Conditions: Leukemia, Myeloid, Acute
Keywords: FLT3
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 1
Healthy volunteers: no

Brief summary:
This is a research study to be done at multiple sites in participants with advanced acute myeloid leukemia (AML) that have a mutation in Fms-like tyrosine kinase-3 internal tandem duplications (FLT3-ITD). This study is to learn more about an investigational drug, quizartinib, being tested with the anti-cancer medicine CPX-351 (also called Vyxeos™), which is approved and widely used to treat AML.

The purpose of this study is to assess the safety, tolerability and survival of patients receiving the combination of CPX-351 and quizartinib.

Detailed description:
This is an open-label, two-part Phase II clinical trial in patients with relapsed or refractory FLT3-ITD mutation-positive acute myeloid leukemia (AML). The study is designed to assess the safety and tolerability as well as the efficacy of administering CPX-351 (cytarabine:daunorubicin liposome complex) with quizartinib. CPX-351 is a formulation of two drugs, cytarabine and daunorubicin, that is administered as the first part of treatment to get rid of as many leukemia cells in your bone marrow as possible. Quizartinib is an investigational drug made of a protein that inhibits FLT3 and will be given after CPX-351 has been given. The plan for administration is divided into three phases: induction, consolidation, and maintenance.

Arms:
arm 1: Participants with FLT3 mutation positive AML will be given CPX-351 followed by quizartinib in three phases: induction, consolidation, and maintenance.

Interventions: intervention 1: CPX-351 intervention 2: Quizartinib
Intervention descriptions: intervention 1: Given during the induction and consildation phase and will consist of 44 mg/m\^2 daunorubicin with 100 mg/m\^2 cytarabine administered intravenously on Days 1, 3, and 5 during induction phase and Days 1 and 3 of consolidation phase. intervention 2: Given during induction, consolidation, and maintenance phases and will be taken orally at a dose of 30mg on Days 8-21 of induction phase, Days 6-21 of consolidation phase, and daily in maintenance phase.

Protocol document:
Prot_SAP_000.pdf: 
 
CONFIDENTIAL 
This document is confidential and is the property of Sarah Cannon Development Innovations, LLC.  No part of this 
document may be transmitted, reproduced, published, or used by other persons without prior written authorization 
from Sarah Cannon Development Innovations, LLC. 
 
AML 48 
A Phase II Study Assessing CPX-351 (Vyxeos™) with Quizartinib for the 
Treatment of Relapsed or Refractory FLT3-ITD Mutation-Positive AML 
 
DEVELOPMENT INNOVATIONS STUDY 
NUMBER: 
AML 48 
STUDY DRUG: 
Quizartinib 
SPONSOR: 
Sarah Cannon Development Innovations, LLC 
1100 Dr. Martin L. King Jr. Blvd 
Suite 800 
Nashville, TN 37203 
844-710-6157 
CANN.SCRIInnovationsEnr@scri-innovations.com 
STUDY CHAIR: 
Michael Tees, MD, MPH 
Oncologist 
Colorado Blood Cancer Institute 
1721 E. 19th Avenue 
Suite 300 
Denver, CO 80218 
720-754-4800 Office 
DATE FINAL: 
11 March 2019 
AMENDMENT NUMBER: 
1 
AMENDMENT DATE:      
08 October 2019 
AMENDMENT NUMBER: 
2 
AMENDMENT DATE:      
20 November 2019 
AMENDMENT NUMBER: 
3 
AMENDMENT DATE:      
 10 August 2020 


 
 
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 DEVELOPMENT INNOVATIONS STUDY NUMBER: AML 48 
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Clinical Study Statement of Compliance 
AML 48 
A Phase II Study Assessing CPX-351 (Vyxeos™) with Quizartinib for the 
Treatment of Relapsed or Refractory FLT3-ITD Mutation-Positive AML 
 
 
This clinical study shall be conducted in compliance with the protocol, as referenced herein, 
and all applicable local, national, and international regulatory requirements to include, but 
not be limited to: 
• 
International Council for Harmonisation (ICH) Guidelines on Good Clinical 
Practice (GCP) 
• 
Ethical principles that have their origins in the Declaration of Helsinki 
• 
Food and Drug Administration (FDA) Code of Federal Regulation (CFR): 
o 
Title 21CFR Part 50 & 45 CFR Part 46, Protection of Human Subjects 
o 
Title 21CFR Part 54, Financial Disclosure by Clinical Investigators 
o 
Title 21CFR Part 56, Institutional Review Boards (IRBs) 
o 
Title 21CFR Part 312, Investigational New Drug Application 
o 
Title 45 CFR Parts 160, 162, and 164, Health Insurance Portability and 
Accountability Act (HIPAA) 
 
As the Study Chair and/or Principal Investigator, I understand that my signature on the 
protocol constitutes my agreement and understanding of my responsibilities to conduct the 
clinical study in accordance with the protocol and applicable regulations.  Furthermore, it 
constitutes my understanding and agreement that any changes initiated by myself, without 
prior agreement in writing from the Sponsor, shall be defined as a deviation from the 
protocol, and shall be formally documented as such. 


 
 
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Clinical Study Protocol Approval Page 
A Phase II Study Assessing CPX-351 (Vyxeos™) with Quizartinib for the 
Treatment of Relapsed or Refractory FLT3-ITD Mutation-Positive AML 
 
DEVELOPMENT INNOVATIONS STUDY 
NUMBER: 
AML 48 
STUDY DRUG: 
Quizartinib 
DATE FINAL: 
11 March 2019 
AMENDMENT 1 
8 October 2019 
AMENDMENT 2 
20 November 2019 
AMENDMENT 3 
10 August 2020 
 
 
Michael Tees, MD, MPH_______ 
__________________________         ______________ 
Study Chair 
Oncologist 
Colorado Blood Cancer Institute 
1721 E. 19th Avenue 
Suite 300 
Denver, CO 80218 
720-754-4800 Office 
Study Chair Signature 
 
Date 
 
 
 
 
 
Marcy Vallone                    __ 
__________________________         _____________ 
Sarah Cannon Development 
Innovations, LLC 
President 
Sarah Cannon Development Innovations 
 
Sarah Cannon Development Innovations, 
LLC Representative Signature 
 
Date 
 
 
 


 
 
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 DEVELOPMENT INNOVATIONS STUDY NUMBER: AML 48 
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Clinical Study Principal Investigator Signature Form 
A Phase II Study Assessing CPX-351 (Vyxeos™) with Quizartinib for the 
Treatment of Relapsed or Refractory FLT3-ITD Mutation-Positive AML 
 
DEVELOPMENT INNOVATIONS STUDY 
NUMBER: 
AML 48 
STUDY DRUG: 
Quizartinib 
DATE FINAL: 
11 March 2019 
AMENDMENT 1 
8 October 2019 
AMENDMENT 2 
20 November 2019 
AMENDMENT 3 
10 August 2020 
 
By signing this protocol acceptance page, I confirm I have read, understand, and agree to conduct the 
study in accordance with the current protocol. 
 
 
 
___________________________            _______________________________     _______  
Principal Investigator Name 
(Please Print) 
 
Principal Investigator Signature 
 
Date 
 
Please retain a copy of this page for your study files and return the original signed and dated 
form to: 
 
Sarah Cannon Development Innovations, LLC 
1100 Dr. Martin L. King Jr. Blvd., Suite 800 
Attention:  AML 48 Study Team 
Nashville, TN 37203 
 


 
 
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 DEVELOPMENT INNOVATIONS STUDY NUMBER: AML 48 
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AML 48 CONTACT INFORMATION 
Development Innovations Contact 
Address and Phone#: 
Sarah Cannon Development Innovations 
1100 Dr. Martin L. King Jr. Blvd. 
Suite 800 
Nashville, TN 37203 
844-710-6157 
CANN.SCRIInnovationsEnr@scri-innovations.com 
 
Study Chair: 
Michael Tees, MD, MPH 
Hematologist/Oncologist 
Colorado Blood Cancer Institute 
1721 E. 19th Avenue 
Suite 300 
Denver, CO 80218 
720-754-4800 Office 
Michael.Tees@HealthONECares.com 
 
Safety Department Fax #: 
Safety Department Email: 
1-866-807-4325 
CANN.SAE@SCRI-Innovations.com 
Medical Support Center Phone #: 
Regulatory Department Email: 
844-710-6157 
CANN.InnovationsMedical@sarahcannon.com 
Development Innovations 
Enrollment Fax #: 
Development Innovations 
Enrollment Email: 
866-346-1062 or 615-524-4012 
CANN.SCRIInnovationsEnr@scri-innovations.com 
 


 
 
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AML 48 AMENDMENT SUMMARY OF CHANGES 
AMENDMENT NUMBER: 
3 
AMENDMENT DATE:  10 August 2020      
Additions are noted by bolding. Deletions are noted by cross outs.  Only the parts of sections with 
changes are presented.  Please note that formatting changes and minor changes to punctuation, spelling, 
and abbreviations that do not affect meaning are not noted in this summary.  
Global Changes 
• 
Throughout the document “Sarah Cannon Development Innovations” is now abbreviated as 
“Sarah Cannon Development Innovations” 
• 
Sarah Cannon Development innovations address has been updated to 1100 Dr. Martin L.uther 
King Jr. Blvd 
• 
Throughout the study the time hematologic toxicities have for count recovery 56 42 days  
Protocol Synopsis-Study Drug and Mode of Administration: 
• 
The following statements have been added: 
o Any patient with neutropenia or thrombocytopenia lasting ≥56 days from 
the initiation of CPX-351 will not receive consolidation and will instead 
proceed to the maintenance phase. 
o The maintenance phase is a 28-day cycle beginning 7 days (± 7) after neutrophil 
recovery (ANC >1000/µL) from the consolidation phase or induction phase  
Protocol Synopsis-Inclusion Criteria: 
• 
Several erroneous “?” symbols were removed and replaced with “≤” 
Protocol-Synopsis Exclusion Criteria: 
• 
The following statement has been revised to include contraception exclusion criteria “Female 
patients who are lactating or have a positive serum pregnancy test during the screening period.  
Female patients of childbearing potential who are not willing to employ highly effective 
birth control (as defined in Appendix C) from screening to 6 months following the last dose 
of CPX-351 and/or quizartinib.” 
• 
The following statement has been added to include male reproductive exclusion criteria Fertile 
male patients, defined as all males physiologically capable of conceiving offspring, with 
female partners of childbearing potential must use condoms plus a spermicidal agent 
during the study treatment period and for 6 months following their last dose of CPX-351 
and/or quizartinib, and must not father a child during this period.  (Refer to Appendix C)  
• 
“QTcF interval using Fridericia’s correction factor (QTcF) interval prolongation, defined as >450 
msec at screening and day 8 prior to first administration of quizartinib.” 
• 
The following sentence has been added “Any patients with known significant impairment in 
gastrointestinal (GI) function or GI disease that may significantly alter the absorption of 
quizartinib.”  The following redundant statement has been removed “Any patients with known 
significant impairment in gastrointestinal function or gastrointestinal disease that may 
significantly alter the absorption of quizartinib.” 


 
 
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• 
“Patients with inadequate adequate pulmonary function will be excluded.  Inadequate 
pulmonary function is defined as requiring (no supplemental O2, or diffusing capacity of the 
lungs for carbon monoxide [DLCO] <40%)” 
Section 1.5 Risks and Benefits 
• 
In early phase studies, quizartinib has been associated with Grade 2 or higher QTc Fridericia’s 
correction factor (QTcF) prolongation (11%) (Hills et al 2015).  Quizartinib has been associate 
with QT prolongation in a dose dependent manner.  In study AC220-007 (Quantum-R) in 
the relapse/refractory FLT3+ AML population, Eight (3.3%) subjects in the quizartinib 
arm had ECG QTcF values >500 ms (Grade 3 QTcF) by central ECG reading.  
(Quizartinib Investigator Brochure 2020 
Section 2.3.1 Primary Endpoints 
• 
“Complete remission (CR) defined as a complete morphologic response with complete blood 
count recovery ANC > ≥1000/µL and/or platelet count > ≥100,000/µL), 
Section 3.2 Exclusion Criteria 
• 
The following statement has been revised to include contraception exclusion criteria “Female 
patients who are lactating or have a positive serum pregnancy test during the screening period.  
Female patients of childbearing potential who are not willing to employ highly effective 
birth control (as defined in Appendix C) from screening to 6 months following the last dose 
of CPX-351 and/or quizartinib.” 
• 
The following statement has been added to include male reproductive exclusion criteria Fertile 
male patients, defined as all males physiologically capable of conceiving offspring, with 
female partners of childbearing potential must use condoms plus a spermicidal agent 
during the study treatment period and for 6 months following their last dose of CPX-351 
and/or quizartinib, and must not father a child during this period.  (Refer to Appendix C)  
• 
“QTcF interval using Fridericia’s correction factor (QTcF) interval prolongation, defined as >450 
msec at screening and day 8 prior to first administration of quizartinib.” 
• 
 “Patients with inadequate adequate pulmonary function will be excluded.  Inadequate 
pulmonary function is defined as requiring (no supplemental O2, or diffusing capacity of the 
lungs for carbon monoxide [DLCO] <40%)” 
Section 3.3 Discontinuation from Study Treatment 
• 
Pregnancy and breastfeeding 
• 
After discontinuation from protocol treatment, patients must be followed for adverse events 
(AEs) for 30 days after their last dose of study drug.  All new AEs occurring during this period 
must be reported and followed at the site until resolution for AEs attributed to the study 
medication(s)., unless, in the opinion of the Investigator, these values are not likely to improve 
because of the underlying disease.  In this case, the Investigator must record his or her reasoning 
for this decision in the patients’ medical records. 
All patients who have Grade 3 or 4 laboratory abnormalities (per National Cancer Institute [NCI] 
Common Terminology Criteria for Adverse Events [CTCAE] Version 5.0) at the time of 
discontinuation must be followed until the laboratory values have returned to Grade 1 or 2, unless 
it is, in the opinion of the Investigator, not likely that these values will improve.  In this case, the 


 
 
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Investigator must record his or her reasoning for making this decision in the patients’ medical 
records. 
Section 5 Study Design  
• 
A total of 10 patients will be enrolled in the safety lead-in.  The safety lead-in portion of the study 
is designated as Part 1. If the first 10 patients meet the pre-specified safety parameters, an 
additional 24 patients will be enrolled in Part 2 of the study If >3 patients experience delayed 
neutrophil count recovery >56 days from the first day on the study regimen, or delayed 
thrombocytopenia recovery >56 days from the first day on the study regimen, or if >3 
patients develop a non-hematologic toxicity, defined as a Grade 4 non-hematologic adverse 
event determined to be probably related to the combined treatment, or a Grade 4 
neutropenia, then the study will be terminated.  Assuming safety parameters are met, the 
first 10 patients will be followed for response in the Part 2 of the study.  If the first 10 patients 
meet the pre-specified safety parameters, An additional 24 patients will be enrolled in Part 2 of 
the study (induction, consolidation, and maintenance).  All patients will be assessed for response. 
• 
Patients who experience an AE that results in the discontinuation of study treatment will be 
followed until resolution/stabilization for AEs attributed to the medication.  resolution of the 
AE.  Outcomes for all patients will be assessed for 24 months from the start of study treatment 
date of last treatment.   
• 
The study schema and study schema footnotes have been updated for clarity. 
Section 5.2.4 Maintenance Phase 
• 
The maintenance phase consists of 28-day cycles.  Patients will receive quizartinib once daily for 
a total of 24 cycles or until disease relapse.  Maintenance dosing of quizartinib will begin at 30 
mg PO once daily on Days 1-14, and if there are no non-hematologic Grade ≥3 toxicities and 
QTcF is maintained ≤450 msec, the quizartinib dose will increase to 60 mg/day on Day 15.  If 
consolidation therapy is not advised at all or if only 1 cycle of consolidation is advised based on 
prolonged toxicities, maintenance therapy will begin 7 days (±7) after neutrophil recovery (ANC 
>1000/µL) from the consolidation phase or induction phase.  Patients will receive quizartinib 
once daily for a total of 24 cycles or until disease relapse.  
• 
Patients who proceed to alloHCT or other CT intervention after consolidation will resume 
quizartinib maintenance no earlier than Day 30 from the intervention or transplant.  For a total 
of 24 cycles or until disease relapse.  In patients who proceed to alloHCT, initiation of quizartinib 
maintenance should begin no earlier than Day 30 after transplant.  If ≥2 CT interventions (e.g., 
repeat DLI) are planned after maintenance, a 28-day hold is acceptable, with resumption of 
quizartinib with the next cycle.  If the patient is on quizartinib prior to HCT or CT 
intervention, quizartinib should be discontinued 7 days prior if a conditioning therapy is 
utilized.  If proceeding to a CT intervention without conditioning therapy (e.g., DLI), 
quizartinib should be discontinued one day prior to CT intervention. 
Section 5.3.2 Prohibited Concomitant Medications 
• 
Links to Appendix F and Appendix I have been added, an erroneous link to Appendix H has 
been removed.  
Section 6.2 Baseline Study Assessments 


 
 
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• 
12-lead ECGs need to be completed pre-dose and 5 minutes apart, if QTcF prolongation is 
identified assess electrolyte levels (including potassium and magnesium) as clinically 
indicated. 
Section 6.4.1 Induction Phase 
• 
Serum pregnancy test once per cycle during the induction phase  
Section 6.4.1.1 Cycle 1, Days 1, 3 and 5 
• 
Physical examination and vital signs (Days 3 and 5) 
• 
ECOG performance status (Days 3 and 5) 
• 
Removed duplicative statement: Confirmation and/or placement of central venous catheter or 
peripherally inserted central catheter  
Section 6.4.1.4 Cycle 1 Day 21 (Response assessment) 
• 
ECG  
Section 6.4.1.6 Cycle 2, Days 1 and 3 (re-induction, only applicable if patient achieves PR with recovery 
bone marrow after Cycle 1) 
• 
Physical examination and vital signs (Days 3 and 5) 
• 
ECOG performance status (Days 3 and 5) 
Section 6.4.1.9 
• 
ECG  
Section 6.4.2 Consolidation Phase (If applicable) 
• 
Serum pregnancy test once per cycle during the consolidation phase 
Section 6.4.2.1 Cycle 1, Day 1 and 3 
• 
ECG (Day 3) 
Section 6.4.2.3 Cycle 1 Days 14 and 21 
• 
ECG 
Section 6.4.2.4 Cycle 1 Day 35 (±7 days) (BM recovery) 
• 
Update of medical history 
Section 6.4.2.5 Cycle 2, Days 1 and 3 (if applicable) 
• 
ECG (Day 3) 
Section 6.4.2.7 Cycle 2 Days 14 and 21 
• 
ECG 
Section 6.4.4 Maintenance Phase 
• 
Serum pregnancy test once every 3 cycles during the maintenance phase 
Section 6.4.4.1 Cycles 1-24, Days 1 and 15 


 
 
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• 
ECG and QTcF assessment (if QTcF ≤470 msec, continue quizartinib; if QTcF >470 msec, see 
Appendix F) (Day 1 only) 
Section 6.4.6 Long-Term Follow-up 
• 
“Underlying dDisease response assessment per ASBMT/CIBMTR disease classification” 
Section 6.5.3 12-Lead Electrocardiogram 
• 
“If QTcF prolongation develops from the time of initial screening to the day of quizartinib 
administration (i.e. Day +8 of induction), concomitant medications and electrolytes should 
be assessed for a reversible cause.  ECGs may be repeated daily for up to 3 days from the 
original start date to assess for correction and to meet the eligibility criteria to administer 
quizartinib (see Section 3.2).” 
Section 6.5.5 Pregnancy Testing 
• 
Serum Pregnancy tests are also required prior to the start of each cycle during the 
induction and consolidation phases, during maintenance phase a serum pregnancy 
test will obtained once every 3 cycles.   
Section 6.5.12 Minimal Residual Disease Assessment 
• 
MRD analysis of FLT3-ITD mutations will occur with all recovery marrows with 
induction and consolidation cycles (if applicable) Day+ 2835 (+/- 7 days) post-cellular 
therapy intervention (if applicable), as well as with bone marrow biopsies obtained 
during the maintenance phase.  To monitor for molecular recurrence of disease, BM 
biopsies and aspirates will be collected at Day 24 (+/- 3 days) Cycles 3, 6, 12, and 24 
during the maintenance phase.  
Section 7.2 Quizartinib Treatment Duration  
• 
Prior to initiation (≤24 hour) an ECGs in triplicate will be obtained to assess QTcF. 
Section 7.5.1 Precautions and Risks Associated with Quizartinib 
• 
“QTc Prolongation, Torsades de Pointes” has been revised to refect an updated  IB. 
• 
Additionally in greater than 10% of patients infection, decreased appetite, abdominal pain, 
painful swelling, sores in the mouth, rash, asthenia or fatigue, pyrexia, peripheral edema, 
abnormal hepatic function, mineral deficiency, enzyme deficiency, anemia, and weight loss 
were reported. 
• 
Differentiation Syndrome has been added as a risk associated with Quizartinib. 
Section 7.5.2 Precautions and Risks Associated with  CPX-351 
• 
Because of the potential for serious adverse reactions in breastfed infants, advise lactating women 
not to breastfeed during treatment with CPX-351. and for at least 2 weeks after the last dose 
Section 8.1, Table 2 and Table 3 
• 
For AE toxicity management with concomitant strong CYP3A4 inhibitor, the dose of 
quizartinib will not be reduced lower than 20 mg/day refer to Table 2 for more 
information). 


 
 
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• 
The title to table 2 has been updated to state “Induction and Consolidation Phase’ Footnotes in 
Table 2 and Table 3 have been corrected to link to the appropriate reference. 
Section 8.2.1 Criteria and Procedures for Dose Modifications due to QTcF prolongation 
• 
“Electrolytes (potassium, calcium, and magnesium) should be checked and supplementation 
given to correct any values outside the normal range.”   
• 
The following text has been added 
o “In addition, hypomagnesemia and hypokalemia abnormalities can affect the QT 
interval.  Upon identification of QTcF prolongation, it is advised to assess the 
subject’s electrolytes (including potassium and magnesium) and manage per local 
institutional standards.” 
o  “If QTcF is > 450, evaluation of concomitant medications are advised as well as a 
magnesium level is advised to assess for potential etiologies.  Repeating ECGs daily 
for up to 3 days can occur to determine if the QTcF improves to allow 
administration of quizartinib.” 
Section 8.3.1 Criteria and Procedures for Dose Interruptions and Adjustments of CPX-351 
• 
Criteria and Procedures for Dose Interruptions and Adjustments of CPX-351 has been moved to 
Section 8.3.1 for readability. 
Section 9.1 Complete Response (CR) 
• 
Patients with a CR but with residual MRD positivity (CR MRD+) are classified as 
indicated. 
Section 9.7 Event-free Survival (EFS) 
• 
The following sentence has been added “This calculation does not pertain to Long Term 
Follow-up data.” 
Section 10.5.1 Safety Review 
• 
If > ≥3 patients experience delayed neutrophil count recovery >56 days from the first day 
receiving the study regimen, defined as having a peripheral blood ANC <500/µL without 
evidence of residual disease by BM biopsy, or if > ≥3 patients develop a non-hematologic 
toxicity, defined as a Grade 4 non-hematologic AE determined to be probably related to 
the combined treatment, then the study will be terminated 
References  
• 
Sexauer A, Perl A, Yang X, Borowitz M, Gocke C, Trivikram R, et al. Terminal myeloid 
differentiation in vivo is induced by FLT3 inhibition in FLT3/ITD AML. Blood. 
2012;120(20):4205-14. 
Appendix D Schedule of Assessments  
• 
Added the word ‘Day’ to the first row of the table for readability 
• 
Clarified assessment: Physical examination, height (screening only), and weight.   
• 
The assessment ‘TTE or MUGA scan’ has been updated to remove the Day 1 of consolidation 
phase assessment.   


 
 
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• 
Serum pregnancy tests have been added to start of each cycle during the induction and 
consolidation phases, during maintenance phase a serum pregnancy test will obtained once every 
3 cycles. 
o Footnote ‘J’ has been revised to include: “Serum Pregnancy tests are also required 
prior to the start of each cycle during the induction and consolidation phases, 
during maintenance phase a serum pregnancy test will obtained once every 3 
cycles.”   
• 
Footnote ‘D’ has been revised to include the following: “If the patient is on quizartinib prior to 
HCT or CT intervention, quizartinib should be discontinued 7 days prior if a conditioning 
therapy is utilized” 
Appendix F Management of Quizartinib-Associated Adverse Events 
• 
Addition of additional instructions for Grade 2 QTcF prolongation: “Following dose reduction, 
the quizartinib/placebo dose may be resumed at the previous level in the next cycle if the 
QTcF has decreased to within 30 msec of baseline or <450 msec but subject must be 
monitored closely for QT prolongation for the first cycle at the increased dose.” 
• 
Differentiation Syndrome management instructions have been added. 


