Clinical trial NCT03335267
Conditions: Leukemia, Myeloid, Acute
Sponsor: Weill Medical College of Cornell University
Start date: 2017-10-19; Completion date: 2020-05-29
Enrollment: 30 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This is an open label study to assess the suitability of CPX-351 as first intensive therapy in elderly (age ≥60 years) patients with AML. Patients may have received prior AML treatment with non-intensive regimens, e.g. hypomethylating agents, low dose Ara C or lenolidomide, but may not have received intensive AML treatment with anthracyclines and/or cytarabine prior to enrollment on this trial. The outcome of elderly patients following intensive treatment with CPX-351 will be measured by clinical endpoints for efficacy and safety and by biological/functional response.

Detailed description:

Arms: arm 1: Dosing for first induction: CPX-351

• CPX-351 at 100u/m2 will be administered on study days 1, 3 and 5

Dosing for second induction:

• CPX-351 at 100 u/m2 will be administered on days 1 and 3

Dosing for consolidation:

• CPX-351 at 65 u/m2 will be administered on days 1 and 3
Interventions: intervention 1: CPX-351
Intervention descriptions: intervention 1: Cytarabine:Daunorubicin Liposome Injection

Protocol documents:
Prot_SAP_000.pdf: 
Phase II Trial of CPX (Cytarabine:Daunorubicin) Liposome 
Injection in Patients >/=60 Years of Age With AML Previously 
Untreated By Intensive Chemotherapy 
 
NCT Number: NCT03335267 
 
Document Date: 25-JUN-2018 


 
 
Protocol CEL11001 
 
PHASE II TRIAL OF CPX-351 (CYTARABINE:DAUNORUBICIN) LIPOSOME 
INJECTION IN PATIENTS WITH ACUTE MYELOID LEUKEMIA >60 YEARS 
OF 
AGE 
WHO 
HAVE 
NOT 
BEEN 
TREATED 
WITH 
INTENSIVE 
CHEMOTHERAPY  
 
Sponsor 
Weill Cornell Medicine 
 
Investigator Initiated Trial 
 
 
Principal Investigator 
Ellen Ritchie 
Weill Cornell Medical College 
525 East 68th Street 
New York, NY  10065 
646-962-2700 
Fax 646-962-5115 
ritchie@med.cornell.edu 
 
Co-investigators 
Gail Roboz 
Sangmin Lee 
Pinkal Desai 
Michael Samuel 
Jeffrey Ball 
 
Confidential 
 
Statistician 
Lynn Shemanski 
 
 
Version 4.0 dated 09-FEB-2018 
 
IND# 136240 
CPX-351 
 
 
 
 
 
 
 
 
 


 
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Not for Publication  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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PROTOCOL SYNOPSIS 
Title: 
PHASE II TRIAL OF CPX-351—(CYTARABINE:DAUNORUBICIN) LIPOSOME 
INJECTION IN PATIENTS WITH ACUTE MYELOID LEUKEMIA >60 YEARS 
OF 
AGE 
WHO 
HAVE 
NOT 
BEEN 
TREATED 
WITH 
INTENSIVE 
CHEMOTHERAPY  
 
Sponsor: Weill Cornell Medicine 
Investigator Initiated Trial:  
Principal Investigator: Ellen Ritchie 
Weill-Cornell Medical Center 
Objectives: 
Primary 
x To assess the suitability of CPX-351 as first intensive therapy in older (age ≥60 
years) patients with AML based on safety and efficacy.  The primary efficacy 
endpoint will be overall survival (OS).  The primary safety endpoint will be 30-day 
mortality.   
 
Secondary 
x To assess efficacy by response (CR, CRp, CRi, and CR+CRp+CRi)) rate, response 
duration, and Event Free Survival (EFS) 
x To assess safety by 30-day mortality, serious adverse events (SAE) and adverse 
event frequency and severity 
x To assess QOL using FACT-LEU 
x To assess the relationship of cognitive function to outcome using the Blessed 
Orientation-Memory-Concentration Test and the Montreal Cognitive Assessment 
x To confirm the safety of CPX-351 as a post-remission (consolidation) therapy 
x To supplement efficacy assessment by determining the rate of morphologic 
leukemia-free state (MLFS) 
 
 
Study Design: 
This is an open label study to assess the safety and efficacy of CPX-351 as first intensive 
therapy in elderly (age >60 years) patients with AML with companion cognitive function 
testing to determine whether this contributes to outcome in these patients. Patients may 
have received prior AML treatment with non-intensive regimens, e.g. hypomethylating 
agents, low-dose cytarabine, or lenolidomide, but may not have received intensive AML 
treatment with anthracyclines and/or infusional cytarabine prior to enrollment on this trial.  
The cohort will include 30 patients treated with single-agent CPX-351. These patients will 
be assessed for efficacy and safety. Quality of life will be assessed using the FACT-LEU 
in all patients.  Cognitive function will be assessed using the Blessed Orientation-Memory-
Concentration Test and the Montreal Cognitive Assessment. 
 
Study enrollment is expected to be completed within approximately 2 years.   
Sample Size: 
30 patients 


 
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Study Drugs: 
CPX-351 (cytarabine:daunorubicin) Liposome Injection 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 shown to act synergistically in pre-
clinical studies. The liposome membrane is composed of a 7:2:1 molar ratio of 
distearoylphosphatidylcholine, distearoylphosphatidylglycerol and cholesterol.   
 
CPX-351 is provided as a sterile, pyrogen-free, purple, lyophilized product in 50 mL glass, 
single-use vials.  Each 50 mL vial after reconstitution contains 20 mL of CPX-351 (5 
units/mL). Each unit (u) contains 1.0 mg cytarabine and 0.44 mg daunorubicin base in 
liposomes suspended in sucrose. Product is stored at 5˚ ± 3oC. 
 
 
Efficacy Variables & Analysis: 
 
x To assess the suitability of CPX 351 in older patients with AML and the 
relationship of cognitive function to outcome 
x Response rate (CR, CRp, CRi, and CR+CRp+CRi), (morphologic, cytogenetic and 
molecular response) 
x Response duration (relapse-free survival) 
x EFS 
x Evaluation of QOL of CPX treated patients 
x Evaluation of relationship of cognitive function to outcome in treated patients 
 
 
 
Safety Variables & Analysis: 
Patients will be monitored for all clinical adverse events as well as laboratory evaluations. 
x Induction Mortality:  assessed at Day 30 and 60; therapies may be changed after 30 
days.  
x Serious Adverse Events 
x Adverse Events: Grades 1-5 and Grades 3-5 
x Laboratory Evaluations 
o Routine hematology (CBC+diff+Platelet count) and chemistry (with LDH) 
o Time to hematologic recovery and proportion with prolonged cytopenias (≥ 
56 days) 
x Cardiac Evaluations 
o Cardiac AEs: Grades 1-5 and Grades 3-5 
o ECG changes (pre-dose for each course, and at the end of each course) 
o LVEF changes (pre and post treatment) 
 
Other Variables & Analysis: 
Quality of Life Assessment:  FACT-Leu will be used to assess patients at the start of 
treatment and one month after treatment completion.  


 
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Cognitive Assessment:  The Blessed Orientation-Memory-Concentration Test and the 
Montreal Cognitive Assessment Mini will be administered at the start of treatment and one 
month after completion of therapy.  
Cardiac Assessments: All ECG and ECHO/cardiac MRI assessments will be obtained and 
read locally for patient care. 
 
 
 


 
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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 
BID 
 
Twice daily 
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 Remission 
CRi 
 
Complete Remission with incomplete hematologic recovery 
CRp 
 
Complete remission with incomplete platelet recovery 
CRF 
 
Case Report Form 
CMMoL 
Chronic Myelomonocytic Leukemia 
CTCAE 
Common Terminology Criteria for Adverse Events 
d 
 
day 
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 
FDA  
Food and Drug Administration 
FISH  
Fluorescence in situ Hybridization 
g 
 
gram(s) 


 
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GCP  
Good Clinical Practice 
HCl 
 
Hydrogen Chloride 
HIPAA 
Health Information Protection and Portability Act 
HIV 
 
Human Immunodeficiency Virus 
HMA  
Hypomethylating Agent 
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 
MLS  
Morphologic Leukemia-free State 
MRU  
Medical Resource Usage 
MTD  
Maximum Tolerated Dose 
MUGA 
Multiple Gated Acquisition scan 
mw 
 
molecular weight 
N 
 
Number, Population 
NF 
 
National Formulary 
OS 
 
Overall Survival 
PD 
 
Persistent Disease 
PhEur  
European Pharmacopoeia 
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 


 
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u 
 
Units 
μL 
 
Microliter 
ULN  
Upper Limits of Normal 
USP 
 
United States Pharmacopeia 
V 
 
Volume 
WHO  
World Health Organization 
 


 
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TABLE OF CONTENTS 
1 General Information .....................................................................................................11 
2 Background Information ..............................................................................................11 
2.1 Acute Myeloid Leukemia in the Elderly and its Treatment ..................................11 
2.2 CombiPlex Technology and CPX-351 ...............................................................11 
2.3 CPX-351 Product Label ........................................................................................12 
2.4 Rationale for CPX-351 use in Patients suitable for non-intensive therapy ..........12 
2.5 Rationale for Assessment of Non-Hematologic Factors that Influence Outcome 
in Older AML Patients ........................................................................................14 
3 Study Objectives and Rationale ...................................................................................16 
3.1 Primary Objectives................................................................................................16 
3.2 Secondary Objectives............................................................................................16 
4 Study Design ................................................................................................................16 
4.1 Patient Recruitment ...............................................................................................16 
4.2 Patient Sample Size...............................................................................................17 
4.3 Induction ...............................................................................................................17 
4.4 Repeat of Induction ...............................................................................................17 
4.5 Consolidation Therapy ..........................................................................................17 
4.6 Follow-up Phase....................................................................................................18 
4.7 Study Modification/Discontinuation .....................................................................18 
5 Selection and Withdrawal of Patients ..........................................................................18 
5.1 Study Population ...................................................................................................18 
5.2 Withdrawal of Patients ..........................................................................................20 
6 Treatment of Patients ...................................................................................................20 
6.1 Pre-Treatment Evaluations....................................................................................20 
6.2 Evaluation during Treatment Phase ......................................................................22 
6.3 Early Termination or End of Treatment Phase .....................................................23 
6.4 Evaluation during Follow-up Phase ......................................................................24 
7 Drug Administration ....................................................................................................24 
7.1 Drug Preparation and Administration ...................................................................25 
7.2 Drug Accountability..............................................................................................26 
7.3 Dose Reductions and Delays ................................................................................26 
7.4 Concomitant Therapy............................................................................................27 
7.5 Duration of Protocol Treatment ............................................................................28 
8 Assessment of Efficacy ................................................................................................28 
8.1 Efficacy Population ...............................................................................................28 
8.2 Overall Survival ....................................................................................................28 
8.3 Event-free Survival ...............................................................................................28 
8.4 Response Assessment Criteria ..............................................................................29 
8.5 Remission Duration ..............................................................................................30 
8.6 Morphologic Leukemia-free State ........................................................................30 
8.7 Stem Cell Transplant.............................................................................................30 
9 Assessment of Safety ...................................................................................................30 
9.1 Safety Population ..................................................................................................30 
9.2 Adverse Events .....................................................................................................30 
9.3 Cardiac Toxicity Monitoring ................................................................................33 


