Clinical trial NCT03575325
Conditions: Lymphoid Leukemia Acute Lymphoblastic Leukemia Refractory Acute Lymphoblastic Leukemia Relapsed Acute Lymphoblastic Leukemia
Keywords: T-cell acute lymphoblastic leukemia B-cell acute lymphoblastic leukemia
Sponsor: H. Lee Moffitt Cancer Center and Research Institute
Start date: 2018-10-11; Completion date: 2023-09-14
Enrollment: 11 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This study involves Vyxeos (CPX-351), a formulation of a fixed combination of the two anti-tumor drugs, cytarabine and daunorubicin that will be given as an infusion over 90 minutes. This study will use what is called a "liposome" injection. This is a special fat capsule (called a liposome) that surrounds the cytarabine and daunorubicin and protects the drugs from being eliminated/destroyed by the body.

Detailed description:

Arms: arm 1: Participants will receive induction with CPX-351 at a dose of 100 u/m\^2 administered intravenously over 90 minutes on days 1, 3 and 5 of a 28 day cycle.

This may be followed by consolidation with CPX-351 at a dose of 65 u/m\^2 administered intravenously over 90 minutes on days 1 and 3 of a 28 day cycle (up to 3 cycles).
Interventions: intervention 1: CPX-351
Intervention descriptions: intervention 1: 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.

Protocol documents:
Prot_SAP_000.pdf: 
A Single-Arm, Open-Label Phase 2 Pilot Study of Vyxeos (CPX-351) in Adults with 
Relapsed or Refractory Acute Lymphoblastic Leukemia 
NCT03575325 
Version 3.0 
December 11, 2019 


 
A Single-Arm, Open-Label Phase 2 Pilot Study of Vyxeos (CPX-351) in 
Adults with Relapsed or Refractory Acute Lymphoblastic Leukemia. 
Protocol Identifying Number: 19482 
Principal Investigator: Bijal Shah, MD 
 IND/IDE Sponsor: Bijal Shah, MD 
IND Number: 138773 
Funded by:  
Jazz Pharmaceuticals, Inc. 
Version Number:  v.1.0 
25 January 2018 
 
Version Number: v.1.1 
21 Feb 2018 
Version Number: v.1.2 
30 Mar 2018 
Version Number: v.1.3 
20 Apr 2018 
Version Number: 2.0 
03 Jun 2019 
Version Number 2.1 
04 Oct 2019 
Version Number 3.0 
11 Dec 2019 


 
Table of Contents 
LIST OF ABBREVIATIONS .......................................................................................................vi 
STATEMENT OF COMPLIANCE .............................................................................................vii 
STUDY SUMMARY ................................................................................................................. viii 
SCHEMATIC OF STUDY DESIGN ............................................... Error! Bookmark not defined. 
1 
KEY ROLES ............................................................................................................... 1 
2 
INTRODUCTION: BACKGROUND INFORMATION AND SCIENTIFIC RATIONALE 1 
2.1 
BACKGROUND INFORMATION .............................................................................. 1 
2.2 
RATIONALE ................................................................................................................ 2 
2.3 
POTENTIAL RISKS AND BENEFITS ....................................................................... 3 
2.3.1 
KNOWN POTENTIAL RISKS ................................................................................ 3 
2.3.2 KNOWN POTENTIAL BENEFITS ........................................................................ 4 
3 
OBJECTIVES AND PURPOSE ................................................................................ 4 
4 
STUDY DESIGN AND ENDPOINTS ....................................................................... 5 
4.1 
DESCRIPTION OF THE STUDY DESIGN ............................................................... 5 
4.2.1 PRIMARY ENDPOINT .......................................................................................... 5 
4.2.2 SECONDARY ENDPOINTS ................................................................................. 5 
4.2.3 EXPLORATORY ENDPOINTS ............................................................................. 5 
5 
STUDY ENROLLMENT AND WITHDRAWAL ......................................................... 6 
5.1 
PARTICIPANT INCLUSION CRITERIA ...................................................................... 6 
5.2 
PARTICIPANT EXCLUSION CRITERIA ..................................................................... 6 
5.3 
STRATEGIES FOR RECRUITMENT AND RETENTION........................................ 7 
5.4 
PARTICIPANT WITHDRAWAL OR TERMINATION .................................................. 8 
5.4.1 
REASONS FOR WITHDRAWAL OR TERMINATION ..................................... 8 
5.4.2 HANDLING OF PARTICIPANT WITHDRAWALS OR TERMINATION .............. 8 
5.5 
PREMATURE TERMINATION OR SUSPENSION OF STUDY ................................ 9 
6 
STUDY AGENT .......................................................................................................... 9 
6.1 
STUDY AGENT(S) AND CONTROL DESCRIPTION ............................................... 9 
6.1.1 ACQUISITION ....................................................................................................... 9 
6.1.2 FORMULATION, APPEARANCE, PACKAGING, AND LABELING ................... 9 
6.1.3 PRODUCT STORAGE AND STABILITY ............................................................ 9 
6.1.4 PREPARATION, PRODUCT STORAGE AND STABILITY ...................................10 
6.1.5 DOSING AND ADMINISTRATION & ROUTE OF ADMINISTRATION ...............10 
6.1.7 
STARTING DOSE AND DOSE ESCALATION SCHEDULE .........................10 
6.1.8 DOSE ADJUSTMENTS/MODIFICATIONS/DELAYS ...........................................11 
6.1.9 DURATION OF THERAPY ..................................................................................11 
6.2 
STUDY AGENT ACCOUNTABILITY PROCEDURES ...........................................11 
7 
STUDY PROCEDURES AND SCHEDULE .............................................................11 
7.1 
STUDY PROCEDURES/EVALUATIONS ..................................................................11 
7.1.1 
STUDY-SPECIFIC PROCEDURES ..................................................................11 


7.1.2 STANDARD OF CARE STUDY PROCEDURES ..............................................11 
7.1.3 Informed Consent ..............................................................................................11 
7.1.4 Inclusion/Exclusion Criteria ..................................................................................12 
7.1.5 
Demographics and Medical History ......................................................................12 
7.1.6 
Baseline Symptoms..............................................................................................12 
7.1.7 
Eastern Cooperative Oncology Group (ECOG) Performance Status ....................12 
7.1.8    Concomitant Medications Review ........................................................................12 
7.1.9 
Adverse Event Review .........................................................................................12 
7.1.10  Physical Exam ......................................................................................................12 
7.1.11 Vital Signs ............................................................................................................12 
7.1.12 Laboratory Procedures .........................................................................................12 
7.1.13 Bone Marrow Biopsy ............................................................................................13 
7.1.14 Correlative Studies ...............................................................................................13 
7.1.15 CSF for ALL Involvement/IT Chemotherapy .........................................................13 
7.1.16 CT Scan…………………………………………………………………………… …….13 
7.2 
LABORATORY PROCEDURES/EVALUATIONS .....................................................13 
7.2.1 CLINICAL LABORATORY EVALUATIONS .......................................................13 
7.2.2 
OTHER ASSAYS OR PROCEDURES ..............................................................14 
7.3 
STUDY SCHEDULE .................................................................................................14 
7.3.1 SCREENING ........................................................................................................14 
7.3.2 ENROLLMENT/BASELINE/STUDY VISITS .........................................................15 
7.3.3 FOLLOW-UP ........................................................................................................19 
7.3.4 
FINAL STUDY VISIT .........................................................................................19 
7.3.5 
EARLY TERMINATION VISIT ..........................................................................19 
7.3.6 
UNSCHEDULED VISIT .....................................................................................19 
7.3.7 
SCHEDULE OF EVENTS TABLE .....................................................................20 
7.4 
CONCOMITANT MEDICATIONS, TREATMENTS, AND PROCEDURES ...........21 
7.5 
JUSTIFICATION FOR SENSITIVE PROCEDURES .................................................21 
7.5.1 PRECAUTIONARY MEDICATIONS, TREATMENTS, AND PROCEDURES .22 
7.6 
PROHIBITED MEDICATIONS, TREATMENTS, AND PROCEDURES ..................22 
7.7 
PROPHYLACTIC MEDICATIONS, TREATMENTS, AND PROCEDURES ............22 
7.8 
RESCUE MEDICATIONS, TREATMENTS, AND PROCEDURES ........................22 
8 
ASSESSMENT OF SAFETY ...................................................................................22 
8.1 
SPECIFICATION OF SAFETY PARAMETERS ........................................................22 
8.1.1 
DEFINITION OF ADVERSE EVENTS (AE) ....................................................22 
8.1.2 
DEFINITION OF SERIOUS ADVERSE EVENTS (SAE) ................................23 
8.1.3 DEFINITION OF UNANTICIPATED PROBLEMS .............................................23 
8.2 
CLASSIFICATION OF AN ADVERSE EVENT .......................................................23 
8.2.1 
SEVERITY OF EVENT........................................................................................23 
8.2.2 RELATIONSHIP TO STUDY AGENT ................................................................24 
8.2.3 EXPECTEDNESS ................................................................................................24 


8.3 
TIME PERIOD AND FREQUENCY FOR EVENT ASSESSMENT AND 
FOLLOW-UP ............................................................................................................24 
8.4 
REPORTING PROCEDURES ...................................................................................25 
8.4.1 
ADVERSE EVENT REPORTING ......................................................................25 
8.4.2 SERIOUS ADVERSE EVENT REPORTING ......................................................25 
8.4.3 UNANTICIPATED PROBLEM REPORTING .......................................................25 
8.4.4 
EVENTS OF SPECIAL INTEREST ...................................................................26 
8.4.5 REPORTING OF PREGNANCY........................................................................26 
8.5 
STUDY HALTING RULES .........................................................................................27 
8.6 
SAFETY OVERSIGHT ..............................................................................................27 
9 
CLINICAL MONITORING .........................................................................................27 
10 
STATISTICAL CONSIDERATIONS ..........................................................................28 
10.1 STATISTICAL AND ANALYTICAL PLANS ............................................................28 
10.2 STATISTICAL HYPOTHESES .................................................................................28 
10.3 ANALYSIS DATASETS .............................................................................................28 
10.4 DESCRIPTION OF STATISTICAL METHODS .......................................................28 
10.4.1 GENERAL APPROACH .....................................................................................28 
10.4.2 ANALYSIS OF THE PRIMARY EFFICACY ENDPOINT(S) ............................28 
10.4.3 ANALYSIS OF THE SECONDARY ENDPOINT(S) ..........................................29 
10.4.4 SAFETY ANALYSES .........................................................................................29 
10.4.5 ADHERENCE AND RETENTION ANALYSES .................................................29 
10.4.6 BASELINE DESCRIPTIVE STATISTICS ...........................................................29 
10.4.10 
TABULATION OF INDIVIDUAL RESPONSE DATA .............................29 
10.4.11 
EXPLORATORY ANALYSES .............................................................30 
10.5 SAMPLE SIZE ..........................................................................................................30 
10.6 MEASURES TO MINIMIZE BIAS .............................................................................30 
10.6.1 ENROLLMENT ...................................................................................................30 
11 
SOURCE DOCUMENTS AND ACCESS TO SOURCE DATA/DOCUMENTS ...30 
12 
QUALITY ASSURANCE AND QUALITY CONTROL .............................................30 
13 
ETHICS/PROTECTION OF HUMAN SUBJECTS ...................................................31 
13.1 ETHICAL STANDARD ..............................................................................................31 
13.2 INSTITUTIONAL REVIEW BOARD .........................................................................31 
13.3 INFORMED CONSENT PROCESS .........................................................................31 
13.3.1 CONSENT/ASSENT AND OTHER INFORMATIONAL DOCUMENTS PROVIDED 
TO PARTICIPANTS .............................................................................................31 
13.3.2 CONSENT PROCEDURES AND DOCUMENTATION ......................................31 
13.4 PARTICIPANT AND DATA CONFIDENTIALITY ......................................................32 
13.4.1 RESEARCH USE OF STORED HUMAN SAMPLES, SPECIMENS, OR DATA 32 
13.5 FUTURE USE OF STORED SPECIMENS.............................................................32 
14 
DATA HANDLING AND RECORD KEEPING .........................................................32 
14.1 DATA COLLECTION AND MANAGEMENT RESPONSIBILITIES .......................32 


14.2 STUDY RECORDS RETENTION .............................................................................32 
14.3 PROTOCOL DEVIATIONS ........................................................................................32 
14.4 PUBLICATION AND DATA SHARING POLICY ....................................................32 
15 
CONFLICT OF INTEREST POLICY ........................................................................32 
16 
LITERATURE REFERENCES .................................................................................32 
APPENDIX A Response Criteria .............................................................................................32 
APPENDIX B ECOG Performance Status…………………………………………………..……..38 
 r 


LIST OF ABBREVIATIONS 
Protocol Title: CPX-351 for Relapsed/Refractory ALL                                                                                          Protocol V.3.0 
                                         
Protocol #: 19482                                                                                                                                                             11 Dec 2019 
 
 
 
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12123 
LIST OF ABBREVIATIONS 
 
AE 
Adverse Event 
ALL 
Acute Lymphoblastic Leukemia 
ANCOVA 
Analysis of Covariance 
ALT 
Alanine Aminotransferase 
ALP 
Alkaline Phosphatase 
aPTT 
Activated Partial Thromboplastin Time 
AST 
Aspartate Aminotransferase 
BUN 
Blood Urea Nitrogen 
CFR 
Code of Federal Regulations 
CLIA 
Clinical Laboratory Improvement Amendments 
CMP 
Clinical Monitoring Plan 
CMS 
Centers for Medicare and Medicaid Services 
CNS 
Central Nervous System 
CR 
Complete Response 
CRF 
Case Report Form 
CRi 
Complete Remission with incomplete hematologic recovery 
CSF 
Cerebral Spinal Fluid 
DCC 
Data Coordinating Center 
DHHS 
Department of Health and Human Services 
DSMB 
Data Safety Monitoring Board 
eCRF 
Electronic Case Report Forms 
EKG 
Electrocardiogram 
EOT 
End of Treatment 
FDA 
Food and Drug Administration 
FDAAA 
Food and Drug Administration Amendments Act of 2007 
GCP 
Good Clinical Practice 
GLP 
Good Laboratory Practices 
HIPAA 
Health Insurance Portability and Accountability Act 
IB 
Investigator’s Brochure 
ICH 
International Conference on Harmonisation 
ICH E6 
International Conference on Harmonisation Guidance for Industry, Good Clinical Practice: 
Consolidated Guidance 
IND 
Investigational New Drug Application 
IRB 
Investigational Review Board 
IT 
Intrathecal 
LDH 
Lactate Dehydrogenase 
MedDRA 
Medical Dictionary for Regulatory Activities 
MOP 
Manual of Procedures 
MRD 
Minimal Residual Disease 
OHRP 
Office for Human Research Protections 
PI 
Principal Investigator 
QA 
Quality Assurance 
QC 
Quality Control 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SMC 
Safety Monitoring Committee 
SOP 
Standard Operating Procedure 
UP 
Unanticipated Problem 
US 
United States 


LIST OF ABBREVIATIONS 
Protocol Title: CPX-351 for Relapsed/Refractory ALL                                                                                          Protocol V.3.0 
                                         
Protocol #: 19482                                                                                                                                                             11 Dec 2019 
 
 
 
vii 
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STATEMENT OF COMPLIANCE
 
 
The trial will be conducted in accordance with the ICH E6, the Code of Federal Regulations on the 
Protection of Human Subjects (45 CFR Part 46). The Principal Investigator will assure that no deviation 
from, or changes to the protocol will take place without prior agreement from the sponsor and 
documented approval from the Institutional Review Board, except where necessary to eliminate an 
immediate hazard(s) to the trial participants. All personnel involved in the conduct of this study have 
completed Human Subjects Protection Training. 
 
I agree to ensure that all staff members involved in the conduct of this study are informed of their 
obligation to meet the above commitments. 
 
 
Principal Investigator: 
  Bijal Shah, MD   
 
Print/Type Name 
 
 
Signed: 
   
 Date: 
 


LIST OF ABBREVIATIONS 
Protocol Title: CPX-351 for Relapsed/Refractory ALL                                                                                          Protocol V.3.0 
                                         
Protocol #: 19482                                                                                                                                                             11 Dec 2019 
 
 
 
viii 
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STUDY SUMMARY 
 
 
Title: 
A Single-Arm, Open-Label Phase 2 Pilot Study of Vyxeos (CPX-351) in Adults 
with Relapsed or Refractory Acute Lymphoblastic Leukemia. 
 