 
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AML 48 PROTOCOL SYNOPSIS 
Title of Study: 
A Phase II Study Assessing CPX-351 (Vyxeos™) with Quizartinib for the Treatment of 
Relapsed or Refractory FLT3-ITD Mutation-Positive AML 
Development 
Innovations Study 
Number: 
AML 48 
Sponsor: 
Sarah Cannon Development Innovations, LLC 
Study Duration: 
The total duration of the study is planned to be 
approximately 4 years. 
Phase of Study:  II 
Number of Study 
Centers: 
This study will be conducted at approximately 5 sites in the United States. 
Number of Patients: 
Approximately 34 patients are planned to be enrolled in this study. 
Objectives: 
Primary Objectives 
The primary objectives of this study are to: 
• 
Determine the safety and tolerability of CPX-351 (cytarabine:daunorubicin liposome 
complex) with quizartinib in patients with relapsed or refractory fms-like tyrosine 
kinase 3 (FLT3)-internal tandem duplication (ITD) mutation-positive acute myeloid 
leukemia (AML). 
• 
Determine the overall complete morphologic (per World Health Organization) and 
molecular remission rate of CPX-351 and quizartinib in patients with relapsed or 
refractory FLT3-ITD mutation-positive AML. 
Secondary Objectives 
The secondary objectives of this study are to: 
• 
Define the time to absolute neutrophil count and platelet count recovery  
• 
Define the number of patients proceeding to an allogeneic stem cell transplant 
(alloHCT) 
• 
Determine time to disease progression or duration of response  
• 
Determine event-free survival  
• 
Determine overall survival  
• 
Define the percentage of patients who develop late responses 
• 
Define the number of patients who can receive consolidation and maintenance 
therapy on this study 
• 
Define the treatment-related mortality rate of this combination 
• 
Determine the percentage of patients who achieve a PR or molecular complete 
remission (CR) 
• 
Determine the mean elapsed time for patients to achieve molecular CR 
• 
Determine whether quizartinib is tolerable after alloHCT or donor lymphocyte 
infusion. 
Study Design: 
This is a multi-center, non-randomized, open-label, two-part prospective Phase II clinical 
trial in patients with relapsed or refractory FLT3-ITD mutation-positive AML.  The study 
is designed to assess the safety and tolerability as well as the efficacy of administering 
CPX-351 (cytarabine:daunorubicin liposome complex) with quizartinib, a second-
generation FLT3 inhibitor.  The plan for administration is divided into three phases: 
induction, consolidation, and maintenance.  Approximately 34 patients are planned to be 
screened and enrolled.   


 
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A total of 10 patients will be enrolled in the safety lead-in, which is designated as Part 1 of 
the study.  If ≥8 patients meet the pre-specified safety parameters, an additional 24patients 
will be enrolled in Part 2 of the study.  All patients will be assessed for response. 
Study Drug, Dose, 
and Mode of 
Administration: 
Induction phase: CPX-351 (daunorubicin 44 mg/m2 IV and cytarabine 100 mg/m2 IV) will 
be given on Days 1, 3, and 5 followed by 30 mg quizartinib by mouth (PO) once daily on 
Days 8-21.  Patients with an incomplete response, but a >50% reduction in the blast 
count/cellularity ratio compared to the most recent bone marrow (BM) biopsy prior to 
treatment, should receive one additional cycle of induction therapy (re-induction) with 
CPX-351 (daunorubicin 44 mg/m2 IV and cytarabine 100 mg/m2 IV) on Days 1 and 3 
only.  Re-induction will begin after a 72-hour washout period from the last dose of 
quizartinib.  During re-induction, treatment with quizartinib will resume on Day 6 and 
continue through Day 21.  Any patient with neutropenia or thrombocytopenia lasting ≥56 
days from the initiation of CPX-351 will not receive consolidation and will instead 
proceed to the maintenance phase. 
Consolidation phase: At the Investigator’s discretion, patients who achieve CR and do not 
proceed to an alloHCT or other CT intervention will proceed to the consolidation phase 
beginning 7 days (± 7) after neutrophil recovery (ANC >1000/µL).  Administer up to 2 
consolidation cycles of CPX-351 (daunorubicin 29 mg/m2 IV and cytarabine 65 mg/m2 
IV) on Days 1 and 3.  Begin quizartinib 30 mg PO once daily on Days 6-21. 
Maintenance phase: Maintenance dosing of quizartinib will begin at 30 mg/day on Days 1-
14, and if there are no non-hematologic Grade ≥3 toxicities, the quizartinib dose will 
increase to 60 mg/day on Day 15.  The maintenance phase is a 28-day cycle beginning 7 
days (± 7) after neutrophil recovery (ANC >1000/µL) from the consolidation phase or 
induction phase.  Patients will receive quizartinib once daily for a total of 24 cycles or 
until disease relapse 
Inclusion Criteria : 
1. Written informed consent form (ICF), according to local guidelines, signed by the 
patient or by a legal guardian prior to the performance of any study-related screening 
procedures 
2. Male and female patients between ≥18 and ˂80 years old 
3. Patients with the following types of AML with >5% blasts: 
- Relapsed FLT3-ITD mutation-positive AML, diagnosed by BM biopsy with 
FLT3 mutation by polymerase chain reaction (PCR) 
- Refractory FLT3-ITD mutation-positive AML, diagnosed by BM biopsy with 
FLT3 mutation by PCR 
- Relapsed or refractory FLT3-ITD mutation-positive AML after hematopoietic 
cell transplantation (HCT), diagnosed by BM biopsy with FLT3 mutation by 
PCR 
- Relapsed or refractory AML with de novo FLT3-ITD mutation, diagnosed by 
BM biopsy with FLT3 mutation by PCR 
- Relapsed or refractory AML after HCT with de novo FLT3-ITD mutation, 
diagnosed by BM biopsy with FLT3 mutation by PCR 
4. First-line therapy must have contained a standard induction chemotherapy (e.g., 7+3, 
FLAG-IDA, FLAG, CLAG, MEC, hypomethylating agent with venetoclax) with or 
without receiving a prior FLT3 inhibitor (e.g., midostaurin) or multi-tyrosine kinase 
inhibitor (e.g., sorafenib).  Patients who relapsed after an alloHCT are included, 
except patients with active graft-versus-host disease (GVHD) requiring >10 mg 
prednisone. 
5. Patients must be able to swallow and retain oral medication. 


 
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6. Eastern Cooperative Oncology Group (ECOG) Performance Status score of 0, 1, or 2 
(Appendix A) 
7. Adequate renal and hepatic parameters (aspartate aminotransferase [AST], alanine 
aminotransferase [ALT] ≤2.5 institutional upper limit of normal [ULN]; total 
bilirubin ≤2.0 institutional ULN; serum creatinine [Cr] ≤2.0). In patients with 
suspected liver infiltration, ALT can be ≤5 institutional ULN. 
Exclusion Criteria : 
1. Acute promyelocytic leukemia (t[15;17]) 
2. Female patients who are lactating or have a positive serum pregnancy test during the 
screening period.  Female patients of childbearing potential who are not willing to 
employ highly effective birth control (as defined in Appendix C) from screening to 6 
months following the last dose of CPX-351 and/or quizartinib. 
3. Fertile male patients, defined as all males physiologically capable of conceiving 
offspring, with female partners of childbearing potential must use condoms plus a 
spermicidal agent during the study treatment period and for 6 months following their 
last dose of CPX-351 and/or quizartinib, and must not father a child during this 
period.(refer to Appendix C). 
4. Evidence of active and uncontrolled bacterial, fungal, parasitic, or viral infection.  
Infections are considered controlled if appropriate therapy has been instituted and, at 
the time of screening, no signs of active infection progression are present.  This is 
assessed by the site clinicians, including an infectious disease consulting physician, if 
requested by the Principal Investigator (PI), regarding adequacy of therapy.  These 
infections include, but are not limited to: 
- Known human immunodeficiency virus (HIV) infection 
- Active hepatitis B or C infection with rising transaminase values 
- Active tuberculosis infection  
5. History of hypersensitivity to cytarabine, daunorubicin, or an FLT3 inhibitor 
6. Any patients with known significant impairment in gastrointestinal (GI) function or 
GI disease that may significantly alter the absorption of quizartinib 
. 
7. Psychological, familial, sociological, or geographical conditions that do not permit 
compliance with the protocol. 
8. Uncontrolled or significant cardiovascular disease, including any of the following: 
- 
Bradycardia of less than 50 beats per minute, unless the patient has a 
pacemaker 
- 
QTcF interval using Fridericia’s correction factor (QTcF) interval 
prolongation, defined as >450 msec at screening and  prior to first 
administration of quizartinib. 
- 
Diagnosis of or suspicion of long QT syndrome (including family history of 
long QT syndrome) 
- 
Systolic blood pressure ≥180 mmHg or diastolic blood pressure ≥110 mmHg 
- 
History of clinically relevant ventricular arrhythmias (i.e., ventricular 
tachycardia, ventricular fibrillation or Torsades de pointes) 


 
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- 
History of second or third degree heart block without a pacemaker 
- 
Right bundle branch and left anterior hemiblock (bifascicular block), complete 
left bundle branch block 
- 
Ejection fraction <50% by transthoracic echocardiogram (TTE) or multigated 
acquisition (MUGA) scan 
- 
History of uncontrolled angina pectoris or myocardial infarction within 6 
months prior to Screening 
9. History of New York Heart Association Class 3 or 4 heart failure 
10. Prior anthracycline (or equivalent) cumulative exposure ≥368 mg/m2 daunorubicin 
(or equivalent) 
11. Any serious underlying medical condition that, in the opinion of the Investigator or 
Medical Monitor, would impair the ability to receive or tolerate the planned 
treatment 
12. Patients with inadequate pulmonary function will be excluded. Inadequate 
pulmonary function is defined as requiring supplemental O2 or diffusing capacity of 
the lungs for carbon monoxide [DLCO] <40%.   
13. Active acute or chronic GVHD requiring prednisone >10 mg or equivalent 
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Statistical 
Methodology: 
A response rate (CR + CR with incomplete hematologic recovery [Cri]) of ≥50% is 
targeted, with 40% or less considered unacceptable.  This is assumed to be an acceptable 
estimate based on CR + CRi/CRp of 48.2% reported with quizartinib monotherapy in a 
relapsed or refractory patient with FLT3-ITD AML (Cortes et al, 2019).  Of note, prior 
FLT3-targeting inhibitor exposure is permitted on this study.  However, patients receiving 
a prior FLT3-targeting inhibitor were excluded in the QUANTUM-R study.  Expected 
CR+CRi in relapsed or refractory patients receiving standard intensive or non-intensive 
salvage chemotherapy harboring an FLT3 mutation is 27%.  The estimated response in 
those with relapsed/refractory FLT3-ITD AML receiving CPX-351 alone cannot be 
estimated.  However, in a poor-risk EPI patient population, CR+CRi was reported as 
39.3% (Cortes et al 2015).  However, FLT3-ITD mutation presence was not utilized in the 
generation of EPI prognostication, and those with FLT3-ITD mutation could in fact have a 
reduced response within all EPI risk groups.  Thus, the expected response must be based 
upon the QUANTUM-R study of those receiving standard salvage options harboring a 
FLT3-ITD mutation. 
In the safety lead-in, 10 patients will be enrolled to receive CPX-351 with quizartinib.  If 
>3 patients experience delayed neutrophil count recovery >56 days from the first day on 
the study regimen, or delayed thrombocytopenia recovery >56 days from the first day on 
the study regimen, or if >3 patients develop a non-hematologic toxicity, defined as a 
Grade 4 non-hematologic adverse event determined to be probably related to the 
combined treatment, or a Grade 4 neutropenia, then the study will be terminated. 
Assuming safety parameters are met, the first 10 patients will be followed for response in 
Part 2 of the study. 
The null hypothesis that the overall response rate (ORR, defined as CR + CRi) is ≤27% 
will be tested against a one-sided exact alternative ORR of 50% at a target significance 
level of 0.05.  A sample size of 30 evaluable patients achieves 80% power if the true 
overall response rate is ≥50%.  The null hypothesis will be rejected if 13 or more 
responses are observed in 30 evaluable patients.  In order to allow for a non-evaluable rate 
of 10%, a total of 34 patients will be enrolled in the study. 


 
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LIST OF ABBREVIATIONS 
AE 
Adverse event 
AESI 
AE of special interest 
alloHCT 
Allogeneic hematopoietic cell transplantation 
ALT 
Alanine aminotransferase 
AML 
Acute myeloid leukemia 
ANC 
Absolute neutrophil count 
ASBMT 
American Society for Blood and Marrow Transplantation 
AST 
Aspartate aminotransferase 
BM 
Bone marrow 
CBC 
Complete blood count 
CFR 
Code of Federal Regulations 
CIBMTR 
Center for International Blood and Marrow Transplant Research 
CNS 
Central nervous system 
CR 
Complete remission/response 
Cr 
Creatinine 
CRi 
Complete remission/response with incomplete hematologic recovery 
CT 
Cellular therapy 
Development Innovations 
Sarah Cannon Development Innovations 
DLI 
Donor lymphocyte infusion 
DOR 
Duration of response 
DS 
Differentiation Syndrome 
ECG 
Electrocardiogram 
ECOG  
Eastern Cooperative Oncology Group  
eCRF 
Electronic Case Report Form 
EFS 
Event-free survival 
EPI 
European Prognostic Index 
FDA 
Food and Drug Administration 
FLT3 
Fms-like tyrosine kinase-3 
GCP 
Good Clinical Practice 
GI 
Gastroinestinal 
GVHD 
Graft-versus-host disease 
HCT 
Hematopoietic cell transplantation  
HIPAA 
Health Insurance Portability and Accountability Act of 1996 
HIV 
Human Immunodeficiency Virus 
IB 
Investigator’s Brochure 
ICF 
Informed consent form 
ICH 
International Council for Harmonisation 
IRB 
Institutional Review Board 
ISF 
Investigator study file 
IT 
Intrathecal 
ITD 
Internal tandem duplication 


 
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MRD 
Minimal residual disease 
MUGA 
Multigated acquisition scan 
NCI CTCAE 
National Cancer Institute Common Terminology Criteria for Adverse Events 
NGS 
Next-generation sequencing  
ORR 
Overall response rate 
OS 
Overall survival 
PCR 
Polymerase chain reaction 
PD 
Progressive disease 
P-gp 
P-glycoprotein 
PHI 
Protected health information 
PI 
Principal Investigator 
PICC 
Peripherally inserted central catheter 
PO 
By mouth (orally) 
PR 
Partial response 
QT 
ECG interval measured from the onset of the QRS complex to the end of the T 
wave 
QTc 
QT interval corrected for heart rate 
QTcF 
QT interval corrected for heart rate using Fridericia’s formula 
SAE 
Serious adverse event 
SAR 
Suspected adverse reaction 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
TdP 
Torsades de pointes 
TEAE 
Treatment-emergent AE 
TKD 
Tyrosine kinase domain 
TTE 
Transthoracic echocardiogram 
ULN 
Upper limit of normal 
USPI 
US package insert 
WHO 
World Health Organization 


 
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TABLE OF CONTENTS 
AML 48 AMENDMENT SUMMARY OF CHANGES ......................................................... 6 
AML 48 PROTOCOL SYNOPSIS ........................................................................................ 13 
LIST OF ABBREVIATIONS ................................................................................................ 18 
1. 
INTRODUCTION ................................................................................................. 25 
 
Background ........................................................................................................... 25 
 
Quizartinib ............................................................................................................. 25 
 
CPX-351 ................................................................................................................ 26 
 
Rationale for the Study .......................................................................................... 26 
 
Risks and Benefits ................................................................................................. 27 
 
Hypothesis ............................................................................................................. 28 
2. 
STUDY OBJECTIVES ......................................................................................... 28 
 
Primary Objectives ................................................................................................ 28 
 
Secondary Objectives ............................................................................................ 29 
 
Endpoints ............................................................................................................... 29 
 
Primary Endpoints ................................................................................................. 29 
 
Secondary Endpoints ............................................................................................. 30 
3. 
STUDY PATIENT POPULATION AND DISCONTINUATION ...................... 30 
 
Inclusion Criteria ................................................................................................... 30 
 
Exclusion Criteria .................................................................................................. 31 
 
Discontinuation from Study Treatment ................................................................. 32 
4. 
PATIENT REGISTRATION ................................................................................ 33 
5. 
STUDY DESIGN .................................................................................................. 33 
 
Assignment of Treatment ...................................................................................... 36 
 
Treatment Plan ...................................................................................................... 36 
 
Treatment Location ............................................................................................... 36 
 
Induction Phase ..................................................................................................... 36 
 
Consolidation Phase .............................................................................................. 37 
 
Maintenance Phase ................................................................................................ 37 
 
Concomitant Medications...................................................................................... 37 
 
Permitted Concomitant Medications ..................................................................... 38 
 
Prohibited Concomitant Medications .................................................................... 38 
6. 
STUDY ASSESSMENTS AND EVALUATIONS .............................................. 39 
 
Overview ............................................................................................................... 39 


 
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Baseline Study Assessments ................................................................................. 39 
 
Central Nervous System (CNS) Prophylaxis ........................................................ 40 
 
Study Assessment Timing ..................................................................................... 40 
 
Induction Phase ..................................................................................................... 40 
 
Consolidation Phase .............................................................................................. 43 
 
alloHCT or other CT intervention (within the 30-60 day time period between 
consolidation and maintenance treatment) ............................................................ 44 
 
Maintenance Phase ................................................................................................ 45 
 
End of Treatment/Early Termination Visit ........................................................... 45 
 
Long-Term Follow-up ........................................................................................... 46 
 
Study Assessments ................................................................................................ 46 
 
Medical History and Demographics ...................................................................... 46 
 
Physical Examinations (Including Performance Scale and Vital Signs) ............... 46 
 
12-Lead Electrocardiogram ................................................................................... 46 
 
Cardiac Echocardiogram ....................................................................................... 47 
 
Pregnancy Testing .................................................. Error! Bookmark not defined. 
 
Laboratory Assessments ........................................................................................ 47 
 
FLT3 Mutation PCR Testing ................................................................................. 47 
 
Response and Activity Assessments ..................................................................... 47 
 
Adverse Event Assessments .................................................................................. 47 
 
Prior and Concomitant Medications ...................................................................... 47 
 
Bone Marrow Aspirates and Biopsies ................................................................... 47 
 
Minimal Residual Disease Assessment ................................................................. 48 
7. 
DRUG FORMULATION, AVAILABILITY, ADMINISTRATION, AND 
TOXICITY INFORMATION ............................................................................... 48 
 
Quizartinib ............................................................................................................. 48 
 
Quizartinib Treatment Duration ............................................................................ 48 
 
Labeling, Packaging, and Supply of Quizartinib .................................................. 49 
 
Preparation and Administration of Quizartinib ..................................................... 49 
 
CPX-351 Treatment Duration ............................................................................... 49 
 
Labeling, Packaging, and Supply of CPX-351...................................................... 49 
 
Preparation and Administration of CPX-351 ........................................................ 49 
 
Accountability for All Study drugs ....................................................................... 50 
 
Toxicity of Study Treatments and Study Regimens .............................................. 50 
 
Precautions and Risks Associated with Quizartinib .............................................. 50 
 
Precautions and Risks Associated with CPX-351 ................................................. 53 
8. 
DOSE MODIFICATIONS .................................................................................... 55 
 
Criteria and Procedures for Dose Interruptions and Adjustments of 
Quizartinib ............................................................................................................. 55 


 
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Management of Quizartinib-Associated Adverse Events ..................................... 56 
 
Criteria and Procedures for Dose Modification due to QTcF Prolongation .......... 56 
 
Management of CPX-351-Related Adverse Events .............................................. 56 
 
Criteria and Procedures for Dose Interruptions and Adjustments of CPX-351 .... 56 
9. 
RESPONSE EVALUATIONS AND MEASUREMENTS .................................. 56 
 
Complete Response (CR) ...................................................................................... 56 
 
Complete Response with Incomplete Hematologic Recovery (CRi) .................... 57 
 
Partial Response (PR) ............................................................................................ 57 
 
Treatment Failure .................................................................................................. 57 
 
Duration of Response (DOR) ................................................................................ 57 
 
Time-to-Progression (TTP) ................................................................................... 57 
 
Event-free Survival (EFS) ..................................................................................... 57 
 
Recurrence of Disease ........................................................................................... 57 
 
Overall Survival (OS) ............................................................................................ 57 
 
Time to Absolute Neutrophil Count (ANC) and Platelet Count Recovery ........... 58 
10. 
STATISTICAL CONSIDERATIONS .................................................................. 58 
 
Statistical Design ................................................................................................... 58 
 
Sample Size Considerations .................................................................................. 58 
 
Analysis Population ............................................................................................... 59 
 
Data Analysis ........................................................................................................ 59 
 
Demographics and Baseline Characteristics ......................................................... 59 
 
Efficacy Analysis .................................................................................................. 59 
 
Safety Analysis ...................................................................................................... 59 
 
Analysis Time Points............................................................................................. 60 
 
Safety Review........................................................................................................ 60 
 
Final Analysis ........................................................................................................ 60 
11. 
SAFETY REPORTING AND ANALYSES ......................................................... 60 
 
Definitions ............................................................................................................. 60 
 
Adverse Events ...................................................................................................... 60 
 
Serious Adverse Events ......................................................................................... 61 
 
Adverse Reaction .................................................................................................. 61 
 
Suspected Adverse Reaction ................................................................................. 61 
 
Recording and Reporting of Adverse Events ........................................................ 62 
 
Assessment of Adverse Events.............................................................................. 62 
 
Serious Adverse Event Reporting by Investigators ............................................... 63 


 
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Recording of Adverse Events and Serious Adverse Events .................................. 64 
 
Diagnosis versus Signs and Symptoms ................................................................. 64 
 
Persistent or Recurrent Adverse Events ................................................................ 64 
 
Abnormal Laboratory Values ................................................................................ 64 
 
Deaths .................................................................................................................... 64 
 
Hospitalization, Prolonged Hospitalization, or Surgery ........................................ 65 
 
Pre-Existing Medical Conditions .......................................................................... 65 
 
New Cancers.......................................................................................................... 65 
 
Pregnancy, Abortion, Birth Defects/Congenital Anomalies ................................. 66 
 
Overdose ................................................................................................................ 66 
 
Protocol-Defined Adverse Events of Special Interest (AESI) .............................. 66 
 
Funding Partner Serious Adverse Event Reporting Requirements ....................... 67 
 
Sponsor Assessment of Unexpected Events .......................................................... 67 
 
Funding Partner Reporting for Clinical Studies Under an Investigational New 
Drug Application ................................................................................................... 68 
12. 
QUALITY ASSURANCE AND QUALITY CONTROL .................................... 68 
 
Study Monitoring, Auditing, and Inspecting ......................................................... 68 
13. 
ETHICAL, FINANCIAL, AND REGULATORY CONSIDERATIONS ............ 68 
 
Institutional Review Board Approval.................................................................... 68 
 
Regulatory Approval ............................................................................................. 69 
 
Informed Consent .................................................................................................. 69 
 
Confidentiality ....................................................................................................... 69 
 
Financial Information ............................................................................................ 70 
14. 
RESEARCH RETENTION AND DOCUMENTATION OF THE STUDY ........ 70 
 
Amendments to the Protocol ................................................................................. 70 
 
Documentation Required to Initiate the Study ...................................................... 71 
 
Study Documentation and Storage ........................................................................ 72 
 
Data Collection ...................................................................................................... 73 
 
Disclosure and Publication Policy ......................................................................... 73 
15. 
REFERENCES ...................................................................................................... 75 
16. 
APPENDICES ....................................................................................................... 80 
 
LIST OF TABLES 
Table 1 
Cumulative Exposure of Daunorubicin per Cycle of CPX-351............... 53 
Table 2 
Dose Level Modifications – Induction and Consolidation Phases .......... 55 
Table 3 
Dose Level Modifications – Maintenance Phase ..................................... 55 


 
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LIST OF FIGURES 
Figure 1 
Study Schema........................................................................................... 35 
 
LIST OF APPENDICES 
Appendix A: 
ECOG Performance Status Criteria ......................................................... 80 
Appendix B: 
New York Heart Association (NYHA) Classification of Cardiac 
Disease ..................................................................................................... 81 
Appendix C: 
Guidelines for Female Patients of Childbearing Potential and Fertile 
Male Patients ............................................................................................ 82 
Appendix D: 
Schedule of Assessments ......................................................................... 84 
Appendix E 
ASBMT RFI 2017 – Disease Classifications Corresponding to 
CIBMTR Classifications .......................................................................... 88 
Appendix F 
Management of Quizartinib-Associated Adverse Events ........................ 90 
Appendix G 
Management of CPX-351-Related Adverse Events ................................ 93 
Appendix H 
Cytochrome P450 3A4 Inhibitors and Inducers....................................... 94 
Appendix I 
Drugs That Prolong QT Interval and/or Induce Torsades De Pointes ..... 95 
 


 
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1. 
INTRODUCTION 
 
Background 
Fms-like tyrosine kinase-3 (FLT3) mutations are identified in approximately 30% of patients 
with acute myeloid leukemia (AML) and confer a poor prognosis, with an estimated 5-year 
overall survival (OS) of approximately 32% (Kottaridis et al 2001).  FLT3 is a receptor tyrosine 
kinase for the cytokine Flt3 ligand (FLT3L) and is expressed on hematopoietic progenitor cells.  
The FLT3L transduces signals that promote proliferation and survival, and mutations of the 
FLT3 receptor present as two general types: internal tandem duplications (ITDs) near the 
receptor juxtamembrane domain, and single amino acid substitutions within the activation loop 
of the tyrosine kinase domain (TKD) (Levis 2013).  While FLT3-TKD mutations do not confer 
the same poor prognosis as FLT3-ITD mutations, their presence is associated with resistance to 
chemotherapy (Whitman et al 2001, Takahashi et al 2016). 
In both young and old AML patients, approximately 60% will achieve a complete response to 
standard induction chemotherapy for acute myeloid leukemia (Rowe 2009).  While response to 
initial therapy is comparable among all patients, in those who relapse with a FLT3 mutation, 
response to re-induction is significantly less compared to non-FLT3 mutated patients, with a 
complete response (CR) of 22-24% in two analyses (Ravandi et al 2010, Wagner et al 2011).  
Due to the poorer prognosis of patients with FLT3 mutation-positive AML, allogeneic 
hematopoietic cell transplant (alloHCT) is indicated in the first CR (CR1) (Pratz et al 2017).  In 
patients who are able to proceed to hematopoietic cell transplantation (HCT), the relapse rate 
after transplant is higher compared to non-FLT3 mutated patients (Fleischmann et al 2017, Deol 
et al 2016).  Additional therapeutic options are necessary for those who fail to achieve a CR1 or 
for those whose disease relapses. 
Recent Phase III data combining the first-generation FLT3 inhibitor midostaurin with standard 
induction daunorubicin and cytarabine identified a statistically significant improvement in 
median OS with the FLT3 inhibitor of 74.7 months (95% confidence interval [CI] 31.5, not 
reached) compared to placebo with 25.6 months (95% CI 18.6, 42.9) (Stone et al 2017).  
Midostaurin as well as sunitinib and sorafenib are multi-kinase inhibitors with non-FLT3 targets.  
Second-generation FLT3 inhibitors, including quizartinib and gilteritinib, are more selective and 
potent, with a possible reduction in the development of FLT3-TKD mutations that may confer 
resistance to FLT3 inhibition therapy (Smith et al 2012, Perl et al 2017).   
 
