Clinical trial NCT02484391
Conditions: Granulocytic Sarcoma Recurrent Adult Acute Myeloid Leukemia
Sponsor: Wake Forest University Health Sciences
Start date: 2015-09-01; Completion date: 2022-02-02
Enrollment: 48 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This pilot phase I trial studies how well CPI-613 (6,8-bis\[benzylthio\]octanoic acid), cytarabine, and mitoxantrone hydrochloride work in treating patients with acute myeloid leukemia or granulocytic sarcoma (a malignant, green-colored tumor of myeloid cells \[a type of immature white blood cell\]) that has returned (relapsed) or that does not respond to treatment (refractory). 6,8-bis(benzylthio)octanoic acid is thought to kill cancer cells by turning off their mitochondria. Mitochondria are used by cancer cells to produce energy and are the building blocks needed to make more cancer cells. By shutting off these mitochondria, 6,8-bis(benzylthio)octanoic acid deprives the cancer cells of energy and other supplies that they need to survive and grow in the body. Drugs used in chemotherapy, such as cytarabine and mitoxantrone hydrochloride, work in different ways to stop the growth of cancer cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Giving 6,8-bis(benzylthio)octanoic acid together with cytarabine and mitoxantrone hydrochloride may kill more cancer cells.

Detailed description:
PRIMARY OBJECTIVES:

I. To determine the feasibility of CPI-613 when administered with high dose cytarabine, and mitoxantrone (mitoxantrone hydrochloride) in all three phases of salvage therapy (induction, consolidation and maintenance).

SECONDARY OBJECTIVES:

I. To observe the response rate (complete remission \[CR\], and CR with incomplete recovery \[CRi\]) of CPI-613 in combination with high dose cytarabine and mitoxantrone.

II. To observe the overall survival of patients treated with CPI-613 in combination with high dose cytarabine and mitoxantrone in induction, consolidation and maintenance.

III. To monitor toxicities experienced by patients treated with CPI-613 in combination with high dose cytarabine and mitoxantrone in induction, consolidation and maintenance.

OUTLINE:

SALVAGE INDUCTION COURSE 1: Patients receive 6,8-bis(benzylthio)octanoic acid intravenously (IV) over 2 hours on days 1-5, cytarabine IV over 3 hours every 12 hours starting on day 3 for 5 doses, and mitoxantrone hydrochloride IV over 15 minutes after the first, third, and fifth doses of cytarabine.

SALVAGE INDUCTION COURSE 2 (OPTIONAL, AT DISCRETION OF TREATING PHYSICIAN): Patients receive 6,8-bis(benzylthio)octanoic acid, cytarabine, and mitoxantrone hydrochloride as in course 1 or an abbreviated second course at the discretion of the treating physician. In the abbreviated course, patients receive 6,8-bis(benzylthio)octanoic acid IV over 2 hours on days 1-3, cytarabine IV over 3 hours every 12 hours starting on day 2 for 3 doses, and mitoxantrone hydrochloride IV over 15 minutes after the first and third cytarabine doses.

SALVAGE CONSOLIDATION: Patients achieving response receive up to 2 courses of the abbreviated course of 6,8-bis(benzylthio)octanoic acid, high dose cytarabine, and mitoxantrone hydrochloride. Patients achieving response may undergo stem cell transplant at the discretion of the treating physician. Patients may proceed to maintenance after 1, 2 or no courses of consolidation at the discretion of the treating physician.

MAINTENANCE THERAPY: Patients achieving response receive 6,8-bis(benzylthio)octanoic acid IV over 2 hours on days 1-5. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up periodically.

Arms: arm 1: See Detailed Description
Interventions: intervention 1: 6,8-Bis(benzylthio)octanoic Acid intervention 2: Cytarabine intervention 3: Hematopoietic Cell Transplantation intervention 4: Mitoxantrone Hydrochloride
Intervention descriptions: intervention 1: Given IV intervention 2: Given IV intervention 3: Undergo stem cell transplant intervention 4: Given IV

Protocol documents:
Prot_SAP_001.pdf: 
CCCWFU 22215 
 
Comprehensive Cancer Center of Wake Forest University 
An Open Label Study to Evaluate the Feasibility of CPI-613 Given with High Dose Cytarabine and 
Mitoxantrone in Patients with Relapsed or Refractory Acute Myeloid Leukemia (AML) 
NCT Clinicaltrials.gov:  NCT02484391 
 
Principal Investigator: 
Bayard Powell 
Hematology and Oncology 
CCCWFU 
 
 
Sub-Investigators: 
Leslie Ellis 
Hematology and Oncology 
CCCWFU 
 
Rupali Roy Bhave 
Hematology and Oncology 
CCCWFU 
 
Dianna Howard, MD 
Hematology and Oncology 
CCCWFU 
 
Timothy S. Pardee, MD, PhD 
Hematology and Oncology 
CCCWFU 
 
Biostatistician: 
Scott Isom, MS 
 
Study Nurse: 
Sharon Averill, RN 
CCCWFU 
 
Study Coordinator 
Rebecca Dellinger-Johnston 
CCCWFU 
 
Data Manager: 
Sheila Staszkiewicz 
CCCWFU 
 
Regulatory: 
Cindy Miller 
CCCWFU 
 
Participating Institution: 
CCCWFU 
Funding Sponsor: 
Wake Forest University Comprehensive Cancer Center 
Medical Center Blvd 
Winston-Salem, NC 27157 
IND Number: 
107800   
 
Date: 
06/04/18 
 


CCCWFU 22215 
 
Comprehensive Cancer Center of Wake Forest University 
An Open Label Study to Evaluate the Feasibility of CPI-613 Given with High Dose Cytarabine and 
Mitoxantrone in Patients with Relapsed or Refractory Acute Myeloid Leukemia (AML) 
NCT Clinicaltrials.gov:  NCT02484391 
 
CONFIDENTIAL: This document is proprietary property of the Comprehensive Cancer Center of Wake 
Forest University Health Sciences.  


CCCWFU 22215 
 
Comprehensive Cancer Center of Wake Forest University 
An Open Label Study to Evaluate the Feasibility of CPI-613 Given with High Dose Cytarabine and 
Mitoxantrone in Patients with Relapsed or Refractory Acute Myeloid Leukemia (AML) 
NCT Clinicaltrials.gov:  NCT02484391 
 
 
 
SCHEMA 
 
This is a Pilot open label trial to establish the feasibility of CPI-613 in combination with high dose 
cytarabine and mitoxantrone: 
 
Salvage Induction: CPI-613 at doses of 1,500 mg/m²/day will be given over 2 hours on days 1-5. 
Cytarabine will be given at 3gm/m2 for age <60 or 1.5 gm/m2 for age >60 in 500 mL NS over 3 
hours every 12 hours for 5 doses starting on day 3. Mitoxantrone will be given at 6mg/m2 daily for 
3 doses given in 50 mL NS over 15 minutes after 1st, 3rd and 5th doses of Cytarabine. A day 14 
marrow will be obtained to assess disease response. If there is a response to therapy but residual 
disease remains patients may receive either a repeated courses identical to the above or a shortened 
3 day course with CPI-613 on days 1-3, cytarabine starting on day 2 for 3 total doses and 
Mitoxantrone after 1st and 3rd doses at the discretion of the treating physician. 
 
 There will be 20 patients recruited at a CPI-613 dose of 500mg/m2/day following the same 
treatment guidelines outlined above. Individuals recruited to this dose level of CPI-613 will remain 
on this dose level for consolidation and maintenance therapy. 
 
Salvage Consolidation: All responding patients are eligible for consolidation therapy with up to 2 
cycles of the shortened 3 course of CPI-613 (same dose as induction cycle), high dose cytarabine 
and mitoxantrone. Responding patients can be removed from trial at any time to receive a stem cell 
transplant at the discretion of the treating physician. Patients can move to maintenance following 1, 
2 or no cycles of consolidation at the discretion of the treating physician.    
 
Maintenance Therapy: Any patient who has completed all planned consolidation therapy (i.e. 0, 1 or 
2 cycles) and is not eligible for, faces a significant delay or refuses a stem cell transplant may 
receive maintenance therapy with CPI-613 at a dose of 2,500 mg/m²/day over 2 hours on days 1-5 
of a 28 day cycle. Patients treated during induction and consolidation at the 500 mg/m2 dose will 
receive that dose during maintenance therapy. Patients may continue on maintenance therapy until 
evidence of disease progression or occurrence of intolerable side effects.   
 
Eligibility: 
A. Pathologic or cytologic evidence of relapsed or refractory acute myeloid leukemia or granulocytic 
sacroma. 
B. ECOG Performance Status of ≤3. 
C. Must be ≥18 years of age. 
D. Expected survival >3 months. 
E. Women & Men of child-bearing potential must use accepted contraceptive methods and must have a 
negative serum or urine pregnancy test within 1 week prior to treatment initiation. (Note: Pregnant 
patients are excluded because the effects of CPI-613 on a fetus are unknown.)  
F. No pregnant/lactating women 
G. Mentally competent, ability to understand and willingness to sign the informed consent form. 
H. No radiotherapy, treatment with cytotoxic agents (except CPI-613), treatment with biologic agents or 
any anti-cancer therapy within the 2 weeks prior to treatment with CPI-613.  Hydroxyurea and oral 
tyrosine kinase inhibitors being used without ≤ Grade 2 toxicity can be taken until day 1 of therapy.     
I. No serious medical illness that would potentially increase patients’ risk for toxicity. 


CCCWFU 22215 
 
Comprehensive Cancer Center of Wake Forest University 
An Open Label Study to Evaluate the Feasibility of CPI-613 Given with High Dose Cytarabine and 
Mitoxantrone in Patients with Relapsed or Refractory Acute Myeloid Leukemia (AML) 
NCT Clinicaltrials.gov:  NCT02484391 
 
 
 
J. No patients with active central nervous system (CNS) or epidural tumor. 
K. No active uncontrolled bleeding/bleeding diathesis. 
L. No life expectancy shorter than 3 months. 
M. No condition or abnormality which may, in the opinion of the investigator, compromise the safety of 
patients. 
N. No unwillingness or inability to follow protocol requirements. 
O. No large and recurrent pleural or peritoneal effusions or clinically significant pericardial effusion. 
P. No active heart disease including myocardial infarction within previous 6 months, symptomatic 
coronary artery disease, arrhythmias requiring medication, or symptomatic congestive heart failure. 
Q. No evidence of ongoing, uncontrolled infection. 
R. No patients with known HIV infection. 
S. No patients receiving any other standard or investigational treatment for their cancer, or any other 
investigational agent for any indication within the past 2 weeks prior to initiation of CPI-613 treatment 
(the use of Hydrea is allowed). 
T. No patients who have received immunotherapy of any type within the past 4 weeks prior to initiation of 
CPI-613 treatment. 
U. No requirement for immediate palliative treatment of any kind including surgery. 
V. No patients that have received a chemotherapy regimen with stem cell support in the previous 6 
months. 
W. 
No history of additional risk factors for torsade de pointes (e.g., clinically significant heart failure, 
hypokalemia, family history of Long QT Syndrome). 
X. Laboratory values ≤2 weeks must be: 
- Adequate hepatic function (aspartate aminotransferase [AST/SGOT] ≤3x upper normal limit [UNL], 
alanine aminotransferase [ALT/SGPT] ≤3x UNL (≤5x UNL if liver metastases present), bilirubin 
≤1.5x UNL). 
- Adequate renal function (serum creatinine ≤1.5 mg/dL or 133 μmol/L). 
Y. Left Ventricular Ejection Fraction sufficient to safely administer mitoxantrone as determined by the 
treating physician 
 
 
 


CCCWFU 22215 
 
Comprehensive Cancer Center of Wake Forest University 
An Open Label Study to Evaluate the Feasibility of CPI-613 Given with High Dose Cytarabine and 
Mitoxantrone in Patients with Relapsed or Refractory Acute Myeloid Leukemia (AML) 
NCT Clinicaltrials.gov:  NCT02484391 
 
 
 
ABBREVIATIONS USED 
 
AE 
= adverse events 
AEMD 
= altered energy metabolism-
directed 
ADR 
= adverse drug reactions 
ALT 
= alanine aminotransferase 
ALP 
= alkaline phosphatase 
ANC 
= absolute neutrophil count 
AST 
= aspartate aminotransferase 
AUC 
= area under the curve 
AUC0-t  
= AUC from time 0 to last 
measurable concentration 
AUC0-infinity = AUC from time 0 to infinity 
BUN 
= blood urea nitrogen 
CAS 
= Chemical Abstract Society 
Cl 
= clearance 
Cmax  
= maximum observed 
concentration 
Cend  
= concentration immediately 
post-infusion 
CFR  
= Code of Federal Regulations 
CK or CPK 
= creatine kinase 
CNS 
= central nervous system 
Rafael 
= Rafael Pharmaceuticals, Inc. 
CRF  
= case report form 
CTC  
= common toxicity criteria 
D5W  
= 5% dextrose water 
DLT  
= dose-limiting toxicity 
FBS  
= Fetal Bovine Serum 
FDA  
= Food and Drug 
Administration 
GLP  
= Good Laboratory Practices 
GCP  
= Good Clinical Practices 
GGT  
= gamma-glutamyl transferase 
GI  
= gastrointestinal 
hERG            = Ether-a-Go-Go-Related 
Gene 
Hgb  
= hemoglobin 
IEC  
= Independent Ethics 
Committee 
IND  
= Investigational New Drug 
INR  
= International Normalized 
Ratio 
IRB  
= Institutional Review Board 
IUD  
= intrauterine device 
IV  
= intravenous or intravenously 
Kel  
= terminal elimination rate 
constant 
EPS  
= ECOG Performance Status 
LC-MS  
= Liquid Chromatography - 
Mass Spectroscopy 
LD10  
= the dose that induce death or 
significant toxicity in 10% of 
the animals tested 
LDH  
= lactate dehydrogenase 
MRT  
= mean residence time 
MTD  
= maximum tolerated dose 
NCI  
= National Cancer Institute 
NSCLC  
= non-small cell lung carcinoma 
PDC  
= pyruvate dehydrogenase 
complex 
PK  
= pharmacokinetic 
QA  
= Quality Assurance 
RECIST  
= Response Evaluation Criteria 
in Solid Tumors 
RPMI  
= Roswell Park Memorial 
Institute 
RSA  
= Research Study Assistant 
SAE  
= serious adverse event 
SGOT  
= serum glutamic-oxaloacetic 
transaminase 
SGPT  
= serum glutamic-pyruvic 
transaminase 
SOP  
= Standard Operating 
Procedures 
STD  
= the dose that induces 10% 
incidence of significant toxicity 
t1/2  
= elimination half-life 
TEA  
= triethanol, triethanolamine or 
tri-ethanolamine 
TLS  
= tumor lysis syndrome 
UNL  
= upper normal limit 
US  
= United States 
USP  
= United States Pharmacopoeia 
Vd  
= volume of distribution 
WBC  
= white blood cell 


CCCWFU 22215 
 
Comprehensive Cancer Center of Wake Forest University 
An Open Label Study to Evaluate the Feasibility of CPI-613 Given with High Dose Cytarabine and 
Mitoxantrone in Patients with Relapsed or Refractory Acute Myeloid Leukemia (AML) 
NCT Clinicaltrials.gov:  NCT02484391 
 
 
 
Table of Contents 
SCHEMA ....................................................................................................................................................... i 
ABBREVIATIONS USED .......................................................................................................................... iii 
Table of Contents ......................................................................................................................................... iv 
1.0  Introduction and Background ................................................................................................................. 8 
1.1 
Proposed Mechanism of Action .................................................................................................... 8 
1.2 
Background on Preclinical Studies ............................................................................................... 9 
1.3 
Background on Clinical Studies .................................................................................................. 13 
1.4 
Rationale ..................................................................................................................................... 13 
1.5 
Justification of the Dose of CPI-613 ........................................................................................... 14 
2.0 Objectives ............................................................................................................................................. 14 
2.1 
Primary Objective ....................................................................................................................... 14 
2.2 
Secondary Objectives .................................................................................................................. 14 
3.0 Patient Selection .................................................................................................................................... 14 
3.1 
Inclusion Criteria ........................................................................................................................ 15 
3.2 
Exclusion Criteria ....................................................................................................................... 15 
3.3 
Inclusion of Women and Minorities ........................................................................................... 16 
4.0 Registration Procedures ........................................................................................................................ 18 
5.0 Treatment Plan ...................................................................................................................................... 18 
5.1 
Table of Study-Related Interventions ......................................................................................... 20 
5.2 
Pre-Enrollment Medical Screening ............................................................................................. 22 
5.3 
CPI-613 Dosing .......................................................................................................................... 22 
5.4 
CPI-613 Administration Guidelines ............................................................................................ 23 
5.5 
General Concomitant Medication and Supportive Care Guidelines ........................................... 24 
5.6 
Study Procedures – Assessment of Safety, Plasma Concentration, and Possible Anti-Tumor 
Efficacy ....................................................................................................................................... 24 
5.7 
Specifics of Tests Performed During the Study .......................................................................... 26 
5.8 
Future Research .......................................................................................................................... 28 
5.9 
Criteria for Removal from Study ................................................................................................ 29 
6.0 Dosing Delays/Dose Modifications for CPI-613 .................................................................................. 29 


CCCWFU 22215 
 
Comprehensive Cancer Center of Wake Forest University 
An Open Label Study to Evaluate the Feasibility of CPI-613 Given with High Dose Cytarabine and 
Mitoxantrone in Patients with Relapsed or Refractory Acute Myeloid Leukemia (AML) 
NCT Clinicaltrials.gov:  NCT02484391 
 
 
 
7.0 Adverse Events List and Reporting Requirements ............................................................................... 30 
7.1 
Adverse Event Characteristics .................................................................................................... 30 
7.2 
STRC SAE Reporting Requirements .......................................................................................... 32 
7.3  
WFUHS IRB AE Reporting Requirements................................................................................. 32 
8.0 Pharmaceutical Information .................................................................................................................. 33 
8.1 
Pharmaceutical Accountability ................................................................................................... 33 
8.2 
Study Drug .................................................................................................................................. 33 
9.0 Measurement of Effect .......................................................................................................................... 38 
9.1 
Antitumor Effect ......................................................................................................................... 38 
9.1.1 Definitions .................................................................................................................................. 39 
10.0 Statistical Considerations .................................................................................................................... 39 
References ................................................................................................................................................... 41 
APPENDIX A – REGISTRATION GUIDELINES ................................................................................... 43 
APPENDIX B – Safety and Toxicity Review Committee SAE Reporting Guidelines .............................. 49 
APPENDIX C- Response Criteria: ............................................................................................................. 54 
APPENDIX D – CCCWFU 22215 Pre-Study Data Collection Form ......................................................... 55 
APPENDIX E - CCCWFU 22215 Day 14 Nadir Marrow Form ................................................................ 57 
APPENDIX F - CCCWFU 22215 Data Collection Form – FOLLOW-UP Form ...................................... 58 
APPENDIX G – CCCWFU 22215 Urine Collection ................................................................................. 60 


CCCWFU 22215 
 
Comprehensive Cancer Center of Wake Forest University 
An Open Label Study to Evaluate the Feasibility of CPI-613 Given with High Dose Cytarabine and 
Mitoxantrone in Patients with Relapsed or Refractory Acute Myeloid Leukemia (AML) 
NCT Clinicaltrials.gov:  NCT02484391 
 
8 
Revision Date:06/04/18 
1.0 
Introduction and Background 
1.1 
Proposed Mechanism of Action 
CPI-613, the investigational drug, is a novel anti-tumor compound presumably 
with a novel mechanism of action that does not belong to any existing 
pharmacological class of anticancer agents currently used in the clinics. 
Specifically, CPI-613 is referred to as an Altered Energy Metabolism-Directed 
(AEMD) compound, and it is selective against tumor cells (but not normal cells) 
according to preclinical studies. The anti-tumor effects of CPI-613 are believed to 
be exerted by the inhibition of the pyruvate dehydrogenase complex (PDC).  
 
