Clinical trial NCT02286726
Conditions: Acute Myeloid Leukemia Acute Myeloid Leukemia Arising From Previous Myelodysplastic Syndrome Secondary Acute Myeloid Leukemia
Sponsor: M.D. Anderson Cancer Center
Start date: 2015-05-04; Completion date: 2020-01-22
Enrollment: 56 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This phase II trial studies the best dose and how well liposomal cytarabine-daunorubicin CPX-351 (CPX-351) works in treating patients with newly diagnosed acute myeloid leukemia and who are at risk for not responding well to treatment. Liposomal cytarabine-daunorubicin CPX-351 combines two chemotherapy drugs that are known to help each other work better, and may work to stop the growth of cancer cells by blocking the cells from dividing.

Detailed description:
PRIMARY OBJECTIVE:

I. To assess preliminary efficacy (as determined by the rate of complete response \[CR\] or CR with incomplete blood count recovery \[CRi\]) of two or three dose levels of CPX-351 in patients with newly diagnosed acute myeloid leukemia (AML) at high risk for induction mortality, defined as 30-50% predicted risk of death by day 60, and to select the most promising dose level for further efficacy testing.

SECONDARY OBJECTIVE:

I. To confirm the rate of dose limiting toxicities, including induction mortality (at day 60) for two different sub-maximum tolerated dose (MTD) dose levels (50 and 75 U/m\^2).

EXPLORATORY OBJECTIVES:

I. To investigate the effect of CPX-351 on immune response, as determined by the effect on recovery of functional pathogen-specific and leukemia-specific immune responses and the recovery and function of natural killer (NK) cells.

II. To investigate the role of troponin-T as an early marker for CPX-351-induced cardiotoxicity.

III. To investigate ex vivo the cytotoxicity of combination of Pim-1 proto-oncogene, serine/threonine kinase (Pim) kinase inhibitor(s) and CPX-351 on circulating leukemia cells.

OUTLINE:

INDUCTION: Patients are randomized to 1 of 2 arms. After safety is established for both dose levels, and escalation is deemed feasible, an additional arm will be studied at the standard dose level.

ARM I: Patients receive lower-dose liposomal cytarabine-daunorubicin CPX-351 intravenously (IV) over 90 minutes on days 1, 3, and 5 of a 28-day course. Patients with persistent disease may receive a second course with treatment on days 1 and 3.

ARM II: Patients receive intermediate-dose liposomal cytarabine-daunorubicin CPX-351 IV over 90 minutes on days 1, 3, and 5. Patients with persistent disease may receive a second course with treatment on days 1 and 3.

ARM III: Patients receive standard-dose liposomal cytarabine-daunorubicin CPX-351 IV over 90 minutes on days 1, 3, and 5. Patients with persistent disease may receive a second course with treatment on days 1 and 3.

CONSOLIDATION THERAPY: Patients achieving CR receive liposomal cytarabine-daunorubicin CPX-351 on days 1 and 3. Treatment may repeat every 28 days for up to 4 courses in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up monthly for as long as the study doctor thinks it is needed, every 2-3 months for up to 1 year, and every 3-4 months for up to 1 year.

Arms: arm 1: Patients receive lower-dose liposomal cytarabine-daunorubicin CPX-351 IV over 90 minutes on days 1, 3, and 5 of a 28-day course. Patients with persistent disease may receive a second course with treatment on days 1 and 3. arm 2: Patients receive intermediate-dose liposomal cytarabine-daunorubicin CPX-351 IV over 90 minutes on days 1, 3, and 5. Patients with persistent disease may receive a second course with treatment on days 1 and 3. arm 3: Patients receive standard-dose liposomal cytarabine-daunorubicin CPX-351 IV over 90 minutes on days 1, 3, and 5. Patients with persistent disease may receive a second course with treatment on days 1 and 3.
Interventions: intervention 1: Laboratory Biomarker Analysis intervention 2: Liposome-encapsulated Daunorubicin-Cytarabine
Intervention descriptions: intervention 1: Correlative studies intervention 2: Given IV

Protocol documents:
Prot_SAP_000.pdf: 
Protocol Page
Phase II Study of CPX-351 (Cytarabine:Daunorubicin) Liposome Injection in 
Patients with Newly Diagnosed AML at High Risk for Induction Mortality
2014-0548
Core Protocol Information
Short Title 
Phase II CPX-351 in AML
Study Chair: 
Ghayas C. Issa
Additional Contact:
Maesen M. Ash
Rachel R. Abramowicz
Leukemia Protocol Review Group
Additional Memo Recipients:
Recipients List
OPR Recipients (for OPR use only)
OHSP DSMB
PDOL OPR DMC Addl Cont
Study Staff Recipients
None
Department:
Leukemia
Phone:
713-745-6798
Unit:
428
Study Manager:
Maesen M. Ash
Full Title: 
Phase II Study of CPX-351 (Cytarabine:Daunorubicin) Liposome Injection 
in Patients with Newly Diagnosed AML at High Risk for Induction Mortality
Public Description:
 
Protocol Type:
Standard Protocol
Protocol Phase:
Phase II
Version Status:
Activated -- Closed to new patient entry as of 09/20/2019
Version:
18
Document Status:
Saved as "Final"
Submitted by:
Rachel R. Abramowicz--9/19/2019 8:42:38 AM
OPR Action:
Accepted by:  Amber M. Cumpian -- 9/20/2019 10:45:29 AM
Which Committee will review this protocol?
 The Clinical Research Committee - (CRC)


Protocol Body
 
  


MDACC Protocol No. 2014-0548 
 
PHASE II STUDY OF CPX-351 (CYTARABINE:DAUNORUBICIN) LIPOSOME 
INJECTION IN PATIENTS WITH NEWLY DIAGNOSED AML AT HIGH RISK 
FOR INDUCTION MORTALITY 
 
 
 
INVESTIGATOR: 
The University of Texas M.D. Anderson Cancer Center 
 
 
Ghayas C. Issa, MD 
 
STUDY CO-CHAIR:  
The University of Texas M.D. Anderson Cancer Center 
 
 
 
Hagop Kantarjian, MD 
 
 
 
 
Srdan Verstovsek, MD 
 
 
 
 
COLLABORATORS: 
The University of Texas M.D. Anderson Cancer Center 
 
 
 
Elias Jabbour, MD 
 
 
 
 
Gautam Borthakur, MD 
 
 
 
 
Naveen Pemmaraju, MD 
 
 
 
 
Naval Daver, MD 
 
 
 
 
Tapan Kadia, MD 
 
 
 
 
 
Confidential 
FINAL 
September 9, 2019 
 
Not for Publication  
The information in this document contains trade secrets and commercial information that are privileged or 
confidential and may not be disclosed unless such disclosure is required by federal or state law or regulations. 
In any event, persons to whom the information is disclosed must be informed that the information is 
privileged or confidential and may not be further disclosed by them. These restrictions on disclosure will 
apply equally to all future information supplied to you which is indicated as privileged or confidential.  


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ABBREVIATIONS 
7+3 
Seven days of continuous infusion of cytarabine at 100 mg/m2/day and 
three days of daunorubicin at 60 mg/m2/day 
5+2 
Five days of continuous infusion of cytarabine at 100 mg/m2/day and 2 
days of daunorubicin at 60 mg/m2/day 
ADR  
Adverse Drug Reaction 
AE 
 
Adverse Event 
AHD  
Antecedent Hematologic Disorders 
ALL 
 
Acute Lymphocytic Leukemia 
ALT 
 
Alanine Transaminase (SGPT) 
AML  
Acute Myeloid Leukemia 
ANC  
Absolute Neutrophil Count 
Ara-U  
Arabinosyluracil 
ASCO  
American Society of Clinical Oncology 
AST 
 
Aspartate Transaminase (SGOT) 
ATPase 
Adenosine triphosphatase 
AUC  
Area under the plasma concentration-time curve 
BSA 
 
Body Surface Area 
BUN  
Blood Urea Nitrogen 
C 
 
Celsius 
Cmax  
Maximum plasma concentration 
CL 
 
Clearance 
CNS 
 
Central nervous system 
CPX-351 
CPX-351 (cytarabine:daunorubicin) Liposome Injection 
CR 
 
Complete Response 
CRi 
 
Complete Response with incomplete hematologic recovery 
CRF 
 
Case Report Form 
CMMoL 
Chronic Myelomonocytic Leukemia 
CTCAE 
Common Terminology Criteria for Adverse Events 
DEHP  
di(2-ethylhexyl)phthalate 
dL 
 
deciliter 
DSMB  
Data and Safety Monitoring Board 
DSPG  
Distearoylphosphatidylglycerol 
DSPC  
Distearoylphosphatidylcholine 
EC 
 
Ethics Committee 
ECG  
Electrocardiogram 
ECOG  
Eastern Cooperative Oncology Group 
EFS 
 
Event-free Survival 
ELN 
 
European LeukemiaNet 
EOI 
 
End of Infusion 
EP 
 
European Pharmacopoeia 
EU 
 
European Union 
FDA  
Food and Drug Administration 
g 
 
grams 
GCP 
 
Good Clinical Practice 
HCl 
 
Hydrogen Chloride 


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HIPAA 
Health Information Protection and Portability Act 
HIV 
 
Human Immunodeficiency Virus 
HOVON 
Hemato-Oncologie voor Volwassenen Nederland 
HP 
 
High Purity 
HSCT   
Hematopoietic Stem Cell Transplantation 
ICF 
 
Informed Consent Form 
ICH 
 
International Committee on Harmonization 
ITT 
 
Intent-to-treat 
IRB/EC  
Institutional Review Board/Ethics Committee 
iv, IV  
intravenous 
K-M 
 
Kaplan-Meier 
L 
 
liter 
LDH  
Lactate Dehydrogenase 
LVEF  
Left ventricular ejection fraction 
m2 
 
square meters 
MDR  
Multi-drug Resistance 
MDS  
myelodysplastic syndrome 
MedDRA 
Medical Dictionary for Regulatory Activities 
mg 
 
milligram(s) 
mL 
 
milliliter(s) 
MLL  
Mixed Lineage Leukemia 
MPN  
Myeloproliferative neoplasm 
MTD  
Maximum Tolerated Dose 
MUGA 
Multiple Gated Acquisition scan 
mw 
 
molecular weight 
N 
 
Number, Population 
NF 
 
National Formulary 
OS 
 
Overall Survival 
PD 
 
Persistent Disease 
PHI 
 
Protected Health Information 
PK 
 
Pharmacokinetics 
PS 
 
Performance Status 
q.s. 
 
Quantum sufficiat 
RBC  
Red blood cells 
SAE 
 
Serious Adverse Event 
SD 
 
Standard deviation 
sAML  
Secondary AML 
T1/2 
 
Half-life 
t-AML  
Therapy-related AML 
Tmax  
Time of occurrence of Cmax 
u 
 
Units 
μL 
 
Microliter 
ULN  
Upper Limits of Normal 
USP 
 
United States Pharmacopeia 
WHO  
World Health Organization 


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TABLE OF CONTENTS 
1.0 
General Information .................................................................................................6 
2.0 
Background Information ..........................................................................................6 
2.1 
Acute Myeloid Leukemia in the Elderly and its Treatment ..................................6 
2.2 
CombiPlex Technology ......................................................................................7 
2.3 
Physical, Chemical and Pharmaceutical Information ...........................................8 
2.4 
Product Label ........................................................................................................9 
2.5 
Pre-clinical Pharmacology & Toxicology ............................................................9 
2.6 
Brief Summary of Prior Clinical Studies ..............................................................9 
2.7 
Copper Background ............................................................................................18 
3.0 
Study Objectives and Rationale .............................................................................20 
3.1 
Primary Objectives ..............................................................................................20 
3.2 
Secondary Objectives ..........................................................................................20 
3.3 
Exploratory Objectives .......................................................................................20 
3.4 
Study Rationale ...................................................................................................20 
4.0 
Study Design ..........................................................................................................21 
4.1 
Patient Recruitment .............................................................................................22 
4.2 
Registration Procedures ......................................................................................22 
4.3 
Patient Sample Size.............................................................................................23 
4.4 
Toxicity Assessment ...........................................................................................23 
4.5 
Second Inductions ...............................................................................................23 
4.6 
Consolidation Therapy ........................................................................................23 
4.7 
Salvage Therapy ..................................................................................................24 
4.8 
Patient Follow-up ................................................................................................24 
4.9 
Study Modification/Discontinuation ...................................................................25 
5.0 
Selection and Withdrawal of Patients ....................................................................25 
5.1 
Study Population .................................................................................................25 
5.2 
Withdrawal of Patients ........................................................................................26 
6.0 
Treatment of Patients .............................................................................................27 
6.1 
Pre-Treatment Evaluations ..................................................................................27 
6.2 
Evaluation during Treatment ..............................................................................28 
6.3 
Early Termination or End of Treatment ..............................................................30 
6.4 
Evaluation during Follow-up ..............................................................................31 
7.0 
Drug Administration ..............................................................................................32 
7.1 
Drug Preparation and Administration .................................................................33 
7.2 
Drug Accountability............................................................................................33 
7.3 
Dose Reductions and Delays ..............................................................................34 
7.4 
Concomitant Therapy..........................................................................................34 
7.5 
Duration of Protocol Treatment ..........................................................................35 
8.0 
Assessment of Efficacy ..........................................................................................35 
8.1 
Evaluable for Efficacy ........................................................................................35 
8.2 
Overall Survival ..................................................................................................36 
8.3 
Event-free Survival .............................................................................................36 
8.4 
Response Assessment Criteria ............................................................................37 
8.5 
Remission Duration ............................................................................................38 
8.6 
Morphologic Leukemia-free State ......................................................................38 


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9.0 
Assessment of Safety .............................................................................................38 
9.1 
Evaluable for Safety ............................................................................................38 
9.2 
Adverse Events ...................................................................................................38 
9.3 
Cardiac Toxicity Monitoring ..............................................................................41 
9.4 
Laboratory Data ..................................................................................................41 
10.0 
Statistical Considerations .......................................................................................41 
11.0 
References ..............................................................................................................48 
12.0 
APPENDIX 1: Patient Evaluation Flow Sheet – Treatment Phase .......................50 
13.0 
APPENDIX 2: Patient Evaluation Flow Sheet –Follow-up ..................................52 
14.0 
APPENDIX 4: Performance Status – ECOG .........................................................53 
15.0 
APPENDIX 5: Common Terminology Criteria for Adverse Events V4.0 
(CTCAE) ............................................................................................................................54 
16.0 
APPENDIX 6:  Immune Reconstitution After Chemotherapy with CPX-351…..52 
17.0 
APPENDIX 7:  Early Detection of CPX-351-Induced Cardiotoxicity using High 
Sensitivity Troponin T………………………………...…………………………………53 
18.0 
APPENDIX 8:  Pharmacodynamic Investigations During CPX-351 THerapy….55 
19.0 
APPENDIX 9: AML with MDS-Associated Karyotype………..……………….58 
20.0 
APPENDIX 10 European Leukemia Net (ELN) Classification……………...….59 
 
 
 


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1.0 General Information 
This document is a protocol for a human research study. This study is to be conducted 
according to United States and international standards of Good Clinical Practice (FDA 
Title 21 parts 11, 50, 54, 56, 312, International Conference on Harmonization and the 
Declaration of Helsinki), applicable government regulations and Institutional research 
policies and procedures. 
2.0 Background Information 
2.1 
Acute Myeloid Leukemia in the Elderly and its Treatment 
Acute myeloid leukemia represents a group of clonal hematopoietic stem cell disorders in 
which both failure to differentiate and excessive proliferation in the stem cell 
compartment result in accumulation of non-functional cells termed myeloblasts.(1) 
 
Untreated AML in all ages is rapidly fatal, with patients dying on average within a few 
months of diagnosis.  Even with treatment, particular groups of AML patients continue to 
have a poor prognosis.  AML in the elderly (age ≥60) is associated with increased risk of 
not responding to therapy and increased risk of dying from the treatment.  Appelbaum, et 
al.(2) and Kantarjian, et al.(3) summarize the factors that contribute to poor outcomes in 
elderly patients with AML. Risk factors that decrease patient tolerance to therapy or 
sensitivity of the leukemia to therapy include increasing age, poor performance status, co-
morbid medical conditions, accumulated chromosomal abnormalities, adverse mutations, 
and multi-drug resistance. 
 
There is broad overlap of these risk factors with most elderly AML patients having one or 
more adverse features.  The poor results of treatment in elderly AML lead to a reluctance 
to treat elderly patients with intensive regimens designed to induce aplasia and complete 
remission. 
 
