject’s medical information relevant to the study. 
 
14.5.15 
Data and Safety Monitoring/Auditing 

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This study will also use the UCI Data Safety and Monitoring Board (DSMB) to provide oversight 
in the event that this treatment approach leads to unforeseen toxicities. This is a risk level 1 
study, as defined in the Chao Family Comprehensive Cancer Center (CFCCC) Data and Safety 
Monitoring Plan (DSMP) because although Glasdegib and Vyxeos are FDA approved, the 
toxicity of the combination is not well established. 
 
The Principal Investigator (PI), co-investigator, clinical research coordinator, and statistician are 
responsible for monitoring of data and safety for this study.  For studies that have stopping rules 
for safety and efficacy, the PI will be responsible for the implementation and make changes as 
applicable. The CFCCC Data and Safety Monitoring Board (DSMB) is an independent body 
responsible for the safety of study subjects as well as the data integrity of the protocol.  Data 
and safety will be reported to the DSMB with submission of progress reports that include 
aggregated reports of adverse events, serious adverse events, deviations, and violations.  In 
addition, certain adverse events, serious adverse events, deviations, violations, and 
unanticipated problems will be reported promptly to the DSMB for review according to Section 
11.3 and Section 11.4.   
 
The CFCCC Stern Center for Cancer Clinical Trials and Research Quality Assurance Unit will 
conduct monitoring and auditing activities as per the UC Irvine CFCCC Quality Assurance 
Monitoring and Auditing Plan and at the discretion of the CFCCC DSMB in order to ensure 
patient safety and data integrity oversight. By conducting internal monitoring and auditing, the 
CFCCC will ensure compliance with high quality standards and all applicable regulations, 
guidelines, and institutional policies. Trial monitoring and auditing may be completed remotely or 
on-site. Participating sites may follow their own internal quality assurance policies in order to 
maintain patient safety and data integrity oversight. The investigator must permit study-related 
monitoring/auditing and provide access to study-related materials. 
 
Risk Levels 
 
 Risk Level  
Definition  
Monitoring  
Level 1  
High Risk - UCI investigator-
initiated interventional trials for 
which the PI holds Investigational 
New Drug (IND) or Investigation 
Device Exemption (IDE).  
Example: Gene therapy, dendritic 
cell products from GMP suite, 
phase I/II development and phase 
I studies, first in human, etc.  
Two months after subject 
enrollment  
 
14.5.16 
Adherence to the Protocol 
Except for an emergency situation in which proper care for the protection, safety, and well-being 
of the study patient requires alternative treatment, investigators are required to conduct their 
research according to the plans reviewed and approved by the IRB. Any planned or prospective 
deviations must require proper approval from the initiating site and the IRB. Please refer to 
section 11.3 and 11.4 to ensure when and who must be informed of any planned deviations.    
 
14.5.17 
Emergency Modifications  

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Investigators may implement a deviation from, or a change of, the protocol to eliminate apparent 
immediate hazards/risks to trial subjects without prior IRB approval. Any such emergency 
modification implemented must be noted and reported to the IRB and inform the initiating site PI 
along the lines of a protocol deviation or violation, depending on the nature of the modification.  
 
14.5.18 
Protocol Violations  
Any unplanned variance from an IRB approved protocol is considered a violation and must be 
reported to the IRB in a timely fashion. 
A. All major protocol deviations will be reported in accordance with UCI IRB, UCI CFCCC 
Stern Center policies, UCI DSMB and the participating site’s IRB policies.  
Major violations include: 
• 
Instances that have harmed or increased the risk of harm to one or more 
research participants. 
• 
Instances that have damaged the scientific integrity of the data collected for the 
study. 
• 
Results from willful or knowing misconduct on the part of the investigator(s). 
• 
Demonstrates serious or continuing noncompliance with federal regulations, 
State laws, or University policies. 
B. Minor violations may be reported to the IRB at the time of the continuing review. 
Minor violations have no substantive effect on the risks to participants or on the scientific 
integrity of the research plan or the value of the data collected.  
 
14.5.19 
Amendments to the Protocol 
Should amendments to the protocol be required, the amendments will be originated and 
documented by the Study Chair. It should also be noted that when an amendment to the 
protocol substantially alters the study design or the potential risk to the patient, a revised 
consent form might be required.  
 
The written amendment, and if required the amended consent form, must be sent to the IRBs 
and any applicable entities or committees (FDA, RSC, IBC, when applicable) for approval prior 
to implementation. 
 
14.5.20 
Record Retention 
Study documentation includes all Case Report Forms, data correction forms or queries, source 
documents, correspondence, monitoring logs/letters, and regulatory documents (e.g., protocol 
and amendments, IRB correspondence and approval, signed patient consent forms). 
 
Source documents include all recordings of observations or notations of clinical activities and all 
reports and records necessary for the evaluation and reconstruction of the clinical research 
study. 
 
