Clinical trial NCT03957876
Conditions: Myelodysplastic Syndrome (MDS)
Sponsor: Case Comprehensive Cancer Center
Start date: 2019-07-25; Completion date: 2022-12-20
Enrollment: 4 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The purpose of this study is to evaluate the efficacy of treatment with CPX-351 (an FDA approved drug for the treatment of AML) in individuals with MDS while using a new stratification tool to predict outcomes of participants following HMA failure. This approach is intended to gain a better understanding and insight into identifying new opportunities for drug approvals in this setting.

Detailed description:
This study will evaluate efficacy of treatment with CPX-351in participants with MDS while using a new stratification tool to predict outcomes of patients following HMA failure in order to gain a better understanding and insight into identifying new opportunities for drug approvals in this setting.

CPX-351is an investigational (experimental) drug for the indication of myelodysplastic syndrome that works by delivering two chemotherapy medications (daunorubicin and cytarabine) together which are then concentrated into the bone marrow (the part of the body that makes blood cells). CPX-351 is experimental because it is not approved by the Food and Drug Administration (FDA) for the indication of myelodysplastic syndrome. This drug is approved by theFDA for the indication of acute myeloid leukemia. One or more of the Investigators conducting this study serve as consultants for the company that makes products used in this study. These financial interests are within permissible limits established by the local institutional Conflict of Interest Policy.

Prior to beginning treatment, all eligible participants will be grouped into low risk versus high risk based on a stratification tool used to determine their disease. Group 1 will be low risk participants and group 2 will be high risk participants. All study participants will get the same study drug, CPX-351. Participants will receive the CPX-351 on days 1, 3 and 5 of the first 28 day cycle. After participants finish the first round of treatment and based on their response they may be eligible for another 4 cycles of treatment. The participant's doctor will inform them if this is an available option when the time comes. Once participant have finished treatment, their doctor will continue observe for side effects and follow their condition for 1 year.

Arms: arm 1: Single agent CPX-351 administered at the standard FDA approved dose of 44 mg/m2 intravenously on days 1, 3, 5 of the induction cycle. If participants achieve complete remission (CR), complete remission with incomplete count recovery (CRi) or partial remission (PR), they will be eligible to continue on to maintenance therapy, which will consist of CPX351 at a dose of 15.4 mg/m2 every 28 days. Participants can receive up to 4 cycles of maintenance therapy.
Interventions: intervention 1: CPX-351
Intervention descriptions: intervention 1: CPX-351 is a liposomal formulation of a fixed combination of the antineoplastic drugs cytarabine and daunorubicin.

Protocol documents:
Prot_SAP_000.pdf: 
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STUDY NUMBER:  CASE 2918 
 
ClinicalTrials.gov #: NCT03957876 
 
Protocol Date: 18 January 2021  
 
STUDY TITLE: A Phase II Study of CPX-351 as a Novel Therapeutic Approach for 
Patients with Myelodysplastic Syndromes (MDS) after Hypomethylating Agent Failure 
 
 
PRINCIPAL INVESTIGATOR: Sudipto Mukherjee, MD, MPH 
Taussig Cancer Center, Cleveland Clinic  
Tel: 216-444-0506 
 
 
 
E-mail: mukhers2@ccf.org 
  
 
STATISTICIAN:  
 
Brian Hobbs 
 
STUDY COORDINATOR: 
Allison Unger  
 
 
 
 
Case Comprehensive Cancer Center 
 
SPONSOR:  
 
 
Case Comprehensive Cancer Center  
 
 
 
 
SUPPORT/FUNDING: 
 
Jazz Pharmaceutical   
 
SUPPLIED AGENT(S):  
CPX-351 
 
IND #:  
 
 
 
143227 
 
 
 
 
 
 
 


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 SUMMARY OF CHANGES 
 
Protocol Date 
Section 
Change 
Protocol Version 5.0 
01/18/2020 
All 
Updated PI and contact information to Dr. Mukherjee throughout protocol 
 
6.4 
Clarified adverse event reporting requirements during follow-up period.  
Protocol Version 4.0 
06/01/2020 
4.1 
Updated inclusion criteria to include MDS/MPN 
06/01/2020 
4.1 
Updated inclusion criteria for creatinine requirements 
Protocol Version 3.0 
11/13/2019 
1.2 
Corrected dosing reconstitution from 5mg - 8.8mg/mL to 5mg - 
2.2mg/mL 
11/13/2019 
9.1 
Corrected dosing reconstitution from 5mg - 8.8mg/mL to 5mg - 
2.2mg/mL 
11/13/2019 
11.1.1 
Added language which will allow ECHO, EKG and Bone marrow 
biopsy and aspirate to be used for screening if completed within 28 
days of C1D1 and prior to consent.  
11/13/2019 
11.2 
Added footnote r, which will allow ECHO, EKG and Bone marrow 
biopsy and aspirate if completed prior to consent and within 28 days of 
C1D1 to be used for screening.  
Protocol Version 2.0 
09/18/2019 
11.2 
Updated requirements of ECHO at C1D1. 
09/18/2019 
11.2 
Removed serum chemistry from follow-up visits. 
09/18/2019 
11.2 
Updated requirements of vitals at induction and during consolidation. 
09/18/2019 
All 
Updated remission bone marrow biopsy from D28 +/- 7 days to D35 
+/- 10 days.  
09/18/2019 
11.2 
Removed windows from follow-up and survival follow-up visits.  
09/30/2019 
SOC 
Updated summary of changes table. 
Protocol Version 1.0 
03/27/2019 
4.1 
Changed inclusion criteria from serum creatinine to creatinine 
clearance, and changed bilirubin inclusion criteria 
03/27/2019 
4.2 
Added criteria to exclude all patients with AML and Wilsons disease 
03/27/2019 
6.1 
Added information regarding premedication 
03/27/2019 
6.3 
Added new EOT criteria for toxicities 
03/27/2019 
6.3 
Added new EOS criteria. Table 2. 
03/27/2019 
11.2 
Changed frequency of ECHO to D1 of every cycle 
03/27/2019 
14.0 
Added toxicity monitoring plan 
 


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Protocol Summary 
 
Protocol Number/Title 
CASE 2918: A Phase II Study of CPX-351 as a Novel 
Therapeutic Approach for Patients with Myelodysplastic 
Syndromes (MDS) after Hypomethylating Agent Failure 
Study Phase 
Phase II 
Brief Background/Rationale 
Epigenetic changes such as alterations in DNA methylation 
and histone modification play an important role in the 
pathophysiology of myelodysplastic syndromes (MDS). 
While hypomethylating agents (HMAs) such as azacitidine 
and decitabine have become the standard of care for patients 
with higher-risk MDS, they have limited efficacy. Response 
rates range from 20-40% and last a median of 9-10 months. 
Complete remissions are rare and the majority (50-70%) of 
patients remains resistant/refractory to these drugs. The 
poor success of HMAs is due, in part, to the limited 
understanding of mechanisms that underlie resistance. 
Given the poor survival of patients who fail HMAs, novel 
agents that overcome HMAs failure are desperately needed. 
Despite several novel compounds that have been 
investigated at the time of HMA failure, no therapy has 
proven to show overall survival (OS) compared to 
conventional care. This in part is due to the lack of our 
understanding into the mechanisms of resistance to HMA 
and the failure of accurately risk stratifying patients in this 
setting. 
We have previously shown that IPSS, IPSS-R and 
other commonly used MDS prognostic models, (e.g., the 
World Health Organization (WHO) classification-based 
Prognostic Scoring System (WPSS), and the MD Anderson 
Prognostic Scoring System (MDAPSS) have limited 
predictive power in the HMA failure setting1-4. We 
therefore developed and validated a new model to predict 
outcome of patients after hypomethylating agent failure 
(HMAF) that includes 6 clinical variables: age, performance 
status, complex cytogenetics (>4 abnormalities), marrow 
blast percentage >20%, platelet count, and red cell 
transfusion dependency4. This model separates patients into 
two risk categories: lower-risk, with a median OS of 11.0 
months (95% CI 8.8-13.6); and higher-risk disease, with 
median OS of 4.5 months (95% CI 3.9-5.3)4. The model 


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was subsequently validated in an independent cohort of 223 
MDS patients derived from the Groupe Francophone des 
Myélodysplasies (GFM) database and in a phase III 
randomized clinical trial. Thus, risk stratifying MDS 
patients by the new model at the time of HMA failure may 
open new opportunity for drug approvals in this setting5-6.  
Identifying novel drugs that can improve the 
outcome of MDS patients after HMA failure remains an 
unmet need.   
Primary Objective 
Evaluate the efficacy of CPX-351 as measured by overall 
response rate (ORR), i.e. by IWG 2006 criteria for MDS 
patients after Hypomethylating agent failure. 
Endpoint and time frame:  
Overall response rate (ORR), i.e. by IWG 2006 criteria for 
MDS and patients at end of induction (C1D35 +/-10). 
Secondary Objective(s) 
 To determine the time to response (TTR) associated with 
CPX-351 in patients with MDS  
Endpoint and time frame:  
TTR associated with CPX-351 in patient with MDS at the 
end of induction (C1D35 +/-10). 
 To evaluate the duration of response (DOR) in patients 
achieving a response  
Endpoint and time frame:  
DOR in patients achieving a response at the time of 
response (C1D35 +/-10) and up to 1 year after the end of 
treatment. 
 To evaluate the event-free survival (EFS) and the overall 
survival (OS) probability of all patients enrolled in this 
trial.   
Endpoint and time frame:  
EFS and OS probability of all patients enrolled in this trial 
at end of induction (C1D35 +/-10) and up to 1 year after the 
end of treatment. 
Estimated Study Duration 
Estimated date first subject enrolled: March, 2019 
Estimated date last subject enrolled: March, 2020 
Duration of Participation 
Patient participation is expected to average 6 to 12 months 
Sample Size 
25 patients 


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Disease sites/Conditions 
Myelodysplastic Syndrome (MDS) 
Interventions 
 CPX-351 44mg/m2 (daunorubicin 44 mg/m2 and 
cytarabine 100 mg/m2), IV days 1, 3, and 5 during the 
induction phase.  
 CPX-351 15.4mg/m2 (daunorubicin 15.4 mg/m2 and 
cytarabine 35 mg/m2), IV every 28 days for up to 4 
cycles during the consolidation phase for patients 
achieving a response.  
 
 
 
 
 


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Abbreviations 
 
AE 
Adverse Event 
ALL 
Acute Lymphoblastic Leukemia 
ALT  
Alanine Aminotransferase 
AML 
Acute Myeloid Leukemia 
AML-MRC Acute Myeloid Leukemia with Myelodysplasia Related Changes 
ANC 
Absolute Neutrophil Count 
AST 
Aspartate Aminotransferase 
AZA 
Azacitidine 
BSA 
Body Surface Area 
BUN 
Blood Urea Nitrogen 
CCCC 
Case Comprehensive Cancer Center 
CCF 
Cleveland Clinic Foundation 
CI 
Confidence Intervals 
CTCAE 
Common Terminology Criteria for Adverse Events 
CR 
Complete remission 
CRi  
Complete remission with incomplete count recovery 
CRF 
Case Report Form 
DAC 
Decitabine 
DCRU 
Dahm’s Clinical Research Unit 
DLT 
Dose Limiting Toxicity 
DOR 
Duration of response 
DSMP 
Data Safety Monitoring Plan 
DSTC 
Data Safety and Toxicity Committee 
ECOG 
Eastern Cooperative Oncology Group 
EFS 
Event free survival 
EOS 
End of Study 
EOT 
End of Treatment 
FDA 
Food and Drug Administration 
FU 
Follow-up 
GCP 
Good Clinical Practice 
G-CSF 
Granulocyte-colony stimulating factor 
GM-CSF 
Granulocyte-macrophage colony-stimulating factor 
GFM 
Groupe Francophone des Myélodysplasies 
Hgb 
Hemoglobin 
HI 
Hematologic Improvement 
HIPAA 
Health Insurance Portability and Accountability Act of 1996 
HMA 
Hypomethylating agent 
HMAF 
Hypomethylating agent failure 
HR 
Hazard Ratio 
HSCT 
Hematopoietic stem cell transplant 
HU 
Hydrea 


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ICF 
Informed Consent Form 
ICH 
International Conference on Harmonization 
IEC 
Institutional Ethics Committee 
IRB 
Institutional Review Board 
IWG 
International Working Group 
LLN 
Lower Limit of Normal 
MDAPSS 
MD Anderson Prognostic Scoring System 
MDS  
Myelodysplastic Syndrome 
MPN 
Myeloproliferative Neoplasm 
ORR 
Overall Response Rate 
OS 
Overall survival 
PD 
Progressive Disease 
PI 
Principle Investigator 
PR 
Partial remission 
PRMC 
Protocol Review and Monitoring Committee 
SAE 
Serious Adverse Event 
SD 
Stable Disease 
SOC 
Standard of Care 
tAML 
Therapy Related Acute Myeloid Leukemia 
TLS 
Tumor lysis syndrome 
TTR 
Time to response 
UH 
University Hospitals 
ULN 
Upper Limit of Normal 
WHO 
World Health Organization 
WPSS 
World Health Organization Classification-Based Prognosis 
Scoring System 


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TABLE OF CONTENTS 
 
1.0  
INTRODUCTION  
 
1.1 
Background of Study Disease  
1.2  
Name/description of CPX-351 
1.3  
Rationale   
 
2.0 
OBJECTIVES 
2.1 
Primary Objective 
 
2.2  
Secondary Objective(s) 
 
3.0 
STUDY DESIGN 
3.1 
Study design 
3.2 
Number of Subjects 
3.3 
Replacement of Subjects 
3.4 
Expected Duration of Treatment and Subject Participation 
 
 
4.0  
SUBJECT SELECTION 
4.1 
Inclusion Criteria 
4.2  
Exclusion Criteria 
4.3 
Inclusion of Women and Minorities 
 
5.0 
REGISTRATION  
 
 
6.0  
TREATMENT PLAN 
6.1 
Treatment Regimen Overview  
6.2 
Phase I Dose Escalation  
6.3  
Definition of Dose Limiting Toxicity 
6.4 
General Concomitant Medications and Supportive Care Guidelines 
6.5 
Criteria for Removal from Study 
6.6 
Duration of Follow-Up 
 