Clearing the marrow of leukemia has historically been the only means of obtaining 
prolonged survival in AML patients.  This is usually accomplished by use of intensive 
cytotoxic/cytoreductive therapy.(4)  The intensity of treatment needed to induce aplasia 
and complete remission is associated with early mortality rates of 10-20% in elderly 
patients considered fit for intensive therapy and is higher in patients with risk factors 
indicating less sensitive leukemia, co-morbidities, and poor performance status.(2, 3, 5-7) 
 
A randomized study reported in 2009 showed that a double induction regimen with 90 
mg/m2 daunorubicin with cytarabine (first induction) followed by a second induction 
with intermediate dose cytarabine (1 g/m2) could be safely administered with high rates 
of complete remission in older patients. The second induction was given even to patients 
already morphologically leukemia-free after first induction, a practice that is not routinely 
used in the U. S. and Canada.  This publication from the HOVON group noted 
improvement in remission rate when compared to a traditional regimen of cytarabine plus 
daunorubicin (45 mg/m2) but no improvement in disease-free survival or overall survival 


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was noted.(8)  At the present time, the HOVON study has not been replicated in elderly 
patients by any other group.  
 
Another study by Fernandez, et al., reported success for the same higher dose 
daunorubicin regimen (90 mg/m2) versus 45 mg/m2 of daunorubicin when used for first 
induction for younger patients.(9) For second inductions, the dose of daunorubicin was 
reduced to 45 mg/m2 for all patients.  Responding patients were taken to transplant.  
Neither this study nor the HOVON study used daunorubicin 90 mg/m2 for second 
induction courses or in consolidation and neither study demonstrated that 90 mg/m2 is 
more effective than 60 mg/m2.  Although of great interest, neither regimen is ready to be 
used as the control arm in a comparative study with CPX-351. 
 
For patients at high risk of relapse (e.g. those with high-risk cytogenetics, underlying 
MDS, or therapy-related AML), allogeneic stem cell transplantation is usually 
recommended if the patient is able to tolerate a transplant and has a suitable donor. 
 
For patients with older age or co-morbidities the risk of induction treatment remains high.  
Patients age 65 or older treated with standard 3+7-like chemotherapy have been reported 
to have an induction mortality rate of 20%.(8, 10) Those with adverse cytogenetic 
abnormalities have a significantly higher risk of early mortality.(8, 11) At MD Anderson, 
patients at relatively high (30-50%) risk for induction mortality (60-day) can be 
identified.  Patients in this age group with adverse cytogenetic abnormalities have an 
early mortality rate of 35% compared to 22% for those in the same age group with 
diploid cytogenetics (Tambaro et al. ASH 2012). In addition, an analysis of 998 patients 
age 65 or older with AML or high-risk MDS analyzed the factors associated with 
increased risk for early mortality and, consequently, poor long-term outcome. By 
multivariate analysis, age 75 years or older, performance status ≥2, complex karyotype, 
treatment outside a laminar air-flow setting, antecedent hematologic disorder of at least 
12 months duration prior to the diagnosis of AML, and a creatinine >1.3 mg/dL were 
identified as independent factors associated with increased risk of mortality by 8-weeks 
from the start of induction chemotherapy.(3) Patients with none of these risk factors have 
an 8-week mortality probability of 10%, with a median survival of 16 months and 1-year 
projected survival of 58% and are considered a low-risk group. In contrast, for those with 
1 or 2 risk factors (i.e., the intermediate risk group) the 8-week mortality rate is 19-36% 
with median survival of 4-9 months and 1-year survival rates of 22-35%. Those with 3 or 
more risk factors (the high-risk group) have a 65% probability of early mortality, median 
survival of 1 month and 1 year projected survival of 8%.(3) For patients with intermediate 
or high risk the decision to treat with intensive chemotherapy is difficult because the 
benefits have been approximately equal to the risks.  Studies using non-intensive 
treatment have been performed indicating reduced early risk with reduced benefit.  The 
need for effective treatment with acceptable treatment safety remains urgent.   
 
2.2 
CombiPlex Technology 
In vitro studies have shown that antitumor activity can be enhanced when cytotoxic drugs 
are used in combination.  This has led to cytotoxic drug combinations as standard therapy 


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in many forms of cancer treatment.  New anticancer drugs are typically first introduced in 
patients as single agents.  After a maximum tolerated dose is determined for one agent, a 
second agent is added and the dose of one or both agents is adjusted on the basis of 
toxicity.  The development of these combination regimens then is determined empirically 
on the basis of tolerability.  However, in vitro, where the molar ratio of drugs used in 
combination can be controlled, it has been demonstrated that drug combinations 
providing synergy at one ratio may be simply additive or even antagonistic at other 
ratios.(12)  When individual free drugs are administered, each agent is handled 
differently by the body, resulting in differences in the distribution and elimination of the 
individual drugs to tumor sites which must result in drug ratios that are sometimes 
suboptimal or ineffective.  The manufacturer’s technology is based on findings that in 
vitro synergistic activity of antineoplastic drugs depends on specific drug ratios and that 
the in vivo activity of a combination depends on maintaining the synergistic ratio.  In this 
way, the development of a particular chemotherapeutic regimen can be based on the most 
efficacious ratio rather than empirically based on toxicity. 
 
The development of CPX-351 (cytarabine:daunorubicin) Liposome Injection was based 
on 1) defining a synergistic ratio of the two active moieties, cytarabine and daunorubicin, 
using cell-based screening assays and 2) designing a liposomal drug carrier to maintain 
this ratio after intravenous administration.  This ratio was not based on the empirically-
derived, toxicity-guided regimens currently used for cytarabine and anthracyclines. 
 
2.3 
Physical, Chemical and Pharmaceutical Information 
CPX-351 is a liposomal formulation of a fixed combination of the antineoplastic drugs 
cytarabine and daunorubicin. The two drugs are present inside the liposome in a 5:1 
molar ratio.  The liposome membrane is composed of distearoylphosphatidylcholine, 
distearoylphosphatidylglycerol and cholesterol in a 7:2:1 molar ratio.  These liposomes 
have a nominal diameter of approximately 100nm and are suspended in sucrose.  
Sterilization is achieved by filtration through a 0.22 µm filter. 
 
CPX-351 is provided as a sterile, pyrogen-free lyophilized formulation in 50 ml glass, 
single-use vials.  Each vial contains 100 units of CPX-351 where each unit contains 1.0 
mg cytarabine and 0.44 mg daunorubicin base in liposomes.  The lyophilized cake is 
reconstituted with water for injection to obtain a homogeneous dispersion at 5 units/mL.  
The composition of the formulation after reconstitution is listed in Table 1 below. 
 
Table 1:  Quantitative Composition  
 
Component 
mw 
Amount per 
Vial 
Amount 
per unit 
Cytarabine, USP/EP 
243 
100 mg 
1.0 mg 
Daunorubicin HCl USP/EP(reported as the free base) 
528 
44 mg 
0.44 mg 
Distearoylphosphatidylcholine 
790 
454 mg 
4.5 mg 
Distearoylphosphatidylglycerol 
801 
132 mg 
1.3 mg 
Cholesterol, HP 
387 
32 mg 
0.3 mg 
Copper gluconate, USP 
454 
92 mg 
0.9 mg 
Triethanolamine, NF 
149 
7 mg 
0.07 mg 


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Sucrose, NF 
342 
2054 mg 
20.54 mg 
 
2.4 
Product Label 
OLD LABEL DELETED 
 
NEW LABEL ADDED 
 
 
2.5 
Pre-clinical Pharmacology & Toxicology 
The pre-clinical pharmacology and toxicology is summarized in the Investigator’s 
Brochure for CPX-351. 
 
2.6 
Brief Summary of Prior Clinical Studies 
Three clinical studies have been conducted with CPX-351.  One Phase I study, 
CLTR0305-101 and two Phase II studies:  CLTR0308-204 and CLTR0308-205.  Below 
is a summary of these studies. 
 


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2.6.1 Phase I Study of CPX-351: CLTR0305-101 
The primary goal for this study was to establish the MTD for CPX-351 and recommend a 
dose for further study in a Phase II setting.  Pharmacokinetics was assessed at every dose 
level and patients were monitored for signs of antileukemic activity. 
 
The dosage regimen was designed to mimic the 7-day drug exposure provided by 
conventional 7+3 treatment.   A single induction course administers doses on Days 1, 3, 
and 5, by 90 minute infusion.  Patients with AML (multiply relapsed, refractory, or with 
first CR duration of 6 months or less), ALL, and high risk MDS were eligible. 
 
Dose limiting toxicities were observed at the 10th dose level: 134 u/m2 (134 mg/m2 
cytarabine + 59 mg/m2 daunorubicin).  One patient had significant reduction in post 
treatment LVEF and as a result both Phase II studies included a cap (500 mg/m2) on 
cumulative anthracycline dose after one induction course of CPX-351 and patients with 
significant pre-existing cardiac disease were excluded.  Other dose-limiting toxicities 
included hypertensive crisis and prolonged (>56 days) cytopenias. 
 
The Phase I study of CPX-351 assessed the concentrations of cytarabine, daunorubicin, 
uracil arabinoside, and daunorubicinol at multiple dose levels and found that they 
exhibited mono-exponential, first order elimination with minimal early phase 
distribution.  (Figure 1) 
 
Figure 1:  CPX-351 Day 1 and 5 Pharmacokinetics from Protocol CLTR0305-101 
 
 
The day 1 (single dose) and day 5 (multiple dose) Cmax and AUC(0-) were linear and the 
5:1 molar ratio of cytarabine to daunorubicin was maintained for up to 24 hours at all 
dose levels on days 1 and 5.  
 
 
Figure 1a:  Day 1 Mean Plasma Cytarabine, 
Daunorubicin, Ara-U and Daunorubicinol 
concentrations, Time 0-48hr (101u/m2, 90 min 
infusion) 
Figure 1b.  Day 5 Mean Plasma Cytarabine, 
Daunorubicin, Ara-U and Daunorubicinol 
concentrations, Time 0-168hr (101u/m2, 90 min 
infusion) 


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The pharmacokinetic analysis confirmed higher absolute plasma concentrations of both 
drugs compared to that expected with the conventional 7+3 regimen with a markedly 
prolonged mean half-life for both cytarabine and daunorubicin and greater drug exposure 
(AUC).  Measurable drug levels were present seven days after the last infusion of CPX-
351 (Study Day 12).  Compared to infusions of the conventional drugs, CPX-351 
administration was associated with substantially greater AUC and half-lives for plasma 
cytarabine and daunorubicin.(13)  (Table 2) 
 
Table 2:  Cytarabine and Daunorubicin Pharmacokinetics following CPX-351 (101 
u/m2, Day 5) 
Variable 
Cmax 
(ng/mL) 
Tmax 
(hr) 
AUC(0-) 
(ng*hr/mL) 
T1/2 
(hr) 
CL 
(mL/hr/m2) 
Cytarabine 
N 
13 
13 
13 
13 
13 
Median 
55,800 
2 
1,487,638 
31.1 
67.9 
Mean 
64,608 
3.02 
1,851,089 
36.9 
67.3 
SD 
23,230 
2.25 
934,523 
24.5 
30.6 
Daunorubicin 
N 
13 
13 
13 
13 
13 
Median 
29,200 
2 
633,579 
21.9 
70.1 
Mean 
30,185 
1.87 
666,640 
25.2 
72.9 
SD 
6,198 
0.74 
209,198 
11.6 
23 
Abbreviations: Cmax, maximum serum concentration; Tmax, time to maximum serum 
concentration; AUC(0-), area under the serum concentration-time curve from time 0 to time 
 (end of the dosing interval); t1/2, terminal half-life; CL, clearance; SD, standard deviation. 
 
Three of the 48 patients entering the study had ALL and a transient CR was achieved in 
one patient at the 43 unit/m2 dose level.  Two patients with high risk MDS were treated at 
lower dose levels and neither responded. The remaining 43 patients had AML; 20 
patients after multiple relapses or multiple treatment regimens, 18 after relapse from a 
first CR, and 5 after primary induction failure.  Complete response was observed in 10 of 
43 AML patients, a notable observation because most patients had received cytarabine 
and daunorubicin in the past and because of the low frequency of non-hematological 
toxicities observed with CPX-351. 
 
In conclusion, the Phase I study defined the maximally tolerated dose (101 u/m2) for a 
day 1, 3 and 5 induction course of treatment and confirmed persistence of the 5:1 molar 
ratio for up to 24 hours in the plasma with markedly prolonged median half-life for both 
cytarabine and daunorubicin.  Multiple responses in previously treated AML patients 
provided proof of antileukemic activity. 
2.6.2 Phase II Study of CPX-351: CLTR0308-204 
The 204 study was designed as a randomized study comparing CPX-351 head-to-head 
against 7+3, in newly diagnosed, older (age 60-75) patients with AML.  The comparison 
of encapsulated cytarabine and daunorubicin (CPX-351) versus free cytarabine and 
daunorubicin (7+3) would be fully interpretable for relative efficacy and safety and 
would begin to provide evidence supporting or refuting the hypothesis that dosing based 
on molar ratios would lead to improved efficacy. 


PROTOCOL MDACC 2014-0548 
CPX-351 (cytarabine:daunorubicin) Liposome Injection 
September 9, 2019 
 
CONFIDENTIAL 
Page 12 of 61 
FINAL 
 
One hundred twenty-seven patients were randomized from 18 of 28 study sites. The study 
was amended to extend follow-up to 2 years when it became apparent that 1 year follow-
up would be insufficient to capture median survival in both study groups. 
 
A two to one randomization was used to maximize experience using CPX-351.  Response 
rate (CR+CRi) was the primary endpoint and superior response with a one-sided p-value 
of <0.1 was deemed sufficient for moving forward in development. Secondary endpoints 
were overall survival, event-free survival, CR+CRi duration, rate of aplasia, safety and 
practicality of CPX-351 as consolidation therapy and the response rate of CPX-351 
between de novo and secondary AML. 
 
 
 
At entry patients were stratified by age (60-69 vs. 70-75), cytogenetics (< or ≥3 
cytogenetic abnormalities), and type of AML (de novo vs. secondary).  High risk patients 
were older (age 70-75) or had complex cytogenetics (≥3 cytogenetic abnormalities) or 
had secondary AML.  Standard risk patients were younger (age 60-69), had non-complex 
cytogenetics (<3 abnormalities) and had de novo AML.  After accrual was complete, Dr. 
Jeffrey Lancet (H.L. Moffitt Cancer Center, Tampa, FL) reviewed all of the cytogenetic 
reports and confirmed/corrected assignment of patients to <3 or ≥3 cytogenetic 
abnormalities.  In addition he also assigned each patient to a specific cytogenetic risk 
group (adverse vs. intermediate vs. unknown) according to National Comprehensive 
Cancer Network guidelines 
(NCCN:www.nccn.org/professionals/physician_gls/PDF/aml.pdf).  Dr. Lancet’s 
assessment of cytogenetic risk is shown in Table 3. 
 
Table 3 demonstrates balanced assignment of patients to both arms of the study 
indicating successful randomization and stratification. 
 
CPX-351 100 u/m2 IV days 1, 3, 5* 
(80 pts) 
“7+3” Regimen* 
Cytarabine 100 mg/m2 7-day infusion 
Daunorubicin 60 mg/m2 days 1, 2, 3 
 (40 pts) 
Two arms, n=120 patients
Newly diagnosed AML 
Age ≥60 and <76 years 
Able to tolerate intensive 
chemotherapy 
High-risk and standard-risk based 
on age, karyotype and AML type 
PS 0-2 
*Up to 2 inductions/ 2 consolidations 


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September 9, 2019 
 
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Table 3: CLTR0308-204 Demographics 
 
CPX-351 
7+3 
n=85 
n=41 
Gender 
Male 
53 (62.4%) 
25 (61.0%) 
Race 
Caucasian 
76 (89.4%) 
39 (95.1%) 
Risk 
Standard Risk 
28 (32.9%)  
14 (34.1%)  
High Risk 
57 (67.1%)  
27 (65.9%) 
Age Group 
≥70yrs 
34 (40.0%) 
15 (36.6%) 
Median (yrs) 
68 
68 
AML Type 
De novo AML 
53 (62.4%) 
22 (53.7%) 
Secondary AML 
 32 (37.6%)  
19 (46.3%) 
ECOG PS 
0-1 
70 (82.4%) 
36 (87.8%) 
2 
15 (17.6%)  
5 (12.2%) 
Cytogenetic Risk 
Adverse 
23 (27.1%) 
13 (31.7%) 
Intermediate 
54 (63.5%) 
26 (63.4%) 
unknown 
7 (8.2%) 
2 (4.9%) 
 
Table 4 demonstrates that CPX-351 produced superior rates of aplasia/hypoplasia and 
response with similar duration of remission.  It was notable that the improvement in 
response occurred in the form of CRi (CR with incomplete hematologic recovery). 
 