Quizartinib 
Quizartinib is a potent and selective class III fms-like tyrosine kinase 3 (FLT3)-ITD inhibitor 
under active investigation (Kampa-Schittenhelm et al 2013).  A Phase I dose-finding study using 
quizartinib as monotherapy in refractory AML demonstrated an overall response rate (ORR) of 
30% and a median duration of response (DOR) of 13.3 weeks (Cortes et al 2013).  All grades of 
toxicities included nausea (16%), prolonged QT interval (12%), vomiting (11%), and dysgeusia 
(11%).  In a historical control analysis, patients with refractory AML receiving standard salvage 
therapy or those who relapsed after stem cell transplantation were evaluated.  Those receiving 
quizartinib achieved a CR of 43% compared to 11% in those who did not receive the agent, and a 


 
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statistically significant improvement in OS was identified (Hills et al 2015).  In a randomized 
Phase II study using quizartinib as monotherapy in patients with at least one second-line therapy 
or after an HCT, ORR was 47% (Schiller et al 2014).  
 
 
CPX-351 
Other novel therapies for the treatment of AML have demonstrated improved outcomes. CPX-
351 is a cytarabine:daunorubicin liposomal complex demonstrated to improve the induction 
response rate to 66.7%, compared to 51.2% for  in patients with previously untreated AML 
receiving 7+3 (7 days of standard dose cytarabine and 3 days of daunorubicin) (Lancet et al 
2014).  A Phase III analysis in patients with secondary AML aged 60 - 75 demonstrated a CR of 
47.7% with CPX-351 versus 33.3% with standard regimens (Medeiros et al 2016).  In addition, a 
significant improvement in OS was seen in a subset of patients who proceeded to HCT (Lancet et 
al 2016a).  
CPX-351 was also evaluated in patients who failed to respond to 7+3 induction.  Four out of 10 
patients who received CPX-351 alone achieved a morphologic CR (Lancet et al 2010).  The 
explanation may be that intracellular 5:1 drug concentration of cytarabine:daunorubicin with 
cytarabine achieves a half-life of 31.1 hours and daunorubicin 21.9 hours.  Compared to standard 
dosing of free-drug, the half-life of cytarabine and daunorubicin was 13 hours (Lim et al 2010, 
Tardi et al 2009, Fathi et al 2013, Feldman et al 2011).  CPX-351 alone compared to 
investigator’s choice for re-induction in refractory AML achieved a morphologic CR rate of 
49.4% compared to 40.9%, although this did not meet a pre-defined statistically significant 
benefit for 1 year OS (Cohen 2007, Cortes et al 2015).  However, a sub-group analysis 
demonstrated that poor-risk European Prognostic Index (EPI) patients receiving CPX-351 had a 
statistically significant improvement in OS compared to poor-risk EPI patients receiving 
standard re-induction therapies (Cortes et al 2015).  Patients with FLT3 mutations are not 
factored into the EPI risk stratification, although associated patient characteristics in those with 
FLT3-ITD AML, including time of recurrence and non-favorable cytogenetics, could place this 
patient population into poor-risk EPI, suggesting a benefit with CPX-351 (Breems et al 2005). 
The poor prognosis in patients with FLT3 mutation-positive AML who have relapsed or failed to 
respond to induction therapy is an unmet medical need that warrants investigation with novel 
therapeutic combinations. 
 
Rationale for the Study 
The purpose of this study is to assess the safety, tolerability, and efficacy of the combination of 
CPX-351 and quizartinib.  The ability to deliver a stable liposomal formulation of 
cytarabine:daunorubicin packaged at a 5:1 molar ratio combined with continuous potent FLT3 
inhibition is hypothesized to potentially provide disease control.  A recent pre-clinical study 
demonstrated synergistic activity when CPX-351 was dosed with an FLT3 inhibitor.  This 
synergy was demonstrated when the FLT3 inhibitor was administered after CPX-351, but not 
when the FLT3 inhibitor was administered simultaneously or prior to CPX-351 (Edwards et al 
2017).  Investigation of this novel combination in the relapsed/refractory population is 
reasonable in this high-risk disease population.  Since OS in AML is directly related to achieving 


 
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disease control (a molecular CR), the goal of this study is to determine if novel cytoreduction 
with CPX-351 combined with targeted FLT3 inhibition can achieve improved disease control 
over what has been previously reported in the literature. 
Patients with relapsed or refractory FLT3 mutation-positive AML have limited options.  A goal 
of this treatment is to achieve adequate disease control that may potentially allow a bridge to 
consolidative cellular therapeutic intervention (e.g., HCT or donor lymphocyte infusion [DLI]) 
for some patients.  In patients who are not candidates for or decline a cellular intervention, the 
treatment goal is to achieve definitive disease control with the combination of CPX-351 and 
quizartinib followed by quizartinib maintenance. 
In all patients with AML who relapse after an alloHCT, those who receive treatment with 
chemotherapy, DLI, and/or a second alloHCT achieve a CR rate of 29% with a 5-year OS ≤11% 
in those who relapse less than 2 years after first transplant and ≤31% for those who relapse 2 
years or more after first transplant (Weisdorf et al 2013).  Currently, it is believed that many 
relapsed FLT3 mutation-positive AML patients would not have received an FLT3 inhibitor as 
part of a prior regimen.  Novel chemotherapy in combination with a targeted FLT3 inhibitor may 
provide a significant improvement in survival for this patient population compared to the current 
standard of care. 
 
Risks and Benefits 
The risks associated with the study derive from the novel combination of CPX-351 with 
quizartinib.  The most anticipated side effect is pancytopenia, with potentially prolonged 
neutropenia and thrombocytopenia compared to standard induction or salvage chemotherapy.  In 
a randomized study in AML patients, CPX-351 demonstrated a median time to absolute 
neutrophil count (ANC) ≥1000 of 36 days compared to 32 days with standard cytarabine and 
daunorubicin (7+3).  In addition, there was a statistically significant increase in Grade 3 or Grade 
4 infections.  However, infection-related mortality has not been demonstrated.  In the same 
study, platelet count recovery to >100,000 was 37 days compared to 28 days in those receiving 
7+3.  Quizartinib in combination with cytarabine and daunorubicin was associated with 21% of 
study participants showing Grade ≥3 toxicity for both neutropenia and thrombocytopenia.  
However, there was no prolonged period of pancytopenia, suggesting that the proposed novel 
combination of CPX-351 and quizartinib may not contribute to a longer period of 
myelosuppression than what is expected with CPX-351 alone.  Grade 3 and higher febrile 
neutropenia was identified in 63.5% of patients receiving CPX-351 alone (Lancet et al 2014) and 
in 47% of patients receiving quizartinib alone (Altman et al 2018).   
CPX-351 contains daunorubicin, an anthracycline that has a known association with 
cardiomyopathy at threshold doses of 550 mg/m2.  Patients will be excluded if their cumulative 
dose of an anthracycline exceeds this threshold.  To date, quizartinib has not been associated 
with cardiomyopathy or a reduction in the ejection fraction.    Quizartinib has been associate 
with QT prolongation in a dose dependent manner.  In study AC220-007 (Quantum-R) in the 
relapse/refractory FLT3+ AML population, Eight (3.3%) subjects in the quizartinib arm had 
ECG QTcF values >500 ms (Grade 3 QTcF) by central ECG reading.  (Quizartinib Investigator 
Brochure 2020.  CPX-351 has not been associated with significant QTc prolongation (CPX-351 
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and accounted for independently.  Dose modifications for QTcF prolongation will be based upon 
pre-specified monitoring and criteria (see Section 8). 
All grades of gastrointestinal toxicities associated with CPX-351 were similar to standard 
induction 7+3, with the most frequent being nausea (47%), diarrhea/colitis (45%), mucositis 
(44%), and constipation (40%).  However, Grade 3 and higher gastrointestinal toxicities were 
less than 10% (Lancet et al 2016b).  In Phase I/II investigations, quizartinib was found to be 
associated with all grades of nausea (16%), vomiting (11%), and diarrhea (18%)  (Cortes et al 
2013, Schiller et al 2014). 
Given that the toxicities identified with each agent have minimal overlap, it is hoped that the 
novel combination will not result in the potentiation of the toxicity of either agent alone.  A 
potential beneficial effect of this combination may be the protective effect of quizartinib on 
normal hematopoietic progenitor cells after exposure to chemotherapy.  If dosed sequentially 
following CPX-351, this may attenuate the effects that CPX-351 has on healthy stem cells 
without compromising the effect on the leukemic cells (Taylor et al 2017.  This potential benefit 
of the novel combination will be measured based on the timing of myeloid count recovery and 
comparing this data to data from prior CPX-351 studies. 
It is assumed that there are four patient groups who may derive benefit on study for relapsed or 
refractory FLT3 mutation-positive AML.  The first group includes patients who have primary 
refractory FLT3 mutation-positive AML and who fail first-line therapy with routine induction 
regimens with or without an FLT3 inhibitor.  The second group includes patients with FLT3 
mutation-positive AML who have relapsed after HCT.  In both scenarios, the study intervention 
will likely act as a bridge to either an HCT or a DLI.  The third group includes patients with 
relapsed FLT3 mutation-positive AML who were excluded from or declined alloHCT.  In this 
patient population, the FLT3 inhibitor would continue as maintenance therapy.  The final group 
of patients includes those who acquire an FLT3 mutation at relapse.  This occurs more frequently 
in patients with epigenetic-modifying gene mutations at diagnosis (IDH1/2, DNMT3A, TET2) 
(Shih et al 2002, Wakita et al 2013).  Depending on the management choice at the initial 
diagnosis and initial CR, the last clinical scenario may be a bridge to a first or second HCT or to 
a DLI. 
 
Hypothesis 
The purpose of this study is to explore the safety, tolerability and efficacy of CPX-351 with 
quizartinib in patients with FLT3 mutated AML.  The investigators hypothesize: 
The combination of liposomal nanomolar cytarabine:daunorubicin (CPX-351) with quizartinib, a 
second-generation FLT3 inhibitor, will be safe, tolerable and enhance the tumor response in 
patients with FLT3-mutated AML who have relapsed or whose tumor did not respond to 
standard and other therapeutic regimens. 
2. 
STUDY OBJECTIVES 
 
Primary Objectives 
The primary objectives of this study are to: 


 
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• Determine the safety and tolerability of CPX-351 with quizartinib in patients with 
relapsed or refractory FLT3-ITD mutation-positive AML. 
• Determine the overall complete morphologic (per World Health Organization) and 
molecular remission rate of CPX-351 and quizartinib in patients with relapsed or 
refractory FLT3-ITD. 
 
Secondary Objectives 
The secondary objectives of this study are to: 
• Define the time to ANC and platelet count recovery 
• Define the number of patients proceeding to an alloHCT 
• Determine time to progressive disease (PD) or DOR 
• Determine event-free survival (EFS) 
• Determine OS 
• Define the percentage of patients who develop late responses 
• Define the number of patients who can receive consolidation and maintenance therapy on 
this study 
• Define the treatment-related mortality rate of this combination 
• Determine the percentage of patients who achieve a PR or molecular CR 
• Determine the mean elapsed time for patients to achieve molecular CR 
• Determine whether quizartinib is tolerable after alloHCT or DLI 
 
Endpoints 
 
Primary Endpoints 
• Response rate determination: 
- Complete remission (CR) defined as a complete morphologic response with 
complete blood count recovery ANC ≥1000/µL and platelet count ≥100,000/µL), 
per the revised International Working Group response criteria (Cheson et al 2003) . 
- Complete remission with minimal residual disease (CR with MRD): Achievement 
of a complete morphologic CR with persistent disease detected by flow or 
molecular MRD analysis.  
- A complete morphologic response with an incomplete blood count recovery                        
([CRi] ANC <1000/µL and/or platelet count <100,000/µL), per the revised 
International Working Group response criteria (Cheson et al 2003).  Patients will 
be further divided into MRD+ and MRD- subgroups. 


 
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- A partial response (PR) is defined as having persistence of disease, with a ≥50% 
decrease in the blast percentage with or without the presence of FLT3-ITD 
mutations. 
 
Secondary Endpoints 
• Time to ANC recovery >56 days (≥500/µL) and platelet count recovery>56 days 
(≥50,000/µL) 
• Number of patients proceeding to an alloHCT 
• Time to PD or DOR 
• EFS 
• OS 
3. 
STUDY PATIENT POPULATION AND DISCONTINUATION 
 
Inclusion Criteria  
Patients must meet all of the following criteria in order to be included in this research study: 
1. Written informed consent form (ICF), according to local guidelines, signed by the patient 
or by a legal guardian prior to the performance of any study-related screening procedures 
2. Male and female patients between ≥18 and ˂80 years old 
3. Patients with the following types of AML with >5% blasts: 
- Relapsed FLT3-ITD mutation-positive AML, diagnosed by bone marrow (BM) 
biopsy with FLT3 mutation by polymerase chain reaction (PCR) 
- Refractory FLT3-ITD mutation-positive AML, diagnosed by BM biopsy with FLT3 
mutation by PCR 
- Relapsed or refractory FLT3-ITD mutation-positive AML after HCT, diagnosed by 
BM biopsy with FLT3 mutation by PCR 
- Relapsed or refractory AML with de novo FLT3-ITD mutation, diagnosed by BM 
biopsy with FLT3 mutation by PCR 
- Relapsed or refractory AML after HCT with de novo FLT3-ITD mutation, diagnosed 
by BM biopsy with FLT3 mutation by PCR 
4. First-line therapy must have contained a standard induction chemotherapy (e.g., 7+3, 
FLAG-IDA, FLAG, CLAG, MEC, hypomethylating agent with venetoclax) with or 
without receiving a prior FLT3 inhibitor (e.g., midostaurin) or multi-tyrosine kinase 
inhibitor (e.g., sorafenib).  All patients who relapsed after an alloHCT are included, 
except patients with active graft-versus-host disease (GVHD) requiring >10 mg 
prednisone. 
5. Patients must be able to swallow and retain oral medication. 


 
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6. Eastern Cooperative Oncology Group (ECOG) Performance Status score of 0, 1, or 2 
(Appendix A) 
7. Adequate renal and hepatic parameters (aspartate aminotransferase [AST], alanine 
aminotransferase [ALT] ≤2.5 institutional upper limit of normal [ULN]; total bilirubin 
≤2.0 institutional ULN; serum creatinine [Cr] ≤2.0). In patients with suspected liver 
infiltration, ALT can be ≤5 institutional ULN. 
 
Exclusion Criteria  
Patients who meet any of the following criteria will be excluded from study entry: 
1. Acute promyelocytic leukemia (t[15;17]) 
2. Female patients who are lactating or have a positive serum pregnancy test during the 
screening period.  Female patients of childbearing potential who are not willing to 
employ highly effective birth control (as defined in Appendix C) from screening to 6 
months following the last dose of CPX-351 and/or quizartinib. 
3. Fertile male patients, defined as all males physiologically capable of conceiving 
offspring, with female partners of childbearing potential must use condoms plus a 
spermicidal agent during the study treatment period and for 6 months following their last 
dose of CPX-351 and/or quizartinib, and must not father a child during this period.(refer 
to Appendix C)  
4. Evidence of active and uncontrolled bacterial, fungal, parasitic, or viral infection.  
Infections are considered controlled if appropriate therapy has been instituted and, at the 
time of screening, no signs of active infection progression are present.  This is assessed 
by the site clinicians, including an infectious disease consulting physician, if requested by 
the Principal Investigator (PI), regarding adequacy of therapy.  These infections include, 
but are not limited to: 
- Known human immunodeficiency virus (HIV) infection 
- Active hepatitis B or C infection with rising transaminase values 
- Active tuberculosis infection  
5. History of hypersensitivity to cytarabine, daunorubicin, or an FLT3 inhibitor 
6. Any patients with known significant impairment in gastrointestinal (GI) function or GI 
disease that may significantly alter the absorption of quizartinib 
7. Psychological, familial, sociological, or geographical conditions that do not permit 
compliance with the protocol 
8. Uncontrolled or significant cardiovascular disease, including any of the following: 
- Bradycardia of less than 50 beats per minute, unless the patient has a pacemaker 
- QTcF interval using Fridericia’s correction factor (QTcF) interval prolongation, 
defined as >450 msec at screening andprior to first administration of quizartinib.  


 
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- Diagnosis of or suspicion of long QT syndrome (including family history of long 
QT syndrome) 
- Systolic blood pressure ≥180 mmHg or diastolic blood pressure ≥110 mmHg 
- History of clinically relevant ventricular arrhythmias (i.e., ventricular tachycardia, 
ventricular fibrillation or Torsades de pointes) 
- History of second or third degree heart block without a pacemaker 
- Right bundle branch and left anterior hemiblock (bifascicular block), complete 
left bundle branch block  
- Ejection fraction <50% by transthoracic echocardiogram (TTE) or multigated 
acquisition (MUGA) scan 
- History of uncontrolled angina pectoris or myocardial infarction within 6 months 
prior to Screening 
9. History of New York Heart Association Class 3 or 4 heart failure (Appendix B) 
10. Prior anthracycline (or equivalent) cumulative exposure ≥368 mg/m2 daunorubicin (or 
equivalent) 
11. Any serious underlying medical condition that, in the opinion of the Investigator or 
Medical Monitor, would impair the ability to receive or tolerate the planned treatment. 
12. Patients with inadequate pulmonary function will be excluded.  Inadequate pulmonary 
function is defined as requiring supplemental O2 or diffusing capacity of the lungs for 
carbon monoxide [DLCO] <40%.    
13. Active acute or chronic GVHD requiring prednisone >10 mg or equivalent. 
 
Discontinuation from Study Treatment 
Patients will be discontinued from study treatment for any of the following reasons: 
• 
Irreversible or intolerable toxicity or abnormal laboratory values thought to be related to 
drug toxicity 
• 
Conditions requiring therapeutic intervention not permitted by the protocol 
• 
Intercurrent illness (this will be at the Investigator’s discretion) 
• 
Inability of the patient to comply with study requirements 
• 
Patient requests to discontinue treatment, but agrees to finish study procedures 
• 
Patient withdraws consent from the study and is discontinued from the study 
• 
Non-compliance/lost to follow-up 
• 
Pregnancy and breastfeeding 
• 
Further participation would be injurious to the patient’s health or well-being, in the 
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• 
The study is terminated by the Sponsor, Sarah Cannon Development Innovations 
(“Development Innovations”) or the Institutional Review Board (IRB) 
After discontinuation from protocol treatment, patients must be followed for adverse events 
(AEs) for 30 days after their last dose of study drug.  All new AEs occurring during this period 
must be reported and followed at the site until resolution for AEs attributed to the study 
medication(s). 
. 
4. 
PATIENT REGISTRATION 
The patient must willingly consent to participate after being informed of the procedures to be 
followed, the experimental nature of the treatment, potential benefits, treatment alternatives, 
side-effects, risks, and discomforts.  Institutional Review Board (IRB) approvals of this protocol 
and consent form are required.  Eligible patients who wish to participate in the study will be 
enrolled into the study. 
Registration must occur prior to the initiation of protocol therapy.  Patients eligible to participate 
in the study may be enrolled by each site following the patient registration instructions provided 
by the Sarah Cannon Development Innovations (Development Innovations) study contact. 
Patient registration follow-up and/or confirmation will be provided via email within 
approximately 24 hours or by the next business day. 
5. 
STUDY DESIGN 
This is a multi-center, non-randomized, open-label, two-part prospective Phase II clinical trial in 
patients with relapsed or refractory FLT3-ITD mutation-positive AML.  The study is designed to 
assess the safety and tolerability as well as the efficacy of administering CPX-351 
(cytarabine:daunorubicin liposome complex) with quizartinib, a second-generation FLT3 
inhibitor.  The plan for administration is divided into three phases: induction, consolidation, and 
maintenance.  Approximately 34 patients are planned to be screened and enrolled.  Patient 
participation is expected to be 4 years.   
A total of 10 patients will be enrolled in the safety lead-in.  The safety lead-in portion of the 
study is designated as Part 1.  If >3 patients experience delayed neutrophil count recovery >56 
days from the first day on the study regimen, or delayed thrombocytopenia recovery >56 days 
from the first day on the study regimen, or if >3 patients develop a non-hematologic toxicity, 
defined as a Grade 4 non-hematologic adverse event determined to be probably related to the 
combined treatment, or a Grade 4 neutropenia, then the study will be terminated. 
Assuming safety parameters are met, the first 10 patients will be followed for response in the 
Part 2 of the study.  An additional 24 patients will be enrolled in Part 2 of the study (induction, 
consolidation and maintenance).  All patients will be assessed for response. 
Patients who fail to respond to therapy will be followed until a new therapy is instituted.  .  
Patients who experience an AE that results in the discontinuation of study treatment will be 


 
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followed until resolution/stabilization for AEs attributed to the medication.  Outcomes for all 
patients will be assessed for 24 months from the date of last treatment. 


 
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Figure 1 
Study Schema 
 
*All treatment phases follow a 28-day cycle.  Induction and re-induction consist of: CPX-351 (liposomal daunorubicin 44 mg/m2 IV and 
cytarabine 100 mg/m2 IV) + quizartinib 30 mg PO QD.  The maintenance phase: begin quizartinib 30 mg PO QD on Days 1-14.  If there are no 
toxicities and QTcF is maintained ≤450 msec, increase dose to 60 mg QD on Day 15. 
†For one cycle 
‡For up to two cycles 
 


 
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Assignment of Treatment 
All patients will receive CPX-351 with quizartinib according to the treatment plan (Section 5.2). 
 