Government agency regulations and directives require that the study investigator must retain all 
study documentation pertaining to the conduct of a clinical trial. Study documents should be 
kept on file until 10 years after the completion and final study report of this investigational study. 
 
14.5.21 
Obligations of Investigators 
The Principal Investigator is responsible for the conduct of the clinical trial at the site in 
accordance with Title 21 of the Code of Federal Regulations and/or the Declaration of Helsinki. 

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The Principal Investigator is responsible for personally overseeing the treatment of all study 
patients. The Principal Investigator must assure that all study site personnel, including sub-
investigators and other study staff members, adhere to the study protocol and all FDA/GCP/NCI 
regulations and guidelines regarding clinical trials both during and after study completion. 
 
The Principal Investigator at each institution or site will be responsible for assuring that all the 
required data will be collected and entered onto the Case Report Forms. Periodically, 
monitoring visits will be conducted and the Principal Investigator will provide access to his/her 
original records to permit verification of proper entry of data. At the completion of the study, all 
case report forms will be reviewed by the Principal Investigator and will require his/her final 
signature to verify the accuracy of the data. 
 
15.0 UCHMC Publication Policy 
15.1 
Overview 
The process of preparation, clearance, and publication of any manuscript which results from a 
UCHMC study is complete when the study results are disseminated to the scientific community 
by means of a formal referred publication.  The UCHMC Steering Committee has oversight over 
the use and publication of UCHMC data.  Each institution participating in protocol studies must 
be acknowledged and each contributing institution should have the opportunity to review the 
manuscript. 
 
15.2 
Publication Preparation and Review 
The responsibility for writing manuscripts describing a UCHMC study belongs to the Study 
Principal Investigator.  The Biostatistics Core provides analytic assistance and review for 
manuscripts based on UCHMC clinical protocols, and as requested by the Study Chair.  The 
Clinical Trials Steering Committee reviews manuscripts based on UCHMC clinical protocols.  
The timeline for preparing, reviewing, and revising the manuscript will be decided by the Study 
Chair and the UCHMC Steering Committee on a case-by-case basis.   
 
 
15.3 
Publication Acknowledgements  
All manuscripts should acknowledge in the title of the paper that the manuscript is a group 
effort.  A suggested mechanism is to follow the title of the paper with the phrase "University of 
California Hematologic Malignancies Consortium (UCHMC) Study."    The manuscript should 
indicate UCHMC protocol by number.   
 
15.4 
Authorship  
First author will be assigned to the study chair or PI at the initiating site. Senior authorship will 
be assigned based on contribution to protocol development, not specifically to study enrollment.  
The order of authorship assignments outside of first and last (senior) author will be based on 
study enrollment numbers with highest enrolling sites placed earlier in authorship order. Both 
the local PI and steering committee member, if different, from each site will be included as 
authors on the publication.  References to Patient Data in Publications 
In order to ensure that the privacy and confidentiality of UCHMC patients is maintained in 
publications, measures must be taken to ensure that no personal identifiable data (PID) is 

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released in any publication.  When publishing information pertaining to the given patient data 
and/or samples, investigators are to utilize the study specific ID number.   
 
 

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16.0 REFERENCES 
1. National Cancer Institute – Surveillance, Epidemiology, and End Results Program. Cancer 
Stat Facts: Leukemia – Acute Myeloid Leukemia (AML) 
https://seer.cancer.gov/statfacts/html/amyl.html. Accessed April 26, 2019 
 
2. Kayser S, Dohner K, Krauter J, et al. The impact of therapy-related acute myeloid leukemia 
on outcome in 2853 adult patients with newly diagnosed AML. Blood 2011; 117: 2137-2145. 
 
3. Arber DA, Orazi A, Hasserjian R, et al. The 2016 revision to the World health organization 
classification of myeloid neoplasms and acute leukemia. Blood. 2016; 127(20): 2391-2405. 
 
4. Falini B, Macijewski K, Weiss T, et al. Multilineage dysplasia has no impact on biologic, 
clinicopathologic, and prognostic features of AML with mutated nucleophosmin (NMP1). 
Blood 2010; 115(18): 3776-3786. 
 
5. Diaz-Beya M, Rozman M, Pratcorona M, et al. The prognostic value of multilineage 
dysplasia in de novo acute myeloid leukemia patients with intermediate risk cytogenetics in 
dependent on NPM1 mutational status. Blood 2010; 116(26): 6147-6148. 
 
6. Bacher U, Schnittger S, Macijewski K, et al. Multilineage dysplasia does not influence 
prognosis in CEBPA-mutated AML, supporting the WHO proposal to classify these patients 
as a unique entity. Blood 2012; 119(20):4719-4722. 
 
7. Rozman M, Navarro JT, Arenillas L, et al. Grup Catala de Citologia Hematologica and 
Spanish CETLAM Group (Grupo Cooperativo Para el Estudio y Tratamiento de las 
Leucemias Agudas Mieloblasticas). Multilineage dysplasia is associated with a poorer 
prognosis in patients with de novo acute myeloid leukemia with intermediate cytogenetics 
and wild-type NPM1. Ann. Hematolog. 2014;93(10): 1695-1703. 
 