Table 4: CLTR0308-204 Response Rate and Duration of Remission 
 
CPX-351 
7+3 
 
 
n=84* 
n=41 
 
Aplasia rate after 1st induction 
64/81 (79.0%) 
23/38 (60.5%) 
 
Aplasia rate after any induction 
71/81 (87.7%) 
27/38 (71.1%) 
 
CR+CRi 
56 (66.7%) 
21 (51.2%) 
p=0.0712 
CR 
41 (48.8%) 
20 (48.8%) 
 
CRi 
15 (17.9%) 
1 (2.4%) 
 
Median Duration of Remission (days) 
271  
262  p= ns 
*Patient 12-003 was diagnosed with Philadelphia chromosome + AML and removed from study for 
treatment with imatinib 
 
The study met the primary endpoint with a response rate of 66.7% compared to 51.2% 
(p= 0.0712).  Further analysis of response according to the stratification factors 
demonstrated consistent benefit for CPX-351 in response rate across every subgroup. 
 
Table 5: CLTR0308-204 Response Rate by Sub-group 
 
CPX-351 
7+3 
n=84* 
n=41 
Risk 
Standard Risk 
22/28 (78.6%) 
8/14 (57.1%) 
High Risk 
34/56 (60.7%)  
13/27 (48.1%) 
Cytogenetic Risk 
Intermediate 
33/54 (61.1%) 
15/26 (57.7%) 
Adverse 
17/23 (73.9%) 
5/13 (38.5%) 
Age Group 
60-69 yrs 
34/50 (68.0%) 
14/26 (53.8%) 
≥70yrs 
22/34 (64.7%) 
7/15 (46.7%) 
AML Type 
De novo AML 
38/52 (73.1%) 
15/22 (68.2%) 
Secondary AML 
 18/32 (56.3%)  
6/19 (31.6%) 
*Patient 12-003 was diagnosed with Philadelphia chromosome + AML and removed from study for 
treatment with imatinib 
 


PROTOCOL MDACC 2014-0548 
CPX-351 (cytarabine:daunorubicin) Liposome Injection 
September 9, 2019 
 
CONFIDENTIAL 
Page 14 of 61 
FINAL 
Kaplan-Meier (K-M) analysis after a minimum follow up of 1-year for Event Free 
Survival (EFS, based on documentation of persistent leukemia, relapse after CR, or 
death) and Overall Survival (OS) demonstrated non-significant improvements for CPX-
351 in the overall study population and the high risk population.  K-M analysis of the 
secondary AML population (including treatment-related AML and AML occurring in the 
setting of antecedent hematologic disorders, e.g. myelodysplasia, myeloproliferative 
disease, and chronic myelomonocytic leukemia) showed a significant improvement in 
overall survival (p-value=0.01) with a median survival improvement of 6 months (12.1 
vs. 6.1 months).  The overall survival and event-free survival curves shown in Figure 2 
through Figure 4 include crossover patients in the Control Arm based on their original 
treatment assignment.  This confounds the interpretation of OS, but as the patients are 
considered as having an event at crossover, this confounding is not present in the EFS 
curves.  Given the number of EFS events, the EFS curves are relatively mature.  The OS 
curves, with only about 50% of the events, are less mature. 
 
Figure 2: Kaplan-Meier estimates of OS and EFS in the Overall Population 
Overall Survival 
 
 
 
Event-free Survival 
 
 
Figure 3: Kaplan-Meier estimates of OS and EFS in the High Risk Strata 
Overall Survival 
 
 
 
Event-free Survival 
 
 
0%
20% 
40% 
60% 
80% 
100%
0
6 
12 
18 
24 
Months from randomization
N at Risk
78
CPX-351 
67 
60
38 
8 
3
0
0
30
7+3
28 
23 
17 
1 
0
0
0
Arm A: CPX-351 
Arm B: 7+3 
Events / N 
44 / 85 
20 / 41 
Median 
in Months 
14.7  (10.6,16.7) 
12.9  (6.7,12.9)
Logrank P-value = 0.61 
HR = 0.87 
0% 
20% 
40% 
60% 
80% 
100%
0
3
6
9
12
15 
18 
Months from randomization
N at Risk
54 
CPX-351
38 
24 
17 
4 
0
17 
7+3
13 
8
4
0 
0
Arm A: CPX-351 
Arm B: 7+3 
Events / N 
62 / 85
32 / 41
Median 
in Months 
5.4  (4.2,7.9) 
2.0  (1.2,6.7) 
Logrank P-value = .11 
HR = 0.71 
0% 
20% 
40% 
60% 
80% 
100% 
0 
6 
12 
18 
24 
Months from randomization 
N at Risk 
18 
7+3: 
16 
1
6 
1 
0 
0 
0 
51 
CPX-351: 
42 
38 
22 
8 
3 
0 
0 
7+3: High Risk 
CPX-351: High Risk 
Events / N 
15 / 27 
32 / 57 
Median 
in Months 
7.5  (5.6,9.4) 
11.0 (9.2,16.7) 
Logrank P-value = .34 
HR=0.74 
0% 
20% 
40% 
60% 
80% 
100% 
0 
3 
6 
9 
12 
15 
18 
Months from randomization 
N at Risk 
10 
7+3: 
7 
4
1 
0
0 
33 
CPX-351: 
21 
15 
9 
4
0 
7+3: High Risk 
CPX-351: High Risk 
Events / N 
22 / 27 
45 / 57 
Median 
in Months 
1.8  (1.2,3.7) 
4.5  (2.4,6.1) 
Logrank p=0.25 


PROTOCOL MDACC 2014-0548 
CPX-351 (cytarabine:daunorubicin) Liposome Injection 
September 9, 2019 
 
CONFIDENTIAL 
Page 15 of 61 
FINAL 
Figure 4: Kaplan-Meier estimates of OS and EFS in Patients with Secondary 
Leukemia 
Overall Survival 
 
 
 
Event-free Survival 
 
 
Induction mortality was assessed at Day 30 and 60.  A lower rate of early mortality was 
observed for CPX-351 treated patients (See Table 6).  This result is the best evidence that 
CPX-351 treatment is safe and suggests that rapid clearance of leukemia may assist in 
reducing the early death rate. 
 
Table 6: CLTR0308-204 Induction Mortality (30 and 60 days) 
  
CPX-351 
7+3 
 
 
n=85 
n=41 
 
30 Day Mortality 
3 (3.5%) 
 3 (7.3%) 
p=0.35 
95% CI* 
[0.01, 0.10] 
[0.02, 0.20] 
 
60 Day Mortality 
4 (4.7%) 
6 (14.6%) 
p=0.053 
 95% CI*  
[0.01, 0.12] 
[0.06, 0.29] 
 
*Two-sided confidence intervals (CIs) were calculated using the Fisher’s exact method 
 
Adverse events were qualitatively similar between both study arms.  Adverse events with 
increased frequency in the CPX-351 arm were linked to greater myelosuppression with 
higher rates of febrile neutropenia (63.5% vs. 51.2%), bacteremia (42.4% vs. 22%), 
epistaxis (36.5% vs. 19.5%), and petechiae (32.9% vs. 12.2%).  This appears to be due to 
more prolonged myelosuppression (median ANC recovery to ≥1000/L: 36 vs. 29 days 
and median platelet recovery to ≥100,000/L: 37 vs. 27 days).  Serious fungal infections 
were more frequent on CPX-351 versus 7+3.  These tended to occur during the period of 
nadir neutropenia and resolved at recovery. There were no grade 5 fungal events.  A 
variety of non-hematologic adverse events appear to be more frequent after CPX-351, but 
most, including cough, rash, and headache were usually of grade 1-2 severity and were 
transient.  The key safety findings were that CPX-351 had lower than expected 60-day 
mortality (4.7% vs. 14.6%), lower rates of adverse events with grade 5 outcome (11.8 vs. 
17.1),  and more prolonged myelosuppression with higher rates of febrile neutropenia, 
infections and bleeding events but no increase in deaths associated with infection when 
compared to 7+3.  Non-myelosuppressive adverse events were similar in quality in both 
study arms and there was no evidence of excess cardiac events, in this group of 
anthracycline-naïve patients. 
 
0% 
20% 
40% 
60% 
80% 
100% 
0 
6 
12 
18 
24 
Months from randomization 
N at Risk 
11 
7+3: 
9 
5 
3 
1 
0 
0 
0 
29 
CPX-351: 
23 
22 
13 
6 
3 
0 
0 
7+3: Secondary 
CPX-351: Secondary 
Events / N 
14 / 19 
17 / 32 
Median 
in Months 
6.1  (1.4,7.5) 
12.1  (9.1,16.7) 
Logrank P-value = .01 
HR = 0.41 
0% 
20% 
40% 
60% 
80% 
100% 
0 
3 
6 
9 
12 
15 
18 
Months from randomization 
N at Risk 
4 
7+3:  
3 
2 
0 
0 
0 
17 
CPX-351: 
10 
8 
3 
2 
0 
7+3: Secondary 
CPX-351: Secondary 
Events / N 
17 / 19 
26 / 32 
Median 
in Months 
1.4  (1.1,1.8) 
3.8  (1.5,6.1) 
Logrank P-value = .07 
HR = 0.56 


PROTOCOL MDACC 2014-0548 
CPX-351 (cytarabine:daunorubicin) Liposome Injection 
September 9, 2019 
 
CONFIDENTIAL 
Page 16 of 61 
FINAL 
The 7+3 control arm performed as expected, based on the literature, with moderate 
induction mortality (60 day death rate=14.6%) and a 51.2% CR+CRi rate.  However, a 
projected median overall survival of slightly greater than 12 months (12.9 months) was 
slightly better than expected. 
 
A search for imbalances that could have biased study results in favor of CPX-351 was 
performed and no imbalance in post-induction bone marrow transplants, no major 
imbalance in the characteristics of secondary AML patients (including type of antecedent 
hematologic disorder), and no imbalance in prior treatment with hypomethylating agents 
was found.  Fewer patients on the 7+3 arm received subsequent therapy after persistent or 
relapsed disease, but most of this imbalance was due to the high rate of early mortality 
among control arm patients, preventing subsequent therapies from being given to control 
arm patients.  
 
2.6.3 Phase II Study of CPX-351: CLTR0308-205 
This study compared CPX-351 (100u/m2; Day 1, 3, 5) with salvage therapy in first 
relapse AML patients.  This trial planned to accrue 120 patients with a 2:1 randomization.  
Investigator choice of control salvage regimen was expected to be between (1) high dose 
cytarabine with or without daunorubicin, (2) 7+3 or (3) mitoxantrone, etoposide and 
cytarabine.  The allowance of investigator’s choice reflects the fact that no single salvage 
therapy is superior and the necessity of individualizing treatment.  Responding patients 
were expected to receive allogeneic stem cell transplant for consolidation if donors were 
available. 
 
The European Prognostic Index was used to stratify patients.  For this trial, the primary 
endpoint was survival at one year, which for the control arm was expected to be 30% 
based on previous clinical trials and the literature.  Secondary endpoints were CR+CRi 
rate, remission duration, event-free survival and 30/60/90 day mortality.  The 1 year 
survival rate was selected as the primary endpoint rather than response rate because of the 
substantial variability of the CR rate for different salvage regimens reported in the 
literature.  Accrual was completed in November 2010 with 81 patients randomized to 
CPX-351 and 45 randomized to salvage therapy. 
 
Patient demographics were well balanced between the two arms for durations of first 
complete remission, cytogenetics, and age.  There was a slight imbalance in history of 
prior stem cell transplants with more patients in the CPX-351 arm having a history of 
transplant.  Study stratification was successful with approximately 2/3’s of patients in 
both study arms in the unfavorable EPI risk group.   
 
205 Study Patient Demographics 
 
 
CPX-351 
Control 
 
n=81 
n=44 
 
EPI Points 
n (%) 
n (%) 
Risk Group 
Favorable 
1-6 
9 (11.1) 
6 (13.6) 
Intermediate 
7-9 
16 (19.8) 
9 (20.5) 


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September 9, 2019 
 
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Unfavorable 
10-14 
56 (69.1) 
29 (65.9) 
Relapse-Free Interval 
from CR1 (months) 
> 18 
0 
11 (13.6) 
8 (18.2) 
7-18 
3 
43 (53.1) 
20 (45.5) 
≤ 6 
5 
27 (33.3) 
16 (36.4) 
Cytogenetics at     
Diagnosis 
Inv(16) or t(16;16) 
0 
7 (8.6) 
4 (9.1) 
t(8;21) 
3 
2 (2.5) 
1 (2.3) 
Other 
5 
72 (88.9) 
39 (88.6) 
Age at First Relapse   
(years) 
≤ 35 
0 
10 (12.3) 
4 (9.1) 
36 - 45 
1 
14 (17.3) 
7 (15.9) 
> 45 
2 
57 (70.4) 
33 (75.0) 
HSCT before 
Relapse 
No 
0 
59 (72.8) 
37 (84.1) 
Yes 
2 
22 (27.2) 
7 (15.9) 
 
Consistent with results observed in Study 204, this study in patients with first relapse 
AML also demonstrated higher rates of treatment induced hypoplasia/aplasia and 
response with improvements in median EFS and OS. 
 
Aplasia, Response, and Early Mortality Results 
 
Overall 
(n=125) 
Unfavorable EPI Risk 
(n=85) 
 
CPX-351 
(n=81) 
Salvage     
(n=44) 
CPX-351 
(n=56) 
Salvage    
(n=29) 
Aplasia Rate 
77.3%* 
59.5%* 
66.10% 
44.80% 
CR Rate 
37.00% 
31.80% 
28.60% 
20.70% 
CRi Rate 
12.40% 
9.10% 
10.70% 
6.90% 
Response Rate 
49.40% 
40.90% 
39.30% 
27.60% 
60-Day Mortality 
14.80% 
15.90% 
16.10% 
24.10% 
EFS (median) 
4.0 months 
1.4 months 
2.0 months 
1.2 months 
OS (median) 
8.5 months 
6.3 months 
6.6 months 
4.2 months 
 
The EFS and OS results did not demonstrate statistically significant improvements for the 
group as a whole, but significance was found for survival in the subset of relapsed 
patients with EPI Unfavorable disease.  These results echo those found for the secondary 
AML population in Study 204, in that significant differences in patient outcomes were 
observed in patients with less sensitive AML because of a substantial fall off in efficacy 
for the control arm.   
Overall Survival and Event-free survival in patients with EPI Unfavorable disease 
 
 
 
Overall Survival 
Unfavorable Risk 
0% 
20% 
40% 
60% 
80% 
100% 
0 
3 
6 
9 
12 
15 
Months from randomization 
N at Risk
44 
CPX-351 
31 
25 
7 
0 
18 
Salvage 
10 
7 
2 
0 
CPX-351 Unfav. Risk
Salvage Unfav. Risk
Deaths / N 
40 / 56 
26 / 29 
Median 
in Mos 
6.6  (5.4,10.2) 
4.2  (2.8,5.7) 
logrank p=0.02, HR=0.55 
 
Event-Free Survival 
Unfavorable Risk
0% 
20% 
40% 
60% 
80% 
100% 
0 
3 
6 
9 
12 
15 
Months from randomization 
N at Risk
18 
CPX-351 
8 
5 
1 
0 
5 
Salvage 
2 
0 
0 
0 
CPX-351 Unfav. Risk
Salvage Unfav. Risk
Events / N 
39 / 56 
23 / 29 
Median 
in Mos 
1.9  (1.2,4.3) 
1.2  (0.6,1.5) 
Logrank p=0.08, HR=0.63 


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CPX-351 (cytarabine:daunorubicin) Liposome Injection 
September 9, 2019 
 
CONFIDENTIAL 
Page 18 of 61 
FINAL 
A search for imbalances that could have biased study results in favor of CPX-351 was 
also performed and imbalances in post-induction bone marrow transplants were not 
found.  The rate of post-induction HSCT was similar between the two study arms among 
patients with CR, CRi, and persistent AML, suggesting that transplants did not bias the 
study. 
 
Safety data were consistent with those from Study 204.  Patients with no history of prior 
stem cell transplant at study entry were in the majority (96/125, 76.8%) and were found 
to have slightly lower 60-day mortality (10.2% vs. 16.2%) and higher complete response 
rates (54.2% vs. 37.8%).   Patients with prior stem cell transplants had poorer results after 
CPX-351 with somewhat higher 60-day mortality (27.3% vs. 14.3%) and lower response 
rate (35.4% vs. 57.1%).  The prior stem cell transplant group was too small to reach 
definitive conclusions but it is possible that patient groups with extensive prior 
chemotherapy may be at higher risk following CPX-351 treatment. 
 