Objectives: 
Primary Objective:  
1) To estimate the complete response rate following treatment with 
CPX-351 
 
Important Secondary Objectives:  
1) To evaluate the safety and tolerability of CPX-351 
2) To estimate minimal residual disease burden following treatment with 
CPX-351 
3) To estimate the progression free survival (PFS) following treatment CPX-
351 
4) To estimate the overall survival (OS) following treatment with CPX-351 
 
Endpoint 
Primary Endpoint: 
 
1) Complete remission rate 
 
 
Important Secondary Endpoints:   
1) To evaluate the safety and tolerability of CPX-351 
2) Minimal Residual Disease Burden 
3) PFS 
4) OS 
 
Population: 
Patients >18 years old with relapsed acute lymphoblastic leukemia (ALL) who 
are registered at the Moffitt Cancer Center.  
 
Phase: 
2, pilot  
 
Number of Sites 
 
enrolling participants: 
1 
 
Description of Study 
 
Agent : 
1) Induction: Vyxeos (CPX-351), 100 units/m2 days 1, 3, & 5 
2) Consolidation: Vyxeos (CPX-351) 65 units/m2 days 1 & 3 (up to 3 
cycles) 
 
Study Duration: 
24 months 
 
Participant Duration: 
30 months 
 
 
 
 
 


LIST OF ABBREVIATIONS 
Protocol Title: CPX-351 for Relapsed/Refractory ALL                                                                                          Protocol V.3.0 
                                         
Protocol #: 19482                                                                                                                                                             11 Dec 2019 
 
 
 
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12123 
 
 
 
 
Induction 
CPX-351 100 u/m2   90 minute infusion days 1,3,5 
Consolidation 
Per section 7.3.2.11 
CPX-351  65 u/m2   90 minute infusion days 1,3 
(administered 35-75 days after start of induction) for up to 3 
cycles. 
 
 
SCHEMATIC OF STUDY DESIGN 


LIST OF ABBREVIATIONS 
Protocol Title: CPX-351 for Relapsed/Refractory ALL                                                                                          Protocol V.3.0 
                                         
Protocol #: 19482                                                                                                                                                             11 Dec 2019 
 
 
 
x 
12123 


LIST OF ABBREVIATIONS 
Protocol Title: CPX-351 for Relapsed/Refractory ALL                                                                                          Protocol V.3.0 
                                         
Protocol #: 19482                                                                                                                                                             11 Dec 2019 
 
 
 
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Principal Investigator: 
Bijal Shah, MD 
 
 
 
Moffitt Cancer Center 
 
 
12902 Magnolia Dr. FOB-3 
Tampa, FL 33612 
 
 
 
 
813-745-8158 
 
 
 
 
Bijal.Shah@moffitt.org   
 
Sub-Investigator: 
Jianguo Tao, MD, PhD 
Department of Hematopathology 
Moffitt Cancer Center 
12902 Magnolia Dr.  
Tampa, FL 33612 
813-745-3885 
Jianguo.Tao@moffitt.org 
 
Sub-Investigator: 
Jason Brayer, MD, PhD 
Department of Malignant Hematology 
Moffitt Cancer Center 
12902 Magnolia Dr.  
Tampa, FL 33612 
813-745-4748 
Jason.Brayer@moffitt.org 
 
Statistician: 
Jongphil Kim, PhD 
Department of Biostatistics and Bioinformatics 
Moffitt Cancer Center 
12902 Magnolia Dr.  
Tampa, FL 33612 
813-745-6908 
Jongphil.Kim@moffitt.org 
 
Clinical Research Nurse: 
Elyce Turba, MSN, RN, OCN 
Moffitt Cancer Center 
 
 
12902 Magnolia Dr. FOB 3 
 
 
 
Tampa, FL 33612 
 
 
 
 
813-745-1706 
Elyce.Turba@moffitt.org 
 
 
 
 
Outcomes are poor among adults with relapsed and refractory ALL, with most chemotherapy regimens 
demonstrating a CR rate of ~40%, coupled with a median EFS of ~6mo. (ref 1-10). To this end, several 
1 
KEY ROLES 
2 
INTRODUCTION: BACKGROUND INFORMATION AND SCIENTIFIC RATIONALE 
2.1 
BACKGROUND INFORMATION 


LIST OF ABBREVIATIONS 
Protocol Title: CPX-351 for Relapsed/Refractory ALL                                                                                          Protocol V.3.0 
                                         
Protocol #: 19482                                                                                                                                                             11 Dec 2019 
 
 
 
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novel therapies have emerged, including blinatumomab (CR/CRi rate 43%, med OS 7.7mo), inotuzumab 
ozagomycin (CR/CRi rate 80.7%, med OS 7.7mo), and liposomal vincristine (CR/CRi rate 20%, 6mo OS 
35%). (ref 11-13). While these therapies have advanced the management of relapsed ALL, relapse and 
shortened life expectancy remain the expectation for most patients. 
Chemotherapy resistance has been related in part to the overexpression of cell proteins implicated in 
drug transmembrane transport, such as PGP and LRP. (ref 14-18). Attempts to intensify therapy by 
increasing anthracycline dose or with the use of novel anthracycline derivatives have not significantly 
improved outcome. (ref 8-9,19). More recently, trials using liposomal daunorubicin in conjunction with 
high dose cytarabine demonstrated improved clinical efficacy (CR 80%, 12mo OS 39%). Notably, in cells 
from those with increased expression of multi-drug resistant proteins (72% of patients), the in vitro 
retention of liposomal daunorubicin and subsequent apoptosis were both significantly higher, when 
compared with free daunorubicin. (ref 18) Recent work further suggests molar ratio of 
cytarabine:daunorubicin, in addition to drug uptake, may be important in yielding therapeutic 
response. (ref 20-21) 
 
CPX-351 (or Vyxeos) is a liposomal formulation of cytarabine and daunrobicin at a fixed molar ratio.  A 
randomized study of CPX-351 (vs non-liposomal cytarabine and daunorubicin) in high risk acute 
myeloid leukemias demonstrated a significant benefit in complete remission rates (47.7% vs 33.3%) 
and median overall survival (9.56 vs. 5.95 months), culminating in FDA approval August 2017.   
 
Preclinical and early clinical data using primary ALL cell samples suggests that this benefit may extend 
to those with lymphoblastic leukemias.  Specifically, “high sensitivity” to CPX-351 was observed in 20% 
of samples. (ref 22). This was further corroborated with xenograft modeling using samples derived 
from pediatric patients with relapsed ALL, wherein response was estimated via ORM modeling to be 
100%, with response in 4 of 5 mouse groups suggestive of CR. Notably, activity was also observed in a 
Philadelphia chromosome positive patient derived xenograft. (ref 23) Finally, CPX-351 was also tested 
clinically during phase 1 testing in 3 patients with ALL, with one showing subsequent CR. (ref 24) 
 
Based on these data, the author believes there is rationale for further study of this approach in 
relapsed and refractory ALL. 
 
 
Remission rates vary considerably depending on population studies (children vs adults), relapsed vs 
refractory status, and timing of salvage (first relapse vs beyond first relapse) making it difficult to 
extrapolate baseline rate. If focusing specifically on 2 trials that used an induction composed of 
cytarabine (3gm/m2 x5d) and idarubicin (40mg/m2 on d3), complete remission rates are 
approximately 40% (38-44%, total n=54). (ref 4-5). Alternatively, a more recent phase 3 
trial of inotuzumab vs standard of care in patients in first or second relapse shows a composite CR rate 
in the standard of care arm (Cytarabine+Mitoxantrone,high dose Cytarabine, and Fludarabine, 
Cytarabine, and GCSF, total n=109) of 29%. (ref 13). Given these data, it is determined that a baseline 
CR rate of 35% is likely to estimate activity with a standard salvage regimen.  
 
Data using liposomal anthracyclines among those with relapsed ALL, including FLAD (Fludarabine, 
Cytarabine, Liposomal Daunorubicin) and Cytarabine+Liposomal Daunorubicin, have shown an 
improvement in CR rates, at 65% and 80%, respectively. (ref 18,28) Together these data suggest a CR 
rate of 65% should be attainable using CPX-351. 
 
However, at this stage, a phase 2 pilot trial is proposed to explore response rates among 10 patients 
with ALL.  Should sufficient activity be observed, consideration may be made in consultation with Jazz 
2.2 
RATIONALE 


LIST OF ABBREVIATIONS 
Protocol Title: CPX-351 for Relapsed/Refractory ALL                                                                                          Protocol V.3.0 
                                         
Protocol #: 19482                                                                                                                                                             11 Dec 2019 
 
 
 
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Pharmaceuticals, to increase the budget to increase accrual to formally test our hypothesis, possibly in 
a multicenter setting. 
 
Safety will be monitored as per standard routine, accounting for adverse events using CTCAE v. 5.0.  
Myelotoxicity is anticipated, in addition to associated infections. Frequency of these events will be 
monitored for comparison with historical rates, referencing against historical regimens noted above.  
Adverse events of special interest include bone marrow aplasia (hypocellular marrow without 
adequate count recovery >42 days from start of therapy), and symptomatic heart failure (accompanied 
by a decrease in the ejection fraction >10% from baseline greater than 42 days from start of therapy). 
 
 
 
 
The table below summarizes adverse reactions obtained directly from the Investigator Brochure  
Version 13.0. The table includes pooled data from five clinical trials of 375 patients with AML. The 
frequency  is referenced using the following MedDRA scale: 
∙ Very common: ≥1/10 (≥10%);  
∙ Common (frequent): ≥1/100 and <1/10 (≥1% and <10%);  
∙ Uncommon (infrequent): ≥1/1,000 and <1/100 (≥0.1% and <1%);  
∙ Rare: ≥1/10,000 and <1/1,000 (≥0.01% and <0.1%);  
∙ Very rare: <1/10,000 (<0.01%), including isolated reports. 
 
System Organ Class  
 
 
All AEs/Frequency 
Grade 3-5 AEs/Frequency 
Blood and lymphatic system disorders 
Very Common 
Febrile neutropenia 
Common 
Neutropenia 
Thrombocytopenia 
     Anemia 
Very Common 
Febrile neutropenia 
Common 
Neutropenia 
Thrombocytopenia 
     Anemia 
Cardiac disorders 
Very Common 
    Cardiotoxicity 
    Arrhythmia 
    Chest pain  
Very Common 
Cardiotoxicity 
 Common 
Arrhythmia 
    Chest pain 
Eye disorders 
Very Common 
    Visual impairment  
Uncommon 
     Visual impairment 
Gastrointestinal disorders 
Very Common 
    Mucositis  
    Abdominal pain  
    Constipation  
    Decreased appetite  
    Diarrhea/colitis  
    Nausea  
    Vomiting  
 Common 
    Dyspepsia  
Common 
Mucositis 
Abdominal pain 
Constipation 
Decreased appetite 
Diarrhea/colitis 
Nausea 
Uncommon 
Vomiting 
     Dyspepsia 
General disorders and administration site 
conditions 
Very Common 
     Edema       
Pyrexia 
Fatigue 
    Chills 
Very Common 
Fatigue 
Common 
Edema 
Pyrexia 
Uncommon 
    Chills 
Immune system disorders 
Very Common 
     Hypersensitivity  
Common 
     Hypersensitivity  
Infections and infestations 
Very Common 
     Infection 
Very Common 
     Infection 
Metabolism and nutrition disorders 
Common 
     Tumor lysis syndrome 
Common 
     Tumor lysis syndrome 
2.3 
POTENTIAL RISKS AND BENEFITS 
2.3.1 
KNOWN POTENTIAL RISKS 


LIST OF ABBREVIATIONS 
Protocol Title: CPX-351 for Relapsed/Refractory ALL                                                                                          Protocol V.3.0 
                                         
Protocol #: 19482                                                                                                                                                             11 Dec 2019 
 
 
 
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Musculoskeletal and tissue disorders 
Very Common 
     Musculoskeletal pain 
Common 
     Musculoskeletal pain 
Nervous system disorders 
Very Common 
    Headache  
    Dizziness  
Common 
     Headache  
 Uncommon 
      Dizziness  
Psychiatric disorders 
Very Common 
Delirium 
Sleep disorders 
     Anxiety 
Common 
Delirium 
Uncommon 
     Sleep disorders 
Renal and urinary disorders 
Very Common 
    Renal insufficiency  
Common 
    Renal insufficiency  
Respiratory, thoracic and mediastinal 
disorders  
 
Very Common 
     Dyspnea  
     Pleural effusion  
     Cough  
Very Common 
     Dyspnea  
Uncommon 
     Pleural effusion  
Skin and subcutaneous disorders 
Very Common 
     Pruritis  
     Hyperhidrosis  
Common 
     Alopecia  
     Night sweats  
Uncommon 
    Palmar-plantar  
    erythrodysesthesia  syndrome  
Uncommon 
    Hyperhidrosis  
Vascular disorders 
Very Common 
    Hemorrhage  
    Hypertension  
    Hypotension  
Very Common 
     Hemorrhage  
Common 
    Hypertension  
    Hypotension  
 
 
 
 
 
Initial work with primary ALL cell samples suggested “high sensitivity” to CPX-351 in 20% of samples. (ref 
22). This was further corroborated with xenograft modeling using samples derived from pediatric patients 
with relapsed ALL. Specifically, response was estimated via ORM modeling to be 100%, with response 4 of 
5 mouse groups suggestive of CR. Notably, activity was also observed in a Philadelphia chromosome 
positive patient derived xenograft. (ref 23) Finally, CPX-351 was also tested clinically during phase 1 testing 
in 3 patients with ALL, with one showing subsequent CR. (ref 24) Based on these data, there is reason to 
believe there could be benefit to subjects with relapsed and refractory ALL. 
 
To date we have treated 7 patients with CPX-351.  We have seen CR in two patients and PR in 3 other 
evaluable patients  following induction (ORR 83%).  Relevant grade 3-5 SAE’s to date include: bleeding, 
veno-occlusive disease of the liver, and fungal pneumonia. 
 
 
Primary Objective:  
To estimate the complete response rate following treatment with CPX-351.  Complete remission will 
be evaluated by bone marrow biopsy at day 28 of therapy in all patients with medullary disease 
receiving at least one full cycle of CPX-351.  For patients with extramedullary disease, CT or PET/CT 
will be used for response. Cheson criteria (2003) will be used to evaluate remission status, specifically 
complete remission (CR), complete remission with incomplete hematologic recovery (CRi/CRh), 
partial response (PR), and aplasia.   
 
Important Secondary Objectives: 
2.3.2 
KNOWN POTENTIAL BENEFITS 
3 
OBJECTIVES AND PURPOSE 


LIST OF ABBREVIATIONS 
Protocol Title: CPX-351 for Relapsed/Refractory ALL                                                                                          Protocol V.3.0 
                                         
Protocol #: 19482                                                                                                                                                             11 Dec 2019 
 
 
 
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Additional clinical endpoints will include  
1) To evaluate safety and tolerability of CPX-351 using CTCAE 5.0. 
2) Minimal residual disease assessment (MRD) by 10 color flow cytometry and next generation 
sequencing (NGS) by Clonoseq (for Philadelphia negative leukemia) or PCR for BCR-ABL (for 
Philadelphia positive leukemia).   
3) Progression Free Survival as defined by Cheson Criteria, namely progression, failure to respond, or 
death, as assessed from time of first treatment. 
4) Overall Survival as defined by Cheson Criteria, namely death due to any cause as assessed from 
time of first treatment. 
 
 
 
 
 
This is an open label, single arm, single center, phase 2 pilot study of Vyxeos induction & 
consolidation in relapsed and refractory ALL. 
 
 
 
 
• 
We will measure remission rate at day 28 to address the primary endpoint of complete remission (with 
or without complete hematologic recovery), as defined by Cheson Criteria (ref 27).  For those with 
extramedullary disease, Lugano criteria will be used to assess response (ref 32). This is a standard 
assessment of drug efficacy for phase 2 clinical trial design in acute leukemias, as response correlates 
closely with progression free- and overall survival (PFS and OS). 
 
 
Secondary Endpoints will include 
1) Evaluation of safety of CPX-351 using CTCAE 5.0.   
2) Minimal residual disease assessment (MRD) by 10 color flow cytometry and next generation 
sequencing (NGS) by Clonoseq (for Philadelphia negative leukemia) or PCR for BCR-ABL (for 
Philadelphia positive leukemia) at day 28.  Using a threshold of 0.01% leukemic cells, MRD provides 
a better estimate leukemic cell sensitivity to therapy, and correlates with both PFS and OS.   
3) Progression Free Survival as defined by Cheson and Lugano Criteria (ref 27 and 32), namely 
progression, failure to respond, or death, as assessed from time of first treatment.  The 12 month 
progression free survival rate with standard chemotherapeutic approaches in relapsed ALL is 
estimated at 10%.  PFS is a standard estimate that accounts for response rate, response duration, 
and mortality to estimate therapeutic benefit in clinical trials.  
4) Overall Survival as defined by Cheson and Lugano Criteria (ref 27 and 32), namely death due to any 
cause as assessed from time of first treatment.  The 12 month overall survival for those with 
standard chemotherapeutic approaches in relapsed ALL estimated at 20%.  Overall survival is a 
standard criteria for assessing therapeutic benefit in clinical trials. 
 