7.0 
DOSE DELAYS / DOSE MODIFICATIONS 
 
8.0 
ADVERSE EVENTS AND POTENTIAL RISKS 
8.1  
Agent Adverse events 
8.2 
Definitions 
8.3 
Serious Adverse Event Report Form 
8.4 
Reporting Procedures for Serious Adverse Event  
8.5 
Serious Adverse Events and OnCoreTM    
8.6 
Data Safety Toxicity Committee 
8.7 
Data and Safety Monitoring Plan 
 
9.0 
PHARMACEUTICAL INFORMATION  
9.1 
Investigational Agent(s) 
 
9.2 
Commercial Agent(s) 


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10.0 
EXPLORATORY/CORRELATIVE  
 
11.0 
STUDY PARAMETERS AND CALENDAR 
11.1 
Study Parameters 
11.2 
Calendar 
 
12.0 
MEASUREMENT OF EFFECT  
 
13.0 
RECORDS TO BE KEPT/REGULATORY CONSIDERATIONS 
13.1 
Data Reporting 
13.2 
Regulatory Considerations  
 
 
14.0 
STATISTICAL CONSIDERATIONS 
 
REFERENCES 
 
  
APPENDICES  
 
 
 
APPENDIX I:  
 
ECOG / Karnofsky Performance Status Criteria  
 
 
APPENDIX II:  
 
STUDY DESIGN TIME POINT DEFINITIONS 
 
 
APPENDIX III:  
RESPONSE CRITERIA FOR CONSOLIDATION PERIOD 
 
APPENDIX IV:  
STUDY DESIGN TIME POINT DEFINITIONS 
 
APPENDIX V:  
POST-HMA FAILURE MODEL 
 
 
 


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1.0 
Introduction  
 
1.1 
Background of Study Disease  
 
 
Epigenetic changes such as alterations in DNA methylation and histone 
modification play an important role in the pathophysiology of myelodysplastic 
syndromes (MDS). While hypomethylating agents (HMAs) such as azacitidine and 
decitabine have become the standard of care for patients with higher-risk MDS, they have 
limited efficacy. Response rates range from 20-40% and last a median of 9-10 months. 
Complete remissions are rare and the majority (50-70%) of patients remains 
resistant/refractory to these drugs. The poor success of HMAs is due, in part, to the 
limited understanding of mechanisms that underlie resistance. Given the poor survival of 
patients who fail HMAs, novel agents that overcome HMAs failure are desperately 
needed. Despite several novel compounds that have been investigated at the time of 
HMA failure, no therapy has proven to show overall survival (OS) compared to 
conventional care. This in part is due to the lack of our understanding into the 
mechanisms of resistance to HMA and the failure of accurately risk stratifying patients in 
this setting. 
We have previously shown that IPSS, IPSS-R and other commonly used MDS 
prognostic models, (e.g., the World Health Organization (WHO) classification-based 
Prognostic Scoring System (WPSS), and the MD Anderson Prognostic Scoring System 
(MDAPSS) have limited predictive power in the HMA failure setting1-4. We therefore 
developed and validated a new model to predict outcome of patients after 
hypomethylating agent failure (HMAF) that includes 6 clinical variables: age, 
performance status, complex cytogenetics (>4 abnormalities), marrow blast percentage 
>20%, platelet count, and red cell transfusion dependency4. This model separates patients 
into two risk categories: lower-risk, with a median OS of 11.0 months (95% CI 8.8-13.6); 
and higher-risk disease, with median OS of 4.5 months (95% CI 3.9-5.3)4. The model 
was subsequently validated in an independent cohort of 223 MDS patients derived from 
the Groupe Francophone des Myélodysplasies (GFM) database and in a phase III 
randomized clinical trial. Thus, risk stratifying MDS patients by the new model at the 
time of HMA failure may open new opportunity for drug approvals in this setting5, 6.  


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Identifying novel drugs that can improve the outcome of MDS after HMA failure 
remains an unmet need.   
 
1.2  
Name and Description of Investigational Agent CPX-351 
 
1.2.1  Preclinical Data  
 
CPX-351 is a liposomal formulation of a fixed combination of the antineoplastic 
drugs cytarabine and daunorubicin. These two drugs are present inside the liposome in a 
5:1 molar ratio. The liposome membrane is composed of distearoylphosphatidylcholine, 
distearoylphosphatidylglycerol and cholesterol in a 7:2:1 molar ratio. These liposomes 
have a nominal diameter of approximately 100nm and are suspended in sucrose. 
Sterilization is achieved by filtration through a 0.22 μm filter. 
CPX-351 is provided as a sterile, pyrogen-free lyophilized formulation in 50 mL 
glass, single-use vials. Each vial contains 100mg/m2 of CPX-351 where each vial 
contains 100 mg cytarabine and 44 mg daunorubicin base in liposomes. The lyophilized 
cake is reconstituted with sterile water for injection to obtain a homogeneous dispersion 
at 5 mg-2.2mg/mL (cytarabine-daunorubicin). 
The pre-clinical pharmacology and toxicology are summarized in the 
Investigator’s Brochure for CPX-351. 
1.2.2 Clinical Data 
Phase I study of CPX-351 
In a phase 1 dose-escalation trial, CPX-351 induction was administered on days 1, 
3, and 5 by 90-minute infusion to 48 relapsed or refractory patients with acute myeloid 
leukemia (AML) or high-risk myelodysplasia. Doses started at 3 mg/m2 with dose 
doublings in single-patient cohorts until a pharmacodynamic effect (treatment-related 
adverse events or reduction in bone marrow cellularity or blast count) was observed, 
followed by 33% escalations in three patient cohorts until dose-limiting toxicity (DLT) 
occurred. The maximum-tolerated dose was 101 mg/m2. DLTs consisted of hypertensive 
crisis, congestive heart failure, and prolonged cytopenias. Identified adverse events were 
similar with cytarabine and daunorubicin treatment. Response occurred at doses as low as 
32 mg/m2. Of 43 patients with AML, nine had complete response (CR) and one had CR 


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with incomplete platelet recovery; of patients with acute lymphoblastic leukemia (ALL), 
one of three had CR. Eight CRs were achieved among the 31 patients with prior 
cytarabine and daunorubicin treatment. CR in AML occurred in 5 of 26 patient’s age > 60 
years and in 5 of 17 patients younger than 60 years of age. Median half-life was 31.1 
hours (cytarabine) and 21.9 hours (daunorubicin), with both drugs and their metabolites 
detectable > 7 days after the last dose. The targeted 5:1 molar ratio was maintained at all 
dose levels for up to 24 hours7. 
 
Phase II study of CPX-351 
A randomized, multicenter, open-label, phase 2 trial was conducted to evaluate 
the efficacy and safety of CPX-351 compared with investigators’ choice of first salvage 
treatment in adult patients with first relapse AML. The primary endpoint of the study was 
1-year overall survival (OS), and Kaplan-Meier analysis did not show a significant 
difference between the two treatment groups (HR, 0.75; P = 0.33). Survival at 1-year was 
36% and 27% (P = 0.33) for CPX-351 and salvage treatment arms, respectively. Patients 
were stratified at baseline according to the European Prognostic Index (EPI), and results 
showed that CPX-351-treated patients with the EPI-defined poor-risk strata demonstrated 
higher response rates (39.3% CPX-351 versus 27.6% salvage arm) and improvements in 
event-free survival (EFS) (HR, 0.63; P = 08) and OS (HR, 0.55; P = 0.22). The overall 
rates of grade 5 AEs were similar between the CPX-351 (23.5%) and salvage treatment 
arms (20.5%)8. 
 
Phase III study of CPX-351 
A phase 3, randomized, multicenter, open-label study evaluated the efficacy and 
safety of CPX-351 compared with conventional 7 + 3 (cytarabine for 7 days plus 
daunorubicin for 3 days) regimen in adult patients (60 to 75 years) with newly-diagnosed 
therapy-related Acute Myeloid Leukemia (tAML) or Acute Myeloid Leukemia with 
Myelodysplasia related changes (AML-MRC). The primary efficacy endpoint was overall 
survival (OS). The results showed OS was significantly greater in the CPX-351 group 
compared with the 7 + 3 group. The median OS was 9.56 months with CPX-351 and 5.95 
months with 7 + 3 (Hazard Ratio [HR] 0.69; P = 0.005). Grade 3-5 non-hematologic 


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adverse events (AEs) occurring ≥ 5% were similar between the two groups, except 
pneumonia (20% vs 15%) and bacteremia (10% vs 2%) were numerically higher in the 
CPX-351 compared with 7 + 3 groups, respectively. Also, median time to recovery of 
absolute neutrophil count (ANC) ≥ 500/μL and platelets ≥ 50,000/μL were longer in the 
CPX-351 group than 7 + 3 group9.  
 
1.4 
Rationale  
 
 
Treatment options are limited for patients diagnosed with MDS at the time of 
HMA failure. Although the outcome remains poor, hematopoietic stem cell transplant 
(HSCT) may prolong survival for a subset of patients10. However, achievement of CR 
prior to transplant is important for improved outcomes10. Treatment with 7+3 
chemotherapy regimen has been used, resulting in a response rate of approximately 30% 
in this patient population. Especially, in patients who progress to AML11. Transplant 
remains an important option for these patients who can tolerate chemotherapy. 
CPX-351 has shown better overall response rate and improved overall survival in 
patients with AML with underlying MDS changes compared to 7+3 suggesting that CPX-
351 can be used in this patient population.  Thus, we hypothesize that treating MDS 
patients, who failed or are intolerant to their initial treatment with HMA’s, with CPX-351 
will overcome HMA resistance and sensitize the MDS cells to this treatment.  
 
2.0  
Study Objectives 
 
2.1  
Primary Objective  
 
 
 Evaluate the efficacy of CPX-351 as measured by overall response rate (ORR), 
i.e. by IWG 2006 criteria for MDS patients after Hypomethylating agent failure. 
 
2.2 
Secondary Objective(s) 
 
 To determine the time to response (TTR) associated with CPX-351 in patients 
with MDS. 
 To evaluate the duration of response (DOR)  


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 To evaluate the event-free survival (EFS) and the overall survival (OS) 
probability of all patients enrolled in this trial.   
 
 
3.0 
Study Design 
 
3.1  
Overview of Study Design  
 
This is a phase II study of single agent CPX-351 administered at the standard 
FDA approved dose of 44 mg/m2 (daunorubicin 44 mg/m2 and cytarabine 100 mg/m2) 
intravenously on days 1, 3, 5 of the induction cycle. If patients achieve complete 
remission (CR), complete remission with incomplete count recovery (CRi) or partial 
remission (PR) (section 12.0, Table 2) they will be eligible to continue on to 
consolidation therapy, which will consist of CPX-351 at a dose of 15.4 mg/m2 
(daunorubicin 15.4 mg/m2 and cytarabine 35 mg/m2) every 28 days Patients can receive 
up to 4 cycles of consolidation therapy.  
 
3.2  
Number of Subjects 
 
Approximately 25 patients will be enrolled in this trial.  
 
3.3 
Replacement of Subjects  
 
 
Patients who receive any doses of CPX-531 will be not be replaced. Patient’s slots 
will only be replaced if they are discontinued from the study prior to dosing with CPX-
351. Missed doses of CPX-351 will be re-administered at the discretion of the treating 
physician. 
 
3.4  
Expected Duration of Treatment and Subject Participation 
 
Enrollment to this study is estimated to occur over three years. Upon signing 
consent, patients will undergo screening to determine if the patient meets all inclusion 
and exclusion criteria, as outlined in section 4.1 and 4.2. Following screening, all eligible 
patients will be enrolled and begin induction therapy which will occur over a 35 day 
cycle and/or at count recovery with CPX-351 dosing on days 1, 3 and 5.  


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Patients who achieve a response (section 12.0, Table 2) may proceed with the 
consolidation phase of the trial with CPX-351 dosing on days 1 and 3 of every 28 days.  
Patients can receive up to 4 cycles of consolidation.  Treatment will continue during the 
duration of the study unless patients exhibit evidence of treatment failure, disease 
progression, experience an unacceptable toxicity, or the investigator determines that 
discontinuation of treatment is in the best interest of the patient. Patients will be treated 
with CPX-351 based on a calculation determined from the patient's body surface area 
(BSA). BSA will be calculated before each day of dosing and will be based on the 
patient's height (measured at baseline) and weight (measured each visit). 
 
4.0 
Subject Selection 
 
  
4.1 
Inclusion Criteria 
 
Each patient must meet all of the following inclusion criteria to be eligible for 
enrollment:  
1. Patients must be > 18 years of age 
2. Patients must give voluntary written consent before performance of any study 
related procedures not part of standard medical care 
3. Diagnosis of MDS or MDS/MPN according to 2016 WHO criteria12  
4. Primary therapy failure with either hypomethylating agents (decitabine or 
azacitidine) defined as: 
 Progression (according to 2006 IWG criteria)13 after initiation of 
azacitidine or decitabine treatment; or 
 Failure to achieve complete or partial response or hematological 
improvement (according to 2006 IWG)13 after at least 4-6 cycles (4-weeks 
cycle) of azacitidine or decitabine; or 
 Relapse after initial complete or partial response or hematological 
improvement (according to 2006 IWG criteria)13 observed after at least 4 
cycles of azacitidine or decitabine. 
5. Eastern Cooperative Oncology Group (ECOG) Performance Status < 2 
6. Subjects must have normal organ and marrow function defined as:   
 If total bilirubin < 2x upper limit of normal (≤ 3 x ULN if considered to be 
due to leukemic involvement or Gilbert’s syndrome) at the discretion of 
the treating physician following discussion with PI) Patients with a 
bilirubin level of >3 mg/dL will be excluded 


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 Calculated creatinine clearance value of  > 30ml/min AND a serum  
creatinine < 1.5mg/dL 
 LVEF > 50% 
7. Female patients who: 
 Are postmenopausal for at least 1 year before the screening visit, OR 
 Are surgically sterile, OR 
 Agree to practice true abstinence from heterosexual contact or agree to use 
effective contraception without interruption during the study therapy and 
90 days after the last dose 
8. Male patients who: 
 Are surgically sterile, OR 
 Agree to practice true abstinence from heterosexual contact or agree to use 
effective contraception without interruption during the study therapy and 
90 days after the last dose 
4.2 
Exclusion Criteria 
 
The presence of any of the following will exclude a subject from study enrollment. 
1. Prior treatment with CPX-351, or known hypersensitivity to CPX-351 or its 
components. 
2. Prior treatment with intensive chemotherapy.  
3. Patients with confirmed Wilson’s disease will be excluded. 
4. Diagnosis of acute myeloid leukemia (AML) 
5. Any serious medical condition, laboratory abnormality, or psychiatric illness that, 
in the view of the treating physician, would place the participant at an 
unacceptable risk if he or she were to participate in the study or would prevent 
that person from giving informed consent.  
6. Any active malignancy (unrelated, non-hematological malignancy) diagnosed 
within the past 6 months of starting the study drug (other than curatively treated 
carcinoma-in-situ of the cervix or non-melanoma skin cancer).  
7. Patients with uncontrolled intercurrent illness including, but not limited to 
ongoing or active infection, symptomatic congestive heart failure, unstable angina 
pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would 
limit compliance with study requirements.  
8. Known history of HIV or active hepatitis B or C.  
9. Active Wilsons disease  
10. Major surgery within 2 weeks prior to study enrollment.  