 
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9.4 Laboratory Data ....................................................................................................32 
10 
Other Evaluations....................................................................................................33 
11 Statistical Considerations ...........................................................................................34 
11.1 Primary and Secondary Endpoints ......................................................................35 
11.2 Sample Size and Power Justification for Primary Endpoint ...............................35 
11.3 Analysis Populations ...........................................................................................36 
11.4 Analysis of Primary Endpoints ...........................................................................36 
11.5 Analysis of Secondary Endpoints .......................................................................36 
11.6 Safety Analysis ...................................................................................................36 
12 Administrative, Regulatory and Ethical Issues ..........................................................36 
12.1 Direct Access to Source Documents ...................................................................37 
12.2 Study Monitoring and Quality Inspections/Audits .............................................38 
12.3 Ethics...................................................................................................................38 
12.4 Adherence to the Protocol ...................................................................................38 
12.5 Protocol Revisions ..............................................................................................39 
12.6 Retention of Patient Records and Study Files.....................................................39 
12.7 Patient Confidentiality ........................................................................................39 
12.8 Informed Consent................................................................................................40 
12.9 Publication Policy ...............................................................................................41 
13 References ..................................................................................................................42 
14 APPENDIX 1: Patient Evaluation Flow Sheet – Treatment Phase ...........................44 
15 APPENDIX 2: Patient Evaluation Flow Sheet –Follow-up ......................................45 
16 APPENDIX 3: Performance Status – ECOG.............................................................46 
17 APPENDIX 4: Common Terminology Criteria for Adverse Events V4.0 
(CTCAE) ............................................................................................................................47 
18 APPENDIX 5:  Elements of the HIPAA Privacy Rule Authorization ......................48 
19 APPENDIX 6:  Declaration of Helsinki ....................................................................49 
20 APPENDIX 7: Anthracyclines Equivalents Guidelines ............................................50 
 
 


 
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1 
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 
Background Information 
2.1 
Acute Myeloid Leukemia in the Elderly and its Treatment 
Acute Myeloid Leukemia in older patients is a poor prognosis disease.  While progress in 
supportive care, such as better antibiotic and antifungal therapy, have improved outcomes 
for younger persons with this disease, the overall survival of older patients has not changed 
through the years.  The reasons for the poorer prognosis of elderly patients are multifocal 
and include disease biology, comorbid illness, geriatric syndromes and social factors. 
Intensive treatment and consolidation chemotherapy can be difficult to administer to an 
older population. The intensiveness of treatment can be difficult to tolerate in older patients 
with other comorbid illnesses and geriatric syndromes. Physicians may modify doses to 
standard regimens to decrease presumed toxicities and inadvertently decrease the efficacy 
of treatment.   Once patients have recovered from induction chemotherapy, they may be 
too weak to withstand subsequent cycles of consolidation therapy and never achieve a deep, 
MRD negative, response to treatment and a durable response to therapy.   
 
2.2 
CombiPlex Technology and CPX-351 
Combination chemotherapy regimens have traditionally been designed empirically on the 
basis of tolerability.  However, in vitro, where the 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.15  When individual free 
drugs are administered, each agent is handled differently by the body, resulting in varying 
distribution of the individual drugs to tumor sites which can result in drug ratios that are 
suboptimal or ineffective.  Jazz’s technology is based on the 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. 
 
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 


 
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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 sterile 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/PhEur 
243 
100 mg 
1.0 mg 
Daunorubicin HCl USP/ PhEur (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 
Sucrose, NF 
342 
2054 mg 
20.54 mg 
 
2.3 
CPX-351 Product Label 
CPX-351 (cytarabine:daunorubicin) LIPOSOME FOR INJECTION 
 
100 units/Vial 
Each unit contains 1.0 mg (±10%) Cytarabine and 0.44 mg (±10%) Daunorubicin (base) in liposomes 
containing DSPC, DSPG and cholesterol.  Also contains copper as copper gluconate, triethanolamine and 
sucrose. 
Store refrigerated at 5qC (r3qC) in an upright position. 
FRAGILE: Do not drop 
Caution: New Drug – Limited by Federal Law to Investigational Use 
Manufactured for 
Jazz Pharmaceuticals, Inc., 200 PrincetonSouth Corporate Center 
Ewing, NJ 08628 
 
Lot #______________ 
 
 
Expiration Date:_________________ 
 
 
2.4 
Rationale for CPX-351 use in Patients suitable for non-intensive therapy 
Three clinical studies have been completed with CPX-351 and a detailed presentation is 
available in the Investigator’s Brochure.  A brief summary of observations pertinent to 
treatment of AML patients, particularly those with co-morbidities and patients whose age 
tends of limit treatment to non-intensive regimens is discussed below.   
 
The rationale for using CPX-351 to treat older patients thought to be unsuitable for 
treatment with intensive chemotherapy is rooted in the characteristics of AML in older 
patients, the pharmacology and mechanism of CPX-351 action, and clinical observations 


 
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of the dose-response and safety of CPX-351.  It is well known that both the incidence of 
AML and the risk of AML resistance to chemotherapy increase in an age related manner.   
Younger patients, particularly those younger than 45 years of age, have higher response 
rates, lower rates of primary refractory disease, and longer survival than patients over the 
age of 70.  This is associated with an age related rising risk of adverse cytogenetics and 
multidrug resistance phenotype.  CPX-351 packages cytarabine and daunorubicin within 
liposomes at a 5:1 molar ratio, found in vitro to maximize drug synergy and minimize 
antagonism.   CPX-351 liposomes are stable and persist in the plasma for extended periods 
of time leading to cytarabine and daunorubicin half-lives of approximately 24 hours.  This 
result suggests that CPX-351 may be effective for both in rapidly and slowly cycling 
leukemias.  Exposure of leukemia cells from cell lines and circulating blast cells from 
patients demonstrate direct entry of CPX-351 liposomes and subsequent intracytoplasmic 
release of drug.  These observations suggest that effective treatment may be possible even 
in patients with multidrug resistance phenotype due to increased P-glycoprotein 
expression.  Clinical observations of CPX-351 safety and efficacy come almost exclusively 
from patients considered fit for intensive chemotherapy and indicate a safety profile that is 
very similar to that of 7+3 chemotherapy except for more prolonged myelosuppression.  In 
the clinic the dose-toxicity/response curve appears to be shallow with most of the grade 
3/4 adverse events associated with prolonged myelosuppression rather than severe non-
hematologic toxic events.   
 
Taken together these findings suggest that treatment at the MTD (100 units/m2/dose on day 
1, 3, and 5) is likely to be feasible, even in patients of advanced age and with some co-
morbidities because the toxicities of treatment are mostly confined to myelosuppression 
and because supportive care with anti-infective prophylaxis is effective.  It is thought that 
full dose treatment is likely to maximize the probability of response and that response is 
possible even in patient populations enriched for adverse cytogenetics and multi-drug 
resistance phenotype.  The mode of action of CPX-351 should enable rapid clearance of 
leukemia from the peripheral blood and bone marrow with most patients achieving 
complete response after one induction course of treatment with recovery from neutropenia 
usually within 5-7 weeks.   
 
Treating an AML patient population usually considered suitable for non-intensive 
regimens with CPX-351 is not without risk.  This patient population is expected to be older 
with some baseline comorbidities and cannot be expected to be as resilient as the fit older 
population treated in Phase II with CPX-351.  In that study induction mortality was 
assessed at Day 30 and 60 and a lower rate of early mortality was observed for CPX-351 
treated patients (4/85, 4.7% vs. 6/41, 14.6% at 60 days, p=0.053).  This result is the best 
evidence that CPX-351 treatment at full dose is likely to be acceptably safe and suggests 
that rapid clearance of leukemia due to full dose treatment may assist in reducing the 
contribution of leukemia to the early death rate. 
 
The greater myelosuppression and more prolonged neutropenia following CPX-351 
treatment was associated with a higher frequency of febrile neutropenia (63.5% vs. 51.2%), 
grade 3 and 4 infections (e.g. bacteremia (42.4% vs. 22%)), and bleeding events (e.g. 
epistaxis (36.5% vs. 19.5%)).  In spite of this the lower mortality rate at 30 and 60 days 


 
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indicates that CPX-351 was safe and strongly suggests that anti-infection prophylaxis was 
effective in preventing infection-related deaths in spite of risks of myelosuppression.  
 
Most recently, a phase 3 trial comparing CPX-351 to standard induction chemotherapy 
with daunorubicin and cytarabine in older patients aged 60-75 with high risk AML was 
completed.  The Phase 3 trial compared to the standard of care regimen of cytarabine and 
daunorubicin known as 7+3. 
 
The median overall survival for patients treated with CPX-351 in the study was 9.56 
months compared to 5.95 months for patients receiving 7+3, representing a 3.61 month 
improvement in favor of CPX-351. The hazard ratio (HR) was 0.69 (p=0.005) which 
represents a 31% reduction in the risk of death versus 7+3. The percentage of patients alive 
12 months after randomization was 41.5% on the VYXEOS arm compared to 27.6% on 
the 7+3 arm. The percentage of patients alive 24 months after randomization was 31.1% 
on the CPX-351 arm compared to 12.3% on the 7+3 arm.  
 
Event-free survival was also statistically significant in favor of CPX-351. The HR was 0.74 
(p-value=0.021). The median event-free survival was 2.53 months in the CPX-351 arm 
compared to 1.31 months in the 7+3 arm.  
 
CPX-351 also demonstrated a statistically significant improvement in induction response 
rate (CR+CRi of 47.7% versus 33.3%; p=0.016) and this significance was maintained for 
the analysis of CR alone (CR of 37.3% versus 25.6%, p=0.040).  
 
Thirty-four percent of CPX-351 treated patients received a stem cell transplant (SCT) 
compared to 25% of 7+3 treated patients. In a landmark survival analysis of patients 
receiving a SCT, CPX-351 patients had significantly improved survival post-transplant 
(HR was 0.46 (p-value=0.0046)). The median overall survival had not been reached in the 
CPX-351 treated patients compared to 10.25 months in the 7+3 treated patients. 
 