 
 
Exploratory Endpoints will include: 
1) An exploration of the activity of CPX-351 ex vivo using live image capture in a reconstituted tumor 
micro-environment (EVOS system) as a potential biomarker for response.   
4 
STUDY DESIGN AND ENDPOINTS 
4.1 
DESCRIPTION OF THE STUDY DESIGN 
4.2 
STUDY ENDPOINTS 
4.2.1 
PRIMARY ENDPOINT 
4.2.2 
SECONDARY ENDPOINTS 
4.2.3 
EXPLORATORY ENDPOINTS 


LIST OF ABBREVIATIONS 
Protocol Title: CPX-351 for Relapsed/Refractory ALL                                                                                          Protocol V.3.0 
                                         
Protocol #: 19482                                                                                                                                                             11 Dec 2019 
 
 
 
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2) An assessment of apoptotic threshold as a measure of tumor cell fitness (dynamic BH3 profiling). 
These data may additionally support combinatorial approaches using clinical inhibitors of apoptosis. 
3) An assessment of the T-cell repertoire using multi-parameter flow, and tumor/stromal PDL1 
expression.  These data will similarly be used to support potential future combinatorial strategies. 
 
 
 
 
 
      Patients must meet all of the following criteria to be eligible for study entry: 
 
1. Be willing and able to provide written informed consent/assent for the trial. 
 
2. Be ≥ 18 years of age on day of signing informed consent.  
3. Able to adhere to the study visit schedule and other protocol requirements.  
4. Pathologically confirmed B- or T-cell acute lymphoblastic or mixed phenotype acute leukemia, with 
>5% peripheral blood or bone marrow lymphoblasts and/or extramedullary disease >1x1cm. 
 
5. Relapsed or refractory acute lymphoblastic leukemia after at least 1 prior cycle of therapy.  Patients 
with Philadelphia chromosome positive disease must have failed at least two prior tyrosine kinase 
inhibitors. 
 
6. Eastern Cooperative Oncology Group (ECOG) performance status 0-1. 
 
7. Cardiac ejection fraction ≥ 50% by echocardiography or MUGA.  
 
8. Must be at least 2 weeks out from any prior systemic chemotherapy, blinatumumab, radiation, 
and/or other investigational agents, and have recovered to grade 1 from any toxicity related to prior 
therapy.  Glucocorticoids are permitted up to 1 day prior to the first dose. 
 
9. Serum bilirubin and creatinine < 1.5x upper limit of normal (ULN).  AST and ALT must be <3x  ULN, 
unless there is suspected liver involvement. 
 
10. Females of childbearing potential (FCBP) must have a negative serum pregnancy test at screening. A 
FCBP is considered when a sexually mature female: 1) has not undergone a hysterectomy or bilateral 
oophorectomy; or 2) has not been naturally postmenopausal for at least 12 consecutive months. 
 
11. A FCBP must agree to use of two methods of highly effective contraception, be surgically sterile, or 
abstain from heterosexual activity for the course of the study through 30 days after the last dose of 
study treatment. 
 
12. Male subjects must agree to use an adequate method of contraception starting with the first dose of 
study therapy through 30 days after the last dose of study therapy. Men must agree to not donate 
sperm during and after the study 
 
 
 
 
5 
STUDY ENROLLMENT AND WITHDRAWAL 
5.1 
PARTICIPANT INCLUSION CRITERIA 
5.2 
PARTICIPANT EXCLUSION CRITERIA 


LIST OF ABBREVIATIONS 
Protocol Title: CPX-351 for Relapsed/Refractory ALL                                                                                          Protocol V.3.0 
                                         
Protocol #: 19482                                                                                                                                                             11 Dec 2019 
 
 
 
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Any of the following is a criterion for exclusion from the study: 
1. Clinical evidence of active central nervous system (CNS) leukemia. 
 
2. Any major surgery or radiation therapy within four weeks.  
 
3. Any active infection requiring systemic therapy, including HIV, Hepatitis B, and/or Hepatitis C. 
 
 
4. Has a history or current evidence of any condition, therapy, or laboratory abnormality that might 
confound the results of the trial, interfere with the subject’s participation for the full duration of 
the trial, or is not in the best interest of the subject to participate, in the opinion of the treating 
investigator (including but not limited to severe graft-versus-host disease, unstable angina, 
pulmonary hypertension, active/prior veno-occlusive disease of the liver, or severe CHF (NYHA III-
IV).  
5. Patients with active (uncontrolled, metastatic) second malignancies are excluded. 
6. Is pregnant or breastfeeding, or expecting to conceive or father children within the projected 
duration of the trial, starting with the screening visit through 30 after the last dose of trial 
treatment.  
7. Hypersensitivity to cytarabine, daunorubicin, or liposomal products. 
 
8. History of Wilson’s disease or other copper-metabolism disorder. 
9. Patients with prior cumulative anthracycline exposure of greater than 368 mg/m2 daunorubicin 
(or equivalent). 
 
 
 
Recruitment of the 10 participants for this trial will occur from new or established patients treated at 
the Hematology Clinic at Moffitt Cancer Center. Screen failure is anticipated to be less than 10%. The 
target accrual is expected to be reached in 24 months. All faculty members in the Lymphoma Section 
will be sub-investigators on the trial. They will be trained on the trial design, study agents, and eligibility 
criteria. This will equip each investigator to discuss the trial with potential participants as appropriate. 
The trial will be listed on the Moffitt Cancer Center website (www.moffitt.org) for the availability of local 
physicians to refer patients who could be eligible for the trial.  
 
All investigators will be made aware of the emphasis to enroll women and minorities. The design of the 
trial and eligibility criteria are not restrictive relative to women and minorities. According to the National 
Cancer Institute Surveillance, Epidemiology, and End Results Program, there are approximately 6000 
new cases of ALL per year, of which nearly half will occur among those over age 20 years. (ref. 29) In a 
currently enrolling Moffitt trial (MCC18329) for patients with ALL, 50% of participants were young adults 
(age 18-39), 25% were female, and 100% were Hispanic/Portuguese. The sex, ethnicity, and race of each 
participant on this trial will be captured in the Oncore electronic data base for reporting purposes.  
 
The multi-modal aspect of this disease will require knowledge of the barriers to recruitment and 
retention present to young adults, older adults, and those who may be Hispanic. The young adult 
population can be challenging to interest in trial participation. The article by Pearce (ref. 30) provides 
understanding of communication strategies, the need of young adults to feel autonomous, and the 
importance young adults place on being treated in a specialist care setting to facilitate trial participation. 
5.3 
STRATEGIES FOR RECRUITMENT AND RETENTION 


LIST OF ABBREVIATIONS 
Protocol Title: CPX-351 for Relapsed/Refractory ALL                                                                                          Protocol V.3.0 
                                         
Protocol #: 19482                                                                                                                                                             11 Dec 2019 
 
 
 
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The article could be utilized as a resource for trial staff. Once consented, the young adult participant will 
have contact with the research nurse frequently during trial participation to maintain continuity and 
provide support, which Pearce describes as a way to impact retention. 
 
Potential participants will be assessed prior to screening for any perceived barriers related to the clinical 
trial process. Referrals will be made to a social worker, supportive care services, financial services, or the 
research nurse to address barriers prior to consent.  
 
 
 
 
 
Subjects may withdraw consent at any time for any reason or be dropped from the trial at the discretion of 
the investigator should any untoward effect occur that may jeopardize participant safety.  In addition, a 
subject may be withdrawn by the investigator if enrollment into the trial is inappropriate, the trial plan is 
violated, or for administrative and/or other safety reasons.   
 
A subject must be discontinued from the trial for any of the following reasons: 
• 
The subject or legal representative (such as a parent or legal guardian) withdraws consent 
• 
Unacceptable adverse events 
• 
Intercurrent illness that prevents further administration of treatment 
• 
Investigator’s decision to withdraw the subject 
• 
The subject has a confirmed positive serum pregnancy test 
• 
Noncompliance with trial treatment or procedure requirements 
• 
The subject is lost to follow-up 
• 
Administrative reasons 
 
The End of Treatment and Follow-up visit procedures are listed in the Schedule of Events and Section 
7.3 (Visit Requirements).  After the end of treatment, each subject will be followed for 30 days for 
adverse event monitoring. Subjects who discontinue for reasons other than progressive disease will 
have post-treatment follow-up for disease status and toxicity up to 30 days.  Follow-up rules will apply 
unless participant initiates a non-study cancer treatment, withdraws consent, or becomes lost to 
follow-up (unsuccessful attempts to contact for 3 months).  After documented disease progression, 
each subject will be followed 12 months for overall survival until death, withdrawal of consent, or the 
end of the study, whichever occurs first. 
 
 
 
 
Every effort will be made to maintain contact with a subject who withdraws early. If the subject remains 
at MCC for further care, clinic visits may be tracked and the condition of the subject followed. If the 
subject is not continuing care at MCC, contact information will be updated at the end of treatment visit, 
including accurate phone numbers, and email address. The importance of the follow-up period for AEs 
and SAEs will be stressed to the subject. 
5.4 
PARTICIPANT WITHDRAWAL OR TERMINATION 
5.4.1 
REASONS FOR WITHDRAWAL OR TERMINATION 
5.4.2 
HANDLING OF PARTICIPANT WITHDRAWALS OR TERMINATION 


LIST OF ABBREVIATIONS 
Protocol Title: CPX-351 for Relapsed/Refractory ALL                                                                                          Protocol V.3.0 
                                         
Protocol #: 19482                                                                                                                                                             11 Dec 2019 
 
 
 
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All subjects receiving at least 1 day of therapy will be evaluable for safety.  Replacement of participants 
is permitted for those who screen fail or drop out prior to completing initial response assessment at day 
28 of treatment, in order to meet the accrual goal of this study.  
 
 
 
This study may be temporarily suspended or prematurely terminated if there is sufficient reasonable 
cause. Written notification, documenting the reason for study suspension or termination, will be 
provided by the suspending or terminating party to investigator, funding agency, the IND/IDE sponsor 
and regulatory authorities.  If the study is prematurely terminated or suspended, the PI will promptly 
inform the IRB and will provide the reason(s) for the termination or suspension. 
 
Circumstances that may warrant termination or suspension include, but are not limited to: 
1. Quality or quantity of data recording is inaccurate or incomplete 
2. Poor adherence to protocol and regulatory requirements 
3. Incidence or severity of adverse drug reaction in this or other studies indicates a potential health 
hazard to subjects 
4. Plans to modify or discontinue the development of the study drug 
5. Determination of futility 
In the event Jazz Pharmaceuticals, Inc. decides to no longer supply study drug, ample notification will 
be provided so that appropriate adjustments to subject treatment can be made. 
 
 
 
 
 
 
Study agent will be supplied by the manufacturer or IND/IDE sponsor to the Moffitt Research Pharmacy. 
 
 
• 
CPX-351 (Vyxeos) is stored as a dry powder at 2ºC to 8ºC 
• 
CPX-351 (Vyxeos) is provided by Jazz Pharmaceuticals.   
• 
CPX-351 is FDA approved and commercially marketed for patients with Acute Myeloid 
Leukemia 
• 
For this trial we will be using investigational supply for this trial in Acute Lymphoblastic 
Leukemia.   
 
 
 Vials of CPX-351 should be refrigerated prior to use (at 2-8oC) and should be utilized prior to expiration 
as indicated on the individual vials. If reconstituted product is not diluted into an infusion bag 
immediately, store in refrigerator at 2ºC to 8ºC for up to 4 hours. 
 
5.5 
PREMATURE TERMINATION OR SUSPENSION OF STUDY 
6 
STUDY AGENT 
6.1 
STUDY AGENT(S) AND CONTROL DESCRIPTION 
6.1.1 
ACQUISITION 
6.1.2 
FORMULATION, APPEARANCE, PACKAGING, AND LABELING 
6.1.3 
PRODUCT STORAGE AND STABILITY 


LIST OF ABBREVIATIONS 
Protocol Title: CPX-351 for Relapsed/Refractory ALL                                                                                          Protocol V.3.0 
                                         
Protocol #: 19482                                                                                                                                                             11 Dec 2019 
 
 
 
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The appropriate number of vials of CPX-351 (cytarabine:daunorubicin) Liposome Injection should be 
removed from the refrigerator, and allowed to equilibrate to room temperature for 30 minutes prior to 
reconstitution.  
 
Then, reconstitute each vial with 19 mL of Sterile Water for Injection using a sterile syringe and 
immediately thereafter start a 5-minute timer.  Carefully swirl the contents of the vial for 5 minutes 
while gently inverting the vial every 30 seconds.  Do not heat, vortex, or shake vigorously.  After 
reconstitution, let rest for 15 minutes.  After reconstitution (but before final dilution), the 
concentration is 5 u/mL..  The reconstituted product should be an opaque, purple, homogeneous 
dispersion, essentially free from visible particulates.  Gently invert each vial 5 times prior to 
withdrawing the reconstituted product for further dilution. If the reconstituted product is not diluted 
into an infusion bag immediately, store in refrigerator at 2ºC to 8ºC for up to 4 hours. 
 
Aseptically withdraw the calculated volume of the reconstituted product from the vial(s) with a sterile 
syringe and transfer it to an infusion bag containing 500 mL of 0.9% Sodium Chloride Injection, USP or 
5% Dextrose Injection, USP. There may be residual product remaining in the vial. Discard unused 
portion.  Gently invert the bag to mix the solution. The dilution of the reconstituted product results in a 
deep purple, translucent, homogeneous dispersion, free from visible particulates.  If the diluted infusion 
solution is not used immediately, store in refrigerator at 2ºC to 8ºC for up to 4 hours.  Parenteral drug 
products should be inspected visually for particulate matter and discoloration prior to administration, 
whenever solution and container permit. Only solutions without visible particles should be used. 
 
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. 
 
 
 
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. 
 
 
Patients will receive induction with CPX-351 at a dose of 100 u/m2 administered intravenously over 90 
minutes on days 1, 3 and 5 of a 28 day cycle.   
 
This may be followed by consolidation with CPX-351 at a dose of 65 u/m2 administered intravenously 
over 90 minutes on days 1 and 3 of a 28 day cycle. 
 
 
6.1.4 
PREPARATION, PRODUCT STORAGE AND STABILITY 
6.1.5 
DOSING AND ADMINISTRATION & ROUTE OF ADMINISTRATION 
6.1.7 
STARTING DOSE AND DOSE ESCALATION SCHEDULE 


LIST OF ABBREVIATIONS 
Protocol Title: CPX-351 for Relapsed/Refractory ALL                                                                                          Protocol V.3.0 
                                         
Protocol #: 19482                                                                                                                                                             11 Dec 2019 
 
 
 
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It is the intention of the study to treat every patient at full dose. 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. 
 
 
All patients completing induction will be evaluable for efficacy.  Consolidation may be started at the 
time of hematologic recovery (28-75 days after start of induction) for those achieving a complete 
remission or complete remission with incomplete hematologic recovery.  Consolidation cycles may be 
repeated at the time of hematologic recovery for a maximum total of 3 consolidation cycles. 
 
 
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 the Sponsor. Records 
of storage conditions (temperature logs) must be kept for the entire period that CPX-351 is maintained 
at the institution. 
 
 
 
 
 
 
The Schedule of Events - Section 7.3.7 summarizes the trial procedures to be performed at each visit.  
Individual trial procedures are described in detail below.  It may be necessary to perform these 
procedures at unscheduled time points if deemed clinically necessary by the investigator. 
 
Furthermore, additional evaluations/testing may be deemed necessary by the PI and/or Jazz 
Pharmaceuticals for reasons related to subject safety. In some cases, such evaluation/testing may be 
potentially sensitive in nature (e.g., HIV, Hepatitis C, etc.), and thus local regulations may require that 
additional consent be obtained from the subject.  In these cases, such evaluations/testing will be 
performed in accordance with those regulations. 
 