Overall, Study 205 confirmed and extended observations first made in Study 204.  CPX-
351 is highly active with improved clearance of leukemia and higher response rate, even 
in patients with prior exposure to cytarabine and anthracycline.   CPX-351 was also 
shown to be safe with improved 60-day mortality in the majority of patients with no prior 
history of HSCT.  These results suggest that CPX-351 will be an excellent candidate to 
test in newly diagnosed AML patients with high risk of treatment mortality. 
 
2.7 
Copper Background 
Copper is an essential element that is a component of a number of metalloenzymes acting 
as oxidases (e.g. diamine oxidase, monoamine oxidase, cytochrome c oxidase).  The 
median absorption of copper from food (by an American adult) is 1.0 to 1.6 mg/day.  The 
tolerable Upper Intake Level for adults is 10 mg/day.  At a dose of CPX-351 of 100 u/m2, 
a patient with a BSA of 2.0 m2 would receive a maximum of 36 mg of elemental copper 
per dose.  In the animal toxicology investigations for CPX-351, elevated copper levels 
were seen following dosing with levels generally returning to baseline 1 to 2 weeks after 
the last dose (see Figure 5).  No toxicity seen in animal studies was attributable to copper. 
 
The data from the clinical studies are consistent with the preclinical findings.  Since 
CPX-351 contains copper (0.18 mg copper per unit, in the form of copper gluconate), 
serum total copper levels were monitored in the Phase 1 clinical study (Study 
CLTR0305-101).  Figure 5 shows this data for cohort 9 (n=20, dose 101 units/m2) 
graphically: 
 


PROTOCOL MDACC 2014-0548 
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September 9, 2019 
 
CONFIDENTIAL 
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Figure 5:  Median and Mean Serum Copper in Cohort 9 after the First Induction 
 
 
 
As Figure 5 shows, both the median and mean copper levels in patients receiving 3 doses 
of CPX-351 at 101 units/m2 was very high on day 7 (2 days after the last dose) but 
returned to normal levels in most patients by day 14.  All patients had serum copper 
levels in the normal range by day 42 after the first induction.  In summary, no safety 
problems are expected due to systemic copper exposure from CPX-351. 
 
In this trial, serum copper levels will be monitored and elevated levels are assumed to be 
due to copper gluconate encapsulated within the CPX-351 liposome rather than free 
circulating copper.  Clinical observation from a single patient treated with the identical 
copper-containing liposome encapsulating a different chemotherapy doublet (CPX-1, 
floxuridine and irinotecan) demonstrated sustained elevations of copper in a patient 
during a period of biliary obstruction, with return to baseline levels after stenting relieved 
the obstruction.  This anecdote suggests that copper elimination after CPX-351 is likely 
via biliary excretion and elimination in the feces.  Preclinical studies completed by 
Celator (acquired by Jazz Pharmaceuticals) demonstrated that virtually all of the copper 
administered in the form of CPX-351 is excreted via the feces within approximately 2 
weeks of administration.  It is expected that eligible patients with unobstructed biliary 
systems should be able to eliminate the copper administered within a few weeks.  Serum 
copper levels will be monitored until they return to baseline levels (±20%) and patients 
will be monitored for hepatic dysfunction, a common manifestation of copper-related 
toxicity. 
 
Median serum copper in cohort 9 after first induction 
0 
100 
200 
300 
400 
500 
0 
7 
14 
21 
28 
35 
42
Serum copper (ug/dL) 
Days after induction 1 
Mean serum copper in cohort 9 after first induction + standard deviation 
0 
200 
400 
600 
800 
1000 
0 
7 
14 
21
28 
35 
42
Days after induction 1 
Serum copper (ug/dL) 


PROTOCOL MDACC 2014-0548 
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September 9, 2019 
 
CONFIDENTIAL 
Page 20 of 61 
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3.0 Study Objectives and Rationale 
3.1 
Primary Objectives 
The primary objective of this study is to assess preliminary efficacy (as determined by the 
rate of CR or CRi) of two or three dose levels of CPX-351 in patients with newly 
diagnosed AML at high risk for induction mortality, defined as 30-50% predicted risk of 
death by Day 60, and to select the most promising dose level for further efficacy testing.  
Estimation of risk for induction mortality at patient screening will be based on factors 
associated with lower likelihood of AML response with or without factors that reduce 
tolerance to treatment-associated adverse events.   
 
3.2 
Secondary Objectives 
To confirm the rate of dose limiting toxicities, including induction mortality (at day 60) 
for two different sub-MTD dose levels (50 and 75 U/m2).  If safety results suggest 
feasibility to test the MTD dose level of CPX-351 (100 U/m2) in patients believed to be at 
high risk for induction mortality, the rate of dose limiting toxicities and induction 
mortality will be tested in this group as well.  
 
 
3.3 
Exploratory Objectives 
To investigate the effect of CPX-351 on immune response, as determined by the effect on  
recovery of functional pathogen-specific and leukemia-specific immune responses and 
the recovery and function of NK cells. 
To investigate the role of Troponin-T as an early marker for CPX-351-induced 
cardiotoxicity.  
To investigate ex vivo the cytotoxicity of combination of Pim kinase inhibitor(s) and 
CPX-351 on circulating leukemia cells. 
 
3.4 
Study Rationale 
The Phase I study identified the MTD in fit relapsed and refractory adult leukemia 
patients and confirmed that the intended 5:1 molar ratio was maintained for 
cytarabine:daunorubicin across multiple dose levels with markedly prolonged plasma half 
life of cytarabine and daunorubicin.  At the MTD, CPX-351 was detectable in plasma at 
least 7 days after the last dose (Study Day 12).  A substantial number of responses were 
observed among late stage patients already previously treated with cytarabine and 
daunorubicin.   
 
The randomized Phase II results with CPX-351 suggest that CPX-351 is likely better 
tolerated than conventional cytarabine and daunorubicin-based chemotherapy with 
reduced 60-day mortality (4.6%) observed among newly diagnosed patients.  Moreover, 
preclinical observations that CPX-351 concentrates in bone marrow with evidence for 
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suggests that CPX-351 action will be potent and that non-hematopoietic toxicities will be 
modest.  Clinical observations from the Phase I study of complete response occurring at 
dose levels as low as one third to one half the MTD (32 to 43 units/m2), strongly suggest 
that 25% and 50% dose reductions to 75 and 50 units/m2 will still be effective and should 
be better tolerated.  By using reduced dose CPX-351 as induction therapy it may be 
possible to improve the outcome of patients with AML considered at high risk for 60-day 
mortality, patients not ordinarily offered induction therapy for AML at all.   
 
Data from the Phase I and both Phase II studies also demonstrated a relatively shallow 
dose/toxicity curve, with relatively little increase in non-hematopoietic toxicities with 
increasing doses up to the MTD.  If sub-MTD dose levels of CPX-351 are well tolerated 
in patients at higher risk of early mortality, it may be possible to evaluate treatment at the 
MTD for patients at high risk for induction mortality.   To the extent that higher dose 
levels maximize treatment efficacy, demonstration of treatment safety and feasibility at 
the MTD may permit treatment with the most efficacious dose level in patients at high 
risk for induction mortality.  
 
4.0 Study Design 
One cycle equals 28 days. 
 
This study is an open-label, two-arm or possibly 3-arm, phase II trial.   CPX-351 is 
administered as approximately a 90-minute infusion on days 1, 3, and 5 with one study 
arm receiving 50 units/m2 and the other receiving 75 units/m2.   Both the 50 and the 75 
unit/m2 dose levels are considered to have acceptable safety based on observations from a 
pair of randomized Phase II studies conducted in adult patients, where the observed 60-
day mortality results in patients considered fit for intensive chemotherapy and with no 
prior history of stem cell transplant, was observed to be reduced compared to control.   
 
Patients with newly diagnosed AML who are predicted to be at high risk (30-50%) for 
induction mortality (death by day 60) are eligible.  Every patient entered must have at 
least one AML-related factor (adverse cytogenetics, secondary AML, MDR phenotype, 
etc.) that contributes to elevated risk of induction mortality.   Patients may or may not 
have patient-related factors (poor performance status, co-morbidities, poor organ 
function, etc.) that also contribute to elevated risk of induction mortality. 30 patients will 
be randomized with a 1:1 ratio to the two dose arms with 15 patients per arm to assess for 
safety and efficacy.  If safety is demonstrated for both of the sub-MTD dose levels, and 
escalation is deemed feasible above 75 units/m2, a cohort of 15 patients will be studied at 
100 units/m2, the MTD dose level. The latter dose (i.e., 100 units/m2) was found safe and 
an additional 25 patients will be enrolled at this dose (for a total of 40 evaluable patients) 
to define efficacy at this standard dose. 
 
At the end of the study a single dose level will be confirmed to have acceptable safety if 
the observed rate of dose limiting toxicity (DLT) is <5 DLT/15 patients.<33%).  Dose 
limiting toxicity is defined as induction mortality (death occurring during the first 60 
days from start of study therapy), grade 3 or 4 non-hematologic toxicity, or dose limiting 


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hematologic toxicity at least possibly related to the study drug occurring during the first 
60 days from the start of study therapy (i.e., during the first cycle of therapy).   
 
For non-hematologic toxicity the following are counted as dose limiting toxicities only 
under the conditions noted: 
 Liver toxicity: Grade 4, related to the study drug, not resolving to grade 2 within 7 
days.  
 Decrease in ejection fraction: Grade ≥3 (nadir LVEF <40-20%), related to study 
drug 
 Creatinine elevation:  Grade ≥3, related to study drug. 
 Any other adverse event of Grade ≥3, related to study drug that in the opinion of 
the PI is inconsistent with the expected adverse events with standard 
chemotherapy.  
 
Dose limiting hematologic toxicity is defined by bone marrow and peripheral blood 
examination at Day >56 showing: 
 Absence of recurrent or persistent leukemia AND 
 Persistently hypocellular marrow (<20% cellularity) AND 
 Peripheral blood: 
o ANC< 500 and/or 
o Platelet count <10,000 
 
If more than one dose level is considered acceptably  safe, the decision about which one 
to use for future clinical study will be based on efficacy.  Efficacy success for an 
individual patient is defined as achievement of CR or CRi.  Observation of <3 CR or CRi 
among 15 patients (<20%) defines a non-efficacious study arm.  In situations where both 
study arms are considered equally safe, the study arm with the higher rate of response 
will be recommended for future study, provided it equals or exceeds 20%.   
When the dose recommended for future study is defined, 10 additional newly diagnosed 
patients will be treated at that dose level (not to exceed a total of 25 patients at that dose 
level) to obtain additional evidence of safety and efficacy among previously untreated 
patients with high risk of induction mortality.   
 
4.1 
Patient Recruitment 
All patients will be screened by a principal investigator or sub-investigator prior to entry 
on the study.  An explanation of the study and discussion of the expected risks and 
benefits will be fully discussed with patients prior to the screening process in order for 
the patient to provide a voluntary written informed consent.  Only eligible and consenting 
patients will be entered into the study. 
 
4.2 
Registration Procedures 
Patients will be registered through CORe. 
 


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4.3 
Patient Sample Size 
A maximum of 80 patients will be treated. 
 
A minimum of 15 patients will be treated at each dose level, unless conditions for early 
stopping are met based on excessive toxicity or insufficient safety (see section 10.0).  
 
4.4 
Toxicity Assessment 
Toxicities will be evaluated and graded according to the NCI Common Terminology 
Criteria for Adverse Events, version 4 (CTCAE). 
 
If a patient is discontinued due to progressive disease or intercurrent illness unrelated to 
toxicity attributable to CPX-351 and before safety can be assessed to rule out DLT, an 
additional patient will be recruited, to ensure that the minimum number of patients are 
evaluable for safety at each dose level. 
4.5 
Second Inductions 
A second induction may be given if: 
 
The first induction does not produce a day 28 bone marrow demonstrating 
morphologic leukemia free state (≤5% blasts)  
 
Second inductions are given at the discretion of the investigator but are 
recommended in any patient with documentation of reduced leukemic burden, 
especially those with evidence of partial remission (≥50% reduction in % blasts 
count to 5-25% blasts).  
 
Second induction may be started on Day 28 from 1st cycle.  In patients with 
rapidly proliferating disease second induction may be started earlier (but not 
earlier than Day 21) provided there is no residual study drug-related grade 2 non-
hematologic toxicity after discussion with the principal investigator. 
 
The CPX-351 dose for second induction is the same as for initial induction except that 
doses are given on Days 1 and 3 only.  Patients unable to achieve a response (CR+CRi) 
after two inductions are discontinued from further treatment and are followed for survival 
only. 
 
4.6 
Consolidation Therapy 
Only patients with documented response (CR or CRi) are eligible for consolidation.  
Consolidation with stem cell transplant (HSCT) is permitted either in place of 
chemotherapy consolidation or after chemotherapy consolidation.  Prior to beginning 
every other chemotherapy consolidation after the cumulative DNR dose exceeds 300 
mg/m2,or  prior to every course of treatment after the cumulative DNR dose exceeds 500 
mg/m2, patient LVEF must be documented to be ≥50% and patient PS must be 0-2.   
 
Patients in CR with full recovery of peripheral blood counts within 56 days may be 
consolidated starting within one week of documentation of response.  Patients with CRi 
may start consolidation no earlier than 42 days after the start of the last induction course 


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and only if ANC is >500/L and Platelets are >50,000/L.  Consolidation courses consist 
of 2 doses administered at 65 units/m2 on days 1 and 3.    
A maximum of 4 courses of consolidation will be administered. It is understood that 
variations in timing of second induction and consolidations may be necessary and will be 
decided on a case by case basis by the PI. The rationale for variations in schedule will be 
documented by the PI.  If consolidation is well tolerated and hematopoietic recovery is 
not delayed beyond 56 days, additional courses of consolidation may be offered 
immediately at time of recovery.  In cases of poor patient tolerance or delayed 
hematopoietic recovery, the principal investigator will document his decision to either 
continue or terminate consolidation treatment. 
 
Consolidation dosing: 
First Consolidation  
Induction Outcome 
Consolidation Dose 
CR after induction 56 days 
May start within one week of 
documentation of CR 
CR after >56 days 
Delay start of consolidation until day 70 
CRi with at least ANC to ≥500/μL and platelets 
to ≥50,000/μL 
Starts after day 42. 
CRi with ANC<500/ μL 
or platelets <50,000/ μL  
No consolidation to be given 
Second and Subsequent Consolidations 
 Previous Consolidation Outcome 
Consolidation Dose 
Count recovery to pre-consolidation baseline by 
Day 56 
Same as first consolidation 
Partial count recovery ANC (≥500/μL and 
platelets to ≥50,000/μL by Day 56 
Delay second induction until day 70 
Failure to recover (ANC <500/μL or platelets to 
<50,000/μL) by Day 56  
No consolidation to be given 
 
Variations of the schedule mentioned above may be considered in individual patients if 
felt to be in the best interest of the patient after discussion with the principal investigator 
and with proper documentation of the rationale for the change. 
4.7 
Salvage Therapy 
Patients who never achieve CR/CRi following initial induction and patients who achieve 
CR/CRi and later relapse may receive salvage therapy.   
 
4.8 
Patient Follow-up 
Follow-up for CR duration, EFS and safety (if applicable) terminates at the time of 
relapse, start of salvage or non-protocol treatment for leukemia (for persistent disease or 
transplant conditioning chemotherapy).   
  


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4.9 
Study Modification/Discontinuation 
Any amendments to the study will be documented in a revised protocol with a new 
assigned version.  
 
The Investigator and the IND Office may stop the trial early for the following reasons: 
 
Unacceptable toxicity 
 
Discontinuation of drug development 
 
Poor enrollment 
 
Request by a regulatory authority 
In the case of study discontinuation, the principal investigator will notify and discontinue 
patients from the trial and inform the IRB. 
 