Thirty-day and sixty-day all-cause mortality favored CPX-351. Thirty-day mortality was 
5.9% compared to 10.6% and sixty-day mortality was 13.7% versus 21.2%. 
Grade 3-5 non-hematologic and hematologic adverse events were similar between the 
VYXEOS and 7+3 arms. 
 
On the basis of the phase 3 trial data, CPX 351 was approved by the FDA for treatment of 
older patients aged 60-75 with prior myeloid hematologic disease. 
 
 
2.5 Rationale for Assessment of Non-Hematologic Factors that Influence 
Outcome in Older AML Patients 
 
Treatment outcome of older AML patients is closely linked to the age of the patient.  
Data from the Swedish Acute Leukemia Registry confirms that patient outcome worsens 
with increasing age.  Presumably, the older the age of the patient, the more complicated 
the disease: the biology of the disease is more severe in the elderly and patients have more 


 
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difficulty tolerating the consequences of chemotherapy treatment. Determining the fitness 
of an older patient for chemotherapy treatment can be quite challenging. The biologic age 
of an older person may differ significantly from the numeric age: there can tremendous 
variability in the fitness and function of older people at any given chronologic age after age 
60. There is no scientific algorithm to assess the actual biologic age of an older adult. 
Adverse disease related prognostic factors are more easily measured. Older patients are 
much more likely to have adverse cytogenetics and unfavorable molecular mutations.  
Older patients have a higher rate of multi-drug resistant phenotypes and antecedent 
hematologic disorders. The patient-specific prognostic factors such as severity of comorbid 
illness, fitness and social support are more difficult to quantify.  Many older patients have 
comorbid illnesses that may or may not be apparent at the time of leukemia diagnosis.  
Drug metabolism is different in older patients and is influenced by diminished renal and 
hepatic function that also may not be clinically apparent at the time of diagnosis.  The 
elderly have deficits in immune function that make the tolerance of infections less robust. 
Patients often have diminished physical conditioning and endurance that may not be visible 
on routine physical examination.  In addition, numerous psychosocial factors influence the 
outcome of older adults with AML including cognitive decline, social isolation, and lack 
of a caretaker.  The patient-related prognostic factors are more difficult to measure and 
their significance may not emerge until after treatment for their leukemia has already been 
given.   
Through using the Comprehensive Geriatric Assessment (CGA) to evaluate elderly 
patients with AML, studies have shown that there appears to be a relationship between 
cognitive function and outcome in older patients treated for AML.  This study will explore 
this relationship further by implementing cognitive testing to determine this relationship in 
patients treated with CPX 351. Klepin et al. conducted a study of 74 older AML patients 
treated with intensive daunorubicin/cytarabine induction and used the CGA to assess 
patients for chemotherapy fitness. This study demonstrated that impaired cognition 
(defined as <77 by the Modified Mini-Mental State Exam) and impaired objective physical 
function (defined as an SPPB<9) predicted a worse overall survival in older adults with 
AML.   Ritchie et al. (unpublished data) completed an analysis using the CGA to predict 
overall survival in patients aged 60 or older receiving induction therapy for AML with 
either standard induction with daunorubicin and cytarabine or low intensity induction with 
decitabine. One hundred and twenty-six patients were enrolled.  Cognitive function as 
measured by the Blessed Orientation-Memory-Concentration Test. Patients with impaired 
cognitive function had worse overall survival in univariate analysis but in multivariate 
analysis this variable lost significance. A small percentage of patients with normal 
cognitive function on the Blessed Test were given the Montreal Cognitive Assessment and 
were impaired by measurement on this test.  The Blessed may not have been sensitive 
enough to stratify the cognitive deficits in the population tested.  Alternatively, the level of 
family and social support given to these patients may be more important than cognitive 
function in the survival of older patients with AML.  Given that Klepin’s analysis of 
patients suggested that cognitive function is important to the survival of older patients with 
AML and that more sensitive testing may be needed to determine the level of cognitive 
impairment in this population, cognitive testing using both the Blessed and the MOCA will 
be used in this study to determine whether this is an important factor in the survival of older 
patients with AML.  


 
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3 
Study Objectives and Rationale 
3.1 
Primary Objectives 
x 
To assess the feasibility of CPX-351 as first intensive therapy in elderly (age ≥60 
years) patients with AML based on safety and efficacy and to evaluate cognitive 
function in these patients and its relationship to outcome.  CPX-351 alone will be 
declared feasible if one or two induction courses (3 doses or 5 doses) can be 
delivered to patients with acceptable 30-day mortality. The primary efficacy 
endpoint will be overall survival (OS).  The primary safety endpoint will be early 
mortality defined as 30-day mortality.   
 
3.2 
Secondary Objectives 
x To assess efficacy by response (CR, CRp, CRi, and CR + CRp + CRi) rate and  
duration and Event Free Survival (EFS) 
 
x 
To assess safety by 30-day mortality, serious adverse events (SAE) and adverse event 
frequency and severity  
 
x 
To assess QOL using FACT-LEU  
 
x 
To assess the relationship of cognitive function to outcome using the Blessed 
Orientation-Memory-Concentration Test and the Montreal Cognitive Assessment  
 
x To confirm the safety and practicality of CPX-351 as consolidation therapy 
 
x To supplement efficacy assessment by determining the rate of morphologic 
leukemia-free state (MLFS) 
 
4 
Study Design 
This is an open label study to assess the suitability of CPX-351 as first intensive therapy in 
elderly (age ≥60 years) patients with AML. Patients may have received prior AML 
treatment with non-intensive regimens, e.g. hypomethylating agents, low dose Ara C or 
lenolidomide, but may not have received intensive AML treatment with anthracyclines 
and/or cytarabine prior to enrollment on this trial.  The outcome of elderly patients 
following intensive treatment with CPX-351 will be measured by clinical endpoints for 
efficacy and safety and by biological/functional response.   
 
4.1 
Patient Recruitment 
All patients will be screened for study suitability 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. 
 


 
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4.2 
Patient Sample Size 
Early mortality (30 day mortality) in newly diagnosed fit older (age > 60 years) patients 
with AML initially treated with standard induction therapy with daunorubicin and 
cytarabine is approximately 20%.  Older patients with AML who are less fit, particularly 
those initially treated with non-intensive regimens, are expected to have 60-day mortality 
of approximately 40%.  After 15 patients have been treated and followed for 30 days or 
more, early mortality will be assessed.  If 30-day mortality exceeds 20% (>3 of the initial 
15 patients), all further accrual will stop.  Subsequent enrollment after the first 15 subjects 
should ideally resume after the safety analysis is complete, however recognizing the acute 
nature of AML, it might not be possible to deny treatment to subjects in screening for 
ethical reasons sufficiently long to evaluate safety or efficacy. In other words, if the 30-
day mortality for the preceding patients is less than 20%, study accrual will continue during 
the DSMB’s safety analysis. 
 
 In the event that more than 15 subjects have enrolled before the safety analysis, only the 
first 15 subjects dosed will be informative for determining need for dose reduction. 
 
Study enrollment will be completed within approximately 2 years.   
 
4.3 
Induction 
Following registration, patients will be monitored closely for response and safety. 
Depending on the type and extent of response as well as toxicity, the patient may continue 
on to consolidation therapy, receive a second induction, or be discontinued from the 
Treatment Phase and monitored in the Follow-up Phase. 
 
Dosing for first induction: CPX-351 alone 
x 
CPX-351 at 100u/m2 will be administered on study days 1, 3 and 5 
 
4.4 
Repeat of Induction 
Patients achieving aplasia/hypoplasia (<5% blast count) will not receive second inductions.  
Patients with reduced tumor burden and evidence of persistent leukemia who remain fit for 
additional intensive chemotherapy can be given second inductions up to 60 days (measured 
from day 1 of chemotherapy treatment) after the first induction treatment date.  
 
Patients unable to achieve a response (CR, CRp, or CRi) after up to 2 inductions are 
discontinued from further treatment and followed for survival. 
 
Dosing for second induction: 
x 
CPX-351 at 100 u/m2 will be administered on days 1 and 3 
 
4.5 
Consolidation Therapy 
 
Only patients with confirmed response (CR or CRp or CRi) and who remain fit for 
additional chemotherapy are eligible for chemotherapy consolidation.  Investigators may 


 
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use post remission therapy of their choice or they may choose to use CPX-351.  Before 
consolidation treatment can begin, patients need a repeat echocardiogram and labs to 
evaluate renal and liver function and must fulfill eligibility criteria initiation of treatment.   
For patients given CPX-351 post remission therapy: prior to starting consolidation, LVEF 
must be documented to be ≥50% and patients must have recovered to ANC >500/μL and 
platelets >50,000/μL within 56 days after last dose of CPX-351.  A second consolidation 
cycle is permitted provided the first consolidation course was well tolerated and repeat 
echocardiogram shows an LVEF > 50% and ANC and platelets have recovered within 56 
days of the start of the last consolidation cycle.  Up to 2 consolidation courses are permitted.  
Scheduling and dose of consolidation treatment may be adjusted depending on degree and 
rate of patient recovery. 
 
Dosing for consolidation: 
x 
CPX-351 at 65 u/m2 will be administered on days 1 and 3 
 
4.6 
Follow-up Phase 
Patients will be followed at monthly intervals or more frequently depending on clinical 
circumstances until start of the next salvage treatment, death or for 1 year from date of 
enrollment. Patients alive and in remission after 1 year will be followed annually or more 
frequently depending on clinical circumstances for up to 5 years from enrollment.  For EFS 
evaluation, events include: documentation of persistent AML after induction, relapse after 
achievement of CR/CRp/ CRi, or death.  Bone marrow assessments will be performed at 
any time during follow up when recurrent cytopenias raise the suspicion of AML relapse.  
After documentation of persistent leukemia or relapse, follow-up for OS will continue. At 
the start of HSCT or non-protocol AML treatment of any sort or 30-days following the last 
dose, whichever occurs first, AE data collection will stop.   
 
4.7 
Study Modification/Discontinuation 
Any modifications to the study will be documented in a revised protocol with a new 
assigned version.  The revised protocol will have an appendix which will detail the 
revisions to the document. 
 