Treatment Plan 
The plan for administration is divided into three phases: induction, consolidation, and 
maintenance. In patients who decline HCT or cellular therapy (CT) intervention or are ineligible, 
the patient would proceed through induction, consolidation, and maintenance.   
Patients who achieve a CR (CR or CRi) after induction(s), will proceed to consolidation 
followed by the maintenance phase.  In patients who achieve a PR, re-induction can occur for 
one additional cycle followed by consolidation and maintenance phases if a CR is achieved with 
re-induction. In patients who achieve a CR or PR after induction and/or consolidation and an 
HCT or other CT intervention (e.g., HCT or DLI) is indicated, maintenance therapy would be 
initiated no earlier than Day 30 after the HCT or CT intervention. If the patient is on quizartinib 
prior to HCT or CT intervention, quizartinib should be discontinued 7 days prior if a 
conditioning therapy is utilized.  If proceeding to a CT intervention without conditioning therapy 
(e.g., DLI), quizartinib should be discontinued one day prior to CT intervention. 
Response assessment will occur by BM biopsy/aspirate 21 days (±2 days) from CPX-351 
induction and/or re-induction therapy as well as Day 35 (±7 days) during induction and 
consolidation therapy (within 4 days after neutrophil as defined as a peripheral ANC ≥500/µL 
for 24 hours).  In the event of a delayed neutrophil recovery, defined as having a peripheral ANC 
<500/µL at Day 42 from the first day of CPX-351 treatment, a BM biopsy will be taken to assess 
persistent disease. During the maintenance phase, subsequent response assessments by BM 
biopsy/aspirate will be done on Day 24 (± 3 days) of a 28-day treatment cycle during Cycles 3, 6, 
12, and 24. 
 
Treatment Location 
5.2.1.1 
Inpatient procedures 
Patients will be admitted to the clinic as inpatients to start induction therapy.  If the Day +21 (±2 
days) BM aspirate shows no evidence of disease, the patient is stable based on PI assessment, 
and close outpatient follow-up is available, then the patient can be discharged with three weekly 
lab checks (Monday, Wednesday, and Friday) and weekly provider visits. 
5.2.1.2 
Outpatient procedures 
Consolidation cycles may be administered on an outpatient basis with IV infusion of CPX-351 
and three weekly lab checks (Monday, Wednesday, and Friday) and weekly provider visits.  
Maintenance cycles are all outpatient with monthly lab/provider visits. 
 
Induction Phase 
Treatment consists of CPX-351 (liposomal daunorubicin 44 mg/m2 IV and cytarabine 100 mg/m2 
IV) on Days 1, 3, and 5 followed by quizartinib (30 mg by mouth [PO] once daily) on Days 8-21.  
If there is a PR at the recovery BM biopsy, patients may be re-treated with one additional 
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mg/m2 IV) on Days 1 and 3. Quizartinib (30 mg by PO once daily) will resume on Day 6 and 
continue through Day 21.  If re-induction is required, a minimum 72-hour period is necessary 
between the dose of quizartinib on Day 21 and the administration of CPX-351 with re-induction.  
If it is believed by the PI and/or sub-investigator that a patient with prolonged Grade ≥3 toxicity 
after the induction phase would be likely to experience additional toxicities during the 
consolidation phase, the patient could bypass the consolidation phase and proceed to a cellular 
intervention or the maintenance phase. Any patient with neutropenia or thrombocytopenia lasting 
≥56 days from the initiation of CPX-351 will not receive consolidation and will instead proceed 
to the maintenance phase. 
 
Consolidation Phase 
Patients who achieve a CR and do not proceed to an alloHCT or other CT intervention will 
proceed from induction to the consolidation phase beginning 7 days (±7 days) after neutrophil 
recovery (ANC >1000/µL), receiving up to 2 consolidation cycles consisting of CPX-351 
(daunorubicin 29 mg/m2 IV and cytarabine 65 mg/m2 IV) on Days 1 and 3.  Quizartinib therapy 
(30 mg PO once daily) will start on Day 6 and continue through Day 21. 
After the first consolidation cycle, if it is believed by the PI and/or sub-investigator that a patient 
with prolonged Grade ≥3 toxicity would have additional adverse toxicities during the second 
consolidation phase, and/or there is CRi with persistent ANC <1000/µL and/or platelets 
<50,000/µL more than 14 days from the recovery marrow assessment, then the patient could 
proceed to a cellular intervention or the maintenance phase.  
 
Maintenance Phase 
The maintenance phase consists of 28-day cycles. Patients will receive quizartinib once daily for 
a total of 24 cycles or until disease relapse. Maintenance dosing of quizartinib will begin at 30 
mg PO once daily on Days 1-14, and if there are no non-hematologic Grade ≥3 toxicities and 
QTcF is maintained ≤450 msec, the quizartinib dose will increase to 60 mg/day on Day 15. If 
consolidation therapy is not advised at all or if only 1 cycle of consolidation is advised based on 
prolonged toxicities, maintenance therapy will begin 7 days (±7) after neutrophil recovery (ANC 
>1000/µL) from the consolidation phase or induction phase.  
Patients who proceed to alloHCT or other CT intervention after consolidation will resume 
quizartinib maintenance no earlier than Day 30 from the intervention or transplant.    If ≥2 CT 
interventions (e.g., repeat DLI) are planned after maintenance, a 28-day hold is acceptable, with 
resumption of quizartinib with the next cycle. If the patient is on quizartinib prior to HCT or CT 
intervention, quizartinib should be discontinued 7 days prior if a conditioning therapy is utilized.  
If proceeding to a CT intervention without conditioning therapy (e.g., DLI), quizartinib should 
be discontinued one day prior to CT intervention. 
 
Concomitant Medications 
Patients will be instructed not to take any additional medications during the course of the study 
without prior consultation with the research team.  At each visit, the patient will be asked about 
any new medications he/she is taking or has taken after the start of the study drug. 


 
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Permitted Concomitant Medications 
Patients with hematologic malignancies receiving therapy are at an increased risk for infections, 
and antiviral, antifungal, and antibacterial prophylactic agents should be administered per 
institutional guidelines.  It is considered routine practice to administer acyclovir or a similar anti-
viral to reduce the risk of herpes simplex virus (HSV) or varicella zoster virus (VZV) 
reactivation, voriconazole or other anti-fungal agent to reduce the risk of a fungal infection, and 
an antibiotic such as levofloxacin to reduce the risk of neutropenic fever.  It is important to note 
that many antifungal agents require a dose modification of quizartinib.  Electrocardiograms 
(ECGs) will need to be performed on patients who receive medications that cause significant 
QTc prolongation. 
Additional supportive care measures (e.g., anti-emetics for nausea, anti-motility agents for 
diarrhea management) are permitted at the Investigator’s discretion.  Concomitant treatments 
and/or procedures that are required to manage a patient's medical condition during the study will 
be recorded in the electronic case report form (eCRF). 
 
Prohibited Concomitant Medications 
The following treatments are prohibited during the treatment period of the study: 
• Other investigational therapies (e.g., chemotherapy, radiation therapy, surgery, 
immunotherapy, biologic therapy, or hormonal therapy not required by this protocol) 
should not be given to patients.  If such agents are required for a patient, then the patient 
must first be withdrawn from the study. 
• Herbal preparations/medications are not allowed throughout the study unless approved by 
the Investigator.  Herbal medications include, but are not limited to: St. John’s wort, kava, 
ephedra (ma huang), ginkgo biloba, dehydroepiandrosterone (DHEA), yohimbe, saw 
palmetto, and ginseng.  Patients should stop using herbal medications 7 days prior to first 
dose of study drug. 
• While receiving quizartinib, concomitant medications that prolong the QT/QTc interval are 
prohibited except when regarded by the Investigator as essential for patient care (Appendix F 
and Appendix I). 
• Strong CYP3A4 inhibitors are not prohibited, although quizartinib dose adjustments are 
required.  Weak or moderate CYP3A4 inhibitors, such as fluconazole, may be used without 
dose reduction (Appendix H). 
o When treatment with a strong CYP3A4 inhibitor is initiated, reduce quizartinib 
one dose level (60 mg to 30 mg or 30 mg to 20 mg) 
o A patient taking a strong CYP3A4 inhibitor at enrollment will begin quizartinib 
treatment at 20 mg/day. The dose will be escalated to 30 mg/day at Day 15 of the 
maintenance phase if the QTcF interval is ≤450 msec prior to or at the Day 14 
ECG evaluation. 
• Concomitant strong or moderate CYP3A4 inducers are prohibited (Appendix H). 
• Concomitant agents that prolong QTc are prohibited (Appendix I) 


 
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If quizartinib is co-administered with drugs that inhibit P-glycoprotein (P-gp) or are substrates of 
P-gp, increased concentrations of quizartinib are possible and caution should be exercised. The 
co-administration of P-gp inhibitors and inducers with quizartinib should be avoided if possible.  
6. 
STUDY ASSESSMENTS AND EVALUATIONS 
 
Overview 
All patients should visit the study center on the days specified within this protocol.  The 
complete Schedule of Assessments for this study is presented in Appendix D. 
 
Baseline Study Assessments 
The following information will be collected and procedures will be performed for each patient at 
a baseline study assessment. This screening assessment will take place following written 
informed consent (see Section 13.3) and within 7 days prior to initiating study treatment.  
• Medical history and demographics 
• Physical examination (including height [screening only] and weight) 
• Vital signs (pulse, resting blood pressure, respiratory rate, and body temperature) 
• ECOG performance status (Appendix A) 
• 12-lead ECG need to be completed pre-dose and 5 minutes apart, if QTcF prolongation is 
identified assess electrolyte levels (including potassium and magnesium ) as clinically 
indicated. 
• Concomitant medication review 
• Complete blood count (CBC) including differential count 
• Chemistry panel: sodium (Na), potassium (K), phosphorus (PO4), chloride (Cl), Cr, 
calcium (Ca), bicarbonate (CO2), AST, ALT, alkaline phosphatase (ALP), total bilirubin, 
lactate dehydrogenase (LDH), uric acid, glucose, and blood urea nitrogen (BUN) 
• Urinalysis 
• Serum pregnancy test for women of child-bearing potential  
• Review of viral studies: hepatitis serology (Hepatitis B surface antigen and antibody and 
Hepatitis C antibody), HIV-1, 2  
• Underlying disease assessment per American Society for Blood and Marrow 
Transplantation/Center for International Blood and Marrow Transplant Research 
(ASBMT/CIBMTR) disease classification (Appendix E) 
• BM biopsy and aspiration with FLT3 mutation testing via PCR 
• TTE or MUGA scan 
• Central line placement: peripherally inserted central line (PICC) or port 


 
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• Baseline signs and symptoms 
 
Central Nervous System (CNS) Prophylaxis 
Patients with a history of CNS involvement of leukemia, with monocytic differentiation, or with  
a WBC >40,000 cells/µL should receive a lumbar puncture using either intrathecal (IT) 
methotrexate or cytarabine, following site-specific standard operating procedures during the first 
induction cycle of CPX-351 with quizartinib.   
The CNS prophylaxis regimen may be modified by the attending physician in consultation with 
the PI as clinically indicated. No further IT chemotherapy is required in this study if there is no 
evidence of disease. However, additional administrations, per the treating physician or per 
institutional standard operating procedures, are permitted. 
In patients who have CNS disease involvement, IT chemotherapy should continue every 4 days 
(±1 day) until disease clearance, followed by every 7 days (±2 days) for 2 additional 
administrations.  Thereafter, administer IT chemotherapy every 28 days (±7 days) for at least 12 
cycles.  
 
Study Assessment Timing 
The treatment period begins on the day the patient receives the first administration of CPX-351.  
Dates for study visits and assessments will be determined based upon the first day of treatment 
and should occur based on the timing parameters outlined in this protocol.   
 
Induction Phase 
• Serum pregnancy test once per cycle during the induction phase 
6.4.1.1 
Cycle 1, Days 1, 3 and 5 
• Physical examination and vital signs (Days 3 and 5) 
• ECOG performance status (Days 3 and 5) 
• AE monitoring  
• Concomitant medication review 
• CBC and clinical chemistry panel 
• CPX-351 administration (Days 1, 3, and 5) 
 
6.4.1.2 
Cycle 1, Day 8 
• Physical examination and vital signs 
• ECOG performance status 
• AE monitoring  
• Concomitant medication review 
• CBC and clinical chemistry panel 


 
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• ECG and QTc assessment 
• Quizartinib daily on Days 8-21 (if QTcF ≤450 msec) 
6.4.1.3 
Cycle 1 Day 14  
• Physical examination and vital signs 
• ECOG performance status 
• AE monitoring 
• Concomitant medication review 
• CBC and clinical chemistry panel 
• ECG and QTc assessment (if QTcF >470 msec, see Appendix F)  
6.4.1.4 
Cycle 1 Day 21 (Response assessment) 
• Physical examination and vital signs 
• ECOG performance status 
• AE monitoring 
• Concomitant medication review 
• CBC and clinical chemistry panel 
• BM biopsy and aspirate with FLT3 mutation testing via PCR  
• ECG 
6.4.1.5 
 Cycle 1 Day 35 (± 7 days) (BM recovery) 
• Physical examination and vital signs 
• ECOG performance status 
• AE monitoring 
• Concomitant medication review 
• CBC and clinical chemistry panel 
• BM biopsy and aspirate for MRD assessment via next-generation sequencing (NGS) and 
FLT3 mutation testing via PCR 
6.4.1.6 
Cycle 2, Days 1 and 3 (re-induction, only applicable if patient achieves PR with 
recovery bone marrow after Cycle 1) 
• Physical examination and vital signs (Days 3 and 5) 
• ECOG performance status (Days 3 and 5) 
• AE monitoring 
• Concomitant medication review 
• CBC and clinical chemistry panels 


 
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• CPX-351 administration (Days 1 and 3) 
6.4.1.7 
Cycle 2, Day 6 
• Physical examination and vital signs 
• ECOG performance status 
• AE monitoring 
• Concomitant medication review 
• CBC and clinical chemistry panels 
• ECG and QTcF assessment (if QTcF ≤470 msec, resume quizartinib) 
• Quizartinib (daily on Days 6-21, if QTcF ≤470 msec) 
6.4.1.8 
Cycle 2 Day 14  
• Physical examination and vital signs 
• ECOG performance status 
• AE monitoring 
• Concomitant medication review 
• CBC and clinical chemistry panel 
• ECG and QTc assessment (if QTcF >470 msec, see Appendix F) 
6.4.1.9 
Cycle 2 Day 21 (Response assessment) 
• Physical examination and vital signs 
• ECOG performance status 
• AE monitoring 
• Concomitant medication review 
• CBC and clinical chemistry panel 
• BM biopsy and aspirate with FLT3 mutation testing via PCR 
• ECG  
6.4.1.10 Cycle 2 Day 35 (±7) (BM recovery) 
• Physical examination and vital signs 
• ECOG performance status 
• AE monitoring 
• Concomitant medication review 


 
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• CBC and clinical chemistry panel 
• BM biopsy and aspirate for MRD assessment via next-generation sequencing (NGS) and 
FLT3 mutation testing via PCR 
 
Consolidation Phase (If applicable) 
• Patients who achieve CR and do not receive an alloHCT or other CT intervention will 
receive up to 2 cycles of consolidation therapy with CPX-351 and quizartinib.  
• Serum pregnancy test once per cycle during the consolidation phase 
6.4.2.1 
Cycle 1, Day 1 and 3 
• Physical examination and vital signs 
• ECOG performance status 
• AE monitoring 
• Concomitant medication review 
• CBC and clinical chemistry panel 
• CPX-351 (Days 1 and 3) 
• ECG (Day 3) 
6.4.2.2 
Cycle 1, Day 6 
• Physical examination and vital signs 
• ECOG performance status 
• AE monitoring 
• Concomitant medication review 
• CBC and clinical chemistry panel 
• ECG and QTcF assessment (if QTcF ≤470 msec, resume quizartinib on Day 4) 
• Quizartinib (begin daily until Day 21) 
6.4.2.3 
Cycle 1 Days 14 and 21 
• ECG 
6.4.2.4 
Cycle 1 Day 35 (±7 days) (BM recovery) 
• Physical examination and vital signs 
• ECOG performance status 
• AE monitoring 
• Concomitant medication review 
• CBC and clinical chemistry panel 
• BM biopsy and aspirate for MRD assessment via next-generation sequencing (NGS) and 
FLT3 mutation testing via PCR 


 
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6.4.2.5 
Cycle 2, Days 1 and 3 (if applicable)  
• Physical examination and vital signs 
• ECOG performance status 
• AE monitoring 
• Concomitant medication review 
• CBC and clinical chemistry panel 
• CPX-351 (Days 1 and 3) 
• 
 ECG (Day 3) 
6.4.2.6 
Cycle 2, Day 6 
• Physical examination and vital signs 
• ECOG performance status 
• AE monitoring 
• Concomitant medication review 
• CBC and clinical chemistry panel 
• ECG and QTcF assessment (if QTc ≤470 msec, resume quizartinib) 
• Quizartinib (begin daily until Day 21) 
6.4.2.7 
Cycle 2 Days 14 and 21 
• ECG 
6.4.2.8 
Cycle 2, Day 35 (±7 days) 
• Physical examination and vital signs 
• ECOG performance status 
• AE monitoring 
• Concomitant medication review 
• CBC and clinical chemistry panel 
• BM biopsy and aspirate with FLT3 mutation testing via PCR 
• MRD assessment with BM biopsy and aspirate via NGS 
 
alloHCT or other CT intervention (within the 30-60 day time period between 
consolidation and maintenance treatment) 
• Physical examination and vital signs 


 
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• ECOG performance status 
• AE monitoring 
• Concomitant medication review 
• CBC and clinical chemistry panel 
• BM biopsy and aspirate with FLT3 mutation testing via PCR (~ Day 30) 
• MRD assessment with BM biopsy and aspirate via NGS 
 
Maintenance Phase 
The maintenance phase consists of quizartinib monotherapy once daily in 28-day cycles for a 
total of 24 cycles or until disease relapse. Maintenance dosing of quizartinib PO will begin at 
30 mg/day on Days 1-14, and if there are no toxicities and QTcF is maintained ≤450 msec, the 
dose will increase to 60 mg/day on Day 15. The following procedures and tests will be 
performed at these visits: 
• Serum pregnancy test once  every 3 cycles during the maintenance phase 
6.4.4.1 
Cycles 1-24, Days 1 and 15 
• Physical examination and vital signs 
• ECOG performance status 
• AE monitoring 
• Concomitant medication review 
• CBC and clinical chemistry panel 
• BM biopsy and aspirate with FLT3 MRD NGS mutation testing (Day 24 ±3 days) at 
Cycle 3, 6, 12 and 24 
• ECG and QTcF assessment (if QTcF ≤470 msec, continue quizartinib; if QTcF >470 
msec, see Appendix F)  
 
End of Treatment/Early Termination Visit 
Patients will complete the study at the time of PD, if they withdraw consent, if they withdraw 
due to an AE, or at the time the study is terminated. If either study treatment or patients are 
discontinued, the reason will be recorded in the eCRF and source document.  Patients who are 
removed from treatment for reasons other than death or disease progression (PD) are considered 
to be patients who have terminated early. Reasons for discontinuation include one of the 
following: AEs, protocol violation, patient withdraws consent, patient is lost to follow-up, 
administrative reasons (including study closure), death, or other.  Patients who complete or 
discontinue from the study should have the following study completion/early withdrawal 
evaluations performed as soon as possible after the day of study completion/early withdrawal.  
• Physical examination and vital signs 


 
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• ECOG performance status 
• AE monitoring 
• Concomitant medication review 
• CBC and clinical chemistry panels 
• BM biopsy and aspirate with FLT3 mutation testing, if applicable 
• ECG and QTcF assessment, if applicable 
Patients prematurely discontinuing from the study must be followed for AE and concomitant 
medication use for 30 days following the last administration of study drugs or until 
resolution/stabilization of an ongoing AE attributed to the medication.  
Patients who discontinue from the study may be treated with other therapies at the discretion of 
the Investigator. 
 
Long-Term Follow-up  
A formal end-of-study visit will be performed every 6 months for 2 years post-study treatment. 
The following procedures and tests will be done: 
• Disease response assessment per CIBMTR classification (Appendix E) 
• Survival status 
 
Study Assessments 
 
Medical History and Demographics 
A complete medical history will be taken.  Information to be documented includes 
demographics, prior medical illnesses and conditions, prior surgical procedures, date and stage of 
original diagnosis and details of prior chemotherapy/radiotherapy administered and other 
treatments for cancer (including type of drugs, dosages, schedule or administration, response and 
response duration). 
 
Physical Examinations (Including Performance Scale and Vital Signs) 
A complete physical examination will be done at baseline, at each visit, at the end-of-treatment 
visit, and long-term follow-up visit as well as at the discretion of the Investigator.  Examinations 
will include documentation of height (at screening only), weight, vital signs, and ECOG 
performance status (Appendix A).  Any abnormal or clinically significant findings from the 
physical examination must be recorded on the appropriate eCRF page. 
 
12-Lead Electrocardiogram 
Triplicate ECGs recording will be performed according to Appendix D and at the discretion of 
the Investigator.  Each will be performed with the patient in a supine position having rested in 
this position for at least 5 minutes before the reading.  If QTcF prolongation develops from the 
time of initial screening to the day of quizartinib administration (i.e. Day +8 of induction), 
concomitant medications, and electrolytes should be assessed for a reversible cause.  ECGs may 


 
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be repeated daily for up to 3 days from the original start date to assess for correction and to meet 
the eligibility criteria to administer quizartinib (see Section 3.2).   
 
Cardiac Echocardiogram 
A TTE or MUGA will be obtained upon enrollment, prior to initiation of treatment, and within 1 
week prior to consolidation treatment (Day 1). 
 
Pregnancy Testing 
In women of child-bearing potential, a serum beta human chorionic gonadotropin pregnancy test 
must be done 72 hours prior to the start of treatment.  Serum Pregnancy tests are also required prior 
to the start of each cycle during the induction and consolidation phases, during maintenance phase a 
serum pregnancy test will obtained once every 3 cycles.   
 
Laboratory Assessments 
Laboratory samples (CBC, clinical chemistry, urinalysis, and virology) are to be collected as 
outlined in Appendix D.  Laboratory results will be graded using NCI CTCAE Version 5.0. 
 
FLT3 Mutation PCR Testing 
The presence of the FLT3-ITD mutation will be detected using PCR from bone marrow 
aspiration samples collected with all planned BM samples.  Next-generation sequencing of MRD 
by FLT3-ITD mutational analysis will be performed with all planned BM biopsies, excluding 
screening and the Day +21 induction response assessment.  The presence of FLT3-ITD for 
inclusion is defined as positive if the PCR assay detects tandem duplication at 3% or higher. 
 
Response and Activity Assessments 
See Section 6.5.11 and Section 9. 
 
Adverse Event Assessments  
Information regarding the occurrence of AEs, including infections, will be collected from the 
time the patient signs the ICF throughout their participation in the study, including a period of 
30 days after the last dose of study drug.  Adverse event severity will be determined using the 
CTCAE Version 5.0 grading scale.  See Section 11 for more details. 
 
Prior and Concomitant Medications 
All concomitant medications are to be collected and recorded from the time the patient signs the 
ICF and throughout the patient’s participation in the study.  
 
Bone Marrow Aspirates and Biopsies 
Response assessment by BM biopsies and aspirates will be collected at Day 21 (±2 days) of 
induction (and re-induction therapy, if applicable), as well as at the time of count recovery after 
CPX-351 + quizartinib, defined as obtaining a BM biopsy within 4 days of having an ANC >500µL 
for ≥24 hours (at Day 35 [±7 days] during induction and consolidation therapy).  Bone marrow 
biopsies and aspirates will also be collected after Cycles 3, 6, 12, and 24 in the maintenance 
phase.  Thereafter, assessment of disease status will be at the discretion of the primary treating 
hematologist/oncologist.   


 
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All biopsies will include monitoring for FLT3 mutation by PCR.  Additional studies, including 
fluorescence in situ hybridization (FISH), cytogenetics, and/or molecular analyses, should be 
obtained based upon known mutations at the discretion of the physician. 
 