 
The majority of procedures and laboratory tests on this trial will performed per standard of care for ALL. 
Standard of care screening testing will include: bone marrow biopsy, echocardiogram/MUGA, EKG, 
serum pregnancy test, physical examination, CBC/differential, serum chemistry, vital signs, CSF/IT 
chemotherapy. During hospitalization, laboratory testing, supportive care measure, and procedures will 
be following standard of care as for any other ALL treatment.  
 
 
 
Prior to any study procedure that is not considered standard of care, informed consent must be 
obtained and documented by the subject’s dated signature or by the subject’s legally acceptable 
representative’s dated signature on a consent form. The dated signature of the person conducting the 
consent discussion must also appear on the consent form.  
6.1.8 
DOSE ADJUSTMENTS/MODIFICATIONS/DELAYS 
6.1.9 
DURATION OF THERAPY 
6.2 
STUDY AGENT ACCOUNTABILITY PROCEDURES 
7 
STUDY PROCEDURES AND SCHEDULE 
7.1 
STUDY PROCEDURES/EVALUATIONS 
7.1.1 
STUDY-SPECIFIC PROCEDURES 
7.1.2 
STANDARD OF CARE STUDY PROCEDURES 
7.1.3 
Informed Consent 


LIST OF ABBREVIATIONS 
Protocol Title: CPX-351 for Relapsed/Refractory ALL                                                                                          Protocol V.3.0 
                                         
Protocol #: 19482                                                                                                                                                             11 Dec 2019 
 
 
 
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Prior to any trial treatment, all inclusion and exclusion criteria will be reviewed and signed by the PI or 
Sub-Investigator to ensure the subject qualifies for the trial.  
 
 
Demographical information collected will include birth date, age, sex, race, and ethnicity. A medical 
history will be obtained by the investigator or qualified designee.  Medical history will include all active 
conditions and any condition diagnosed that is considered to be clinically significant by the 
Investigator.  Details regarding the disease for which the subject has enrolled in this study will be 
recorded separately and not listed as medical history.   
 
Baseline symptoms are defined as those present at the closest time before the start of study drug 
administration.  
 
 
The investigator or qualified designee will assess ECOG status (see Appendix B) as specified in the 
Schedule of Events.   
 
      
 
 
The investigator or qualified designee will record medication, if any, taken by the subject starting at 
screening until end of trial treatment.  All medications related to reportable SAEs should be recorded 
as defined in the SAE section of the protocol. 
 
 
The investigator or qualified designee will assess each subject to evaluate for potential new or 
worsening AEs as specified in the Schedule of Events and more frequently if clinically indicated.  
Adverse events will be collected from the time of consent until 30 days after last dose or until 
subsequent anti-leukemic therapy for those failing to show adequate response. 
 
 
The investigator or qualified designee will perform a complete physical exam during the screening 
period.  Clinically significant abnormal findings should be recorded as medical history.   
 
 
The investigator or qualified designee will take vital signs at screening and prior to the administration 
of each dose of trial treatment. Vital signs should include temperature, pulse, respiratory rate, weight 
and blood pressure.  Height will be measured at screening only. 
 
7.1.4 
Inclusion/Exclusion Criteria 
7.1.5 
Demographics and Medical History 
7.1.6 
Baseline Symptoms 
7.1.7 
Eastern Cooperative Oncology Group (ECOG) Performance Status 
7.1. 8        Concomitant Medications Review 
7.1.9 
Adverse Event Review 
7.1.10  
Physical Exam 
7.1.11 
Vital Signs 
7.1.12 
Laboratory Procedures 


LIST OF ABBREVIATIONS 
Protocol Title: CPX-351 for Relapsed/Refractory ALL                                                                                          Protocol V.3.0 
                                         
Protocol #: 19482                                                                                                                                                             11 Dec 2019 
 
 
 
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At screening laboratory procedures will include a CBC with differential, CMP (albumin, BUN, creatinine, 
alkaline phosphatase, ALT, AST, CO2, calcium, chloride, glucose, potassium, sodium, total bilirubin, 
total protein), LDH, uric acid, magnesium, phosphorus, coagulation studies, and urinalysis with 
microscopy. Laboratory testing on day one and during the hospitalization period, EOT, and follow-up 
will be at physician discretion per standard of care.  
 
A bone marrow biopsy will be performed at screening and at day 28. If determined the subject has 
extramedullary disease (as permitted in inclusion criterion #4), biopsy of the involved area will be the 
method by which correlative samples will be obtained, provided this can be safely obtained. If 
extramedullary disease is confirmed and the bone marrow biopsy is shown to be negative prior to trial 
participation, no bone marrow biopsy will be required at day 28. If subject discontinues treatment early 
or progression of disease is suspected, a bone marrow biopsy will be done at the discretion of the 
investigator. During follow-up, bone marrow biopsies will be performed per investigator discretion.  
 
 
Three different tests will be performed during the course of the trial. At screening, samples will be 
collected from bone marrow aspirate and peripheral blood. If determined the subject has 
extramedullary disease (as permitted in inclusion criterion #4), biopsy of the involved area will be the 
method by which correlative samples will be obtained. Biopsy will involve at least 6 core biopsies from 
the disease sites. If the biopsy of an extramedullary site is considered to put the subject at considerable 
risk, the subject may still participate in the trial without collection of the correlative samples.  At the day 
28 time point, the samples will be obtained from peripheral blood. Correlatives will be performed at 
investigator’s discretion if early study termination. For sampling requirements, see Section 7.2. 
 
 
If a potential study subject demonstrates clinical signs or symptoms of CNS involvement, a CSF sample will 
be obtained through a spinal tap. If CNS involvement is confirmed, the subject will not be eligible for study 
participation. Provided there are no contra-indications, prophylactic intrathecal methotrexate will be 
administered per standard of care, 7-10 days after initiation of CPX dosing.  
 
 
 
If a study subject is found to have extramedullary disease as permitted by inclusion criterion #4, the 
method for baseline disease assessment will be CT or PET/CT scan per standard of care. This method will 
also be used for determining response assessment on Day 28.  
 
 
 
 
• 
Hematology: hemoglobin, hematocrit, white blood cells (WBC) with differential count, platelet 
count. 
• 
Metabolic Panel: albumin, BUN, alkaline phosphatase, CO2, calcium, chloride, 
glucose, potassium, sodium, total protein, LDH, uric acid, magnesium, 
phosphorus, creatinine, total bilirubin, alanine aminotransferase (ALT), aspartate 
aminotransferase (AST). 
7.1.13 
Bone Marrow Biopsy 
7.1.14 
Correlative Studies 
7.1.15 
CSF for ALL Involvement/IT Chemotherapy 
7.1.16 
Imaging 
7.2 
LABORATORY PROCEDURES/EVALUATIONS 
7.2.1 
CLINICAL LABORATORY EVALUATIONS 


LIST OF ABBREVIATIONS 
Protocol Title: CPX-351 for Relapsed/Refractory ALL                                                                                          Protocol V.3.0 
                                         
Protocol #: 19482                                                                                                                                                             11 Dec 2019 
 
 
 
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• 
Urinalysis: complete urinalysis with microscopic evaluation 
• 
Pregnancy test: to be done within 24 hours prior to study intervention and results must be 
available prior to administration of study product. 
• 
Laboratory testing on day one and during the hospitalization period, EOT, and follow-up will 
be at physician discretion per standard of care. 
 
 
 
 
1. To explore the activity of CPX-351 ex vivo using live image capture in a reconstituted tumor micro-
environment (EVOS system) as a potential biomarker for response:  Primary patient ALL cells will 
be seeded into a 384-well plate onto reconstructed TME, which includes extracellular matrix 
(collagen 1) and human bone marrow derived stromal cells (BMSC).  CPX-351 dosed at 5 different 
concentrations will be added to the media, and plate is then continuously imaged for 96 hours.  A 
digital image analysis algorithm detects tumor cells based on cell size and membrane motion. 
Changes in viability are quantified by area under curve (AUC).  HBL-2 cells are used as a control. 
 
2. To identify potential drug candidates for future combinatorial approaches, including assessment 
of the T-cell repertoire, PDL1 expression by conventional immunohistochemistry, and BH3 
profiling.   
T-cell assessment:   Leukocytes will be isolated from BMBx aspirate sample by Ficoll-Hypaque 
gradient separation from RBCs (and other stromal elements, in the case of BMBx aspirate 
samples). Cells will be enumerated after 2 washes in PBS and allocated for flow cytometric 
analysis or for ex vivo culture in stimulation conditions.  Cells will be aliquoted into 200,000 cell 
fractions in preparation for subsequent analysis.  Leukocytes from each patient sample will be 
stained with fluorochrome-conjugated antibodies according to each of 3 analysis panels.  Panels 
have been designed to assess lymphocytes subsets, effector/memory maturation, and exhaustion. 
 
3. PDL1 expression: Will be determined on blasts/stroma using Dako antibody on formalin fixed 
paraffin embedded bone marrow core biopsy slides per routine. 
 
4. BH3 Profiling:  Briefly following membrane permeablization with digitonin, BH3 mimetic peptides 
targeting BIM, BAD, HRK, and MS-1 will be used to interrogate the contribution of BCL2, BCLXL, 
and MCL1 to mitochondrial outer membrane permeablization (MOMP).  The collapse of the 
transmembrane mitochondrial potential is used as a surrogate for MOMP, and estimated by 
fluorescence following rhodamine dye accumulation. 
 
5. Sampling of extramedullary disease will involve CT guided or excisional biopsy collection of 6 core 
biopsy samples (if possible), to be divided evenly between the two investigators’ laboratories 
assigned to perform the above tests. This will be done in accordance with the Moffitt Total Cancer 
Care (TCC) protocol. 
 
 
 
 
 
Screening Visit (Day -28 to -1)  
 
• 
Obtain and review medical history to determine eligibility based on inclusion/exclusion criteria. 
7.2.2 
OTHER ASSAYS OR PROCEDURES 
7.3 
STUDY SCHEDULE 
7.3.1 
SCREENING 


LIST OF ABBREVIATIONS 
Protocol Title: CPX-351 for Relapsed/Refractory ALL                                                                                          Protocol V.3.0 
                                         
Protocol #: 19482                                                                                                                                                             11 Dec 2019 
 
 
 
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• 
Written informed consent to be obtained prior to any screening procedures 
• 
Review medications history (including over-the-counter drugs, vitamins, herbs, alcohol) to 
determine eligibility based on inclusion/exclusion criteria.  
• 
Perform physical examination needed to determine eligibility based on inclusion/exclusion 
criteria 
• 
Vital signs measurements  
• 
Evaluation of ECOG performance status 
• 
Twelve-lead ECG and Echocardiogram or MUGA. 
• 
Serum beta-human chorionic gonadotropin (β-hCG) pregnancy test for women of childbearing 
potential 
• 
Clinical laboratory testing including urinalysis, serum chemistry, hematology, and coagulation 
parameters. Clinical assessments (laboratory tests, ECHO/MUGA, EKG) performed as part of the 
subject’s routine clinical evaluation and not specifically for this study need not be repeated after 
signed informed consent has been obtained provided the assessments fulfill the study 
requirements and are performed within 28 days of starting study treatment.  
• 
Bone marrow biopsy and peripheral blood sample will need to be repeated in order to collect 
correlative samples.  
• 
CT or PET/CT scan of affected areas for subjects determined to have extramedullary disease or 
for staging purposes prior to treatment.  
• 
Spinal tap if subject is determined to be symptomatic for CNS involvement 
 
 
 
 
 
7.3.2.1  Induction Baseline Visit (Day 1) 
 
• 
In-patient admission 
• 
Verify subject still meets inclusion/exclusion criteria. 
• 
Review results of serum pregnancy test, if applicable.  
 
• 
Assess and record baseline symptoms prior to study drug administration. 
• 
CBC with differential 
• 
Chemistry profile (ALT, AST, alkaline phosphatase, total bilirubin, calcium, bicarbonate, 
sodium, potassium, chloride, creatinine, BUN, total protein and albumin) 
• 
LDH, uric acid, magnesium, phosphorus 
• 
Initiation of induction therapy- study drug administration (CPX-351 intravenously) 
7.3.2.2  Induction Day 2 
7.3.2 
ENROLLMENT/BASELINE/STUDY VISITS 


LIST OF ABBREVIATIONS 
Protocol Title: CPX-351 for Relapsed/Refractory ALL                                                                                          Protocol V.3.0 
                                         
Protocol #: 19482                                                                                                                                                             11 Dec 2019 
 
 
 
16 
12123 
• 
CBC with differential 
• 
Chemistry profile (ALT, AST, alkaline phosphatase, total bilirubin, calcium, bicarbonate, 
sodium, potassium, chloride, creatinine, BUN, total protein and albumin) 
• 
LDH, uric acid, magnesium, phosphorus 
7.3.2.3  Induction Day 3 
• 
CBC with differential 
• 
Chemistry profile (ALT, AST, alkaline phosphatase, total bilirubin, calcium, bicarbonate, 
sodium, potassium, chloride, creatinine, BUN, total protein and albumin) 
• 
LDH, uric acid, magnesium, phosphorus 
• 
Study drug administration (initiation of CPX-351 intravenously) 
7.3.2.4  Induction Day 4 
• 
CBC with differential 
• 
Chemistry profile (ALT, AST, alkaline phosphatase, total bilirubin, calcium, bicarbonate, 
sodium, potassium, chloride, creatinine, BUN, total protein and albumin) 
• 
LDH, uric acid, magnesium, phosphorus 
7.3.2.5  Induction Day 5 
• 
CBC with differential 
• 
Chemistry profile (ALT, AST, alkaline phosphatase, total bilirubin, calcium, bicarbonate, 
sodium, potassium, chloride, creatinine, BUN, total protein and albumin) 
• 
LDH, uric acid, magnesium, phosphorus 
• 
Study drug administration (initiation of CPX-351 intravenously) 
7.3.2.6  Induction Day 6 
• 
CBC with differential 
• 
Chemistry profile (ALT, AST, alkaline phosphatase, total bilirubin, calcium, bicarbonate, 
sodium, potassium, chloride, creatinine, BUN, total protein and albumin) 
• 
LDH, uric acid, magnesium, phosphorus 
 
7.3.2.7  Induction Day 7 
• 
CBC with differential 


LI S T  O F  A B B R E VI A TI O N S  
Pr ot oc ol Titl e: C P X -3 5 1 f or R el a ps e d/ R efr act or y ALL                                                                                           Pr ot oc ol V. 3. 0 
                                         
Pr ot oc ol #: 1 9 4 8 2                                                                                                                                                             1 1 D ec 2 0 1 9   
 
 
 
1 7  
1 2 1 2 3  
•  
C h e mistr y pr ofil e ( AL T, A S T, al k ali n e p h os p h at as e, t ot al bilir u bi n, c alci u m, bic ar b o n at e, 
s o di u m, p ot assi u m, c hl ori d e, cr e ati ni n e, B U N, t ot al pr ot ei n a n d al b u mi n) 
•  
L D H, uric aci d, m a g n esi u m, p h os p h or us 
•  
P eri p h er al bl o o d s a m pl e f or c orr el ativ e st u di es  
•  
C S F s a m pl e/I T c h e m o ( if n o c o ntr ai n dic ati o ns, will b e p erf or m e d d ay 7 -1 0  s e e S ecti o n 
7. 1. 1 5)  
7. 3. 2. 8  I n d ucti o n D a y 1 0  
•  
C B C wit h diff er e nti al  
•  
C h e mistr y pr ofil e ( AL T, A S T, al k ali n e p h os p h at as e, t ot al bilir u bi n, c alci u m, bic ar b o n at e, 
s o di u m, p ot assi u m, c hl ori d e, cr e ati ni n e, B U N, t ot al pr ot ei n a n d al b u mi n) 
•  
L D H, uric aci d, m a g n esi u m, p h os p h or us 
•  
C S F s a m pl e/I T c h e m o (if n ot p erf or m e d o n d a y 7, 8, or 9)  
•  
C o nti n u o us h os pit aliz ati o n u ntil d et er mi n e d t o h av e acc e pt a bl e b o n e m arr o w r ec o v er y  
7. 3. 2. 9  I n d ucti o n D a y 2 8  
•  
C B C wit h diff er e nti al  
•  
C h e mistr y pr ofil e ( AL T, A S T, al k ali n e p h os p h at as e, t ot al bilir u bi n, c alci u m, bic ar b o n at e, 
s o di u m, p ot assi u m, c hl ori d e, cr e ati ni n e, B U N, t ot al pr ot ei n a n d al b u mi n) 
•  
L D H, uric aci d, m a g n esi u m, p h os p h or us 
•  
B o n e m arr o w bi o psy , if b o n e m arr o w bi o psy is p ositiv e at scr e e ni n g 
•  
C T or  P E T/ C T  sc a n of  aff ect e d  ar e as  f or  r es p o ns e  ass ess m e nt  f or  s u bj ects  wit h  
extr a m e d ull ar y dis e as e  
•  
P eri p h er al bl o o d s a m pl e f or c orr el ativ e st u di es  
7. 3. 2. 1 0  I n d ucti o n D a y 2 9 +  
•  
C o nti n u o us h os pit aliz ati o n u ntil d et er mi n e d t o  h av e acc e pt a bl e b o n e m arr o w r ec o v er y  
•  
L a b or at ory t esti n g c o nti n u es p er st a n d ar d of c ar e u ntil h os pit al disc h ar g e  
7. 3. 2. 1 1  First C o ns oli d ati o n T h er a p y  D a y 1  
•  
S u bj ect h as d oc u m e nt e d r es p o ns e  (C R , Cri, or P R, s e e A p p e n dix A), or i n t h e o pi ni o n of 
t h e pri nci p al i nv esti g at or is s h o wi n g cli nic al b e n efit wit h a d e q u at e c o u nt r ec ov ery ( A N C > 
5 0 0/ L a n d plat e le t s > 5 0, 0 0 0/  L). 
•  
C B C wit h diff er e nti al  