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11. Pregnant or lactating females 
12. Male and female patients who are fertile who do not agree to use an effective 
barrier methods of birth control (i.e. abstinence or 2 forms of contraception) to 
avoid pregnancy while receiving study treatment.  
 
4.3       Inclusion of Women and Minorities  
 
Men, women and members of all races and ethnic groups are eligible for this trial. 
 
5.0 
Registration 
 
 
All subjects who have been consented are to be registered in the OnCore™ 
Database. For those subjects who are consented, but not enrolled, the reason for exclusion 
must be recorded. 
All subjects will be registered through Cleveland Clinic and will be provided a 
study number by contacting the study coordinator listed on the cover page.  
 
 
6.0  
Treatment Plan 
 
6.1 
Treatment Regimen Overview 
Consent and Screening  
Upon signing consent, patients will begin the screening phase. The screening 
period begins the day the patient signs consent and can take place over a 28 day period 
leading up to dosing on day 1 (D1). During the screening period patients will be assessed 
to determine if they meet eligibility for this study per the inclusion and exclusion criteria 
as outlined in sections 4.1 and 4.2. Once the patient is deemed eligible they will be 
stratified into two arms based on the post-HMA failure model (Appendix V).   
 
Stratification 
Prior to beginning treatment, all eligible patients will be stratified into low vs. 
high risk based on the post-HMA failure model (Appendix V)4. Seven patients will be 
enrolled into the low risk arm and seven patients will be enrolled into the high risk arm. 
Once 14 patients, across both arms, have been enrolled and evaluated for a response (D35 
+/- 10 days bone marrow), an interim analysis will be conducted to determine benefit in 


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each arm. The arm with the greatest response will then enroll an additional 11 patients, 
for a total of 18 patients in that arm. Overall, this study will enroll 25 patients.  
 
Induction 
The induction phase is defined as the time between the first day (D1) of study 
drug to day 35 and/or count recovery. During the induction phase of the study, all 
patients will be treated with the FDA approved standard dose of CPX-351 at 44mg/m2 
(daunorubicin 44 mg/m2 and cytarabine 100 mg/m2) on days 1, 3, and 5. Study drug will 
be administered per the study calendar (section 11.2) unless patient exhibits any EOT 
criteria. Premedication with anti-emetics is recommended prior to treatment with CPX-
351. No re-induction will be allowed and no day 14 bone marrow biopsy is required. A 
bone marrow biopsy and aspirate will be obtained on day 35 +/-10 days to confirm 
response. If no evidence of blasts > 5%, G-CSF will be allowed to improve counts at the 
discretion of the treating physician. Following the bone marrow, patients who meet the 
response criteria per section 12.0 can then continue onto the consolidation phase of this 
study.  
 
Consolidation 
The consolidation phase is defined as C2D1 to C5D28 or once the patients meet 
EOT criteria (section 6.3, Table 1). Only patients with a documented response (CR, CRi, 
or PR) from the D35 (+/-10 days) bone marrow are eligible for consolidation therapy. 
Prior to the first cycle of consolidation therapy the patients must have a PS of 0-2. During 
the consolidation phase, CPX-351 must be given no earlier than 35 days after the start of 
induction and no later than 75 days after the start of induction. For all subsequent cycles, 
there must be at least 35 days between the start of each cycle.  Patients must have 
recovered to ANC >500/ μL and platelets >50,000/μL to be eligible for any consolidation 
therapy.  
During the consolidation phase, CPX-351 will be given at 15.4 mg/m2 
(daunorubicin 15.4 mg/m2 and cytarabine 35 mg/m2) on days 1 and 3 of each 28 day 
cycle. Consolidation therapy can be continued up to 4 cycles in the absences of toxicities 
or reasons that require discontinuation and/or any EOT criteria (section 6.3, Table 1). 


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Premedication with anti-emetics is recommended prior to treatment with CPX-351.  No 
other chemotherapy consolidation treatment is permitted. Only HSCT (hematopoietic 
stem cell transplant) is permitted in place of, or following, chemotherapy consolidation. 
Delays in administrating consolidation cycles will be allowed at the discretion of the 
treating physician and after discussion with the PI.  
 
End of Treatment and Follow-up 
 
At the point in which the patient completes therapy per protocol or meets any 
EOT criteria (section 6.3, Table 1), the patient will enter into the follow-up period. The 
patient will be followed for survival for 1 year and/or until death, whichever occurs first. 
During the first 6 months of follow-up the patient will be seen in clinic as standard of 
care (SOC) every 30 days, per the study calendar (section 11.2). End of study (EOS) is 
defined as the time the patient completes 1 year of follow, withdraws consent and/or 
patient’s death, whichever occurs first.  
 
 
6.1.1 Name of Investigational Agent  
 
CPX-351 
 
 
6.2 
General Concomitant Medications and Supportive Care Guidelines 
 
 
Patients should be off any prior treatment or line of therapy at least 2 weeks prior 
to D1 of induction therapy with the exception of hydrea. Hydrea will be allowed at the 
discretion of the treating physician but must be stopped prior to starting CPX-351. 
 
Necessary supportive measures for optimal medical care will be given throughout 
the treatment as determined by the treating physician and the patient’s medical needs. No 
concomitant chemotherapy, immunotherapy, or therapy with monoclonal antibodies will 
be allowed during the study.  
Prophylactic antibiotics and antiviral agents (e.g. levofloxacin, valacyclovir, etc.) 
are recommended while on study; however, the use of these or other drugs will be left to 
the treating physician’s discretion. Use of colony-stimulating factors or combinations 


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thereof (e.g. G-CSF, GM-CSF, or erythropoietin) are at the discretion of the treating 
physician and are permitted if judged in the patient’s best medical interest. At the D35 
(+/- 10 days) bone marrow, if there is no evidence of blasts > 5%, G-CSF will be allowed 
to improve counts at the discretion of the treating physician. 
 
6.3 
Criteria for Removal from Study 
 
In the absence of treatment delays due to adverse events, treatment may continue for one 
cycle of induction therapy and up to four cycles of consolidation therapy if patients 
achieve response criteria per section 12.0 or until one of the following criteria applies: 
 
End of Treatment Criteria:  
 Disease progression (section 12.0), 
 Intercurrent illness that prevents further administration of treatment, 
 The investigator and/or treating physician considers it, for safety reasons, to be in 
the best interest of the subject. Unacceptable adverse events defined as following: 
• 
Any unacceptable treatment related grade 3 or 4 toxicities that fail to 
recover to baseline or < Grade 3 in the absence of treatment within 4 
weeks  
 Impaired cardiac function 
 Severe OR life-threatening hypersensitivity reactions 
 Grade 4 non-hematological organ toxicities regardless of time to recovery, 
excluding: 
 Grade 4 fatigue, asthenia fever, anorexia or constipation 
 Grade 4 nausea, vomiting or diarrhea not requiring tube feeding, 
total parenteral nutrition, or requiring or prolonging hospitalization 
 Infection, bleeding, or other expected direct complication of 
cytopenias due to active underlying leukemia 
 Grade 4 infusion reaction including cytokine release syndrome 
(CRS), if successfully managed and which resolves within 72 
hours 
 Grade 4 tumor lysis syndrome (TLS) if it is successfully managed 
clinically and resolves within 7 days without end-organ damage 
 Grade 4 isolated electrolyte abnormalities that last <72 hours  
 Patient decision to withdraw from treatment (partial consent) or from the study 
(full consent), 
 Pregnancy during the course of the study for a child-bearing participant 
 Death while patient is on the study 
Table 1: End of Treatment Criteria 
 
End of Study Criteria:  


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 Patient decision to withdraw from the study (full consent), 
 Non-compliance with the study protocol,  
 Death while patient is in the follow-up phase, 
 Patient completed treatment and follow-up phase per protocol. 
Table 2: End of Study Criteria 
 
6.4 
Duration of Follow Up 
 
Following completion of active treatment (EOT) and while still on study (Follow up), 
patients will be followed for survival as for 1 year. During the first 6 months of follow-
up, the patient will be seen in clinic as standard of care every 30 days, per the study 
calendar (section 11.2). The clinical course of all grade 3 or 4 events will be followed 
until resolution, stabilization, or until it has been determined study treatment or study 
participation is not the cause. New onset adverse events will not be recorded during 
follow-up.  
Serious adverse events that are ongoing at the end of active treatment (EOT), will 
necessitate follow-up to determine the final outcome. Any serious adverse events that 
occur after the study period (EOT) and are considered related or possibly related to study 
treatment or study participation will be recorded and reported immediately, per 
institutional review board (IRB) requirement.  
 
7.0  
Dose Delays/Dose Modifications 
 
No dose reductions of CPX-351 will be allowed during the study. Dose delays 
will be at the discretion of the treating physician after discussion with the PI. Missed 
doses of CPX-351 can be made up on subsequent days if felt to be in the best interest of 
the patient. CPX-351 doses must be given at least 24 hours apart. This will be determined 
by the treating physician following discussion with the PI.   
If at any time during an infusion the patient experiences moderate hypersensitivity 
reactions, discontinuation of that infusion is mandatory. Premedicate with antihistamines 
and/or corticosteroids prior to all subsequent infusions. If a patient experiences a mild 
hypersensitivity reaction, regardless or premedication, infusion must be interrupted and 
can be re-initiated at half the prior rate.  
 


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8.0 
Adverse Events and Potential Risks  
 
8.1 
Definitions  
 
8.1.1 
Adverse Event   
An adverse event (AE) is any unfavorable or unintended event, physical or 
psychological, associated with a research study, which causes harm or injury to a 
research participant as a result of the participant’s involvement in a research study. The 
event can include abnormal laboratory findings, symptoms, or disease associated with the 
research study. The event does not necessarily have to have a causal relationship with the 
research, any risk associated with the research, the research intervention, or the research 
assessments.  
Adverse events may be the result of the interventions and interactions used in the 
research; the collection of identifiable private information in the research; an underlying 
disease, disorder, or condition of the subject; and/or other circumstances unrelated to the 
research or any underlying disease, disorder, or condition of the subject.  
8.1.2   Serious Adverse Events  
A serious adverse event (SAE) is any adverse experience occurring at any dose that 
results in any of the following outcomes:  
 Results in death.  
 Is a life-threatening adverse experience.  The term life-threatening in the 
definition of serious refers to an adverse event in which the subject was at risk 
of death at the time of the event.  It does not refer to an adverse event which 
hypothetically might have caused death if it were more severe.  
 Requires 
inpatient 
hospitalization 
or 
prolongation 
of 
existing 
hospitalization.  Any adverse event leading to hospitalization or prolongation 
of hospitalization will be considered as Serious, UNLESS at least one of the 
following expectations is met: 
o The admission results in a hospital stay of less than 24 hours OR 


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o The admission is pre-planned (e.g., elective or scheduled surgery 
arranged prior to the start of the study) OR 
o The admission is not associated with an adverse event (e.g., social 
hospitalization for purposes of respite care. 
However, it should be noted that invasive treatment during any hospitalization 
may fulfill the criteria of “medically important” and as such may be reportable as 
a serious adverse event dependent on clinical judgment.  In addition, where local 
regulatory authorities specifically require a more stringent definition, the local 
regulation takes precedent.  
 Results in persistent or significant disability/incapacity.  The definition of 
disability is a substantial disruption of a person’s ability to conduct normal 
life’s functions. 
 Is a congenital anomaly/birth defect.  
 Is an important medical event.  Important medical events that may not result 
death, be life-threatening, or require hospitalization may be considered a 
serious adverse experience when, based upon appropriate medical judgment, 
they may jeopardize the subject and may require medical or surgical 
intervention to prevent one of the outcomes listed in this definition.  Examples 
of such medical events include allergic bronchospasm requiring intensive 
treatment in an emergency room or at home, blood disease or disorders, or 
convulsions that do not result in inpatient hospitalization, or the development 
of drug dependency or drug abuse. The development of a new cancer is 
always considered an important medical event. 
 
8.1.3 Adverse Event Evaluation  
 
The investigator or designee is responsible for ensuring that all adverse events 
(both serious and non-serious) observed by the clinical team or reported by the subject 
which occur after the subject has signed the informed consent are fully recorded in the 


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subject’s medical records. Source documentation must be available to support all adverse 
events.  
 
A laboratory test abnormality considered clinically relevant as deemed by the 
treating physician should be reported as an adverse event.   
 
The investigator or sub-investigator (treating physician if applicable) will provide 
the following for all adverse events (both serious and non-serious): 
 Event term (as per CTCAE) 
 Description of the event 
 Date of onset and resolution 
 Expectedness of the toxicity 
 Grade of toxicity  
 Attribution of relatedness to the investigational agent- (this must be assigned 
by an investigator, sub-investigator, or treating physician) 
 Action taken as a result of the event, including but not limited to; no changes, 
dose interrupted, reduced, discontinued, etc. or action taken with regard to the 
event, i.e. no action, received conmed or other intervention, etc. 
 Outcome of event 
Descriptions and grading scales found in the NCI Common Terminology Criteria for 
Adverse Events (CTCAE) version 5.0 will be utilized for AE reporting.  
An expected adverse event is an event previously known or anticipated to result from 
participation in the research study or any underlying disease, disorder, or condition of the 
subject. The event is usually listed in the Investigator Brochure, consent form or research 
protocol.  
An unexpected adverse event is an adverse event not previously known or anticipated to 
result from the research study or any underlying disease, disorder, or condition of the 
subject.  