5 
Selection and Withdrawal of Patients 
5.1 
Study Population 
5.1.1 Inclusion criteria 
5.1.1.1 Ability to understand and voluntarily give informed consent 
5.1.1.2 Age≥60 years at the time of study treatment 
5.1.1.3 Pathological diagnosis of AML according to WHO criteria (with >20% blasts in 
the peripheral blood or bone marrow) including: 
5.1.1.4 De novo AML with normal karyotype or adverse karyotypes (including patients 
with karyotypic abnormalities characteristic of MDS) 
5.1.1.5 Secondary AML: transformed from prior MDS or MPN, confirmed by bone 
marrow documentation of prior antecedent hematologic disorder 


 
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5.1.1.6 Therapy-related AML: t-AML, requires documented history of prior cytotoxic 
therapy or ionizing radiotherapy for an unrelated disease 
5.1.1.7 Performance status >50% KPS, ECOG 0-2 
5.1.1.8 Laboratory values fulfilling the following: 
5.1.1.9 Serum creatinine < 2.5 mg/dL 
5.1.1.10 Serum total bilirubin < 2.5 mg/dL,  
5.1.1.11 Serum alanine aminotransferase or aspartate aminotransferase < 3 times the ULN  
5.1.1.12 Patients with elevated liver enzymes and serum creatinine values secondary to 
AML are eligible after discussion with PI 
5.1.1.13 Cardiac ejection fraction ≥ 50% by echocardiography, MUGA, or Cardiac MRI 
5.1.1.14 Patients with history of second malignancies in remission may be eligible if there 
is clinical evidence of disease stability off cytotoxic chemotherapy, documented 
by imaging, tumor marker studies, etc., at screening. Patients maintained on long-
term non-chemotherapy treatment, e.g., hormonal therapy, are eligible. 
5.1.2 Exclusion Criteria 
5.1.2.1 Acute promyelocytic leukemia [t(15;17)] 
5.1.2.2 Clinical or morphologic evidence of active CNS leukemia 
5.1.2.3 Prior intensive chemotherapy for AML with anthracycline/cytarabine-based 
regimens and/ or prior HSCT. Patients may have been treated with commercially 
available or investigational hypomethylating agents (e.g. decitabine, azacitidine, 
SGI-110), lenalidomide, or low-dose cytarabine (not to exceed 20 mg/m2 daily 
for 14 days for ≤ 6 cycles) 
5.1.2.4 Prior treatment including HMA, systemic chemotherapy, surgery, or radiation 
therapy must have been completed at least 7 days before start of study treatment 
or after discussion with PI.  Treatment with investigational agents must have been 
completed at least 14 days prior to study drug treatment.  Hydroxyurea is 
permitted for control of blood counts before the start of study treatment. Toxicities 
associated with prior therapies must have recovered to grade 1 or less prior to start 
of study treatment. 
5.1.2.5 Patients with prior cumulative anthracycline exposure of greater than 368 mg/m2 
daunorubicin (or equivalent). 
5.1.2.6 Any serious medical condition, laboratory abnormality or psychiatric illness that 
would prevent obtaining informed consent 
5.1.2.7 Patients with myocardial impairment of any cause (e.g. cardiomyopathy, ischemic 
heart disease, significant valvular dysfunction, hypertensive heart disease, and 
congestive heart failure) resulting in heart failure by New York Heart Association 
Criteria (Class III or IV staging) 
5.1.2.8 Active or uncontrolled infection. Patients with an infection receiving treatment 
(antibiotic, antifungal or antiviral treatment) may be entered into the study but 
must be afebrile and hemodynamically stable for ≥72 hrs. 


 
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5.1.2.9 Patients with current or recent evidence of invasive fungal infection (blood or 
tissue culture); patients with recent fungal infection must have a subsequent 
negative cultures to be eligible  
5.1.2.10 Known HIV (new testing not required) or evidence of active hepatitis B or C 
infection (with rising transaminase values) 
5.1.2.11 Hypersensitivity to cytarabine, daunorubicin or liposomal products 
5.1.2.12 History of Wilson’s disease or other copper-metabolism disorder 
5.1.2.13 History of prior bone marrow or solid organ transplantation 
 
5.2 
Withdrawal of Patients 
Patients will be discontinued from the Treatment Phase and enter the Follow-up Phase for 
assessment of efficacy endpoints under the following circumstances: 
x 
Completion of Treatment Phase 
x 
Persistent disease:  lack of a response to treatment  
x 
Relapsed disease:  re-appearance of disease following CR, CRp, or CRi 
x 
Unacceptable toxicity 
x 
Patient non-compliance with protocol 
x 
Administration of non-protocol chemotherapy 
x 
Concurrent illness which, in the judgment of the investigator, effects assessment of 
clinical status to a significant degree, and requires discontinuation of protocol 
therapy. 
 
Any adverse event that, in the judgement of the investigator, may cause severe or 
permanent harm if the study intervention is continued will result in subject discontinuation 
from the study.  Any treatment related grade 3 or higher non-hematological toxicity that 
does not resolve to grade 2 within 14 days of receiving treatment for the event will result 
in subject discontinuation from the study. 
 
During any phase of the study, if a patient requests to stop treatment and/or follow-up, the 
patient will be discontinued and no further information will be collected.  The patient will 
be classified as withdrawal of consent.   
 
6 
Treatment of Patients 
See APPENDIX 1: Patient Evaluation Flow Sheet 
 
6.1 
Pre-Treatment Evaluations 
After providing informed consent, eligible patients are registered to the study.  
 
The date of the first test or exam will be considered as the date of the screening visit. 


 
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Procedure  
Evaluation 
Timing 
Informed Consent 
It should be personally signed and dated by 
the patient. The responsible 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 induction 
1, day 1 visit is ≥30 days the 
patient must sign another 
ICF. 
 
Demography 
Date of birth, sex, race, ethnicity 
Within 14 days prior to  
Registration 
Medical History 
Complete medical history 
x 
Resolved conditions 
x 
Intermittent conditions 
x 
Concurrent illnesses 
x 
Previous surgeries 
Within 14 days prior to 
registration 
Leukemia History 
Leukemia, MDS, and MPN History 
Prior chemotherapies 
Prior leukemia treatment 
Within 14 days prior to 
registration 
Physical Exam 
Objective review of body systems  
Height 
Weight 
BSA 
ECOG Performance Status 
Within 3 days prior to 
registration 
Vital Signs 
Heart rate 
Blood pressure 
Temperature 
Respiratory rate 
Within 3 days prior to 
registration 
Hematology 
Hemoglobin 
White Blood Count 
Platelets 
Differential Count 
Within 1 day prior to 
registration 
Biochemistry 
 
BUN 
Creatinine 
Uric Acid 
Electrolytes (Sodium, Potassium, Chloride) 
Bilirubin 
Alkaline phosphatase 
AST or ALT 
LDH 
Protein 
Calcium 
Albumin 
Glucose 
Within 1 day prior to 
registration 
Urinalysis 
pH 
specific gravity 
glucose 
protein 
ketones 
blood 
Within 3 days prior to 
registration 
Questionnaires 
MOCA, Blessed, FACT-Leu 
Within 7 days prior to 
registration 


 
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Procedure  
Evaluation 
Timing 
Bone 
Marrow 
Aspiration/Biopsy 
Morphology 
 
Within 14 days prior to 
registration 
Diagnostic Imaging 
Chest X-ray or Chest CT 
 
Within 28 days prior to 
registration 
Diagnostic Imaging 
Echocardiography, MUGA or cardiac MRI 
scan  
Within 14 days prior to 
registration 
Electrocardiogram (ECG) 
ECG 
Within 14 days prior to 
registration  
Cytogenetics  
 
Cytogenetics (performed locally) 
Within 3 months prior to 
registration 
Molecular Studies 
Central or local laboratory evaluation of 
CEBPA, FLT3, and NPM1 (either PB or 
BM) 
Within 3 months prior to 
registration 
 
 
6.2 
Evaluation during Treatment Phase 
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 4.4).  Induction is completed when a patient has 
x 
A confirmed CR (see section 8.4) 
x 
A CRp or CRi (see section 8.4) and is to begin consolidation treatment before 
hematologic count recovery 
x 
Persistent/recurrent disease (PD/relapse) 
x 
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 up to 2 consolidation treatments.  
 
Procedure 
Evaluation 
Timing 
Physical Exam 
Objective review of body systems  
Weight 
BSA 
Days 14 and 42 
Vital Signs 
Heart rate 
Blood pressure 
Temperature 
Respiratory rate 
Days 14 and 42 
Hematology 
Hemoglobin 
White Blood Count 
Platelets 
Differential Count 
Days 1, 3, 5, 7±3, 10±1, 14±2, then 
weekly (±2days) until whichever occurs 
last: 
- Day 42  
- peripheral blood count recovery 
- removed from Treatment Phase 


 
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Procedure 
Evaluation 
Timing 
Biochemistry 
BUN 
Creatinine 
Uric Acid 
Electrolytes (Sodium, Potassium, 
Chloride) 
Bilirubin 
Alkaline phosphatase 
AST or ALT 
LDH 
Protein 
Calcium 
Albumin 
Glucose 
Days 1, 3, 5, 7±3, 10±1, 14±2, then 
weekly (±2days) until whichever occurs 
last: 
- Day 42  
- peripheral blood count recovery 
- removed from Treatment Phase 
 
 
 
 
 
 
 
Bone Marrow Evaluation 
Morphology 
 
 
As needed to confirm response or 
determine antileukemic effect and need 
for second induction. 
Cytogenetics  
Molecular Studies 
Cytogenetics  
Molecular Studies  
Required in patients with a CR, CRp, or 
CRi with positive baseline findings 
(perform at the time of bone marrow 
assessment for CR or CRi). Optional in 
patients 
with 
normal 
baseline 
cytogenetics/molecular studies. 
Diagnostic Imaging 
Echocardiography, 
MUGA 
or 
cardiac MRI scan 
After the last induction and before each 
consolidation cycle.  
Questionnaires 
MOCA, Blessed, FACT-Leu 
Days 7±3, 42±3, Induction 2 Day 1(±3) 
Adverse Events/Toxicity 
CTCAE v.4 assessment 
Continual assessment starting from the 
first dose until 30 days after completion 
of the Treatment Period. 
Concomitant Medications 
 
Continual assessment during Treatment 
Period. 
 