LI S T  O F  A B B R E VI A TI O N S  
Pr ot oc ol Titl e: C P X -3 5 1 f or R el a ps e d/ R efr act or y ALL                                                                                           Pr ot oc ol V. 3. 0 
                                         
Pr ot oc ol #: 1 9 4 8 2                                                                                                                                                             1 1 D ec 2 0 1 9   
 
 
 
1 8  
1 2 1 2 3  
•  
C h e mistr y pr ofil e ( AL T, A S T, al k ali n e p h os p h at as e, t ot al bilir u bi n, c alci u m, bic ar b o n at e, 
s o di u m, p ot assi u m, c hlori d e, cr e ati ni n e, B U N, t ot al pr ot ei n a n d al b u mi n)  
•  
D a y 1 m ust b e gi v e n 2 8  d ays -7 5 d ays aft er st art of i n d ucti o n  
•  
St u dy dr u g a d mi nistr ati o n (i niti ati o n of C P X -3 5 1 i ntr av e n o usl y)  
7. 3. 2. 1 2  First C o ns oli d ati o n T h er a p y D a y 3  
•  
C B C wit h diff er e nti al  
•  
C h e mistr y pr ofil e ( AL T, A S T, al k ali n e p h os p h at as e, t ot al bilir u bi n, c alci u m, bic ar b o n at e, 
s o di u m, p ot assi u m, c hl ori d e, cr e ati ni n e, B U N, t ot al pr ot ei n a n d al b u mi n) 
•  
St u dy dr u g a d mi nistr ati o n (i niti ati o n of C P X -3 5 1 i ntr av e n o usl y)  
7. 3. 2. 1 3 First C o ns oli d ati o n D a y 2 8  
•  
C B C  wit h diff er e nti al  
•  
C h e mistr y pr ofil e ( AL T, A S T, al k ali n e p h os p h at as e, t ot al bilir u bi n, c alci u m, bic ar b o n at e, 
s o di u m, p ot assi u m, c hl ori d e, cr e ati ni n e, B U N, t ot al pr ot ei n a n d al b u mi n) 
•  
L D H, uric aci d, m a g n esi u m, p h os p h or us 
•  
B o n e m arr o w bi o psy , if b o n e m arr o w bi o psy is p ositiv e at scr e e ni n g 
•  
C T or P E T/ C T sc a n of aff ect e d ar e as t o ass ess r es p o ns e f or s u bj ects wit h extr a m e d ull ar y 
dis e as e  
7. 3. 2. 1 4 S ec o n d,  a n d  T hir d C o ns oli d ati o n T h er a p y D a y 1  
•  
S u bj ect h as d oc u m e nt e d r es p o ns e  (C R ,C Ri , or P R, s e e A p p e n dix A), or i n t h e o pi ni o n of 
t h e pri nci p al  i nv esti g at or is d e m o nstr ati n g  cli nic al b e n efit wit h a d e q u at e c o u nt r ec ov ery 
( A N C > 5 0 0/L a n d plat elets > 5 0, 0 0 0/
L) 
•  
C B C wit h diff er e nti al  
•  
C h e mistr y pr ofil e ( AL T, A S T, al k ali n e p h os p h at as e, t ot al bilir u bi n, c alci u m, bic ar b o n at e, 
s o di u m, p ot assi u m, c hl ori d e, cr e ati ni n e, B U N, t ot al pr ot ei n a n d al b u mi n) 
•  
Ec h oc ar di o gr a m  will  b e  r e p e at e d  f or  a ny  p ati e nt  wit h  > 5 5 0 m g/ m 2  d a u n or u bici n  ( or  
d a u n or u bici n  a nt hr ac ycli n e e q ui v al e nt) ex p os ur e.  T h er a py will o nl y b e p er mitt e d if t h e 
ej ecti o n fr acti o n r e m ai ns > 5 0 %  a n d wit h o ut > 1 0 % d ecr e as e i n ej ecti o n fr acti o n fr o m 
b as eli n e.  
•  
D a y 1 m ust b e gi v e n 2 8  d ays -5 6 d ays aft er st art of t h e pr e vi o us c o ns oli d ati o n 
•  
St u dy dr u g a d mi nistr ati o n (i niti ati o n of C P X -3 5 1 i ntr av e n o usl y)  
7. 3. 2. 1 5  S ec o n d a n d T hir d C o ns oli d ati o n D a y 3  


LIST OF ABBREVIATIONS 
Protocol Title: CPX-351 for Relapsed/Refractory ALL                                                                                          Protocol V.3.0 
                                         
Protocol #: 19482                                                                                                                                                             11 Dec 2019 
 
 
 
19 
12123 
• 
CBC with differential 
• 
Chemistry profile (ALT, AST, alkaline phosphatase, total bilirubin, calcium, bicarbonate, 
sodium, potassium, chloride, creatinine, BUN, total protein and albumin) 
• 
Study drug administration (initiation of CPX-351 intravenously) 
7.32.16 Second and Third Consolidation Day 28 
• 
CBC with differential 
• 
Chemistry profile (ALT, AST, alkaline phosphatase, total bilirubin, calcium, bicarbonate, 
sodium, potassium, chloride, creatinine, BUN, total protein and albumin) 
• 
LDH, uric acid, magnesium, phosphorus 
• 
Bone marrow biopsy, if bone marrow biopsy is positive at screening 
• 
CT or PET/CT scan of affected areas to assess response for subjects with extramedullary 
disease 
7.3.2.17  End of Treatment Visit  
• 
Visit occurs 30 days (+10 days) after the last dose of study drug 
• 
May occur earlier if initiating subsequent antineoplastic therapy 
• 
Assess adverse events 
 
 
After the end of treatment assessment, all subjects will be followed with procedures and physical 
examinations per standard of care.  
 
 
When it is determined the study is to be final closed, a Final Study Visit will be performed. This visit will 
occur at the next regularly scheduled standard of care Follow-Up Visit after trial closure is confirmed. 
Any AE that is ongoing will be considered ongoing at the Final Study Visit.  
 
Final instructions will be provided to the subject and the subject will be informed if results will be 
available or any planned presentation or publication of study data.   
 
 
If a subject terminates study participation for any reason prior to completion of the protocol treatment plan, 
any subsequent procedures or evaluations will be per physician discretion as part of standard of care. 
Evaluation of AEs will continue as outlined in Section 7.1.9.  
 
 
Any visit not included on the Schedule of Events Table that includes examination in the Moffitt 
hematology clinic, inpatient hospitalization or any unexpected extended hospitalization, laboratory 
7.3.3 
FOLLOW-UP 
7.3.4 
FINAL STUDY VISIT 
7.3.5 
EARLY TERMINATION VISIT 
7.3.6 
UNSCHEDULED VISIT 


LIST OF ABBREVIATIONS 
Protocol Title: CPX-351 for Relapsed/Refractory ALL                                                                                          Protocol V.3.0 
                                         
Protocol #: 19482                                                                                                                                                             11 Dec 2019 
 
 
 
20 
12123 
evaluations or management of adverse events, will be considered an Unscheduled Visit. It will be 
documented in the subject’s medical record and included on the adverse event log. Adverse event or 
serious adverse event data will be collected in Oncore. No separate Oncore form for an unscheduled 
visit will be used to collect additional data. 
 
 
 
 
 
 
 
Procedures:                                   
Day: 
Screeninga 
1 
2 
3 
4 
5 
6 
7 
10 
28 
29+i 
End of  
Treatment/ 
Early 
Term.g 
Follow-
Up 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics and  
Medical History 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Baseline Symptomsb 
 
X 
 
 
 
 
 
 
 
 
 
 
 
day Performance Status 
X 
 
 
 
 
 
 
 
 
 
Concomitant Medication 
Review 
X 
Assess throughout Induction and 
Consolidation 
 
 
Review Adverse Eventsc 
 
Assess throughout Induction and 
Consolidation 
X 
 
CPX-351 Administrationd 
 
X 
 
X 
 
X 
 
 
 
 
 
 
 
Physical Examination 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Serum pregnancy teste 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Vital signs (temp, pulse, resp, 
BP, weight) 
X 
X 
 
X 
 
X 
Per SOC 
Height 
X 
 
 
 
 
 
 
 
 
 
 
 
 
12-lead EKG 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Echocardiography/MUGA 
X 
 
 
 
 
 
 
 
 
 
Xl 
 
 
CBC with differential 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Per SOC 
Serum chemistry testing f 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Per SOC 
LDH, uric acid, magnesium, 
phosphorus  
X 
X 
X 
X 
X 
X 
X 
X 
As needed 
 
 
Coagulation studies  
(PT/INR, aPTT, fibrinogen) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Urinalysis with microscopy 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Bone marrow biopsyk 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
CT or PET/CT Scanm 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
Correlative studiesh 
      X1,2,3 
 
 
 
 
 
 
 
 
X3 
 
 
 
CSF for ALL involvement/IT 
chemoj 
X 
 
 
 
 
 
 
X 
 
 
 
 
Follow-Up 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
a. Screening assessments will be performed within 28 days of the dose of study drug Day 1. Any standard of care 
procedure performed within 28 days of Day 1, may be used for screening/eligibility even if performed prior to 
consent. 
b. Baseline symptoms are defined as those present at the closest time before the start of study drug 
administration. 
c. 
Adverse event data will be captured from the time of consent until 30 days after the last dose of CPX-351.  
7.3.7 
SCHEDULE OF EVENTS TABLE 


LIST OF ABBREVIATIONS 
Protocol Title: CPX-351 for Relapsed/Refractory ALL                                                                                          Protocol V.3.0 
                                         
Protocol #: 19482                                                                                                                                                             11 Dec 2019 
 
 
 
21 
12123 
d. CPX-351 induction therapy will only be administered to a subject following hospital admission. One induction 
will be administered.  Patients with a CR, CRi, PR or determined by the PI to be experiencing clinical benefit 
after induction, may receive up to 3 consolidation treatments, all administered as an outpatient. First 
consolidation must be administered no earlier than 35-75 days after day 1 of induction. Second and third 
consolidations will be administered no earlier than 35-56 days after the start of the previous consolidation.  
e. Serum pregnancy test will be performed on females of childbearing potential (FCBP). A FCBP is considered 
when a sexually mature female: 1) has not undergone a hysterectomy or bilateral oophorectomy; or 2) has not 
been naturally postmenopausal for at least 12 consecutive months.    
f. 
Serum chemistry testing will include the following: albumin, BUN, creatinine, alkaline phosphatase, ALT, AST, 
CO2, calcium, chloride, glucose, potassium, sodium, total bilirubin, total protein.  
g. 
The EOT visit will occur 30 days (+10 days) after the last dose of study drug or before the start of subsequent 
antineoplastic therapy if that occurs sooner. 
h. Correlative studies will be performed as below: 
1. BH3 protein- bone marrow/core biopsy 
2. Ex vivo drug sensitivity assay- bone marrow/core biopsy 
3. T-cell profile- bone marrow/core biopsy/peripheral blood 
4. PDL1 immunohistochemistry- bone marrow/core biopsy 
i. 
After induction day 28 and through consolidation therapy, laboratory testing will be continued as necessary per 
standard of care.  
j. 
Only obtained at screening if symptomatic.  Per standard of care, CSF (if no contraindications) will be obtained 
7-10 days after initiation of CPX dosing and IT methotrexate will be administered. See Section 7.1.15. 
k. 
Bone marrow biopsy will be at screening and day 28 of induction therapy. During consolidation therapy, a bone 
marrow biopsy will be performed on day 28 (+7 days) after the start of each consolidation per standard of care.  
l. 
Echocardiogram will be repeated for any patient with >550mg/m2 daunorubicin (or daunorubicin anthracycline 
equivalent) exposure.  Therapy will only be permitted if the ejection fraction remains >50% and without >10% 
decrease in ejection fraction from baseline. 
m. CT or PET/CT scan will be utilized at screening and Day 28 as response assessment for subjects with 
extramedullary disease or for staging purposes as determined by the investigator.  
 
 
All subjects should be maintained on the same medications throughout the study period, as medically 
feasible. 
The investigator should instruct the subject to notify the study staff about any new medications he/she 
takes after the start of the study drug. All medications (other than study drug) and significant non-drug 
therapies (including physical therapy and blood transfusions) administered after the subject starts 
treatment with study drug must be recorded: 
 
• 
Administration of pegfilgrastim or filgrastim following initiation of protocol therapy will occur for all 
patients. It is suggested dosing start at Day 6.  
• 
Administration of erythropoietin or darbopoietin is allowed; 
• 
Patients must be instructed not to take any additional medications (including herbal supplements and 
over-the-counter products) during the trial without prior consultation with the investigator. All 
medications taken within 30 days of screening should be recorded. If concomitant therapy must be 
added or changed, the reason and name of the drug/therapy should be recorded; 
• 
In general, the use of any concomitant medication/therapies deemed necessary for the care of the 
patient are allowed, including drugs given prophylactically (e.g. antiemetics). 
 
 
7.4 
CONCOMITANT MEDICATIONS, TREATMENTS, AND PROCEDURES 
7.5 
JUSTIFICATION FOR SENSITIVE PROCEDURES 


LIST OF ABBREVIATIONS 
Protocol Title: CPX-351 for Relapsed/Refractory ALL                                                                                          Protocol V.3.0 
                                         
Protocol #: 19482                                                                                                                                                             11 Dec 2019 
 
 
 
22 
12123 
 
 
• 
Subjects will not routinely be pre-medicated for hypersensitivity or infusion-related reactions initially 
during the first infusion of the first treatment course. If a reaction occurs, pre-medications for 
subsequent infusions will be at investigator discretion. Infusion reactions will be treated per Moffitt 
institutional standards.  
• 
In previous clinical trials, no drug or food interactions were identified as being associated with CPX-
351. 
 
 
• 
An evaluation of prior exposure to anthracyclines should be performed during screening. Per the 
study Exclusion Criteria, subjects with prior cumulative anthracycline exposure of greater than 368 
mg/m2 daunorubicin will be excluded. 
• 
High dose corticosteroids used for management of ALL symptoms are permitted up to one day 
prior to the first dose of study drug. Corticosteroids required as pre-medication for CT scans or for 
short-term use as treatment for adverse events, are permitted in consultation with the PI.  
• 
Other anti-cancer treatment is not permitted during the treatment phase of the study. 
 
 
• 
Subjects may be pre-medicated for nausea and vomiting at investigator discretion. 
• 
Patients may receive ongoing supportive and palliative care (e.g. pain control) as clinically 
indicated throughout the study. 
• 
Prophylactic use of anti-infectives is highly recommended during the period of profound 
neutropenia until ANC returns to 500/μL or greater. The choice of anti-infectives will be per Moffitt 
institutional standard of care.  
• 
Growth factor support will be administered according to Moffitt protocol. 
• 
The use of transfusion support (RBCs and platelets) will be according to standard of care. 
 
 
• 
Growth factor support with granulocyte stimulating factor will be administered according to 
Moffitt protocol for the treatment of cytopenias 
• 
The use of transfusion support (RBCs and platelets) will be according to standard of care as rescue 
therapy for anemia or thrombocytopenia. 
• 
Corticosteroids and antihistamines may be administered per Moffitt protocol for the treatment of 
hypersensitivity reactions should they emerge.  
 
 
 
 
 
 
An adverse event means any untoward medical occurrence associated with the use of an intervention in 
humans, whether or not considered intervention-related (21 CFR 312.32 (a)). 
 