8. Ravandi F, Walter RB, Freeman SD. Evaluating measurable residual disease in acute 
myeloid leukemia. Blood advances 2018 June 12; 12(11): 135601366. 
 
9. Jongen-Lavrencic M, Grob T, Hanekamp D, et al. Molecular minimal residual disease in 
AML. NEJM 2018; 378(13): 1189-1199. 
 
10. Deng D, Zhu H, Liu Y, et al. Minimal Residual Disease detected by multiparameter flow 
cytometry is complementary to genetics for risk stratification treatment in AML with biallelic 
CEBPA mutation. Leukemia Lymphoma 2019 Feb 18: 1-9. 
 
11. Ravandi F, Jorgensen J, Borthakur G, et al. Persistence of minimal residual disease 
assessed by multiparameter flow cytometry is highly prognostic in younger patients with 
acute myeloid leukemia. Cancer. 2017;123(3):426-435. 
 
12. Othus M, Wood BL, Stirewalt DL, et al. Effect of measurable (‘minimal’) residual disease 
(MRD) information on prediction of relapse and survival in adult acute myeloid leukemia. 
Leukemia. 2016;30(10):2080-2083. 
 
13. Munchhof MJ, Li Q, Shavnya A, et al. Discovery of PF-04449913, a potent and orally 
bioavailable inhibitor of smoothened. ACS Med Chem Letter 2012; 3: 106-11. 
 
14. Sadarangani A, Pineda G, Lennon KM et al. GLI2 inhibition abrogates human leukemia 
stem cell dormancy. J Transl Med 2015; 13: 98. 

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15. Fukushima N, Minami Y, Kakiuchi S, et al. Small molecular Hedgehog inhibitor attenuates 
the leukemia-initiation potential of acute myeloid leukemia cells. Cancer Sci 2016; 107: 
1422-9. 
 
16. Jackson-Fisher A, McMahon MJ, Lam J et al. PF-04449913, a small molecule inhibitor of the 
hedgehog signaling pathway, is effective in inhibiting tumor growth in preclinical models. 
Clin Cancer Rev 2011; 71: 4504. 
 
17. Martinelli G, Oehler VG, Papayannidis C, et al. Treatment with PF-04449913, an oral 
smoothened antagonist in patients with myeloid malignancies: a phase 1 safety and 
pharmacodynamic study. Lancet Haematology 2015; 2: e339-46. 
 
18. Minami Y, Minami H, Miyamoto T, et al. Phase 1 study of Glasdegib (PF-04449913) an oral 
smoothened inhibitor in Japanese patients with select hematologic malignancies. Cancer 
Sci 108 (2017) 1628-1633. 
 
19. Teglund S, Toftgard R. Hedgehog beyond medulloblastoma and basal cell carcinoma. 
Biochim Biophys Acta 2010; 1805: 181-208. 
 
20. Epstein EH. Basal cell carcinomas: attack of the hedgehog. Nat Rev Cancer 2008; 8: 743-
54. 
 
21. Savona MR, Pollyea DA, Stock W, et al. Phase 1b study of Glasdegib, a hedgehog pathway 
inhibitor, in combination with standard chemotherapy in patients with AML or high-risk MDS. 
Clin Cancer Res. 2018; 1-10.  
 
22. Cortes JE, Heidel FH, Heuser M, et al. A phase 2 randomized study of low dose Ara-C with 
or without Glasdegib (PF-04449913) in untreated patients with acute myeloid leukemia or 
high-risk myelodysplastic syndrome. Blood 2016; 128: 99. 
 
23. US Food and Drug Administration. FDA approves new treatment for patients with acute 
myeloid leukemia. November 21, 2018. 
www.fda.gov/newsevents/newsroom/pressannouncements/ucm626443.htm. Accessed 
February 25, 2019. 
 
24. Cortes JE, Heidel FH, Hellman A, et al. Randomized combination of low dose cytarabine 
with or without Glasdegib in patients with newly diagnosed Acute myeloid leukemia or high 
risk MDS. Leukemia. Published online on 11/2/18. 
 
25. Cortes JE, Smith BD, Wang ES, et al. Glasdegib in combination with cytarabine and 
daunorubicin in patients with AML or high-risk MDS: Phase 2 study results. Am J 
Hematology. 2018; 93: 1301-1310. 
 
26. Cortes JE, Biomarkers of Overall survival and response to Glasdegib and intensive or non-
intensive chemotherapy in patients with acute myeloid leukemia. Blood supplement 2018: 
paper 2733. 
 
27. Mayer LD, Harasym TO, Tardi PG, et al. Ratiometric dosing of anticancer drug 
combinations: controlling drug ratios after systemic administration regulares therapeutic 
activity in tumor-bearing mice. Mol Cancer ther. 2006;5(7): 1854-1863. 
 