6.3 
Early Termination or End of Treatment Phase 
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 
Diagnostic Imaging 
Echocardiography, 
MUGA 
or 
cardiac MRI 
Within 30 days after discontinuation if a 
study has not been performed since last 
treatment or before the initiation of any 
non-protocol treatment 
Electrocardiogram (ECG) 
ECG 
Within 30 days after discontinuation 
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) 
Response Assessment 
Best Response 
Reason for End of Treatment 
Within 30 days after discontinuation 
Questionnaires 
MOCA, Blessed, FACT-Leu 
Within 30 days after discontinuation 
 


 
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6.4 
Evaluation during Follow-up Phase 
The following evaluations are completed during the follow-up phase: 
Procedure 
Evaluation 
Timing 
Patient status report 
Survival status  
 
Once monthly until 1 year from first 
treatment. After the first year record only 
the date of death or alive at Year 5 (Day 
1825).  
Relapse status 
New anti-leukemic therapies 
Once monthly until 1 year from first 
treatment. After the first year record only 
the date of relapse and any new leukemic 
therapies. 
Hematology 
Hemoglobin 
White Blood Count 
Platelets 
Differential Count 
Once monthly until 1 year from first 
treatment.  After the first year record only 
the date of relapse and any new leukemic 
therapies. 
Bone Marrow Evaluation 
Morphology 
 
For patients in CR or CRi perform at any 
time that there is a suspicion of relapse. 
Following the first year of follow up, 
record relapse information, including any 
bone marrow evaluations.  Not required 
following relapse. 
Diagnostic Imaging 
Echocardiography, 
MUGA 
or 
cardiac MRI 
If last treatment phase LVEF was reduced 
>10% from baseline and is less than 50% 
repeat every 3 months until LVEF returns 
to baseline ± 5% or until 1 year from first 
treatment. Persistent reductions in LVEF 
of >10% with nadir values below 50% 
documented at 1 year are considered 
permanent sequelae.  
Biochemistry 
BUN 
Creatinine 
Electrolytes (Sodium, Potassium, 
Chloride) 
Bilirubin 
Alkaline phosphatase 
AST or ALT 
Protein 
Calcium 
Albumin 
Glucose 
Perform monthly only if abnormality(ies) 
persists at the end of the Treatment Phase.  
Perform until abnormality(ies) returns to 
baseline, until 1 year from first treatment 
or the initiation of new therapy and/or 
relapse. (whichever is earliest) 
Adverse Events/Toxicity 
CTCAE v.4 assessment  
Assess AEs that were ongoing at the time 
of discontinuation. Do NOT record any 
new AEs.  AEs that persist without 
evidence of recovery for >30 days are 
considered permanent sequelae and do 
not require further follow-up. 
 
7 
Drug Administration 
The responsibility for treatment of patients rests with the individual investigator.  Protocol 
treatment must begin within 72 hours of registration. 
 


 
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First Induction: 
  
Agent 
Dose 
Route 
Duration 
Schedule 
CPX-351 
100u/m2/day 
IV 
90 minutes* 
Days 1, 3 and 5  
 
 
Second Induction: 
Agent 
Dose 
Route 
Duration 
Schedule 
CPX-351 
100u/m2/day 
IV 
90 minutes* 
Days 1 and 3  
 
Consolidations (up to 2 are permitted): 
*Approximately 
 
Agent 
Dose 
Route 
Duration 
Schedule 
CPX-351 
65u/m2/day 
IV 
90 minutes* 
Days 1 and 3  
 
 
7.1 
Drug Preparation and Administration 
7.1.1 CPX-351 
7.1.1.1 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 sterile 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 and repeat vial inversion prior to withdrawing drug for 
dilution.  The concentration of the reconstituted dispersion is 5 u/mL.  CPX-351 
(cytarabine:daunorubicin) Liposome Injection should be diluted in approximately 500 mL 
of sodium chloride 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. 
 
7.1.1.2 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. 


 
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(Reconstitution information to be obtained from pharmacy as well as infusional instruction) 
 
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.  Institutions should maintain records that document adequately that 
the patients were provided the doses specified by the protocol and reconcile all 
investigational product received from Jazz Pharmaceuticals.  Records of storage conditions 
(temperature logs) must be kept for the entire period that CPX-351 is maintained at the 
institution. 
 
7.3 
Dose Reductions and Delays 
It is the intention of the study to treat every patient at full dose.  Dose delays or 
modifications will be recommended at the discretion of the treating physician and PI. Doses 
may be delayed due to toxicities (for example hypersensitivity reactions).  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 
4: Common Terminology Criteria for Adverse Events V4.0 (CTCAE)).  Toxicities for 
cytarabine and daunorubicin are relatively well known, and are outlined in the product 
information for each of these drugs. Furthermore, dose reductions or protocol closure will 
be considered:  
 
1) If >2 of the first 5 patients or >3 of the first 15 patients experience grade 4 toxicities, 
accrual will stop, the protocol reviewed, and dose modifications considered. If the 
incidence of grade 4 toxicity exceeds 20% of patients at any point after the first 15 
patients have been treated, accrual will stop, the protocol will be reviewed, and dose 
modifications considered. 
 
 
2)  If 30-day mortality exceeds 20% (>3 of the initial 15 patients), all further accrual 
will stop.  Subsequent enrollment after the first 15 subjects should ideally resume 
after the safety analysis is complete, however recognizing the acute nature of AML, 
it might not be possible to deny treatment to subjects in screening for ethical reasons 
sufficiently long to evaluate safety or efficacy. In other words, if the 30-day 
mortality for the preceding patients is less than 20%, study accrual will continue 
during the DSMB’s safety analysis.  
 
In the event that more than 15 subjects have enrolled before the safety analysis, 
only the first 15 subjects dosed will be informative for determining need for dose 
reduction as outlined in section 4.2. 
 


 
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7.4 
Concomitant Therapy 
7.4.1 Premedication 
7.4.1.1 CPX-351 
Nausea and vomiting: 
Patients may be premedicated for nausea and vomiting according to institutional standards. 
 
Hypersensitivity/Infusion-related reactions: 
Patients will not be routinely premedicated 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. 
 
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.  Premedicate on re-treatment.  Retreat at 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 as a serious adverse event. 
 
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. 
 
 
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 antibiotics, antifungals, and antiviral drugs is 
highly recommended during the period of profound neutropenia until ANC returns to 
500/μL or greater. The choice of medications will be according to institutional protocol. 
Use of anti-infective agents as prophylaxis and treatment must be documented on the case 
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Growth Factor support: The use of growth factors will be according to institutional protocol 
and according to ASCO criteria.16 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. 
 
7.4.2 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 and is followed for survival. 
 
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).  Patients may receive up to 2 induction courses followed by 
up to 2 consolidation courses.  After the Treatment Phase, patients will be followed for up 
to 5 years.  
 
8 
Assessment of Efficacy 
8.1 
Efficacy Population 
All registered patients are evaluable for efficacy.  Patients that die on or before Day 7 will 
be replaced. 
 
8.2 
Overall Survival  
Overall survival is measured from the date of registration to death from any cause. Patients 
not known to have died will be censored on the date they were last known to be alive. 
Patients will be followed for up to 5 years.    
 
8.3 
Event-free Survival 
Event-free survival is defined as the time from study registration to the date of induction 
treatment failure (persistent disease), progressive disease (PD) or death from any cause, 
whichever comes first.  Patients alive and not known to have any of these events will be 
censored on the date of their last tumor assessment. 


 
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8.4 
Response Assessment Criteria 
During the Treatment Phase patients will be assessed for response according to the 
following criteria1: 
Complete 
remission 
(CR)a 
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); independence from red cell transfusions 
CR 
with 
incomplete 
recovery (CRi)b 
All CR criteria except for residual neutropenia (<1.0 x 
109/L [1000/μL]) or thrombocytopenia (<100 x 109/L 
[100,000/μL]) 
Best Response 
See Section 8.4.1 
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  (blasts in 
peripheral blood, extramedullary leukemia, or persistence 
in the bone marrow)  
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 at 
recovery 
Relapsec 
Bone marrow blasts ≥5%; or reappearance of blasts in the 
blood after achievement of a CR or CRi; or development of 
extramedullary disease 
aBone marrow assessment REQUIRED to confirm CR. All 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. 
bBone marrow assessment REQUIRED to confirm CRi. Some patients may not achieve complete 
hematologic recovery prior to initiation of consolidation.  CRi cannot be declared earlier than Day 35 to 
allow adequate time for documentation of peripheral blood recovery.  Consolidation may begin no earlier 
than 35 days after the last induction course. 
cIn 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. 
 
A subject who is alive in a state of aplasia with no evidence of continued disease will be 
considered as having “no response.”  
 
The response of patients with no post-baseline bone marrow assessment will be entered as 
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8.4.1 Best Response 
Patients who complete the induction(s) with a response of CRp or CRi may be upgraded to 
CR during or after consolidation if the patient’s peripheral blood counts meet the criteria 
for CR (ANC>1000/μL and Platelets >100,000/μL).  To upgrade a response to CR after 
peripheral blood count recovery, a new bone marrow assessment must be performed within 
14 days of documented peripheral blood count recovery.    
 
8.5 
Remission Duration 
Only patients achieving CR or CRp or CRi are assessed for remission duration. Remission 
duration is measured from the date of achievement of a remission until the date of relapse 
or death from any cause; patients not known to have relapsed or died at last follow-up will 
be censored on the date of their last tumor assessment.   
 
8.6 
Morphologic Leukemia-free State 
All registered patients that have at least one evaluable post registration bone marrow 
assessment performed on or after Day 14 after the last induction will be 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.1 
 
8.7 
Stem Cell Transplant 
The number and percentage of patients transferred for stem cell transplant will be 
summarized. 
 
9 
Assessment of Safety 
 
9.1 
Safety Population 
All patients who receive at least one dose of study drug 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: 
 


 
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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 
“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 to the last day of the treatment period, 30 days after the last dose, with the exception 
of serious adverse events. (See Section 9.2.2). 
 
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 Definition of a Serious Adverse Event 
A serious adverse event (SAE) is any adverse event that: 
 
Results in death (grade 5) 
Is life-threatening 
Requires inpatient hospitalization or prolongation of existing hospitalization 
Results in persistent or significant disability or incapacity 
Is a congenital anomaly/birth defect 
 
These events are to be reported as serious from the start of the infusion on Day 1 to 30 days 
after completion of the treatment period.  Medical and scientific judgment should be 
exercised in deciding whether expedited reporting is appropriate in other situations such as 
important medical events that may not be immediately life-threatening or result in death or 
hospitalization but may jeopardize the patient or may require intervention to prevent one 
of the events listed above. 
 
9.2.3 Serious Adverse Event Reporting Instructions 
The investigator must complete the Serious Adverse Event Report Form in English, assess 
the relationship to study treatment and send the completed form by fax within 24 hours to 
the Sponsor or its designee.  The original and the duplicate copies of the Serious Adverse 
Event Form, and the fax confirmation sheet must be kept with the case report forms at the 
study site. 
 