The investigator or qualified designee will assess each subject to evaluate for potential new or 
worsening AEs as specified in the Schedule of Events and more frequently if clinically indicated.  
Adverse experiences will be graded and recorded throughout the study and during the follow-up 
7.5.1 
PRECAUTIONARY MEDICATIONS, TREATMENTS, AND PROCEDURES 
7.6 
PROHIBITED MEDICATIONS, TREATMENTS, AND PROCEDURES 
7.7 
PROPHYLACTIC MEDICATIONS, TREATMENTS, AND PROCEDURES 
7.8 
RESCUE MEDICATIONS, TREATMENTS, AND PROCEDURES 
8 
ASSESSMENT OF SAFETY 
8.1 
SPECIFICATION OF SAFETY PARAMETERS 
8.1.1 
DEFINITION OF ADVERSE EVENTS (AE) 


LIST OF ABBREVIATIONS 
Protocol Title: CPX-351 for Relapsed/Refractory ALL                                                                                          Protocol V.3.0 
                                         
Protocol #: 19482                                                                                                                                                             11 Dec 2019 
 
 
 
23 
12123 
period. The descriptions and grading scales found in the revised NCI Common Terminology Criteria for 
Adverse 
Events 
(CTCAE) 
version 
5.0 
will 
be 
utilized 
for 
adverse 
event 
reporting. 
(http://ctep.cancer.gov/reporting/ctc.html) 
Toxicities will be characterized in terms regarding seriousness, causality, toxicity grading, and action 
taken with regard to trial treatment.  
 
 
Adverse events and suspected adverse reactions are considered "serious" if, in the view of either the 
investigator or sponsor, they result in any of the following outcomes: death, a life-threatening adverse 
event, inpatient hospitalization or prolongation of existing hospitalization, a persistent or significant 
incapacity or substantial disruption of the ability to conduct normal life functions, or a congenital 
anomaly/birth defect. Important medical events that may not result in death, be life-threatening, or 
require hospitalization may be considered serious when, based upon appropriate medical judgment, 
they may jeopardize the patient or subject and may require medical or surgical intervention to prevent 
one of the outcomes listed in this definition.  
 
 
 
Unanticipated problems (UPs) involving risks to participants or others to include, in general, any 
incident, experience, or outcome that meets all of the following criteria: 
 
• 
Unexpected in terms of nature, severity, or frequency given (a) the research procedures that are 
described in the protocol-related documents, such as the IRB-approved research protocol and 
informed consent document; and (b) the characteristics of the participant population being 
studied; 
• 
Related or possibly related to participation in the research (“possibly related” means there is a 
reasonable possibility that the incident, experience, or outcome may have been caused by the 
procedures involved in the research); and 
• 
Suggests that the research places participants or others at a greater risk of harm (including 
physical, psychological, economic, or social harm) than was previously known or recognized.  
 
 
 
 
 
 
All AEs will be graded using the CTCAE 5.0 criteria.  
 
For AEs not included in the protocol-defined grading system, the following guidelines will be used to 
describe severity. 
 
• 
Mild – Events require minimal or no treatment and do not interfere with the participant’s daily 
activities. 
• 
Moderate – Events result in a low level of inconvenience or concern with the therapeutic 
measures. Moderate events may cause some interference with functioning. 
• 
Severe – Events interrupt a participant’s usual daily activity and may require systemic drug 
therapy or other treatment. Severe events are usually potentially life-threatening or 
8.1.2 
DEFINITION OF SERIOUS ADVERSE EVENTS (SAE) 
8.1.3 
DEFINITION OF UNANTICIPATED PROBLEMS 
8.2 
CLASSIFICATION OF AN ADVERSE EVENT 
8.2.1 
SEVERITY OF EVENT 


LIST OF ABBREVIATIONS 
Protocol Title: CPX-351 for Relapsed/Refractory ALL                                                                                          Protocol V.3.0 
                                         
Protocol #: 19482                                                                                                                                                             11 Dec 2019 
 
 
 
24 
12123 
incapacitating. 
 
 
For all collected AEs, the investigator will evaluate the participant and will determine the AE’s causality 
based on temporal relationship and his/her clinical judgment. The degree of certainty about causality 
will be graded using the categories below. 
 
 
• 
Definitely Related – There is clear evidence to suggest a causal relationship, and other possible 
contributing factors can be ruled out. The clinical event, including an abnormal laboratory test 
result, occurs in a plausible time relationship to drug administration and cannot be explained by 
concurrent disease or other drugs or chemicals. The response to withdrawal of the drug 
(dechallenge) should be clinically plausible. The event must be pharmacologically or 
phenomenologically definitive, with use of a satisfactory rechallenge procedure if necessary. 
• Probably Related – There is evidence to suggest a causal relationship, and the influence of other 
factors is unlikely. The clinical event, including an abnormal laboratory test result, occurs within 
a reasonable time after administration of the drug, is unlikely to be attributed to concurrent 
disease or other drugs or chemicals, and follows a clinically reasonable response on withdrawal 
(dechallenge). Rechallenge information is not required to fulfill this definition. 
• 
Possibly Related – There is some evidence to suggest a causal relationship (e.g., the event 
occurred within a reasonable time after administration of the trial medication). However, other 
factors may have contributed to the event (e.g., the participant’s clinical condition, other 
concomitant events). Although an AE may rate only as “possibly related” soon after discovery, it 
can be flagged as requiring more information and later be upgraded to “probably related” or 
“definitely related,” as appropriate. 
• 
Unlikely to be related – A clinical event, including an abnormal laboratory test result, whose 
temporal relationship to drug administration makes a causal relationship improbable (e.g., the 
event did not occur within a reasonable time after administration of the trial medication) and in 
which other drugs or chemicals or underlying disease provides plausible explanations (e.g., the 
participant’s clinical condition, other concomitant treatments). 
• 
Unrelated – The AE is completely independent of study drug administration, and/or evidence 
exists that the event is definitely related to another etiology. There must be an alternative, 
definitive etiology documented by the clinician. 
 
 
 
The PI will be responsible for determining whether an AE is expected or unexpected. An AE will be 
considered unexpected if the nature, severity, or frequency of the event is not consistent with the risk 
information previously described for the study agent. 
 
 
The occurrence of an AE or SAE may come to the attention of study personnel during study visits and 
interviews with study participants presenting for medical care, or upon review by a study monitor. All 
AEs, including local and systemic reactions not meeting the criteria for SAEs, will be captured on the 
appropriate CRF. Information to be collected includes event description, time of onset, clinician’s 
assessment of severity, relationship to study product (assessed only by those with the training and 
authority to make a diagnosis), and time of resolution/stabilization of event. All AEs occurring during 
the study must be documented appropriately, regardless of relationship. All AEs will be followed to 
adequate resolution. 
8.2.2 
RELATIONSHIP TO STUDY AGENT 
8.2.3 
EXPECTEDNESS 
8.3 
TIME PERIOD AND FREQUENCY FOR EVENT ASSESSMENT AND FOLLOW-UP 


LIST OF ABBREVIATIONS 
Protocol Title: CPX-351 for Relapsed/Refractory ALL                                                                                          Protocol V.3.0 
                                         
Protocol #: 19482                                                                                                                                                             11 Dec 2019 
 
 
 
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Any medical condition that is present at the time that the participant is screened will be considered as 
baseline and not reported as an AE. However, if the study participant’s condition deteriorates at 
anytime during the study, it will be recorded as an AE. UPs will be recorded in the data collection system 
throughout the study. 
 
Changes in the severity of AEs will be documented to allow an assessment of the duration of the event 
at each level of severity to be performed. AEs characterized as “intermittent” require documentation of 
onset and duration of each episode in the medical record. 
 
Adverse events for the purpose of this study will be will be reported from the time period beginning 
when the consent form is signed until 30 days after study drug discontinuation. Events will be followed 
for outcome information until resolution or stabilization is achieved. Any AE present at the time of final 
study closure will be considered ongoing.  
 
 
 
 
Adverse event documentation will be performed by entry into the Moffitt OnCore electronic database. 
Reporting of adverse events to the FDA for IND renewal will occur annually by a report obtained from 
the AEs collected in OnCore.  Reporting to Jazz Pharmaceuticals will be as noted in the section on AEs of 
special interest.   
 
All AEs will be documented on a paper log with columns for the replication of the fields in the OnCore 
AE data form. The treating physician/investigator will review the log for accuracy and assign CTCAE 
grade and the attribution of a study agent to the AE.  
 
Adverse events for the purpose of this study will be reported from the time period beginning when the 
consent form is signed until 30 days after study drug discontinuation.  
 
 
 
All SAEs will be followed until satisfactory resolution or until the site investigator deems the event to be 
chronic or the adherence to be stable. Other supporting documentation of the event may be requested 
by Jazz Pharmaceuticals, Inc. and should be provided as soon as possible. Moffitt as the study sponsor 
will be responsible for notifying FDA of any unexpected fatal or life-threatening suspected adverse 
reaction as soon as possible but in no case later than 7 calendar days after the sponsor's initial receipt 
of the information. 
 
 
 
Incidents or events that meet the OHRP criteria for UPs require the creation and completion of an UP 
report form. It is the site investigator’s responsibility to report UPs to their IRB and to Jazz 
Pharmaceuticals, Inc. The UP report will include the following information: 
 
• 
Protocol identifying information: protocol title and number, PI’s name, and the IRB project 
number; 
• 
A detailed description of the event, incident, experience, or outcome; 
8.4 
REPORTING PROCEDURES 
8.4.1 
ADVERSE EVENT REPORTING 
8.4.2 
SERIOUS ADVERSE EVENT REPORTING 
8.4.3 
UNANTICIPATED PROBLEM REPORTING 


LIST OF ABBREVIATIONS 
Protocol Title: CPX-351 for Relapsed/Refractory ALL                                                                                          Protocol V.3.0 
                                         
Protocol #: 19482                                                                                                                                                             11 Dec 2019 
 
 
 
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• 
An explanation of the basis for determining that the event, incident, experience, or outcome 
represents an UP; 
• 
A description of any changes to the protocol or other corrective actions that have been taken or 
are proposed in response to the UP. 
 
To satisfy the requirement for prompt reporting, UPs will be reported using the following timeline: 
 
• 
UPs that are SAEs will be reported to the IRB and to the study sponsor within 24 hours of 
the investigator becoming aware of the event. 
• 
Any other UP will be reported to the IRB and to the study sponsor within 2 business days of the 
investigator becoming aware of the problem. 
• 
All UPs should be reported to appropriate institutional officials (as required by an institution’s 
written reporting procedures) and the supporting agency head (or designee), within 7 days of 
the IRB’s receipt of the report of the problem from the investigator.  
 
 
 
1. Cardiotoxicity: Current studies estimate the risk of cardiotoxicity to be low, perhaps related to the 
liposomal formulation.  However, given that patients will have likely had prior anthracycline exposure 
(up to a maximum of 368 mg/m2 daunorubicin or equivalent), we will obtain baseline echocardiogram 
or MUGA to ensure adequate ejection fraction.  Followup echocardiogram or MUGA will be performed 
in all patients with symptomatic heart failure, defined as follows: worsening 1) dyspnea on exertion, 2) 
orthopnea, and/or 3) paroxysmal nocturnal dyspnea - with following concomitant findings of fluid 
overload on exam not well explained by prior therapy (such as hydration related to an episode of 
sepsis), including: 1) development of a third heart sound, 2) jugular venous distention with positive 
hepatojugular reflex,  3) pulmonary rales, and/or 4) lower extremity edema (ref 31).  Follow-up 
echocardiogram or MUGA prior to each cycle of consolidation will be performed for all patients 
exceeding 550 mg/m2 daunorubicin (or equivalent) .  Patients with an ejection fraction of <50% or a 
decrease of >10% from baseline will discontinue consolidation therapy. The development of 
symptomatic heart failure and/or decrease in ejection fraction to <50%, or >10% from baseline will be 
reported to Jazz Pharmaceuticals. 
 
2. Bone marrow aplasia: Liposomal delivery of chemotherapy may facilitate increased deposition within 
hematopoietic stem cells, culminating in delay or failure to recover hematopoietic cell reconstitution 
following therapy.  In particular, a hypocellular marrow without adequate count recovery >42 days 
from start of induction or consolidation cycles will be reported to the sponsor. 
 
 
 
If a pregnancy occurs in a female subject enrolled into the study, or a female partner of a male subject 
within 30 days of completing the CPX-351 infusion, the pregnancy must be reported to the key sponsor 
contact. Information regarding the pregnancy and/or the outcome may be requested by the key 
sponsor.  
 
In addition to reporting any pregnancies occurring during the study, investigators will monitor for 
pregnancies that occur after the last dose of CPX-351 through 3 months for female subjects and for 6 
months for the female partner of the male subjects.  
 
The pregnancy should be reported to the key sponsor contact within 24 hours of the investigators 
knowledge of the pregnancy event.  
8.4.4 
EVENTS OF SPECIAL INTEREST 
8.4.5 
REPORTING OF PREGNANCY 


LIST OF ABBREVIATIONS 
Protocol Title: CPX-351 for Relapsed/Refractory ALL                                                                                          Protocol V.3.0 
                                         
Protocol #: 19482                                                                                                                                                             11 Dec 2019 
 
 
 
27 
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If a lactation case occurs while the female subject is taking protocol required therapies report the 
lactation case to the key sponsor contact.  
 
In addition to reporting a lactation case during the study, investigators should monitor for lactation 
cases that occur after the last dose of protocol required therapies through 3 months.  
 
 
Safety assessments will consist of monitoring and recording all adverse events and serious adverse 
events, the regular monitoring of hematology and blood chemistry parameters and regular physical 
examinations. Adverse events will be evaluated continuously throughout the study. Safety and 
tolerability will be assessed according to the NIH/NCI Common Terminology Criteria for Adverse Events 
version (CTCAE v5.0) that is available at: http://evs.nci.nih.gov/ftp1/CTCAE/About.html 
The Protocol Monitoring Committee (PMC) at Moffitt monitors its assigned ongoing research protocols 
for: adverse event reporting, data and safety monitoring, and internal audit findings. The PMC, upon 
review of any agenda item, may approve the study for continuation, require revisions, suspend or close 
a protocol.  The PMC meets monthly and reviews accrual, patterns and frequencies of all adverse 
events, protocol violations and when applicable, internal audit results. 
 
Investigators of studies which are designated to be reviewed by the PMC for data and safety monitoring,  
shall provide a statistical report of the study’s progress and summary of adverse events and deviations 
based on the phase of the study and the associated risk of the study or more often if applicable. The PI 
will be notified for recommendations or notifications after the PMC review in regards of continuation or 
stopping the clinical trial. 
 
 
 
 
Serious Adverse Events: Serious Adverse Events (SAEs) from this protocol will be reported concurrently 
to the IRB (per IRB guidelines) and Jazz Pharmaceuticals, Inc. within 24 hours of staff awareness of the 
event. The Protocol Monitoring Committee (PMC) will review these SAEs in accordance with their 
policy. The data and safety plan will define dose limiting toxicities and criteria for stopping the trial 
according to rules set forth by this protocol. This trial will be continuously monitored by the PI and the 
research team. A final safety and monitoring report will be submitted to the PMC. This protocol will be 
subject to periodic internal audits based on risk or as recommended by the PMC. 
 
 
 
Data will be captured in OnCore, Moffitt’s electronic Clinical Trials Database. For each participant 
enrolled, the electronic CRF must be completed by the assigned data manager or other authorized 
study staff. Any paper forms should be typed or filled out indelible ink and must be legible. Errors 
should be crossed out but not obliterated, the correction inserted, and the change initialed and dated 
by the investigator or his/her authorized delegate. This also applies to records for those patients who 
fail to complete the study. If a patient stops dosing or terminates from the study, the dates and 
reasons must be noted on the CRF. If a patient terminates from the study because of a DLT, thorough 
efforts should be made to clearly document the outcome.  
 
Regulatory documents and case report forms will be monitored internally according to Moffitt Cancer 
Center Monitoring Policies. Monitoring will be performed regularly by the MCC Clinical Monitoring 
8.5 
STUDY HALTING RULES 
8.6 
SAFETY OVERSIGHT 
9 
CLINICAL MONITORING 


LIST OF ABBREVIATIONS 
Protocol Title: CPX-351 for Relapsed/Refractory ALL                                                                                          Protocol V.3.0 
                                         
Protocol #: 19482                                                                                                                                                             11 Dec 2019 
 
 
 
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Core for accuracy, completeness, and source verification of data entry, validation of appropriate 
informed consent process, reporting of SAEs, adherence to the protocol, Good Clinical Practice (GCP) 
guidelines, and applicable regulatory requirements. 
 