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Attribution is the relationship between an adverse event or serious adverse event and the 
study drug.  Attribution will be assigned as follows: 
 Definite – The AE is clearly related to the study drug. 
 Probable – The AE is likely related to the study drug. 
 Possible – The AE may be related to the study drug. 
 Unlikely – The AE is doubtfully related to the study drug. 
 Unrelated – The AE is clearly NOT related to the study drug. 
Protocol must specify if attribution is required for individual components of the treatment 
regimen or the treatment regimen as a whole. 
 
8.2 
Potential Risks of CPX-351 
 
 
COMMON, SOME MAY BE SERIOUS 
In 100 people receiving CPX-351 more than 10 and up to 100 may have: 
 Abdominal pain 
 Anemia 
 Anxiety 
 Arrhythmia 
 Chest pain 
 Chills 
 Constipation 
 Cough 
 Decreased appetite 
 Delirium 
 Diarrhea 
 Dizziness 
 Dyspnea 
 Edema 
 Fatigue 
 Febrile neutropenia 
 Fungal infection 
 Headache 
 Hemorrhage 
 Hypertension 
 Hypotension 
 Hypoxia 
 Rash 
 Mucositis 
 Musculoskeletal pain 


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 Nausea 
 Neutropenia 
 Non-conduction cardio toxicity 
 Pleural effusion 
 Pneumonia 
 Pruritus 
 Pyrexia 
 Rash 
 Sleep disorders 
 Vomiting 
 
OCCASIONAL, SOME MAY BE SERIOUS 
In 100 people receiving CPX-351 from 4 to 20 may have: 
 Acute renal failure 
 Cellulitis 
 Catheter/injection site reaction 
 Ejection fraction decreased 
 Fatigue 
 Hemorrhoids 
 Hypokalemia 
 Malignant neoplasm progressive 
 Petechiae 
 Pneumonia 
 Pyrexia 
 Rash 
 Sepsis 
 Urinary tract infection 
 Renal insufficiency 
 Respiratory failure 
 Transfusion reactions 
 Upper respiratory induction (excluding fungal) 
 Visual impairments (except bleeding) 
 
 
8.3  
SAE Report Form 
SAEs will be recorded on the FDA Form 3500A (MedWatch) but should only be reported 
as instructed below.  The electronic FDA SAE reporting forms should not be used.   
 
8.4  
Reporting Procedures for Serious Adverse Events 
 
For the purposes of safety reporting, all adverse events will be reported that occur 
through 30 days after the final dose of study drug. Adverse events, both serious and non-


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serious, and deaths that occur during this period will be recorded in the source 
documents. All SAEs should be monitored until they are resolved or are clearly 
determined to be due to a subject’s stable or chronic condition or intercurrent illness(es). 
Related AEs will be followed until resolution to baseline or grade 1 or stabilization.  
 
8.4.1 SAE Reporting Requirements 
 Participating investigators (all sites) must report all serious adverse events to the 
Lead Site Principal Investigator (e.g. Sponsor-Investigator) within 24 hours of 
discovery or notification of the event. The participating investigator must also 
provide follow-up information on the SAE until final resolution.  
 The Lead Site Principal Investigator will review the SAE and report the event to 
the FDA, external collaborator(s), and IRB as applicable. 
 The Principal Investigator must send all SAEs (initial and follow-up) that require 
collection and reporting per protocol, and which occur in a subject who received 
CPX-351 as study drug, to Jazz Pharmaceuticals within 1 business day of their 
awareness of the SAE to AEreporting@jazzpharma.com. 
 It is the Sponsor-Investigator’s responsibility (e.g. lead site PI) to ensure that ALL 
serious adverse events that occur on the study (e.g. ALL SAEs that occur at each 
enrolling institution) are reported to all participating sites. 
 
Institutional Review Board Reporting Requirements: 
 Investigative sites will report adverse events to their respective IRB according to 
the local IRB’s policies and procedures in reporting adverse events.  
 
8.5 
SAEs and OnCore 
 All SAEs will be entered into OnCore.   
 A copy of the SAE form(s) submitted to the sponsor-investigator is also uploaded 
into Oncore. 
 
8.6  
Data Safety and Toxicity Committee 
It is the responsibility of each site PI to ensure that ALL SAEs occurring on this 
trial (internal or external) are reported to the Case Comprehensive Cancer Center’s Data 


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and Safety Toxicity Committee. This submission is simultaneous with their submission to 
the sponsor and/or other regulatory bodies.  
The sponsor-investigator is responsible for submitting an annual report to the 
DSTC as per CCCC Data and Safety Monitoring Plan. 
  
8.7 
Data and Safety Monitoring Plan (DSMP) 
This protocol will adhere to the policies of the Case Comprehensive Cancer 
Center Data and Safety Monitoring Plan in accordance with NCI guidelines.  
 
9.0 
PHARMACEUTICAL INFORMATION  
A list of the adverse events and potential risks associated with the investigational 
or commercial agents administered in this study can be found in Section 8.  
 
9.1 Investigational Agents 
 
9.1.1  Name of Agent 
CPX-351 
Other Names:   
CPX-351 
Product description: CPX-351 (daunorubicin and cytarabine) liposome for injection is a 
combination of daunorubicin and cytarabine in a 1:5 molar ratio encapsulated in 
liposomes for intravenous administration. The liposome membrane is composed of 
distearoylphosphatidylcholine (DSPC), distearoylphosphatidylglycerol (DSPG), and 
cholesterol in a 7:2:1 molar ratio. 
Solution preparation: The appropriate number of vials of CPX-351 
(cytarabine:daunorubicin) Liposome Injection should be removed from the refrigerator 
prior to reconstitution. Reconstitute with 19 mL of sterile water for injection using a 20 
mL syringe. Do not heat CPX-351 (cytarabine:daunorubicin) Liposome Injection. After 
reconstitution, invert vials gently 3- 4 times and let rest for 15 minutes and repeat vial 
inversion prior to withdrawing drug for dilution.  The concentration of the reconstituted 
dispersion is 5 mg-2.2mg/mL (cytarabine-daunorubicin). CPX-351 should be diluted in 
approximately 500 mL of sodium chloride injection or dextrose injection.  
The IV bags and infusion sets must be non-DEHP. Aseptic technique must be strictly 
observed throughout the handling of CPX-351 (cytarabine:daunorubicin) Liposome 


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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. 
Storage requirements: Store un-reconstituted CPX-351 vials in a refrigerator at 2°C to 
8°C (36°F to 46°F) in an upright position. The vial should be stored in its original carton 
to protect from light. 
Stability: If the diluted infusion solution is not used immediately, store in refrigerator at 
2ºC to 8ºC for up to 4 hours. 
Route of administration: The infusion of CPX-351 (cytarabine:daunorubicin) Liposome 
Injection will be performed through a central venous catheter, using an infusion pump to 
ensure that the drug is infused over the specified time period. Non-DEHP containing 
administration sets should be used. Do not use an in-line filter. CPX-351 should never 
be given by the intramuscular or subcutaneous route. Administer CPX-351 over 
approximately 90 minutes via an infusion pump. Flush the line to ensure administration 
of the full dose. The dosage (total mg/m2), start/stop time of the infusion, total volume 
infused, must be documented in the patient’s chart. 
Drug Procurement: CPX-351 will be supplied for this study by Jazz Pharmaceutical.  
Drug Accountability: The study pharmacist or designee must maintain records of the 
delivery of CPX-351 to the study site, the inventory at the site, the use by each patient, 
and the disposition of unused product. These records should include dates, quantities, lot 
numbers, expiration dates and patient identifications. Institutions should maintain records 
that document adequately that the patients were provided the doses specified by the 
protocol and reconcile all investigational product received from the Sponsor. Records of 
storage conditions (temperature logs) must be kept for the entire period that CPX-351 is 
maintained at the institution. 
Drug Destruction: At the completion of the study, there will be a final reconciliation of 
drug shipped, drug consumed, and drug remaining. This reconciliation will be logged on 


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the drug reconciliation form, signed and dated. Any discrepancies noted will be 
investigated, resolved, and documented prior to return or destruction of unused study 
drug. Drug destroyed on site will be documented in the study files. 
 
10.0 
EXPLORATORY or CORRELATIVE STUDIES 
Bio specimens (whole blood, 10 mL) will be collected as outlined in section 11.2 
at screening, C1D35 (+/- 10 days) and EOT for general research purposes, potentially 
including genetic analysis research. All subjects must consent to provide archived sample 
for future research.  
All samples obtained will be stored at the Cleveland Clinic Translational 
Hematology and Oncology Research laboratory. Samples will remain at the Cleveland 
Clinic to be used for research purposes for this study as well as for future research 
projects approved by the IRB.  
 
10.1 Collection of Samples 
10mL of whole blood will be collected in an extra lab tube at screening, C1D35 
(+/- 10 days) and EOT (section 11.2). Details and instructions about the collection, 
processing and shipping can be found in the Lab Manual. All samples will be housed at 
and should be delivered and/or shipped to:  
 
Principle Research Technologists 
Translational Hematology and Oncology Laboratory 
Cleveland Clinic, LC – NE6 – 250 
9620 Carnegie, Avenue 
Cleveland, OH 44195 
Phone: (216) 444-0256 
 
 
11.0  STUDY PARAMETERS AND CALENDAR  
11.1 
Study Parameters 
 
11.1.1 Screening Evaluations (Consent to D-1) 
 
1. History and physical examination.  
2. ECOG performance status (Appendix I). 


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3. Vitals. 
4. Hematology exam (Appendix IV). 
5. Serum chemistry exam (Appendix IV). 
6. Echocardiogram and electrocardiogram (If completed prior to consent and within 
28 days of C1D1, may count towards screening procedures). 
7. Bone marrow aspirate and biopsy, including cytogenetics, within 28 days of 
therapy start to confirm diagnosis (If completed prior to consent and within 28 
days of C1D1, may count towards screening procedures). 
8. Serum pregnancy test for women of childbearing potential within Child bearing 
potential is defined as not post-menopausal for 12 months or no previous surgical 
sterilization. 
9. Documentation in the medical record (consisting of start date, dose, frequency, 
route, and if applicable stop date) of all medications including vitamins and other 
over the counter medications. 
10. Documentation in the medical record (consisting of start and stop date, dose, 
frequency and route) of any prior administration of cancer agent therapy.  
11. Documentation in the medical record of all adverse events (graded per CTCAE V. 
5.0) present at baseline. Documentation must include start and stop dates (if 
resolved), relationship to CPX-351 and grade.  
 
11.1.2 Induction Therapy (C1D1 to C1D35 and/or count recovery). 
 
1. Physical examination will occur daily while inpatient (Appendix IV). 
2. ECOG performance status will be collected daily while in-patient (Appendix I). 
3. Vitals will be collected daily while in-patient (Appendix IV). 
4. Echocardiogram will be completed on day 1 prior to dosing.  
5. Hematology exam on days 1-5, and twice weekly during days 6-27 (Appendix 
IV). 
6. Serum chemistry exam on days 1-5, and twice weekly days 6-27 (Appendix IV). 
7. Administration of CPX-351 at 44mg/m2 on days 1, 3 and 5. 
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9. Disease response assessment will be assessed by the treating physician on D35 
(+/- 10 days) (Table 2). 
10. Serum pregnancy test on C1D1 only for women of childbearing potential. Child 
bearing potential is defined as not post-menopausal for 12 months or no previous 
surgical sterilization. 
11. Documentation in the medical record (consisting of start date, dose, frequency, 
route, and if applicable stop date) of all medications including vitamins and other 
over the counter medications. 
12. Documentation in the medical record (consisting of start and stop date, dose, 
frequency and route) of any prior administration of cancer agent therapy.  
13. Documentation in the medical record of all adverse events (graded per CTCAE V. 
5.0). Documentation must include start and stop dates (if resolved), relationship to 
CPX-351 and grade. 
 
Consolidation Therapy (C2D1 to C5D28) 
 
1. Physical examination on day 1 of each 28 day cycle (Appendix IV). 
2. ECOG performance status will be collected on day 1 of each 28 day cycle 
(Appendix I). 
3. Vitals will be collected prior to dosing on days 1 and 3 (Appendix IV). 
4. Echocardiogram will be completed prior to dosing on day 1 of every cycle 
5. Hematology exam on dosing days 1 and 3 of and twice weekly during each 28 
day cycle (Appendix IV). 
6. Serum chemistry exam on dosing days 1 and 3 and twice weekly during each 28 
day cycle (Appendix IV). 
7. Administration of CPX-351 at 15.4mg/m2 (daunorubicin 15.4 mg/m2 and 
cytarabine 35 mg/m2) on days 1 and 3 of every 28 day cycle 
8. Serum pregnancy test will be collected on day 1 of every 28 day cycle, only for 
women of childbearing potential. Child bearing potential is defined as not post-
menopausal for 12 months or no previous surgical sterilization. 


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9. Documentation in the medical record (consisting of start date, dose, frequency, 
route, and if applicable stop date) of all medications including vitamins and other 
over the counter medications will be collected on day one of every 28 day cycle. 
10. Documentation in the medical record (consisting of start and stop date, dose, 
frequency and route) of any prior administration of cancer agent therapy will be 
collected on day one of every 28 day cycle. 
11. Documentation in the medical record of all adverse events (graded per CTCAE V. 
5.0). Documentation must include start and stop dates (if resolved), relationship to 
CPX-351 and grade will be collected on day one of every 28 day cycle. 
 