Follow-up information should be sent to the Sponsor or its designee via the original Serious 
Adverse Event Form, re-stating the date of the original report.  Either a new Serious 
Adverse Event Form should be sent (stating that this is a follow-up), or the original one 
resent (with the new information highlighted and a new date provided).  The follow-up 
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whether the patient continued or discontinued study participation.  The form and fax 
confirmation sheet must be retained. 
 
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 Sponsor or 
its designee 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. 
 
9.2.4 Reporting Serious Adverse Events to Regulatory Agencies and Review Boards 
All SAEs must be reported to Jazz Pharmaceuticals, Inc. within 24 hrs of awareness, 
irrespective of relatedness, causality, expectedness. The WCM research team will complete 
and submit the US-FDA Form 3500A (MedWatch form) to AEreporting@jazzpharma.com 
within 1 business day of the awareness of the SAE.  
 
 
All AEs and SAEs will be reported to the WCM IRB per the policies outlined below: 
 
All SAEs will be reported with an SAE cover sheet that documents relatedness, 
expectedness, and risk determination. SAE reports will be saved in the study’s regulatory 
binder. SAE reports will be compiled to complete the Data and Safety Monitoring Board 
(DSMB) periodic report. 
 
The WCM IRB must be notified within 7 calendar days of investigator notification of an 
SAE when all of the following conditions are met, as determined by the Principal 
Investigator. These SAEs are considered “immediately reportable”: 
 
a. The event is unexpected – when its specificity and severity are not accurately 
reflected in the WCM consent document, Investigators Brochure, or package insert; 
AND 
b. The harm is “related” or “possibly related” – where there is a reasonable possibility 
that the harm may have been caused by the research procedure(s), or interventions; 
AND 
c. The harm suggests that the research places WCM subjects at greater risk of harm 
(including physical, psychological, economic or social harm) than was previously 
known or recognized. 
 
For events that are considered immediately reportable to the WCM IRB, the SAE report 
must be emailed to irb@med.cornell.edu. 
 
AEs grade 3 or higher and all SAEs will be listed on the Adverse Event & IND Safety 
Reporting Cumulative Table and reported to the WCM IRB at the time of continuing 
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All AEs that are serious, unexpected and associated with the use of CPX-351 will be 
reported to the applicable regulatory authority (FDA in the US and to Health Canada in 
Canada).  The period we have to report the SAE to the FDA depends on the severity of the 
SAE, as follows: 
 
- 
Within 7 days of becoming aware of the SAE for fatal (Grade 5), life-threatening 
(Grade 4) events 
 
- 
Within 15 days of becoming aware of all other qualifying SAEs (i.e., 
hospitalizations, second cancers, etc.) 
 
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 and LVEF 
below 50% will be recorded as an adverse event. Any decrease in LVEF >10% resulting 
in a nadir LVEF <50% will be reported as an SAE.  
 
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 
should 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 
and recorded on the CRF. 
 
10 Other Evaluations 
10.1 Blessed Orientation-Memory-Concentration Test (BOMC) 
This is a short six item test designed to evaluate older patients for early dementia.  The 
assessment is not affected by age or educational level.  The six-item Blessed Orientation-
Memory-Concentration (BOMC) test was developed by Katzman, Brown, Fuld, et al. 
(1983) from the longer (29-item) Blessed Information-Memory-Concentration (BIMC) test 
(Blessed, Tomlinson, and Roth, 1968). Katzman and colleagues (1983) selected 6 of the 
original 29 BIMC items based on a series of statistical analyses. The scores from each of 
the six items are multiplied as detailed below to yield a weighted score. Possible total scores 
on the BOMC range from 0 (all items answered correctly) to 28 (all items answered 
incorrectly). Weighted error scores greater than 10 are consistent with dementia, according 
to Katzman et al. (1983). 
10.2 Montreal Cognitive Assessment (MOCA) 
The MoCA test is a one-page 30-point test administered in approximately 10 minutes. The 
test and administration instructions are freely accessible for 
clinicians at 
www.mocatest.org. The test is available in 35 languages or dialects. There are 3 alternate 
forms in English, designed for use in longitudinal settings. 


 
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The MoCA assesses several cognitive domains. The short-term memory recall task (5 
points) involves two learning trials of five nouns and delayed recall after approximately 5 
minutes. Visuospatial abilities are assessed using a clock-drawing task (3 points) and a 
three-dimensional cube copy (1 point). Multiple aspects of executive functions are assessed 
using an alternation task adapted from the trail-making B task (1 point), a phonemic fluency 
task (1 point), and a two-item verbal abstraction task (2 points). Attention, concentration 
and working memory are evaluated using a sustained attention task (target detection using 
tapping; 1 point), a serial subtraction task (3 points), and digits forward and backward (1 
point each). Language is assessed using a three-item confrontation naming task with low-
familiarity animals (lion, camel, rhinoceros; 3 points), repetition of two syntactically 
complex sentences (2 points), and the aforementioned fluency task. Finally, orientation to 
time and place is evaluated (6 points). 
 
10.3 The Functional Assessment of Cancer Therapy – Leukemia (FACT-Leu) 
The FACT-Leu is a validated measurement of quality of life parameters for patients 
undergoing treatment for acute leukemia. This questionnaire is standardly used in leukemia 
treatment protocols to measure quality of life parameters. 
 
10.4 Medical Resource Use 
Medical resource use (MRU) data will be collected for all study participants and analyzed 
by health outcomes (overall survival and response (CR+CRp+CRi) for CPX-351. The 
MRU data collected in the trial will be used to identify costs associated with planned 
induction and consolidation treatment and for unplanned medical interventions necessary 
for patient support. Specific MRU data collected will include but may not be limited to: 
x 
hospitalization nights (general ward and intensive care); 
x 
blood product support (PRBC, Platelets, other);  
x 
non-chemotherapy drugs (anti-infectives, growth factors, etc.); and  
x 
AML chemotherapy (induction vs. consolidation). 
 
11  Statistical Considerations 
The primary objective of this non-randomized open label study is to evaluate the safety 
and efficacy of CPX-351 as a treatment for AML in elderly (≥ 60 years of age) patients. 
Dose reductions or protocol closure will be considered:  
 
1) If >2 of the first 5 patients or >3 of the first 15 patients experience grade 4 toxicities, 
accrual will stop, the protocol reviewed, and dose modifications considered. If the 
incidence of grade 4 toxicity exceeds 20% of patients at any point after the first 15 
patients have been treated, accrual will stop, the protocol will be reviewed, and dose 
modifications considered. 
 
 
2)  If 30-day mortality exceeds 20% (>3 of the initial 15 patients), all further accrual 
will stop.  Subsequent enrollment after the first 15 subjects should ideally resume 
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it might not be possible to deny treatment to subjects in screening for ethical reasons 
sufficiently long to evaluate safety or efficacy. In other words, if the 30-day 
mortality for the preceding patients is less than 20%, study accrual will continue 
during the DSMB’s safety analysis.  
 
In the event that more than 15 subjects have enrolled before the safety analysis, 
only the first 15 subjects dosed will be informative for determining need for dose 
reduction as outlined above. 
 
Patients who die within the first 7 days because of leukemia related toxicity will be 
replaced.  Those patients will be included in the analysis given the intention to treat for 30 
day mortality and overall survival.  
 
Analyses will primarily be descriptive in nature.  Categorical variables will be summarized 
as frequency counts with associated percentages and continuous variables will be 
summarized as mean, standard deviation, median and range.  Exact confidence intervals 
will be computed using the Clopper-Pearson method. 
 
All analyses will be performed using SAS version 9.2 or higher. 
 
Additional details regarding statistical analyses may be presented in a Statistical Analysis 
Plan (SAP). 
 
11.1 Primary and Secondary Endpoints 
11.1.1 Primary Endpoints 
In the CPX-351 cohort, the primary efficacy endpoint is overall survival (OS) as defined 
in Section 8.2; the primary safety endpoint is the 30-day mortality rate.    
 
11.1.2 Secondary Endpoints 
Secondary efficacy endpoints include complete response (CR, CRp, CRi, and 
CR+CRp+CRi), the relationship of cognitive function to treatment response and OS, event-
free survival and morphologic leukemia free state (as defined in Section 8).   Secondary 
safety endpoints include incidence of AEs and SAEs, laboratory measurements 
(hematology and biochemistry), vital signs and physical examinations. 
 
11.2 Sample Size and Power Justification for Primary Endpoint 
With 24 months for accrual, and a minimum of 36 months of follow-up, using a one-sided 
alpha-level of 0.05, a sample size of 30 patients has 80% power to detect a difference 
between the null hypothesis of 10 months median survival versus 16 months median 
survival in this patient population. 
 
In regards to safety, with a sample size of 30 the maximum width of the one-sided 95% 
exact confidence interval for estimated 30-day or 60-day mortality rates is less than 19%. 
 


 
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Analysis of the relationship of cognitive function to outcome and overall survival will be 
hypothesis generating. 
  
11.3 Analysis Populations 
 
Efficacy and safety analysis populations will be comprised of all patients who receive at 
least one dose of study drug.  
 
11.4 Analysis of Primary Endpoints 
 
Overall survival will be analyzed using Kaplan-Meier methods. Patients who have not died 
at the time of analysis will be censored on the date they were last known to be alive.  
Median survival and the associated 95% confidence interval will be computed using the 
Brookmeyer-Crowley method.  The estimated survival curve will be generated. 
 
Estimates of 30- and 60-day mortality rates will be computed using Kaplan-Meier methods 
along with associated two-sided 95% confidence intervals computed using the 
Brookmeyer-Crowley method.   
 
11.5 Analysis of Secondary Endpoints 
 
Time dependent endpoints, such as remission duration (relapse-free survival) and event-
free survival (EFS), will be evaluated using Kaplan-Meier methods; estimates of event 
rates will be computed and a survival curve generated.    
 
Binary Endpoints 
 
The response (CR, CRp, CRi, and CR+CRp+CRi) rate and best response (CR, CRp, CRi, 
and CR+CRp+CRi) rate will be calculated based on the responses achieved as defined in 
section 8.4. The number of patients who achieve response will be divided by the number 
of patients in the efficacy population to determine response rate.  
 
Likewise, the morphologic leukemia-free rate will be calculated as the number of patients 
who achieve morphologic leukemia-free state, as defined in section 8.6, divided by the 
number patients in the safety population who have at least one evaluable post-
randomization bone marrow assessment. 
 
The rate of stem cell transplant will be calculated by the number of patients who have a 
stem cell transplant divided by the number of patients in the safety population. 
 
11.6 Safety Analysis 
 
Safety data will be analyzed and reported for all patients who receive at least one dose of 
study drug.  Safety data summarized will include hematology, chemistries, vital signs, 


 
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adverse events (AEs) and physical examinations.  Safety data will be summarized using 
descriptive statistics.   
 