5.0 Selection and Withdrawal of Patients 
5.1 
Study Population 
5.1.1 Inclusion criteria 
5.1.1.1 
Ability to understand and voluntarily sign an informed consent form 
5.1.1.2 
Age >18 years at the time of diagnosis of AML 
5.1.1.3 
Pathological diagnosis of AML according to WHO criteria (with at least 20% 
blasts in the peripheral blood or bone marrow): 
o Newly Diagnosed De novo AML; except for APL  
o Newly Diagnosed Secondary AML, defined as having a history of an 
antecedent hematologic disorder (myelodysplastic syndromes [MDS], 
myeloproliferative disease [MPD] or history of cytotoxic treatment for 
non-hematologic malignancy) or apparent de novo AML with MDS-
associated karyotype. (Appendix 9) 
5.1.1.4 
Eastern Cooperative Oncology Group (ECOG) performance status 0-3 
5.1.1.5 
Laboratory values fulfilling the following: 
o Serum creatinine ≤ 2.0 mg/dL 
o Serum total bilirubin ≤ 2.0 mg/dL 
o Serum alanine aminotransferase < 3 times the ULN Note:  If elevated liver 
enzymes are related to disease ALT should be <5 times ULN. 
5.1.1.6 
To be considered at high risk for induction mortality patients must have 1 or 2 
of the following risk factors (patients ≥60 must have at least 1 risk factor, 
patients <60 must have at least 2 risk factors) present.  At least one risk factor 
in every patient must be an AML-related factor: 
AML-related factors include: 
o AHD (MDS, CMML, or MPD) or history of exposure to cytotoxic 
chemotherapy (t-AML)), or WHO-defined AML with MDS-related 
changes or apparent de novo AML with MDS-associated karyotype. 
o Unfavorable cytogenetics as defined by the European Leukemia Net 
(Appendix F) Appendix 11 


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Patient-related factors: 
o Age ≥70 
o ECOG PS ≥2 
o Co-morbidities:  Serum creatinine >1.3 g/dL  
5.1.1.7 
Cardiac ejection fraction ≥ 50% by echocardiography or MUGA (when LVEF 
expressed as a range, at least the upper limit should include 50%).  
5.1.1.8 
Able to adhere to the study visit schedule and other protocol requirements 
5.1.1.9 
All men and women must agree to practice effective contraception during the 
study period if not otherwise documented to be infertile. 
 
5.1.2 Exclusion Criteria 
5.1.2.1 
Patients with history of second malignancy are eligible if they have 
documentation of disease stability, off therapy, based on CT scan or other 
measures for the 6 months prior to entry in core. 
5.1.2.2 
Any serious medical condition or psychiatric illness that would prevent the 
patient from providing informed consent. 
5.1.2.3 
Chemotherapy or other investigational anticancer therapeutic drugs in the two 
weeks prior to study entry; in the event of rapidly proliferative disease, 
however, the use of hydroxyurea is permitted up to 24 hours before study 
entry in core 
5.1.2.4 
Evidence of active CNS leukemia 
5.1.2.5 
Pregnant or lactating women  
5.1.2.6 
Uncontrolled infection; to be eligible, patients receiving treatment for an 
infection (antibiotic, antifungal or antiviral treatment) must be afebrile 
(<38.3oC) and without hemodynamic instability or dyspnea from pneumonia 
for >48 hrs prior to the start of induction therapy. 
5.1.2.7 
Hypersensitivity to cytarabine, daunorubicin or liposomal products 
5.1.2.8 
History of Wilson’s disease or other copper-metabolism disorder 
5.2 
Withdrawal of Patients 
Patients will be discontinued from treatment and begin follow-up for survival under the 
following circumstances: 
 
Persistent disease:  lack of a response to treatment after two cycles of induction 
therapy 
 
Relapsed disease:  re-appearance of disease following CR or CRi 
 
Unacceptable toxicity 
 
Patient non-compliance with protocol 
 
Administration of non-protocol chemotherapy 
 
Intercurrent illness which, in the judgment of the investigator, affects assessment 
of clinical status to a significant degree, and requires discontinuation of protocol 
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During any phase of the study, if a patient requests termination of treatment and/or 
follow-up, the patient will be discontinued and no further information collected.  The 
patient will be classified as withdrawal of consent.   
6.0 Treatment of Patients 
See APPENDIX 1: Patient Evaluation Flow Sheet 
 
Copper Levels:  MDACC will draw the serum copper, send it out for processing and will 
report the results in clinic station in approximately 4 days.  This will be included in the 
budget for the cost incurred by the MDACC lab.  MDACC will be reimbursed by the 
Supporter of this study (Jazz Pharmaceuticals) for this test. 
 
6.1 
Pre-Treatment Evaluations 
The date of the first test or exam will be considered as date of the screening visit. 
Procedure  
Evaluation 
Timing 
Informed Consent 
It should be personally signed and dated by 
the patient. The investigator must also 
personally sign and date the document. 
A copy of the Informed Consent must be 
given to the patient. 
The patient’s study screening must be 
conspicuously noted in the source 
documentation. 
Informed consent should be 
obtained prior to initiation 
of screening procedures. If 
the period between ICF 
signature date and screening 
visit is ≥30 days the patient 
must sign another ICF. 
 
Demography 
Date of birth, sex 
Basis for high risk of induction mortality 
Within 14 days prior to 
registration in core 
Medical History 
Complete medical history 
 
Within 14 days prior to 
registration in core 
Physical Exam 
Objective review of body systems  
ECOG Performance Status 
Within 3 days prior to 
registration in core 
Vital Signs 
Heart rate 
Blood pressure 
Temperature 
Respiratory rate 
Within 3 days prior to 
registration in core 
Hematology 
Hemoglobin 
White Blood Count 
Platelets 
Differential Count (may be omitted if WBC 
≤0.5 x109/L) 
Within 1 day prior to 
registration in core 
Biochemistry 
 
BUN 
Creatinine 
Electrolytes (Sodium, Potassium, Chloride) 
Bilirubin 
AST or ALT 
Within 1 day prior to 
registration in core 
Bone Marrow Aspiration 
and/or Biopsy 
Morphology 
 
Within 14 days prior to 
registration in core 
Copper levels 
Serum copper 
Within 14 days prior to 
registration in core 


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Procedure  
Evaluation 
Timing 
Diagnostic Imaging 
Chest X-ray 
Echocardiography or MUGA scan 
Within 28 days prior to 
registration in core 
ECG 
 
Within 14 days prior to 
registration in core 
Cytogenetics  
Cytogenetics (performed locally) 
Molecular abnormalities:  Evaluation of 
CEBPA, FLT3, and NPM1  
Within 3 months prior to 
registration in core:  patients 
may be registered and 
treated prior to the 
cytogenetic test results; 
however, every attempt 
should be made to have the 
results prior to registration 
in core 
Correlative studies 
(optional)* 
Immune reconstitution 
Before the start of induction 
therapy 
Correlative studies 
(optional)* 
BNP, Troponin I, high-sensitivity troponin 
(I or T) 
Before the start of induction 
chemotherapy 
Correlative studies 
(optional)* 
Pharmacodynamics 
Before the start of induction 
chemotherapy 
Pregnancy Test 
Urine or serum pregnancy test 
Within 7 days prior to 
registration in core  
* Failure to collect samples for optional studies will not constitute a protocol deviation.  
 
6.2 
Evaluation during Treatment 
Inductions and consolidations are administered as courses.  A course consists of the 
administration of therapy with scheduled assessments to evaluate the response to 
treatment.  The first induction may end before the completion of all evaluations if a 
second induction is necessary, (see Section 4.5).  Induction is completed when a patient 
has 
 
A confirmed CR (see section 8.4) 
 
A CRi (see section 8.4) and is to begin consolidation treatment before 
documentation of hematologic count recovery 
 
Persistent/recurrent disease (PD/relapse) 
 
Response evaluation cannot be performed because of the patient’s condition and 
no further study treatment can or will be administered. 
 
Patients with a CR or CRi may receive consolidation treatments.  Evaluations on Days 1-
10 must be performed on the day indicated (±2 day); all other evaluations are to be 
performed on the Study Day indicated ±3 days, except when specifically indicated.  Each 
course requires the following evaluations: 
 
Procedure 
Evaluation 
Timing 
Physical Exam 
Objective review of body systems  
 
Days 14 and 42 
Vital Signs 
Heart rate 
Blood pressure 
Temperature 
Respiratory rate 
Days 14 and 42 


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Procedure 
Evaluation 
Timing 
Hematology 
Hemoglobin 
White Blood Count 
Platelets 
Differential Count (may be 
omitted if WBC ≤0.5 x109/L) 
Days 1, 3, 5, 7, 10±2, 14±3, then 
weekly (±3days) until Day 42 or 
peripheral blood count recovery 
Biochemistry 
BUN 
Creatinine 
Electrolytes (Sodium, Potassium, 
Chloride) 
Bilirubin 
AST or ALT 
 
Days 1, 3, 5, 7, 10±2, 14±3, then 
weekly (±3days) until Day 42  
Copper levels 
Serum Copper  
Perform prior to next treatment course  
Bone Marrow Aspiration 
and/or Biopsy 
Morphology 
 
Day 28 (±7 days) after every induction. 
Cytogenetics  
Cytogenetics (performed locally) 
Molecular abnormalities:  
Evaluation of CEBPA, FLT3, and 
NPM1  
Required in patients with a CR or CRi 
with positive baseline findings 
(perform at the time of bone marrow 
assessment for CR or CRi). Optional in 
patient with normal findings at baseline 
Diagnostic Imaging 
Echocardiography or MUGA scan 
to assess LVEF 
Prior to every other course of treatment 
after the cumulative DNR dose exceeds 
300 mg/m2, prior to every course of 
treatment after the cumulative DNR 
dose exceeds 500 mg/m2, or 30 days 
after the last course.    
Response Assessment 
 
See Section 8.4.1 
Adverse Events/Toxicity 
CTCAE v.4 assessment 
Beginning at the start of the first 
infusion, continually assess during 
Treatment Period and record and report 
any new serious adverse events (up to 
30 days after completion of Treatment 
Period) 
Concomitant Medications 
 
Continually assess during Treatment 
Period 
Correlative studies 
(optional)* 
Immune effects 
Before induction and at start of 1st and 
2nd consolidation 
Correlative studies 
(optional)* 
BNP, Troponin I, high-sensitivity 
troponin (I or T) 
Before the start of each cycle, and 
approximately 24 hrs from end of 
infusion on day 1 and day 5 of each 
cycle, and approximately on day 14 (±4 
days) of each cycle, end of treatment. 
Correlative studies 
(optional)* 
Pharmacodynamics 
Pre-dose and 24-hrs (±4 hrs) after first 
dose. 
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6.3 
Early Termination or End of Treatment 
Any patient that completes or discontinues treatment must have the following evaluations 
performed within 30 days after termination and prior to the initiation of any salvage 
therapy, if not performed within the last 30 days: 
 
Procedure 
Evaluation 
Timing 
Physical exam 
Objective review of body systems  
ECOG Performance Status 
Within 30 days after discontinuation 
Vital signs 
Heart rate 
Blood pressure 
Temperature 
Respiratory rate 
Within 30 days after discontinuation 
Hematology 
Hemoglobin 
White Blood Count 
Platelets 
Differential Count (may be omitted if 
WBC ≤0.5 x109/L) 
Within 30 days after discontinuation 
Biochemistry 
BUN 
Creatinine 
Electrolytes (Sodium, Potassium, 
Chloride) 
Bilirubin 
AST or ALT 
Within 30 days after discontinuation 
Diagnostic Imaging 
Echocardiography/MUGA 
Within 30 days after discontinuation 
if a study has not been performed 
since last treatment but before the 
initiation of any non-protocol 
treatment 
ECG 
 
Within 30 days after discontinuation 
Copper levels 
Serum Copper  
Within 30 days after discontinuation 
if a study has not been performed 
since last treatment 
Adverse Events/Toxicity 
CTCAE v.4 assessment  
Assess Adverse events that were 
ongoing at the time of 
discontinuation and record and report 
any new serious adverse events (up 
to 30 days after discontinuation) 
Correlative studies 
(optional)* 
BNP, Troponin I, high-sensitivity 
troponin (I or T) 
Within 30 days after discontinuation 
* Failure to collect samples for optional studies will not constitute a protocol deviation.  
 


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6.4 
Evaluation during Long-term Follow-up  
The following evaluations are completed during the follow-up phase (i.e., after 
completion of all therapy to continue for one year except for survival and relapse status 
which will continue until death and relapse, respectively): 
 


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Procedure 
Evaluation 
Timing 
Patient status report 
Survival status  
 
Until death  
Relapse status 
New anti-leukemic therapies 
Monthly until relapse or the 
initiation of new therapy 
Hematology 
Hemoglobin 
Hematocrit  
Red Blood Count 
White Blood Count 
Platelets 
Differential Count (may be omitted if 
WBC ≤0.5 x109/L) 
Every 2-3 months for one year until 
relapse or the initiation of new 
therapy, then as clinically indicated. 
Bone Marrow Aspiration 
and/or Biopsy 
Morphology 
 
Every 3-4 months. For patients in 
CR, consider performing if 
peripheral blood counts fall below 
1000/μL for ANC or 100,000/μL for 
platelets for >1 month with no 
obvious explanation for the drop or 
at any time there is suspicion of 
relapse; for patients in CRi perform 
if counts fall significantly below 
peak recovery.  If the peripheral 
blood counts in a patient with a CRi 
recover to CR levels (>1000/μL for 
ANC or >100,000/μL for platelets), 
consider performing a bone marrow 
evaluation to confirm full CR.  
Following the first year of follow 
up, aspirations will be done as 
clinically indicated; record relapse 
information, including any bone 
marrow evaluations.  Not required 
following the initiation of new 
therapy and or relapse. 
Diagnostic Imaging 
Echocardiography or MUGA 
Perform every 3-4 months  if last 
Treatment Phase LVEF was reduced 
>10% from baseline and is less than 
50%.  Continue assessments until 
LVEF returns to baseline or until 1 
year from start of therapy. 
Biochemistry 
BUN 
Creatinine 
Bilirubin 
AST or ALT 
 
Every 2-3 months for one year until 
relapse or the initiation of new 
therapy, then as clinically indicated. 
Copper levels 
Serum Copper  
Perform monthly only if elevated 
copper (>20% above ULN) present 
at EOT.  Perform every 1 month 
until abnormality returns to within 
20% of ULN, or until 1 year, or the 
initiation of new therapy, or relapse 
(whichever is earliest) 
 
7.0 Drug Administration 


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The responsibility for treatment of patients rests with the individual investigator.   
 
7.1 
Drug Preparation and Administration 
7.1.1 Drug Preparation 
The appropriate number of vials of CPX-351 (cytarabine:daunorubicin) Liposome 
Injection should be removed from the refrigerator prior to reconstitution.  Reconstitute 
with 19 mL of water for injection using a 20 mL syringe. Do not heat CPX-351 
(cytarabine:daunorubicin) Liposome Injection.  After reconstitution, invert vials gently 3-
4 times and let rest for 15 minutes prior to withdrawing drug for dilution.  CPX-351 
(cytarabine:daunorubicin) Liposome Injection should be diluted in approximately 500 
mL of saline injection or dextrose injection. 
 
The IV bags and infusion sets must be non-DEHP.  Aseptic technique must be strictly 
observed throughout the handling of CPX-351 (cytarabine:daunorubicin) Liposome 
Injection, since no bacteriostatic agent or preservative is present.  The infusion of CPX-
351 (cytarabine:daunorubicin) Liposome Injection must be started within 4 hours of 
dilution.  Vials are for single use.  Unused material should be recorded as such and 
discarded according to institutional policies.  Procedures for proper handling and disposal 
of anticancer drugs should be implemented. 
 
7.1.2 Drug Administration 
The infusion of CPX-351 (cytarabine:daunorubicin) Liposome Injection will be 
performed through a central venous catheter, using an infusion pump to ensure that the 
drug is infused over the specified time period.  Non-DEHP containing administration sets 
should be used.  Do not use an in-line filter.  CPX-351 should never be given by the 
intramuscular or subcutaneous route.  Administer CPX-351 over approximately 90 
minutes via an infusion pump.  Flush the line to ensure administration of the full dose. 
 
The dosage (total units and u/m2), start/stop time of the infusion, total volume infused, 
must be documented in the patient’s chart. 
 
7.2 
Drug Accountability 
The study pharmacist or designee must maintain records of the delivery of CPX-351 to 
the study site, the inventory at the site, the use by each patient, and the disposition of 
unused product. These records should include dates, quantities, lot numbers, expiration 
dates and patient identifications.  The institution should maintain records that document 
adequately that patients were provided the doses specified by the protocol and reconcile 
all investigational product received from the manufacturer.  Records of storage conditions 
(temperature logs) must be kept for the entire period that CPX-351 is maintained at the 
institution.  Unused or expired drug will be disposed per MDACC policy. 
 