In both normal and tumor cells, energy is derived from glucose, first by breaking 
down glucose to pyruvate via the glycolytic cycle in the cell cytoplasm. Once 
formed in mammalian cells, pyruvate is then converted by PDC to acetyl-CoA 
that is in turn metabolized via the tricarboxylic acid (TCA) cycle in the 
mitochondria. 
 
Most tumor cells display profound perturbation of energy metabolism that tightly 
correlates with malignant transformation (Baggetto 1992). The PDC is regulated 
by the phosphorylation state of the E1 subunit. When phosphorylated by the PDC 
kinase the enzyme is inhibited and the conversion of pyruvate to acetyl-CoA is 
inhibited. Preclinical studies have shown that CPI-613 causes phosphorylation of 
the E1 subunit in tumor cells with little to no effect on normal cells. As a result of 
this phosphorylation ATP levels in tumors cells fall and cancer cell death ensues.  
 
Consistent with the proposed mechanism is the fact that CPI-613 has been shown 
to have anti-tumor activity in cell culture and animal tumor models against 
diverse cancers independent of multiple drug resistance, cell cycle phase and 
activated signal transduction pathways. The novelty in the presumed mechanism 
of action for CPI-613 is further supported by the results from an ex vivo study 
demonstrating that CPI-613 is effective against various types of tumor cells 
excised from patients that were resistant to different anti-cancer drugs currently 
used in the clinics.  
 
The significance of CPI-613 having a novel mechanism of action that is not 
shared by any existing pharmacological class of anti-cancer agents currently used 
in the clinics is that CPI-613 may be effective not only against naive tumors that 
have never been treated with any anti-cancer agents, but also effective against 
tumors that are resistant to anti-cancer agents currently used in the clinics. This is 
an important aspect because tumors frequently develop resistance to anti-cancer 
agents, rendering a shortage of treatment options. The availability of a novel anti-
cancer agent would provide a new tool to treat cancer. 


CCCWFU 22215 
 
Comprehensive Cancer Center of Wake Forest University 
An Open Label Study to Evaluate the Feasibility of CPI-613 Given with High Dose Cytarabine and 
Mitoxantrone in Patients with Relapsed or Refractory Acute Myeloid Leukemia (AML) 
NCT Clinicaltrials.gov:  NCT02484391 
 
9 
Revision Date:06/04/18 
1.2 
Background on Preclinical Studies 
CPI-613 is being developed as an anti-tumor agent for the treatment of cancer. A 
number of preclinical anti-tumor efficacy studies; Administration, Distribution, 
Metabolism, and Elimination (ADME) studies; safety pharmacology studies; and 
toxicity studies of CPI-613 have been conducted. These studies are briefly 
described below, and the Investigator’s Brochure provides detailed information 
regarding these preclinical studies. 
 
In Vitro and Animal Efficacy Studies 
In vitro cell culture studies have shown that CPI-613 is effective against a 
variety of tumor cell lines such as human BxPC-3 pancreatic tumors, human 
AsPC-1 pancreatic tumors, human H-460 non-small cell lung carcinoma 
(NSCLC), and human A2780 ovarian tumors, as well as explants of different 
types of fresh human tumors including NSCLC, colon, breast, and pancreatic 
tumors. Additionally the drug has activity against human AML cell lines 
including MV4-11 and HL60.  Additional work has shown that the 
immortalized NIH 3T3 cell line is not affected by CPI-613.  Once these cells 
have been transformed by oncogeneic RAS expression they become sensitive. 
This is a mutation commonly found in hematologic malignancies including 
the acute leukemias. Consistent with the in vitro studies are animal efficacy 
studies, which showed that CPI-613 was effective against xenograft of human 
BxPC-3 and AsPC-1 pancreatic tumors, and human H-460 NSCLC.   
 
Additionally, in vitro cell culture studies have shown that CPI-613 was 
equally effective against tumor cell lines with well-characterized mechanisms 
of drug resistance and their parental tumor cell lines. The equal effectiveness 
against resistant and parental tumor cell lines is consistent with the proposed 
novel mechanism of action of CPI-613 that is not shared by any 
chemotherapeutic agents currently used in the clinics. The drug-resistant 
tumor cell lines and the parental studied are listed below: 
 
Parental Tumor Cell Lines 
Drug-Resistant Derivative 
MCF-7 breast carcinoma line 
NCI/ADR-RES adriamycin-resistant derivative(Recently 
reclassified as an Ovarian Cancer derivative of OVCAR-8 
FYI) 
A2780 ovarian carcinoma cell line 
A2780DX doxorubicin-resistant derivative 
NCI/H69 small cell lung cancer cells 
H69-AR anthracycline-resistant derivative 
MES-SA uterine sarcoma cells 
MES-SA/MX2 mitoxanthrone-resistant derivative 
 
Pharmacokinetic Studies 
In rats, the toxicokinetic profile of CPI-613 administered 2x weekly for 3 
weeks by IV administration at dose levels of 25, 30 or 35 mg/kg (i.e., 150, 
180 or 210 mg/m2, respectively) was characterized by an apparent biphasic 
profile – an initial distribution phase followed by an elimination phase. 


CCCWFU 22215 
 
Comprehensive Cancer Center of Wake Forest University 
An Open Label Study to Evaluate the Feasibility of CPI-613 Given with High Dose Cytarabine and 
Mitoxantrone in Patients with Relapsed or Refractory Acute Myeloid Leukemia (AML) 
NCT Clinicaltrials.gov:  NCT02484391 
 
10 
Revision Date:06/04/18 
Systemic exposure was proportional to dose level, and there was no evidence 
of test article accumulation or sex differences in exposure. In minipigs, the 
toxicokinetic profile of CPI-613 administered 2x weekly for 3 weeks by IV 
administration at dose levels of 45, 42 and 46 mg/kg (i.e., 1575, 1470 and 
1617 mg/m², respectively) was also characterized by an apparent biphasic 
profile.There was also no evidence of test article accumulation or sex 
differences in exposure. 
 
ADME Studies 
A PK study in minipigs showed that the log scale of the half-life (t1/2) values 
tended to be directly and linearly related to the log of the dose. Specifically, 
t1/2 was ~1hour at 3 mg/kg (105 mg/m²), ~1.7 hours at 10 mg/kg (350 
mg/m²), and 10 hours at 30 mg/kg (1050 mg/m²).  
 
The tissue distribution pattern of radioactivity, after an intravenous (IV) 
administration of 14C-labeled CPI-613 in rats showed that: 
1. The liver might be involved in the metabolism of CPI-613 and/or 14C-
containing metabolites of CPI-613. 
2. Both the GI tract and the kidneys might be involved in the elimination 
of CPI-613 and/or 14C-containing metabolites of CPI-613. 
3. CPI-613 and 14C-containing metabolites of CPI-613 were mostly 
present in the extracellular space in the circulation.  
 
An in vitro human plasma protein binding study showed that CPI-613 
exhibited 99.7% binding to human plasma proteins, a value that was similar to 
warfarin. These results are consistent with findings from tissue distribution 
studies (see above) which showed CPI-613 was mostly present in the 
extracellular space in the circulation, consistent with findings of extensive 
plasma protein binding.  
 
An in vitro human CYP450 enzyme inhibition study showed CPI-613 does 
not significantly inhibit various CYP450 isozymes, including 1A2, 2C9, 
2C19, 2D6, and 3A4.  
 
An in vitro human liver S9 fraction hepatocyte study showed that CPI-613 
was oxidized to form a sulfoxide metabolite rapidly, with a half-life of <19 
minutes. CPI-613 was also glucuronidated rapidly at the terminal carboxyl 
group, with a half-life of <15 minutes. Due to oxidation and glucuronidation, 
potential metabolites are a sulfoxide, a metabolite with glucuronidation in the 
terminal carboxyl group; and/or a metabolite with combination of 
sulfoxidation and glucuronidation. 
 
 
 


CCCWFU 22215 
 
Comprehensive Cancer Center of Wake Forest University 
An Open Label Study to Evaluate the Feasibility of CPI-613 Given with High Dose Cytarabine and 
Mitoxantrone in Patients with Relapsed or Refractory Acute Myeloid Leukemia (AML) 
NCT Clinicaltrials.gov:  NCT02484391 
 
11 
Revision Date:06/04/18 
In Vitro and Animal Pharmacology Safety Studies 
An in vitro study showed that CPI-613 did not inhibit Ether-a-Go-Go-Related 
Gene (hERG) channels. Since hERG channel inhibition is the predominant 
cause of QTc interval prolongation which has been linked to Torsades de 
Pointes conditions such as sudden cardiac death and ventricular arrhythmia, 
this study suggested that CPI-613 may not induce Torsades de Pointes 
conditions. This is consistent with the subsequent animal toxicology studies 
showing that CPI-613 did not induce abnormal ECG pattern.  
 
The potential influence of air in the dead space of an IV catheter on the acute 
toxicity of CPI-613 in rats has been evaluated. The results suggested that 
standard drug administration procedures in the elimination of dead air space 
within indwelling IV catheters should be followed, since air in the catheter air 
space may enhance the acute toxicity of CPI-613 at supra-antitumor doses. 
 
The acute toxicity of CPI-613 administered IV as a bolus vs. by infusion has 
been compared in a preliminary study in rats. The results suggested that CPI-
613 at supra-antitumor doses might be less toxic when administered as a 1-hr 
IV infusion than as a 1-min IV bolus. 
 
Animal Toxicology Studies 
 
Single Dose: A toxicology study involving a single IV administration of CPI-
613 in mice has been conducted. The results indicated that 0.3-3 mg/kg (0.9-9 
mg/m²) of CPI-613 did not induce any toxicity, whereas 10-100 mg/kg (30-
300 mg/m²) also did not induce toxicity, except inflammatory reactions at or 
around the site of injection with intensity that was dose-related. 
 
Twice Weekly for 1 Week Dosing: Animal toxicology studies involving IV 
administrations of CPI-613 twice weekly for 1 week have been conducted in 
mice and minipigs. In mice, CPI-613 at 100 mg/kg (300 mg/m²) induced 
mortality in all female mice but not male mice. Also, CPI-613 at 30 and 75 
mg/kg (90 and 215 mg/m², respectively) did not induce any toxicity, except 
inflammation around the site of injection and a small increase in the spleen 
weight in mice treated with 75 mg/kg (215 mg/m²) and in the surviving mice 
treated with 100 mg/kg (300 mg/m²) of CPI-613.  
 
In minipigs, when given 2x weekly for 1 week, CPI-613 at doses up to 30 
mg/kg (1,050 mg/m²), the highest dose investigated in this study, did not 
induce toxicity, other than local inflammatory reactions at and around the site 
of injection. These results are consistent with those observed with the mouse 
study (see above).  
 


CCCWFU 22215 
 
Comprehensive Cancer Center of Wake Forest University 
An Open Label Study to Evaluate the Feasibility of CPI-613 Given with High Dose Cytarabine and 
Mitoxantrone in Patients with Relapsed or Refractory Acute Myeloid Leukemia (AML) 
NCT Clinicaltrials.gov:  NCT02484391 
 
12 
Revision Date:06/04/18 
Twice Weekly for 3 Weeks Dosing: Animal toxicology studies involving IV 
administrations of CPI-613 twice weekly for 3 weeks have been conducted in 
rats and minipigs, as described below. 
 
In rats, when administered at dose levels of 25, 30 or 35 mg/kg (i.e., 150, 180 
or 210 mg/m², respectively), CPI-613 enhanced inflammatory responses in the 
body in a dose related manner, as reflected by dose-related exaggeration in the 
incidence and severity of granulomatous or acute, chronic, or chronic active 
inflammation at the administration site inguinal vein), skin and subcutaneous 
tissue near the port, and inguinal skin and subcutaneous tissue near the 
inguinal vein, when compared to control treatment. CPI-613 at the 
toxicological doses of 30-35 mg/kg (180-210 mg/m²) in rats induced dose-
related incidence of mortality. The cause of death was due to significant 
systemic inflammation, and might be related to an over enhancement of the 
inflammatory responses induced by CPI-613. Deaths due to significant 
systemic inflammation were also observed in minipigs treated with the 
minipig toxicological dose of 46.2 mg/kg (i.e., 1617 mg/m²) of CPI-613 in 
another toxicology study. CPI-613 at 25, 30 and 35 mg/kg (i.e., 150, 180 and 
210 mg/m², respectively) elevated GGT levels in a dose-dependent manner in 
rats. This elevation is not associated with histopathology findings or other 
parameters of kidney or liver functions, and therefore not related to toxicity of 
the kidney or liver. However, it may be related to systemic inflammation 
(Yamada J, Tomiyama H, et. al. 2006), since systemic inflammation was 
observed in CPI-613 treated rats in this study. Finally, CPI-613 at the rat 
toxicological doses of 30 and 35 mg/kg (i.e., 180 and 210 mg/m², 
respectively) increased reticulocyte levels, which appeared to be associated 
with hematopoietic cell proliferation of the spleen, and sternal bone marrow 
hyperplasia that were secondary to inflammation initiated at the 
administration site or port in rats. The no-observable-adverse effect levels 
were 25 mg/kg (150 mg/m²) CPI-613. The LD10 or STD10 is approximately 
35 mg/kg (210 mg/m²).  
 
In minipigs, when administered at dose levels of 42, 45, 46.2, 50 and 55 
mg/kg (i.e., 1470, 1575, 1617, 1750 and 1925 mg/m², respectively), CPI-613 
at all dose levels induced transient vomiting that was transient and reversible. 
Mortality (2 of 8 minipigs) was observed in minipigs treated with CPI-613 at 
46.2 mg/kg (i.e., 1617 mg/m²), due to significant systemic inflammation. 
Significant systemic inflammation was also observed in rats treated with CPI-
613, resulting in dose-dependent incidence of mortality at the toxicological 
doses of 30-35 mg/kg (180-210 mg/m²) and might be due to an over 
enhancement of inflammatory responses induced by toxic doses of CPI-613, 
as supported by dose-related exaggeration in inflammatory effects according 
to gross necropsy and histopathology findings (see below). 


CCCWFU 22215 
 
Comprehensive Cancer Center of Wake Forest University 
An Open Label Study to Evaluate the Feasibility of CPI-613 Given with High Dose Cytarabine and 
Mitoxantrone in Patients with Relapsed or Refractory Acute Myeloid Leukemia (AML) 
NCT Clinicaltrials.gov:  NCT02484391 
 
13 
Revision Date:06/04/18 
 
Overall Summary of Preclinical Studies 
Preclinical efficacy studies, ADME studies, tissue distribution studies, and 
toxicology studies on CPI-613 have been conducted. The efficacy studies 
demonstrated the anti-tumor effects of CPI-613, whereas the ADME studies 
provided PK, biodistribution, metabolism and plasma protein binding 
information on CPI-613 in the body. Finally, for the toxicology studies, CPI-
613 was administered in a way that mimicked that in the proposed clinical 
study, which involved IV administration given twice weekly. The results of 
the animal toxicology showed that CPI-613 is sufficiently non-toxic. 
1.3 
Background on Clinical Studies 
Six single-patient physician-sponsored clinical studies have been conducted for 
compassionate use.  Three of these single-patient studies were conducted in the 
US, whereas the other 3 were conducted in Israel. 
 
Additionally, a Phase I clinical study involving CPI-613 as a single agent in 
patients with solid tumors and lymphomas is ongoing.  A phase I clinical study 
involving CPI-613 as a single agent in patients with advanced hematologic 
malignancies is ongoing. A phase I study of CPI-613 in combination with high 
dose cytarabine and mitoxantrone has recently been completed. This trial 
established the MTD of CPI-613 as 2,500 mg/m2. A Phase I/II clinical study 
involving CPI-613 in combination with Gemcitabine is ongoing.  
1.4 
Rationale 
Chemotherapy resistance is a major cause of death in patients with relapsed or 
refractory AML. CPI-613 can increase the sensitivity of leukemia cells to 
chemotherapy in petri dishes and mice. As a single agent in a phase I clinical trial 
several relapsed/refractory AML patients had an objective response. Additionally, 
a phase I study of CPI-613 in combination with high dose cytarabine and 
mitoxantrone has recently been completed. This trial established the MTD ofCPI-
613 as 2,500 mg/m2. Preliminary analysis of the study revealed an overall 
complete remission or complete remission with incomplete count recovery rate of 
45%. This compares favorably with our historical experience of this regimen 
without CPI-613. In this trial patients with poor risk cytogenetics had a 46% 
response rate, far superior to the 19% response seen with historical data. This trial 
established that CPI-613 can be safely administered at 2,500 mg/m2 in this 
combination and results in superior response rates. The novel mechanism of 
action, non-cross resistance with chemotherapeutic agents, lack of CPI-613-
related myelosuppression clinically and increase response rate make this regimen 
a suitable candidate for the proposed pilot study.    