End of Treatment (EOT) 
 
1. Physical examination (Appendix IV). 
2. ECOG performance status (Appendix I). 
3. Vitals (Appendix IV). 
4. Hematology exam (Appendix IV). 
5. Serum chemistry exam (Appendix IV). 
6. Bone marrow aspirate and biopsy, including cytogenetics. 
7. Disease assessment (Table 2). 
8. Documentation in the medical record (consisting of start date, dose, frequency, 
route, and if applicable stop date) of all medications including vitamins and other 
over the counter medications will be collected. 
9. Documentation in the medical record (consisting of start and stop date, dose, 
frequency and route) of any prior administration of cancer agent therapy will be 
collected. 
10. Documentation in the medical record of all adverse events (graded per CTCAE V. 
5.0). Documentation must include start and stop dates (if resolved), relationship to 
CPX-351 and grade will be collected. 


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11.2 
Calendar  
 
 
Period 
Screening 
Period  
 
Induction Phase 
Consolidation  Phase 
 
End of 
Treatment 
(EOT) 
 
 
Follow-
upg 
 
 
 
1 cycle 
Up to 4 cycles 
 
 
Day 
28 Days 
1 
2 
3 
4 
5 
6-27 
35l 
1dij 
2 
3 
4 - 28  
 
CPX-351 Administrationa 
 
X 
 
X 
 
X 
 
 
X 
 
X 
 
 
 
Informed Consent Form (ICF) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Disease history and prior therapies 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
History and physical examb 
X 
 
 
 
 
 
 
 
X 
 
 
 
X 
 
Vital signsb 
X 
Xop 
 
Xop 
 
 
 
X 
Xop 
 
Xop 
 
 
Concomitant medications 
X 
X 
 
 
 
 
X 
 
 
 
X 
 
ECOG performance statusc 
X 
 
 
 
 
 
 
 
X 
 
 
 
X 
 
Hematologyb 
X 
X 
X 
X 
X 
X 
Xn 
X 
Xe 
 
 
Xn 
X 
Xg 
Serum chemistryb 
X 
X 
X 
X 
X 
X 
Xn 
X 
Xe 
 
 
Xn 
X 
 
Pregnancy test 
X 
Xk 
 
 
 
 
 
 
Xk 
 
 
 
 
 
Echocardiogram 
Xr 
Xq 
 
 
 
 
 
 
X 
 
 
 
 
 
Electrocardiogram 
Xr 
 
 
 
 
 
 
 
 
 
 
 
 
 
Bone marrow biopsy and aspirationb 
Xr 
 
 
 
 
 
 
X 
 
 
 
 
X 
 
Disease response assessmentf 
X 
 
 
 
 
 
 
X 
 
 
 
 
X 
 
Correlative analysis blood drawm 
X 
 
 
 
 
 
 
X 
 
 
 
 
X 
 
Survival follow-up 
 
 
 
 
 
 
 
 
 
 
 
 
 
Xh 
Adverse event assessment 
 X  


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 a: During the induction phase all patients will receive 44mg/m2. Following the induction phase if patients achieve a response (per 
section 12.0) they may continue onto the consolidation phase. During the consolidation phase patients will receive 15.4mg/m2 
(daunorubicin 15.4 mg/m2 and cytarabine 35 mg/m2) for up to 4 cycles.  
b: See Appendix IV for required tests. 
c: See Appendix I for performance status grading. 
d: Indicates at +/-3 day window. 
e: Required twice weekly to monitor counts, can be completed at a local laboratory. 
f: See Section 12.0 for MDS response assessment criteria. 
g: Follow up will occur monthly as SOC for the first 6 months of follow-up. See section 6.4 for adverse event reporting requirements. 
h: Survival Follow up will occur bimonthly (60 days) for a duration of 1 year from patient’s EOT visit. 
i: During only the first cycle in consolidation phase, CPX-351 must be given no earlier than 35 days after the start of induction and no 
later than 75 days after the start of induction. There should be 35 days between the start of each subsequent consolidation cycles 
Patients must have recovered to ANC >500/μL and platelets >50,000/μL to be eligible for any consolidation therapy. 
j: Prior to the first cycle of consolidation therapy, patient must have an ECOG PS of 0-2. 
k: Must be negative prior to dosing. 
l: Indicates a +/-10 day window. 
m: 10mL of whole blood will be collected in an extra lab tube for these tests.  
n: Hematology and serum chemistry will be assessed 1-3x weekly at the discretion of the treating physician to monitor counts. These 
can be completed at a local laboratory. 
o: On dosing days, for induction phase only, vitals must be collected prior to infusion, 5, 10, 30 and 60 minutes post the start of 
infusion and at the end of infusion.  On dosing days, for consolidation phase, vitals must be collected prior to infusion and at the 
end of infusion. 
p: Indicates a (+/-) 5 minute window. 
q: Required if patient has not had an ECHO within 28 days of C1D1.  
r: If completed prior to consent and within  28 days of C1D1, may count towards screening procedures. 
 
 
 
 
 
 


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12.0  MEASUREMENT OF EFFECT  
 
Response criteria will be defined by the IWG criteria ET 2006. Patients will be assessed 
for response at the end of induction cycle. 
Response criteria will be defined as follow: 
 
Response 
Definition  
Responses must be for at least 4 weeks) 
Complete remission 
(CR) 
Marrow: 
< 5% myeloblasts with normal maturation 
of all cell lines. 
Persistent dysplasia will be noted (dysplastic 
changes should consider the normal range of 
dysplastic changes.) 
Blood: 
- Hemoglobin (Hgb) > 11 g/dL (un 
transfused, patient not on EPO) 
- Neutrophils > 1x109/L (not on myeloid 
growth factor) 
- Platelets > 100 x 109/L (not on 
thrombopoietic agent) 
- No blasts 
Partial remission (PR) 
All CR criteria (if abnormal prior to 
treatment), except: 
Marrow blasts decreased by >50% 
compared with pretreatment but still > 5%. 
Cellularity and morphology not relevant 
Marrow CR 
Marrow: 
< 5% myeloblasts and decrease by > 50% 
over pretreatment 
Blood: 
if hematologic improvement (HI) responses, 
they will be noted in 
addition to the marrow CR 
Stable disease (SD) 
Failure to achieve at least PR, but no 
evidence of progression for > 8 weeks 
Failure 
Death during treatment or disease 
progression characterized by worsening of 
cytopenias, increase in percentage of 
marrow blasts, or progression to an MDS 
FAB subtype more advanced than 
pretreatment. 


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Relapse after CR or PR (PD) 
At least one of the following: 
- Return to pretreatment bone marrow blast 
percentage 
- Decrement of > 50% from maximum 
remission/response levels in granulocytes or 
platelets 
- Reduction in Hgb concentration by > 1.5 
g/dL or transfusion dependence (in the 
absence of another explanation, such as 
acute infection, GI bleeding, hemolysis, 
etc.) 
 
Cytogenetic response 
Complete: 
Disappearance of the chromosomal 
abnormality without appearance 
of new ones 
Partial: 
At least 50% reduction of the chromosomal 
abnormality 
Hematologic Improvement 
 
 
Response Criteria 
(responses must last at least 8 weeks) 
Erythroid response 
(pretreatment, < 11 g/dL) 
Hgb increase by > 1.g/dL 
Relevant reduction of units of RBC 
transfusions by an absolute number of at 
least 4 RBC transfusions/8wk compared 
with the pretreatment transfusion number in 
the previous 8 wk. 
Only RBC transfusions given for a Hgb of < 
9 g/dL pretreatment will count in the RBC 
transfusion response evaluation 
Platelet response 
(pretreatment, < 100x109/L) 
Absolute increase of > 30 x 109/L for 
patients starting with > 20 x 
109/L 
Increase from < 20 x 109/L to > 20 x 109/L 
and by at least 100% 
Neutrophil response 
(pretreatment, < 1 x 109/L) 
At least 100% increase an absolute increase 
> 0.5 x 109/L 
Progression or relapse after HI 
At least 1 of the following: 
At least 50% decrement from maximum 
response levels in granulocyte or platelets 
Reduction in Hgb by >1.5 g/dL 
Transfusion dependence (in the absence of 
another explanation, such as acute infection, 
GI bleeding, hemolysis, etc.) 
 


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Table 3: Response Criteria for MDS Patients 
 
 
13.0 
DATA REPORTING / REGULATORY CONSIDERATIONS  
 
Adverse event lists, guidelines, and instructions for AE reporting can be found in Section 
8.0 (Adverse Events: List and Reporting Requirements). 
 
13.1 
Data Reporting  
The OnCore® Database will be utilized, as required by the Case Comprehensive 
Cancer Center, to provide data collection for both accrual entry and trial data 
management. OnCore® is a Clinical Trials Management System housed on secure 
servers maintained at Case Western Reserve University. OnCore® Access to data 
through OnCore® is restricted by user accounts and assigned roles. Once logged into the 
OnCore® system with a user ID and password, OnCore® defines roles for each user 
which limits access to appropriate data. User information and password can be obtained 
by contacting the OnCore® Administrator at OnCore-registration@case.edu. 
OnCore® is designed with the capability for study setup, activation, tracking, 
reporting, data monitoring and review, and eligibility verification. This study will utilize 
electronic Case Report Form completion in the OnCore® database. A calendar of events 
and required forms are available in OnCore®. 
 
13.2 
Regulatory Considerations 
The study will be conducted in compliance with ICH guidelines and with all 
applicable federal (including 21 CFR parts 56 & 50), state or local laws. 
13.2.1 Written Informed consent 
Provision of written informed consent must be obtained prior to any study-related 
procedures. The Principal Investigator will ensure that the subject is given full and 
adequate oral and written information about the nature, purpose, possible risks and 
benefits of the study as well as the subject’s financial responsibility. Subjects must also 
be notified that they are free to discontinue from the study at any time. The subject 


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should be given the opportunity to ask questions and be allowed time to consider the 
information provided.  
The original, signed written Informed Consent Form must be kept with the 
Research Chart in conformance with the institution’s standard operating procedures. A 
copy of the signed written Informed Consent Form must be given to the subject. 
Additionally, documentation of the consenting process should be located in the research 
chart. 
13.2.2 Subject Data Protection 
In accordance with the Health Information Portability and Accountability Act 
(HIPAA), a subject must sign an authorization to release medical information to the 
sponsor and/or allow the sponsor, a regulatory authority, or Institutional Review Board 
access to subject’s medical information that includes all hospital records relevant to the 
study, including subjects’ medical history.  
 
13.2.3  Retention of records 
The Principal Investigator of The Case Comprehensive Cancer Center supervises 
the retention of all documentation of adverse events, records of study drug receipt and 
dispensation, and all IRB correspondence for as long as needed to comply with local, 
national and international regulations. No records will be destroyed until the Principal 
Investigator confirms destruction is permitted.  
 
13.2.4  Audits and inspections  
 
Authorized representatives of the sponsor, a regulatory authority, an Independent 
Ethics Committee (IEC) or an Institutional Review Board (IRB) may visit the site to 
perform audits or inspections, including source data verification. The purpose of an audit 
or inspection is to systematically and independently examine all study-related activities 
and documents to determine whether these activities were conducted, and data were 
recorded, analysed, and accurately reported according to the protocol, Good Clinical 
Practice (GCP), guidelines of the International Conference on Harmonization (ICH), and 


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any applicable regulatory requirements.  For multi-center studies, participating sites must 
inform the sponsor-investigator of pending audits.  
 
14.0 STATISTICAL CONSIDERATIONS  
 
In determining the sample size for the patient cohort, Minimax Simon's two-stage 
design (Simon, 1989) will be used. The null hypothesis that the true response rate is 0.1 
will be tested against a one sided alternative. In the first stage, 7 patients will be accrued 
in each arm.  If there are two or less responses in these 7 patients, the arm will be 
stopped. Interim analysis will conducted to determine the benefit of applying the drug in 
each arm. In the winning arm, 11 additional patients will be accrued for a total of 18. The 
null hypothesis will be rejected if 4 or more responses are observed in 18 patients. This 
design yields a type I error rate of 0.1 and power of 0.8 when the true response rate is 0.3. 
Descriptive statistical analysis will be calculated, including histograms or box-
plots, proportions, range, means and standard deviations. Fisher’s exact test and 
Wilcoxon rank test will be used in univariate analyses of categorical and continuous 
variables, respectively. Overall response (CR + CRi +) rate and its 95% CI. Given there 
is no adjustment for multiple comparisons, need to note the p-values from the univariate 
analyses will be nominal and not used to infer significance. 
 
Toxicity Monitoring Rules 
 
The following toxicity monitoring plan will terminate the trial early given 
evidence for excessive rates of toxicity with CPX-351based on the method of Thall et 
al.14 Early termination will be applied to evaluate patients experiencing toxicity defined 
as any grade >3 non-hematologic AE that is determined to be at least possibility related 
to CPX-351. A total of 25 patients will be enrolled. The monitoring rules target a toxicity 
rate of 20% and assume a non-informative Beta (0.2, 0.8) prior distribution. The trial will 
stop early for toxicity if Pr(Toxicity Rate > 0.20 | data) > 0.85, i.e. stop early if the 
evidence for excessive toxicity (higher than 20%) for the target population given 
observed data is sufficiently high (probability > 0.85). Monitoring will be carried out 


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from the 3rd patient. Table 5 summarizes the resultant stopping boundaries and Table 6 
summarizes the trial’s operating characteristics. 
 
Table 5. Summary of early stopping boundaries from the 3rd patient.  Target toxicity rate is 
20%. Using prior of Beta (0.2, 0.8) and posterior probability threshold of 0.85. E.g. If 3 or more 
patients experience grade >3 non-hematologic AEs out of the first 6 patients, the trial will stop 
early. Whenever a grade >3 non-hematologic AE is observed, check this table to see if the 
boundary has been crossed. E.g. if a total of 4 grade >3 non-hematologic AEs has been 
observed on trial, and the total number of patients treated is 9 or less, then stop the trial for 
excessive toxicity. 
Stop Early if #Patients Experienced grade 
>3 non-hematologic AE 
2 
3 
4 
5 
5 
6 
7 
8 
Total #Patients Treated 
3 
6 
9 
12 
15 
18 
21 
24 
 
Table 6. Summary of operating characteristics based on 10,000 simulations using boundaries in Table 
5 for early stopping. For example, if the true toxicity rate is 20%, the probability of early stopping is 
0.27, and if the true toxicity rate is 40%, the probability of early stopping is 0.88. 
Scenario 
True Toxicity 
Rate 
Pr(Early 
Stop) 
Average #Patients 
Treated 
Average 
#Toxicities 
1 
- 0.10 
 0.05 
 23.2 
 2.3 
2 
 0.20 
 0.27 
 19.8 
 4.0 
3 
 0.30 
 0.62 
 14.6 
 4.4 
4 
 0.40 
 0.88 
 9.8 
 3.9 
 
Summary statistics of toxicity will be provided in frequencies and percentages. 
Toxicity rate will be estimated along with 95% CIs. Other statistical analyses will be 
carried out as appropriate. 
 