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7.3 
Dose Reductions and Delays 
Induction doses are not reduced.  Consolidation doses are 65 units/m2 on days 1 and 3.  In 
instances with prolonged myelosuppression or other medical conditions where the 
investigator feels further dose reduction might be required, 50 units/m2 on days 1 and 3 
may be used after discussion with PI and sponsor and documentation of rationale.  
Patients with evidence of delayed recovery from cytopenias or acute toxicities following 
induction or consolidation (>56 days) may have consolidation doses delayed by up to 2 
weeks to permit recovery.   Any doses missed or delayed due to toxicity may be 
administered as soon as the patient has recovered from the toxicity.  Toxicities will be 
graded using the CTCAE Version 4.0 (See APPENDIX 5: Common Terminology 
Criteria for Adverse Events V4.0 (CTCAE)).   
7.4 
Concomitant Therapy 
7.4.1 Premedication 
Nausea and vomiting: 
Patients may receive prophylaxis or therapy for nausea and/or vomiting according to 
institutional standards. 
 
Hypersensitivity/Infusion-related reactions: 
Patients will not be routinely pre-medicated for hypersensitivity or infusion-related 
reactions initially during the first infusion of the first treatment course.  If the patient 
develops a hypersensitivity reaction then he/she should be pre-medicated at all 
subsequent infusions. 
 
7.4.2 Suggested guidelines for management of hypersensitivity reactions: 
 
Mild symptoms (e.g., mild flushing, rash, pruritus): 
Stop infusion and supervise at bedside with monitoring of vital signs 
Reinitiate infusion slowly (halving the rate of infusion) +/- premedication 
 
Moderate symptoms (e.g. moderate rash, flushing, mild dyspnea, chest discomfort): 
Stop infusion and give IV diphenhydramine, 20-25 mg (or equivalent) and IV 
dexamethasone 10 mg. 
Do not reinitiate infusion.  Subsequent doses should be administered with premedication 
(e.g., IV diphenhydramine, 20-25 mg (or equivalent) and IV dexamethasone 10 mg) and 
may be given at the same dose and rate.  
 
Severe/life-threatening symptoms (e.g. hypotension requiring vasopressor therapy, 
angioedema, respiratory distress requiring bronchodilation therapy, generalized 
urticaria): 
Stop infusion.  Administer IV diphenhydramine and dexamethasone as indicated above.  
Add epinephrine (adrenaline) or bronchodilators if indicated.  Do not reinitiate infusion.  
Do not retreat.  Report this event as a serious adverse event. 
 


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If hypersensitivity or infusion-related reactions become a clinically relevant toxicity, then 
premedication for hypersensitivity reactions will be instituted with drugs, doses and 
schedule according to each investigator’s preference.  Additionally, a decision may be 
made to prolong the infusion time to two hours or more. 
 
7.4.3 Permitted therapy 
Patients may receive ongoing supportive and palliative care (e.g. pain control) as 
clinically indicated throughout the study. 
 
Infection Prophylaxis:  Prophylactic use of anti-infectives is highly recommended during 
the period of profound neutropenia until ANC returns to 500/μL or greater. The choice of 
anti-infectives will be according to institutional protocol. Use of anti-infective agents as 
prophylaxis and treatment must be documented on the case report forms. 
 
Growth Factor support: The use of growth factors will be according to institutional 
protocol and/or according to ASCO criteria.(14) Use of growth factors must be 
documented on the case report forms. 
 
Transfusion support:  The use of transfusion support (RBCs and platelets) will be 
according to institutional protocol.  Use of transfusion support must be documented on 
the case report forms. 
 
7.4.4 Therapy that is not permitted 
Other anti-cancer treatment and other investigational therapy(ies) are not permitted 
during the Treatment Phase.  In the event of persistent disease or relapse the patient may 
receive other anti-leukemic therapies. Administration of isolated doses of intrathecal 
chemotherapy is allowed.  
 
7.5 
Duration of Protocol Treatment 
Patients may continue on study provided they have not met the criteria for 
discontinuation of therapy (See Section 5.2).  The table below summarizes the expected 
duration of the Treatment Phase.  Patients may receive up to two induction courses 
followed by consolidation courses.  After the Treatment Phase, patients are followed until 
death.  
 
8.0 Assessment of Efficacy 
8.1 
Evaluable for Efficacy 
All patients receiving one or more doses of study therapy are evaluable for efficacy.   


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8.2 
Overall Survival  
All enrolled patients are assessed for overall survival.  Overall survival is measured from 
the date of registration to death from any cause, patients not known to have died at last 
follow-up are censored on the date they were last known to be alive.  
8.3 
Event-free Survival 
All enrolled patients are assessed for Event-free survival. Event-free survival is defined 
as the time from study registration to the date of induction treatment failure (persistent 
disease), relapse from CR or CRi, initiation of non-protocol chemotherapy (e.g. salvage 
therapy), or death from any cause, whichever comes first.  Patients transferred to 
transplant will be censored for Event-free Survival at the start of conditioning therapy.  
Patients alive and not known to have any of these events are censored on the date they 
were last examined. 


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8.4 
Response Assessment Criteria 
During the Treatment Phase patients will be assessed for response according to the 
following criteria(15): 
Complete remission 
(CR)1 
Bone marrow blasts <5%; absence of blasts with Auer 
rods; absence of extramedullary disease; absolute 
neutrophil count >1.0 x 109/L (1000/μL); platelet count 
>100 x 109/L (100,000/μL). 
CR with incomplete 
recovery (CRi)2 
All CR criteria except for residual neutropenia (<1.0 x 
109/L [1000/μL]) and/or thrombocytopenia (<100 x 109/L 
[100,000/μL]) 
Treatment failure 
 
Persistent Disease (PD) 
 
Failure to achieve CR or CRi; only includes patients 
surviving ≥7 days following completion of initial 
treatment, with evidence of persistent leukemia by blood 
and/or bone marrow examination 
Death in aplasia 
Deaths occurring ≥7 days following completion of initial 
treatment while cytopenic; with an aplastic or hypoplastic 
bone marrow obtained within 7 days of death, without 
evidence of persistent leukemia 
Death from 
indeterminate cause 
Deaths occurring before completion of therapy, or <7 days 
following its completion; or deaths occurring ≥7 days 
following completion of initial therapy with no blasts in 
the blood, but no bone marrow examination available 
Relapse3 
Bone marrow blasts ≥5% (confirmed); or confirmed, 
sustained reappearance of blasts in the blood after 
achievement of a CR or CRi, not considered due to 
recovery from chemotherapy; or development of 
extramedullary disease 
1All criteria need to be fulfilled; marrow evaluation should be based on a count of 200 nucleated cells in an 
aspirate with spicules; if ambiguous, consider repeat exam after 5 to 7 days; flow cytometric evaluation 
may help to distinguish between persistent leukemia and regenerating normal marrow; a marrow biopsy 
should be performed in cases of dry tap, or if no spicules are obtained; no minimum duration of response 
required. 
2Some patients may not achieve complete hematologic recovery prior to initiation of consolidation.  CRi 
usually cannot be declared earlier than Day 42 to allow for adequate time for documentation of peripheral 
blood recovery.  Consolidation usually begins no earlier than 42 days after the last induction course. 
3In cases with low blast percentages (5-10%), a repeat marrow should be performed to confirm relapse. 
Appearance of new dysplastic changes should be closely monitored for emerging relapse. In a patient who 
has been recently treated, dysplasia or a transient increase in blasts may reflect a chemotherapy effect and 
recovery of hematopoiesis. 
 
The response of patients with no post-baseline bone marrow assessment is entered as not 
done. 
8.4.1 Timing of response assessment 
In general, the patient’s response to induction therapy is made on the first day when all 
criteria for CR or treatment failure are met.  The bone marrow assessment and the 


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peripheral counts are not required to be performed on the same day but recovery of 
counts (including absence of peripheral blasts) must be performed within 14 days of the 
bone marrow assessment.   
 
8.4.2 Best Response 
Patients who complete the induction(s) with a response of CRi may be upgraded to a CR 
during or after consolidation if the patient’s peripheral blood counts meet the criteria for 
CR after declaration of a CRi.  To upgrade a response to CR both peripheral blood and 
bone marrow assessment must be obtained within a 14 day period and all criteria for CR 
must be met. 
8.5 
Remission Duration 
Only patients achieving CR or CRi are assessed for remission duration (relapse-free 
survival). Remission duration is measured from the date of achievement of a remission 
(CR/CRi) until the date of relapse or death from any cause; patients not known to have 
relapsed or died at last follow-up are censored on the date they were last examined. 
8.6 
Morphologic Leukemia-free State 
All randomized patients that have at least one evaluable post-randomization bone marrow 
assessment performed on or after Day 14 after the last induction are assessed for 
morphologic leukemia-free state.  Morphologic leukemia-free state is defined as bone 
marrow blasts <5% AND absence of Auer rods and/or extramedullary disease. 
9.0 Assessment of Safety 
 
9.1 
Evaluable for Safety 
All patients who have received at least one dose will be considered evaluable for safety. 
9.2 
Adverse Events 
9.2.1 Definition of an Adverse Event 
An adverse event is any untoward medical occurrence in a patient or clinical 
investigation subject administered with a pharmaceutical product and which does not 
necessarily have to have a causal relationship with this treatment. An adverse event can 
therefore be any unfavorable and unintended sign (including an abnormal laboratory 
finding, for example), symptom, or disease temporally associated with the use of a 
medicinal product, whether or not considered related to the medicinal product. This 
includes worsening of a pre-existing condition or increase in frequency of a pre-existing 
condition. An adverse event is considered serious if it meets any of the serious criteria 
listed in Section 9.2.2.  To ensure no confusion or misunderstanding of the difference 
between the terms “serious” and “severe”, which are not synonymous, the following 
clarification is provided: 
 
The term “severe” is often used to describe the intensity (severity) of a specific event (as 
in mild, moderate, or severe myocardial infarction); the event itself, however, may be of 
relatively minor medical significance (such as severe headache). This is not the same as 


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“serious”, which is based on patient/event outcome or action criteria usually associated 
with events that pose a threat to a patient’s life or functioning. Seriousness (not severity) 
serves as a guide for defining regulatory reporting obligations. 
 
Adverse events are to be recorded in the case report form from the start of the infusion on 
Day 1 until 30 days after the last dose of study drug, with the exception of serious 
adverse events. (See Section 9.2.2).  Leukemia Department Guidelines for AE recording 
will be used. 
 
The Investigator or physician designee is responsible for verifying and providing source 
documentation for all adverse events and assigning the attribution for each event for all 
subjects enrolled on the trial. 
 
Adverse events and protocol specific data will be entered into CORe/PDMS.  
CORe/PDMS will be used as the electronic case report form for this protocol. 
 
Adverse drug reactions (ADRs) are all noxious and unintended responses to a medicinal 
product related to any dose that a causal relationship between the medicinal product and 
an adverse event is at least a reasonable possibility, i.e., the relationship cannot be ruled 
out. An unexpected ADR is any adverse reaction not identified in nature or intensity in 
the current Investigator’s Brochure. 
9.2.2 Serious Adverse Event Reporting 
An adverse event or suspected adverse reaction is considered “serious” if, in the view of 
either the investigator or the sponsor, it results in any of the following outcomes: 
 
 Death 
 A life-threatening adverse drug experience – any adverse experience that places the 
patient, in the view of the initial reporter, at immediate risk of death from the 
adverse experience as it occurred. It does not include an adverse experience that, 
had it occurred in a more severe form, might have caused death. 
 Inpatient hospitalization or prolongation of 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 a serious adverse drug experience when, based upon 
appropriate medical judgment, they may jeopardize the patient or subject 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 inpatient hospitalization, or the development of drug dependency or drug abuse 
(21 CFR 312.32). 
 


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 Important medical events as defined above, may also be considered serious adverse 
events. Any important medical event can and should be reported as an SAE if 
deemed appropriate by the Principal Investigator or the IND Sponsor, IND Office. 
 All events occurring during the conduct of a protocol and meeting the definition of 
a SAE must be reported to the IRB in accordance with the timeframes and 
procedures outlined in “The University of Texas M. D. Anderson Cancer Center 
Institutional Review Board Policy for Investigators on Reporting Serious 
Unanticipated Adverse Events for Drugs and Devices”.  Unless stated otherwise in 
the protocol, all SAEs, expected or unexpected, must be reported to the IND 
Office, regardless of attribution (within 5 working days of knowledge of the event). 
 All life-threatening or fatal events, that are unexpected, and related to the study 
drug, must have a written report submitted within 24 hours (next working day) of 
knowledge of the event to the Safety Project Manager in the IND Office.   
 Unless otherwise noted, the electronic SAE application (eSAE) will be utilized for 
safety reporting to the IND Office and MDACC IRB.  
 Serious adverse events will be captured from the time of the first protocol-specific 
intervention, until 30 days after the last dose of drug, unless the participant 
withdraws consent. Serious adverse events must be followed until clinical recovery 
is complete and laboratory tests have returned to baseline, progression of the event 
has stabilized, or there has been acceptable resolution of the event. 
 Additionally, any serious adverse events that occur after the 30 day time period 
that are related to the study treatment must be reported to the IND Office. This may 
include the development of a secondary malignancy. 
 
Reporting to FDA: 
 Serious adverse events will be forwarded to FDA by the IND Sponsor (Safety 
Project Manager IND Office) according to 21 CFR 312.32. 
 
It is the responsibility of the PI and the research team to ensure serious adverse 
events are reported according to the Code of Federal Regulations, Good Clinical 
Practices, the protocol guidelines, the sponsor’s guidelines, and Institutional Review 
Board policy. 
 
9.2.3 Communication between Investigator and Jazz Pharmaceuticals 
The Investigator must send all SAEs (initial and follow up) that require collection and 
reporting per protocol, and which occur in a patient who received CPX-351, to Jazz 
Pharmaceuticals within 1 business day of their awareness of the SAE via email to 
AEreporting@jazzpharma.com.  In addition, all other adverse events must be reported to 
Jazz in summary of line-item form upon Jazz’s request.   
 
Follow-up information is sent either via a new Serious Adverse Event Form (stating that 
this is a follow-up), or via the original one form (with the new information highlighted 
and a new date provided).  The follow-up should describe whether the event has resolved 


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or continues, if and how it was treated, whether the patient continued or discontinued 
study participation.   
 
The telephone and fax numbers of the local Clinical Research contact person and the 
contact person in the local department of Clinical Safety, specific to the site, must be 
listed in the investigator folder provided for each individual site and provided to the 
manufacturer at the start of the trial.  Questions referring to a specific serious adverse 
event occurring in a study patient should be directed to the local Clinical Research 
contact person specified in the investigator folder provided for the site. 
 
9.3 
Cardiac Toxicity Monitoring 
As anthracyclines are known to have an adverse effect on cardiac function, each patient’s 
cardiac function will be monitored through the Treatment and Follow-up Phases.  Any 
left ventricular ejection fraction below 50% will be recorded as adverse events.  If the left 
ventricular ejection fraction is reduced >10% to below 50% from the baseline assessment 
at the last Treatment Phase measurement, left ventricular ejection fraction will continue 
to be monitored every 3 months until a return to baseline or 1 year, whichever comes 
first. 
9.4 
Laboratory Data 
Laboratory data obtained according to the schedule of assessments will be recorded on 
the CRF or other data collection instrument. Only laboratory data requested by the 
protocol need be recorded unless specific findings result in a clinical event such as an 
adverse event or documentation of peripheral blood count recovery.   These results will 
be collected. 
9.4.1 Copper Assessment 
Patients will have serum copper assessed routinely and the percentage of patients with 
persistent (>1 year) copper elevations will be reported.  Also, patients with persistently 
elevated serum copper will be evaluated for clinical abnormalities associated with copper 
toxicity (e.g. unexplained increase in liver function tests).  Serum copper elevations are 
laboratory values and are not reported as adverse events unless associated clinical signs 
and symptoms of copper toxicity.  
 
MDACC will draw the serum copper, send it out for processing and will report the results 
in clinic station in approximately 4 days.   
10.0 Statistical Considerations(16, 17) 
 
General Description: 
This is a Phase II study of CPX-351 Liposome Injection in newly diagnosed AML patients 
with high risk of induction mortality.  Two dose levels (50 units/m2 and 75 units/m2) of 
CPX-351 will be studied initially. The primary objective is to evaluate treatment response. 
The efficacy outcome is CR or CRi within two induction cycles.  A maximum of 30 patients 
will be equally randomized to the two dose levels. A Bayesian method by Thall et al (1995) 


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will be used for futility and toxicity monitoring. After 15 patients have been accrued to 
each dose level, an assessment of overall safety/dose limiting toxicities and efficacy will 
be made and one dose level will be chosen for further study. OR if both dose levels are safe 
and further dose escalation seems possible, one additional cohort with a dose of 100 
units/m2 will be open. A maximum of 15 patients will be enrolled in this arm and the same 
toxicity and futility monitor rules will be applied. After 2 or 3 dose levels have been 
studied, one dose levels will be chosen for further study. An expansion cohort of 10 patients 
will be treated at the dose level with a favorable response and/or toxicity profile for further 
evaluation for safety and efficacy. Consequently, the preferred dose level has 25 patients 
evaluable. 
 