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28. Lim WS, Tardi PG, Dos Santos N, et al. Leukemia-selective uptake and cytotoxicity of CPX-
351, a synergistic fixed ratio cytarabine:daunorubicin formulation,in bone marrow 
xenografts. Leuk Res 2010; 34: 1214-1223. 
 
29. Kim HP, Gerhard B, Harasym To et al. Liposomal encapsulation of a synergistic molar ratio 
of cyatarabine and daunorubicin enhances selective toxicity for acute myeloid leukemia 
progenitors as compared to analogous normal hematopoietic cells. Exp Hematol 2011; 39: 
741-750. 
 
30. Feldman EJ, Lancet JE, Kolitz JE, et al. First in man study of CPX-351: a liposomal carrier 
containing cytarabine and daunorubicin in a fixed 5:1 molar ratio for the treatment of 
relapsed and refractory acute myeloid leukemia. Journal of clinical oncology 2011; 29(8): 
979-985.  
 
31. Cortes JE, Goldberg SL, Feldman EJ, et al. Phase II, multicenter, randomized trial of CPX-
351 (cytarabine:daunorubicin) Liposomal injection versus intensive salvage therapy in adults 
with first relapse AML. Cancer 2015 January 15; 121(2): 234-242. 
 
32. Lancet JE, Cortes JE, Hogge DE, et al. Phase II trial of CPX-351, a fixed 5:1 molar ratio of 
cytarabine/daunorubicin, versus cytarabine/daunorubicin in older adults with untreated AML. 
Blood 2014; 123(21): 3239-3246. 
 
33. Lancet JE, Rizzieri D, Cortes JE, et al. Overall survival with CPX-351 versus 7+3 in older 
adults with newly diagnosed therapy-related acute myeloid leukemia (tAML): subgroup 
analysis of a phase III study [abstract]. J Clin Onc 2017; 35: 703. 
 
34. Medeiros BC, Hogge D, Strickland SA, et al. Overall survival (OS) and stem cell transplant 
(SCT) in patients with FLT3 mutations treated with CPX-351 versus 7+3: subgroup analysis 
of a phase III study of older adults with newly diagnosed, high risk acute myeloid leukemia 
(AML) [abstract]. J Clin Onco 2017; 35:e18507. 
 
35. Lancet JE, Hoering A, Uy GL, et al. Survival following allogeneic hematopoietic cell 
transplantation in older high-risk acute myeloid leukemia patients initially treated with CPX-
351 liposome injection versus standard cytarabine and daunorubicin: subgroup analysis of a 
large phase III trial 2016 American Society of Hematology Annual Meeting: abstract 906. 
 
36. Borucka, J. Methods for handling tied events in the cox proportional hazards model. Studia 
Oeconomica Posnaniensia, 2(2), 91-105, 2014. 
 
37. Ivanova A, Qaqish BF, Schell MJ. Continuous toxicity monitoring in phase II trials in 
oncology. Biometrics (61) 540-545, 2005. 
 
 
 
 

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17.0 
APPENDICES 
Appendix A. Cytogenetic abnormalities 
Cytogenetic abnormalities sufficient to diagnose AML with myelodysplasia-related changes 
when ≥ 20% PB or BM blasts are present and prior therapy has been excluded 
Cytogenetic abnormalities 
Complex karyotype (3 or more abnormalities) 
Unbalanced abnormalities 
-7/del(7q) 
del(5q)/t(5q) 
i(17q)/t(17p) 
-13/del(13q) 
del(11q) 
del(12p)/t(12p) 
idic(X)(q13) 
Balanced abnormalities 
t(11;16)(q23.3;p13.3) 
t(3;21)(q26.2;q22.1) 
t(1;3)(p36.3;q21.2) 
t(2;11)(p21;q23.3) 
t(5;12)(q32;p13.2) 
T(5;7)(q32;q11.2) 
t(5;17)(q32;p13.2) 
t(5;10)(q32;q21.2) 
t(3;5)(q25.3;q35.1) 
 
 

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Appendix B. Performance Status 
 
ECOG Performance Status Scale 
Grade 
Descriptions 
0 
Normal activity.  Fully active, able to carry on all pre-disease 
performance without restriction. 
1 
Symptoms, but ambulatory. Restricted in physically 
strenuous activity, but ambulatory and able to carry out work 
of a light or sedentary nature (e.g., light housework, office 
work). 
2 
In bed < 50% of the time. Ambulatory and capable of all 
self-care, but unable to carry out any work activities.  Up and 
about more than 50% of waking hours. 
3 
In bed > 50% of the time.  Capable of only limited self-care, 
confined to bed or chair more than 50% of waking hours. 
4 
100% bedridden.  Completely disabled.  Cannot carry on any 
self-care.  Totally confined to bed or chair. 
5 
Dead. 
 