 
 
 
 
The following study is a phase 2 pilot trial.  Exploratory analyses of remission rate, safety, progression free 
survival, and overall survival are planned. 
 
 
• 
All Endpoints are exploratory, and may be used to facilitate design of an expansion or subsequent 
phase 2 study. 
• 
Primary Efficacy Endpoint: 
• 
Complete Remission and Complete Remission with incomplete hematologic recovery will 
serve as the primary endpoint.   
• 
Secondary Efficacy Endpoint(s): 
• 
Safety 
• 
Minimal Residual Disease Remission Rate 
• 
Progression Free Survival 
• 
Overall Survival 
 
• 
All patients receiving at least one dose of CPX-351will be evaluable for safety.   
• 
Efficacy analyses will be restricted to those receiving a full cycle of induction therapy. 
 
 
 
This will be a phase 2 pilot trial to assess efficacy of CPX-351 in relapsed and refractory acute 
lymphoblastic leukemia. If 4 or more CR/CRi are observed in the first 10 patients, Jazz Pharmaceuticals 
will consider an increase in the budget to facilitate accrual to a total of 19 patients (ie, 9 additional 
subjects), possibly in a multi-center setting.  This would be sufficient to test our hypothesis that CPX-
351 will increase the CR/CRi rate from a historical standard of 35% to 65% (as summarized in section 
2.2) using a power of 90% and type I error rate of 0.1. 
 
 
As noted above, this is a phase 2 pilot trial.  However, expansion to a phase II trial will depend on 
demonstration of CR/CRi amongst 4 of the initial 10 treated patients.  For illustration only, we have 
provided Simon Two-Stage Calculation, using power of 90% and Type I error rate of 0.1.    
 
 
 
 
 
 
N1 
R1 
PET 
N 
R 
Ave N 
Alpha 
Beta 
10 
3 
0.514 
19 
9 
14.38 
0.084 
0.095 
10 
STATISTICAL CONSIDERATIONS 
10.1 
STATISTICAL AND ANALYTICAL PLANS 
10.2 
STATISTICAL HYPOTHESES 
10.3 
ANALYSIS DATASETS 
10.4 
DESCRIPTION OF STATISTICAL METHODS 
10.4.1 
GENERAL APPROACH 
10.4.2 
ANALYSIS OF THE PRIMARY EFFICACY ENDPOINT(S) 


LIST OF ABBREVIATIONS 
Protocol Title: CPX-351 for Relapsed/Refractory ALL                                                                                          Protocol V.3.0 
                                         
Protocol #: 19482                                                                                                                                                             11 Dec 2019 
 
 
 
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Currently, we see approximately 50 new ALL patients per year, with around 70 in active followup.  
Given this, we can anticipate enrollment of the first 6 patients over a 12 month interval.   
 
 
 
• 
Minimal Residual Disease (MRD) will be studied as a dichotomous endpoint using a cutoff of 1x10-4 
cells/transcripts as the lower limit for residual leukemia, and presented as the percentage of 
patients reaching this landmark as their best response.  MRD assessment will be obtained with each 
bone marrow biopsy assessment, as described below. 
• 
Progression Free Survival and Overall Survival will be reported as per Cheson and Lugano Criteria, 
and analyzed using a standard Kaplan-Meier approach.  Patients will undergo bone marrow biopsy 
evaluation after each cycle of therapy per standard of care to facilitated assessment.  Patients 
achieving CR/CRi at the end of consolidation with marrow involvement will have follow-up bone 
marrow biopsy evaluation every 3 months in the first year following their last cycle of therapy, and 
every 6 months in the subsequent 2 years following their last cycle.  Patients who remain in 
remission greater than 3 years from their last cycle of therapy will have bone marrow biopsy 
evaluation performed as needed.  Patients without marrow involvement will have follow-up 
imaging (CT or PET/CT) every 3 months in the first year following their last cycle of therapy, and 
every 6 months in the subsequent 2 years following their last cycle. Patients progressing to 
allogeneic transplant following therapy will be censored at the time of conditioning.   
• 
Safety will be continually assessed during the course of induction and consolidation cycles.  Safety 
assessment will continue at a minimum of every 3 months for those who do not progress to 
allogeneic transplant or alternative therapy. 
 
 
Using summary statistics, safety data will be coded using CTCAE 5.0 criteria, with each AE being counted 
only once for a given participant.  The severity, frequency, duration, outcome, and relationship of AEs to 
study agent, as defined by the treating investigator, will be presented by System Organ Class (SOC) and 
preferred term groupings.  Adverse events leading to premature discontinuation from the study drug, 
adverse events of special interest, and serious treatment-emergent AEs will be presented in a table.   
 
 
Patients will be hospitalized to receive induction therapy, and remain so until sufficient recovery permits 
safe hospital discharge, in accordance with standard of care.  Consolidation therapy will be administered 
as an outpatient.  Patients will be monitored as an outpatient in accordance with standard of care until 
recovery or study discontinuation.   Study discontinuation due to adverse events, related or unrelated to 
study drug, will be assessed. 
 
 
Planned baseline statistics include age, ethnicity, gender, genetic risk group (Philadelphia positive, 
Philadelphia-like, MLL rearranged, p53 mutant, etc…), baseline marrow blast burden, number of prior 
therapies, response to prior therapies (i.e., relapsed vs refractory), and prior exposure to selected 
therapeutic modalities (including allogeneic transplant, CAR T-cell therapy, blinatumomab, and 
inotuzumab).  Demographics will be presented using summary statistics. 
 
 
Responses will be presented in aggregate only. 
 
10.4.3 
ANALYSIS OF THE SECONDARY ENDPOINT(S) 
10.4.4 
SAFETY ANALYSES 
10.4.5 
ADHERENCE AND RETENTION ANALYSES 
10.4.6 
BASELINE DESCRIPTIVE STATISTICS 
10.4.10 TABULATION OF INDIVIDUAL RESPONSE DATA 


LIST OF ABBREVIATIONS 
Protocol Title: CPX-351 for Relapsed/Refractory ALL                                                                                          Protocol V.3.0 
                                         
Protocol #: 19482                                                                                                                                                             11 Dec 2019 
 
 
 
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10.6.1 
ENROLLMENT 
 
As previously noted, all endpoints are presently exploratory in nature, and may be used to support 
expansion of the present study, and/or development of a separate study. 
 
 
Moffitt is a high volume center for ALL, with approximately 50 new cases referred to our center yearly, 
of whom ~10% are anticipated to be refractory to therapy, and ~50% will relapse within 2 years of 
therapy.  The current inclusion and exclusion criteria developed within this protocol, as well as prior 
enrollment to protocols targeting ALL, support a screen failure rate of less than 10%. Similarly, internal 
experience  with CPX-351 supports a drop-out rate (ie, failure to complete induction) of less than 10%.  
Accordingly, we anticipate full accrual of 10 evaluable patients within 24 months. 
 
As previously noted, this is a phase 2 pilot study designed to assess the feasibility and provide a 
preliminary assessment of safety and efficacy to support a more formal phase 2 study. 
 
 
 
 
 
 
Patients with relapsed ALL will be enrolled from the Malignant Hematology clinic at the Moffitt Cancer 
Center.  Patients will not be blinded to therapy.  Given the exploratory nature of this study, stratification 
of patients will not be performed.  Patients who are unable to complete a full course of induction may 
be replaced to facilitate assessment of overall remission rate.   
 
 
 
 
The PI and other appropriate study staff are responsible for maintaining appropriate medical and 
research records for this trial, in compliance with ICH E6 and regulatory and institutional requirements 
for the protection of confidentiality of participants. Representatives of Jazz Pharmaceuticals and federal 
regulatory agencies may examine records for the purpose of quality assurance reviews, evaluation of 
the study safety, progress of the trial, and data validity.  
 
Source documentation in both electronic and paper form shall be retained for at least two years after 
the final closure of the trial. These include hospital records, clinical research subject charts (with paper 
AE logs), research laboratory notes, electronic CRFs, and pharmacy dispensing records.  
 
 
 
Quality control procedures will be implemented beginning with the OnCore data entry system and data 
QC checks that will be run on the database will be generated. Any missing data or data anomalies will 
be communicated to the staff for clarification/resolution. 
 
Following written SOPs, the Moffitt internal monitors will verify that the clinical trial is conducted and 
data are generated, documented (recorded), and reported in compliance with the protocol, GCP, and 
the applicable regulatory requirements (e.g., good laboratory practices (GLP), good manufacturing 
10.4.11 EXPLORATORY ANALYSES 
10.5 
SAMPLE SIZE 
10.6 
MEASURES TO MINIMIZE BIAS 
11 
SOURCE DOCUMENTS AND ACCESS TO SOURCE DATA/DOCUMENTS 
12 
QUALITY ASSURANCE AND QUALITY CONTROL 


LIST OF ABBREVIATIONS 
Protocol Title: CPX-351 for Relapsed/Refractory ALL                                                                                          Protocol V.3.0 
                                         
Protocol #: 19482                                                                                                                                                             11 Dec 2019 
 
 
 
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practices (GMP)). 
 
The investigational site will provide direct access to source data/documents, and reports for the 
purpose of monitoring and auditing, and inspection by local and regulatory authorities. 
 
All staff will be trained by the PI through a site initiation presentation, power point training for training 
on the initial protocol for those staff unable to attend the initiation presentation, and ongoing self-study 
as protocol amendments are approved. Training will be documented on a signature log that will be filed 
in the electronic regulatory binder.  
 
 
. 
 
 
The investigator will ensure that this study is conducted in full conformity with Regulations for the 
Protection of Human Subjects of Research codified in 45 CFR Part 46, 21 CFR Part 50, 21 CFR Part 56, 
and/or the ICH E6. 
 
 
 
The protocol, informed consent form(s), recruitment materials, and all participant materials will be 
submitted to the IRB for review and approval. Approval of both the protocol and the consent form must 
be obtained before any participant is enrolled. Any amendment to the protocol will require review and 
approval by the IRB before the changes are implemented to the study. All changes to the consent form 
will be IRB approved; a determination will be made regarding whether previously consented 
participants need to be re-consented. 
 
 
 
13.3.1 
CONSENT/ASSENT AND OTHER INFORMATIONAL DOCUMENTS PROVIDED TO PARTICIPANTS  
 
Consent forms describing in detail the study agent, study procedures, and risks will be given to the 
participant and written documentation of informed consent will be required prior to starting 
intervention/administering study product. 
 
 
 
Informed consent is a process that is initiated prior to the individual’s agreeing to participate in the 
study and continues throughout the individual’s study participation. Extensive discussion of risks and 
possible benefits of participation will be provided to the participants and their families. Consent forms 
will be IRB-approved and the participant will be asked to read and review the document. The 
investigator will explain the research study to the participant and answer any questions that may arise. 
All participants will receive a verbal explanation in terms suited to their comprehension of the purposes, 
procedures, and potential risks of the study and of their rights as research participants.  Participants will 
have the opportunity to carefully review the written consent form and ask questions prior to signing. 
 
The participants should have the opportunity to discuss the study with their surrogates or think about it 
prior to agreeing to participate. The participant will sign the informed consent document prior to any 
13 
ETHICS/PROTECTION OF HUMAN SUBJECTS 
13.1 
ETHICAL STANDARD 
13.2 
INSTITUTIONAL REVIEW BOARD 
13.3 
INFORMED CONSENT PROCESS 
13.3.2 
CONSENT PROCEDURES AND DOCUMENTATION 


LIST OF ABBREVIATIONS 
Protocol Title: CPX-351 for Relapsed/Refractory ALL                                                                                          Protocol V.3.0 
                                         
Protocol #: 19482                                                                                                                                                             11 Dec 2019 
 
 
 
32 
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procedures being done specifically for the study. The participants may withdraw consent at any time 
throughout the course of the trial. A copy of the informed consent document will be given to the 
participants for their records. The rights and welfare of the participants will be protected by 
emphasizing to them that the quality of their medical care will not be adversely affected if they decline 
to participate in this study. 
 
 
Participant confidentiality is strictly held in trust by the participating investigators, their staff, and the 
sponsor and their agents. This confidentiality is extended to cover testing of biological samples and 
genetic tests in addition to the clinical information relating to participants. Therefore, the study 
protocol, documentation, data, and all other information generated will be held in strict confidence. No 
information concerning the study or the data will be released to any unauthorized third party without 
prior written approval of the sponsor. 
 
The Moffitt study monitor, other authorized representatives of Moffitt, representatives of the IRB or 
pharmaceutical companies supplying study products may inspect all documents and records required to 
be maintained by the investigator, including but not limited to, medical records (office, clinic, or 
hospital) and pharmacy records for the participants in this study. The clinical study site will permit 
access to such records. 
 
The study participant’s contact information will be securely stored at each clinical site for internal use 
during the study. At the end of the study, all records will continue to be kept in a secure location for as 
long a period as dictated by local IRB and Institutional regulations. 
 
Study participant research data, which is for purposes of statistical analysis and scientific reporting, will 
be transmitted to and stored at Moffitt. This will not include the participants’ contact or identifying 
information. Rather, individual participants and their research data will be identified by a unique study 
identification number. The study data entry and study management systems used by clinical sites and 
by Moffitt research staff will be secured and password protected. At the end of the study, all study 
databases will be de-identified and archived at the Moffitt. 
 
 
 
 
Evaluation of correlative biomarkers will be performed on fresh tissue, with the exception of 
PLD1 immunohistochemistry.  Patients consenting to the TCC platform may have additional 
unused material archived for future use – however, this will occur outside the context of this 
protocol, and will be governed independently.   
 
A database will be created to store the clinical and analytical data for this project.  This 
database will be located on a password-protected hard drive, and additionally, the database 
will be itself password-protected to ensure maximal security with regards to maintained 
privacy of patient-related information.  Specific information included in this database will 
entail patient name, age, gender, medical record number, clinical diagnosis, molecular 
phenotype, treatment history, and survival.  Database access will be limited to the PI and Co-
PIs described above. 
 
Patients will be selected according to established inclusion criteria as identified above. 
Patients will be identified primarily according to clinical documentation of disease status 
13.4 
PARTICIPANT AND DATA CONFIDENTIALITY 
13.4.1 
RESEARCH USE OF STORED HUMAN SAMPLES, SPECIMENS, OR DATA 


LIST OF ABBREVIATIONS 
Protocol Title: CPX-351 for Relapsed/Refractory ALL                                                                                          Protocol V.3.0 
                                         
Protocol #: 19482                                                                                                                                                             11 Dec 2019 
 
 
 
33 
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included in clinical notes contained in the patient record; however, appropriate patients may 
also be identified in the context of clinical evaluation up front with names and medical 
record numbers referred to prior to scheduling the bone marrow biopsy procedure to 
facilitate sample identification and collection.  
 
 
Data collected for this study will be analyzed and stored at the Moffitt Cancer Center. Permission to 
transmit data will be included in the informed consent. 
 
For patients consenting to the Moffitt Total Cancer Care (TCC) protocol, de-identified biological samples 
will be stored within the Moffitt TCC biosample repository with the same goal as the sharing of data 
with Jazz Pharmaceuticals. These samples could be used for research into the causes of acute 
lymphoblastic leukemia, its complications and other conditions for which individuals with acute 
lymphoblastic leukemia are at increased risk, and to improve treatment. The Moffitt TCC biosample 
repository will also be provided with a code-link that will allow linking the biological specimens with the 
phenotypic data from each participant, maintaining the masking of the identity of the participant. 
 
During the conduct of the study, an individual participant can choose to withdraw consent to have 
biological specimens stored for future research. However, withdrawal of consent with regard to 
biosample storage will not be possible after the study is completed. 
 
When the study is completed, access to study data and/or samples will be provided through the Moffitt 
TCC repository. 
 
 
 
 
 
Data collection is the responsibility of the clinical trial staff at the site under the supervision of the site 
PI. The PI is responsible for ensuring the accuracy, completeness, legibility, and timeliness of the data 
reported. 
 
All source documents should be completed in a neat, legible manner to ensure accurate interpretation 
of data. Black ink is required to ensure clarity of reproduced copies. When making changes or 
corrections, cross out the original entry with a single line, and initial and date the change.  All paper 
source documents will be scanned into the electronic medical record of each subject for storage. DO 
NOT ERASE, OVERWRITE, OR USE CORRECTION FLUID OR TAPE ON THE ORIGINAL. 
 
Copies of the electronic CRF (eCRF) will be provided for use as source documents and maintained for 
recording data for each participant enrolled in the study. Data reported in the eCRF derived from 
source documents should be consistent with the source documents or the discrepancies should be 
explained and captured in a progress note and maintained in the participant’s official electronic study 
record. 
 