Additional 25 patients will be added to the arm with the dose of 100 units/m2, the sample 
size for this arm will be up to 40, and the maximum number of patients for all three arms 
will be up to 80. 
 
Multc Lean software version 2.1 developed in the Department of Biostatistics MDACC 
was used for the study design.  
 
The study will monitor futility and toxicity, and the monitoring rules will be applied to 
each dose separately.  If study in one of the two doses is stopped early due to futility or 
excessive toxicity, all the future patients will be enrolled in the open dose arm (i.e.,  without 
randomization).  In the case the lower dose (50 units/m2) has been shown to be too toxic 
at an interim look (thus stop further patient enrollment) the higher dose (75 units/m2) will 
also stop accrual.   
 
Futility monitoring: 
Treatment success is defined as achievement of CR or CRi. We will accrue a maximum of 
15 patients at each dose level and test the null hypothesis that the true response is at most 
5% (meaning little or no activity) versus the alternative hypothesis that the true response 
is 30% or greater, independently in each treatment arm. Assuming that the success rate is 
binomially distributed, this design with 15 patients in each arm has 87% power and a one-
sided type I error rate of 0.05 using an exact test.  
 
 To monitor futility, the study in one dose level will be stopped early if the data in that dose 
level suggest that: 
 
                                     Pr(E <0.25 + S |data)>0.95 
 
That is, if at any time during the study we determine that there is a greater than 95% chance 
that the response rate is less likely to improve by 25% than the null hypothesis in one dose 
level, we will terminate the enrollment in that dose. Here E  represents the response rate 
for experimental drug in this study and  S represents the response rate for the standard 
practice (null hypothesis).  We assume that S has a distribution of beta (10, 190) to reflect 
the information on 200 patients for the historical data, which has a mean response rate of 
0.05 and a variance of 0.0002.  We also assume that E has a non-informative flat prior 
beta(0.1, 1.9) with mean of 0.05 and variance of 0.0158.  


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The futility stopping boundaries for the overall response based on these assumptions and 
monitoring condition is shown in table 7. For example, accrual will be stopped in one dose 
if there is no response observed in the first 5 patients treated in that dose. 
 
The toxicity monitoring/efficacy summary will be submitted to the IND Office Medical 
Monitor (Dr. Agueda Cohen) for every 5 subjects treated in each Arm (per Table7, 8, 11 
& 12). 
 
Table 7: Stopping boundaries for futility monitoring for the initial cohort of each dose 
(n=15) 
# Patients 
(in complete 
 cohorts of 5) 
(inclusive) 
Stop the enrollment in one dose if there are 
this many responses total in that dose: 
# Responses 
(inclusive) 
5  
0  
10  
0-1 
15  
Always stop with this many patients 
 
 
Toxicity monitoring 
In addition, toxicity will be monitored closely. Denote the probability of toxicity by TE, 
where toxicity is defined as DLTs. We assume toxicity rate beta (0.66, 1.34) for the 
experimental treatment in this study.  Our safety monitoring rule is described as follows: 
Pr(TE > 0.33 | data)  > 0.85. That is, we will stop the enrollment in one dose if, at any time 
during the study, we determine that there is more than 85% chance that the DLT rate is 
more than 33% in that dose. Stopping boundaries corresponding to this stopping rule is 
listed in table 8. For example, the enrollment in one dose will be stopped if the first 4 of 
the first 5 patients experienced toxicity in that dose. 
 
Table 8: Stopping boundaries for toxicity monitoring for the initial cohort of each dose 
(n=15) 
# Patients 
(in complete 
 cohorts of 5) 
(inclusive) 
Stop the enrollment in dose level if there are 
this many DLTs total in that dose level: 
# DLTs 
(inclusive) 
5  
4-5 
10  
6-10 
15  
Always stop with this many patients 
  


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The operating characteristics for this design are presented in table 9. If the enrollment in 
one dose continues until 15 patients are evaluated in each arm and 5 CR or CRi are 
observed, then the 95% credible interval for the response rate would be (11.6%, 47.7%). 
 
 
Table 9: Operating characteristics of the initial cohort of each dose (n=15) 
True CR+CRi  
Rate 
True DLT Rate 
Early Stopping 
Probabilities 
Average 
sample 
size  
treated 
0.05 
0.1 
0.931 
6.47 
0.05 
0.2 
0.932 
6.46 
0.05 
0.33 
0.938 
6.39 
0.05 
0.5 
0.959 
6.12 
0.1 
0.1 
0.784 
88.13 
0.1 
0.2 
0.787 
8.10 
0.1 
0.33 
0.804 
7.94 
0.1 
0.5 
0.872 
7.30 
0.2 
0.1 
0.462 
11.1 
0.2 
0.2 
0.468 
11.0 
0.2 
0.33 
0.512 
10.66 
0.2 
0.5 
0.681 
9.33 
0.3 
0.1 
0.229 
13.01 
0.3 
0.2 
0.237 
12.95 
0.3 
0.33 
0.30 
12.5 
0.3 
0.5 
0.543 
10.67 
0.3 
0.6 
0.735 
9.08 
0.4 
0.1 
0.098 
14.11 
0.4 
0.2 
0.108 
14.04 
0.4 
0.33 
0.181 
13.50 
0.4 
0.5 
0.465 
11.42 
0.4 
0.6 
0.691 
9.61 
 
 
If three dose arms continue until 15 patients in each arm evaluated, the toxicity profile and 
response will be summarized for them. The dose chosen for further study will be the dose 
with the highest CR+CRi rate, provided that toxicity profile are also acceptable. The 
probability of correctly selecting the superior dose for different success rate scenarios in 
the three arms is summarized in table 10 below [Simon R et al 1985].  
 
Table 10: Probability of the best arm being chosen 
True Response rate in 
Superior Dose  
True 
Response 
rate in inferior 
Dose 1 
True Response rate in 
inferior  Dose 2 
Probability of the 
best arm is chosen 


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30% 
10% 
10% 
86% 
30% 
15% 
15% 
71% 
40% 
25% 
25% 
63% 
40% 
30% 
25% 
56% 
40% 
30% 
30% 
50% 
50% 
25% 
25% 
83% 
50% 
30% 
25% 
78% 
50% 
30% 
30% 
73% 
50% 
40% 
30% 
59% 
60% 
25% 
25% 
94% 
60% 
30% 
25% 
91% 
60% 
30% 
30% 
89% 
60% 
40% 
30% 
79% 
60% 
50% 
30% 
63% 
 
The arm with a favorable toxicity profile and/or a favorable might be chosen for further 
evaluation by expanding a cohort of 10 additional patients in that arm. We will use the 
same criteria (e.g. expansion will be stopped if Pr(TE > 0.33 | data)  > 0.85) to monitor 
toxicity for the expansion cohort by using a total sample size of 25 for the winner arm. The 
stop boundaries are summarized in the following table. If 10 or more patients out of the 1st 
20 patients experienced DLT, the trial will be stopped and no expansion cohort will be 
evaluated.  If 10 or more patients out of 20 patients experienced DLT (by adding 5 more 
patients to the 15 patients in that arm), the expansion will be stopped. 
 
Table 11.  Toxicity monitoring for the expanded cohort at a dose of 75 units/m2 
# Patients 
(in complete 
 cohorts of 5) 
(inclusive) 
Stop the arm with expansion cohort if there are 
this many dose limiting toxicities total: 
# Toxicities 
(inclusive) 
5  
4-5 
10  
6-10 
15  
8-15 
20  
10-20 
25  
Always stop with this many patients 
 
Expansion of arm with the dose of 100 units/m2 
 
Up to additional 25 patients will be enrolled in this arm, thus total sample size for this arm 
is up to 40. Assuming that the success rate is binomially distributed, 40 patients will have 
has 99% power to detect a difference of 5% vs. 30% in success rate at a one-sided type I 
error rate of 0.05 using an exact test.  


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Similar futility and toxicity monitoring rules listed above will also be applied for the 
expansion of arm with 100 units/m2. That is, the trial will be stopped early if    
                         Pr(E <0.25 + S |data)>0.98 for futility  
                                               or 
                         Pr(TE > 0.33 | data)  > 0.95 for toxicity 
where E represents the response rate for experimental drug in this study and S represents 
the response rate for the standard practice (null hypothesis).  TE represents DLT rate. For 
trial simulation, we use the same assumption for prior distributions listed above for each 
parameter. That is, S has a prior distribution of beta (10, 190), E has a non-informative 
flat prior beta(0.1, 1.9), and TE has a prior distribution of  beta (0.66, 1.34). 
 
Table 12 and 13 present the corresponding stopping boundary and operating characteristics 
(OCs). 
 
Table 12: Stopping boundaries for futility and toxicity of the expansion cohort with the 
dose of 100 units/m2 
N patients evaluated 
Stop for toxicity if >= this number 
of patients experience DLT 
Stop for futility if <= this number of 
patients achieve CR/Ci 
5 
 4‐5 
0 
10 
7‐10 
0  
15 
9‐15 
0‐1 
20 
11‐20 
0‐2 
25 
13‐25 
0‐3 
30 
15‐30 
0‐4 
35 
17‐35 
0‐5 
40 
19‐40  
0‐6  
 
Table 13: OCs of the expansion cohort with the dose of 100 units/m2  
True CR+CRi  Rate 
True DLT Rate 
Early Stopping Probabilities 
Average sample size  treated 
0.05 
0.1 
 0.9965 
 8.16 
0.05 
0.2 
 0.9965 
 8.14 
0.05 
0.33 
 0.9969 
 7.99 
0.05 
0.5 
 0.999 
 7.26 
0.1 
0.1 
 0.9294 
 13.16 
0.1 
0.2 
 0.930 
 13.10 
0.1 
0.33 
 0.9372 
 12.63 
0.1 
0.5 
 0.9803 
 10.19 
0.2 
0.1 
 0.5119 
 25.54 
0.2 
0.2 
 0.5156 
 25.39 
0.2 
0.33 
 0.5654 
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0.2 
0.5 
 0.8637 
 16.36 
0.3 
0.1 
 0.2029 
 33.50 
0.3 
0.2 
 0.209 
 33.30 
0.3 
0.33 
 0.2903 
 31.31 
0.3 
0.5 
 0.7774 
 20.23 
0.4 
0.1 
 0.0817 
 37.19 
0.4 
0.2 
 0.0887 
 36.96 
0.4 
0.33 
 0.1824 
 34.70 
0.4 
0.5 
 0.7436 
 22.12 
0.4 
0.6 
 0.9612 
 14.02 
 
Statistical methods: 
 
Data analysis will be performed using SAS or S-plus, as appropriate. For each arm, the 
CR/CRi rate and the DLT rate will be estimated with95% confidence intervals. The intent-
to-treat patients will be used for the primary efficacy analysis, patients who lost-to-follow 
up in the first 2 cycles will be treated as failures.   Patients who received at least one dose 
of the treatment drug will be evaluable for toxicity outcomes. In addition, Fisher’s exact 
test will be used to compare the response rate and toxicity rate between the two dose levels. 
For the exploratory objectives, Fisher’s exact test will be used to compare immune 
responses between different doses of CPX-351.  Two-sample t test or ANOVA or Fisher’s 
exact test will be used to check the association between Troponin – T and cardiotoxicity, 
and t test or ANOVA will be used to compare the apoptosis of ex-vivo cultured leukemia 
cells. 
 
 
 


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11.0 References 
1. 
Stone RM, O'Donnell MR, Sekeres MA. Acute myeloid leukemia. Hematology 
Am Soc Hematol Educ Program. 2004:98-117. 
2. 
Appelbaum FR, Gundacker H, Head DR, Slovak ML, Willman CL, Godwin JE, et 
al. Age and acute myeloid leukemia. Blood. 2006;107(9):3481-5. 
3. 
Kantarjian H, O'Brien S, Cortes J, Giles F, Faderl S, Jabbour E, et al. Results of 
intensive chemotherapy in 998 patients age 65 years or older with acute myeloid 
leukemia or high-risk myelodysplastic syndrome: predictive prognostic models 
for outcome. Cancer. 2006;106(5):1090-8. 
4. 
Cheson BD, Bennett JM, Kopecky KJ, Buchner T, Willman CL, Estey EH, et al. 
Revised recommendations of the International Working Group for Diagnosis, 
Standardization of Response Criteria, Treatment Outcomes, and Reporting 
Standards for Therapeutic Trials in Acute Myeloid Leukemia. J Clin Oncol. 
2003;21(24):4642-9. 
5. 
Estey E. Acute myeloid leukemia and myelodysplastic syndromes in older 
patients. J Clin Oncol. 2007;25(14):1908-15. 
6. 
Hiddemann W, Kern W, Schoch C, Fonatsch C, Heinecke A, Wormann B, et al. 
Management of acute myeloid leukemia in elderly patients. J Clin Oncol. 
1999;17(11):3569-76. 
7. 
Burnett AK, Milligan D, Prentice AG, Goldstone AH, McMullin MF, Hills RK, et 
al. A comparison of low-dose cytarabine and hydroxyurea with or without all-
trans retinoic acid for acute myeloid leukemia and high-risk myelodysplastic 
syndrome in patients not considered fit for intensive treatment. Cancer. 
2007;109(6):1114-24. 
8. 
Lowenberg B, Ossenkoppele GJ, van Putten W, Schouten HC, Graux C, Ferrant 
A, et al. High-dose daunorubicin in older patients with acute myeloid leukemia. N 
Engl J Med. 2009;361(13):1235-48. 
9. 
Fernandez HF, Sun Z, Yao X, Litzow MR, Luger SM, Paietta EM, et al. 
Anthracycline dose intensification in acute myeloid leukemia. N Engl J Med. 
2009;361(13):1249-59. 
10. 
Vey N, Coso D, Bardou VJ, Stoppa AM, Braud AC, Bouabdallah R, et al. The 
benefit of induction chemotherapy in patients age > or = 75 years. Cancer. 
2004;101(2):325-31. 
11. 
Leith CP, Kopecky KJ, Godwin J, McConnell T, Slovak ML, Chen IM, et al. 
Acute myeloid leukemia in the elderly: assessment of multidrug resistance 
(MDR1) and cytogenetics distinguishes biologic subgroups with remarkably 
distinct responses to standard chemotherapy. A Southwest Oncology Group study. 
Blood. 1997;89(9):3323-9. 
12. 
Mayer LD, Harasym TO, Tardi PG, Harasym NL, Shew CR, Johnstone SA, et al. 
Ratiometric dosing of anticancer drug combinations: controlling drug ratios after 
systemic administration regulates therapeutic activity in tumor-bearing mice. Mol 
Cancer Ther. 2006;5(7):1854-63. 
13. 
Feldman EJ, Lancet JE, Kolitz JE, Ritchie EK, Roboz GJ, List AF, et al. First-In-
Man Study of CPX-351: A Liposomal Carrier Containing Cytarabine and 


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Daunorubicin in a Fixed 5:1 Molar Ratio for the Treatment of Relapsed and 
Refractory Acute Myeloid Leukemia. J Clin Oncol. 2011;29(8):979-85. 
14. 
Ozer H, Armitage JO, Bennett CL, Crawford J, Demetri GD, Pizzo PA, et al. 
2000 update of recommendations for the use of hematopoietic colony-stimulating 
factors: evidence-based, clinical practice guidelines. American Society of Clinical 
Oncology Growth Factors Expert Panel. J Clin Oncol. 2000;18(20):3558-85. 
15. 
Dohner H, Estey EH, Amadori S, Appelbaum FR, Buchner T, Burnett AK, et al. 
Diagnosis and management of acute myeloid leukemia in adults: 
recommendations from an international expert panel, on behalf of the European 
LeukemiaNet. Blood. 2010;115(3):453-74. 
16. 
Thall PF, Simon RM, Estey EH. Bayesian sequential monitoring designs for 
single-arm clinical trials with multiple outcomes. Stat Med. 1995;14(4):357-79. 
17. 
Simon R, Wittes RE, Ellenberg SS. Randomized phase II clinical trials. Cancer 
Treat Rep. 1985;69(12):1375-81. 
 