 
 

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Appendix C. CYP35A Inhibitors/Inducers 
 
Strong CYP3A4/5 Inducers 
Inducer 
Therapeutic Class 
Rifampin 
Antibiotics 
Rifabutin 
Antibiotics 
Avasimibe 
Antilipedimics 
Phenytoin 
Anticonvulsants 
Carbamazepine 
Anticonvulsants 
Phenobarbital 
Anticonvulsants 
Enzalutamide 
Antiandrogens 
St. John’s Wort 
Herbal Medications 
Mitotane 
Antineoplastic 
Moderate CYP3A4/5 Inducers 
Inducer 
Therapeutic Class 
semagacestat 
Alzheimers 
efavirenz 
NNRTI 
bosentan 
Endothelin Receptor Antagonist 
genistein 
Food Product 
Thioridazine 
Antipsychotics 
Naficillin 
Antibiotics 
Talviraline 
NNRTI 
Lopinavir 
Protease Inhibitor 
Modafinil 
Psychostimulant 
Etravirine 
NNRTI 
Lersivirine 
NNRTI 
Source: University of Washington Drug Interaction Database. “Copyright University of 
Washington 1999-2015, UW Metabolism and Transport Drug Interaction Database, accessed: 
May 2017” 
 
Strong CYP3A4/5 Inhibitors 
Inhibitor  
Therapeutic Class 
Ketoconazole  
Antifungal 
Itraconazole  
Antifungal 
Voriconazole  
Antifungal 
Posaconazole  
Antifungal 
Troleandomycin  
Antibiotics 
Clarithromycin  
Antibiotics 
Telithromycin  
Antibiotics 
Mibefradil  
Calcium Channel Blocker 
Conivaptan  
Diuretics 

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Nefazodone  
Antidepressants 
Cobicistat  
-- 
Indinavir/Ritonavir  
Protease Inhibitors 
Tipranavir/Ritonavir  
Protease Inhibitors 
Ritonavir  
Protease Inhibitors 
Indinavir  
Protease Inhibitors 
Nelfinavir  
Protease Inhibitors 
Saquinavir  
Protease Inhibitors 
Saquinavir/Ritonavir  
Protease Inhibitors 
Lopinavir/Ritonavir  
Protease Inhibitors 
Telaprevir  
Antivirals 
Boceprevir  
Antivirals 
Danoprevir/Ritonavir  
Antivirals 
Elvitegravir/Ritonavir  
Antivirals 
LCL161  
Antivirals 
Idelalisib  
Kinase Inhibitors 
Grapefruit Juice DS  
Food Products 
Source: University of Washington Drug Interaction Database. “Copyright University of 
Washington 1999-2015, UW Metabolism and Transport Drug Interaction Database, accessed: 
May 2017” 
 
Moderate CYP3A4/5 Inhibitors  
Inhibitor 
Therapeutic Class 
Fluconazole  
Antifungals 
Erythromycin  
Antibiotics 
Ciprofloxacin  
Antibiotics 
Diltiazem  
Calcium Channel Blockers 
Verapamil  
Calcium Channel Blockers 
Dronedarone  
Antiarrhythmics 
Aprepitant  
Antiemetics 
Casopitant  
Antiemetics 
Netupitant  
Antiemetics 
Tofisopam  
Benzodiazepines 
Cyclosporine  
Immunosuppressant 
Schisandra sphenanthera  
Herbal Medication 
ACT-178882  
Renin Inhibitor 
Cimetidine  
H2 Receptor Antagonist 
FK1706  
Central Nervous System Agent 
Faldaprevir  
Antivirals 
Crizotinib  
Kinase Inhibitor 
Nilotinib  
Kinase Inhibitor 

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Atazanivir/Ritonavir  
Protease Inhibitor 
Darunavir  
Protease Inhibitor 
Darunavir/Ritonavir  
Protease Inhibitor 
Atazanavir  
Protease Inhibitor 
Amprenavir  
Protease Inhibitor 
Imatinib  
Antineoplastic agent 
Grapefruit Juice  
Food Products 
Isavuconazole  
Antifungal 
GSK2647544  
Alzheimer’s/Dementia 
Source: University of Washington Drug Interaction Database. “Copyright University of 
Washington 1999-2015, UW Metabolism and Transport Drug Interaction Database, accessed: 
May 2017” 
 
 