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REFERENCES 
1. 
Greenberg P, Cox C, LeBeau MM, Fenaux P, Morel P, Sanz G et al. International 
scoring system for evaluating prognosis in myelodysplastic syndromes. Blood 
1997; 89(6): 2079-88. 
 
2. 
Kantarjian H, O'Brien S, Ravandi F, Cortes J, Shan J, Bennett JM et al. Proposal 
for a new risk model in myelodysplastic syndrome that accounts for events not 
considered in the original International Prognostic Scoring System. Cancer 2008; 
113(6): 1351-61. 
 
3. 
Malcovati L, Germing U, Kuendgen A, Della Porta MG, Pascutto C, Invernizzi R 
et al. Time-dependent prognostic scoring system for predicting survival and 
leukemic evolution in myelodysplastic syndromes. Journal of clinical oncology : 
official journal of the American Society of Clinical Oncology 2007; 25(23): 3503-
10. 
 
4. 
Nazha A, Komrokji RS, Garcia-Manero G, Barnard J, Roboz GJ, Steensma DP et 
al. The efficacy of current prognostic models in predicting outcome of patients 
with myelodysplastic syndromes at the time of hypomethylating agent failure. 
Haematologica 2016; 101(6): e224-7. 
 
5. 
Nazha A, Sekeres MA, Komrokji R, Steensma DP, Kantarjian H, Roboz G et al. 
Validation of a post-hypomethylating agent failure prognostic model in 
myelodysplastic syndromes patients treated in a randomized controlled phase III 
trial of rigosertib vs. best supportive care. Blood cancer journal 2017; 7(12): 644. 
 
6. 
Prebet T, Fenaux P, Vey N. Predicting outcome of patients with myelodysplastic 
syndromes after failure of azacitidine: validation of the North American MDS 
consortium scoring system. Haematologica 2016; 101(10): e427-e428. 
 
7. 
Feldman EJ, Lancet JE, Kolitz JE, Ritchie EK, Roboz GJ, List AF et al. First-In-
Man Study of CPX-351: A Liposomal Carrier Containing Cytarabine and 
Daunorubicin in a Fixed 5:1 Molar Ratio for the Treatment of Relapsed and 
Refractory Acute Myeloid Leukemia. Journal of Clinical Oncology 2011; 29(8): 
979-985. 
 
8. 
Cortes JE, Goldberg SL, Feldman EJ, Rizzeri DA, Hogge DE, Larson M 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; 121(2): 234-42. 
 
9. 
Lancet JE, Uy GL, Cortes JE, Newell LF, Lin TL, Ritchie EK et al. CPX-351 
(cytarabine and daunorubicin) Liposome for Injection Versus Conventional 
Cytarabine Plus Daunorubicin in Older Patients With Newly Diagnosed 


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Secondary Acute Myeloid Leukemia. Journal of Clinical Oncology 2018; 36(26): 
2684-2692. 
 
10. 
Festuccia M, Baker K, Gooley TA, Sandmaier BM, Deeg HJ, Scott BL. 
Hematopoietic Cell Transplantation in Myelodysplastic Syndromes after 
Treatment with Hypomethylating Agents. Biology of blood and marrow 
transplantation : journal of the American Society for Blood and Marrow 
Transplantation 2017; 23(9): 1509-1514. 
 
11. 
Ball B, Komrokji RS, Ades L, Sekeres MA, DeZern AE, Pleyer L et al. 
Evaluation of induction chemotherapies after hypomethylating agent failure in 
myelodysplastic syndromes and acute myeloid leukemia. Blood advances 2018; 
2(16): 2063-2071. 
 
12. 
Arber DA, Orazi A, Hasserjian R, Thiele J, Borowitz MJ, Le Beau MM et al. The 
2016 revision to the World Health Organization classification of myeloid 
neoplasms and acute leukemia. Blood 2016; 127(20): 2391-405. 
 
13. 
Cheson BD, Greenberg PL, Bennett JM, Lowenberg B, Wijermans PW, Nimer 
SD et al. Clinical application and proposal for modification of the International 
Working Group (IWG) response criteria in myelodysplasia. Blood 2006; 108(2): 
419-25. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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APPENDIX I 
 
PERFORMANCE STATUS CRITERIA 
 
ECOG Performance Status Scale 
Karnofsky Performance Scale 
Grade 
Description 
Percent 
Description 
 
0 
 
Normal activity. Full active, able 
to carry on all pre-disease 
performance without restriction.  
 
100 
 
Normal, no complaints, no 
evidence of disease. 
 
90 
Able to carry on normal 
activity; minor signs or 
symptoms of disease. 
 
1 
Symptoms, but ambulatory. 
Restricted in physically strenuous 
activity, but ambulatory and able 
to carry out work of a light or 
sedentary nature (e.g., light 
housework, office work). 
 
80 
Normal activity with effort; 
some signs or symptoms of 
disease. 
 
70 
Cares for self, unable to carry 
on normal activity or to do 
active work.  
 
2 
In bed < 50% of the time.  
Ambulatory and capable of all 
self-care, but unable to carry out 
any work activities. Up and about 
more than 50% if waking hours. 
 
60 
Requires occasional assistance, 
but is able to care for most of 
his/her needs. 
 
50 
Requires considerable 
assistance and frequent 
medical care. 
 
3 
In bed > 50% of the time.  
Capable of only limited self-care, 
confined to bed or chair more than 
50% of waking hours. 
 
40 
 
Disabled, requires special care 
and assistance. 
 
30 
 
Severely disabled, 
hospitalization indicated.  
Death not imminent. 
 
4 
100% bedridden.  Completely 
disabled.  Cannot carry on any 
self-care. Totally confined to bed 
or chair. 
 
20 
Very sick, hospitalization 
indicated. Death not imminent.  
 
10 
Moribund, fatal processes 
progressing rapidly. 
5 
Dead. 
0 
Dead 
 
 
 
 
 
 
 
 


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APPENDIX II: STUDY DESIGN TIME POINT DEFINITIONS 
 
Study Time Points 
Definitions 
Screening 
The screening period will occur over 28 
days from the time of consent to day -1. 
Induction Period 
Day 1a to D35 and/or count recovery 
Disease Response 
The D35 (+/-10 days) bone marrow. 
Consolidation Period 
The consolidation period is defined as 
C2D1 through C5D28. Patients who meet 
disease response criteria will be eligible to 
receive up to 4 cycles of consolidation 
therapy. 
End of Treatment (EOT) 
The day patients meets the defined EOT 
criteria (Table 1) and discontinues study 
treatment. 
Follow up 
Patient will be followed monthly as SOC 
every 30 days for the duration of 6 months 
after EOT. 
End of Study (EOS) 
The time the patient completes 1 year of 
follow up and/or patient’s death, whichever 
were to occur first. 
a: Day 1 is defined as the first dose of CPX-351 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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APPENDIX IV: STUDY DESIGN TIME POINT DEFINITIONS 
 
Hematology 
Serum 
Chemistry 
Vitals 
Physical 
Exam 
Bone Marrow Biopsy 
& Aspirate 
RBC count 
Total protein 
Temperature 
Heighta 
Marrow blast percent 
WBC count 
Albumin 
Respirations 
Weightb 
Marrow cellularity 
Hematocrit 
Sodium 
Blood Pressure 
 
Auer Rods 
Hemoglobin 
Potassium 
Pulse 
 
Dysplasia 
MCV 
Chloride 
 
 
Cytogenetics 
MCHC 
Bicarbonate 
 
 
 
Platelet count 
Glucose  
 
 
 
Neutrophils 
AST 
 
 
 
Eosinophils 
ALT 
 
 
 
Basophils 
Creatinine 
 
 
 
Monocytes 
Calcium 
 
 
 
Lymphocytes 
Bilirubin 
 
 
 
Blast percent 
Alkaline 
phosphate 
 
 
 
 
Phosphorus 
 
 
 
 
Uric acid 
 
 
 
 
Magnesium 
 
 
 
a: Height will only be collected at screening 
b: On dosing days, weight will be collected prior to dosing  
 
 
 
 
 
 
 


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APPENDIX V: Post-HMA Failure Model 
 


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ICF_001.pdf: 
 
 
CASE 2918  
 1 
Consent Version 4.0 
18 January 2021 
 
 
 
The Cleveland Clinic Foundation 
Consent to Participate in a Research Study 
 
Study title: CASE 2918: A Phase II Study of CPX-351 as a Novel Therapeutic Approach for 
Patients With Myelodysplastic Syndromes (MDS) after Hypomethylating Agent Failure 
 
Sponsor: Cleveland Clinic Foundation, NCT03957876 
Funding Source: Jazz Pharmaceuticals 
Principal Investigator:  Sudipto Mukherjee, MD, MPH 
 
 
 
     Department of Hematology/Oncology 
 
 
 
     Cleveland Clinic Foundation 
 
 
 
     9500 Euclid Avenue, Mail Code: CA-6 
 
 
 
     Cleveland, Ohio 44195 
 
 
 
     Phone: (216) 444-0506 
Study Coordinator: Allison Unger, BS 
After hours phone contact #: Page operator at (216) 444-2200 or toll free at (800) 223-2273, 
and ask for the oncologist (cancer doctor) that is on call  
Cancer research studies are coordinated by physicians and scientists from Cleveland Clinic, 
University Hospitals and Case Western Reserve University (CWRU) through the NIH National 
Cancer Institute (NCI) designated Case Comprehensive Cancer Center (Case CCC).  The goal of 
this collaboration is to enhance cancer treatment and research in Northeast Ohio. This study is 
being offered at the Cleveland Clinic (CC). 
KEY INFORMATION 
The following is a short summary of this research study to help you decide whether or not to be a 
part of this research study.  More detailed information is included later on in this document. 
 
What should I know about a research study? 
• 
Someone will explain this research study to you. 
• 
You can choose whether or not to take part. 
• 
You can agree to take part and then later change your mind. 
• 
Your decision whether or not to participate will not be held against you. 
• 
You can ask all the questions you want before you decide. 
 
What is the purpose, procedures and duration of this study?  
 
We are asking you to take part in a research study because you a) have been diagnosed with 
myelodysplasic syndrome (MDS), a bone marrow disorders causing a decrease in red blood cells 
which may cause fatigue and tiredness and b) you’ve had prior treatment  with azacitidine or 
decitabine (hypomethylating agents, HMAs) that has previously failed you. The purpose of this 


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2 
study is to evaluate the effect of treatment with CPX-351 (an FDA approved drug for the 
treatment of certain kinds of acute myeloid leukemia (AML)) in patients with MDS while using 
a new tool to predict outcomes of patients following HMA failure. This approach is intended to 
gain a better understanding and insight into finding new opportunities for drug approvals in this 
setting. 
 
CPX-351 is an investigational (experimental) drug for the treatment of myelodysplastic 
syndrome that works by delivering two chemotherapy medications (daunorubicin and cytarabine) 
together which are then concentrated into the bone marrow (the part of the body that makes 
blood cells). CPX-351 is experimental because it is not approved by the Food and Drug 
Administration (FDA) for the indication of myelodysplastic syndrome. This drug is approved by 
the Food and Drug Administration (FDA) for the indication of certain types acute myeloid 
leukemia. 
 
You will receive the CPX-351 on days 1, 3 and 5 of the first cycle. After you finish your first 
round of treatment and based on your response you may be eligible for another 4 cycles of 
treatment. Your doctor will inform you if this is an available option for you when the time 
comes. Once you have finished treatment your doctor will continue to watch you for side effects 
and follow your condition for 1 year. 
 
Your participation in the research will last about 18 months. 
More detailed information can be found under the section labeled: “Information on the 
Research.” 
Why might you choose not to participate in this research study? 
There may be discomforts, side effects, and risks to using CPX-351 treatment that we do not 
know yet. Sometimes during a study, the sponsor may learn new information about the study 
drug and the risks, which the study doctor/staff will tell you about in a timely manner. This new 
information might make you change your mind about being in the study.  The study drug may 
not be better, and could possibly be worse than the usual approach for your cancer.   
Additionally, you may lose time at work or home and spend more time in the hospital or the 
doctor’s office than usual.  You also may be asked sensitive or private questions which you 
normally do not discuss.  
 
More detailed information about the risks of this study can be found in the section labeled 
“Risks.” 
Why might you choose to volunteer for this study? 
 
We cannot know if you will have any benefit as a result of your participation in the study; it is 
possible the study treatment may improve your condition, which may give you relief from some 
symptoms or improve your quality of life. However, it is possible that your condition could 
worsen. Your participation in this study will help to obtain information about treating subjects 
with myeloid dysplastic syndrome.  


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More detailed information about the benefits of this study can be found in the section labeled 
“Benefits.” 
 
 
What is the usual approach to my myelodysplastic syndrome (MDS)? 
Some patients receive no therapy and only receive red blood cell transfusions as needed (this is 
called supportive care). For lower-risk MDS patients with anemia, doctors often prescribe 
erythropoietin-stimulating agents (ESAs) which help stimulate red blood cell production. For 
patients who do not respond or stop responding to ESA treatment, there are currently two types 
of FDA approved therapies that may be used: HMAs and lenalidomide (Revlimid). You may 
also be a candidate for a bone marrow transplant, which should be further discussed with your 
physician. 
 
What are my other choices if I do not take part in this study? 
If you decide not to take part in this study, you have other choices. For example: 
 you may choose to have the usual approach described above 
 you may choose to take part in a different study, if one is available 
 or you may choose not to be treated for cancer. For example: comfort/palliative care 
 
More detailed information about the alternatives to this study can be found in the section labeled 
“Alternatives.” 
 