CCCWFU 22215 
 
Comprehensive Cancer Center of Wake Forest University 
An Open Label Study to Evaluate the Feasibility of CPI-613 Given with High Dose Cytarabine and 
Mitoxantrone in Patients with Relapsed or Refractory Acute Myeloid Leukemia (AML) 
NCT Clinicaltrials.gov:  NCT02484391 
 
14 
Revision Date:06/04/18 
1.5 
Justification of the Dose of CPI-613 
WFUCCC 22112, a phase I study of CPI-613 in combination with high dose 
cytarabine and mitoxantrone given exactly as proposed in the current study 
established the MTD of CPI-613 to be 2,500 mg/m2.  A detailed analysis of the 
response data indicated that similar response rates were seen at the 2,000 mg/m2 
dose with less toxicity. Further studies have indicated a dose of 1500 mg/m2 has a 
similar efficacy profile as 2,000 mg/m2 but with even less toxicity. The rationale 
behind using a dose of 500mg/m2 is supported by three lines of evidence: 1) pre-
clinical evidence in mice suggesting lower doses may be more efficacious 
overtime than higher doses, 2) a traditional dose response effect of CPI-613 is not 
observed in AML patients thus far, and 3) a previous study in pancreatic cancer 
that showed remarkable synergy between CPI-613 at 500mg/m2 in combination 
with standard chemotherapy. 
2.0 
Objectives 
2.1 
Primary Objective 
To determine the feasibility of CPI-613 when administered with high dose 
cytarabine, and mitoxantrone in all three phases of salvage therapy (induction, and 
maintenance). The regimen will be considered feasible if ≥50% of patients 
eligible for maintenance therapy complete at least 3 cycles.  
2.2 
Secondary Objectives 
To observe the response rate (CR, and CRi) of CPI-613 in combination with high 
dose cytarabine and mitoxantrone. 
 
To observe the overall survival of patients treated with CPI-613 in combination 
with high dose cytarabine and mitoxantrone in induction, consolidation and 
maintenance.  
 
To monitor toxicities experienced by patients treated with CPI-613 in 
combination with high dose cytarabine and mitoxantrone in induction, 
consolidation and maintenance. 
3.0 
Patient Selection 
 
This clinical trial can fulfill its objective only if patients appropriate for this trial are 
enrolled. All relevant medical and other considerations should be taken into account 
when deciding whether this protocol is appropriate for a particular patient. Physicians 
should consider the risks and benefits of any therapy, and therefore only enroll patients 
for whom this treatment is appropriate. 


CCCWFU 22215 
 
Comprehensive Cancer Center of Wake Forest University 
An Open Label Study to Evaluate the Feasibility of CPI-613 Given with High Dose Cytarabine and 
Mitoxantrone in Patients with Relapsed or Refractory Acute Myeloid Leukemia (AML) 
NCT Clinicaltrials.gov:  NCT02484391 
 
15 
Revision Date:06/04/18 
3.1 
Inclusion Criteria  
3.1.1 
Patients must have histologically or cytologically documented relapsed 
and/or refractory Acute Myeloid Leukemia or granulocytic sarcoma.  
3.1.2 
ECOG Performance Status of ≤3. 
3.1.3 
Must be ≥18 years of age. 
3.1.4 
Expected survival >3 months. 
3.1.5 
Women of child-bearing potential (i.e., women who are pre-menopausal or 
not surgically sterile) must use accepted contraceptive methods (abstinence, 
intrauterine device [IUD], oral contraceptive or double barrier device), and 
must have a negative serum or urine pregnancy test within 1 week prior to 
treatment initiation. (Note: Pregnant patients are excluded because the effects 
of CPI-613 on a fetus are unknown.) 
3.1.6 
Fertile men must practice effective contraceptive methods during the study 
period, unless documentation of infertility exists. 
3.1.7 
Mentally competent, ability to understand and willingness to sign the 
informed consent form. 
3.1.8 
No radiotherapy, treatment with cytotoxic agents (except CPI-613), treatment 
with biologic agents or any anti-cancer therapy within the 2 weeks prior to 
treatment with CPI-613.  Hydroxyurea and oral tyrosine kinase inhibitors 
being used without Grade ≤ 2 toxicity can be taken until day 1 of therapy. 
Patients must have fully recovered from the acute, non-hematological, non-
infectious toxicities of any prior treatment with cytotoxic drugs, radiotherapy 
or other anti-cancer modalities (returned to baseline status as noted before 
most recent treatment).  Patients with persisting, non-hematologic, non-
infectious toxicities from prior treatment ≤ Grade 2 are eligible, but must be 
documented as such. 
3.1.9 
Laboratory values ≤2 weeks must be: 
 
Adequate hepatic function (aspartate aminotransferase 
[AST/SGOT] ≤3x upper normal limit [UNL], alanine 
aminotransferase [ALT/SGPT] ≤3x UNL (≤5x ULN if liver 
metastases present), bilirubin ≤1.5x UNL). 
 
Adequate renal function (serum creatinine ≤1.5 mg/dL or 133 
μmol/L). 
3.1.10 Left Ventricular Ejection Fraction (by TTE, MUGA or cardiac MRI) 
sufficient to safely administer mitoxantrone as determined by the treating 
physician 
3.2 
Exclusion Criteria  
3.2.1 Serious medical illness, such as significant cardiac disease (e.g. 
symptomatic congestive heart failure, unstable angina pectoris, myocardial 
infarction within the past 6 months, uncontrolled cardiac arrhythmia, 
pericardial disease or New York Heart Association Class III or IV), or 


CCCWFU 22215 
 
Comprehensive Cancer Center of Wake Forest University 
An Open Label Study to Evaluate the Feasibility of CPI-613 Given with High Dose Cytarabine and 
Mitoxantrone in Patients with Relapsed or Refractory Acute Myeloid Leukemia (AML) 
NCT Clinicaltrials.gov:  NCT02484391 
 
16 
Revision Date:06/04/18 
severe debilitating pulmonary disease, that would potentially increase 
patients’ risk for toxicity. 
3.2.2 Patients with active central nervous system (CNS) or epidural tumor. 
3.2.3 Albumin <2.0 g/dL or <20 g/L. 
3.2.4 Any active uncontrolled bleeding, and any patients with a bleeding 
diathesis (e.g., active peptic ulcer disease). 
3.2.5 Pregnant women, or women of child-bearing potential not using reliable 
means of contraception (because the teratogenic potential of CPI-613 is 
unknown). 
3.2.6 Lactating females because the potential of excretion of CPI-613 into breast 
milk. (Note: Lactating females are excluded because the effects of CPI-
613 on a nursing child are unknown.) 
3.2.7 Fertile men unwilling to practice contraceptive methods during the study 
period. 
3.2.8 Life expectancy less than 3 months. 
3.2.9 Any condition or abnormality which may, in the opinion of the 
investigator, compromise the safety of patients. 
3.2.10 Unwilling or unable to follow protocol requirements. 
3.2.11 Patients with large and recurrent pleural or peritoneal effusions requiring 
frequent drainage (e.g. weekly).  Patients with any amount of clinically 
significant pericardial effusion. 
3.2.12 Active heart disease including symptomatic coronary artery disease, 
uncontrolled arrhythmias, or symptomatic congestive heart failure. 
3.2.13 Evidence of ongoing, uncontrolled infection. 
3.2.14 Patients with known HIV infection. (Note: Patients with known HIV 
infection are excluded because patients with an immune deficiency are at 
increased risk of lethal infections when treated with marrow-suppressive 
therapy, and because there may be unknown or dangerous drug 
interactions between CPI-613 and anti-retroviral agents used to treat HIV 
infections.) 
3.2.15 Patients receiving any other standard or investigational treatment for their 
cancer, or any other investigational agent for any indication within the past 
2 weeks prior to initiation of CPI-613 treatment (the use of Hydrea is 
allowed). 
3.2.16 Patients who have received immunotherapy of any type within the past 4 
weeks prior to initiation of CPI-613 treatment. 
3.2.17 Requirement for immediate palliative treatment of any kind including 
surgery. 
3.2.18 Patients that have received a chemotherapy regimen with stem cell support 
in the previous 6 months. 
3.3 
Inclusion of Women and Minorities 
Both men and women and members of all races and ethnic groups are eligible for 
this trial. 


CCCWFU 22215 
 
Comprehensive Cancer Center of Wake Forest University 
An Open Label Study to Evaluate the Feasibility of CPI-613 Given with High Dose Cytarabine and 
Mitoxantrone in Patients with Relapsed or Refractory Acute Myeloid Leukemia (AML) 
NCT Clinicaltrials.gov:  NCT02484391 
 
17 
Revision Date:06/04/18 
 
 


CCCWFU 22215 
 
Comprehensive Cancer Center of Wake Forest University 
An Open Label Study to Evaluate the Feasibility of CPI-613 Given with High Dose Cytarabine and 
Mitoxantrone in Patients with Relapsed or Refractory Acute Myeloid Leukemia (AML) 
NCT Clinicaltrials.gov:  NCT02484391 
 
18 
Revision Date:06/04/18 
4.0 
Registration Procedures 
 
All patients entered on any CCCWFU trial, whether treatment, companion, or cancer control 
trial, must be linked to the study in EPIC within 24 hours of Informed Consent. Patients must be 
registered prior to the initiation of treatment.   
 
You must perform the following steps in order to ensure prompt registration of your patient: 
 
1. Complete the Eligibility Checklist (Appendix A) 
2. Complete the Protocol Registration Form (Appendix B) 
3. Alert the Cancer Center registrar by phone, and then send the signed Informed 
Consent Form, Eligibility Checklist and Protocol Registration Form to the registrar, 
either by fax or e-mail. 
 
Contact Information: 
Protocol Registrar PHONE (336) 713-6767 
Protocol Registrar FAX (336) 713-6772 
Protocol Registrar E-MAIL (registra@wakehealth.edu) 
            
*Protocol Registration is open from 8:30 AM - 4:00 PM, Monday-Friday. 
 
4. Fax/e-mail ALL eligibility source documents with registration. Patients will not be 
registered without all required supporting documents. 
Note: If labs were performed at an outside institution, provide a printout of the results. 
Ensure that the most recent lab values are sent. 
 
To complete the registration process, the Registrar will:   
 assign a patient study number 
 assign the patient a dose 
 register the patient on the study 
5.0 
Treatment Plan 
Patients recruited at 500 mg/m² will receive this dose for all treatment phases.  
 
Salvage Induction Cycle 1: 
 
The dose of CPI-613 will be 500 mg/m²/day or 1,500 mg/m²/day given over 2 hours on 
days 1-5. Immediately following CPI-613 dosing 50 ml of D5W will be run through the 
central line. Cytarabine will be given following CPI-613 at 3gm/m2 for age <60 or 1.5 
gm/m2 for age >60 in 500 mL NS over 3 hours every 12 hours for 5 doses starting on day 
3. Mitoxantrone will be given at 6mg/m2 daily for 3 doses given in 50 mL NS over 15 
minutes after 1st, 3rd and 5th doses of cytarabine. 
 


CCCWFU 22215 
 
Comprehensive Cancer Center of Wake Forest University 
An Open Label Study to Evaluate the Feasibility of CPI-613 Given with High Dose Cytarabine and 
Mitoxantrone in Patients with Relapsed or Refractory Acute Myeloid Leukemia (AML) 
NCT Clinicaltrials.gov:  NCT02484391 
 
19 
Revision Date:06/04/18 
Dose modifications for cytarabine and mitoxantrone are as follows (Please see section 6 
for CPI-613 dose modifications): 
 
Hold Cytarabine and notify physician if:   
 Bilirubin 1.5-3:  Consider Decrease dose by 25%.   
 Bilirubin greater than 3:  Consider Decrease dose by 50%.   
 Cr Cl less than 60 mL/min:  Consider dose reduction.   
 Hold mitoxantrone and notify physician if:   
 Bilirubin greater than 3:  Consider Decrease dose by 25%. 
 
All dose modifications are at the discretion of the treating physician.  
 
Salvage Induction Cycle 2 (Optional, at the discretion of the treating physician): 
 
A repeat of the initial cycle as outlined above or at the discretion of the treating physician 
an abbreviated second cycle can be given. In the abbreviated course CPI-613 is given as 
above on days 1-3, cytarabine given as above for 3 doses starting on day 2, mitoxantrone 
given as above after the first and third cytarabine doses. 
 
Salvage Consolidation:  
 
All responding patients are eligible for consolidation therapy with up to 2 cycles of the 
abbreviated course of CPI-613 at 500 mg/m²/day or 1,500 mg/m²/day, high dose 
cytarabine and mitoxantrone. Responding patients can be removed from trial at any time 
to receive a stem cell transplant at the discretion of the treating physician. Patients can 
move to maintenance following 1, 2 or no cycles of consolidation at the discretion of the 
treating physician.     
 
Maintenance Therapy:  
 
Any patient that has completed all planned consolidation therapy (i.e. 0, 1 or 2 cycles) 
and refuses or is not eligible for a stem cell transplant may receive maintenance therapy 
with CPI-613.   The dose for the maintenance phase of treatment in this study is 2,500 
mg/m2 except for patients who received 500 mg/m2 at induction. Patients receiving 500 
mg/m2 at induction will continue with this dose during maintenance therapy. Patients may 
continue on maintenance therapy until evidence of disease progression, availability of 
stem cell transplant or occurrence of intolerable side effects.  
 
 


CCCWFU 22215 
 
Comprehensive Cancer Center of Wake Forest University 
An Open Label Study to Evaluate the Feasibility of CPI-613 Given with High Dose Cytarabine and 
Mitoxantrone in Patients with Relapsed or Refractory Acute Myeloid Leukemia (AML) 
NCT Clinicaltrials.gov:  NCT02484391 
 
20 
Revision Date:06/04/18 
5.1 
Table of Study-Related Interventions  
 
 
Assessments 
Pre-
Enrollment 
Screening 
Salvage Induction Cycle 1 
Day1 
Day2 
Day3 
Day4 
Day5 
Day6 
Day7 
Day 8 
Treatment with CPI-613 
 
 
 
 
 
 
 
 
 
Treatment with Cytarabine 
 
 
 
 
 
 
 
 
 
Treatment with Mitoxantrone 
 
 
 
 
 
 
 
 
 
Medical history7 
 
 
 
 
 
 
 
 
 
Physical exam7 and vital signs1 
1 
4 
4 
4 
4 
4 
 
 
 
Pregnancy test for woman of child-bearing 
potential 
 
 
 
 
 
 
 
 
 
TTE, MUGA or MRI 
 
 
 
 
 
 
 
 
 
ECOG performance status 
 
 
 
 
 
 
 
 
 
Evaluation of symptoms & medications 
 
 
 
 
 
 
 
 
 
Clinical chemistry2, hematology & 
coagulation7,11 
 
 
5,6 
 
5,6 
5,6 
5,6 
5,6 
 
5,6 
5,6 
5,6 
Creatinine, BUN 
 
10 
10 
10 
10 
10 
10 
10 
10 
Anti-Tumor Efficacy (i.e., imaging for 
granulocytic sarcoma, bone marrow biopsy 
for AML)3.7 
Obtained 
within 2 
weeks prior 
to the first 
dose. 
Obtained on day 14 of cycle 1. 
Optional blood, urine and plasma samples, 
as well as bone marrow via biopsy9 for 
possible testing of biomarkers, predictors of 
biological responses, toxicity, genotype vs. 
drug response relationship, etc. 
Obtained 
within 2-4 
weeks prior 
to the first 
dose. 
Blood sample to be obtained prior to and following the dose of CPI-613 
at 2, 4, and 6 hours  from end of CPI-613 infusion on day 1 and bone 
marrow sample to be obtained on day 14 of Cycle 1.  Bone marrow 
samples may be collected +/- 1-2 days if falls on a weekend or holiday. 
Optional urine samples will be collected from the first void after the first 
infusion of CPI-613. Details of the collection will be recorded on 
Appendix G. 
 
 1 Height, weight are also determined during pre-enrollment screening. 
2 Renal function will be assessed utilizing the Cockcroft-Gault formula. 
3 The Response Criteria will be assessed by standard criteria (Blood. 2010;115:453-474). 
4 Vital signs will be performed immediately after CPI-613 administration and the patient only re-examined if clinically indicated.   
5 These tests are performed within 24 hrs prior to dosing.  Only the results of the creatinine are needed before CPI-613 is dosed. 
6 For Day 1 of Treatment Cycle 1, the pre-enrollment test results can be used for all labs except creatinine which must be rechecked 24 hours prior to dosing. 
7 The frequency of assessment beyond Cycle 1 is: 
- For medical history, physical exam and vital signs, ECOG PS, evaluation of symptoms and medications, they are assessed within 5 days of the next cycle doses. 
- Clinical chemistry and hematology are assessed on day 5 of each cycle (or day 3 if short dosing cycle is given). 
9   Bone Marrow via biopsy will only be collected if deemed appropriate by physician 
10  Creatinine and BUN to be checked within 24 hours of every dose and at 24, 48 and 72 hours post last dose of CPI-613, mitoxantrone, and cytarabine (i.e., days 6, 7, 
and 8) 
11 Coagulation (PT/PTT) to be completed Day 1 and weekly during Cycle 1. 
 