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Appendix D. Drugs known to prolong QTc 
Drugs that have known risk for QT prolongation 
Generic Name  Drug Class  
Therapeutic Use  
Route 
Amiodarone  
Anti-arrhythmic  
Abnormal heart rhythm  
oral,injection 
Anagrelide  
Phosphodiesterase 3 inhibitor  
Thrombocythemia  
oral 
Arsenic trioxide  Anti-cancer  
Leukemia  
injection 
Azithromycin  
Antibiotic  
Bacterial infection  
oral,injection 
Chloroquine  
Anti-malarial  
Malaria  infection 
oral 
Chlorpromazine  Anti-psychotic /Anti-emetic 
Schizophrenia/nausea 
oral, 
injection 
Cilostazol  
Phosphodiesterase 3 inhibitor  
Intermittent claudication  
oral 
Ciprofloxacin  
Antibiotic 
Bacterial Infection  
oral, 
injection 
Citalopram  
Anti-depressant, SSRI  
Depression  
oral 
Clarithromycin  
Antibiotic  
Bacterial infection  
oral 
Disopyramide  
Anti-arrhythmic  
Abnormal heart rhythm  
oral 
Dofetilide  
Anti-arrhythmic  
Abnormal heart rhythm  
oral 
Donepezil  
Cholinesterase inhibitor 
Dementia  
oral 
Dronedarone  
Anti-arrhythmic  
Atrial Fibrillation  
oral 
Droperidol  
Anti-psychotic / Anti-emetic 
Anesthesia  
adjunct, nausea  
injection 
Erythromycin  
Antibiotic  
Bacterial infection; increase 
GI motility  
oral, 
injection 
Escitalopram  
Anti-depressant, SSRI  
Major depression/ Anxiety 
Disorders  
oral 
Flecainide  
Anti-arrhythmic 
Abnormal heart rhythm  
oral 
Fluconazole  
Anti-fungal  
Fungal infection 
oral, 
injection 
Halofantrine  
Anti-malarial  
Malaria infection 
oral 
Haloperidol  
Anti-psychotic 
Schizophrenia, agitation 
oral, 
injection 
Ibutilide  
Anti-arrhythmic  
Abnormal heart rhythm  
injection 
Levofloxacin  
Antibiotic 
Bacterial infection  
oral, 
injection 
Methadone  
Opiate 
Pain control, narcotic 
dependence  
oral, 
injection 
Moxifloxacin  
Antibiotic 
Bacterial infection  
oral, 
injection 
Ondansetron  
Anti-emetic  
Nausea, vomiting  
oral, 
injection 
Pentamidine  
Antibiotic  
Pneumocystis pneumonia 
injection, 
inhaled 
Pimozide  
Anti-psychotic  
Tourette's tics  
oral 
Propofol  
Anesthetic  
Anesthesia  
injection 

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Quinidine  
Anti-arrhythmic  
Abnormal heart rhythm  
oral, 
injection 
Sevoflurane  
Anesthetic, general 
Anesthesia  
inhaled 
Sotalol  
Anti-arrhythmic  
Abnormal heart rhythm  
oral 
Thioridazine  
Anti-psychotic  
Schizophrenia  
oral 
Vandetanib  
Anti-cancer  
Thyroid cancer  
oral 
Source: Credible Meds.org (http://crediblemeds.org/healthcare-providers/drug-list/?rf=All). TdP 
risk category filtered on Drugs with known TdP risk. Assessed 11 October 2015. 
 
 

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Appendix E. IWG Response Criteria 
International Working Group Response Criteria in AML 
Classification  
Definition  
Complete remission 
(CR) 
Bone marrow blasts < 5 percent; absence of blasts with Auer rods; 
absence of extramedullary disease; ANC > 1000/μL; platelet count > 
100,000/μL; independence of red cell transfusions 
Complete remission with 
incomplete hematologic 
recovery (CRi) 
All CR criteria except for residual thrombocytopenia (platelet counts < 
100,000/μL) and neutropenia (ANC < 1000/uL) 
Complete remission with 
partial hematologic 
recovery (CRp)* 
Bone marrow blasts < 5 percent; absence of blasts with Auer rods; 
absence of extramedullary disease; ANC > 500/μL; platelet count > 
50,000/μL; independence of red cell transfusions 
Morphologic leukemic-
free state 
Bone marrow blasts < 5 percent; absence of blasts with Auer rods; 
absence of extramedullary disease; no hematologic recovery required 
Partial remission (PR) 
Relevant in the setting of phase I and II clinical trials only; all 
hematologic criteria of CR; decrease of bone marrow blast percentage 
to 5 to 25 percent; and decrease of pretreatment bone marrow blast 
percentage by at least 50 percent 
Cytogenetic remission  
Reversion to a normal karyotype at the time of morphologic CR (or 
CRi) in cases with an abnormal karyotype at the time of diagnosis; 
based on the evaluation of 20 metaphase cells from bone marrow 
Molecular remission  
No standard definition; depends on molecular target 
Resistant disease  
Failure to achieve CR or CRi (general practice; Phase 2/3 trials), or 
failure to achieve CR, CRi or PR (Phase 1 trials); only includes 
subjects surviving ≥ 7 days following completion of initial treatment, 
with evidence of persistent leukemia by blood and/or bone marrow 
examination 
Death in aplasia  
Deaths occurring ≥ 7 days following completion of initial treatment 
while cytopenic; with an aplastic or hypoplastic bone marrow obtained 
within 7 days of death, without evidence of persistent leukemia 
Death from 
indeterminate cause 
Deaths occurring before completion of therapy, or < 7 days following 
its completion; or deaths occurring ≥ 7 days following completion of 
initial therapy with no blasts in the blood, but no bone marrow 
examination available 
Relapse  
Bone marrow blasts ≥ 5 percent; or reappearance of blasts in the 
blood; or development of extramedullary disease 
Stable disease  
Failure to achieve a response and not meeting the criteria for disease 
progression 