The number and proportion of patients with reported AEs and SAEs will be summarized 
by maximum grade.  AEs that are related to study drug will be summarized in a separate 
table. 
 
Laboratory values will be summarized both by actual result and by CTC toxicity grade (for 
selected laboratory parameters).  Summaries of laboratory results at each scheduled time 
point will reflect the observed value at that time point as well as change from baseline. For 
selected laboratory parameters, the maximum grade for each patient will be summarized 
for each type of toxicity; a shift table will reflect baseline toxicity grade versus maximum 
observed on-treatment toxicity grade. 
 
Vital signs and physical exam data will be summarized at each scheduled time point. 
 
11.7 Data Safety Monitoring Board (DSMB) 
 
Weill Cornell Medical College requires that all research approved by the WCMC IRB 
include an appropriate plan for the monitoring of data to ensure the safety of human 
subjects. Research supported by Federal agencies will be monitored according to all 
regulations and guidelines of the relevant Federal agency.  
 
The WCMC Data and Safety Monitoring Board (DSMB) will review the IRB approved 
protocol, informed consent documents, and data and safety monitoring plan prior to study 
initiation. During the course of the study, the DSMB will perform safety analysis as 
outlined in 4.2 after 15 subjects have enrolled.  
 
After the initial safety analysis period, the DSMB will review the cumulative study data 
semiannually to evaluate safety, efficacy, study conduct, and scientific validity and 
integrity of the trial. In particular, the results of the Day 30 echocardiogram will be 
included in the DSMB Periodic Reports. The WCMC DSMB may also convene as 
needed if stopping criteria are met or other safety issues arise that the Principal 
Investigator and/or IRB would like the WCMC DSMB to address. The study PI will 
submit all written DSMB recommendations to the IRB upon receipt. 
 
12  Administrative, Regulatory and Ethical Issues  
12.1 Direct Access to Source Documents 
Source data is all information, original records of clinical findings, observations, or other 
activities in a clinical trial necessary for the reconstruction and evaluation of the trial.  
Source data are contained in source documents.  Examples of these original documents and 
data records include but are not limited to: hospital records, clinical and office charts, 
laboratory notes, memoranda, patients’ diaries or evaluation checklists, pharmacy 
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certified after verification as being accurate and complete, microfiches, photographic 
negatives, microfilm or magnetic media, x-rays, patient files, and records kept at the 
pharmacy, at the laboratories, and at medico-technical departments involved in the clinical 
trial.  All data will be collected and stored on a computerized database using a REDCAP 
program.  
 
Case report forms, all copies of test results, and study-related regulatory documents [e.g., 
Informed Consents, Institutional Review Board (IRB)/Ethics Committee (EC) 
approvals/correspondence, etc.] must be available at all times for regulatory agency 
inspection and review by the sponsor or its designee. During the periodic site monitoring 
visits, the source documents will be verified against data entered onto the CRF in order to 
assure that all data is accurately and completely reflected on the patient's CRF. 
 
12.2 Study Monitoring and Quality Inspections/Audits 
 
This study will be monitored by the WCM PI and/or research team according to GCP/ICH 
guidelines.  An internal site initiation visit will be held prior to initiation of patient 
enrollment. The protocol, CRFs, study drug supplies, and relevant procedures will be 
explained in detail at the site visit. Subsequent to patient enrollment, the WCM PI and/or 
research team will review the CRFs and source documents to ensure that the study is 
conducted according to the protocol and GCP/ICH guidelines.   
 
To ensure compliance with GCP/ICH guidelines and all applicable regulatory 
requirements, WCM PI and/or research team may conduct an internal quality assurance 
audit.  Regulatory agencies may also conduct a regulatory inspection of this study.  Such 
audits or inspections can occur at any time during or after completion of the study.  If audits 
or inspections occur, the WCM PI and WCM’s research team agree to allow the 
auditor/inspector direct access to all relevant documents and to allocate his/her time and 
the time of his/her staff to the auditor/inspector to discuss findings and any relevant issues.  
 
12.3 Ethics 
This study will be conducted in accordance with local regulations, GCP, ICH guidelines 
and the Declaration of Helsinki. The WCM PI will be responsible for the overall conduct 
of the clinical trial for the site and will be responsible for ensuring the trial is conducted 
according to the protocol and all regulatory requirements and IRB/EC regulations. 
 
12.4 Adherence to the Protocol 
Except for a change that is intended to eliminate an immediate hazard to patients, the 
approved protocol will be conducted as described.  If a change in the conduct is made to 
eliminate an immediate hazard, the FDA and IRB/EC are notified immediately. 
 
Deviations from the protocol will be considered in two categories, Protocol Violations and 
Protocol Deviations.  Protocol Violations include patients who are not eligible according 
to the inclusion/exclusion criteria in effect at the time of registration.  Protocol Deviations 
include other non-compliance with the protocol, such as missing or skipped procedures or 


 
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evaluations, evaluations performed outside given window, incorrect administration of 
investigational product, etc. 
 
12.5 Protocol Revisions 
All revisions must be discussed with, and be prepared by, the WCM PI.  If the revision is 
an Administrative Letter, the investigator should submit it to the IRB/EC and FDA for their 
information.  If the revision is an Amendment, it will be signed by the WCM PI.  The 
WCM PI must submit the Amendment to the IRB/EC for review and approval prior to 
implementation.  Documentation of approval signed by the Chairperson or designee of the 
IRB/EC must be sent to the FDA. 
 
If an Amendment substantially alters the study design or increases the potential risk to the 
patient: (1) the consent form must be revised and submitted to the IRB/EC for review and 
approval; (2) the revised form must be used to obtain consent from patients currently 
enrolled in the study if they are affected by the Amendment; and (3) the new form must be 
used to obtain consent from new patients prior to enrollment. The revised consent form 
must then also be submitted to the FDA for review and approval. 
 
All revisions will be sent to the national competent authorities in North America. 
 
12.6 Retention of Patient Records and Study Files 
CRFs and other reports (e.g., investigator trial files, source documents, original, 
signed/dated informed consent forms) pertaining to this clinical investigation must be 
maintained for a minimum of 2 years.  
 
12.7 Patient Confidentiality 
The WCM PI and research team will preserve the confidentiality of all patients taking part 
in this trial. In the event of patient names inadvertently appearing on the trial 
documentation, this information will not be entered into the computer database for this 
trial. The WCM PI and research team will seek access to clinical information only after 
approval to do so has been given by the patient and the relevant authorities. The data from 
this trial may be used in publications and submissions to regulatory authorities. 
 
Information about study patients will be kept confidential and managed according to the 
requirements of the Health Insurance Portability and Accountability Act (HIPAA).  Those 
regulations require a signed patient authorization informing the patient of the following: 
What protected health information (PHI) will be collected from patients in this study 
Who will have access to that information and why 
Who will use or disclose that information 
 
The rights of a research patient to revoke their authorization for use of their PHI:   
In the event that a patient revokes authorization to collect or use PHI, the Investigator, by 
regulation, retains the ability to use all information collected prior to the revocation of 
patient authorization.  For patients that have revoked authorization to collect or use PHI, 


 
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attempts should be made to obtain permission to collect at least vital status (i.e. that the 
patient is/is not alive) at the end of their scheduled study period. 
 
12.8 Informed Consent 
Patients will be required to sign a statement of informed consent that meets the 
requirements of the US Code of Federal Regulations (21 CFR 50), Canadian regulations, 
local regulations, ICH guidelines and the IRB/EC of the study center. The medical record 
will include a statement that written informed consent was obtained before the patient was 
enrolled in the study and the date written consent was obtained. 
 
Members of the treating team will review the nature of the study, its purpose, the 
procedures involved, the expected duration, the potential risks and benefits and alternative 
therapies including best supportive care. Patients must be informed that participation in the 
study is voluntary, he/she may withdraw from the study at any time and withdrawal from 
the study will not affect his/her subsequent medical treatment or relationship with the 
treating physician. Financial costs that will or may be incurred as a result of participation 
in the study, as well as the efforts to maintain patient confidentiality will also be discussed. 
 
This consent must be witnessed and dated and retained by the WCM PI as part of the study 
records.  A copy of the informed consent form must be given to the patient.  In the event 
the patient is re-screened, the patient is not required to sign another informed consent form 
unless the patient is re-screened more than 30 days from the previous informed consent 
form signature date. 
 
If an Experimental Subject's Bill of Rights is applicable in the Investigator’s US state, that 
form must also be prepared and signed by each patient and retained as a part of the required 
study records.  A copy of the Bill of Rights must be given to the patient or the patient's 
legally authorized representative. 
 
A copy of the IRB approved consent form must be submitted to the FDA and Jazz 
Pharmaceuticals, Inc. prior to shipment of drug supplies to WCM.  Each patient's signed 
informed consent must be kept on file by the Investigator for regulatory authority 
inspection at any time. 
 
For all US sites, the HIPAA Privacy Rule Authorization language must be included in the 
Informed Consent/authorization form (or a separate authorization document) and approved 
by the IRB (or Privacy Board).  The elements of the HIPAA Privacy Rule Authorization 
are found in APPENDIX 5:  Elements of the HIPAA Privacy Rule Authorization. 
 
The Declaration of Helsinki, as amended, recommendations (2008 version), guiding 
doctors in clinical research must be signed by the Investigator and returned to the Sponsor 
or its designee.  A copy must also be kept on file by the Investigator. 
The IRB/EC of an institution must approve the consent form document to be used at that 
center prior to its local activation; changes to the consent form during the course of the 
study will also require IRB/EC notification/approval. 


 
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The following elements must appear in the consent form: a description of the purpose of 
the study (indication, that the drug is investigational); potential side effects; potential 
benefits; study design; voluntary participation; and confidentiality.  It is essential that the 
consent form contain a clear statement that gives permission for 1) information to be sent 
to and 2) source medical records to be reviewed by the Sponsor and other agencies as 
necessary. 
 
12.9 Publication Policy 
The results of this study will be published by the study investigator and sub-investigators.   
 
The Sponsor requires review of written and oral presentation at least 45 days prior to initial 
submission to the publishing authority.  If necessary to protect proprietary rights of 
information to be disclosed in the publication, the Sponsor may request a further 45 day 
delay in submission for publication, and the investigators agree to make all reasonable 
efforts to grant such further delay to the Sponsor. 
 