 
 


CCCWFU 22215 
 
Comprehensive Cancer Center of Wake Forest University 
An Open Label Study to Evaluate the Feasibility of CPI-613 Given with High Dose Cytarabine and 
Mitoxantrone in Patients with Relapsed or Refractory Acute Myeloid Leukemia (AML) 
NCT Clinicaltrials.gov:  NCT02484391 
 
21 
Revision Date:06/04/18 
 
Assessments 
Salvage Consolidation Cycle 1 and 2 
Day1 
Day2 
Day3 
Day4 
Day5 
Day6 
Day7 
Day 8 
Treatment with CPI-613 
 
 
 
 
 
 
 
 
Treatment with Cytarabine 
 
 
 
 
 
 
 
 
Treatment with Mitoxantrone 
 
 
 
 
 
 
 
 
Medical history7 
7 
 
 
 
 
 
 
 
Physical exam7 and vital signs1 
4 
4 
4 
 
 
 
 
 
Pregnancy test for woman of child-bearing potential 
 
 
 
 
 
 
 
 
TTE, MUGA or MRI 
11 
 
 
 
 
 
 
 
ECOG performance status 
 
 
 
 
 
 
 
 
Evaluation of symptoms & medications 
 
 
 
 
 
 
 
 
Clinical chemistry2 and hematology7,11 
5 
5 
5 
 
 
 
 
 
Creatinine, BUN 
 
 
 
 
 
 
 
 
Anti-Tumor Efficacy (i.e., imaging for granulocytic 
sarcoma, bone marrow biopsy for AML)3.7 
Obtained upon completion of all planned consolidation therapy. 
Optional blood and plasma samples, as well as bone 
marrow via biopsy9 for possible testing of 
biomarkers, predictors of biological responses, 
toxicity, genotype vs. drug response relationship, etc. 
Blood sample to be obtained prior to and following the dose of CPI-613 at 
2, 4, and 6 hours from end of CPI-613 infusion on day  1 and bone marrow 
sample to be obtained at the end of planned consolidation therapy.  Bone 
marrow samples may be collected +/- 1-2 days if falls on a weekend or 
holiday. 
1 Height, weight are determined during pre-enrollment screening. 
2 Renal function will be assessed utilizing the Cockcroft-Gault formula. 
3 The Response Criteria will be assessed by standard criteria (Blood. 2010;115:453-474). 
4 Vital signs will be performed immediately after CPI-613 administration and the patient only re-examined if clinically indicated.   
5 These tests are performed within 24 hrs prior to dosing.  Only the results of the creatinine are needed before CPI-613 is dosed. 
7 The frequency of assessment is: 
- For medical history, physical exam and vital signs, ECOG PS, evaluation of symptoms and medications, they are assessed within 5 days of the next cycle doses. 
9   Bone Marrow via biopsy will only be collected if deemed appropriate by physician 
10  Creatinine and BUN to be checked within 24 hours of every dose of CPI-613 
11 TTE/MUGA/Cardiac MRI can be obtained within 2 weeks of consolidation as long as no other cardiac toxins have been administered. Prior to cycle 2 of 
consolidation TTE/MUGA/Cardiac MRI is at the discretion of the treating physician 
 
 
Assessments 
Maintenance Therapy 
Day1 
Day2 
Day3 
Day4 
Day5 
Day6 
Day7 
Day 8 
Treatment with CPI-613 
 
 
 
 
 
 
 
 
Medical history7 
7 
 
 
 
 
 
 
 
Physical exam7 and vital signs1 
4 
4 
4 
4 
4 
 
 
 
Pregnancy test for woman of child-bearing 
potential 
 
 
 
 
 
 
 
 
ECOG performance status 
7 
 
 
 
 
 
 
 
Evaluation of symptoms & medications 
7 
 
 
 
 
 
 
 
Clinical chemistry2 and hematology7,11 
5 
5 
5 
5 
5 
 
 
 
Creatinine, BUN 
 
 
 
 
 
 
 
 
Anti-Tumor Efficacy (i.e., imaging for 
granulocytic sarcoma, bone marrow biopsy 
for AML)3.7 
Obtained upon completion of every fourth cycle. 
Optional blood and plasma samples, as well 
as bone marrow via biopsy9 for possible 
testing of biomarkers, predictors of 
biological responses, toxicity, genotype vs. 
drug response relationship, etc. 
Blood sample to be obtained prior to and immediately following the dose of CPI-613 
on day 1and  bone marrow sample to be obtained at the end of planned maintenance 
therapy.  Bone marrow samples may be collected +/- 1-2 days if falls on a weekend or 
holiday. 
1 Height, weight are determined during pre-enrollment screening. 
2 Renal function will be assessed utilizing the Cockcroft-Gault formula. 
3 The Response Criteria will be assessed by standard criteria (Blood. 2010;115:453-474). 
4 Vital signs will be performed immediately after CPI-613 administration and the patient only re-examined if clinically indicated.   
5 These tests are performed within 24 hrs prior to dosing.  Only the results of the creatinine are needed before CPI-613 is dosed. 
7 The frequency of assessment for cycles after cycle 1 is: 
- For medical history, physical exam and vital signs, ECOG PS, evaluation of symptoms and medications, they are assessed within 7 days of the next cycle doses. 
9   Bone Marrow via biopsy will only be collected if deemed appropriate by physician. 
10 Creatinine and BUN to be checked within 24 hours of every dose of CPI-613. 


CCCWFU 22215 
 
Comprehensive Cancer Center of Wake Forest University 
An Open Label Study to Evaluate the Feasibility of CPI-613 Given with High Dose Cytarabine and 
Mitoxantrone in Patients with Relapsed or Refractory Acute Myeloid Leukemia (AML) 
NCT Clinicaltrials.gov:  NCT02484391 
 
22 
Revision Date:06/04/18 
5.2 
Pre-Enrollment Medical Screening 
Informed consent must be obtained prior to pre-enrollment medical screening. 
Investigators who are listed on US “Food and Drug Administration (FDA) Form 
1572” or Canadian “Clinical Trial Site Information Form” are authorized to 
obtain informed consent. Pre-enrollment medical screening is used to determine 
the eligibility of each candidate. All enrollment evaluations must be performed 
within the time frame listed below, prior to CPI-613 treatment and include: 
 
Within 2 weeks: 
- Bone marrow biopsy or cytologic evidence of relapsed or refractory AML or 
granulocytic sarcoma 
- Optional blood, plasma and bone marrow biopsy sample for biomarker 
evaluation 
- a complete medical history 
- physical exam, including vital signs, height, and weight 
- ECOG PS 
- baseline evaluation of symptoms and medications 
- clinical chemistry (including renal function), hematology and coagulation (see 
Section 5.6 for specifics) 
 
Within 1 week: 
- a pregnancy test for women of child-bearing potential (performed within 1 week 
prior to CPI-613 treatment) 
5.3 
CPI-613 Dosing 
This is a Pilot trial to determine the feasibility of CPI-613 given with high dose 
cytarabine and mitoxantrone in salvage induction, consolidation and maintenance. 
This is an open-label study, and investigators and subjects are not blinded to the 
treatment. The reason this is an open-label study is because this is a feasibility 
trial, and the investigators need to determine whether this regimen is feasible to be 
tested in larger clinical trials. The assignment of patients will not be randomized, 
since this is a feasibility trial. The doses of CPI-613 for the induction and 
consolidation phases of treatment in this study are 500 mg/m2 or 1,500 mg/m2 
with 20 patients in each cohort for both 500 and 1,500 the study has already 
accrued 17 patients at 2,000 mg/m2 cohort; the dose for the maintenance phase of 
treatment in this study is 2,500 mg/m2 except for patients who received 500mg/m2 
at induction.  Patients receiving 500mg/m2 at induction will continue with this 
dose for all phases of therapy including maintenance. 
 
CPI-613 must be diluted from 50 mg/mL to 12.5 mg/mL with D5W (i.e., 1 
portion of CPI-613 diluted with 3 portions of D5W) and must be administered IV 
at a rate of ~0.5 mL/min via a central venous catheter with D5W running at a rate 
of about 125-150 mL/hr.  Please refer to Section 5.4 for methods of administering 
CPI-613. 


CCCWFU 22215 
 
Comprehensive Cancer Center of Wake Forest University 
An Open Label Study to Evaluate the Feasibility of CPI-613 Given with High Dose Cytarabine and 
Mitoxantrone in Patients with Relapsed or Refractory Acute Myeloid Leukemia (AML) 
NCT Clinicaltrials.gov:  NCT02484391 
 
23 
Revision Date:06/04/18 
5.4 
CPI-613 Administration Guidelines 
Since information on the use of CPI-613 in humans is limited, investigators 
should be aware of potential AEs and toxicities observed in preclinical studies, as 
described below. 
 
According to animal toxicology studies, IV administration of CPI-613 can induce 
reactions at and around the site of administration.  These reactions are consistent 
with local inflammation, which include red/purple/black color, swelling, necrosis, 
warm to touch, etc.  These local reactions occurred more severely when there was 
accidental leakage of CPI-613 into the perivascular space during IV 
administration.  This is possibly because of low perfusion in the perivascular 
areas, causing prolonged exposure of local tissues to CPI-613.  Therefore, care 
must be taken to avoid perivascular leakage of CP-613. 
 
CPI-613 must be administered IV by infusion (not bolus), via a central venous 
catheter that is free flowing, with D5W running at a rate of about 125-150 mL/hr, 
and free of air in the dead space of the IV catheter.  This is to minimize vascular 
irritation, inflammation and acute toxicity of CPI-613.  Accidental co-
administration of extra air that is present in the dead space of an IV catheter has 
been shown to induce excessive acute toxicity of CPI-613 according to animal 
studies (Study NCL-049). 
 
CPI-613 must be diluted prior to administration, as described in Section 5.3.  
Dilution of CPI-613 prior to administration reduces the rates of delivery of CPI-
613 to the body, thus minimizing the acute toxicity of CPI-613. 
 
Accordingly, the following procedures in administering CPI-613 should be taken 
to minimize local reactions and acute toxicity of CPI-613: 
 
A. Confirmation of the placement of the IV line to ensure that there is a lack 
of leakage of CPI-613 into the perivascular space. 
B. Confirmation that the IV line is free flowing and with D5W running at a 
rate of about 125-150 mL/hr. 
C. Confirmation that the IV line is free of air in the dead space. 
D. If necessary, rotate the site of administration for different doses of CPI-
613. 
E. Dilute CPI-613 drug product with D5W, as instructed in the study 
protocol. 
F. Administer CPI-613 by infusion, not bolus, as instructed in the study 
protocol. 
G. Upon completion of administering CPI-613, “slowly” flush the IV line 
with ~10 mL of D5W to remove residual CPI-613. 
 


CCCWFU 22215 
 
Comprehensive Cancer Center of Wake Forest University 
An Open Label Study to Evaluate the Feasibility of CPI-613 Given with High Dose Cytarabine and 
Mitoxantrone in Patients with Relapsed or Refractory Acute Myeloid Leukemia (AML) 
NCT Clinicaltrials.gov:  NCT02484391 
 
24 
Revision Date:06/04/18 
Investigators should be aware of the following toxicity observed in animals 
treated with toxic doses of CPI-613: 
1. CPI-613 at the toxicological doses of 30-35 mg/kg (180-210 mg/m²) 
induced dose-related incidence of mortality in rats.  The cause of death in 
most rats was due to significant systemic inflammation, and might be 
related to an over enhancement in the inflammatory responses induced by 
CPI-613.  Deaths due to significant systemic inflammation were also 
observed in minipigs treated with the minipig toxicological dose of 46.2 
mg/kg (i.e., 1617 mg/m²) of CPI-613.  Additionally, CPI-613 at 30 and 35 
mg/kg (i.e., 180 and 210 mg/m², respectively) in minipigs increased 
reticulocyte levels, which appeared to be associated with hematopoietic 
cell proliferation of the spleen, and sternal bone marrow hyperplasia that 
were secondary to inflammation initiated at the administration site or port.  
Therefore, investigators should be aware of significant increases in 
reticulocyte levels, which can be used as an indication of severe 
inflammation. 
 
2. CPI-613 at 42-55 mg/kg (i.e., 1470-1925 mg/m²) induced transient 
vomiting in minipigs. 
 
3. CPI-613 at 42-46.2 mg/kg (1470-1617 mg/m², respectively) induced 
transient and reversible increases in troponin I and creatine kinase (CPK) 
isoenzyme.  The transient and reversible nature of the troponin and CPK 
isoenzyme results were consistent with necropsy exam and 
histopathology, which indicated that there was no cardiac damage after the 
3-week treatment of different doses of CPI-613. 
5.5 
General Concomitant Medication and Supportive Care 
Guidelines 
Patients will receive standard prophylactic treatment for drug-related symptoms. 
Supportive treatments may include anti-emetic, anti-diarrhea, anti-allergic, anti-
hypertensive medications, analgesics, antibiotics, allopurinol, and others such as 
blood products and bone marrow growth factors. The treating physician may 
utilize marrow growth factors, or blood or platelet transfusions at their discretion. 
For patients with an ANC ≥ 500/mm3 at the time of CPI-613 administration 
loperamide can be administered as a premedication at a dose of 2 to 4 mg PO 30 
minutes prior to CPI-613.   
5.6 
Study Procedures – Assessment of Safety, Plasma 
Concentration, and Possible Anti-Tumor Efficacy 
Safety Assessment: The safety of CPI-613 will be assessed based on: 
- physical exams 
- vital signs 
- clinical pathology 


CCCWFU 22215 
 
Comprehensive Cancer Center of Wake Forest University 
An Open Label Study to Evaluate the Feasibility of CPI-613 Given with High Dose Cytarabine and 
Mitoxantrone in Patients with Relapsed or Refractory Acute Myeloid Leukemia (AML) 
NCT Clinicaltrials.gov:  NCT02484391 
 
25 
Revision Date:06/04/18 
• clinical chemistry 
• renal function 
• hematology 
For physical exams and vital signs, they are to be performed during screening 
(performed within 2 weeks prior to treatment with CPI-613) and after CPI-613 
administration in Cycle 1.  Beyond Cycle 1, physical exam and vital signs will be 
assessed within 5 days of the next cycle doses.  
 
For clinical pathology (i.e., clinical chemistry, renal function, hematology and 
coagulation), they are to be performed during screening (performed within 2 
weeks prior to treatment with CPI-613), and within 24 hrs prior to dosing. 
Creatinine results within the last 24 hours must be reviewed prior to CPI-613 
dosing.  For Day 1 of Treatment Cycle 1, pre-dose assessments of clinical 
pathology are not needed because the pre-enrollment results can be used.  
Beyond cycle 1, laboratory assessments will be assessed on at least day 1 and 5 
of each cycle rather than prior to beginning each cycle. 
 
For left ventricular ejection fraction assessments, they are evaluated during 
screening and prior to consolidation therapy. Additional assessments can be 
made at the discretion of the treating physician.   
 
Anti-Tumor Efficacy – A Secondary Endpoint:  Baseline anti-tumor efficacy (i.e., 
bone marrow biopsy) will be obtained within 2 weeks prior to the first dose of 
treatment cycle 1.  Follow-up anti-tumor efficacy will be obtained on day 14 of 
cycle 1.  In patients treated with additional treatment cycles beyond Cycle 1, 
anti-tumor efficacy will be assessed upon count recovery (defined as 
ANC>1000, freedom from RBC transfusions and platelets>100k) or day 42 
from the first day of the cycle whichever comes first. Anti-tumor efficacy 
assessment will also be based on investigator and institutional routine 
monitoring of the disease progression of the patients, together with baseline 
evaluations performed prior to treatment with CPI-613. During maintenance 
therapy anti-tumor efficacy will be assessed after every 4th cycle. 
 
Optional Sampling and “Banking” of Blood, Plasma, urine and Bone Marrow 
Biopsy Samples:  Optional blood samples (5 mL), urine (5-10 ml) as well as 
bone marrow via biopsy (if deemed appropriate by physician), will be obtained 
and “banked” for possible testing of biomarkers, predictors of biological 
responses, toxicity, relationship between genotype and drug responses, etc. 
These samples will be obtained prior to treatment initiation, as well as prior to 
and following administration of CPI-613 during salvage Cycle 1.  The specific 
procedures are outlined below. 
 
Whole Blood Sample 
• One (5 mL) Lavendar Top K EDTA Vacutainer Tube will be used. 


CCCWFU 22215 
 
Comprehensive Cancer Center of Wake Forest University 
An Open Label Study to Evaluate the Feasibility of CPI-613 Given with High Dose Cytarabine and 
Mitoxantrone in Patients with Relapsed or Refractory Acute Myeloid Leukemia (AML) 
NCT Clinicaltrials.gov:  NCT02484391 
 
26 
Revision Date:06/04/18 
• Do not centrifuge or freeze sample. 
• Label sample and store at refrigerated temperature (2-8°C). 
• Samples will be shipped on ice pack to the address shown at the bottom of this 
section. 
Fresh Bone Marrow Biopsy for Banking of Tumor Cells 
• Samples will be collected into a green top lithium heparin tube. Harvested 
fresh tumor specimens are placed on ice and shipped to the address below. 
(Note the tumor bank will Ficoll separate mononuclear cells and freeze 
aliquots in RPMI media containing 10% DMSO.)  
 
Urine Samples 
Urine samples will be collected from the first void after the first infusion of 
CPI-613 in the first induction cycle only. Details of the collection will be 
recorded on Appendix G. 
 Approximately 5-10 ml of urine will be collected in a 15 mL conical 
tube 
 The tube will placed at 4°C until placed into the Tumor Tissue Core 
Facility (see below) 
 
All optional samples and specimens should be shipped to: 
Wake Forest Cancer Center  
Tumor Tissue Core Facility  
Care of Dr. Greg Kucera 
Hanes Building Rm 4049 
Medical Center Blvd 
Winston-Salem NC 27157 
5.7 
Specifics of Tests Performed During the Study 
ECOG PS: The ECOG performance status (see Table below) will be used to 
classify patient’s functional impairment.  The higher the score, the worse the 
survival for most serious illnesses including AML. 
 
ECOG Performance Scale (EPS)  
Score 
Definition 
0 
Fully active, able to carry on all pre-disease performance without restriction 
1 
Restricted in physically strenuous activity but ambulatory and able to carry out work of a 
light or sedentary nature, e.g., light house work, office work. 
2 
Ambulatory and capable of all self-care but unable to carry out any work activities. Up 
and about more than 50% of waking hours. 
3 
Capable of only limited self-care, confined to bed or chair more than 50% of waking 
hours. 
4 
Completely disabled. Cannot carry on any self-care. Totally confined to bed or chair. 
5 
Dead. 