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Disease progression  
For subjects with 5% to 70% bone marrow blasts at the last 
assessment (including the pretreatment assessment prior to study 
entry): 
- a > 50% increase in bone marrow blast count percentage from the 
last bone marrow blast count to ≥ 20% that persists for at least 2 bone 
marrow assessments separated by at least 1 month. 
For subjects with ≥ 70% bone marrow blasts at the last assessment: 
- a doubling of the nadir absolute peripheral blood blast count that 
persists for at least 1 month and the final absolute peripheral blood 
blast count is > 10 × 109/L. 
 
The date of progressive disease is defined as the first date that there 
was either a > 50% increase in bone marrow blast count from the last 
assessment for subjects with 5 to 70% bone marrow blasts or a 
doubling of the peripheral blood blast count to > 10 × 109/L for subjects 
with ≥ 70% bone marrow blasts. 
 
 
 
 

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Appendix F. Pill Diary 
Glasdegib ______ mg 
Instructions: 
• 
Do not take Glasdegib on the same day as CPX-351 infusion. 
• 
Take by mouth in the morning, with 8 ounces of water.  
• 
Take with or without food.  Swallow the tablet whole.  
• 
Do not chew or crush the tablet before swallowing.  
• 
If you forget to take your dose at the regular time, and LESS than 10 hours have passed since 
the dosing time, take the dose as soon as possible. If MORE than 10 hours have passed since 
the dosing time, skip the dose and continue on your normal dose schedule the next day.  
• 
If you miss a dose, do NOT make it up by taking an extra tablet. If you vomit at any time after 
you have taken your study pill, do NOT make it up by taking an extra tablet. 
Date (MM/DD/YY) 
Time pills 
taken  
Number 
of 
glasdegib 
pills 
taken 
Use the space below to make notes about things you 
would like to tell the doctor (including unusual 
symptoms you experience, other medicine you have 
taken and anything else you think would be of 
interest.  
Example: 
5/22/2020 
 
9:20 AM 
 
1 
 
First dose today, taken with breakfast and glass of water.  
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Additional space for comments: 
 
When completed, please sign below: 
 
 
Patient Signature: ________________________ Date: ____/_____/_____  
 
 
Site Staff Signature: _______________________Date: ____/_____/_____ 
 
 

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Appendix G. Eligibility Checklist 
 
Study Title: Phase II study of the combination of Glasdegib and CPX-351 in previously 
untreated patients with Acute Myelogenous Leukemia with MDS related changes or 
therapy-related Acute myeloid leukemia 
 
Patients Initials: _______________ 
SID: ______________ 
DOB:_____________ 
 
 
 
Inclusion Criteria 
Yes 
No 
1 
Previously untreated therapy-related AML or AML with 
myelodysplastic related changes as described by WHO 
2016  
 
a. AML arising in MDS (including CMML) or MDS/MPN 
syndrome 
b. AML with MDS-related cytogenetic abnormalities 
(Appendix A) (metaphase FISH allowable as surrogate for 
cytogenetics) 
c. AML with multilineage dysplasia involving the presence 
of 50% or more dysplastic cells in at least two cell lines and 
in the absence of mutation in NPM1 or biallelic CEBPA (as 
per WHO 2016).  
  
  
2 
Adults 18 years of age or older 
  
  
3 
ECOG performance status 0 to 2 
  
  
4 
Adequate organ function as defined as:  
 
1. Left Ventricular Ejection Fraction (LVEF) > 50% 
2. Serum total bilirubin < 2.0 mg/dL, unless considered due 
to Gilbert's disease or leukemic involvement 
3. AST, ALT and alkaline phosphatase < 3 times the upper 
limit of normal, unless considered due to leukemic 
involvement 
4. Serum creatinine < 2.0 mg/dL, or creatinine clearance > 
40 mL/min based on Cockcroft-Gault GFR 
  
  
5 
Absence of unstable cardiac disease defined as 
myocardial infarction within 6 months, uncontrolled heart 
failure, or uncontrolled cardiac arrhythmia 
  
  
6 
Ability to understand and the willingness to sign a written 
informed consent or subject’s legally authorized 
representative (LAR) has provided informed consent prior 
to any study-specific activities/procedures being initiated 
when the subject has any kind of condition that, in the 
opinion of the investigator, may compromise the ability of 
the subject to give written informed consent 
  
  