Do the researchers or institution have any conflicts of interest relating to this study? 
One or more of the Investigators conducting this study serve as consultants for the company that 
makes products used in this study.  These financial interests are within permissible limits 
established by the local institutional Conflict of Interest Policy.  If you have any questions 
regarding conflicts of interest, please ask you study doctor or call the Cleveland Clinic 
Institutional Review Board at (216) 444-2924.  
 
DETAILED INFORMATION 
 
The following is more detailed information about this study in addition to the information listed 
above. 
 
1. INFORMATION ON THE RESEARCH 
 
 Why is the research study being done? 
The purpose of this study is to evaluate the efficacy of treatment with CPX-351 (an FDA 
approved drug for the treatment of AML) in patients with MDS while using a new stratification 
tool to predict outcomes of patients following HMA failure. This approach is intended to gain a 
better understanding and insight into identifying new opportunities for drug approvals in this 
setting.  
 
CPX-351 is an investigational (experimental) drug for the indication of myelodysplastic 
syndrome that works by delivering two chemotherapy medications (daunorubicin and cytarabine) 


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together which are then concentrated into the bone marrow (the part of the body that makes 
blood cells). CPX-351is experimental because it is not approved by the Food and Drug 
Administration (FDA) for the indication of myelodysplastic syndrome. This drug is approved by 
the Food and Drug Administration (FDA) for the indication of acute myeloid leukemia. 
 
How Many People Will Take Part in this Study? 
Approximately 30 people will take part in this study at Cleveland Clinic.  
 
What is involved if you decide to take part in this research study? 
Prior to beginning the study you will have to agree to participate by signing this consent form. 
Upon signing consent, you will begin the screening period. The screening period begins the day 
you sign consent and can take place over a 28 day period leading up to dosing on day 1 (D1). 
During the screening period you will be assessed to determine if you meet eligibility for this 
study.  
 
Assessments before you begin the study: 
You will need to have the following tests and procedures to find out if you can be in the study: 
 History and physical examination, questions about how you are feeling and treatments you 
have received. 
 ECHO (echocardiogram) 
 ECG (electrocardiogram) 
 Blood tests for routing testing (about 2 tablespoons) 
 Blood draw for future research purposes (including possible genetic analysis) at screening, 
cycle 1 day 35 and end of treatment (about 1/2 tablespoon) 
 Bone marrow biopsy and aspirate 
 
If you are determined eligible to participate in this study, you will then be grouped into one of 
two groups. Prior to beginning treatment, all eligible patients will be grouped into low risk 
versus high risk based on a stratification tool used to determine your disease.  Group 1 will be 
low risk participants and group 2 will be high risk participants. All study participants will get the 
same study drug, CPX-351. 
 
You will receive the CPX-351 on days 1, 3 and 5 of the first 35 day cycle as outlined in the study 
calendar. After you finish your first round of treatment and based on your response, determined 
by a bone marrow biopsy and blood draw, you may be eligible for another 4 cycles of treatment. 
Your doctor will inform you if this is an available option for you when the time comes. Once you 
have finished treatment your doctor will continue to watch you for side effects and follow your 
condition for 1 year. 
 
What tests and procedures will I have if I take part in this study? 
 
Informed consent:  
The study doctor/staff will talk to you about the study and you will decide if you want to join. 
This will be done during the Screening visit. 


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Review medical history:  
You will discuss your current and past health with the study doctor/staff. This will be done 
during the Screening visit.  
Review of medications:  
You will talk with the study doctor/staff about any medicines you take. This will be done during 
the Screening, Treatment and Follow Up visits. 
Physical examination:  
The study doctor/staff will check your body for general health.  This will be done during the 
Screening and Treatment visits.  
Vital signs:  
The study doctor/staff will take your pulse, temperature, and blood pressure. This will be done 
during the Screening and Treatment visits. 
 
ECG (Electrocardiogram):  
Sticky patches that are connected to a machine that shows the electrical activity of your heart, are 
placed on your chest, arms and legs.  This will be done during the Screening visit and maybe 
during Treatment visits if your Study Doctor advises you need this test. 
Blood draw/tests:  
The study doctor/staff will draw blood from a vein in your arm.  You may get a bruise or 
irritation at the place where the needle goes into your skin.  Some participants may faint and, in 
rare cases, can get an infection. 
Sometimes you will need to repeat a blood test.  
Your blood will be used to check for:  
 Your general health 
 Disease evaluations 
 How your body handles the study drug 
 Pregnancy (if you are a female who could get pregnant.) 
 Scientific Research 
o 10mL of your blood will be taken for exploratory studies 
Bone Marrow Aspirate/Biopsy:  
An area of bone (usually pelvis) will be made numb by injecting a local anesthetic, and then a 
needle will be inserted into the bone.  A small amount of bone and bone marrow will be 
removed.  The bone marrow aspirate/biopsy will be used for disease evaluations, as well as 
Scientific/Genetic Research. This will be done during Screening, Treatment and at the End of 
Treatment visit. If you were to complete this trial, it would be anticipated that you would have 3 
bone marrow tests.  
 


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A calendar of all study procedures and when they will take place can be found on the next page.  
 


 
 
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Study Calendar  
 
 
Period 
Screening 
Period  
Induction Phase 
Consolidation  Phase 
 
End of 
Treatment 
(EOT) 
 
 
Follow-
upg 
 
 
1 cycle 
Up to 4 cycles 
 
 
Day 
28 Days 
1 
2 
3 
4 
5 
6-27 
35l 
1dij 
2 3 
4 - 28  
 
CPX-351 Administrationa 
 
X 
 
X 
 
X 
 
 
X 
 
X 
 
 
 
Informed Consent Form (ICF) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Disease history and prior therapies 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
History and physical examb 
X 
 
 
 
 
 
 
 
X 
 
 
 
X 
 
Vital signsb 
X 
Xop 
 
Xop 
 
 
 
X 
Xop 
 
Xop 
 
 
Concomitant medications 
X 
X 
 
 
 
 
X 
 
 
 
X 
 
ECOG performance statuscj 
X 
 
 
 
 
 
 
 
X 
 
 
 
X 
 
Hematologyb 
X 
X 
X 
X 
X 
X 
Xn 
X 
Xe 
 
 
Xn 
X 
Xg 
Serum chemistryb 
X 
X 
X 
X 
X 
X 
Xn 
X 
Xe 
 
 
Xn 
X 
Xg 
Pregnancy test 
X 
Xk 
 
 
 
 
 
 
Xk 
 
 
 
 
 
Echocardiogram 
Xr 
Xq 
 
 
 
 
 
 
X 
 
 
 
 
 
Electrocardiogram 
Xr 
 
 
 
 
 
 
 
 
 
 
 
 
 
Bone marrow biopsy and aspirationb 
Xr 
 
 
 
 
 
 
X 
 
 
 
 
X 
 
Disease response assessmentf 
X 
 
 
 
 
 
 
X 
 
 
 
 
X 
 
Correlative analysis blood drawm 
X 
 
 
 
 
 
 
X 
 
 
 
 
X 
 
Survival follow-up 
 
 
 
 
 
 
 
 
 
 
 
 
 
Xh 
Adverse event assessment 
 X  


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a: During the induction phase all patients will receive 44mg/m2 on days 1, 3 and 5. Following the induction phase if patients achieve a 
response (per section 12.0) they may continue onto the consolidation phase. During the consolidation phase patients will receive 
15.4mg/m2 on days 1 and 3 (daunorubicin 15.4 mg/m2 and cytarabine 35 mg/m2) for up to 4 cycles.  
b: See Appendix IV for required tests (available to the patient upon request). 
c: See Appendix I for performance status grading (available to the patient upon request). 
d: Indicates at +/-3 day window. 
e: Required twice weekly to monitor counts, can be completed at a local laboratory. 
f: See Section 12.0 for MDS response assessment criteria. 
g: Follow up will occur monthly as standard of care (SOC) for the first 6 months of follow-up. See section 6.4 for adverse event 
reporting requirements. 
h: Survival Follow up will occur bimonthly (60 days) for a duration of 1 year from patient’s EOT visit. 
i: During only the first cycle in consolidation phase, CPX-351 must be given no earlier than 35 days after the start of induction and no 
later than 75 days after the start of induction. There should be 35 days between the start of each subsequent consolidation cycles 
Patients must have recovered to Absolute neutrophil count (ANC) >500/μL and platelets >50,000/μL to be eligible for any 
consolidation therapy. 
j: Prior to the first cycle of consolidation therapy, patient must have a performance status (ECOG PS)(determined by physician based 
on physical ability) of 0-2. 
k: Must be negative prior to dosing 
l: Indicates a +/-10 day window. 
m: 10mL of whole blood will be collected in an extra lab tube and stored for future research testing (specific tests to be run are 
unknown at this time).   
n: Hematology and serum chemistry will be assessed 1-3x weekly at the discretion of the treating physician to monitor counts. These 
can be completed at a local laboratory. 
o: On dosing days, for induction phase only, vitals must be collected prior to infusion, 5, 10, 30 and 60 minutes post the start of 
infusion and at the end of infusion.  On dosing days, for consolidation phase, vitals must be collected prior to infusion and at the 
end of infusion. 
p: Indicates a (+/-) 5 minute window. 
q: Required if patient has not had an ECHO within 28 days of C1D1.  
r: If completed prior to consent and within  28 days of C1D1, may count towards screening procedures. 
 
 
 


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Scientific Research 
At the screening, C1D35 and end of treatment visit an extra 10mL (about 2 tablespoons) of blood 
(correlative analysis blood draw) will be collected for future research studies that are unknown at 
this time.  
 
How will be samples for scientific research be used? 
Your samples collected for this research will be analyzed for the study. As part of the analysis, 
the research might include whole genomic sequencing. This means that researchers may look at 
your sample to learn about your genes (DNA). There are different ways to look at your DNA. 
Researchers often use a technology called sequencing to look at your DNA. Sequencing “reads” 
each letter of the DNA and finds changes (also called “variations” or “mutations”) in your genes 
that may cause disease or affect how your body reacts to a certain disease. 
The research done with your blood may lead to the development of new products in the future.  
You will not receive, either now or in the future, any compensation, royalty, or other financial 
benefits resulting from any product, procedure, or other items developed from studying your 
sample(s). 
 
Will I be notified of the results of the tests/studies on my samples?  
The tests/studies described are for research purposes only. It is not the purpose of these 
tests/studies to look for or provide you with any medical information or diagnoses relating to 
your present condition or any other disease or illness. Therefore, you will not receive results 
from these research tests/studies.    
 
 
2. ALTERNATIVES 
   What are the alternatives to participation in the research study?   
 
If you decide not to take part in this study, you have other choices. For example: 
 you may choose to have the usual approach described above 
 you may choose to take part in a different study, if one is available 
 or you may choose not to be treated for cancer. For example: comfort/palliative care 
 
What is the usual approach to my myelodysplastic syndrome (MDS)? 
Some patients receive no therapy and only receive red blood cell transfusions as needed (this is 
called supportive care). For lower-risk MDS patients with anemia, doctors often prescribe 
erythropoietin-stimulating agents (ESAs) which help stimulate red blood cell production. For 
patients who do not respond or stop responding to ESA treatment, there are currently two types 
of FDA approved therapies that may be used: HMAs and lenalidomide (Revlimid). 
 
 
3. RISKS 
   What are the risks of participating in the research study? 


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If you choose to take part in this study, there is a risk that: 
 You may lose time at work or home and spend more time in the hospital or doctor’s office 
than usual 
 You may be asked sensitive or private questions which you normally do not discuss 
 There is a potential risk that this study may delay or prevent the ability to use bone marrow 
transplant as a subsequent therapy, or may impact the outcome of that therapy. 
 
The chemotherapy used in this study may affect how different parts of your body work such as 
your liver, kidneys, heart, and blood. The study doctor will be testing your blood and will let you 
know if changes occur that may affect your health. 
 
There is also a risk that you could have side effects from the study drug(s)/study approach. 
 
Here are important points about side effects: 
 The study doctors do not know who will or will not have side effects. 
 Some side effects may go away soon, some may last a long time, or some may never go 
away. 
 Some side effects may interfere with your ability to have children. 
 Some side effects may be serious and may even result in death. 
Here are important points about how you and the study doctor can make side effects less of a 
problem: 
 Tell the study doctor if you notice or feel anything different so they can see if you are 
having a side effect. 
 The study doctor may be able to treat some side effects. 
 The study doctor may adjust the study drugs to try to reduce side effects. 
 
The tables below show the most common and the most serious side effects that researchers know 
about. There might be other side effects that researchers do not yet know about. If important new 
side effects are found, the study doctor will discuss these with you. 
 
Possible side effects of CPX-351 are listed below. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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COMMON, SOME MAY BE SERIOUS 
In 100 people receiving  CPX-351 more than 20 and up to 100 may have: 
 
 Abdominal pain  
 Anemia  
 Anxiety  
 Arrhythmia  
 Ataxia (impaired muscle control of walking, picking up objects, etc.) 
 Chest pain  
 Chills  
 Constipation  
 Cough  
 Decreased appetite  
 Delirium  
 Diarrhea  
 Dizziness  
 Dyspnea (Shortness of breath) 
 Edema  
 Extravasation tissue injury (unintentional leakage of IV fluid into surrounding skin 
causing tissue injury and or tissue death) 
 Fatigue  
 Febrile neutropenia (Fever with low neutrophil counts in the blood) 
 Fungal infection  
 Headache  
 Hemorrhage  
 Hypertension  
 Hypotension  
 Hypoxia (Low oxygen levels in the blood) 
 Rash  
 Mucositis (Inflammation and sores of the mouth) 
 Musculoskeletal pain  
 Nausea  
 Neutropenia (Low neutrophil counts in the blood, which leads to increased risk of 
infection) 
 Non-conduction cardio toxicity (Damage to the heart, which can lead to heart failure) 
 Pleural effusion (Water in the lungs) 
 Pneumonia  
 Pruritus (Itching) 
 Pyrexia (Fever) 
 Rash  
 Skin peeling (especially palms of hands and soles of feet) 
 Sleep disorders  
 Vomiting  
 
 
 


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OCCASIONAL, SOME MAY BE SERIOUS 
In 100 people receiving CPX-351, from 4 to 20 may have: 
 
 Acute renal failure or renal insufficiency, which can be so severe as to lead to a need 
for dialysis. 
 Cellulitis (infection in the skin and deeper tissues  
 Catheter/injection site reaction  
 Ejection fraction decreased (Diastolic heart failure) 
 Fatigue  
 Hemorrhoids  
 Hypokalemia (Low potassium in the blood) 
 Progressive cancer – malignant neoplasm progressive (uncontrolled growth of tumor 
cells) 
 Petechiae (bleeding spots in the skin) 
 Pneumonia  
 Pyrexia  
 Rash  
 Sepsis (Infection in the blood) 
 Urinary tract infection  
 Respiratory failure, even to the point of needing to be connected to a breathing, or life 
support machine in an intensive care unit. 
 Transfusion reactions  
 Upper respiratory induction (excluding fungal)  
 Visual impairments (except bleeding, and eye pain)  
 
 
Reproductive Risks 
There may be unforeseen risks to an unborn child associated with your taking CPX-351. 
Therefore, if you are capable of giving birth to or fathering a child, you and your sexual partner 
should use adequate birth control measures while you are in the study.  These measures may 
include abstinence, oral contraceptives (birth control pills), IUD, diaphragm, approved hormone 
injections, condoms, or documentation of medical sterilization.  Discuss with your doctor which 
birth control measures are acceptable.  
 