Minimal Residual Disease Assessment 
Invivoscribe, Inc. will use an assay to determine MRD status after treatment with quizartinib and 
CPX-351. Minimal residual disease is defined as the minimal traceable persistence of leukemia 
after treatment. 
The assay uses PCR amplification of exons 14 and 15 of FLT3.  The PCR primers contain gene-
specific regions that are coupled with NGS adaptors designed to identify ≥1 FLT3-ITD-
containing cell in 10,000 BM cells. An MRD- status will be defined as all results from BM that 
are negative for the presence of residual clonal cells (<1 FLT3-ITD-containing cell in 10,000 
bone marrow cells). A MRD+ status will be defined as all results from whole blood or BM that 
are positive for residual clonal cells (≥1 FLT3-ITD-containing cell in 10,000 bone marrow cells). 
In addition to MRD positivity or negativity, MRD level will be monitored, and the number of 
residual clonal cells per 10,000 cells will be recorded as well as the total number of cells 
evaluated in the sample (Levis 2018b). 
MRD analysis of FLT3-ITD mutations will occur with all recovery marrows with induction and 
consolidation cycles (if applicable) Day 35 (+/- 7 days) post-cellular therapy intervention (if 
applicable), as well as with bone marrow biopsies obtained during the maintenance phase.  To 
monitor for molecular recurrence of disease, BM biopsies and aspirates will be collected at Day 
24 (+/- 3 days) Cycles 3, 6, 12, and 24 during the maintenance phase.  
7. 
DRUG FORMULATION, AVAILABILITY, ADMINISTRATION, AND 
TOXICITY INFORMATION 
 
Quizartinib 
Investigational Product 
Dosage Form and Strength 
Manufacturer 
Quizartinib 
20- and 30-mg tablets 
Daiichi Sankyo 
 
Quizartinib Treatment Duration 
Patients will receive oral quizartinib once daily, on Days 8-21 of the induction cycle and Days 6-
21 of re-induction, if necessary.  Administration cannot begin earlier than 24 hours from the last 
administration of CPX-351.  During the consolidation cycles(s), quizartinib begins on Day 6. 
Prior to initiation (≤24 hour),  ECGs in triplicate will be obtained to assess QTcF.  If the QTcF is 
≤450 msec, treatment with quizartinib may proceed (see Section 8).  Patients proceeding to an 
additional cycle of induction as well as those proceeding to consolidation therapy must ensure 
the FLT3 inhibitor has not been administered before a 4-5 half-life reduction of quizartinib, 
equivalent to 3 days from the date of last administration.  


 
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After induction and consolidation cycles, patients will start maintenance therapy with 
quizartinib, continuing treatment on Days 1-28 of a 28-day cycle for a total of 24 maintenance 
cycles. 
 
Labeling, Packaging, and Supply of Quizartinib 
Quizartinib tablets will be supplied in high density polyethylene (HDPE) bottles with child-
resistant caps. 
All study drugs must be kept in a secure place under appropriate storage conditions.  Storage 
conditions for quizartinib are included in the USPI. 
 
Preparation and Administration of Quizartinib 
Quizartinib is administered orally. Each 20-mg tablet contains 20 mg quizartinib dihydrochloride 
(17.7 mg free base) and 200 mg HPβCD. The 20-mg tablets also contain microcrystalline 
cellulose, magnesium stearate, and Opadry® white film coating. Each 30-mg tablet contains 30 
mg quizartinib dihydrochloride (26.5 mg free base) and 300 mg HPβCD. The tablets also contain 
microcrystalline cellulose, magnesium stearate, and Opadry® yellow film coating. 
Preparation and administration instructions will be provided in the quizartinib Investigator’s 
Brochure (IB) and in the USPI. 
 
CPX-351 Treatment Duration 
Patients will be administered CPX-351 (daunorubicin 44 mg/m2 IV and cytarabine 100 mg/m2 
IV) on Days 1, 3, and 5 of the induction cycle.  As noted in Section 5, re-induction with CPX-
351 (daunorubicin 44 mg/m2 IV and cytarabine 100 mg/m2 IV) on Days 1 and 3 should occur in 
patients with an incomplete response in the recovery marrow biopsy, defined as a >50% 
reduction in the blast count to cellularity ratio compared to the most recent BM biopsy prior to 
induction.  Following induction, a total of 2 cycles of consolidation will occur with CPX-351 
(daunorubicin 29 mg/m2 IV and cytarabine 65 mg/m2 IV) administered on Days 1 and 3. 
 
Labeling, Packaging, and Supply of CPX-351 
Daunorubicin and cytarabine liposome for injection is supplied as a sterile, preservative-free, 
purple, lyophilized cake, in a single-dose vial. Each CPX-351 vial contains 44 mg daunorubicin 
and 100 mg cytarabine.  Store unreconstituted CPX-351 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 it 
from light. 
 
Preparation and Administration of CPX-351 
Intravenous infusion of CPX-351 (cytarabine:daunorubicin liposome complex) requires a 
central venous catheter or a peripherally inserted central catheter. CPX-351 is administered 
over 90 minutes. 
Preparation and administration instructions will be provided in the CPX-351 
(cytarabine:daunorubicin liposome complex) IB and in the USPI. 


 
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Accountability for All Study drugs 
The PI (or designee) is responsible for accountability of all used and unused study drug supplies 
at the site.  Development Innovations representatives must be granted access on reasonable 
request to check drug storage, dispensing procedures, and accountability records. 
All study drug inventories must be made available for inspection by the Sponsor or its 
representatives and regulatory agency inspectors upon request. 
At the end of the study, all Development Innovations Drug Accountability Record Form(s) will 
be completed by the site and sent to the Development Innovations Regulatory Department.  
Study drug supplies must not be destroyed unless prior approval has been granted by the Sponsor 
or its representative.  Please contact the Development Innovations regarding disposal of any 
study drug reserves. 
 
Toxicity of Study Treatments and Study Regimens 
 
Precautions and Risks Associated with Quizartinib 
A Phase I dose-finding study using quizartinib as monotherapy in refractory AML demonstrated 
an ORR of 30% and a median DOR of 13.3 weeks (Cortes et al 2013).  All grades of toxicities 
included nausea (16%), prolonged QT interval (12%), vomiting (11%), and dysgeusia (11%).  In 
a randomized Phase II study using either 30 mg or 60 mg of quizartinib as monotherapy, the 
patients taking the 30 mg daily dose were found to have a lower incidence of Grade ≥2 QTcF 
prolongation (11%) compared to those who received 60 mg daily (17%).  For both dosing 
groups, other toxicities included diarrhea (18%) and febrile neutropenia (16%) (Schiller et al 
2014).  Additionally in greater than 10% of patients infection, decreased appetite, hemorrhagic 
events, abdominal pain, painful swelling, sores in the mouth, rash, asthenia or fatigue, pyrexia, 
peripheral edema, abnormal hepatic function, mineral deficiency, enzyme deficiency, anemia, 
and weight loss were reported (Quizartinib Investigator Brochure 2020). 
 
Myelosuppression 
Serious AEs of myelosuppression (e.g., febrile aplasia, neutropenia, BM hypocellularity, 
lymphocytopenia, anemia, thrombocytopenia, and pancytopenia) have been observed, which 
may result in infections or hemorrhage.  Resulting infections (particularly, but not exclusively, 
fungal and other opportunistic infections, Gram-negative bacterial infections, and 
bacteremia/septicemia/sepsis) or hemorrhage (e.g., epistaxis, hemoptysis, melena, 
gastrointestinal bleeding, and hemorrhage intracranial) may be severe, including fatal outcomes.  
Reports of infection have often been in the context of neutropenia, fever, or both. 
QTc Prolongation, Torsades de Pointes 
Quizartinib is associated with QTc interval prolongation.  QTc interval prolongation may 
increase the risk of ventricular arrhythmias or TdP.   
Regarding review of clinical events potentially associated with QT prolongation (Refer to IB for 
details): 
Completed studies: 


 
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• Of the 241 patients treated with quizartinib in the completed Phase 3 clinical study in adults 
with relapsed or refractory AML (Study AC220-007), 3.3% were found to have a QTcF 
interval greater than 500 msec, and 12.4% had an increase from baseline QTcF greater than 
60 msec based on central review of ECG data; there were no cases of TdP, cardiac arrest or 
sudden death reported at the recommended doses (i.e., 30 mg or 60 mg).  .  In the remaining 
studies (AC220-002, 2689 CL 2004, CP0001, and 2689-CL-0005): there was 1 subject with 
TdP (in a phase 2 study while receiving a dose of 90mg; the event resolved after 
discontinuation of quizartinib, see below for details), 5 subjects with cardiac arrest/cardio-
respiratory arrest, and 3 subjects with ventricular tachycardia reported.  Overall, after 
individual review of these events with two external cardiac electrophysiology experts, the 1 
event of TdP was associated with QT prolongation, and in 1 of the events of cardiac arrest, a 
potential arrhythmia event cannot be excluded. 
• In the ongoing blinded AC220-A-U302 study in which quizartinib is given in combination 
with chemotherapy, 6 events of cardiac arrest/cardio-respiratory arrest (5 fatal and 1 non-
fatal) and 1 event of sudden death have been reported with quizartinib (See IB section 5.3.6 
for further details).  Of these, one fatal and one non-fatal cardiac arrest events were due to 
ventricular fibrillation, and both occurred in the setting of Grade 3 or 4 hypokalemia.  These 
events highlight the importance of monitoring and correcting electrolytes, such as potassium, 
that may result in QT prolongation as an independent risk factor.  The remaining events of 
fatal cardiac arrest occurred in the setting of other significant concurrent disease (severe 
sepsis /septic shock, multi-organ failure) with complications and no subject had evidence of 
QT prolongation at the time of the event (all reported QTcF were <450ms). 
 
 Quizartinib should be not be used in subject with long QT syndrome. Quizartinib should be used 
with caution in patients who are at significant risk of developing QTc interval prolongation.  
These include patients with uncontrolled or significant cardiovascular disease, congestive heart 
failure, , hypokalemia and hypomagnesemia, and history of clinically relevant ventricular 
arrhythmias or TdP and patients receiving concomitant drugs known to prolong the QTc, 
interval.  Electrolytes should be maintained in the normal range.  Concomitant use with CYP3A 
inhibitors may increase quizartinib exposure, and therefore, the dose of quizartinib should be 
reduced.  Specific instructions regarding ECG monitoring, quizartinib dose 
interruption/reduction and restrictions of concomitant use of other QTc-prolonging drugs are 
provided in Section 8 and Appendix F. 
Quizartinib is an IKs inhibitor and is associated with QTc prolongation in a dose-dependent 
manner.  As an IKs inhibitor, quizartinib differs from other agents that can prolong QTc which 
are IKr inhibitors.  Inhibition of either IKs and/or IKr potassium channels may carry increased risk 
of cardiac events.  In Study AC220-007, TEAEs of ECG QT prolonged were reported for 26.6% 
of patients in the quizartinib arm and 2.1% of patients in the salvage chemotherapy arm. Ten 
patients (4.1%) had a Grade 3 event, and no patient had a Grade 4 event. In the quizartinib arm, 
TEAEs of ECG QT prolonged were associated with study drug interruption for 11 (4.6%) 
patients, dose reduction for 23 (9.5%) patients, and study drug discontinuation for 2 (0.8%) 
patients (both Grade 2 events). 


 
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Eight (3.3%) patients in the quizartinib arm had ECG QTcF values >500 msec (Grade 3 QTcF) 
by central ECG reading.  None of these patients had sequelae (e.g., associated ventricular 
arrhythmias), and all were able to either continue with the same dose of quizartinib or resume at 
the same or reduced dose after an interruption with no further occurrences of Grade 3 QTcF. 
There were no cases of cardiac arrest, sudden death, or TdP in the quizartinib arm. 
Torsades de Pointes is an identified ADR for quizartinib.  There was 1 case of TdP in a 63-year-
old female patient in Study AC220-002 with history of atrial fibrillation.  This patient was taking 
concomitant medications known to cause QT prolongation and/or increase quizartinib exposure.  
On Day 20 of quizartinib 90 mg therapy, QTcF was 543 msec (baseline: 418 msec) and a 15-beat 
episode of TdP was noted, which terminated spontaneously.  It should be noted that this patient 
had Klebsiella bacteremia/sepsis with episodes of respiratory arrest prior to TdP and was also 
noted to have hypocalcemia (1.66 mmol/L; reference range: 2.10 to 2.55 mmol/L).  Quizartinib 
was discontinued, and the event resolved the same day. 
In review of all potential arrhythmia events associated with QT prolongation from the entire 
quizartinib program (and presented in IB v 14 Section 5.3.6), the following notable events, 
which occurred while on treatment with quizartinib, are summarized below: 
• Completed Studies: ):  
o A fatal cardiocardiopulmonary arrest occurred in a 39-year-old female patient 
with staph aureus sepsis on Day 40 when dosing of quizartinib monotherapy was 
135 mg daily, increased 4 days prior to event with QTcF values were 471 msec, 
459 msec, and 496 msec at 1 day, 3 days, and 4 days prior to the fatal event, 
respectively. 
• Ongoing studies: (Ongoing study AC220-A-U302  
o A fatal cardiac arrest occurred in a 54-year-old female patient on Day 79 with 
ventricular fibrillation and Grade 3 hypokalemia on the preceding day. While the 
investigator assessed the event as not related, the Sponsor assessment was related. 
o A non-fatal cardiac arrest occurred in a 63-year-old female on Day 5 in the setting 
of Grade 4 hypokalemiaIn the ongoing blinded AC220-A-U302 study in which 
quizartinib is given in combination with chemotherapy, 6 events of cardiac 
arrest/cardio-respiratory arrest (5 fatal and 1 non-fatal) and 1 event of sudden 
death have been reported with quizartinib.  Of these, one fatal and one non-fatal 
cardiac arrest events were due to ventricular fibrillation, and both occurred in the 
setting of Grade 3 or 4 hypokalemia.  These events highlight the importance of 
monitoring and correcting electrolytes, such as potassium, that may result in QT 
prolongation as an independent risk factor.  The remaining events of fatal cardiac 
arrest occurred in the setting of other significant concurrent disease (severe sepsis 
/septic shock, multi-organ failure) with complications and no subject had 
evidence of QT prolongation at the time of the event (all reported QTcF were 
<450ms).  
One case of sudden death was reported with limited information in a 69-year-old male with 
history of hypertension and diabetes who died in his sleep 10 days after the last dose of 


 
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quizartinib on Day 111. The patient was last seen by the site on Day 100, and there were no 
adverse events reported from this visit. During the >3 month duration of the study, no other 
cardiac AE’s were reported, and all QTcF were <480 msec. The investigator reported that the 
cause of death is most likely related to underlying AML. 
These events highlight the importance of ECG monitoring, appropriate dosing and dose 
modifications for QTcF and concomitant use of strong CYP3A inhibitors, monitoring and 
correcting electrolytes, such as potassium, and magnesium, as electrolyte abnormalities are an 
independent risk factor.  
A review of additional safety data inthe Investigator’s Brochure  did not identify new TEAEs in 
the TdP/QT Prolongation SMQ or additional patients with QTcF >450 msec. 
Differentiation Syndrome 
Quizartinib can cause terminal differentiation of AML blast cells in patients with relapsed or 
refractory disease (Sexauer et al 2012).  Terminal differentiation of AML blast cells may be 
associated with the development of differentiation syndrome (DS) and may be life-threatening or 
fatal if not treated.   
DS is a severe inflammatory reaction with increased capillary permeability.  Symptoms of DS are 
dyspnea, hypoxia, fever, peripheral edema, hypotension, weight gain, pleuro-pericardial effusion, 
pulmonary infiltrated, acute renal failure, musculoskeletal pain, and hyperbilirubinemia, 
peripheral edema, hepatic, renal, or multi-organ dysfunction.  Less commonly, DS might present 
with pulmonary hemorrhage or acute febrile neutrophilic dermatosis. 
It is important to promptly recognize the signs and symptoms of DS and implement appropriate 
treatment.  Patients with suspected DS should promptly start treatment with systemic 
glucocorticoids and hemodynamic monitoring until improvement (Quizartinib Investigator 
Brochure 2020). 
 
Precautions and Risks Associated with CPX-351 
• Cardiotoxicity 
The total cumulative dose of non-liposomal daunorubicin >550 mg/m2 has been associated 
with an increased incidence of drug-induced congestive heart failure. In patients who 
received radiation therapy, the maximum tolerable lifetime dose is 400 mg/m2. Calculate 
maximum lifetime exposure prior to each cycle as shown in Table 1. 
Table 1 
Cumulative Exposure of Daunorubicin per Cycle of CPX-351 
Therapy 
Daunorubicin per 
Dose 
Number of Doses per 
Cycle 
Daunorubicin per 
Cycle 
First induction cycle 
44 mg/m2 
3 
132 mg/m2 
Second induction cycle 
44 mg/m2 
2 
88 mg/m2 
Each consolidation cycle 
29 mg/m2 
2 
58 mg/m2 


 
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See dose modification/administration guidelines (Appendix G). 
• Hemorrhage 
12% Grade ≥3 (8% in control/7+3 arm), fatal non-disease associated CNS hemorrhage 2% 
(0.7% in control arm) 
• Hypersensitivity 
Known in patients receiving cytarabine and daunorubicin.  See dose 
modification/administration guidelines (Appendix G). 
• Tissue necrosis 
Administer by central venous catheter 
• Embryo-fetal toxicity 
Counsel to avoid pregnancy, and to use contraception through 6 months after last 
administration of agent.  Because of the potential for serious adverse reactions in breastfed 
infants, advise lactating women not to breastfeed during treatment with CPX-351. In males, 
CPX-351 may cause infertility.  In male patients wishing to conceive in the future, 
cryopreservation of sperm prior to administration is recommended. 
• Cytopenias 
Prolonged thrombocytopenia (<50 beyond Day 42) 28% (versus 12%) in induction and 25% 
(versus 16%) in consolidation; prolonged neutropenia (ANC <500 beyond Day 42) 17% 
(versus 3%) in induction and 10% (versus 3%) in consolidation. See dose 
modification/administration guidelines (Appendix G). 
• Chemistry abnormalities 
Hyponatremia (14%, 6% with consolidation), hypokalemia (9%, 6% with consolidation), 
hypoalbuminemia (7%, 2% with consolidation), hyperbilirubinemia (6%, 2% with 
consolidation), and elevated ALT (5%, 0% with consolidation); all were similar in 
comparison to 7+3.  
The most common serious adverse reactions (incidence ≥5%) were dyspnea, myocardial 
toxicity, sepsis, pneumonia, febrile neutropenia, bacteremia and hemorrhage. Adverse 
reactions led to discontinuation of CPX-351 in 18% of patients (13% in the control arm).  
The adverse reactions leading to discontinuation on the CPX-351 arm included prolonged 
cytopenias, infection, cardiotoxicity, respiratory failure, hemorrhage (GI and CNS), renal 
insufficiency, colitis, and generalized medical deterioration.  
The most common adverse reactions (incidence ≥25%) in patients on the CPX-351 arm were 
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. 


 
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8. 
DOSE MODIFICATIONS 
If toxicity occurs, the toxicity will be graded using the NCI CTCAE Version 5, and appropriate 
supportive care treatment will be administered to decrease the signs and symptoms thereof. Dose 
adjustments will be based on the organ system exhibiting the greatest degree of toxicity. 
 
Criteria and Procedures for Dose Interruptions and Adjustments of Quizartinib 
The following are reasons for quizartinib dose reduction or dosing interruption: 
• Adverse event: QTcF prolongation, other non-hematologic toxicities, or 
myelosuppression 
• Concomitant administration of a strong CYP3A4 inhibitor 
Guidance on dose reductions and interruptions of quizartinib during the induction and 
consolidation phases as well as the maintenance phase are presented in Table 2 and Table 3, 
respectively. 
The dose of quizartinib will not be reduced lower than 30 mg/day in any phase of the study (not 
lower than 20 mg/day for patients receiving strong CYP3A4 inhibitors. For AE toxicity 
management with concomitant strong CYP3A4 inhibitor, the dose of quizartinib will not be 
reduced lower than 20 mg/day refer to Table 2 for more information). 
If quizartinib is interrupted, doses will not be made up. 
Table 3 
Dose Level Modifications – Induction and Consolidation Phases 
Induction and Consolidation Phase 
Full Dose 
AE, no concomitant 
strong CYP3A4 
inhibitor 
Concomitant strong 
CYP3A4 inhibitor 
AE and 
concomitant strong 
CYP3A4 inhibitor 
QTcF  
prolongation 
30 mg/day 
20 mg/day 
20 mg/day 
Interrupta 
See Section 8.2.1 
aRefer to  Appendix F for duration of interruption. Missed doses will not be made up. 
Table 4 
Dose Level Modifications – Maintenance Phase 
Maintenance Phase 
 
 
Full 
Dose 
AE, no 
concomitant 
strong CYP3A4 
inhibitor 
Concomitant 
strong CYP3A4 
inhibitor 
AE and 
concomitant strong 
CYP3A4 inhibitor 
QTcF  
prolongation 
Days 1-
14 
30 
mg/day 
20 mg/day 
20 mg/day 
Interrupta 
See Section 8.2.1 
Days 15 
onward 
60 
mg/day 
40 mg/dayb 
30 mg/dayc 
30 mg/dayd 
See Section 8.2.1 


 
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aRefer to Appendix Ffor duration of interruption. Missed doses will not be made up. 
bCan be further reduced to 30 mg/day, if necessary 
cCan be further reduced to 20 mg/day, if necessary 
dCan be interrupted, if necessary 
 
Management of Quizartinib-Associated Adverse Events 
Management for quizartinib-associated AEs is located in Appendix F. 
 
Criteria and Procedures for Dose Modification due to QTcF Prolongation 
Electrolytes (potassium and magnesium) should be checked and supplementation given to 
correct any values outside the normal range.  Concomitant medications should be reviewed to 
identify and, if appropriate, discontinue any medication with known QT prolonging effects (see 
Appendix F).  In addition hypomagnesemia, hypokalemia, and hypomagnesemia abnormalities 
can affect the QT interval.  Upon identification of QTcF prolongation, it is advised to assess the 
subject’s electrolytes (including potassium and magnesium) and manage per local institutional 
standards. 
Patients who experience >480 msec QTcF prolongation and undergo dose interruption and/or 
reduction must be monitored closely with ECGs, performed twice weekly for the first week of 
the QTcF prolongation and then weekly thereafter until the QTcF prolongation is resolved.  If 
QTcF is > 450, evaluation of concomitant medications and electrolyte levels (including 
potassium and magnesium) are advised to assess for potential etiologies. Repeating ECGs daily 
for up to 3 days can occur to determine if the QTcF improves to allow administration of 
quizartinib.   
 
Management of CPX-351-Related Adverse Events 
Management for CPX-351-related AEs is located in Appendix G. 
 
Criteria and Procedures for Dose Interruptions and Adjustments of CPX-351 
If a patient develops non-hematologic Grade ≥3 AE(s) without resolution by 28 days from the 
first administration, or develop prolonged hematologic toxicities Grade ≥3 without count 
recovery 56 days or longer from first administration, the AEs will be considered severe AEs. 
However, this will not remove the patient from staying on study to receive quizartinib unless the 
PI believes quizartinib will exacerbate or prolong the toxicity. 
9. 
RESPONSE EVALUATIONS AND MEASUREMENTS 
 
Complete Response (CR) 
A CR will be defined as no morphologic, immunohistochemical, or flow cytometric evidence of 
disease by BM biopsy/aspirate and a peripheral CBC with platelet count ≥100,000/µL and ANC 
≥1000/uL  at the time of the bone marrow biopsy/aspirate.  A molecular CR (CRm) is defined as 
having no evidence of disease by BM biopsy/aspirate by morphology, immunohistochemistry, 
flow cytometry, and FLT3 mutation by MRD analysis.  Patients with a CR but with residual 
MRD positivity (CR MRD+) are classified as indicated. 


 
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Complete Response with Incomplete Hematologic Recovery (CRi) 
A CR with incomplete hematologic recovery (CRi) is defined as no morphologic, 
immunohistochemical, or flow cytometric evidence of disease by BM biopsy/aspirate, but with a 
persistent platelet count <100,000/µL and/or ANC <1000/µL at the time of BM biopsy/aspirate. 
 
Partial Response (PR) 
A PR is an incomplete response to treatment, defined as having persistent disease by 
morphology, but a >50% reduction in the blast count/cellularity ratio compared to the most 
recent BM biopsy prior to treatment. 
 
Treatment Failure 
Treatment failure is defined as patients who have achieved less than a PR at the time of response 
assessment. 
 
Duration of Response (DOR) 
Duration of response is defined as the number of days from the time of the first BM 
biopsy/aspirate where CR or CRi is identified to relapse.  Patients who demonstrate no evidence 
of disease and no relapse while on study or who died for reasons other than disease relapse will 
be censored at the date of the last disease assessment.. 
 