CCCWFU 22215 
 
Comprehensive Cancer Center of Wake Forest University 
An Open Label Study to Evaluate the Feasibility of CPI-613 Given with High Dose Cytarabine and 
Mitoxantrone in Patients with Relapsed or Refractory Acute Myeloid Leukemia (AML) 
NCT Clinicaltrials.gov:  NCT02484391 
 
27 
Revision Date:06/04/18 
 
 
 


CCCWFU 22215 
 
Comprehensive Cancer Center of Wake Forest University 
An Open Label Study to Evaluate the Feasibility of CPI-613 Given with High Dose Cytarabine and 
Mitoxantrone in Patients with Relapsed or Refractory Acute Myeloid Leukemia (AML) 
NCT Clinicaltrials.gov:  NCT02484391 
 
28 
Revision Date:06/04/18 
Lab Studies: Clinical chemistry assessed includes the following parameters.  
Renal function will be assessed utilizing the Cockcroft-Gault formula. 
 
glucose 
uric acid 
creatinine 
blood urea nitrogen (BUN) 
total protein 
AST/serum glutamic-oxaloacetic transaminase (SGOT) 
albumin 
ALT/serum glutamic-pyruvic transaminase (SGPT) 
Na+ 
alkaline phosphatase (ALP) 
K+ 
lactate dehydrogenase (LDH) 
Cl- 
total bilirubin 
Mg 
 
Ca+2 
 
PO4 
 
CO2 
 
 
Hematology includes: 
Complete blood count with differential 
Coagulation includes: 
INR 
partial thromboplastin time 
5.8 
Future Research 
Optional blood samples will be collected before and at various times after the 1st 
dose of CPI-613. Provisions should be made to record and report the actual clock 
times when samples are drawn. Whenever possible samples should be taken 5 
minutes before and at completion of the infusion of CPI-613 on day 1 and at 2, 4 
and 6 hours after the completion of the infusion. Blood (5 mL for each sample) 
should be obtained from an IV catheter that is not used for administration of CPI-
613.  The blood samples should be collected in 5-mL lavender top collection 
tubes containing K2- or K3-EDTA anticoagulant.  Immediately after blood 
collection, gently invert tube 3 times to ensure proper mixing of blood and 
anticoagulant.  Blood should then be immediately placed at 4 degrees Celsius. 
Additionally, several milliliters of urine from the first void following completion 
of the CPI-613 infusion on day one will be collected in consenting subjects. Once 
collected 5-10 ml of urine should be placed in a 15 ml conical tube and placed at 
4 degrees Celsius until it can be sent to the tumor tissue core facility (see below). 
 
When all samples have been collected, they should be sent to: 
 
Wake Forest Cancer Center  
Tumor Tissue Core Facility  
Care of Dr. Greg Kucera 
Hanes Building Rm 4049 
Medical Center Blvd 
Winston-Salem NC 27157 


CCCWFU 22215 
 
Comprehensive Cancer Center of Wake Forest University 
An Open Label Study to Evaluate the Feasibility of CPI-613 Given with High Dose Cytarabine and 
Mitoxantrone in Patients with Relapsed or Refractory Acute Myeloid Leukemia (AML) 
NCT Clinicaltrials.gov:  NCT02484391 
 
29 
Revision Date:06/04/18 
 
 
      Email: gkucera@wakehealth.edu 
5.9 
Criteria for Removal from Study 
Listed below are criteria for the discontinuation of the study. However, patients 
who fail to return for the follow-up visits will be contacted and queried as to the 
reason they have failed to complete the study with special attention to health 
status. 
 
A. Patients have the right to withdraw from the study at any time for any reason. 
 
B. The investigator has the right to withdraw patients from the study according to 
his/her discretion, if the investigator determines that continued participation is 
not in the patient’s best interest. As an excessive rate of withdrawals can 
render the study not interpretable, unnecessary withdrawal of patients should 
be avoided. When a patient discontinues investigational treatment, the 
investigator should make every effort to contact the patient and to perform a 
final evaluation. The reason(s) for withdrawal must be recorded. Criteria for 
terminating subject's participation in the study are listed below: 
 
- Protocol defined disease progression significantly greater than expected 
- Unacceptable toxicity of the investigational product 
- Patient withdrawal of consent 
- Investigator’s discretion 
- Undercurrent illness: a condition, injury, or disease unrelated to the 
intended disease for which the study is investigating, that renders 
continuing the treatment unsafe or regular follow-up impossible 
- General or specific changes in the patient's condition that renders the 
patient ineligible for further investigational treatment 
- Non-compliance with investigational treatment, protocol-required 
evaluations or follow-up visits 
- Termination of the clinical trial by the sponsor  
6.0 
Dosing Delays/Dose Modifications for CPI-613 
 
The occurrence of Grade 1 toxicity does not generally require dose modification for 
subsequent doses for that patient.  However, if Grade 2 non-hematologic, non-infectious 
toxicity develops attributed as at least probably related to CPI-613, treatment can resume 
only after the Grade 2 toxicity has been reduced to Grade 1 or below, and the dose level 
for subsequent doses for that patient will be reduced by 25% of the dose at which such 
Grade 2 toxicity occur.  If Grade 3 or 4 non-hematologic, non-infectious toxicity 
develops, dosing of that patient will be withheld and the patient shall be monitored for 
recovery from, and reversibility of, such Grade 3 or 4 toxicity.  To resume treatment for a 
patient who has had Grade 3 or 4 toxicity, the Grade 3 or 4 toxicity must be reduced to 
Grade 1 or below, and the dose level for subsequent doses for that patient will be reduced 


CCCWFU 22215 
 
Comprehensive Cancer Center of Wake Forest University 
An Open Label Study to Evaluate the Feasibility of CPI-613 Given with High Dose Cytarabine and 
Mitoxantrone in Patients with Relapsed or Refractory Acute Myeloid Leukemia (AML) 
NCT Clinicaltrials.gov:  NCT02484391 
 
30 
Revision Date:06/04/18 
to 50% of the dose at which such Grade 3 or 4 toxicity occur. If the reduced dose of CPI-
613 results in no toxicity, patients may be dose escalated to the prior dose at the 
discretion of the treating physician.   
 
Dose adjustments during maintenance therapy will be done as described above with the 
addition that should patients experience hematologic toxicity ≥ Grade 2 attributed to CPI-
613 the next dose of maintenance therapy must be held until the Grade 2 toxicity has 
been reduced to Grade 1 or below, and the dose level for subsequent doses for that patient 
will be reduced by 25% of the dose at which such Grade 2 toxicity occurred.  If Grade 3 
or 4 hematologic toxicity develops, dosing of that patient will be withheld and the patient 
shall be monitored for recovery from, and reversibility of, such Grade 3 or 4 hematologic 
toxicity.  To resume treatment for a patient who has had Grade 3 or 4 hematologic 
toxicity, the Grade 3 or 4 hematologic toxicity must be reduced to Grade 1 or below, and 
the dose level for subsequent doses for that patient will be reduced to 50% of the dose at 
which such Grade 3 or 4 hematologic toxicity occurred. If the reduced dose of CPI-613 
results in no toxicity, patients may be dose escalated to the prior dose at the discretion of 
the treating physician.  
 
7.0 
Adverse Events List and Reporting Requirements 
 
Given the severe nature of the disease and treatment modalities associated with this 
patient population, any adverse event lower than grade 3 during a patient’s treatment AE 
evaluation period will not be part of data analysis or subject to expedited reporting. 
7.1 
Adverse Event Characteristics 
 
CTCAE term (AE description) and grade:  The CTEP Active Version of 
the NCI Common Terminology Criteria for Adverse Events (CTCAE 4.0) will 
be utilized for AE reporting.  The CTEP Active Version of the CTCAE is 
identified and located on the CTEP website at 
(http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm. 
 All appropriate treatment areas should have access to a copy of the CTEP 
Active Version of CTCAE. 
 
 
‘Expectedness’: AEs can be ‘Unexpected’ or ‘Expected’ (see Section 7.1 
above) for expedited reporting purposes only.   
 
 
Attribution of the AE: 
- Definite – The AE is clearly related to the study treatment. 
- Probable – The AE is likely related to the study treatment. 
- Possible – The AE may be related to the study treatment. 
- Unlikely – The AE is doubtfully related to the study treatment. 
- Unrelated – The AE is clearly NOT related to the study treatment. 
 


CCCWFU 22215 
 
Comprehensive Cancer Center of Wake Forest University 
An Open Label Study to Evaluate the Feasibility of CPI-613 Given with High Dose Cytarabine and 
Mitoxantrone in Patients with Relapsed or Refractory Acute Myeloid Leukemia (AML) 
NCT Clinicaltrials.gov:  NCT02484391 
 
31 
Revision Date:06/04/18 
 
 


CCCWFU 22215 
 
Comprehensive Cancer Center of Wake Forest University 
An Open Label Study to Evaluate the Feasibility of CPI-613 Given with High Dose Cytarabine and 
Mitoxantrone in Patients with Relapsed or Refractory Acute Myeloid Leukemia (AML) 
NCT Clinicaltrials.gov:  NCT02484391 
 
32 
Revision Date:06/04/18 
List of Adverse Events to be Reported: 
*Abdominal pain 
*Creatinine 
*Diarrhea 
*Injection site Reaction 
*Nausea 
*Vomiting 
 
All adverse events should be reported on the adverse event log and in ORIS regardless of 
whether they are on this list. 
 
Asterisk (*) denotes expected Adverse Events. 
 
All SAEs are required to be reported to Rafael Pharmaceuticals via the provided SAE 
Reporting Form.  All completed forms must be sent to Claudia Moore at Rafael.  The 
Comprehensive Cancer Center of Wake Forest University will submit any applicable 
SAEs to the FDA.   
 
 
SAE reports must be submitted to Rafael by fax to the following address: 
 
Department of Regulatory and Clinical Affairs 
Rafael Pharmaceuticals, Inc. 
25 Health Sciences Drive 
Stony Brook, NY 11790 
Telephone: 631-444-6868 
Telefax: 631-794-2319 
7.2 
STRC SAE Reporting Requirements 
The Safety and Toxicity Review Committee (STRC) is responsible for reviewing 
SAEs for CCCWFU Institutional studies as outlined in Appendix B. STRC 
currently requires that all unexpected grade 4 and all grade 5 SAE’s on these trials 
be reported to them for review. This procedure is a part of the CCCWFU Data 
Safety Monitoring Plan that our institution has on file at the NCI. All CRM staff 
members assisting a PI in investigating, documenting and reporting an SAE 
qualifying for STRC reporting are responsible for informing a clinical member of 
the STRC committee as well as the entire committee via the email notification 
procedure of the occurrence of an SAE.  
7.3  
WFUHS IRB AE Reporting Requirements 
Any unanticipated problems involving risks to subjects or others and adverse 
events shall be promptly reported to the IRB, according to institutional policy.  
Reporting to the IRB is required regardless of the funding source, study sponsor, 
or whether the event involves an investigational or marketed drug, biologic or 
device.  Reportable events are not limited to physical injury, but include 
psychological, economic and social harm.  Reportable events may arise as a result 


CCCWFU 22215 
 
Comprehensive Cancer Center of Wake Forest University 
An Open Label Study to Evaluate the Feasibility of CPI-613 Given with High Dose Cytarabine and 
Mitoxantrone in Patients with Relapsed or Refractory Acute Myeloid Leukemia (AML) 
NCT Clinicaltrials.gov:  NCT02484391 
 
33 
Revision Date:06/04/18 
of drugs, biological agents, devices, procedures or other interventions, or as a 
result of questionnaires, surveys, observations or other interactions with research 
subjects. 
 
All members of the research team are responsible for the appropriate reporting to 
the IRB and other applicable parties of unanticipated problems involving risk to 
subjects or others.  The Principal Investigator, however, is ultimately responsible 
for ensuring the prompt reporting of unanticipated problems involving risk to 
subjects or others to the IRB.  The Principal Investigator is also responsible for 
ensuring that all reported unanticipated risks to subjects and others which they 
receive are reviewed to determine whether the report represents a change in the 
risks and/or benefits to study participants, and whether any changes in the 
informed consent, protocol or other study-related documents are required. 
 
Any unanticipated problems involving risks to subjects or others occurring at a 
site where the study has been approved by the WFUHS IRB (internal events) 
must be reported to the WFUHS IRB within 7 calendar days of the investigator or 
other members of the study team becoming aware of the event. 
Any unanticipated problems involving risks to subjects or others occurring at 
another site conducting the same study that has been approved by the WFUHS 
IRB (external events) must be reported to the WFUHS IRB within 7 calendar 
days of the investigator or other members of the study team becoming aware of 
the event. 
 
Any event, incident, experience, or outcome that alters the risk versus potential 
benefit of the research and as a result warrants a substantive change in the 
research protocol or informed consent process/document in order to insure the 
safety, rights or welfare of research subjects. 
8.0 
Pharmaceutical Information 
8.1 
Pharmaceutical Accountability 
Drug accountability logs will be maintained for all investigative agents used 
under this protocol.  These logs shall record quantities of study drug received and 
quantities dispensed to patients, including lot number, date dispensed, patient 
identifier number, patient initials, protocol number, dose, quantity returned, 
balance remaining, and the initials of the person dispensing the medication.   
8.2 
Study Drug 
Various Names of Investigational Drug 
 
Chemical Name: 
 
 
 
6,8-bis-benzylsulfanyloctanoic acid 
Alternative Name: 
 
 
 
6,8-bis(benzylthio)octanoic acid; or 
 
 
 
 
 
 
 
6,8-bis-benzylsulfonyloctanoic acid 


CCCWFU 22215 
 
Comprehensive Cancer Center of Wake Forest University 
An Open Label Study to Evaluate the Feasibility of CPI-613 Given with High Dose Cytarabine and 
Mitoxantrone in Patients with Relapsed or Refractory Acute Myeloid Leukemia (AML) 
NCT Clinicaltrials.gov:  NCT02484391 
 
34 
Revision Date:06/04/18 
Chemical Abstract Society (CAS) No.: 
95809-78-2 
Pharmacologic Class:  
 
 
altered energy metabolism-directed 
(AEMD) compound 
Code Name:  
 
 
 
CPI-613 
Trade Name:  
 
 
 
Bylantra (tentative) 
Generic Name: 
 
 
 
None 
 
Description of CPI-613 Drug Product 
 
CPI-613 is provided in 10-mL amber glass vials. Each 10-mL vial contains 10 mL 
of CPI-613 at a concentration of 50 mg/mL (in 1M triethanolamine [TEA, also 
called trolamine]), which is equivalent to 500 mg of CPI-613.  The drug product 
of CPI-613 is a clear and colorless solution that is free of any particulate matter. 
 
Handling of CPI-613 
 
CPI-613 is an investigational drug and the toxicity in humans is not fully 
understood. All necessary precautions in handling potentially toxic chemicals 
must be strictly adhered to. Gloves and protective clothing must be worn when 
handling CPI-613.  Avoid contact by all modes of exposure.  If the solution 
contacts the skin, it must be washed immediately and thoroughly with soap and 
water.  If the solution comes in contact with mucous membranes, the membranes 
must be flushed thoroughly with water. Spills should be picked up with absorbent 
material and the area must be washed at least 3 times with ethyl alcohol followed 
by water.  
 
CPI-613 drug product is slightly photosensitive (Study# PHO-001). Therefore, 
after removal of CPI-613 drug product from the amber vials, CPI-613 drug 
product should be protected from excessive light before administration to patients. 
 
Storage of CPI-613 
 
CPI-613 should be stored under refrigeration, at 2°-8°C (36°-46°F), except when 
being prepared for administration.  
 
If CPI-613 is to be transferred from one storage area to another, or is to be 
prepared for dosing, care must be taken to maintain appropriate product 
temperature. 
 
UNDER NO CIRCUMSTANCES SHOULD CPI-613 BE FROZEN. 
  
IV Infusion Sets, Syringes and IV Bags to be Used for Administration of CPI-613 
 


CCCWFU 22215 
 
Comprehensive Cancer Center of Wake Forest University 
An Open Label Study to Evaluate the Feasibility of CPI-613 Given with High Dose Cytarabine and 
Mitoxantrone in Patients with Relapsed or Refractory Acute Myeloid Leukemia (AML) 
NCT Clinicaltrials.gov:  NCT02484391 
 
35 
Revision Date:06/04/18 
CPI-613 must be administered IV by infusion, via a central IV catheter with D5W 
running at a rate of about 125-150 mL/hr.  Subsequent sections describe the 
appropriate types of IV catheters, IV bags, syringes and clinical solutions that can 
be used in mixing and administering CPI-613 to patients.  
 
Leaching of Diethylhexyl Phthalate (DEHP):  CPI-613 can cause leaching of 
DEHP from IV infusion sets and IV bags (Study COM-003).  Therefore, 
DEHP-containing IV infusion sets, IV bags or syringes should not be used in 
mixing or administration of CPI-613.  Examples of syringes and extension set 
for syringe pump that do not contains DEHP (and therefore can be used in the 
administration of CPI-613) are: 
 
Syringes:  Kendall Monoject syringes, all mono-ject syringes are DEHP free. 
 
Extension Set for Syringe Pump Use:  All extension sets from MED-RX do not 
contains DEHP. 
 
IV Infusion Sets:  A compatibility study has been conducted showing that CPI-
613 is compatible with 4 commonly used IV infusion sets (Study# COM-001).  
Therefore, these 4 types of IV infusion sets, and IV infusion sets that are made 
with the same materials, can be used to administrate CPI-613.  These IV 
infusion sets are: 
 
PVC material - ADDitIV Primary IV Set with Universal Spike, Backcheck 
Valve, 2 Injection Sites, DEHP-Free and Latex-Free, 15 drops/mL, REF 
V14453, B Braun Medical Inc. 
Latex material - Interlink System Secondary Medication Set, 10 drops/mL, 
2C7451, Baxter Healthcare Corporation 
PVC material - SurshieldTM Safety Winged Infusion Set, 0.19 mL Volume, 
Latex-Free, DEHP-Free, SV*S25BLS, Terumo Medical Products Hangzhou 
Co. Ltd. 
Polyethylene material - Interlink System Paclitaxel Set by Baxter HealthCare, 
Non DEHP:  Polyethylene tubing with a 0.22 microfilter Item # 2C7558 10 
drops/mL 
 
Syringes:  Compatibility studies (Studies# COM-001 and COM-002) have shown 
that CPI-613 drug product (50 mg/mL), and drug product diluted with D5W to 
various concentrations (1.6-25 mg/mL) are compatible with various types of 
syringes, as listed below.  Therefore, any of these types of syringes, and 
syringes that are made with the same materials, can be used to administer CPI-
613.  Also, glass syringes can also be used, since glass (such as glass 
containers) is compatible with CPI-613 drug product. 
 