Clinical data (including AEs, concomitant medications, and expected adverse reactions data) and clinical 
laboratory data will be entered into OnCore, a 21 CFR Part 11-compliant data capture system provided 
by Moffitt. The data system includes password protection and internal quality checks, such as 
automatic range checks, to identify data that appear inconsistent, incomplete, or inaccurate. Clinical 
data will be entered directly from the source documents. 
13.5 
FUTURE USE OF STORED SPECIMENS 
14 
DATA HANDLING AND RECORD KEEPING 
14.1 
DATA COLLECTION AND MANAGEMENT RESPONSIBILITIES 


LIST OF ABBREVIATIONS 
Protocol Title: CPX-351 for Relapsed/Refractory ALL                                                                                          Protocol V.3.0 
                                         
Protocol #: 19482                                                                                                                                                             11 Dec 2019 
 
 
 
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Study documents should be retained for a minimum of 2 years after the last approval of a marketing 
application in an ICH region and until there are no pending or contemplated marketing applications in 
an ICH region or until at least 2 years have elapsed since the formal discontinuation of clinical 
development of the drug combination studied in this protocol. No records will be destroyed without 
the written consent of the sponsor, if applicable.  
 
 
 
A protocol deviation is any noncompliance with the clinical trial protocol, GCP, or MOP requirements. 
The noncompliance may be either on the part of the participant, the investigator, or the study site staff. 
As a result of deviations, corrective actions are to be developed by the site and implemented promptly. 
 
These practices are consistent with ICH E6: 
• 
4.5 Compliance with Protocol, sections 4.5.1, 4.5.2, and 4.5.3 
• 
5.1 Quality Assurance and Quality Control, section 5.1.1 
• 
5.20 Noncompliance, sections 5.20.1, and 5.20.2. 
 
It is the responsibility of the site to use continuous vigilance to identify and report deviations as defined 
by the Moffitt Clinical Trials Office standard. All deviations must be addressed in study source 
documents. Protocol deviations must be sent to the local IRB per their guidelines. The site PI/study staff 
is responsible for knowing and adhering to their IRB requirements.  
 
 
 
The International Committee of Medical Journal Editors (ICMJE) member journals have adopted a clinical 
trials registration policy as a condition for publication. The ICMJE defines a clinical trial as any research 
project that prospectively assigns human subjects to intervention or concurrent comparison or control 
groups to study the cause-and-effect relationship between a medical intervention and a health 
outcome. Medical interventions include drugs, surgical procedures, devices, behavioral treatments, 
process-of-care changes, and the like. Health outcomes include any biomedical or health-related 
measures obtained in patients or participants, including pharmacokinetic measures and adverse events. 
The ICMJE policy, and the Section 801 of the Food and Drug Administration Amendments Act of 2007, 
requires that all clinical trials be registered in a public trials registry such as ClinicalTrials.gov, which is 
sponsored by the National Library of Medicine.  
 
The PI will provide to the Protocol Information Specialist at Moffitt Cancer Center, details as requested 
for registering and reporting results for this clinical trial on ClinicalTrials.gov. At the conclusion of the 
trial, the PI will make study results available to the research community and the public-at-large.  
 
Authorship in publications will be determined by the PI depending on participation, enrollment, and 
significant contribution during the trial process and manuscript elaboration. 
 
 
14.2 
STUDY RECORDS RETENTION 
14.3 
PROTOCOL DEVIATIONS 
14.4 
PUBLICATION AND DATA SHARING POLICY 


LIST OF ABBREVIATIONS 
Protocol Title: CPX-351 for Relapsed/Refractory ALL                                                                                          Protocol V.3.0 
                                         
Protocol #: 19482                                                                                                                                                             11 Dec 2019 
 
 
 
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The independence of this study from any actual or perceived influence, such as by the pharmaceutical 
industry, is critical. Therefore any actual conflict of interest of persons who have a role in the design, 
conduct, analysis, publication, or any aspect of this trial will be disclosed and managed. Furthermore, 
persons who have a perceived conflict of interest will be required to have such conflicts managed in a 
way that is appropriate to their participation in the trial.  The study leadership and the Moffitt Cancer 
Center have established policies and procedures for all study group members to disclose all conflicts of 
interest and will establish a mechanism for the management of all reported dualities of interest. 
 
 
 
1. Barba P, Sampol A, Calbacho M, et al. Clofarabine-based chemotherapy for relapsed/refractory adult 
acute lymphoblastic leukemia and lymphoblastic lymphoma. The Spanish experience. Am J Hematol. 
2012;87(6):631–634.  
 
2. Hijiya N, Thomson B, Isakoff MS, et al. Phase 2 trial of clofarabine in combination with etoposide and 
cyclophosphamide in pediatric patients with refractory or relapsed acute lymphoblastic leukemia. 
Blood. 2011;118(23):6043–6049.  
 
3. Gökbuget N, Basara N, Baurmann H, et al. High single-drug activity of nelarabine in relapsed T-
lymphoblastic leukemia/lymphoma offers curative option with subsequent stem cell transplantation. 
Blood. 2011;118(13):3504–3511. 
 
4. Weiss MA, Aliff TB, Tallman MS, et al. A single, high dose of idarubicin combined with cytarabine as 
induction therapy for adult patients with recurrent or refractory acute lymphoblastic leukemia. 
Cancer. 2002;95(3):581–58 
 
5. Tedeschi A, Montillo M, Strocchi E, et al. High-dose idarubicin in combination with Ara-C in patients 
with relapsed or refractory acute lymphoblastic leukemia: a pharmacokinetic and clinical study. 
Cancer Chemother Pharmacol. 2007 May;59(6):771-9.  
 
6. Giona F, Testi AM, Annino L, et al. Treatment of primary refractory and relapsed acute lymphoblastic 
leukaemia in children and adults: the GIMEMA/AIEOP experience. Gruppo Italiano Malattie 
Ematologiche Maligne dell'Adulto. Associazione Italiana Ematologìa ed Ocologia Pediatrica. Br J 
Haematol. 1994 Jan;86(1):55-61 
 
7. Carella AM, Pungolino E, Piatti G, et al. Idarubicin in combination with intermediate-dose cytarabine 
in the treatment of refractory or relapsed acute leukemias. Eur J Haematol. 1989 Oct;43(4):309-13. 
 
8. Li X, Liu L, Zhang Y, et al. Efficacy of cytarabine, aclarubicin and granulocyte colony-stimulating factor 
(CAG) regimen compared to FLAG regimen for adult patients with relapsed/refractory Philadelphia 
chromosome-negative acute lymphoblastic leukemia. Leuk Res. 2015 Aug 28. pii: S0145-
2126(15)30366-0. 
 
9. Liu L, Jiao W, Zhang Y, et al. Efficacy of low-dose cytarabine and aclarubicin in combination with 
granulocyte colony-stimulating factor (CAG regimen) compared to Hyper-CVAD regimen as salvage 
chemotherapy in relapsed/refractory Philadelphia chromosome-negative acute lymphoblastic 
leukemia. Leuk Res. 2015 Mar;39(3):323-8 
 
15 
CONFLICT OF INTEREST POLICY 
16 
LITERATURE REFERENCES 


LIST OF ABBREVIATIONS 
Protocol Title: CPX-351 for Relapsed/Refractory ALL                                                                                          Protocol V.3.0 
                                         
Protocol #: 19482                                                                                                                                                             11 Dec 2019 
 
 
 
36 
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10. Ahn JS, Yang DH, Jung SH, et al. Clinical efficacy of mitoxantrone and Ara-C with or without etoposide 
salvage chemotherapy in adult patients with relapsed or refractory acute lymphoblastic leukemia: 
retrospective multicenter study of the Korean Adult ALL Working Party. Acta Haematol. 
2015;133(1):91-7.  
 
11. O’Brien S, Schiller G, Lister J, et al. High-dose vincristine sulfate liposome injection for advanced, 
relapsed, and refractory adult Philadelphia chromosome-negative acute lymphoblastic leukemia. J 
Clin Oncol Off J Am Soc Clin Oncol. 2013;31(6):676–68 
 
12. Topp MS, Gökbuget N, Stein AS, et al. Safety and activity of blinatumomab for adult patients with 
relapsed or refractory B-precursor acute lymphoblastic leukaemia: a multicentre, single-arm, phase 2 
study. Lancet Oncol. 2015 Jan;16(1):57-66.  
 
13. Kantarjian HM, DeAngelo DJ, Stelljes M, et al. Inotuzumab Ozogamicin versus Standard Therapy for 
Acute Lymphoblastic Leukemia. N Engl J Med. 2016 Aug 25;375(8):740-53. 
 
14. Tafuri A, Gregorj C, Petrucci MT, et al. MDR1 protein expression is an independent predictor of 
complete remission in newly diagnosed adult acute lymphoblastic leukemia. Blood 2002;100:974–
981. 
 
15. Pogorzala M, Kubicka M, Rafinska B, et al. Drug-resistance Profile in Multiple-relapsed Childhood 
Acute Lymphoblastic Leukemia. Anticancer Res. 2015 Oct;35(10):5667-70.  
 
16. Kourti M, Vavatsi N, Gombakis N, et al. Expression of multidrug resistance 1 (MDR1), multidrug 
resistance-related protein 1 (MRP1), lung resistance protein (LRP), and breast cancer resistance 
protein (BCRP) genes and clinical outcome in childhood acute lymphoblastic leukemia. Int J Hematol. 
2007 Aug;86(2):166-73. 
 
17. Swerts K, De Moerloose B, Dhooge C, et al. Prognostic significance of multidrug resistance-related 
proteins in childhood acute lymphoblastic leukaemia. Eur J Cancer. 2006 Feb;42(3):295-309.  
 
18. Candoni A, Michelutti A, Simeone E, et al. Efficacy of liposomal daunorubicin and cytarabine as 
reinduction chemotherapy in relapsed acute lymphoblastic leukaemia despite expression of 
multidrug resistance-related proteins. Eur J Haematol. 2006 Oct;77(4):293-9 
 
19. Thomas D, O'Brien S, Faderl S, et al. Anthracycline dose intensification in adult acute lymphoblastic 
leukemia: lack of benefit in the context of the fractionated cyclophosphamide, vincristine, 
doxorubicin, and dexamethasone regimen. Cancer. 2010 Oct 1;116(19):4580-9.  
 
20. Tardi P, Johnstone S, Harasym N, et al. In vivo maintenance of synergistic cytarabine:daunorubicin 
ratios greatly enhances therapeutic efficacy. Leuk Res. 2009 Jan;33(1):129-39 
 
21. Lim WS, Tardi PG, Dos Santos N, et al. Leukemia-selective uptake and cytotoxicity of CPX-351, a 
synergistic fixed-ratio cytarabine:daunorubicin formulation, in bone marrow xenografts. Leuk Res. 
2010 Sep;34(9):1214-23 
 
22. Tyner JW, Tardi P, Mayer L, et al. Evaluation of CPX-351 (cytarabine:daunorubicin) Liposome Injection 
Anti-Leukemic Activity Against Primary Patient Leukemia Cells. Amer Soc of Hematol Ann Meeting, 
2010. Abstract #32187 
 


LIST OF ABBREVIATIONS 
Protocol Title: CPX-351 for Relapsed/Refractory ALL                                                                                          Protocol V.3.0 
                                         
Protocol #: 19482                                                                                                                                                             11 Dec 2019 
 
 
 
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23. Carol H, Fan MM, Harasym TO, et al. Efficacy of CPX-351, (cytarabine:daunorubicin) liposome 
injection, against acute lymphoblastic leukemia (ALL) xenograft models of the Pediatric Preclinical 
Testing Program. Pediatr Blood Cancer. 2015 Jan;62(1):65-71 
 
 
24. Feldman EJ, Lancet JE, Kolitz JE, et al.  First-in-man study of CPX-351: a liposomal carrier containing 
cytarabine and daunorubicin in a fixed 5:1 molar ratio for the treatment of relapsed and refractory 
acute myeloid leukemia. J Clin Oncol. 2011 Mar 10;29(8):979-85. 
 
25. Lancet JE, Cortes JE, Hogge DE, et al. Phase 2 trial of CPX-351, a fixed 5:1 molar ratio of 
cytarabine/daunorubicin, vs cytarabine/daunorubicin in older adults with untreated AML. Blood. 
2014 May 22;123(21):3239-46 
 
26. Cortes JE, Goldberg SL, Feldman EJ, et al. Phase II, multicenter, randomized trial of CPX-351 
(cytarabine:daunorubicin) liposome injection versus intensive salvage therapy in adults with first 
relapse AML. Cancer. 2015 Jan 15;121(2):234-42 
 
27. 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. 2003 Dec 15;21(24):4642-
4649. 
 
28. De Astis E, Clavio M, Raiola AM, et al. Liposomal daunorubicin, fludarabine, and cytarabine (FLAD) as 
bridge therapy to stem cell transplant in relapsed and refractory acute leukemia. Ann Hematol. 2014 
Dec;93(12):2011-8. 
 
29. SEER Cancer Registry, “Cancer Stat Facts: 
Leukemia” https://seer.cancer.gov/statfacts/html/leuks.html 
 
30. Pearce S., Brownsdon A., Fern L., Gibson F., Whelan J. & Lavender V. (2016) European Journal of 
Cancer Care. The perceptions of teenagers, young adults and professionals in the participation of 
bone cancer clinical trials. DOI: 10.1111/ecc.12476 
 
31. Wang CS, FitzGerald JM, Schulzer M, Mak E, Ayas NT. Does this dyspneic patient in the emergency 
department have congestive heart failure? JAMA. 2005;294(15):1944-1956. 
 
32. Cheson BD, Fisher RI, Barrington SF, Cavalli F, Schwartz LH, Zucca E. Recommendations for Initial 
Evaluation, Staging, and Response Assessment of Hodgkin and Non-Hodgkin Lymphoma: The Lugano 
Classification. J Clin Oncol 32:3059-3067.  
 
 
 


LIST OF ABBREVIATIONS 
Protocol Title: CPX-351 for Relapsed/Refractory ALL                                                                                          Protocol V.3.0 
                                         
Protocol #: 19482                                                                                                                                                             11 Dec 2019 
 
 
 
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Appendix A    Response Criteria 
Complete remission (CR)
a 
 
Bone marrow blasts <5%; absence of blasts 
with Auer rods; absence of extramedullary 
disease; absolute neutrophil count >1.0 x 
10
9
/L (1000/μL); platelet count >100 x 10
9
/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 10
9
/L 
[1000/μL]) or thrombocytopenia (<100 x 
10
9
/L [100,000/μL])  
Partial Response (PR) 
Greater than 50% decrease in blasts, and/or 
decrease to less than 25% blasts with 
recovery of neutrophils (>1.0 x 10
9
/L), and 
platelets  (>100 x 10
9
/L) 
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)  
Relapse
c 
 
Bone marrow blasts ≥5%; or reappearance 
of blasts in the blood after achievement of a 
CR or CRi; or development of 
extramedullary disease  
a
Bone 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.  
b
Bone 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.  
c
In 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. 
 
 
 
 
 
 
 
APPENDIX 


LIST OF ABBREVIATIONS 
Protocol Title: CPX-351 for Relapsed/Refractory ALL                                                                                          Protocol V.3.0 
                                         
Protocol #: 19482                                                                                                                                                             11 Dec 2019 
 
 
 
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Appendix B 
ECOG Performance Status 
 
Grade 
Description 
0 
Normal activity. Fully active, able to carry on all pre-disease performance 
without restriction. 
1 
Symptoms, but ambulatory. Restricted in physically strenuous activity, but 
ambulatory and able to carry out work of a light or sedentary nature (e.g., 
light housework, office work). 
2 
In bed <50% of the time. Ambulatory and capable of all self-care, but 
unable to carry out any work activities. Up and about more than 50% of 
waking hours. 
3 
In bed >50% of the time. Capable of only limited self-care, confined to bed 
or chair more than 50% of waking hours. 
4 
100% bedridden. Completely disabled. Cannot carry on any self-care. 
Totally confined to bed or chair. 
5 
Dead. 
* As published in Am. J. Clin. Oncol.:  Oken, M.M., Creech, R.H., Tormey, D.C., Horton, J., Davis, 
T.E., McFadden, E.T., Carbone, P.P.: Toxicity And Response Criteria Of The Eastern 
Cooperative Oncology Group. Am J Clin Oncol 5:649-655, 1982. The Eastern Cooperative 
Oncology Group, Robert Comis M.D., Group Chair.