Time-to-Progression (TTP) 
Time-to-progression is defined as the number of days between diagnosis of relapse or refractory 
AML to disease progression, confirmed by bone marrow biopsy. 
 
Event-free Survival (EFS) 
Event-free survival is calculated as the number of days from the first date of treatment to the first 
date of evidence of PD by BM biopsy/aspirate, or death, regardless of cause.  Patients who are 
alive without a disease response assessment of relapsed disease will be censored at the last 
adequate disease assessment date.  Patients without a disease response assessment will be 
censored at the first date of treatment.  This calculation does not pertain to Long Term Follow-up 
data.  
 
Recurrence of Disease 
Recurrent malignancy will be defined by hematologic criteria.  Recurrent malignancy will also 
be defined as any unplanned medical intervention designed to prevent progression of malignant 
disease in patients who have molecular, cytogenetic, or flow cytometric evidence of malignant 
cells after transplantation.  
 
Overall Survival (OS)  
Overall survival is defined as the time from the first date of treatment until death as a result of 
any cause.  For OS time, patients that have not died or are lost to follow-up will be censored at 
the date the patient was last known to be alive or the date of last contact. 


 
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Time to Absolute Neutrophil Count (ANC) and Platelet Count Recovery 
Time to neutrophil recovery is defined as the time from each CPX-351 cycle Day 1 to when the 
peripheral ANC is ≥500/µL. Time to platelet recovery is defined as the time from each CPX-351 
cycle to when the peripheral blood platelet count is >50,000/ µL.  Delayed neutrophil recovery is 
defined as having an ANC <500/µL >56 days from each CPX-351 cycle Day 1. Delayed platelet 
recovery is defined as having a platelet count <50,000 >56 days from each CPX-351 cycle 
Day 1. 
10. 
STATISTICAL CONSIDERATIONS 
 
Statistical Design 
This is a multi-center, open-label, two-part prospective Phase II study of patients with relapsed 
or refractory FLT3-ITD mutation-positive AML.  The study is designed to assess the safety and 
tolerability as well as the efficacy of administering CPX-351 with quizartinib, a second-
generation FLT3 inhibitor.  
A response rate (CR + CRi) of ≥50% is targeted with 40% or less considered unacceptable.  This 
is assumed to be an acceptable estimate based on CR + CRi/CRp of 48.2% reported with 
quizartinib monotherapy in a relapsed or refractory patient with FLT3-ITD AML (Cortes et al 
2019). Of note, prior FLT3-targeting inhibitor exposure is permitted on this study. However, 
patients receiving a prior FLT3-targeting inhibitor were excluded in the QUANTUM-R study.  
Expected CR+CRi in relapsed or refractory patients receiving standard intensive or non-intensive 
salvage chemotherapy harboring an FLT3 mutation is 27% (Cortes et al 2019).  The estimated 
response in those with relapsed/refractory FLT3-ITD AML receiving CPX-351 alone cannot be 
estimated. However, in a poor-risk EPI patient population, CR+CRi was reported as 39.3% 
(Cortes et al 2015). However, FLT3-ITD mutation presence was not utilized in the generation of 
EPI prognostication, and those with an FLT3-ITD mutation could in fact have a reduced 
response within all EPI risk groups.  Thus, the expected response must be based upon the 
QUANTUM-R study of those receiving standard salvage options harboring an FLT3-ITD 
mutation. 
In the safety lead-in, 10 patients will be enrolled to receive CPX-351 with quizartinib. If >3 
patients experience delayed neutrophil count recovery >56 days or delayed thrombocytopenia 
recovery >56 days from the first day on the study regimen, or if >3 patients develop a non-
hematologic toxicity, defined as a Grade 4 non-hematologic AE determined to be probably 
related to the combined treatment or a Grade 4 neutropenia, then the study will be terminated. 
Assuming safety parameters are met, the first 10 patients will be followed for response in Part 2 
of the study.  
 
Sample Size Considerations 
The null hypothesis that the ORR (defined as CR + CRi) is ≤27% (Cortes et al 2019) will be 
tested against a one-sided exact alternative ORR of 50% at a target significance level of 0.05. A 
sample size of 30 evaluable patients achieves 80% power if the true ORR is ≥50%. The null 


 
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hypothesis will be rejected if 13 or more responses are observed in 30 evaluable patients. In 
order to allow for a non-evaluable rate of 10%, a total of 34 patients will be enrolled in the study. 
 
Analysis Population 
The following analysis populations will be used: 
• The Safety Analysis Set is defined as all patients who received at least one dose of CPX-
351 or quizartinib. 
• The Efficacy Analysis Set is defined as all patients who received at least one dose of 
CPX-351 or quizartinib, who have an adequate baseline disease assessment, and an 
adequate post-baseline assessment and who discontinue due to death or PD prior to their 
first assessment. 
 
Data Analysis 
Descriptive statistics, including mean, median, standard deviations, and ranges for all continuous 
measures, will be tabulated and reported. Percentages and frequencies for all categorical 
measures will also be presented. Time-to-event endpoints will be reported using Kaplan-Meier 
estimates, with 95% CIs for median time to event. 
 
Demographics and Baseline Characteristics 
Demographic and baseline disease characteristics will be summarized using descriptive statistics. 
Data to be tabulated will include demographic features such as age, sex, and race, as well as 
disease-specific characteristics. 
The number and percentages of patients enrolled, treated, completed the treatment/study and 
withdrawn from treatment/study for any reason will be presented. 
 
Efficacy Analysis 
All efficacy analyses will be performed using the Efficacy Analysis Set. 
The ORR is defined as the proportion of patients achieving a response of CR or CRi at the time 
of the recovery assessment. For ORR, point estimates and the associated 95% CIs (based on the 
Clopper-Pearson method) will be calculated. 
For DOR, the estimate of the median based on Kaplan-Meier analyses will be reported. For EFS 
and OS, the estimated rates at 6, 12, and 24 months based on Kaplan-Meier analyses will be 
reported. 
 
Safety Analysis 
Safety will be assessed through the analysis of the reported incidence of treatment-emergent 
AEs.  Treatment-emergent AEs are those with an onset on or after the initiation of therapy, and 
will be graded according to NCI CTCAE Version 5.0.  A copy of the CTCAE scoring system 
may be downloaded from: 
https://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/CTCAE_v5_Quick_R
eference_8.5x11.pdf. 


 
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The AEs will be coded using the Medical Dictionary for Regulatory Activities (MedDRA) and 
summarized using system organ class and preferred term for all patients in the Safety Analysis 
Set.  In addition, summaries of SAEs, AEs leading to treatment discontinuation, AEs by 
maximum NCI CTCAE grade, and AEs related to study treatment will also be presented. 
Other safety endpoints including laboratory results, vital signs, ECG findings, and other 
protocol-specified tests will be listed and/or summarized for all patients in the Safety Analysis 
Set. 
Concomitant medications will be coded using the WHO-Drug Dictionary, and they will be listed 
and summarized. 
 
Analysis Time Points 
 
Safety Review 
The safety lead-in consists of the first 10 patients enrolled.  If >3 patients experience delayed 
neutrophil count recovery >56 days from the first day receiving the study regimen, defined as 
having a peripheral blood ANC <500/µL without evidence of residual disease by BM biopsy, or 
if >3 patients develop a non-hematologic toxicity, defined as a Grade 4 non-hematologic AE 
determined to be probably related to the combined treatment, then the study will be terminated. 
 
Final Analysis 
The final analysis of the study will occur following the last visit of the last patient. 
11. 
SAFETY REPORTING AND ANALYSES 
Safety assessments will consist of monitoring and recording protocol-defined AEs, SAEs, and 
measurement of protocol-specified hematology, clinical chemistry, and urinalysis variables, and 
measurement of protocol-specified vital signs and other protocol-specified tests that are deemed 
critical to the safety evaluation of the study drug. 
The PI is responsible for recognizing and reporting AEs to the Development Innovations Safety 
Department (Section 11.1.5).  It is the Sponsor’s responsibility to report relevant SAEs to the 
applicable local, national, or international regulatory bodies.  In addition, the Investigator must 
report SAEs and follow-up information to the responsible IRB according to the policies of that 
IRB. 
The PI is also responsible for ensuring that every staff member involved in the study is familiar 
with the content of this section. 
 
Definitions 
 
Adverse Events 
Adverse event means any untoward medical occurrence associated with the use of a drug(s) in 
humans, whether or not considered drug-related.  An AE (also known as adverse experience) can 
be any unfavorable and unintended sign (e.g., an abnormal laboratory finding), symptom, or 
disease temporarily associated with the use of a drug, without any judgment about causality.  An 


 
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AE can arise with any use of the drug (e.g., off-label use, use in combination with another drug) 
and with any route of administration, formulation, or dose (including overdose). 
 
Serious Adverse Events 
An AE or a suspected adverse reaction (SAR) is considered “serious” if it results in any of 
the following outcomes: 
• Death 
• A life-threatening AE 
• Inpatient hospitalization or prolongation of an existing hospitalization 
• A persistent or significant incapacity or substantial disruption of the ability to 
conduct normal life functions 
• A congenital anomaly/birth defect 
Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered serious when, based upon appropriate medical judgment, they 
may jeopardize the patient and may require medical or surgical intervention to prevent one of the 
outcomes listed in this definition.  Examples of such medical events include allergic 
bronchospasm requiring intensive treatment in an emergency room or at home, blood dyscrasias 
or convulsions that do not result in hospitalization, or development of drug dependency or drug 
abuse. 
It is important to distinguish between “serious” and “severe” when describing AEs, as the terms 
are not synonymous.  Severity is a measure of intensity; however, an AE of severe intensity need 
not necessarily be considered serious.  Seriousness serves as the guide for defining regulatory 
reporting obligations.  “Serious” is a regulatory definition and is based on patient/event outcome 
or action usually associated with events that pose a threat to a patient’s life or vital functions.  
For example, nausea which persists for several hours may be considered severe nausea, but may 
not be considered an SAE.  On the other hand, a stroke which results in only a limited degree of 
disability may be considered only a mild stroke, but would be considered an SAE.  Severity and 
seriousness should be independently assessed when recording AEs on the eCRF and SAEs on the 
SAE Report Form. 
 
Adverse Reaction 
An adverse reaction means any AE caused by a drug.  Adverse reactions are a subset of all SARs 
for which there is a reason to conclude that the drug caused the event. 
 
Suspected Adverse Reaction 
Suspected adverse reaction (SAR) means any AE for which there is a reasonable possibility that 
the drug caused the AE.  Reasonable possibility means that there is evidence to suggest a causal 
relationship between the drug and the AE.  An SAR implies a lesser degree of certainty about 
causality than adverse reaction, which means any AE caused by a drug. 


 
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Recording and Reporting of Adverse Events 
11.1.5.1 Recording of Adverse Events 
All AEs will be recorded in the eCRF for all patients during the course of the research study, and 
the Investigator will give his or her opinion as to the relationship of the AE to the study treatment 
(e.g., whether the event is related or unrelated to study drug administration). 
A description of the event, including its date of onset and resolution, whether it constitutes an 
SAE or not, any action taken (e.g., changes to study treatment), and outcome should be provided 
along with the Investigator’s assessment of causality (e.g., the relationship to the study 
treatment).  For an AE to be a suspected TEAE, there should be at least a reasonable possibility 
of a causal relationship between the protocol treatment and the AE.  Adverse events will be 
graded according to the NCI CTCAE Version 5.0, and changes will be documented. 
If the AE is serious, it should be reported immediately to the Development Innovations Safety 
Department.  Other untoward events occurring in the framework of a clinical study are to be 
recorded as AEs (e.g., AEs that occur prior to assignment of study treatment that are related to a 
protocol-mandated intervention, including invasive procedures such as biopsies, medication 
washout, or no treatment run-in). 
Any clinically significant signs and symptoms, abnormal test findings, changes in physical 
examination, hypersensitivity, and other measurements that occur will be reported as AEs and 
collected on the relevant eCRF screen. 
Test findings will be reported as an AE if: the test result requires an adjustment in the study 
drug(s) or discontinuation of treatment; and/or test findings require additional testing or surgical 
intervention; a test result or finding is associated with accompanying symptoms; or a test result is 
considered to be an AE by the Investigator. 
11.1.5.2 Reporting Period for Adverse Events 
All AEs regardless of seriousness or relationship to the study treatment spanning from the 
signing of the ICF until 30 calendar days after discontinuation or completion of study treatment, 
as defined by this clinical study protocol, are to be recorded on the corresponding screen(s) 
included in the eCRF. 
All AEs resulting in discontinuation from the study should be followed until resolution or 
stabilization.  All new AEs occurring during this period must be reported and followed until 
resolution unless, in the opinion of the Investigator, the AEs or laboratory abnormality(ies) are 
not likely to improve because of the underlying disease.  In this case, the Investigator must 
record his or her reasoning for this decision in the patient’s medical record. 
After 100 days after completion of protocol-specific treatment or discontinuation, only AEs, 
SAEs, or deaths assessed by the Investigator as treatment-related are to be reported. 
 
Assessment of Adverse Events 
All AEs and SAEs whether volunteered by the patient, discovered by study personnel during 
questioning, or detected through physical examination, laboratory test, or other means will be 
reported appropriately.  Each reported AE or SAE will be described by its duration (e.g., start 


 
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and end dates), regulatory seriousness criteria if applicable, suspected relationship to the study 
drug (see following guidance), and actions taken. 
To ensure consistency of AE and SAE causality assessments, Investigators should apply the 
following general guideline: 
YES:  There is a plausible temporal relationship between the onset of the AE and 
administration of the study medication, and the AE cannot be readily explained by the 
patient’s clinical state, intercurrent illness, or concomitant therapies, and/or the AE 
follows a known pattern of response to the study drug, and/or the AE abates or resolves 
upon discontinuation of the study drug or dose reduction and, if applicable, reappears 
upon re-challenge. 
NO:  Evidence exists that the AE has an etiology other than the study drug (e.g., pre-
existing medical condition, underlying disease, intercurrent illness, or concomitant 
medication), and/or the AE has no plausible temporal relationship to study drug 
administration (e.g., cancer diagnosed 2 days after first dose of study drug). 
 
Serious Adverse Event Reporting by Investigators 
Adverse events classified by the treating Investigator as serious require expeditious handling and 
reporting to the Development Innovations Safety Department in order to comply with regulatory 
requirements.  Determination of “life-threatening” or “serious” is based on the opinion of the 
Investigator. 
Serious AEs may occur at any time from the signing of the ICF through the 30-day follow-up 
period after the last study treatment.  The Development Innovations Safety Department must 
be notified of all SAEs, regardless of causality, within 24 hours of the first knowledge of the 
event by the treating physician or research personnel. 
To report an SAE, the SAE Report Form should be completed with the necessary information. 
The SAE report should be sent to the Development Innovations Safety Department via fax or e-
mail using the following contact information (during both business and non-business hours): 
Development Innovations Safety Department 
Safety Dept. Fax #:      1-866-807-4325 
Safety Dept. Email:     CANN.SAE@SCRI-Innovations.com 
Transmission of the SAE report should be confirmed by the site personnel submitting the report. 
Follow-up information for SAEs and information on non-serious AEs that become serious should 
also be reported to the Development Innovations Safety Department as soon as it is available; 
these reports should be submitted using the Development Innovations SAE Report Form.  The 
detailed SAE reporting process will be provided to the sites in the SAE reporting guidelines 
contained in the study reference manual. 
Investigators must report SAEs and follow-up information to their responsible IRB according to 
the policies of the responsible IRB. 


 
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Recording of Adverse Events and Serious Adverse Events 
 
Diagnosis versus Signs and Symptoms 
All AEs should be recorded individually in the patient’s own words (verbatim) unless, in the 
opinion of the PI or designated physician, the AEs constitute components of a recognized 
condition, disease, or syndrome.  In the latter case, the condition, disease, or syndrome should be 
named rather than each individual sign or symptom.  If a constellation of signs and/or symptoms 
cannot be medically characterized as a single diagnosis or syndrome at the time of reporting, 
each individual event should be recorded as an AE or SAE as appropriate on the relevant form(s) 
(SAE Report Form and/or AE eCRF screen).  If a diagnosis is subsequently established, it should 
be reported as follow-up information is available.  If a diagnosis is determined subsequent to the 
reporting of the constellation of symptoms, the signs/symptoms should be updated to reflect the 
diagnosis. 
Progression of malignancy (including fatal outcomes), if documented by use of an appropriate 
method (for example, as per Response Evaluation Criteria in Solid Tumors [RECIST] criteria for 
solid tumors), should not be reported as an SAE. 
 
Persistent or Recurrent Adverse Events 
A persistent AE is one that extends continuously, without resolution, between patient evaluation 
time points.  Such events should only be recorded once on the SAE Report Form and/or the AE 
eCRF screen.  If a persistent AE becomes more severe or lessens in severity, it should be 
recorded on a separate SAE Report Form and/or AE eCRF screen. 
A recurrent AE is one that occurs and resolves between patient evaluation time points, and 
subsequently recurs.  All recurrent AEs should be recorded on an SAE Report Form and/or AE 
eCRF screen. 
 
Abnormal Laboratory Values 
If an abnormal laboratory value or vital sign is associated with a clinical sign and/or symptom, 
the sign or symptom should be reported as an AE or SAE, and the associated laboratory value or 
vital sign should be considered additional information that must be collected on the relevant 
eCRF screen.  If the laboratory abnormality is a sign of a disease or syndrome, only the diagnosis 
needs to be recorded on the SAE Report Form or AE eCRF screen. 
Abnormal laboratory values will be reported as an AE if the laboratory result requires an 
adjustment in the study drug(s) or discontinuation of treatment; and/or laboratory findings 
require additional testing or surgical intervention; a laboratory result or finding is associated with 
accompanying symptoms; or a laboratory result is considered to be an AE by the Investigator. 
 
Deaths 
Deaths that occur during the protocol-specified AE reporting period that are attributed solely to 
PD, as determined by the Investigator, will be recorded on the “Study Discontinuation” eCRF 
screen.  All other on-study deaths, regardless of attribution, will be recorded on an SAE Report 
Form and expeditiously reported to the Development Innovations Safety Department. 


 
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When recording a SAE with an outcome of death, the event or condition that caused or 
contributed to the fatal outcome should be recorded as the single medical concept on the SAE 
Report Form and AE screen of the eCRF.  If the cause of death is unknown and cannot be 
ascertained at the time of reporting, record “Death NOS” on the eCRF AE screen.  During post-
study survival follow-up, deaths attributed to PD will be recorded only on the “After Progressive 
Disease Follow-Up” eCRF screen. 
 
Hospitalization, Prolonged Hospitalization, or Surgery 
Any AE that results in hospitalization of >24 hours or prolongation of pre-existing 
hospitalization should be documented and reported as an SAE unless specifically instructed 
otherwise in this protocol.  There are some hospitalizations that do not require reporting as an 
SAE. 
Treatment within or admission to the following facilities is not considered to meet the criteria of 
“inpatient hospitalization” (although if any other SAE criteria are met, the event must still be 
treated as an SAE and immediately reported): 
• Emergency department or emergency room 
• Outpatient or same-day surgery units 
• Observation or short-stay unit 
• Rehabilitation facility 
• Hospice or skilled nursing facility 
• Nursing homes, custodial care or respite care facility 
Hospitalization during the study for a pre-planned surgical or medical procedure (one which was 
planned prior to entry in the study) does not require reporting as an SAE to the Development 
Innovations Safety Department. 
 
Pre-Existing Medical Conditions 
A pre-existing medical condition is one that is present at the start of the study.  Such conditions 
should be recorded on the General Medical History eCRF screen.  A pre-existing medical 
condition should be recorded as an AE or SAE only if the frequency, severity, or character of the 
condition worsens during the study.  When recording such events on an SAE Report Form and/or 
AE eCRF screen, it is important to convey the concept that the pre-existing condition has 
changed by including applicable descriptors. 
 
New Cancers 
The development of a new primary cancer should be regarded as an AE and will generally meet 
at least one of the seriousness criteria (see Section 11.1.2).  New primary cancers are those that 
are not the primary reason for the administration of the study treatment and have developed after 
the inclusion of the patient in the study.  They do not include metastases of the original cancer.  
Symptoms of metastasis or the metastasis itself should not be reported as an AE/SAE, as 
metastasis is considered to be PD. 


 
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Pregnancy, Abortion, Birth Defects/Congenital Anomalies 
If a patient becomes pregnant while enrolled in the study, a Pregnancy Form (a paper report 
form, not available within the eCRF) should be completed and faxed to the Development 
Innovations Safety Department.  The Development Innovations Safety Department should be 
notified expeditiously, irrespective of whether or not it meets the criteria for expedited reporting.  
Abortions (spontaneous, accidental, or therapeutic) must also be reported to the Development 
Innovations Safety Department. 
If a female partner of a male patient becomes pregnant during the male patient’s participation in 
this study, this must be reported to the Development Innovations Safety Department 
immediately.  Every effort should be made to follow the pregnancy for the final pregnancy 
outcome. 
Congenital anomalies/birth defects always meet SAE criteria, and should therefore be 
expeditiously reported as an SAE, using the previously described process for SAE reporting.  A 
Pregnancy Form should also have been previously completed, and will need to be updated to 
reflect the outcome of the pregnancy. 
 
Overdose 
Symptomatic and non-symptomatic overdose must be reported in the eCRF.  Any accidental or 
intentional overdose with the study treatment that is symptomatic, even if not fulfilling a 
seriousness criterion, is to be reported to the Development Innovations Safety Department no 
greater than 24 hours from first knowledge of the event using the corresponding screens in the 
eCRF and following the same process described for SAE reporting (Section 11.2) if the overdose 
is symptomatic. 
For information on how to manage an overdose of quizartinib, see the IB. 
 
Protocol-Defined Adverse Events of Special Interest (AESI) 
The following are adverse events of special interest (AESIs), and will need to be reported 
expeditiously (see Section 11.1.5). 
11.4.1.1 QTc Prolongation, TdP and Other Ventricular Arrhythmias 
Subjects who experience >480 msec QTcF prolongation and undergo dose interruption and/or 
reduction must be monitored closely with ECGs, performed twice weekly for the first week of 
the QTcF prolongation and then weekly thereafter until the QTcF prolongation is resolved, as 
described in Section 8.2.1. A Grade ≥3 QTcF prolongation either serious or non-serious and 
whether or not causally related, must be recorded as AE or SAE in the Electronic Data Capture 
(EDC) system within 24 hours of awareness of the central ECG laboratory reading, with the 
Investigator’s assessment of seriousness, causality, and a detailed narrative. 
11.4.1.2 Combined Elevations of Aminotransferases and Bilirubin 
Combined elevations of aminotransferases and bilirubin, either serious or non-serious and 
whether or not causally related, meeting the laboratory criteria of a potential Hy’s Law case 
[ALT or AST ≥3 x ULN with simultaneous total bilirubin ≥2 x ULN] should always be recorded 
as an AE or SAE within 24 hours of awareness, with the Investigator’s assessment of 


 
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seriousness, causality, and a detailed narrative. Patients will be monitored as described in 
Appendix F. 
 
Funding Partner Serious Adverse Event Reporting Requirements 
The Development Innovations Safety Department will forward SAE, AESI, non-serious AESI, 
and overdose information regarding CPX-351 to Jazz Pharmaceuticals at 
AEreporting@jazzpharma.com and quizartinib to Daiichi Sankyo Clinical Safety and 
Pharmacovigilance (CSPV) at CSPV-Clinical@dsi.com or Daiichi Sankyo fax (732) 906-9621 
within 1 business day of the Development Innovations Safety Department personnel becoming 
aware of the SAE. 
Development Innovations is responsible for reporting relevant SAEs to the competent authority, 
other applicable regulatory authorities, and participating investigators, in accordance with 
International Council for Harmonisation (ICH) guidelines and US Food and Drug Administration 
(FDA) regulations. 
 
Sponsor Assessment of Unexpected Events 
The Sponsor is responsible for assessing an AE or SAR as “unexpected.”  
An AE or SAR is considered “unexpected” when the following conditions occur: 
• Event(s) is not mentioned in the IB (or current USPI) 
• Event(s) is not listed at the specificity or severity that has been observed 
• An event(s) is not consistent with the General Investigative Plan or in the current 
application 
• Includes AEs or SARs that may be anticipated from the pharmacological properties of the 
study drug, or that occur with members of the drug class, but that have previously been 
observed under investigation 
When applicable, an unexpected AE may also apply to an event that is not listed in the current 
USPI or an event that may be mentioned in the USPI, but differs from the event because of 
greater severity or specificity.    
Known as Suspected Unexpected Serious Adverse Reactions (SUSARs), these events suspected 
(by the Investigator) to be related to the study drug, are unexpected (not listed in the IB), and are 
serious (as defined by the protocol) and require expedient submission to relevant health 
authorities within 7 days (fatal or life-threatening event) or 15 days (all serious events), or as 
defined by law.  The term SUSAR is used primarily in the reporting of events to regulatory 
authorities. 
Expected AEs are those events that are listed or characterized in the current IB or Reference 
Safety Information. 