CCCWFU 22215 
 
Comprehensive Cancer Center of Wake Forest University 
An Open Label Study to Evaluate the Feasibility of CPI-613 Given with High Dose Cytarabine and 
Mitoxantrone in Patients with Relapsed or Refractory Acute Myeloid Leukemia (AML) 
NCT Clinicaltrials.gov:  NCT02484391 
 
36 
Revision Date:06/04/18 
Norm-Ject, polythelyene barrel, polyethylene plunger, latex free (Henke Sass 
Wolf GMBH) syringes 
Becton Dickinson syringes 
Terumo syringes 
Monoject syringes 
Glass syringes 
 
Reconstitution and Administration of CPI-613 
 
CPI-613 must be diluted from 50 mg/mL to 12.5 mg/mL with 5% Dextrose Water 
or D5W (i.e., 1 portion of CPI-613 diluted with 3 portions of D5W) prior to 
administration.  The diluted drug product should be visually inspected for clarity.  
If haziness or precipitate is observed, do not use the diluted drug product for 
dosing.  After dilution with sterile D5W, the solution is clear and has a pH of 8.4-
8.8. The diluted CPI-613 drug product has been found to be stable for 24 hrs at 
room temperature and refrigeration temperature (Studies STA-010).  
 
CPI-613 must be administered IV, via a central venous catheter that is free 
flowing, free of air in the dead space, and with D5W running at a rate of about 
125-150 mL/hr. This is to minimize vascular irritation, inflammation and acute 
toxicity of CPI-613 (Study NCL-049). Accidental co-administration of extra air in 
the dead space of IV catheters during administration of CPI-613 has demonstrated 
the potential to induce acute toxicity of CPI-613 according to animal studies 
(Study NCL-049). Also, accidental leakage of CPI-613 into the perivascular space 
during IV administration, which prolongs exposure of perivascular tissue to CPI-
613, can induce significant local inflammation according to animal studies 
(Studies NCL-027 and NCL-030).  
 
CPI-613 must not be administered as a bolus, but by infusion via a central venous 
catheter, over a total of 2 hours.  All doses of CPI-613 will be administered over 2 
hours to simplify PK/PD analysis. The infusion will also minimize potential acute 
toxicity of CPI-613, according to animal studies (Study NCL-049). The following 
precautions must be taken when administering CPI-613: 
 
A. Confirmation of the placement of the IV line to ensure a lack of leakage of 
CPI-613 into the perivascular space. 
B. Confirmation that the IV line is free flowing, and with D5W running at a 
rate of about 125-150 mL/hr. 
C. Confirmation that the IV line is free of dead air space. 
D. Rotate the site of administration for different doses of CPI-613. 
E. Dilute CPI-613 drug product with D5W, as instructed in the study protocol. 
F. Administer CPI-613 by infusion, not as a bolus.  


CCCWFU 22215 
 
Comprehensive Cancer Center of Wake Forest University 
An Open Label Study to Evaluate the Feasibility of CPI-613 Given with High Dose Cytarabine and 
Mitoxantrone in Patients with Relapsed or Refractory Acute Myeloid Leukemia (AML) 
NCT Clinicaltrials.gov:  NCT02484391 
 
37 
Revision Date:06/04/18 
G. After administration of CPI-613, “slowly” flush the IV line with ~10 mL of 
D5W to remove residual CPI-613. 
 
Request for CPI-613 
 
CPI-613 must be requested from Rafael by the Principal Investigator (or 
authorized designees). CPI-613 may not be used outside the scope of this 
protocol, nor can it be transferred or licensed to any party not participating in this 
clinical study. Rafael policy requires that CPI-613 be shipped directly to the 
institution where the patient is to be treated. Rafael does not permit the transfer of 
CPI-613 between institutions (unless with prior written approval from Rafael).  
Requests must be submitted to Rafael by fax or email to the following address: 
 
Department of Regulatory and Clinical Affairs 
Rafael Pharmaceuticals, Inc. 
1 Duncan Dr 
Cranbury NJ 08512 
Telephone: 631-444-6868 
Telefax: 631-794-2319 
Email: sanjeev@Rafaelpharma.com 
  
 
The following information must be provided in the request of CPI-613 from 
Rafael: 
 
- Names of the principal investigator and the requestor (if different) 
- Name of the study site 
- Name of the pharmacist responsible for receiving and storing CPI-613 
- Name of the person and address where CPI-613 is to be shipped to 
- Amount (# vials) requested 
- Date of request 
- Date shipment expected 
- Study Protocol (title and protocol#) for which the requested CPI-613 is to be 
used 
  
Procurement of Investigational Drug 
 
Relevant regulations require investigators to establish a record of the receipt, use 
and disposition of all investigational products.  Investigators may delegate 
responsibility of drug ordering, storage, accountability and preparation to their 
designees.  
 


CCCWFU 22215 
 
Comprehensive Cancer Center of Wake Forest University 
An Open Label Study to Evaluate the Feasibility of CPI-613 Given with High Dose Cytarabine and 
Mitoxantrone in Patients with Relapsed or Refractory Acute Myeloid Leukemia (AML) 
NCT Clinicaltrials.gov:  NCT02484391 
 
38 
Revision Date:06/04/18 
The investigator, or the designee, will be responsible for dispensing and 
accounting of CPI-613 provided by Rafael and for exercising accepted medical 
and pharmacy practices.  
 
Records of inventory, dispensation and disposition (vials received, source and 
dates) must be maintained. In addition, all doses dispensed should be accounted 
for by recording the date, study number and name, patient identification, patient 
initials, patient medical record number and balance forward. These records must 
be maintained and kept at the study site, and will be reviewed by Rafael, or its 
designee, during periodic monitoring visits. 
 
Disposal of CPI-613 
 
The following procedures are to be taken in disposal of CPI-613: 
 
- During the study, store the used CPI-613 vials (which must be separate from the 
unused CPI-613 vials) at room temperature in an access-limited area.  
Alternatively, destroy the used CPI-613 vials according to institutional policy 
after documentation of the number of used CPI-613 vials and remaining 
volume in each used vial. 
- At the end of the study, deface the label (both used and unused vials) with a 
permanent marking pen. 
- For used CPI-613 vials (if not already destroyed according to institutional 
policy), after documentation of the number of used CPI-613 units and 
remaining volume in each container, the used containers should be destroyed 
at the site according to the institutional procedures for destroying toxic 
chemicals.  A certificate documenting the destruction of used vials must be 
kept on file. 
- All unused CPI-613 vials must be returned to Rafael at the address shown 
below. (Note: The return of the CPI-613 to Rafael, as well as the quantity 
returned, must be documented.) 
Department of Regulatory and Clinical Affairs 
Rafael Pharmaceuticals, Inc. 
25 Health Sciences Drive 
Stony Brook, NY 11790 
Telephone: 631-444-6868 
Telefax: 631-794-2319 
Email: king@Rafaelpharma.com 
9.0 
Measurement of Effect 
9.1 
Antitumor Effect  
Although response is not the primary endpoint of this trial, patients with 
measurable disease will be assessed by standard criteria for AML (Blood. 


CCCWFU 22215 
 
Comprehensive Cancer Center of Wake Forest University 
An Open Label Study to Evaluate the Feasibility of CPI-613 Given with High Dose Cytarabine and 
Mitoxantrone in Patients with Relapsed or Refractory Acute Myeloid Leukemia (AML) 
NCT Clinicaltrials.gov:  NCT02484391 
 
39 
Revision Date:06/04/18 
2010;115:453-474). Peripheral blood (PB) cell counts and samples of bone 
marrow aspirates will be assessed for changes in disease status. Hematologic 
improvement (HI) requires improvement in one of the three hematopoietic 
lineages compared with baseline measurements, and stable disease (SD) requires 
the absence of objective disease progression for at least 2 months. Relevant 
responses have to be confirmed by a repeat measurement at least 1 wk later. 
Assessments will be done as described above.  
9.1.1 Definitions  
Evaluable for toxicity.  All patients will be evaluable for toxicity from the 
time of their first treatment with CPI-613. 
Evaluable for objective response.  Only those patients who have 
measurable disease present at baseline, have received at least one cycle of 
therapy, and have had their disease re-evaluated will be considered 
evaluable for response.  These patients will have their response classified 
according to the definitions stated above.  (Note:  Patients who exhibit 
objective disease progression prior to the end of cycle 1 will also be 
considered evaluable.) 
Overall Survival (OS): Time from enrollment on trial to death from any 
cause. 
 
10.0 Statistical Considerations 
 
This is a pilot trial investigating three doses of CPI-613 (500, 1500, and 2,000 
mg/m2. We plan to accrue between 10 and 15 patients per year for a total of 67 
patients (20 at 500, 1,500 mg/m2  and 3 additional patients  at 2,000 mg/m2 ). Of 
note 17 patients at 2,000 mg/m2 and 7 patients at 2,500 mg/m2 were already 
accrued.  
  
Analysis Plan: 
 
The primary objective of determining the feasibility of administering CPI-613 
in combination with high dose cytarabine and mitoxantrone during induction, 
consolidation and maintenance therapies will be completed by determining the 
percentage of patients eligible for maintenance therapy who complete at least 3 
cycles. If ≥50% of eligible patients complete 3 cycles of maintenance therapy we 
will consider this regimen feasible for future study. Given an estimated response 
rate of 50% and a 25% attrition to stem cell transplant, if we enroll 60 patients we 
should be able to assess feasibility of maintenance in approximately 22 patients. 
With 22 evaluable patients, a two-sided 95.0% confidence interval using the large 
sample normal approximation will extend 22% in either direction from the 
observed value when the expected value is 50%.  Within a dose we should be able 
to estimate feasibility in 7 patients with a 95% confidence interval extending 36% 
in either direction.     


CCCWFU 22215 
 
Comprehensive Cancer Center of Wake Forest University 
An Open Label Study to Evaluate the Feasibility of CPI-613 Given with High Dose Cytarabine and 
Mitoxantrone in Patients with Relapsed or Refractory Acute Myeloid Leukemia (AML) 
NCT Clinicaltrials.gov:  NCT02484391 
 
40 
Revision Date:06/04/18 
 
Participants will also be followed and analyzed for secondary outcomes of 
response rate and overall survival both overall and by dose.  Participants will be 
monitored for survival through routine follow-up visits.  Confidence intervals will 
be calculated around the estimates of the response rate (CR and CRi).  Assuming 
a response rate of 0.5, with 60 participants, we would be able to create 95 percent 
confidence intervals with a 0.13 margin of error (0.37, 0.63).  We will use 
Kaplan-Meier estimation to analyze overall survival.  The frequency of toxicities 
experienced by the participants will be presented by type and grade in an effort to 
monitor and report safety of the treatment.  
 
In exploratory analysis we plan to compare both complete response and early 
mortality (death within 60 days of beginning of treatment) to the observed rates in 
a historical cohort of subjects (CCCWFU 22111), both overall and by dose.  In 
the historical cohort the response rate was estimated to be 41%.  Using a one-
sided chi-square test, a 0.05 significance level, null hypothesis of 41%, and 
assuming 70% power, we would be able to show significant improvement in 
response if we are able to achieve a response rate of 56% or higher.  Early 
mortality in the historical cohort was estimated to be 29% at 60 days.  We will use 
a one-sided exact test for a single proportion, a 0.05 significance level, a null 
hypothesis of 29%, and 70% power.  To show a significant decrease in early 
mortality in this study we would need to observe a 60 day mortality rate of 16.8% 
or lower.  
 


CCCWFU 22215 
 
Comprehensive Cancer Center of Wake Forest University 
An Open Label Study to Evaluate the Feasibility of CPI-613 Given with High Dose Cytarabine and 
Mitoxantrone in Patients with Relapsed or Refractory Acute Myeloid Leukemia (AML) 
NCT Clinicaltrials.gov:  NCT02484391 
 
41 
Revision Date:06/04/18 
References 
 
Baggetto LG. 1992. Deviant energetic metabolism of glycolytic cancer cells. Biochimie 74:959-
974. 
 
DeGeorge JJ, Ahn C-H, et. al. 1998. Regulatory considerations for preclinical development of 
anticancer drugs. Cancer Chemother. Pharmacol. 41:173-185. 
 
Lutes RA. 2006. A Dose-Escalation Study of CPI-613 in a Single Patient with Metastatic Breast 
Cancer - Treatment Summary. 
 
Lutes RA. 2008. A Dose-Escalation Study of CPI-613 in a Single Patient with Metastatic Breast 
Cancer - Treatment Summary. 
 
Therasse P, Arbuck S, Eisenhauer EA, et al. 2000. New guidelines to evaluate the response to 
treatment in solid tumours. J Natl Cancer Inst 92:205–216. 
 
Strevel EL, Ing DJ, Siu LL. 2007. Molecularly targeted oncology therapeutics and prolongation 
of the QT interval. J Clin Oncoly 25:3362–3371. 
 
Study COM-001. 2006. Compatibility Testing of CPI-613 Drug Product - Infusion Sets. 
 
Study COM-002. Bhasin R. 2008. Compatibility Testing of CPI-613 Drug Product Dosing 
Solutions with Different Types of Syringes. 
 
Study COM-003.  Gupta D.  2009.  Investigation of the Release Behavior of Diethylhexyl 
Phthalate (DEHP) from the Polyvinyl-Chloride Containing Infusion Sets and Bags for 
Intravenous Administration by CPI-613 Drug Product. 
 
Study CL-CPI613-002.  Ongoing.  An Open Label, Dose-Escalation Study to Evaluate Safety, 
Tolerability, Maximum Tolerated Dose (MTD), Efficacy, and Pharmacokinetics (PKs) of 
CPI-613 Given Twice Weekly for Three Consecutive Weeks in Cancer Patients. 
 
Study NCL-027. Seng J. 2006. Escalating Dose Toxicology Study of Intravenously Administered 
CPI-613 to Miniature Pigs. 
 
Study NCL-030. Seng J. 2006. An Acute Toxicity Study of CPI-613 Administered Via the 
intravenous (Slow Bolus) Route to Mice. 
 
Study NCL-044. Seng J. 2007. A 21-Day Toxicokinetic Study of CPI-613 Administered Twice 
Weekly via the Intravenous Route to Sprague-Dawley Rats with a 14-Day Recovery Period. 
 


CCCWFU 22215 
 
Comprehensive Cancer Center of Wake Forest University 
An Open Label Study to Evaluate the Feasibility of CPI-613 Given with High Dose Cytarabine and 
Mitoxantrone in Patients with Relapsed or Refractory Acute Myeloid Leukemia (AML) 
NCT Clinicaltrials.gov:  NCT02484391 
 
42 
Revision Date:06/04/18 
Study NCL-045. Seng J. 2008. Evalutation of the Toxicity Potential of CPI-613, Given Twice 
Weekly for 3 Weeks by Intravenous Administration, in Hanford Minipigs with a 14-Day 
Recovery Period. 
 
Study NCL-049. Moore C, Karnik S, Lee K. 2007. Preliminary Studies of Comparative Toxicity 
of CPI-613 Administered Intravenously (IV) as Bolus Vs. Infusion, Effects of Air in Dead 
Space of Butterfly IV Infusion Set on Toxicity of CPI-613, and Acute Effects of CPI-613 on 
Clinical Chemistry in Rats. 
 
Study PHO-001 (Covance Study# 7769-101). Potts B. 2007. Photostability Testing of CPI-613 
Drug Product. 
 
Study STA-004. (CR Study# LRH00017SX). McFarlene J. 2006. Long Term Matrix Stability 
Assessment of CPI-613 in K2 EDTA and K3 EDTA Human Plasma. 
 
Study STA-010. Bhasin R. 2007. Stability of CPI-613 Injection dosing solutions after Dilution 
with 5% Dextrose (D5W). 
 
Study VLD-002 (CR Study# LRH00016LX). McFarlene J. 2006. Validation of a High 
Performance Liquid Chromatographic-Mass Spectrometric Method for the Analysis of CPI-
613 in K3 and K2 EDTA Human Plasma. 
 
Yamada J, Tomiyama H, et. al. 2006. Elevated serum levels of alanine aminotransferase and 
gamma glutamyltransferase are markers of inflammation and oxidative stress independent of 
the metabolic syndrome. Atherosclerosis. 189(1):198-205. 


CCCWFU 22215 
 
Comprehensive Cancer Center of Wake Forest University 
An Open Label Study to Evaluate the Feasibility of CPI-613 Given with High Dose Cytarabine and 
Mitoxantrone in Patients with Relapsed or Refractory Acute Myeloid Leukemia (AML) 
NCT Clinicaltrials.gov:  NCT02484391 
 
43 
Revision Date:06/04/18 
APPENDIX A – REGISTRATION GUIDELINES 
 
The following guidelines have been developed in order to ensure timely registration of your 
patient. 
 
All patients entered on any CCCWFU trial, whether treatment, companion, or cancer control 
trial, must be linked to the study in EPIC within 24 hours of Informed Consent .  Patients must 
be registered prior to the initiation of treatment.   
 
In order to ensure prompt registration of your patient, please: 
5. Complete the Eligibility Checklist (attached) 
6. Complete the Protocol Registration Form (attached) 
7. Alert the WFUHS registrar by phone, and then send the signed Informed Consent Form, 
Eligibility Checklist and Protocol Registration Form to the registrar, either by fax or 
 e-mail. 
 
Contact Information: 
Protocol Registrar PHONE (336) 713-6767 
Protocol Registrar FAX (336) 713-6772 
Protocol Registrar E-MAIL (registra@wakehealth.edu) 
              *Protocol Registration is open from 8:30 AM - 4:00 PM, Monday-Friday. 
8. Please fax/e-mail ALL eligibility source documents with registration.  Patients will not 
be registered without all required supporting documents. 
Note:  If labs were performed at an outside institution, please provide a printout of the 
results.  Please ensure that the most recent lab values are sent. 
 