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12.0 
APPENDIX 1: Patient Evaluation Flow Sheet – Treatment Phase 
Evaluations (except screening) to be conducted for each INDUCTION1 and CONSOLIDATION: 
Day: 
Screening 
1 
±2 
2 
±2 
3 
±2 
4 
±2 
5 
±2 
6 
±2 
7 
±2 
10 
±2 
14 
±3 
21
±3 
28
±3 
35
±3 
42
±3 
Weekly3 
±3 
End of Phase/Early 
Termination 
Informed Consent4 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical History 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical Exam 
x 
 
 
 
 
 
 
 
 
x 
 
 
 
x 
 
x 
Vital Signs 
x 
 
 
 
 
 
 
 
 
x 
 
 
 
x 
 
x 
ECOG Performance Status 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
x 
ECG 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
x 
Registration  
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hematology 
x 
x 
 
x 
 
x 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Biochemistry 
x 
x 
 
x 
 
x 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy Test9 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Copper levels 
x 
 
 
 
 
 
 
 
 
 
 
x8 
 
 
 
x 
Bone Marrow Aspiration/Biopsy 
x 
 
 
 
 
 
 
 
 
 
 
x5 
 
 
 
 
Chest X-ray  
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Echocardiography/MUGA 
x 
x10 
 
 
 
 
 
 
 
 
 
 
 
x 
 
x 
Response Assessment 
 
 
 
 
 
 
 
 
 
x6 
 
Cytogenetics/Molecular Markers 
x 
 
 
 
 
 
 
 
 
 
 
x 
 
 
 
 
Adverse Events 
 
Assess throughout Induction and Consolidation 
x 
Concomitant Medications 
 
Assess throughout Induction and Consolidation 
x 
CPX-351 Administration 
x 
 
x 
 
x2 
 
 
 
 
 
 
 
 
 
 
Immune markers* 
x 
x7 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cardiac markers* 
x 
x 
x 
 
 
 
x 
 
 
x 
 
 
 
 
 
x 
 Pharmacodynamics* 
x 
x 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
*Optional 
 
1The first induction may end prematurely if a second induction is necessary, see Section 0.  The schedule of evaluations for the first induction is followed until the second induction starts, then the 
evaluations are followed as indicated in the flow sheet, beginning with Day 1 
2 Second inductions and consolidations of are CPX-351 on Days 1 and 3, see Section 4.6 
3Continue weekly evaluations until confirmation of response (CR/CRi) or persistent disease is declared 
4 Within 30 days prior to start of screening, if informed consent was collected, 30 days elapse and the patient is still not screened he/she must sign another ICF 
5Required after each induction; (in case the Day 28 (+/-7 days)  bone marrow is non-evaluable or assessment of aplasia is equivocal, a repeat evaluation may be performed 5-10 days later, at the 
discretion of the treating physician, in order to determine effect and need for second induction);  as needed thereafter to confirm response/persistence/relapse in second inductions & consolidations 
6Induction(s) only; see Section 8.4.1 for details on when response is assessed. 
7At start of induction, induction 2 (when applicable), each consolidation  


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8Copper levels to be done before start of next cycle  
9Women of childbearing potential 
10Prior to every other course of therapy after cumulative dose of DNR exceeds 300 mg/m2; prior to every course of treatment after the cumulative DNR dose exceeds 500 mg/m2, or 30 days after the 
last course. 
 
 


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13.0 
APPENDIX 2: Patient Evaluation Flow Sheet –Follow-up 
 
Monthly for 1 Year 
(±10 Days) 
Every 2-3 months 
for 1 year 
Every 3-4 months for 1 year 
Early Termination 
Patient status report 
X1 
 
 
x 
Hematology 
 
x 
 
x 
Biochemistry 
 
x 
 
 
Copper levels 
only if abnormal2 
 
 
 
Bone Marrow 
Aspiration/Biopsy 
 
 
x 
For patients in CR, consider performing if peripheral blood 
counts fall below 1000/μL for ANC or 100,000/μL for 
platelets for >1 month with no obvious explanation for the 
drop or at any time there is suspicion of relapse; for patients 
in CRi perform if counts fall significantly below peak 
recovery.  If the peripheral blood counts in a patient with a 
CRi recover to CR levels (>1000/μL for ANC or 
>100,000/μL for platelets), consider performing a bone 
marrow evaluation to confirm full CR.  Following the first 
year of follow up, aspirations will be done as clinically 
indicated; record relapse information, including any bone 
marrow evaluations.  Not required following the initiation of 
new therapy and or relapse.  
 
 
Echocardiography or 
MUGA scan 
 
 
x 
Perform every 3-4 months if last Treatment Phase LVEF was 
reduced >10% from baseline and is less than 50%.  Continue 
assessments until LVEF returns to baseline or until 1 year 
from start of therapy. 
 
1 Survival followed until death 
2>20% above upper limit of normal.  To be performed monthly until return to within 20% of ULN, or until 1 year from the last dose, or the initiation of new therapy, or relapse 
(whichever is earlier). 
 


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14.0 
APPENDIX 4: Performance Status – ECOG 
 
Grade 
Description 
0 
Fully active, able to carry on all pre-disease performance without restriction 
(Karnofsky 90-100) 
1 
Restricted in physically strenuous activity but ambulatory and able to carry 
out work of a light or sedentary nature (e.g., light housework, office work) 
(Karnofsky 70-80). 
2 
Ambulatory and capable of all self-care but unable to carry out any work 
activities.  Up and about more than 50% of waking hours (Karnofsky 50-
60). 
3 
Capable of only limited self-care, confined to bed or chair more than 50% 
of waking hours (Karnofsky 30-40). 
4 
Completely disabled.  Cannot carry on any self-care.  Totally confined to 
bed or chair (Karnofsky 10-20). 


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15.0 
APPENDIX 5: Common Terminology Criteria for Adverse Events V4.0 
(CTCAE) 
 
This 80 page document can be obtained as a pdf file from http://ctep.cancer.gov. 
The publication date is May 28, 2009 
  
 


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16.0 APPENDIX 6: Immune resonstitution after chemotherapy with CPX-351 
Immune reconstitution is believed to constitute a major element that determines the risk 
of relapse and the possibility of late infectious complications. Immune reconstitution after 
standard cytarabine and anthracycline combination has not been well studied and not at 
all after therapy with CPX-351. To this effect we propose the following: 
 
To determine how  CPX-351 influences the recovery of functional pathogen-specific 
and leukemia-specific immune responses. 
We will conduct analyses of T cell phenotype, estimate antigen-specific T cell precursor 
frequencies (by intracellular cytokine flow cytometry and peptide/dextramer staining) 
and determine antigen-specific cytokine production capacity (cytokine bead array assay). 
We will evaluate antigen-specific T cell recovery following treatment with CPX-351 by 
analyzing 1) Immunophenotypic recovery of Th1, Th2, Th17 and regulatory T cells; 2) 
The number and function of recovering CMV and Flu-specific T cells capable of 
responding functionally to in vitro stimulation with overlapping pools of peptide by 
intracellular cytokine detection; 3) The number and function of T cells capable of 
responding to leukemia-associated antigens including proteinase 3 (PR3), Wilms tumor 
antigen (WT1) and cancer testis antigens (e.g. PRAME) will be assessed following 
stimulation with overlapping pools of peptide and intracellular cytokine assay. 
 
To determine how CPX-351 influences the recovery and function of NK cells 
To evaluate if CPX-351 will impact on NK phenotype and function, we will conduct 
longitudinal analyses of NK phenotype and function during CPX-351 therapy. 
Quantitative 10-color flow cytometric analysis will be performed to 1) characterize the 
functional phenotype of NK cells using an extended panel of antibodies against activating 
(NKp30, NKp44, NKp46, NKG2D, NKG2C, DNAM1) and inhibitory receptors 
(NKG2A and KIRs); 2) assess the effector function of NK product against MHC class I-
deficient leukemia targets and primary AML cells from the recipient by intracellular 
cytokine assay for interferon-gamma (IFN-γ) production, chemokine production 
including CCL3 (MIP1α) and CCL4 (MIP1β) and cytotoxicity, including CD107a 
degranulation and 51chromium release assay; Confocal microscopy will be used to 
directly assess the immune synapse formation with leukemia targets. 
 
Sample collection and distribution 
60 cc of blood (Green top tubes- heparin) and 5 cc in purple top (EDTA) to be collected 
at 3 time points: 
1- Before induction with CPX-351 
2- At recovery from induction, just prior to consolidation #1 
3- At recovery from 1st cycle of consolidation just prior to consolidation #2 
Samples will be sent to Dr. Katy Rezvani’s lab manager, P14.3144; tel: 713-745-0027. 
 
 


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17.0 
APPENDIX 7: Early Detection of CPX-351-induced cardiotoxicity using high 
sensitivity troponin T 
Chemotherapy is an effective treatment in most cancers. Yet all these drugs have a 
various range of side effects. Chemotherapy-induced organ injury remains a major issue 
in cancer patient care. Chemotherapy-induced cardiotoxicity is the most serious one, 
particularly associated with the use of anthracyclines, ultimately impacting the long-term 
cancer survivors and survival time. CPX-351 is a liposomally encapsulated combination 
of cytarabine and daunorubicin. The liposomal encapsulation may lead to a decrease in 
cardiac toxicity. However, the CPX-351-induced cardiotoxicity has not been evaluated.  
 
Identification of chemotherapy-induced cardiac toxicity has been dependent on imaging 
modalities, such as echocardiogram or MUGA scan.  Despite their usefulness, routine 
cardiac imaging alone lacks sensitivity for early detection of subclinical cardiac disease.  
Multiple cardiac biomarkers have been evaluated extensively in both animal models and 
clinical studies such as creatine kinase (CK), creatine kinase – MB fraction (CK-MB), 
troponin T (cTnT), troponin I (cTnI), brain natriuretic peptide (BNP), C-reactive protein 
(CRP), and interleukin family member (ST2).5, 6  In acute coronary syndromes, troponin 
is one of the most well established biomarkers used to guide diagnosis and treatment.  
However, the utility of biomarkers in monitoring myocardial damage secondary to 
chemotherapy is still controversial.   
 
Both cTnT and cTnI have been demonstrated in multiple clinical studies to be sensitive 
and specific markers for detecting myocardial injury after chemotherapy administration.  
The level of troponin released into circulation has a good predictive value for subsequent 
decrease in LV ejection fraction and adverse cardiac events long before the impairment is 
observed by echocardiogram or symptoms have developed.  Elevation in troponin has 
shown a positive predictive value of 50-84%, and a negative predictive value of 90-
99%.5, 7  Furthermore, the peak value and the duration of elevated troponin level have a 
strong relationship with the degree of LV dysfunction.  In contrast, BNP, NT-proBNP, 
CK, CK-MB and CRP have shown to be less sensitive and specific in detecting 
subclinical heart failure in this group of patients.8, 9  
 
Recent advances in assay technology have led to more sensitive and precise cardiac 
troponin T assays that can detect TnT level as low as 0.005 µg per liter.10  With 
increasing in sensitivity, high-sensitive troponin T (hs-TnT) has superiority over standard 
troponin test in early diagnosis of acute myocardial infarction.11  In chronic stable angina, 
higher levels of hs-TnT has been shown to be associated with the higher incidence of 
cardiovascular death and heart failure in the future.12  Recently, hs-TnT has been 
evaluated as a peri-operative risk stratification in non-cardiac surgery patients.13  
Interestingly, they found that hs-TnT level above universal cut-off were associated with a 
2.6-fold increase in in-hospital mortality and morbidities from cardiovascular system.  
 


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To our knowledge, no prior study has ever evaluated hs-TnT during CPX-351 
chemotherapy administration. Therefore, our primary objective is to assess whether hs-
TnT obtained during the course of CPX-351 chemotherapy could allow us to monitor the 
development of acute cardiotoxicity.   
 
 Primary objective:  
To test the feasibility of using high-sensitivity troponin T to monitor acute CPX-351-
induced cardiotoxicity. In addition, BNP and cardiac troponin I will be measured. 
 
 Roche high sensitivity troponin T assay is a sandwich chemiluminescent assay. High 
sensitivity troponin T assay gives detection limit of 5 ng/L and the 99th percentile of 
cutoff 14 ng/L. It can be run on MODULAR ANALYTICS E170, Elecsys 2010, 
cobas e411, cobas e 601 and cobas e 602 analyzers.  
 This high sensitivity troponin T assay will be measured on Cobas e601 using Roche 
reagents including calibrators and controls. 
 
Sample collection and distribution 
3 cc of blood (Green top tubes- heparin) at the following time points: 
1- Before the start of each cycle with CPX-351 (baseline) 
2- Approximately 24 hrs after the end of the first dose (Day 1 + 1) (for each cycle) 
3- Approximately 25 hrs after the end of the dose given on day 5 (Day 5 + 1) (for 
each cycle) 
4- Approximately on day 14 (±4 days) for each cycle 
5- End of treatment 
Samples will be sent to Dr. Qing H. Meng’s lab, on R4.1446, Clinical Chemistry 
Laboratory, Department of Laboratory Medicine; c/o Dr. Qing H. Meng, tel: 713-792-
6320; fax: 713-792-4793; email:  qhmeng@mdanderson.org. 


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18.0 
APPENDIX  8:  Pharmacodynamic Investigations During CPX-351 Therapy 
 
The objectives of the pharmacokinetic and pharmacodynamic investigations during this 
clinical trial are as follows: 
 
(1) To test ex vivo cytotoxicity of combination of Pim kinase inhibitor(s) and CPX-351 on 
circulating leukemia cells.  
(2) To investigate effect of Pim kinase inhibitor on phosphorylated and total protein levels 
in pim kinase signaling pathway.   
 
Only patients entering at MD Anderson Cancer Center will be studied.  All patients with 
>5,000 WBC/l of peripheral blood will be requested to participate in the cellular 
pharmacodynamics studies.  Patients will sign consent forms to enter these investigations.   
 
Once a patient has consented to participate in the investigation, please contact Ms. 
Vrushali Datar (pager 713-606-2212) or Yuling Chen (pager 713-404-2550) in The 
Laboratory of Cellular and Molecular Pharmacology (Dr. Gandhi, phone, 713 792-3336) 
to coordinate scheduling of blood samples.  To facilitate preparedness for laboratory 
studies, please plan on initiating therapy in the subsequent morning if the clinical 
situation allows and please inform us as soon as there is a possibility of patient entering 
the clinical trial.     
 
Blood samples will be collected at the following times from patients in the Dose Escalation 
Phase:  Total of 2 samples will be collected. 
 
Cycle 1.     
Day 1:  0 (pre-dose),   
 
Two green top tubes (2  10mL) 
 
 
24 h 
 
 
 
One green top tube   (1  10mL) 
 
For the pre-dose (sample 1), two tubes of blood (10mL each) will be collected in a 
Vacutainer green top tube.  For the remaining sample (sample 2), one tubes of blood 
(10mL) will be collected in a Vacutainer green top tube.   The samples will be mixed and 
immediately put on ice-bath.  Samples will be brought to Dr. Gandhi’s laboratory in the 
Tan zone (T1.3839).   The blood will be centrifuged and plasma will be separated, 
transferred to storage tubes and immediately frozen, and stored until analysis.  After 
removal of plasma, the blood cells will be resuspended in PBS and AML blasts will be 
isolated by Ficoll-Hypaque density-gradient centrifugation procedures.  Cells will be used 
for the following laboratory endpoints.   
 
NOTE:  We may not be able to do all studies in every patient.  This will be decided based 
on diagnosis and number of leukemia cells recovered from the peripheral blood sample.   
 
Effect of ex-vivo combination with Pim kinase inhibitors on AML blasts during CPX-351 
therapy:  Pre-treatment leukemia cells or cells isolated during CPX-351 therapy will be 
cultured ex-vivo with varying concentrations of Pim kinase inhibitors to evaluate the effect 
of combined DNA damage and anthracyclines with Pim kinase inhibition on AML blasts.  


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Induction of apoptosis will be measured using flow cytometric analysis of Annexin-V and 
PI binding assay.  Cells will be saved as pellets for future testing of phosphorylated and 
total protein levels in pim kinase signaling pathway.   
 
 


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19.0  APPENDIX 9: AML with MDS-Associated Karyotype  
 
With myelodysplastic syndrome-related cytogenetic abnormalities:  
 Complex karyotype (defined as 3 or more chromosomal abnormalities).  
 Unbalanced: -7 or del(7q); -5 or del(5q); i(17q) or t(17p); -13 or del(13q); 
del(11q); del(12p) or t(12p); del(9q); idic(X)(q13).  
 Balanced: t(11;16)(q23;p13.3); t(3;21)(q26.2;q22.1); t(1;3)(p36.3;q21.2); 
t(2;11)(p21;q23), t(5;12)(q33;p12); t(5;7)(q33;q11.2); t(5;17)(q33;p13); t(5; 
10)(q33;q21); t(3;5)(q25;q34)  


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20.0 
APPENDIX 10:  European Leukemia Net (ELN) Classification