 
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Funding Partner Reporting for Clinical Studies Under an Investigational New 
Drug Application 
All written investigational new drug (IND) Safety Reports submitted to the FDA by the 
Development Innovations Safety Department must also be sent to the pharmaceutical company 
that is supporting the study with either funding or drug supply. 
12. 
QUALITY ASSURANCE AND QUALITY CONTROL 
 
Study Monitoring, Auditing, and Inspecting 
The Investigator will permit study-related monitoring, quality audits, and inspections by the 
Sponsor, or its representative(s), government regulatory authorities, and the IRB of all study-
related documents (e.g., source documents, regulatory documents, data collection instruments, 
CRFs).  The Investigator will ensure the capability for inspections of applicable study-related 
facilities.  The Investigator will ensure that the study monitor or any other compliance or Quality 
Assurance reviewer is given access to all study-related documents and study-related facilities. 
At the Sponsor’s discretion, Source Document Verification (SDV) may be performed on all data 
items or a percentage thereof. 
Participation as an Investigator in this study implies the acceptance of potential inspection by 
government regulatory authorities and the Sponsor, or its representative(s). 
13. 
ETHICAL, FINANCIAL, AND REGULATORY CONSIDERATIONS 
This research study will be conducted according to the standards of Good Clinical Practice 
(GCP) outlined in the ICH E6 Tripartite Guideline and the Code of Federal Regulations (CFR) 
Title 21 part 312, applicable government regulations, institutional research policies and 
procedures, and any other local applicable regulatory requirement(s). 
 
Institutional Review Board Approval 
The clinical study protocol, ICF, IB, available safety information, patient documents (e.g., study 
diary), patient recruitment procedures (e.g., advertisements), information about payments (e.g., 
PI payments) and compensation available to the patients, and documentation providing evidence 
of the PI’s qualifications should be submitted to the IRB for ethical review and approval prior to 
the study start. 
The PI/Sponsor and/or designee will follow all necessary regulations to ensure appropriate initial 
and on-going IRB study review.  The PI/Sponsor (as appropriate) must submit to and, where 
necessary, obtain approval from the IRB for all subsequent protocol amendments and changes to 
the ICF document.  Investigators will be advised by the Study Chair/Sponsor or designee 
whether an amendment is considered substantial or non-substantial and whether it requires 
submission for approval or notification only to an IRB. 


 
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Safety updates will be prepared by Jazz Pharmaceuticals and Daiichi Sankyo or their 
representatives as required, for distribution to the Investigator(s) and submission to the relevant 
IRB. 
 
Regulatory Approval 
As required by local regulations, the PI/Sponsor will ensure all legal aspects are covered and 
approval of the appropriate regulatory bodies obtained prior to study initiation.  If required, the 
PI or/Sponsor will also ensure that the implementation of substantial amendments to the protocol 
and other relevant study documents happen only after approval by the relevant regulatory 
authorities. 
 
Informed Consent 
Informed consent is a process by which a patient voluntarily confirms his or her willingness to 
participate in a particular study after having been informed of all aspects of the study that are 
relevant to the patient’s decision to participate.  Informed consent is documented by means of a 
written, signed, and dated ICF. 
The ICF will be submitted for approval to the IRB that is responsible for review and approval of 
the study.  Each consent form must include all of the relevant elements currently required by the 
FDA, as well as local country authority or state regulations and national requirements. 
Before recruitment and enrollment into the study, each prospective candidate will be given a full 
explanation of the research study.  Once the essential information has been provided to the 
prospective candidate, and the Investigator is sure that the individual candidate understands the 
implications of participating in this research study, the candidate will be asked to give consent to 
participate in the study by signing an ICF.  A notation that written informed consent has been 
obtained will be made in the patient’s medical record.  A copy of the ICF, which will include the 
patient’s signature, will be provided by the Investigator to the patient. 
If an amendment to the protocol substantially alters the study design or the potential risks to 
patients, the patients must re-consent to continue participation in the study. 
 
Confidentiality 
13.3.1.1 Patient Confidentiality 
Confidentiality of patients’ personal data will be protected in accordance with the Health 
Insurance Portability and Accountability Act of 1996 (HIPAA).  HIPAA regulations require that, 
in order to participate in the study, a patient must sign an authorization form for the study that he 
or she has been informed of the following: 
• What protected health information (PHI) will be collected from patients in this study 
• Who will have access to that information and why 
• Who will use or disclose that information 
• That health information may be further disclosed by the recipients of the information, and 
that if the information is disclosed, the information may no longer be protected by federal 
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• The information collected about the research study will be kept separate from the 
patient’s medical records, but the patient will be able to obtain the research records after 
the conclusion of the study 
• Whether the authorization contains an expiration date 
• The rights of a research patient to revoke his or her authorization. 
In the event that a patient revokes authorization to collect or use his or her PHI, the Investigator, 
by regulation, retains the ability to use all information collected prior to the revocation of patient 
authorization.  For patients that have revoked authorization to collect or use PHI, attempts should 
be made to obtain permission to collect at least vital status (e.g., that the patient is alive) at the 
end of their scheduled study period. 
In compliance with ICH GCP guidelines and applicable parts of 21CFR, it is a requirement that 
the Investigator and institution permit authorized representatives of the Sponsor and/or funding 
partner, the regulatory authorities and the IRB direct access to review the patient’s original 
medical records at the site for verification of study-related procedures and data. 
Measures to protect confidentiality include a unique study number that will identify patients in 
the eCRF or other documents submitted to the Sponsor.  This information, together with the 
patient’s year of birth, will be used in the database for patient identification.  Patient names or 
addresses will not be entered in the eCRF.  No material bearing a patient’s name will be kept on 
file by the Sponsor.  Patients will be informed of their rights within the ICF. 
13.3.1.2 Investigator and Staff Information 
Personal data of the Investigators and sub-Investigators may be included in the Development 
Innovations database, and shall be treated in compliance with all applicable laws and regulations.  
When archiving or processing personal data pertaining to the Investigator or sub-Investigator, 
Development Innovations personnel shall take all appropriate measures to safeguard and prevent 
access to this data by any unauthorized party. 
 
Financial Information 
The finances for this clinical study will be subject to a separate written agreement between Sarah 
Cannon Development Innovations, LLC, and applicable parties.  Any Investigator’s financial 
disclosures, as applicable to 21CFR Part 54, shall be appropriately provided. 
14. 
RESEARCH RETENTION AND DOCUMENTATION OF THE STUDY 
 
Amendments to the Protocol 
Amendments to the protocol shall be planned, documented, and signature authorized prior to 
implementation. 
If an amendment to the protocol is required, the amendment will be originated and documented 
by the Study Chair/Sponsor.  All amendments require review and approval of the funding 
pharmaceutical company (Daiichi Sankyo and Jazz Pharmaceuticals) and the PI supporting the 
study.  The written amendment must be reviewed and approved by the Study Chair/Sponsor and 


 
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Daiichi Sankyo and Jazz Pharmaceuticals, and submitted to the IRB at the Investigator’s facility 
for the board’s approval. 
Amendments specifically involving change to study design, risk to patients, increase to dosing or 
exposure, patient number increase, or the addition or removal of new tests or procedures shall be 
reviewed and approved by the IRB of record for the Investigator’s facility. 
The amendment will be submitted formally to the FDA or other regulatory authorities by the 
Sponsor as applicable and IRB approval obtained, specifically when an increase to dosing or 
patient exposure and/or patient number has been proposed or when the addition or removal of an 
Investigator is necessitated. 
Items requiring a protocol amendment approval from the IRB and/or FDA or other regulatory 
authorities include, but are not limited to, the following: 
• Change to study design 
• Risk to patient 
• Increase to dose or patient exposure to drug 
• Patient number increase 
• Addition or removal of tests and/or procedures 
• Addition/removal of a new Investigator 
It should be further noted that if an amendment to the protocol substantially alters the study 
design or the potential risks to the patients, their consent to continue participation in the study 
should be obtained. 
 
Documentation Required to Initiate the Study 
Before the study may begin, certain documentation required by FDA regulations and ICH GCP 
must be provided by the Investigator.  The required documentation should be submitted to: 
Sarah Cannon Development Innovations 
Regulatory Department 
1100 Dr. Martin L. King Jr. Blvd., Suite 800 
Nashville, TN 37203 
At a minimum the following documents required to begin a study in the US: 
• A signature-authorized protocol and contract 
• A copy of the official IRB approval of the study and the IRB members list 
• Current curricula vitae for the PI and any associate Investigator(s) who will be involved 
in the study 
• Indication of appropriate accreditation for any laboratories to be used in the study and a 
copy of the normal ranges for tests to be performed by that laboratory 
• Original Form FDA 1572 (Statement of Investigator), appropriately completed and 
signed 


 
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• A copy of the IRB-approved consent form  containing permission for audit by 
representatives of Development Innovations, the IRB, and the FDA and other regulatory 
agencies (as applicable) 
• Financial disclosure forms for all Investigators listed on Form FDA 1572 (if applicable) 
• Site qualification reports, where applicable 
• Verification of PI acceptability from local and/or national debarment list(s). 
 
Study Documentation and Storage 
The PI must maintain a list of appropriately qualified persons to whom he/she has delegated 
study duties and should ensure that all persons assisting in the conduct of the study are informed 
of their obligations.  All persons authorized to make entries and/or corrections on the eCRFs are 
to be included on this document.  All entries in the patient’s eCRF are to be supported by source 
documentation where appropriate. 
Source documents are the original documents, data, records, and certified copies of original 
records of clinical findings, observations, and activities from which the patient’s eCRF data are 
obtained.  These can include, but are not limited to, hospital records, clinical and office charts, 
laboratory, medico-technical department and pharmacy records, diaries, microfiches, ECG 
traces, copies or transcriptions certified after verification as being accurate and complete, 
photographic negatives, microfilm or magnetic media, X-rays, and correspondence. 
The PI and each study staff member is responsible for maintaining a comprehensive and 
centralized filing system (e.g., regulatory binder or Investigator study file [ISF]) of all study-
related (essential) documentation, suitable for inspection at any time by representatives from the 
Sponsor and/or applicable regulatory authorities.  The ISF must consist of those documents that 
individually or collectively permit evaluation of the conduct of the study and the quality of the 
data produced.  The ISF should contain at a minimum all relevant documents and 
correspondence as outlined in ICH GCP Section 8 and 21CFR Part 312.57, including key 
documents such as the IB and any amendments, protocol and any amendments, signed ICFs, 
copies of completed eCRFs, IRB approval documents, financial disclosure forms, patient 
identification lists, enrollment logs, delegation of authority log, staff qualification documents, 
laboratory normal ranges, and records relating to the study drug including accountability records.  
Drug accountability records should, at a minimum, contain information regarding receipt, 
shipment, and disposition.  Each form of drug accountability record, at a minimum, should 
contain PI name, dates the drug was shipped and received, and the date, quantity, and batch/code 
or lot number for identity of each shipment.  In addition, all original source documents 
supporting entries in the eCRF must be maintained and readily available. 
The Sponsor shall maintain adequate investigational product records and financial interest 
records as per 21CFR Part 54.6 and Part 312.57 for no less than 2 years after the last marketing 
application has been approved by the FDA; or, in the event that the marketing application has not 
been approved by the FDA, for no less than 2 years after the last shipment/delivery of the drug 
for investigational use is discontinued and the FDA has been notified of the discontinuation. 
The Investigator shall maintain adequate records of drug disposition, case histories, and any 
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a marketing application is approved for the indication for which it is being investigated, or, if no 
application is to be filed or if the application is not approved for such indication, until 2 years 
after the investigation is discontinued and FDA has been notified of the discontinuation.  
To enable evaluations and/or audits from regulatory authorities or from the Sponsor or its 
representative, the Investigator additionally agrees to keep records, including the identity of all 
participating patients (sufficient information to link records, e.g., eCRFs, medical records), all 
original signed ICFs, and copies of all eCRFs, SAE reporting forms, source documents, detailed 
records of treatment disposition, and related essential regulatory documents.  The documents 
listed above must be retained by the Investigator for as long as needed to comply with national 
and international regulations (generally 2 years after discontinuing clinical development or after 
the last marketing approval).  Sponsor will notify the Investigator(s)/institutions(s) when the 
study-related records are no longer required. 
If the Investigator relocates, retires, or for any reason withdraws from the study, both the 
Sponsor and its representative should be prospectively notified.  The study records must be 
transferred to an acceptable designee, such as another Investigator, another institution, or to the 
Sponsor.  The Investigator must obtain the Sponsor’s written permission before disposing of any 
records, even if retention requirements have been met.  All study files will be maintained by the 
Sponsor throughout the study, and will be held by the Sponsor at the conclusion of the study. 
 
Data Collection 
The study eCRF is the primary data collection instrument for the study.  Case report forms will 
be completed using the English language and should be kept current to enable the Sponsor to 
review the patients’ status throughout the course of the study. 
In order to maintain confidentiality, only study number, patient number, and year of birth will 
identify the patient in the eCRF.  If the patient’s name appears on any other document (e.g., 
laboratory report), it must be obliterated on the copy of the document to be supplied to 
Development Innovations and replaced with the patient number and year of birth.  The 
Investigator will maintain a personal patient identification list (patient numbers with 
corresponding patient identifiers) to enable records to be identified and verified as authentic.  
Patient data/information will be kept confidential, and will be managed according to applicable 
local, state, and federal regulations. 
All data requested in the eCRF must be supported by and be consistent with the patient’s source 
documentation.  All missing data must be explained.  When a required laboratory test, 
assessment, or evaluation has not been done or an “Unknown” box is not an option on the eCRF, 
a note should be created verifying that the field was “Not Done” or “Unknown.”  For any entry 
errors made, the error(s) must be corrected, and a note explaining the reason for the change 
should be provided.  The Investigator will electronically sign and date the patient eCRF 
casebook, indicating that the data in the eCRF has been assessed.  Each completed eCRF will be 
signed and dated by the PI, once all data for that patient is final. 
 
Disclosure and Publication Policy 
All information provided regarding the study, as well as all information collected/documented 
during the course of the study, will be regarded as confidential.  Jazz Pharmaceuticals and 


 
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Daiichi Sankyo reserve the right to release literature publications based on the results of the 
study.  Results from the study will be published/presented as per the Sponsor’s publication 
process. 
Inclusion of the Investigator in the authorship of any multicenter publication will be based upon 
substantial contribution to the design, analysis, and interpretation of data, and the drafting and/or 
critically revising any manuscript(s) derived from the study.  The Investigator acknowledges that 
the site is part of a multicenter study and agrees that any publication by the Investigator of the 
results of the study conducted at his/her research site shall not be made before the first 
multicenter publication.   
In the event there is no multicenter publication within 15 months after the study has been 
completed or terminated at all study sites, and all data has been received, the Investigator shall 
have the right to publish his/her results from the study, subject to the notice requirements 
described herein and subject to acknowledgement of the Sponsor as appropriate.  Investigator 
shall provide the Sponsor thirty (30) days to review a manuscript or any poster presentation, 
abstract or other written or oral material which describes the results of the study for the purpose 
only of determining if any confidential or patentable information is disclosed thereby.  If the 
Sponsor requests in writing, the Investigator shall withhold any publication or presentation an 
additional 60 days solely to permit the Sponsor to seek patent protection and to remove any 
Development Innovations confidential information from all publications. 


 
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15. 
REFERENCES 
 
Altman et al 2018 
Altman JK, Foran JM, Pratz KW, Trone D, Cortes JE, Tallman MS. Phase 1 study of quizartinib 
in combination with induction and consolidation chemotherapy in patients with newly diagnosed 
acute myeloid leukemia. Am J Hematol. 2018;93(2):213-21. 
Breems et al 2005 
Breems DA, Van Putten WL, Huijgens PC, Ossenkoppele GJ, Verhoef GE, Verdonck LF, et al. 
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Cohen PR. Sweet's syndrome--a comprehensive review of an acute febrile neutrophilic 
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Cortes et al 2015 
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Cortes JE, Khaled S, Martinelli G, Perl AE, Ganguly S, Russell N, et al. Quizartinib versus 
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Feldman EJ, Lancet JE, Kolitz JE, Ritchie EK, Roboz GJ, List AF, et al. First-in-man study of 
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Fleischmann et al 2017 
Fleischmann M, Schnetzke U, Schrenk KG, Schmidt V, Sayer HG, Hilgendorf I, et al. Outcome 
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Hills et al 2015 
Hills RK, Gammon G, Trone D, Burnett AK. Quizartinib significantly improves overall survival 
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Kottaridis et al 2001 
Kottaridis PD, Gale RE, Frew ME, Harrison G, Langabeer SE, Belton AA, et al. The presence of 
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chemotherapy: analysis of 854 patients from the United Kingdom Medical Research Council 
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Lancet et al 2010 
Lancet JE, Feldman EJ, Cortes JE, et al. CPX-351 in AML after failed induction with cytarabine 
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Lancet JE, Cortes JE, Hogge DE, Tallman MS, Kovacsovics TJ, Damon LE, et al. Phase 2 trial 
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older adults with untreated AML. Blood. 2014;123:3239-46. 
Lancet et al 2016a 
Lancet JE, Hoering A, Uy GL, et al. Survival following allogeneic hematopoietic cell 
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phase III trial. Blood. 2016;128:906. 
Lancet et al 2016b 
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Perl AE, Altman JK, Cortes J, Smith C, Litzow M, Baer MR, et al. Selective inhibition of FLT3 
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Pratz KW, Levis M. How I treat FLT3-mutated AML. Blood. 2017;129(5):565-71. 


 
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patients with FLT3-mutated acute myeloid leukemia in first relapse. Leuk Res. 2010;34(6):752-6. 
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Rowe JM. Optimal induction and post-remission therapy for AML in first remission. 
Hematology Am Soc Hematol Educ Program. 2009:396-405. 
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Schiller GJ, Tallman MS, Goldberg SL, Perl AE, Marie J-P, Martinelli G, et al. Final results of a 
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Sexauer A, Perl A, Yang X, Borowitz M, Gocke C, Trivikram R, et al. Terminal myeloid 
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Shih L-Y, Huang C-F, Wu J-H, Lin TL, Dunn P, Wang PN, et al. Internal tandem duplication of 
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108 adult patients at diagnosis and relapse. Blood. 2002;100(7):2387-92. 
Smith et al 2012 
Smith CC, Wang Q, Chin CS, Salerno S, Damon LE, Levis MJ, et al. Validation of ITD 
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Stone RM, Mandrekar SJ, Sanford BL, Laumann K, Geyer S, Bloomfield CD, et al. Midostaurin 
plus chemotherapy for acute myeloid leukemia with a FLT3 mutation. N Engl J Med. 
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Takahashi et al 2016 
Takahashi S, Shirahama K. Internal tandem duplication and tyrosine kinase domain mutations in 
FLT3 alter the response to daunorubicin in Ba/F3 cells. Biomed Rep. 2016;4(1):83-6. 
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Tardi P, Johnstone S, Harasym N, Xie S, Harasym T, Zisman N, et al. In vivo maintenance of 
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Taylor et al 2017 
Taylor SJ, Langdon WY. Sleeping through the storm: preventing myelosuppression with 
quizartinib. Oncotarget. 2017;8(51):88255-88256. 
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Wagner K, Damm F, Thol F, Göhring G, Görlich K, Heuser M, et al. FLT3-internal tandem 
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leukemia with normal karyotype. Haematologica. 2011;96(5):681-6. 
Wakita et al 2013 
Wakita S, Yamaguchi H, Omori I, Terada K, Ueda T, Manabe E, et al. Mutations of the 
epigenetics-modifying gene (DNMT3a, TET2, IDH1/2) at diagnosis may induce FLT3-ITD at 
relapse in de novo acute myeloid leukemia. Leukemia. 2013;27(5):1044-52. 
Weisdorf et al 2013 
Bejanyan N, Weisdorf DJ, Logan BR, Wang H, Devine SM, de Lima M, et al. Survival of 
patients with acute myeloid leukemia relapsing after allogeneic hematopoietic cell 
transplantation: a center for international blood and marrow transplant research study. Biol 
Blood Marrow Transplant. 2015;21(3):454-9. 
Whitman et al 2001 
Whitman SP, Archer KJ, Feng L, Baldus C, Becknell B, Carlson BD, et al. Absence of the wild-
type allele predicts poor prognosis in adult de novo acute myeloid leukemia with normal 
cytogenetics and the internal tandem duplication of FLT3: a cancer and leukemia group B study. 
Cancer Res. 2001;61(19):7233-9. 


 
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16. 
APPENDICES 
Appendix A: ECOG Performance Status Criteria 
 
ECOG Performance Status Scale 
 
Karnofsky Performance Scale 
Grade 
Descriptions 
Percent 
Description 
0 
Normal activity. Fully active, able to carry 
on all pre-disease performance without 
restriction. 
 
100 
Normal, no complaints, no evidence of 
disease. 
 
90 
Able to carry on normal activity; minor 
signs or symptoms of disease. 
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). 
 
80 
Normal activity with effort; some signs or 
symptoms of disease. 
 
70 
Cares for self, unable to carry on normal 
activity or to do active 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. 
 
60 
Requires occasional assistance, but is able 
to care for most of his/her needs. 
 
50 
Requires considerable assistance and 
frequent medical care. 
3 
In bed >50% of the time.  Capable of only 
limited self-care, confined to bed or chair 
more than 50% of waking hours. 
 
40 
Disabled, requires special care and 
assistance 
 
30 
Severely disabled, hospitalization 
indicated.  Death not imminent. 
4 
100% bedridden.  Completely disabled.  
Cannot carry on any self-care.  Totally 
confined to bed or chair. 
 
20 
Very sick, hospitalization indicated.  
Death not imminent. 
 
10 
Moribund, fatal processes progressing 
rapidly. 
5 
Dead 
0 
Dead 
 
 


 
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Appendix B: New York Heart Association (NYHA) Classification of Cardiac Disease 
The following table presents the NYHA classification of cardiac disease. 
Class 
Functional Capacity 
Objective Assessment 
I 
Patients with cardiac disease but without resulting limitations of physical 
activity.  Ordinary physical activity does not cause undue fatigue, 
palpitation, dyspnea, or anginal pain. 
No objective evidence of 
cardiovascular disease. 
II 
Patients with cardiac disease resulting in slight limitation of physical 
activity.  They are comfortable at rest.  Ordinary physical activity results in 
fatigue, palpitation, dyspnea, or anginal pain. 
Objective evidence of 
minimal cardiovascular 
disease. 
III 
Patients with cardiac disease resulting in marked limitation of physical 
activity.  They are comfortable at rest.  Less than ordinary activity causes 
fatigue, palpitation, dyspnea, or anginal pain. 
Objective evidence of 
moderately severe 
cardiovascular disease. 
IV 
Patients with cardiac disease resulting in inability to carry on any physical 
activity without discomfort.  Symptoms of heart failure or the anginal 
syndrome may be present even at rest.  If any physical activity is undertaken, 
discomfort is increased. 
Objective evidence of 
severe cardiovascular 
disease. 
Source:  The Criteria Committee of New York Heart Association.  Nomenclature and Criteria for Diagnosis of 
Diseases of the Heart and Great Vessels.  9th Ed. Boston, MA:  Little, Brown & Co; 1994:253-256. 
 


 
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Appendix C: Guidelines for Female Patients of Childbearing Potential and Fertile Male 
Patients 
 
Acceptable Contraception Methods: 
Women of childbearing potential, defined as all women physiologically capable of becoming 
pregnant, must use highly-effective contraception during the study and until 6 months 
following the last dose of CPX-351 and/or quizartinib. 
Fertile male patients, defined as all males physiologically capable of conceiving offspring, 
with female partners of childbearing potential, must use condoms plus a spermicidal agent 
during the study treatment period and for 6 months following their last dose of CPX-351 
and/or quizartinib, and must not father a child during this period. 
Male patients must also refrain from donating sperm during their participation in the study for 
6 months following their last dose of CPX-351 and/or quizartinib. 
 