If you are unwilling to do this, we ask that you not participate in this study.  Pregnancy tests will 
be performed on all women of child-bearing potential before beginning the study and during the 
study approximately every 4 weeks. If you or your sexual partner become pregnant while taking 
part in this study you must notify the study doctor immediately.   
 
Blood Draws 
The insertion of the needle to draw blood can be painful; however, the discomfort is brief.  For 
most people, needle punctures to get blood samples do not cause any serious problems; however, 
they may cause bleeding, bruising, discomfort, infections, dizziness, or fainting.  Most subjects 
will have a central catheter (Hickman catheter), and most blood tests can be drawn through it. 
 


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Bone Marrow Biopsy 
There are also risks associated with taking samples of your bone marrow. Your study doctor or 
his/her designee will insert a needle into your hip or breast bone to withdraw a sample of fluid 
containing bone marrow cells. The risks of bone marrow sampling commonly include 
discomfort, pain, redness, swelling, and/or bruising where the sample is taken from your hip or 
chest. Sometimes bleeding can occur at the place where the sample is drawn. Fainting and 
infection can happen, but rarely. Many patients also experience soreness or stiffness in the hips 
for several days after the procedure. 
 
Electrocardiogram (ECG)  
Some people's skin reacts to the sticky patches that attach the electrodes to the chest for the 
ECG.  This skin irritation usually disappears when the patches are removed. Some men may 
have some chest hair shaved 
 
HIV Testing 
As a part of this study, a sample of your blood is being tested for the presence of HIV (Human 
Immunodeficiency Virus).  HIV is the virus that causes AIDS (Acquired Immunodeficiency 
Syndrome).  If your blood test is positive and you live in the State of Ohio, the result and your 
demographic information will be reported to the Ohio Department of Health as is required by 
law. In addition, this information will be available on the hospital’s laboratory reporting system.  
The results may influence your insurability and/or employability regarding your health status. If 
you test positive for HIV or active hepatitis B or C you will not be eligible to participate in this 
study. 
 
Infectious Disease Testing 
As a part of this study, a sample of your blood is being tested for the presence of hepatitis.   If 
your blood test results are positive and you live in the State of Ohio, the results of that test, if 
positive, and demographic information about you will be reported to the Ohio Department of 
Health as is required by law.   
 
Unknown Risks 
There may be risks or side effects related to the study drugs that are unknown at this time.  You 
will be notified of any significant new findings that become known that may affect your 
willingness to continue in the study.   
 
Confidentiality Risks 
There is a potential risk of loss of confidentiality of your data.  Efforts will be made to keep your 
information confidential through the use of the following safeguards: use of codes, storage in a 
password protected computer accessible only by the research team. If you decide to be in this 
study, the study researchers will get information that identifies you and your personal health 
information. This may include information that might directly identify you, such as your name 
and address. This information will be kept for the length of the study. After that time it will be 
destroyed or de-identified, meaning we will replace your identifying information with a code that 
does not directly identify you. The principal investigator will keep a link that identifies you to 
your coded information, but this link will be kept secure and available only to the principal 
investigator or selected members of the research team. Any information that can identify you 


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will remain confidential. Any personal information that could identify you will be removed or 
changed before files are shared with other researchers or results are made public. 
 
Genetic Risks 
Your medical and genetic information is unique to you. There is a risk that someone outside of the 
research study could get access to your study records or trace information in a database back to you. 
They could use that information in a way that could harm you. While the chance that someone could 
access and misuse your information is believed currently to be very small, it is possible that the risk may 
increase in the future as people find new ways to access information. 
 
A Federal law, called the Genetic Information Nondiscrimination Act (GINA), effective May 21, 
2010, generally makes it illegal for health insurance companies, group health plans, and most 
employers to discriminate against you based on your genetic information. This law generally will 
protect you in the following ways:  
 Health insurance companies and group health plans may not request your genetic 
information that we get from this research. 
 Health insurance companies and group health plans may not use your genetic information 
when making decisions regarding your eligibility or premiums.  
 Employers with 15 or more employees may not use your genetic information that we get 
from this research when making a decision to hire, promote, or fire you or when setting 
the terms of your employment.  
Be aware that this Federal law does not protect you against genetic discrimination by companies 
that sell life insurance, disability insurance, or long-term care insurance. 
 
Let your study doctor know of any questions you have about possible side effects. You can ask the study 
doctor questions about side effects at any time. 
 
     4. BENEFITS 
   What are possible benefits of participating in the research? 
We cannot know if you will have any benefit as a result of your participation in the study; it is 
possible the study treatment may improve your cancer, which may give you relief from some 
symptoms, improve your quality of life or prolong your survival. However, it is possible that 
your condition could worsen. Your participation in this study will help to obtain information 
about treating subjects with MDS. Your participation in this study may provide information that 
may help other people who have a similar medical problem in the future. 
 
5. COSTS 
Are there any costs to you if you participate in this study? 
Your involvement in this research study is voluntary and you will not be paid for your 
participation. 
 
The study agent, CPX-351 will be provided free of charge by Jazz Pharmaceuticals, while you 
are participating in this study.  Neither you nor your insurance provider will be responsible for 
the costs of any research-only tests or procedures.  Some blood work tests and echocardiograms 
for research purposes will not be charged to you.  It will be paid for by the research study.   
 


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You and/or your health plan/insurance company will need to pay for some or all of the costs of 
treating your cancer in this study (i.e., medical history, review of medications, physical exams, 
performance status, routine blood tests, pregnancy test, hospitalizations, x-rays and/or scans for 
tumor measurement). Some health plans will not pay these costs for people taking part in studies. 
Check with your health plan or insurance company to find out what they will pay for. Taking 
part in this study may or may not cost your insurance company more than the cost of getting 
regular cancer treatment. 
 
6. RESEARCH RELATED INJURY 
   What will happen if you are injured as a result of taking part in the research? 
 
In the event you suffer a research related injury as a result of being in this study, Cleveland 
Clinic will provide appropriate medical treatment for such injury in a timely manner. Provision 
of such medical treatment does not imply any negligence or other wrongdoing on the part of 
Cleveland Clinic or any of the physicians or other personnel involved in the study. If you believe 
that you have been injured as a result of participating in the study, please immediately contact 
your Cleveland Clinic study doctor even if you may have already been seen or treated by another 
doctor. If you are seen or treated by a doctor other than the study doctor, you should inform such 
doctor that you are in this study and, if possible, take this document with you as it may help such 
doctor treat you. 
 
In the event you suffer a research related injury as a result of being in this study, the costs for 
medical treatment may be billed to you or your medical insurance plan, if applicable. Medical 
insurance plans may or may not cover costs for medical treatment of research-related injuries. If 
you have insurance, you should check with your medical insurance plan before deciding to 
participate in this research study. In the event your medical insurance plan covers some or all of 
the treatment costs, you may still be responsible for co-pays or deductibles as required by your 
medical insurance plan.   
 
Cleveland Clinic has not set aside any money to pay you or to pay for your treatment if you 
suffer a research related injury as a result of being in the study. There are no plans for Cleveland 
Clinic to provide other forms of compensation (such as lost wages, pain and suffering, or other 
direct or indirect losses) to you for research related injuries. You are not waiving any legal rights 
by signing this form, including the right to seek compensation for an injury.  Further information 
about research related injury is available by contacting the Institutional Review Board at (216) 
444-2924.   
 
 
7. PRIVACY AND CONFIDENTIALITY 
 
   What will happen to your information that is collected for this research? 
 
Cleveland Clinic may share your study information, without anyone knowing that it is related to 
you specifically, with others or use it to research projects not listed in this form. Your blood 
samples may be stored and shared for future research without additional informed consent if 
identifiable private information, such as your name and medical record number, are removed. If 


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your identifying information is removed from your blood samples, we will no longer be able to 
identify and destroy them. 
 
Study results may be shared in medical journals, at scientific meetings, and in other media 
without your identifying information. Your records will be confidential and your identity will not 
be shared in medical journals, at scientific meetings, and in other media without your express 
consent.  
 
Authorization to Use/Disclose Protected Health Information 
Cleveland Clinic has rules and procedures to protect information about you.  Federal and State 
laws also protect your privacy. 
 
The research team working on the study will collect information about you.  This includes your 
health information, data collected for this research study and personal identifying information 
including your name, address, social Security number, date of birth and other identifying 
information. 
 
Generally, only people on the research team will know your identity and that you are in the 
research study.  However, sometimes other people at Cleveland Clinic may see or give out your 
information.  These include people who review research studies including the Institutional 
Review Board and Research Compliance, their staff, lawyers, or other Cleveland Clinic staff. 
 
People outside Cleveland Clinic may see your information for this study.  Examples include 
government groups (such as the Food and Drug Administration), safety monitors, other hospitals 
in the study and the sponsor of the research, their agents, and Jazz Pharmaceuticals.  Cleveland 
Clinic will take steps to ensure your information is kept confidential and that only the health 
information which is minimally required to conduct the study is used or disclosed to people 
outside Cleveland Clinic; however, people outside Cleveland Clinic who receive your 
information may not be covered by this promise. 
 
You do not have to give this permission to use and give out your information; however you will 
not be able to participate in this research study without providing this permission by signing this 
consent form.  The use and disclosure of your information has no expiration date.   
 
You may cancel your permission to use and disclose your information at any time by notifying 
the Principal Investigator in writing at:  
Sudipto Mukherjee, MD, MPH 
Cleveland Clinic Foundation 
9500 Euclid Avenue 
Mail Code: CA-6 
Cleveland, OH 44195 
If you do cancel your permission to use and disclose your information, your participation in this 
study will end and no further information about you will be collected.  Your cancellation would 
not affect information already collected in the study.   
 


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The Genetic Information Nondiscrimination Act (GINA) is a federal law designated to protect 
you from health insurance and employment discrimination based on genetic information.  It is 
illegal for health insurance providers and most employers to ask for genetic information to make 
decisions about a person’s eligibility or coverage or to make employment decisions.   
The law will not stop health insurance companies from using genetic information to decide 
whether to pay claims and also does not apply to life insurance, disability insurance or long-term 
care insurance. 
 
Clinical Trials Language 
A description of this clinical trial will be available on http://www.ClinicalTrials.gov, as required 
by U. S. law.  This Website will not include information that can identify you.  At most, the 
Website will include a summary of the results.  You can search the Website at any time. 
 
8. QUESTIONS 
 
    Who do you call if you have any questions or problems?  
If you have any questions or concerns about the research, or develop a research-related problem, 
you should contact the Principle Investigator and/or research staff at (216) 445-7009. During 
non-business hours, weekends and holidays, please contact the page operator at (216) 444-2200 
or toll free at (800) 223-2273, and ask for the oncologist (cancer doctor) that is on call. . If you 
have questions about your rights as a research subject, you should contact the Institutional 
Review Board at (216) 444-2924.  
 
9. VOLUNTARY PARTICIPATION   
     What are your rights as a research participant? 
 
Taking part in this study is voluntary.  You will be told of any new, relevant information from 
the research that may affect your health, welfare, or willingness to continue in this study.  You 
may choose not to take part or may leave the study at any time.  Withdrawing from the study will 
not result in any penalty or loss of benefits to which you are entitled.  If you decide to withdraw 
from the study you should discuss with your study doctor your decision to ensure a safe 
withdrawal. 
 
If you leave the study early, Cleveland Clinic may use or give out your health information that it 
has already collected if the information is needed for this study or any follow-up activities.  
 
The study doctor will tell you about new information or changes in the study that may affect 
your health or your willingness to continue in the study.  
 
The study doctor may take you out of the study: 
 If your health changes and the study is no longer in your best interest 
 If new information becomes available 
 If you do not follow the study requirements 
 If the study is stopped by the sponsor, Institutional Review Board (IRB) or FDA.  
If you become pregnant. 
 


CASE 2918 
Consent Version 4.0 
18 January 2021 
19 
10. SIGNATURES 
 
Statement of Participant 
 
I have read and have had verbally explained to me the above information and have had all my 
questions answered to my satisfaction.  I understand that my participation is voluntary and that I 
may stop my participation in the study at any time.  Signing this form does not waive any of my 
legal rights.   I understand that a copy of this consent will be provided to me.  By signing below, 
I agree to take part in this research study.   
 
 
_____________________________ 
       Printed name of Participant 
 
 
_____________________________  
___________  
 
           Participant Signature  
 
      Date 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Signature of Witness  
 
 
Date 
 
 
Printed Name of Witness 
I have discussed the information contained in this document with the participant and it is my 
opinion that the participant understands the risks, benefits, alternatives and procedures involved 
with this research study. (Only required when a witness is used in the consenting process). 
 
 
Statement of Person Conducting Informed Consent Discussion 
 
I have discussed the information contained in this document with the participant and it is my 
opinion that the participant understands the risks, benefits, alternatives and procedures involved 
with this research study. 
 
 
_____________________________ 
Printed name of person obtaining consent 
 
 
 
_____________________________  
___________  
 
Signature of person obtaining consent 
      Date