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7 
Women of child-bearing potential and men with partners of 
child-bearing potential must agree to use 2 methods of 
birth control or be surgically sterile, or abstain from 
heterosexual activity for the course of the study through 
120 days after the last dose of study medication 
 
A woman of child-bearing potential is any female 
(regardless of sexual orientation, having undergone a tubal 
ligation, or remaining celibate by choice) who meets the 
following criteria:  
• Has not undergone a hysterectomy or bilateral 
oophorectomy; or  
• Has not been naturally postmenopausal for at least 12 
consecutive months (i.e., has had menses at any time in 
the preceding 12 consecutive months)  
• Women of child-bearing potential has negative pregnancy 
test within 72 hours of initiating study drug dosing.  
• Male subjects must agree to use a latex condom during 
sexual contact with females of childbearing potential even 
if they have had a successful vasectomy starting with the 
first dose of study therapy through 120 days after the last 
dose of study therapy 
  
  
8 
Leukapheresis, corticosteroid and hydroxyurea are 
permitted as initial management of hyperleukocytosis at 
the investigator’s discretion for up to 7 days after starting 
study therapy. Hyperleukocytosis is defined as greater than 
30k WBC. When possible, a bone marrow biopsy for 
screening should be performed prior to the initiation 
hyperleukocytosis management 
  
  
Exclusion Criteria 
Yes 
No 
1 
Prior treatment with Glasdegib or CPX-351 
  
  
2 
Previously treated AML except for initial management of 
hyperleukocytosis. Treatment with hypomethylating therapy 
for MDS is allowable but not since their diagnosis of AML. 
No prior treatment with cytarabine or daunorubicin are 
allowed 
  
  
3 
Concurrent FLT3 mutation that the treating physician 
deems necessary to treat with midostaurin, whereas 
patients with FLT3-mutated AML not treated with 
midostaurin can be enrolled. Patients with known Core 
Binding Factor –t(8;21), inv(16), t(16;16) are allowed for 
study participation at the treating investigator's discretion 
  
  
4 
Active CNS or testicular involvement by leukemia; 
diagnostic lumbar puncture is not required 
  
  
5 
History of neurologic disorder including but not limited to: 
prior seizure, epilepsy, structural brain abnormality, benign 
brain tumor, stroke, brain injuries, dementia, movement 
disorder or other significant CNS abnormalities  
  
  

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6 
Baseline QT corrected interval based on Fridericia’s 
formula (QTcF) interval > 450 ms  
 
 
7 
Acute coronary syndrome in the past 12 months, NYHA 
class III or VI 
 
 
8 
Known history of Wilson’s disease or other copper handling 
disorder 
 
 
9 
History of GI malabsorptive disease 
 
 
10 
Has a known additional malignancy that is progressing or 
requires active treatment. Exceptions include basal cell 
carcinoma of the skin, squamous cell carcinoma of the 
skin, or in situ cervical cancer that has undergone 
potentially curative therapy 
  
  
11 
Known HIV infection 
  
  
12 
Active hepatitis B or hepatitis C infection (patients who 
successfully completed curative hepatitis C therapy can be 
enrolled) 
  
  
13 
Any uncontrolled infection, active bacterial or viral infection 
manifesting as fevers or hemodynamic instability within the 
past 72 hours 
  
  
14 
Proven active invasive fungal infection 
  
  
15 
Is pregnant or breastfeeding, or expecting to conceive or 
father children within the projected duration of the trial, 
starting with the pre-screening or screening visit through 
120 days after the last dose of trial treatment 
  
  
16 
Severe or uncontrolled medical disorder that would, in the 
investigator’s opinion, impair ability to receive study 
treatment (i.e., uncontrolled diabetes, chronic renal 
disease, chronic pulmonary disease or active, uncontrolled 
infection, psychiatric illness/social situations that would limit 
compliance with study requirements 
  
  
17 
Current or anticipated use of other investigational agents  
  
  
18 
For patients with prior anthracycline exposure, the 
cumulative life-time dose should not exceed 386mg/m2 at 
the time of study entry (to convert different anthracycline to 
daunorubicin-equivalent, see Appendix H for conversion 
factors) 
 
 
 
 
 
Investigator Signature: ______________________________________ Date: ____________  
 
 
 
Coordinator Signature: ______________________________________ Date: ____________ 
 
 
 

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Supervisor Signature: _______________________________________ Date: ____________ 
 
 

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Appendix H: Anthracyclines Equivalent Guidelinesa 
 
Drug 
Conversion 
factorb 
Daunorubicin 
1 
Doxorubicin 
2 
Epirubicin 
1 
Idarubicin 
4 
Mitoxantrone 
4.4 
aAdapted from Keefe D, et al. Anthracycline-induced cardiomyopathy. Seminars in Oncology. 
2001;28(4 Suppl 12):2-7. 
bTo calculate the equivalent dose of daunorubicin, the total cumulative dose of anthracycline 
was multiplied by the conversion factor.