Highly effective contraception is defined as either: 
True Abstinence 
When this is in line with the preferred and usual lifestyle of the 
patient.  Periodic abstinence (e.g., calendar, ovulation, 
symptothermal, post-ovulation methods) and withdrawal are not 
acceptable methods of contraception. 
Sterilization  
When a woman of childbearing potential has had surgical 
bilateral oophorectomy (with or without hysterectomy) or tubal 
ligation at least six weeks prior to study entry.  In case of 
oophorectomy alone, only when the reproductive status of the 
woman has been confirmed by follow-up hormone level 
assessment. 
Male Partner Sterilization With the appropriate post-vasectomy documentation of the 
absence of sperm in the ejaculate. 
Use of a combination of any two of the following (one from a + one from b): 
a) Placement of an intrauterine device (IUD) or intrauterine system (IUS) 
b) Barrier methods of contraception: condom or an occlusive cap (diaphragm or cervical/vault 
caps) with spermicidal foam/gel/film/cream/vaginal suppository. 
The following are acceptable forms of barrier contraception: 
• Latex condom, diaphragm or cervical/vault cap when used with spermicidal 
foam/gel/film/cream/suppository 
Unacceptable Contraception Methods: for women of childbearing potential include: 
• IUD progesterone T 


 
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• Female condom 
• Natural family planning (rhythm method) or breastfeeding 
• Fertility awareness 
• Withdrawal 
• Cervical shield. 
Pregnancies 
To ensure patient safety, each pregnancy in a patient on study treatment must be reported to 
the Development Innovations Safety Department within 24 hours of learning of its occurrence.  
The pregnancy should be followed up for 3 months after the termination of the pregnancy to 
determine outcome, including spontaneous or voluntary termination, details of the birth, and 
the presence or absence of any birth defects, congenital abnormalities, or maternal and/or 
newborn complications. 
Pregnancy should be recorded on a Clinical Study Pregnancy Form and reported by the 
Investigator to the Development Innovations Safety Department.  Pregnancy follow-up should 
be recorded on the same form and should include an assessment of the possible relationship to 
the study drug of any pregnancy outcome.  Any SAE experienced during pregnancy must be 
reported on the SAE Report Form. 
Pregnancy outcomes must be collected for the female partners of any males who took study 
treatment in this study.  Consent to report information regarding these pregnancy outcomes 
should be obtained from the mother. 
Women Not of Childbearing Potential are Defined as Follows: 
• Women are considered post-menopausal and not of childbearing potential if they have 
had 12 months of natural (spontaneous) amenorrhea with an appropriate clinical profile 
(e.g., age appropriate, history of vasomotor symptoms).  
• Women who are permanently sterilized (e.g., tubal occlusion, hysterectomy, bilateral 
salpingectomy, bilateral oophorectomy). 
• Women who are >45 years-of-age, not using hormone-replacement therapy and who 
have experienced total cessation of menses for at least 1 year OR who have a follicle 
stimulating hormone (FSH) value >40 mIU/mL and an estradiol value <40 pg/mL 
(140 pmol/L). 
• Women who are >45 years-of-age, using hormone-replacement therapy and who have 
experienced total cessation of menses for at least 1 year OR who have had documented 
evidence of menopause based on FSH >40 mIU/mL and estradiol <40 pg/mL prior to 
initiation of hormone-replacement therapy. 


 
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Appendix D: Schedule of Assessments 
ASSESSMENTS 
Screening 
Induction/Re-inductiona 
Consolidationb 
At ~D30 
interimc 
Maintenanced 
EOT 
F/U 
Day 
 
D1 
D3 
D5 
D6n 
D8 
D14 
D21 
D35 
D1 
D3 
D6 
D14 
D21 
D35 
 
D1 
D15 
 
 
Informed consente 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion 
criteria 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history 
and demographics 
Xf 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical 
examination, 
height (screening 
only), and weight g 
Xf 
 
X 
X 
Xn 
X 
X 
X 
X 
X 
X 
X 
 
 
X 
X 
X 
X 
X 
 
Vital signsh 
Xf 
 
X 
X 
Xn 
X 
X 
X 
X 
X 
X 
X 
 
 
X 
X 
X 
X 
X 
 
ECOG 
performance status 
Xf 
 
X 
X 
Xn 
X 
X 
X 
X 
X 
X 
X 
 
 
X 
X 
X 
X 
X 
 
12-lead 
electrocardiogramf 
Xf 
 
 
 
Xn 
X 
X 
X 
 
 
X 
X 
X 
X 
 
 
X 
X 
X 
 
TTE or MUGA 
scan 
Xf 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Adverse event 
monitoring 
 
X 
X 
X 
Xn 
X 
X 
X 
X 
X 
X 
X 
 
 
X 
X 
X 
X 
X 
 
Concomitant 
medication review 
X 
X 
X 
X 
Xn 
X 
X 
X 
X 
X 
X 
X 
 
 
X 
X 
X 
X 
X 
 
Lumbar puncturei 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
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ASSESSMENTS 
Screening 
Induction/Re-inductiona 
Consolidationb 
At ~D30 
interimc 
Maintenanced 
EOT 
F/U 
Day 
 
D1 
D3 
D5 
D6n 
D8 
D14 
D21 
D35 
D1 
D3 
D6 
D14 
D21 
D35 
 
D1 
D15 
 
 
Central line 
placement (PICC 
or port) 
Per 
institutional 
standards; 
placed prior 
to starting 
study 
treatment 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CPX-351 
 
Once daily (IV) on Days 1, 3 & 5.   
If re-induction is necessary administer on Days 1 & 3. During 
consolidation, administer on Days 1 & 3 for 2 cycles. 
 
 
 
 
 
 
 
 
 
 
Quizartinib 
 
Once daily (PO) Days 8-21 with induction. 
Days 6-21 with re-induction and/or consolidation(s). 
 
 
 
 
 
 
Days 1-28  
until PD 
 
 
Hematology panel 
Xf 
X 
X 
X 
Xn 
X 
X 
X 
X 
X 
X 
X 
 
 
X 
X 
X 
X 
X 
 
Clinical chemistry 
panel 
Xf 
X 
X 
X 
Xn 
X 
X 
X 
X 
X 
X 
X 
 
 
X 
X 
X 
X 
X 
 
Virus testing 
Xf 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urinalysis 
Xf 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Serum  Pregnancy 
Testf,j 
X 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
Every 3 
Cycles 
 
 
 
Bone marrow 
aspirate and biopsy 
(includes FLT3 
mutation test via 
PCR)k 
X 
 
 
 
 
 
 
X 
X 
 
 
 
 
 
X 
Xk 
Day 24 (± 3) at 
cycles 3, 6, 12 
and 24 
 
 


 
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ASSESSMENTS 
Screening 
Induction/Re-inductiona 
Consolidationb 
At ~D30 
interimc 
Maintenanced 
EOT 
F/U 
Day 
 
D1 
D3 
D5 
D6n 
D8 
D14 
D21 
D35 
D1 
D3 
D6 
D14 
D21 
D35 
 
D1 
D15 
 
 
MRD analysis 
(FLT3 via NGS)l 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
Xl 
Day 24 (± 3) at 
cycles 3, 6, 12 
and 24 
 
 
Underlying disease 
assessment 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Xm 
Survival status 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Xm 
 
a 
Induction: CPX-351 (daunorubicin 44 mg/m2 IV and cytarabine 100 mg/m2 IV) will be given IV on Days 1, 3, and 5 during induction 
therapy followed by quizartinib 30 mg orally (PO) once daily on Days 8-21 (hold quizartinib on Day 21). Patients with an incomplete 
response, but a >50% reduction in the blast count/cellularity ratio compared to the most recent BM biopsy prior to treatment, may receive one 
additional cycle of induction therapy (re-induction) with CPX-351 (daunorubicin 44 mg/m2 IV and cytarabine 100 mg/m2 IV) on Days 1 and 
3  (see Section 5.2.2).  During re-induction, begin CPX-351 at least 72 hours after the last dose of quizartinib. Treatment with quizartinib 
will resume on Day 6 and continue through Day 21 (hold quizartinib on Day 21, if proceeding to consolidation phase) (see Section 5.2.3). 
b 
Consolidation: Patients who achieve CR and do not proceed to an alloHCT or other CT intervention will proceed to the consolidation phase 
beginning 7 days (± 7 days) after neutrophil recovery (ANC >1000/µL).  Administer up to 2 consolidation cycles of CPX-351 (daunorubicin 
29 mg/m2 IV and cytarabine 65 mg/m2 IV) on Days 1 and 3.  Begin quizartinib 30 mg PO once daily on Days 6-21 (hold quizartinib on Day 
21) (see Section 5.2.3). Administration cannot begin earlier than 24 hours from the last administration of CPX-351 (see Section 7.2). 
c 
The 60-day period (~Day 30) between the end of consolidation and the start of maintenance therapy. Patients who proceed to alloHCT 
or other CT intervention after consolidation will resume quizartinib maintenance 30-60 days from the intervention. In patients who proceed to 
alloHCT, begin quizartinib maintenance no earlier than day 30 after transplant (see Section 5.2.4). 
d 
Maintenance: Maintenance dosing of quizartinib will begin at 30 mg/day on Days 1-14, and if there are no toxicities and QTcF is 
maintained ≤450 msec, will increase to 60 mg/day on Day 15. The maintenance phase is a 28-day cycle beginning 7 days (± 7 days) after 
neutrophil recovery from the consolidation phase or induction phase. Patients will receive quizartinib once daily for a total of 24 cycles or 
until disease relapse.  Patients who proceed to alloHCT or other CT intervention after consolidation will resume quizartinib maintenance 30-
60 days from the intervention for a total of 24 cycles or until disease relapse.  If the patient is on quizartinib prior to HCT or CT intervention, 
quizartinib should be discontinued 7 days prior if a conditioning therapy is utilized.  If ≥2 CT interventions (e.g., repeat DLI) are planned 
after maintenance, a 28-day hold is acceptable, with resumption of quizartinib with the next cycle (see Section 5.2.4). 
e 
Informed consent must be obtained prior to the initiation of any screening test or procedure. 


 
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f 
The screening medical history, physical examination, vital signs, ECOG performance status, and triplicate ECGs, TTE/MUGA, baseline 
signs and symptoms and safety laboratory tests (including pregnancy and virus testing [hepatitis serology (Hepatitis B surface antigen and 
antibody and Hepatitis C antibody), HIV-1, 2]) should be done following written consent and prior to initiation of therapy.  
g 
Physical examination will include measurements of height (screening only) and weight.    
h 
Vital signs will include resting heart rate, blood pressure, respiratory rate, and temperature. 
i 
Patients will receive a lumbar puncture during pre-transplant workup, per institutional practices and following site-specific standard operating 
procedures within the first 2 weeks on study treatment.  No further intrathecal (IT) chemotherapy is required in this study if there is no 
evidence of disease. In patients who have CNS disease involvement, IT chemotherapy should continue every 4 days (±1 day) until disease 
clearance, followed by every 7 days (±2 days) for 2 additional administrations.  Thereafter, administer IT chemotherapy every 28 days (± 7 
days) for at least 12 cycles (see Section 6.3). 
j 
A serum beta human chorionic gonadotropin pregnancy test must be done 72 hours prior to the start of treatment for women of child-bearing 
potential.  Serum Pregnancy tests are also required prior to the start of each cycle during the induction and consolidation phases, during 
maintenance phase a serum pregnancy test will obtained once every 3 cycles.   
k 
BM biopsies and aspirates will be collected at screening, Day 21 (±7 days) during induction, and Day 35 (±7 days) during both induction and 
consolidation phases (the time of count recovery after CPX-351 + quizartinib, defined as obtaining a BM biopsy within 4 days of having an 
ANC >500 for ≥24 hours) and at Day 28 (+/-7 days) post-alloHCT or other CT intervention (if applicable). In the maintenance phase, BM 
biopsies and aspirates will also be collected on Day 24 (±3 days) during cycles 3, 6, 12, and 24.  Thereafter, assessment of disease status will 
be at the discretion of the haematologist/oncologist. All biopsies should include monitoring for FLT3 mutation by PCR (see Section 6.5.11). 
l 
MRD analyses with BM and aspirates and blood samples: Collect samples during BM recovery at the end of induction and consolidation 
phases (Cycle 1 Day 35 (±7 days) and Cycle 2 Day 35 (±7 days), 30 days post-alloHCT or other CT intervention (if applicable), and during 
the maintenance phase at Day 24 (±3 days) Cycles 3, 6, 12, and 24. 
m 
Patients will be followed every 6 months during the 2 years after discontinuing study treatment for an underlying disease assessment 
(performed per Appendix E) and survival. 
n 
Cycle 2 of induction only.


 
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Appendix E ASBMT RFI 2017 – Disease Classifications Corresponding to CIBMTR Classifications 
ASBMT Diagnosis Category 
ASBMT RFI 
Classification 
CIBMTR 
Classification^ 
AML and ALL 
precursor B-lymphoblastic 
lymphoma/leukemia {per W.H.O. 
reclassified from lymphoma} 
precursor T-lymphoblastic 
lymphoma/leukemia 
Low risk: 
CR 1 
First complete remission (CR1): A treatment response where all of the following criteria are 
met for at least four weeks*†: 
• 
Hematological: no blast cells in the peripheral blood, < 5% blasts in the bone marrow, no 
blasts with Auer rods (AML only), normal maturation of all cellular components in the 
marrow, normal CBC and ANC of > 1,000/µL 
• 
Platelets ≥ 100,000/µL*† 
• 
Transfusion independent 
• 
No other signs or symptoms of disease, including extramedullary disease(e.g., central 
nervous system or soft tissue involvement) 
• 
Include recipients with persistent cytogenetic abnormality who otherwise meet all the 
criteria of CR. CIBMTR collects information about cytogenetic and molecular testing for 
those in CR (hematologic CR), however these are only relevant for RFI reporting in as 
much as the centers judge importance of residual cytogenetic abnormalities in 
determining current status beyond the hematic criteria. 
• 
*In some cases, there may not be a four-week interval between the completion of treatment 
for disease and the disease assessment immediately prior to the HSCT. If this is the case, 
CR should still be reported as the status at transplantation. Although this is an exception to 
the general condition that CR is “durable” beyond four weeks, the status of CR represents 
the “best assessment” prior to HSCT. Similarly, sufficient time may not have elapsed to 
allow for platelet recovery to normal levels and physician judgment is required to interpret 
whether residual low platelet counts may reflect residual disease. 
 
AML and ALL (con‟t) 
Intermediate risk: 
CR2, CR3+ 
Complete remission 2nd or greater (CR2/+)†: Recipient achieved CR as defined 
above, relapsed and achieved CR again. Final pre-HSCT status must be CR. 
AML and ALL (con‟t) 
High risk (not in 
remission): 
Never treated: The recipient was diagnosed with acute leukemia and never treated. For 
example, this disease status may be appropriate if MDS was initially diagnosed and 
NOTE: Recipients with MDS that transformed to AML 
If the recipient has residual MDS following treatment for AML, report the AML 
disease status as either PIF or relapse (i.e., the recipient cannot be in an AML CR if 
there is evidence of MDS at the time of assessment). 


 
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ASBMT Diagnosis Category 
ASBMT RFI 
Classification 
CIBMTR 
Classification^ 
 
Never treated 
Primary Induction 
Failure (PIF) 
Relapse 
treated, the MDS then transformed into AML, and a decision was made to proceed 
immediately to transplant instead of treating the AML with therapy. 
Primary Induction Failure (PIF): The recipient was treated for acute leukemia but never 
achieved durable* complete remission with any therapy (*including relapsed < 1 mo from CR1 
determination). The term “PIF” is not limited to the number of treatments used unsuccessfully. 
Relapse: Recurrence of disease after CR. Relapse is defined as: 
• 
≥ 5% blasts in the marrow 
• 
Extramedullary disease 
• 
Reappearance of cytogenetic abnormalities and/or molecular markers associated with the 
diagnosis that, in the judgement of a physician, are at a level representing relapse. 
• 
Although CIBMTR collects information upon the number of the relapse, this 
information is not needed for the ASBMT RFI 
 
Source: https://higherlogicdownload.s3.amazonaws.com/ASBMT/43a1f41f-55cb-4c97-9e78-
c03e867db505/UploadedImages/ASBMT_RFI_2018B_CIBMTR_Disease_Classifications.pdf


 
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Appendix F Management of Quizartinib-Associated Adverse Events 
 
QTcF (QT interval corrected with Fridericia’s formula) Prolongation 
• Grade 1 
o Check magnesium and potassium levels and correct any abnormalities. If 
possible, stop any medications that may prolong the QTc interval. Continue 
quizartinib at the same dose.  
• Grade 2 (QTcF average of triplicate readings >480 msec) 
o Check magnesium and potassium levels and correct any abnormalities. If 
possible, stop any medications that may prolong the QTc interval. 
o The dose will be reduced without interruption (See Table 2).  Following dose 
reduction, the quizartinib/placebo dose may be resumed at the previous level in 
the next cycle if the QTcF has decreased to within 30 msec of baseline or <450 
msec but subject must be monitored closely for QT prolongation for the first cycle 
at the increased dose. 
o If 20 mg/day is the current dose, dosing will be interrupted for up to 14 days. If 
QTcF returns to within 30 msec of baseline or ≤450 msec within 14 days, 
treatment may be resumed at 20 mg/day. 
• Grade 3 (QTcF average of triplicate readings >500 msec) 
o Check magnesium and potassium levels and correct any abnormalities. If 
possible, stop any medications that may prolong the QTc interval. 
o Dosing will be interrupted for up to 14 days. If QTcF returns to within 30 msec of 
baseline or ≤450 msec within 14 days, treatment may be resumed at a reduced 
dose (See Table 2). 
o If 20 mg/day is the current dose, dosing will be interrupted for up to 14 days. If 
QTcF returns to within 30 msec of baseline or ≤450 msec within 14 days, 
treatment may be resumed at 20 mg/day. If Grade 3 event returns, treatment will 
be discontinued. 
• Grade 4 (QTcF >500 msec or >60 msec change from baseline, and Torsade de pointes or 
polymorphic ventricular tachycardia or signs/symptoms of serious arrhythmia) 
o Treatment will be permanently discontinued. 
 
Differentiation Syndrome  
• Patients with suspected differentiation syndrome should promptly start treatment with 
systemic glucocorticoids and hemodynamic monitoring per local principal investigator or 
institutional preference until improvement. Treatment should be held until resolution to < 
Grade 3.  
 
Non-Hematologic Toxicity 


 
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Grade 3 or 4 non-hematologic toxicity that is at least possibly related to quizartinib and 
persisting >48 hours without improvement to ≤ Grade 2 or without waiting 48 hours if in the 
Investigators judgment the AE poses a serious risk to the patient: 
 
• Dosing will be interrupted for up to 28 days. 
o If toxicity improves to Grade ≤1 within 28 days, treatment may be resumed at the 
previous dose. 
o If toxicity improves to Grade ≤2 within 28 days, treatment may be resumed at a 
reduced dose (1 level) (See Table 2). 
o If toxicity does not improve/resolve within 28 days, then quizartinib will be 
discontinued. 
 
Hepatic Events and Liver Enzyme Elevation 
Elevation of liver enzymes that meet the criteria below should be investigated and the cause 
identified when possible: 
• ALT >8 × ULN; or 
• AST or ALT >5 x ULN for more than two weeks; or 
• ALT or AST >3 x ULN, but not reaching the limits in the above criteria, in combination 
with clinical symptoms suggestive of hepatitis; or 
• ALT or AST >3 x ULN with TBL >2 x ULN* 
o Combined elevations of ALT or AST with TBL as described above will be treated 
as Adverse Events of Special Interest and reported as per Section 11.2.* 
Once the cause of liver enzyme elevation is identified, remove or treat the contributing cause.  If 
the above criteria are met and the elevation is considered to be related or possibly related to 
quizartinib, then quizartinib dosing should be interrupted. 
Liver enzyme level testing will be repeated at least weekly, or more frequently, based on degree 
of hepatic laboratory abnormality. If the liver enzyme levels return to baseline levels, quizartinib 
may be resumed at the full dose. If toxicity does not improve/resolve within 28 days, then 
quizartinib will be discontinued. 
Upon resumption of quizartinib, if liver enzyme elevations recur, treatment may be resumed at a 
reduced dose following return to baseline levels. 
 
Liver Safety Monitoring and Evaluations 
Any patient who temporarily interrupts or permanently discontinues quizartinib due to confirmed 
liver enzyme abnormalities and/or jaundice in the absence of a known cause, must have an 
evaluation to determine the cause of the event. 
Evaluation may include the following depending on the clinical situation: 
• Medical history and physical exam, including focus on medications and substances used: 
alcohol, acetaminophen, azole antifungals, change in medication dosages, new 


 
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medications added, over the counter medication use and recreational drug use. Check for 
change in diet or use of dietary supplements 
• Abdominal ultrasound 
• Hepatitis B, and C screening (hepatitis B surface antigen, and anti-hepatitis C virus plus 
viral titer), antinuclear antibody and anti-Smith antibody, cytomegalovirus, Epstein Barr 
virus 
• Additional evaluations as deemed appropriate by the Investigator to exclude other causes 
of liver enzyme and bilirubin elevations 
• All laboratory results, including local laboratory reference ranges are to be recorded. 
 
Myelosuppression (Maintenance Phase) 
Quizartinib should be reduced or dosing interrupted (See Table 3) at the Investigator’s discretion 
if: 
• The patient has been treated for a minimum of 2 cycles; 
• Platelet count is <100,000/mm3 and ANC ≤1000/mm3; and 
• There is no evidence of relapse. 
The dose of quizartinib may be reduced stepwise from 60 mg/day to 30 mg/day to 20 mg/day. 
For patients experiencing myelosuppression requiring dose reduction while taking a dose of 30 
mg/day (20 mg/day in patients receiving a strong CYP3A4inhibitor), dosing will be interrupted. 
 


 
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Appendix G Management of CPX-351-Related Adverse Events 
 
NCI CTCAE Grade 
CPX-351 Action 
Cardiotoxicity 
Discontinue CPX-351 immediately without resumption 
Hypersensitivity Grade 1 
Once symptoms resolve, reinitiate infusion at half the prior rate of 
infusion. Consider premedication with antihistamines and/or 
corticosteroids for subsequent doses. 
Hypersensitivity Grade 2 
Do not reinitiate infusion. For subsequent doses, pre-medicate with 
antihistamines and/or corticosteroids prior to initiating infusion at 
same rate. 
Hypersensitivity Grade ¾ 
Permanently discontinue treatment, treat according to the standard 
of care to manage symptoms, and monitor patient until symptoms 
resolve. 
Neutropenia lasting ≥56 days 
Proceed to maintenance therapy with quizartinib  
Thrombocytopenia lasting ≥56 
days 
Proceed to maintenance therapy with quizartinib  


 
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Appendix H Cytochrome P450 3A4 Inhibitors and Inducers 
Source:  http://www.mayomedicallaboratories.com/it-
mmfiles/Cytochrome_P450_3A4_and_3A5_Known_Drug_Interaction_Chart.pdf 
CYP3A4 Inhibitors 
CYP3A4 Inducers 
Strong Inhibitors 
Barbiturates 
Clarithromycin 
Carbamazepine 
Indinavir 
Efavirenz 
Itraconazole 
Glucocorticoids 
Ketoconazole 
Modafinil 
Nefazodone 
Nevirapine 
Posaconazole 
Oxcarbazepine 
Ritonavir 
Phenobarbital 
Saquinavir 
Phenytoin  
Suboxone 
Pioglitazone  
Telithromycin 
Rifabutin  
Voriconazole 
St. John's Wort 
Intermediate Strength Inhibitors 
Troglitazone  
Aprepitant 
 
Erythromycin 
 
Fluconazole 
 
Isavuconazole 
 
Verapamil 
 
Diltiazem 
 
Weak Inhibitors 
 
cimetidine 
 
Other Possible Inhibitors 
 
Amiodarone 
 
Boceprevir 
 
Chloramphenicol 
 
Ciprofloxacin 
 
Delaviridine 
 
Diethyl-dithiocarbamate 
 
Fluvoxamine 
 
Gestodene 
 
Imatinib 
 
Mibefradil 
 
Mifepristone 
 
Norfloxacin 
 
Norfluoxetine 
 
Starfruit 
 
Telaprevir 
 


 
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Appendix I 
Drugs That Prolong QT Interval and/or Induce Torsades De Pointes 
Drugs with known or possible risk of QT prolongation and/or Torsades de pointes should be 
avoided for all patients from screening through permanent discontinuation of study treatment.  
Please note that the list below was derived from www.crediblemeds.org on 07 October 2019 and 
serves only as guidance.  Since CredibleMeds® constantly assesses new drug information and 
updates its lists, sites should go directly to the crediblemeds.org website in real-time for 
reference. 
 
 


 
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