 


 
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13 References 
 
1. 
Dohner H, Estey EH, Amadori S, et al: Diagnosis and management of acute 
myeloid leukemia in adults: recommendations from an international expert panel, on behalf 
of the European LeukemiaNet. Blood 115:453-74, 2010 
 
2. 
Stone RM, O'Donnell MR, Sekeres MA: Acute myeloid leukemia. 
Hematology Am Soc Hematol Educ Program:98-117, 2004 
 
3. 
Appelbaum FR, Gundacker H, Head DR, et al: Age and acute myeloid 
leukemia. Blood 107:3481-5, 2006 
 
4. 
Kantarjian H, O'Brien S, Cortes J, 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 106:1090-
8, 2006 
 
5. 
Cheson BD, Bennett JM, Kopecky KJ, 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 21:4642-9, 2003 
 
6. 
Estey E: Acute myeloid leukemia and myelodysplastic syndromes in older 
patients. J Clin Oncol 25:1908-15, 2007 
 
7. 
Hiddemann W, Kern W, Schoch C, et al: Management of acute myeloid 
leukemia in elderly patients. J Clin Oncol 17:3569-76, 1999 
 
8. 
Burnett AK, Milligan D, Prentice AG, 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 109:1114-24, 2007 
 
9. 
Burnett AK, Milligan D, Goldstone A, et al: The impact of dose escalation 
and resistance modulation in older patients with acute myeloid leukaemia and high risk 
myelodysplastic syndrome: the results of the LRF AML14 trial. Br J Haematol 145:318-
32, 2009 
 
10. 
Lowenberg B, Ossenkoppele GJ, van Putten W, et al: High-dose 
daunorubicin in older patients with acute myeloid leukemia. N Engl J Med 361:1235-48, 
2009 
 
11. 
Fernandez HF, Sun Z, Yao X, et al: Anthracycline dose intensification in 
acute myeloid leukemia. N Engl J Med 361:1249-59, 2009 
 
12. 
Cassileth PA, Harrington DP, Hines JD, et al: Maintenance chemotherapy 
prolongs remission duration in adult acute nonlymphocytic leukemia. J Clin Oncol 6:583-
7, 1988 
 
13. 
Leone G, Mele L, Pulsoni A, et al: The incidence of secondary leukemias. 
Haematologica 84:937-45, 1999 
 
14. 
Sekeres MA, Elson P, Kalaycio ME, et al: Time from diagnosis to treatment 
initiation predicts survival in younger, but not older, acute myeloid leukemia patients. 
Blood 113:28-36, 2009 
 
15. 
Mayer LD, Harasym TO, Tardi PG, et al: Ratiometric dosing of anticancer 
drug combinations: controlling drug ratios after systemic administration regulates 
therapeutic activity in tumor-bearing mice. Mol Cancer Ther 5:1854-63, 2006 


 
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16. 
Ozer H, Armitage JO, Bennett CL, 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 18:3558-85, 2000 
 
17. 
Schoenfeld D: The asymptotic properties of nonparametric tests for 
comparing survival distributions. Biometrika 68:316-319, 1981 
 
18. 
Swerdlow SH CE, Harris NL: WHO Classification of Tumours of 
Haematopoitic and Lymphoid Tissues. Lyon, IRAC Press, 2008 
 
 


 
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14 
APPENDIX 1: Patient Evaluation Flow Sheet – Treatment Phase 
Each INDUCTION1, 2 and CONSOLIDATION: 
Day: 
Screening 
1 
2 
3 
4 
5 
6 
7 
±3 
10 
±1 
14 
±2 
21
±2 
28
±2 
35
±2 
42 
±2 
Weekly3 
±2 
1508 
±10 
End of Phase/Early 
Term. ±30 
Informed Consent4 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical/Leukemia History 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical Exam 
x 
 
 
 
 
 
 
 
 
x 
 
 
 
x 
 
 
 
Vital Signs 
x 
 
 
 
 
 
 
 
 
x 
 
 
 
x 
 
 
 
ECOG Performance Status 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
ECG 
x 
x8 
 
 
 
 
 
 
 
 
 
 
 
 
 
x 
x8 
Registration 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hematology 
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 
 
 
Urinalysis 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Bone Marrow Evaluation 
x 
 
 
 
 
 
 
 
 
x5 
As needed to confirm response/persistence 
Chest X-ray/Chest CT 
x 
 
 
 
 
 
 
 
 
 
 
 
 
Echocardiography/MUGA/cardiac 
MRI 
x 
 
 
 
 
 
 
 
 
 
 
 
 
x7 
 
x 
x 
Blessed 
Orientation 
Memory 
Concentration 
x9 
 
 
 
 
 
 
x9 
 
 
 
 
 
x9 
 
 
x9 
MOCA 
x9 
 
 
 
 
 
 
x9 
 
 
 
 
 
x9 
 
 
x9 
FACT-Leu 
x9 
 
 
 
 
 
 
x9 
 
 
 
 
 
x9 
 
 
x9 
Response Assessment 
 
 
 
 
 
 
 
 
 
x6 
 
 
 
 
 
 
 
Cytogenetics/Molecular Studies 
x 
At the time of CR or CRi 
Adverse Events 
 
Assess throughout Induction and Consolidation 
 
 
Concomitant Medications 
 
Assess throughout Induction and Consolidation 
 
 
Treatment Administration 
CPX-351 
See relevant protocol section(s). 
 
x 
1The first induction may end prematurely if a second induction is necessary, see Section 4.4.  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 Sections 4.4 & 4.5, See Section 7 for an alternative consolidation regimen of intermediate dose cytarabine, e.g.  for patients 
that exceed 500mg/m2 cumulative daunorubicin-equivalent dose, or as decided by the investigator 
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 first induction (in case the Day 14 bone marrow is non-evaluable or assessment of aplasia is equivocal, a repeat evaluation may be performed 5-14 days later, at the discretion of the 
treating physician, in order to determine effect and need for second induction  
6Day 150 or 45 Days after the last treatment whichever is later 
7See Section 9.3, Repeat ECHO/MUGA/cardiac MRI before the second consolidation  
8 ECG will be performed pre-dose for each course of treatment, and at the end of each course or EOT.  
9 Blessed, MOCA and FACT-Leu can be administered +/- 3 days from indicated day  
 


 
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15 
APPENDIX 2: Patient Evaluation Flow Sheet –Follow-up 
 
Monthly for 1 Year 
(±10 Days) 
Once 
Years 2-5 
Early 
Termination 
Patient status report 
x 
x 
x 
Hematology 
x 
 
x 
Biochemistry 
Perform monthly only if abnormality(ies) 
persists at the end of the Treatment Phase.  
Perform until abnormality(ies) returns to 
baseline, until 1 year from registration, or 
the initiation of new therapy and/or relapse. 
(whichever is earliest) 
 
 
Bone 
Marrow 
Aspiration/Biopsy 
For patients in CR or CRi perform at any 
time that there is a suspicion of relapse. For 
patients in CR, perform if peripheral blood 
counts fall below 1000/μL for ANC or 
100,000/μL for platelets for >1 month or at 
any time there is suspicion of relapse. For 
patients in CRi perform if counts fall 
significantly below peak recovery levels.  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), perform 
a bone marrow evaluation within 14 days to 
confirm CR.  Following the first year of 
follow up, record relapse information, 
including any bone marrow evaluations.  
Not required following the initiation of new 
therapy and or relapse. 
 
 
Echocardiography, MUGA or 
Cardiac MRI 
If last LVEF treatment phase or Day 150 
was reduced >10% from baseline and is less 
than 50% repeat every 3 months until LVEF 
returns to baseline (±5%) or until 1 year 
from registration.  Persistent reductions in 
LVEF of >10% with nadir values below 
50% documented at 1 year are considered 
permanent sequelae. 
 
 
Adverse Events/Toxicity 
Assess AEs that were ongoing at the time of 
discontinuation. Do NOT record any new 
AEs.  AEs that persist without evidence of 
recovery for >30 days are considered 
permanent sequelae and do not require 
further follow-up. 
 
 


 
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16 
APPENDIX 3: 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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17 
APPENDIX 4: Common Terminology Criteria for Adverse Events 
V4.0 (CTCAE) 
 
This 72 page document can be obtained as a pdf file from http://ctep.cancer.gov. 
The publication date is June 14, 2010  


 
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18 
APPENDIX 5:  Elements of the HIPAA Privacy Rule Authorization 
x 
Written in plain language understandable to the patient or the 
representative; 
x 
A “specific and meaningful” description of Protected Health Information 
(PHI) to be used and disclosed; 
x 
The specific identification of the person/class authorized to make the use or 
disclosure; 
x 
The specific identification of the persons/class to whom the covered entity 
may make the requested use or disclosure; 
x 
Description of the purpose of the disclosure; 
x 
An expiration date or event (i.e., “no expiration date” for data repository 
use, or “for the duration of a specific research study” permits use until end 
of study plus time for wrapping up and reporting); 
x 
A statement of the patient’s right to revoke the authorization and any 
exceptions to the right to revoke; 
x 
Conditions, if any, on authorization; 
x 
A statement about possible re-disclosures of PHI by the recipient and that 
the PHI will no longer be protected by the Privacy Rule in the event of such 
re-disclosures; and 
x 
The signature and date of the patient (or of the patient’s personal 
representative, along with the personal representative’s authority to act). 


 
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19 
APPENDIX 6:  Declaration of Helsinki 
WORLD MEDICAL ASSOCIATION DECLARATION OF HELSINKI ETHICAL PRINCIPLES 
FOR MEDICAL RESEARCH INVOLVING HUMAN SUBJECTS 
(Available at http://www.wma.net/en/20activities/10ethics/10helsinki/) 
  
 
 


 
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20 APPENDIX 7: Anthracyclines Equivalents Guidelines 
According to the exclusion criteria patients with a total lifetime anthracycline 
exposure exceeding the equivalent of 368 mg/m2 of daunorubicin (or equivalent) 
prior to start of study therapy [100 u/m2 of CPX-351 contains 44 mg/m2 of 
daunorubicin x 3 doses (1 induction) = 132 mg/m2 + 368 mg/m2 = 500 mg/m2 = 
maximum allowable limit of daunorubicin from all sources at the end of the 1st 
induction] are excluded from Protocol CLTR0310-301.  
 
  
Conversion factor* 
Daunorubicin 
1 
Doxorubicin 
2 
Epirubicin 
1 
Idarubicin 
4 
Mitoxantrone 
4.4 
 
Multiply the number in the second column by the total cumulative dose a patient 
has received. 
 
For example: 
200mg/m2 of mitoxantrone x 4.4(conversion factor) = 880mg/m2  
This means 200mg/m2 of mitoxantrone is equivalent to 880 mg/m2 of daunorubicin  
 
*Adapted from Keefe D., Anthracycline-Induced Cardiomyopathy. Seminars in 
Oncology, Vol 28, No 4, Suppl 12 (August), 2001: pp 2-7