 


CCCWFU 22215 
 
Comprehensive Cancer Center of Wake Forest University 
An Open Label Study to Evaluate the Feasibility of CPI-613 Given with High Dose Cytarabine and 
Mitoxantrone in Patients with Relapsed or Refractory Acute Myeloid Leukemia (AML) 
NCT Clinicaltrials.gov:  NCT02484391 
 
44 
Revision Date:06/04/18 
CCCWFU # 22215  Eligibility Checklist                                                                         Page 1                            
Yes No N/A Inclusion Criteria (All responses must be YES in order to enter study) 
Eligibility 
Confirmation 
(registrar) 
 
 
 
Patients must have histologically or cytologically documented relapsed and/or 
refractory Acute Myeloid Leukemia or granulocytic sarcoma.  
 
 
 
 
 
ECOG Performance Status of ≤3.    ________________ 
 
 
 
 
Must be ≥18 years of age.                                       ________________ 
 
 
 
 
Expected survival >3 months. 
 
 
 
 
Women of child-bearing potential (i.e., women who are pre-menopausal or not 
surgically sterile) must use accepted contraceptive methods (abstinence, intrauterine 
device [IUD], oral contraceptive or double barrier device), and must have a negative 
serum or urine pregnancy test within 1 week prior to treatment initiation.  
                          Pregnancy Test:  Positive or Negative 
 
 
 
 
Fertile men must practice effective contraceptive methods during the study period, 
unless documentation of infertility exists. 
 
 
 
 
Mentally competent, ability to understand and willingness to sign the informed 
consent form. 
 
 
 
 
No radiotherapy, treatment with cytotoxic agents (except CPI-613), treatment with 
biologic agents or any anti-cancer therapy within the 2 weeks prior to treatment with 
CPI-613.  Hydroxyurea and oral tyrosine kinase inhibitors being used without Grade 
≤ 2 toxicity can be taken until day 1 of therapy. Patients must have fully recovered 
from the acute, non-hematological, non-infectious toxicities of any prior treatment 
with cytotoxic drugs, radiotherapy or other anti-cancer modalities (returned to 
baseline status as noted before most recent treatment).  Patients with persisting, non-
hematologic, non-infectious toxicities from prior treatment ≤ Grade 2 are eligible, 
but must be documented as such 
 
 
 
 
Laboratory values ≤2 weeks must be: 
 
 
 
 
 Adequate hepatic function (aspartate aminotransferase [AST/SGOT] ≤3x upper 
normal limit [UNL]                            _______________ 
 
 
 
 
 alanine aminotransferase [ALT/SGPT] ≤3x UNL (≤5x ULN if liver metastases 
present)                                                   ________________ 
 
 
 
 
 bilirubin ≤1.5x UNL                                   ________________ 
 
 
 
 
 Adequate renal function (serum creatinine ≤1.5 mg/dL or 133 μmol/L).    
                                                                ________________                                   
 
 
 
 
 Left Ventricular Ejection Fraction (by TTE, MUGA or cardiac MRI) sufficient to 
safely administer mitoxantrone as determined by the treating physician 
 
Yes No N/A Exclusion Criteria (All responses must be NO in order to enter study) 
 
 
 
 
Serious medical illness, such as significant cardiac disease (e.g. symptomatic 
congestive heart failure, unstable angina pectoris, myocardial infarction within the 
past 6 months, uncontrolled cardiac arrhythmia, pericardial disease or New York 
Heart Association Class III or IV), or severe debilitating pulmonary disease, that 
would potentially increase patients’ risk for toxicity 
 
 
 
 
Patients with active central nervous system (CNS) or epidural tumor 
 
 
 
 
Any active uncontrolled bleeding, and any patients with a bleeding diathesis (e.g., 
active peptic ulcer disease) 
 


CCCWFU 22215 
 
Comprehensive Cancer Center of Wake Forest University 
An Open Label Study to Evaluate the Feasibility of CPI-613 Given with High Dose Cytarabine and 
Mitoxantrone in Patients with Relapsed or Refractory Acute Myeloid Leukemia (AML) 
NCT Clinicaltrials.gov:  NCT02484391 
 
45 
Revision Date:06/04/18 
 
 
 
Pregnant women, or women of child-bearing potential not using reliable means of 
contraception (because the teratogenic potential of CPI-613 is unknown) 
 
 
 
 
Lactating females because the potential of excretion of CPI-613 into breast milk 
 
 
 
 
Fertile men unwilling to practice contraceptive methods during the study period 
 
 
 
 
Life expectancy less than 3 months 
 
 
 
 
Any condition or abnormality which may, in the opinion of the investigator, 
compromise the safety of patients 
 
 
 
 
Unwilling or unable to follow protocol requirements 
 
 
 
 
Patients with large and recurrent pleural or peritoneal effusions requiring frequent 
drainage (e.g. weekly).  Patients with any amount of clinically significant pericardial 
effusion 
 
 
 
 
Active heart disease symptomatic coronary artery disease, uncontrolled arrhythmias, 
or symptomatic congestive heart failure 
 
 
 
 
Albumin <2.0 g/dL or <20 g/L.                               ________________ 
 
 
 
 
Evidence of ongoing, uncontrolled infection. 
 
 
 
 
Patients with known HIV infection 
 
 
 
 
Patients receiving any other standard or investigational treatment for their cancer, or 
any other investigational agent for any indication within the past 2 weeks prior to 
initiation of CPI-613 treatment (the use of Hydrea is allowed) 
 
 
 
 
Patients who have received immunotherapy of any type within the past 4 weeks 
prior to initiation of CPI-613 treatment 
 
 
 
 
Requirement for immediate palliative treatment of any kind including surgery 
 
 
 
 
Patients that have received a chemotherapy regimen with stem cell support in the 
previous 6 months 
 
 
This subject is      
 eligible /  ineligible     for participation in this study. 
 
ORIS Assigned PID: __________________  
 
 
 
 
 
 
 
 
Signature of research professional confirming eligibility: __________________ Date: ________ 
 
 
Signature of Treating Physician:  ____________________________________ Date:  ________ 
 
 
Signature of Principal Investigator**:  ________________________________ Date:  ________ 
 
 
* Examples of source documents include clinic note, pathology report, laboratory results, etc. When listing 
the source, specifically state which document in the medical record was used to assess eligibility. Also 
include the date on the document. Example: “Pathology report, 01/01/14” or “Clinic note, 01/01/14” 
 
**Principal Investigator signature can be obtained following registration if needed 
 
 


CCCWFU 22215 
 
Comprehensive Cancer Center of Wake Forest University 
An Open Label Study to Evaluate the Feasibility of CPI-613 Given with High Dose Cytarabine and 
Mitoxantrone in Patients with Relapsed or Refractory Acute Myeloid Leukemia (AML) 
NCT Clinicaltrials.gov:  NCT02484391 
 
46 
Revision Date:06/04/18 
CCCWFU # 22215        Protocol Registration Form                                              Page 2 
DEMOGRAPHICS 
Patient: Last Name: _____________________ 
First Name: ____________________________ 
MRN:          ___ ___ ___ ___ ___ ___ ___ ___ 
DOB (mm/dd/yy): ___ ___ / ___ ___ / ___ ___ 
SEX:   
  Male            
  Female 
Ethnicity (choose one):   Hispanic 
Non-Hispanic 
Race (choose all that 
apply): 
 WHITE           BLACK            ASIAN 
 PACIFIC ISLANDER                 NATIVE AMERICAN 
Height:   ___ ___.___ inches 
Weight: ___ ___ ___.___lbs.(actual) 
Surface Area: ___ ___.___m2   
Zip Code: ____________(required if no MRN) 
Primary Diagnosis: _____________________________________________________________ 
Date of Diagnosis: ___ ___ /___ ___/___ ___ 
 
Dose assignment:  500mg/m2/day            1,500mg/m2/day (2,500mg/m2/day maintenance)            
The following are required prior to registration: 
CURRENT DISEASE STATUS AT REGISTRATION: _____________________________________________ 
(1ST relapse, 2nd relapse, 3rd relapse, refractory etc., including allo or auto bone marrow transplant) 
 
Prior Therapies/ 
 
Start / End Date of 
Best Response 
Date of  
 
Date of  
 
Duration of  
Protocol # if applicable 
Prior Therapy 
(CR, PR,  
Best Response 
Relapse 
 
Best Response 
 
 
 
 
 
Treatment Failure) 
 
 
 
 
(in Months) 
 
#1 ___________________ 
_______/________ 
_______________ 
_____________ 
______________ 
________________ 
 
#2 ___________________ 
_______/________ 
_______________ 
_____________ 
______________ 
________________ 
 
#3 ___________________ 
_______/________ 
_______________ 
_____________ 
______________ 
________________ 
 
#4 ___________________ 
_______/________ 
_______________ 
_____________ 
______________ 
________________ 
 
COMMENT:___________________________________________________________________ 
______________________________________________________________________________ 
______________________________________________________________________________ 
______________________________________________________________________________ 
 
 
Protocol Registrar can be contact by calling 336-713-6767 between 8:30 AM and 4:00 PM, 
Monday – Friday. 
PROTOCOL INFORMATION 
Date of Registration: 
___ ___ / ___ ___ / ___ ___ 
MD Name (last) : 
______________________       
Date protocol treatment starts: 
___ ___ / ___ ___ / ___ ___ 
Informed written consent: 
(consent must be signed prior to registration) 
 YES 
  NO 
 
Date Consent Signed: 
___ ___ / ___ ___ / ___ ___ 
 
PID # (to be assigned by ORIS): 
___ ___ ___ ___ ___ ___ ___ ___ 
 


CCCWFU 22215 
 
Comprehensive Cancer Center of Wake Forest University 
An Open Label Study to Evaluate the Feasibility of CPI-613 Given with High Dose Cytarabine and 
Mitoxantrone in Patients with Relapsed or Refractory Acute Myeloid Leukemia (AML) 
NCT Clinicaltrials.gov:  NCT02484391 
 
47 
Revision Date:06/04/18 
Completed Eligibility Checklist and Protocol Registration Form must be hand delivered, faxed 
or e-mailed to the registrar at 336-7136772 or registra@wakehealth.edu 
CCCWFU # 22215 Eligibility Source Documentation Checklist                   Page 3 
(to be submitted with Protocol Registration Form) 
 
Source Documents Needed 
 or 
N/A 
1 
Pathology report confirming patient has relapsed and/or refractory Acute Myeloid Leukemia 
 
2 
Documentation of ECOG Performance Status of ≤3. 
 
3 
Most recent H&P documenting patient is ≥18 years of age 
 
4 
Documentation of expected survival >3 months 
 
5 
Documentation that WOCBP agree to use accepted contraceptive methods 
 
6 
Negative serum or urine pregnancy test within 1 week prior to treatment initiation 
 
7 
Documentation that fertile men agree to practice effective contraceptive methods during the study 
period 
 
8 
Copies of all informed consent documents 
 
9 
Documentation of No radiotherapy, treatment with cytotoxic agents (except CPI-613), treatment with 
biologic agents or any anti-cancer therapy within the 2 weeks prior to treatment with CPI-613.  
Patients must have fully recovered from the acute, non-hematological, non-infectious toxicities of 
any prior treatment with cytotoxic drugs, radiotherapy or other anti-cancer modalities (returned to 
baseline status as noted before most recent treatment).  Patients with persisting, non-hematologic, 
non-infectious toxicities from prior treatment ≤ Grade 2 are eligible, but must be documented as 
such. 
 
10 
Lab report documenting all initial required lab values 
 
11 
Documentation that patient has no serious medical illness, such as significant cardiac disease (e.g. 
symptomatic congestive heart failure, unstable angina pectoris, myocardial infarction within the past 
6 months, uncontrolled cardiac arrhythmia, pericardial disease or New York Heart Association Class 
III or IV), or severe debilitating pulmonary disease, that would potentially increase patients’ risk for 
toxicity 
 
12 
Documentation that patient does not have an active central nervous system (CNS) or epidural tumor 
 
13 
Documentation that patient does not have any active uncontrolled bleeding, and any patients with a 
bleeding diathesis (e.g., active peptic ulcer disease). 
 
14 
Documentation that patient is not pregnant, lactating or a WOCBP not using reliable means of 
contraception 
 
15 
Documentation that patient is not a fertile man unwilling to practice contraceptive methods during the 
study period 
 
16 
Documentation that patient does not have a life expectancy less than 3 months. 
 
17 
Documentation that patient does not have any condition or abnormality which may, in the opinion of 
the investigator, compromise the safety of patients. 
 
18 
Documentation that patient is not unwilling or unable to follow protocol requirements. 
 
19 
Documentation that patient does not have large and recurrent pleural or peritoneal effusions requiring 
frequent drainage (e.g. weekly).  Patients with any amount of clinically significant pericardial 
effusion. 
 
20 
Documentation that patient does not have active heart disease including myocardial infarction within 
previous 6 months, symptomatic coronary artery disease, uncontrolled arrhythmias, or symptomatic 
congestive heart failure. 
 
21 
Lab report showing Albumin ≥2.0 g/dL or ≥20 g/L. 
 


CCCWFU 22215 
 
Comprehensive Cancer Center of Wake Forest University 
An Open Label Study to Evaluate the Feasibility of CPI-613 Given with High Dose Cytarabine and 
Mitoxantrone in Patients with Relapsed or Refractory Acute Myeloid Leukemia (AML) 
NCT Clinicaltrials.gov:  NCT02484391 
 
48 
Revision Date:06/04/18 
22 
Documentation that patients do not have evidence of ongoing, uncontrolled infection. 
 
23 
Documentation that patients do not have known HIV infection.  
 
24 
Documentation that patient is not receiving any other standard or investigational treatment for their 
cancer, or any other investigational agent for any indication within the past 2 weeks prior to initiation 
of CPI-613 treatment (the use of Hydrea is allowed). 
 
25 
Documentation that patient has not received immunotherapy of any type within the past 4 weeks 
prior to initiation of CPI-613 treatment. 
 
26 
Documentation that patient does not Require immediate palliative treatment of any kind including 
surgery. 
 
27 
Documentation that patient has not received a chemotherapy regimen with stem cell support in the 
previous 6 months. 
 
28 
Documentation that patient does not have A history of additional risk factors for torsade de pointes 
(e.g., clinically significant heart failure, hypokalemia, family history of Long QT Syndrome). 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


CCCWFU 22215 
 
Comprehensive Cancer Center of Wake Forest University 
An Open Label Study to Evaluate the Feasibility of CPI-613 Given with High Dose Cytarabine and 
Mitoxantrone in Patients with Relapsed or Refractory Acute Myeloid Leukemia (AML) 
NCT Clinicaltrials.gov:  NCT02484391 
 
49 
Revision Date:06/04/18 
APPENDIX B – Safety and Toxicity Review Committee SAE Reporting 
Guidelines 
 
 
Safety and Toxicity Review Committee 
(STRC; previously known as CROC)  Serious 
Adverse Event (SAE) Notification SOP 
     Date: 11/17/2016 
 
 
Mandatory STRC SAE Reporting Requirements  
 
This document describes STRC reporting and use of the electronic submission form that is 
submitted for unexpected grade 4 and any grade 5 (death during protocol intervention) SAEs 
on CCCWFU Institutional interventional trial patients. There are multiple entities that require 
reporting of SAEs. Each entity has different rules for what is reported, and how it is reported.  
 
Rules used by other entities (Institutional Review Board (IRB), AdEERS, MedWatch, etc.) should 
NOT be used to evaluate whether an event should be reported to STRC. Only the rules for 
reporting described in this document should be considered. 
 
As defined in the NCI Data Table 4 reporting guidelines, CCCWFU Institutional Interventional 
studies covered by these reporting requirements are defined as: In-house, internally reviewed 
trials, including those collaborative studies conducted with industry sponsorship in which the 
center is a primary contributor to the design, implementation, and monitoring of the trial, or 
participation in a multi-site trial initiated by an institutional investigator at another center.  
Institutional trials are almost always authored by a researcher here at CCCWFU. Institutional 
protocols are labeled NCI Code=”I” for Institutional on the protocol screen in ORIS. Cooperative 
group protocols are not considered Institutional, but Research Base trials are classified as 
Institutional. 
 
The STRC is responsible for reviewing SAEs for CCCWFU Institutional Interventional studies, as 
defined above. STRC currently requires that unexpected grade 4 and all grade 5 SAEs on these 
trials be reported to the STRC for review. All Clinical Protocol and Data Management (CPDM) 
staff members assisting a PI in documenting and reporting an SAE that qualifies for STRC 
reporting are responsible for informing a clinical member of the STRC by phone (or in-person), 
followed by informing the entire committee via the required email notification. 
 
THESE REPORTING REQUIREMENTS APPLY TO any faculty or staff member on the study team 
for a CCCWFU Institutional Interventional trial. Once an event is observed, it is the 
responsibility of the person who observed the event to be sure that it is reported. 
 
What is considered an SAE under this mandatory procedure? 


CCCWFU 22215 
 
Comprehensive Cancer Center of Wake Forest University 
An Open Label Study to Evaluate the Feasibility of CPI-613 Given with High Dose Cytarabine and 
Mitoxantrone in Patients with Relapsed or Refractory Acute Myeloid Leukemia (AML) 
NCT Clinicaltrials.gov:  NCT02484391 
 
50 
Revision Date:06/04/18 
Any unexpected grade 4 event and all grade 5 events (death during protocol intervention) 
should be reported. These events should be reported if they occur while a patient is on study 
treatment or if they occur within 30 days of last study treatment (even if patient begins a new 
treatment during the 30 days). This window of 30 days should be the standard window to be 
used in all protocols unless a specific scientific rationale is presented to suggest that a shorter 
window can be used to identify events.  In addition, if it is not clear whether the Grade 4 is 
unexpected it should be reported. 
Table 1: Summary of STRC Reporting Requirements for Institutional Pilot, Phase 1, Phase 2  
and Phase 3 Interventional Trials  
STRC reporting may not be appropriate for specific expected adverse events for protocols. In 
those situations the adverse events that will not require STRC reporting must be specified in 
the text of the approved protocol. 
 
STRC notification responsibilities of the person handling the reporting/documenting of the 
SAE: 
1. Make a phone call (or speak in person) to the appropriate clinical member of the STRC as 
listed below (page if necessary)—see note 2 below 
2. Submit the STRC Notification Form WITHIN 24 HOURS of first knowledge of the event. This 
form is found at either the ORIS main menu page or by going to 
http://ccc.wfubmc.edu/oris/strc.aspx. 
This will ensure that all persons that need to be made aware of the event (i.e., study team 
members and STRC members) will be notified; remember to file a copy of your 
confirmation. (Form instructions will walk you through the required fields, consult the help 
page for further instructions.) 
 
ADVERSE EVENT 
Grade 1, Grade 2, Grade 
3 
Grade 4 
Grade 5 
Unexpected Expected 
Unexpected 
Expected 
Unexpected 
Expected 
Unrelated Not 
Required 
Not 
Required 
REPORT TO 
STRC 
Not 
Required 
REPORT TO 
STRC 
REPORT TO 
STRC 
Unlikely 
Not 
Required 
Not 
Required 
REPORT TO 
STRC 
Not 
Required 
REPORT TO 
STRC 
REPORT TO 
STRC 
Possible 
Not 
Required 
Not 
Required 
REPORT TO 
STRC 
Not 
Required 
REPORT TO 
STRC 
REPORT TO 
STRC 
Probable 
Not 
Required 
Not 
Required 
REPORT TO 
STRC 
Not 
Required 
REPORT TO 
STRC 
REPORT TO 
STRC 
Definite 
Not 
Required 
Not 
Required 
REPORT TO 
STRC 
Not 
Required 
REPORT TO 
STRC 
REPORT TO 
STRC 


CCCWFU 22215 
 
Comprehensive Cancer Center of Wake Forest University 
An Open Label Study to Evaluate the Feasibility of CPI-613 Given with High Dose Cytarabine and 
Mitoxantrone in Patients with Relapsed or Refractory Acute Myeloid Leukemia (AML) 
NCT Clinicaltrials.gov:  NCT02484391 
 
51 
Revision Date:06/04/18 
3. Ensure that you document that the appropriate person(s) on the STRC has been contacted.  
This documentation is placed on the STRC Notification form described above. 
4. Follow up with/update the clinical member(s) of STRC regarding any new developments or 
information obtained during the course of the SAE investigation and reporting process. 
 
Elements to complete the electronic STRC form: 
Please use ‘reply to All’ when responding with one of these terms:  Definite, Probable, 
Possible, Unlikely, or Unrelated 
1. Patient ID (ORIS PID) 
2. Patient Name 
3. Patient MR# 
4. CCCWFU(ORIS) Study Number 
5. Title 
6. PI Name 
7. PI Contact Number 
8. PI Comments 
9. STRC Clinician notified by Phone 
10. Notified Date 
11. Notified Time 
12. STRC Clinician Comments 
13. Category [This is the Grade – Either Unexpected Grade 4 or Grade 5 should be entered] 
14. Additional Information (IRB Reporting)(after discussion with PI or STRC Clinician 
i. Is This Event Related to Protocol Treatment? 
ii. Is Suspension of the Protocol Needed? 
iii. Any Changes to Consent or Protocol Needed? 
iv. Was Nature or Severity of Event Unexpected? 
15. Date of the event.  
16. Brief description (include brief clinical history relevant to this event, including therapies 
believed related to event).  
17. Date of Last Dose before event 
18. Relevant tests/labs.  
19. Other Relevant Treatment Information 
20. Other Comments/Notes (include regimen of chemo and dates the patient received them 
if known). 
21. Cc (email) (include treating Physician; separate email list with comma”,”) 
22. Your Name 
23. Your Email 
24. Confirm Your Email 
 
The Clinical Members of STRC to Notify by Phone or Page: 
Bayard Powell, MD – Director-at-Large, CCCWFU; Section Head, Hematology/Oncology  


CCCWFU 22215 
 
Comprehensive Cancer Center of Wake Forest University 
An Open Label Study to Evaluate the Feasibility of CPI-613 Given with High Dose Cytarabine and 
Mitoxantrone in Patients with Relapsed or Refractory Acute Myeloid Leukemia (AML) 
NCT Clinicaltrials.gov:  NCT02484391 
 
52 
Revision Date:06/04/18 
6-7970 / 6-2701 / Pager 336-806-9308 
Glenn Lesser, MD – Hematology Oncology 6-9527 / 6-7972 / Pager 336-806-8397 
Stefan Grant, MD, JD-Hematology Oncology 3-5172/ 6-5772 Pager 336-806-6453 
Jimmy Ruiz, MD-Hematology Oncology 6-0230/ Pager 336-806-9710 
Kathryn Greven, MD – Vice Chair – Radiation Oncology 
3-3600 / 3-6505 / Pager 336-806-8314 
Marissa Howard-McNatt, MD – General Surgery 6-0545 / Pager 336-806-6438 
Mercedes Porosnicu, MD- Hematology Oncology 6-7980 / 6-0230 / Pager 336-806-9150 
Definition of Unavailable:  
As a general guideline if the first clinician that is contacted does not respond to the phone call 
or page within a reasonable amount of time, then initiate contact with their backup.  Give the 
back-up a reasonable amount of time to respond to a phone call or page before contacting 
another member. This is a general guideline.  You must use your best judgment as a clinical 
research professional given the time of day, severity of the SAE, and other circumstances as to 
when it is appropriate to contact backup clinicians.  If the event occurs near the end of day, 
then leave messages (voice or email) as appropriate and proceed with submitting your STRC 
notification form.  The important criteria is that you have taken reasonable steps to notify and 
document that you have initiated some type of contact to one or more of the clinical members 
of STRC. 
 
STRC CLINICAN RESPONSIBILITY: 
It is the responsibility of the STRC clinician to review all reported events, evaluate the events as 
they are reported; and communicate a response to the Investigator, event reporter and the 
members of STRC. The review will include but not be limited to the information reported; there 
may be times when additional information is needed in order for an assessment to be made 
and further communication directly with the investigator may be warranted. STRC reserves the 
right to agree with the investigator’s assessment if STRC does not agree with the investigator. 
STRC reserves the right to suspend the trial pending further investigation. 
Is there any immediate danger or harm that could be present for a future patient based on the 
information provided in the STRC report – and if so an immediate suspension of enrollment 
should take place. 
 
AMENDMENTS TO PREVIOUS REPORTS 
If you are not able to supply all pertinent information with the initial submission, once the 
additional information is available do not submit a new report. Go to the original email that 
was received by STRC and others “reply to all” and entitle your email “Amendment for (list date 
of event and patient ID) this will avoid duplications of the same event. List the additional 
information which you are reporting. 
 
Acronyms and Definitions 
STRC-Safety and Toxicity Review Committee 


CCCWFU 22215 
 
Comprehensive Cancer Center of Wake Forest University 
An Open Label Study to Evaluate the Feasibility of CPI-613 Given with High Dose Cytarabine and 
Mitoxantrone in Patients with Relapsed or Refractory Acute Myeloid Leukemia (AML) 
NCT Clinicaltrials.gov:  NCT02484391 
 
53 
Revision Date:06/04/18 
SAE-Serious Adverse Event 
IRB-Institutional Review Board 
CCCWFU-Comprehensive Cancer Center Wake Forest University 
ORIS-Oncology Research Information System 
NCI-National Cancer Institute 
CPDM-Clinical Protocol and Data Management 
Interventional Trials-Therapeutic Level 1 and Level 2 trials 
Therapeutic Level 1-A cancer treatment protocol aimed at directly treating/curing the patient’s 
cancer. 
Therapeutic Level 2-A therapeutic protocol not cancer treatment involves clinical activity to 
treat symptoms, improve the patient’s quality of life, or prevent cancer. 
 
 


CCCWFU 22215 
 
Comprehensive Cancer Center of Wake Forest University 
An Open Label Study to Evaluate the Feasibility of CPI-613 Given with High Dose Cytarabine and 
Mitoxantrone in Patients with Relapsed or Refractory Acute Myeloid Leukemia (AML) 
NCT Clinicaltrials.gov:  NCT02484391 
 
54 
Revision Date:06/04/18 
APPENDIX C- Response Criteria: 
 
 
 
Blood. 2010;115:453-474 
 
 
Include hematologic response criteria listed below 
 
 
 


CCCWFU 22215 
 
Comprehensive Cancer Center of Wake Forest University 
An Open Label Study to Evaluate the Feasibility of CPI-613 Given with High Dose Cytarabine and 
Mitoxantrone in Patients with Relapsed or Refractory Acute Myeloid Leukemia (AML) 
NCT Clinicaltrials.gov:  NCT02484391 
 
55 
Revision Date:06/04/18 
APPENDIX D – CCCWFU 22215 Pre-Study Data Collection Form 
 
 
ORIS PID: ______________________    DATE COMPLETED: (mm/dd/yy): ___ ___ / ___ ___ / ___ ___ 
 
 
The following are required prior to registration: 
CURRENT DISEASE STATUS AT REGISTRATION: _____________________________________________ 
(1ST relapse, 2nd relapse, 3rd relapse, refractory etc., including allo or auto bone marrow transplant) 
 
Prior Therapies/ 
 
Start / End Date of 
Best Response 
Date of  
 
Date of  
 
Duration of  
Protocol # if applicable 
Prior Therapy 
(CR, Cri, PR, 
Best Response 
Relapse 
 
Best Response 
 
 
 
 
 
Morph Leukemia-Free, 
 
 
 
(in Months) 
CRc, CRm, Treat Fail) 
 
 
 
 
 
#1 ___________________ 
_______/________ 
_______________ 
_____________ 
______________ 
________________ 
 
#2 ___________________ 
_______/________ 
_______________ 
_____________ 
______________ 
________________ 
 
#3 ___________________ 
_______/________ 
_______________ 
_____________ 
______________ 
________________ 
 
#4 ___________________ 
_______/________ 
_______________ 
_____________ 
______________ 
________________ 
 
COMMENT:_________________________________________________________________________ 
____________________________________________________________________________________ 
____________________________________________________________________________________ 
____________________________________________________________________________________ 
 
 
Date of original cancer diagnosis: ___ ___ / ___ ___ / ___ ___ 
 
Date of 1st Remission: ___ ___ / ___ ___ / ___ ___ 
 
Date of 1st Relapse: ___ ___ / ___ ___ / ___ ___ 
 
Date of 2nd Relapse: ___ ___ / ___ ___ / ___ ___ 
 
 
 
ECOG Performance Status: 
 
 Score 0 – Fully active, able to carry on all pre-disease performance without restriction 
 Score 1 - Restricted in physically strenuous activity but ambulatory and able to carry out work of a 
light or sedentary nature, e.g., light house work, office work 
 Score 2 - Ambulatory and capable of all selfcare but unable to carry out any work activities. Up and 
about more than 50% of waking hours 
 Score 3 - Capable of only limited selfcare, confined to bed or chair more than 50% of waking hours 
 Score 4 - Completely disabled. Cannot carry on any selfcare. Totally confined to bed or chair 
 


CCCWFU 22215 
 
Comprehensive Cancer Center of Wake Forest University 
An Open Label Study to Evaluate the Feasibility of CPI-613 Given with High Dose Cytarabine and 
Mitoxantrone in Patients with Relapsed or Refractory Acute Myeloid Leukemia (AML) 
NCT Clinicaltrials.gov:  NCT02484391 
 
56 
Revision Date:06/04/18 
 
MOLECULAR ABNORMALITIES: 
 
Were Molecular Abnormality Tests Completed?   
 Yes    
 No    
 Unknown   
 Not Done 
 
Date of Molecular Abnormality Report: ___ ___ / ___ ___ / ___ ___ 
 
 
FLT-3:   
 Yes    
 No 
 
NPM:               
 Yes    
 No 
 
Cb alpha:         
 Yes     
 No 
 
 
 
CYTOGENETICS: 
 
Cytogenetics at Diagnosis: 
 
Date of Cytogenetics Report: ___ ___ / ___ ___ / ___ ___ 
 
Risk Category:  
 Good     
 Intermediate    
 Poor   
 Unknown   
 Not Done 
 
*Enter descriptive text from Cytogenetic Report (3 categories) into REDCap database on Pre-Study Data 
Collection Form. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


CCCWFU 22215 
 
Comprehensive Cancer Center of Wake Forest University 
An Open Label Study to Evaluate the Feasibility of CPI-613 Given with High Dose Cytarabine and 
Mitoxantrone in Patients with Relapsed or Refractory Acute Myeloid Leukemia (AML) 
NCT Clinicaltrials.gov:  NCT02484391 
 
57 
Revision Date:06/04/18 
APPENDIX E - CCCWFU 22215 Day 14 Nadir Marrow Form  
 
ORIS Assigned PID ___________________  
Date Completed: ___ / ___ / ____ 
 
Visit Type:   
 Cycle 1     
 Cycle 2 
 
 
  Progressive Disease (No effect or worsening of overall blast burden (cellularity x blasts %) 
 
  Residual Disease (Presence of residual blasts but significant reduction from previous) 
 
  Few Scattered blasts of unclear significance 
 
  Hypoplastic Marrow / no evidence of disease 
 
 
 
Treating Physician Signature: ________________________   Date: _______________________ 
PI Signature: ____________________________    Date: _______________________ 
 
 
 
 
 
 
 
 
 
 


CCCWFU 22215 
 
Comprehensive Cancer Center of Wake Forest University 
An Open Label Study to Evaluate the Feasibility of CPI-613 Given with High Dose Cytarabine and 
Mitoxantrone in Patients with Relapsed or Refractory Acute Myeloid Leukemia (AML) 
NCT Clinicaltrials.gov:  NCT02484391 
 
58 
Revision Date:06/04/18 
APPENDIX F - CCCWFU 22215 Data Collection Form – FOLLOW-UP Form 
Response Evaluation Criteria for Acute Myeloid Leukemia  
 
PID: ______________________ 
 
 
 
Date: ___ ___ / ___ ___ / ___ ___ 
Please check the response that applies to this patient: 
 Complete Remission (CR) 
 Complete Remission with Incomplete Recovery (CRi)  
 Morphological Leukemia-Free State  
 Partial Remission (PR)  
 Cytogenetic Complete Response (CRc)   
 Molecular Complete Response (CRm) 
Treatment Failures 
Treatment Failure due to Resistant Disease (TFRD)  
Treatment Failure due to Complications of Aplasia (TFCA) 
Treatment Failure of Indeterminate Cause (TFIC)  
Induction Death 
Relapse 
Hematologic  Response Criteria 
 Erythroid Response (pretreatment, <11g/dL) 
 Platelet Response (pretreatment, < 100 x 109 /L) 
 Neutrophil Response (pretreatment, <1.0 x 109/L) 
 Progression or Relapse after (HI) Hematologic Improvement 
 
*If the patient has experienced relapse please record cytogenetics and molecular abnormalities at the time 
of relapse on next page. (not required per protocol) 
 
Treating Physician Signature: ________________________   Date: _______________________ 
PI Signature: ____________________________    Date: _______________________ 


CCCWFU 22215 
 
Comprehensive Cancer Center of Wake Forest University 
An Open Label Study to Evaluate the Feasibility of CPI-613 Given with High Dose Cytarabine and 
Mitoxantrone in Patients with Relapsed or Refractory Acute Myeloid Leukemia (AML) 
NCT Clinicaltrials.gov:  NCT02484391 
 
59 
Revision Date:06/04/18 
MOLECULAR ABNORMALITIES (AT RECOVERY MARROW ON STUDY): 
 
Were Molecular Abnormality Tests Completed?   
 Yes    
 No    
 Unknown   
 Not Done 
 
Date of Molecular Abnormality Report: ___ ___ / ___ ___ / ___ ___ 
 
FLT-3:   
 Yes    
 No 
 
NPM:               
 Yes    
 No 
 
Cb alpha:         
 Yes     
 No 
 
 
 
CYTOGENETICS: 
Cytogenetics at Relapse: 
 
Was Cytogenetic Testing Completed?   
 Yes    
 No    
 Unknown   
 Not Done 
 
Date of Cytogenetics Report : ___ ___ / ___ ___ / ___ ___ 
 
Relapse Time:   
 1st Relapse    
 2nd Relapse    
 3rd Relapse   
 
Risk Category:   
 Good     
 Intermediate    
  Poor 
 
*Enter descriptive text from Cytogenetic Report (3 categories) into REDCap database on Data Collection 
Form FOLLOW-UP Form. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


CCCWFU 22215 
 
Comprehensive Cancer Center of Wake Forest University 
An Open Label Study to Evaluate the Feasibility of CPI-613 Given with High Dose Cytarabine and 
Mitoxantrone in Patients with Relapsed or Refractory Acute Myeloid Leukemia (AML) 
NCT Clinicaltrials.gov:  NCT02484391 
 
60 
Revision Date:06/04/18 
 
APPENDIX G – CCCWFU 22215 Urine Collection 
 
OPTIONAL URINE COLLECTION FORM 
This form is for the collection of research urine samples collected from the first void after the 
first infusion of CPI-613 on day 1 of the first induction cycle only to be stored for future use.  
Sample Handling: Once collected 5-10 ml of urine should be placed in a 15 ml conical tube and 
placed at 4 degrees Celsius until it can be sent to the tumor tissue core facility (see below). 
Samples should be frozen and stored in the Tumor Tissue Core at -80 until use. 
 
Tumor Tissue Core 
Wake Forest Baptist Comprehensive Cancer Center 
Tumor Tissue Core Facility 
Care of Dr. Greg Kucera 
Hanes Building Rm 4049 
Medical Center Blvd 
Winston-Salem NC 27157 
 
ORIS PID: _______________________ 
Date: ____ / ____ / ____ 
 
PI: Bayard Powell, M.D.  
 
 
Study Number:_______________ 
 
Urine Sample 
Sample ID: _________________ 
Time of Collection 
Time of CPI infusion completion __________am/pm 
Time of urine collection _______am/pm 
Time urine placed in freezer storage _______am/pm 
Location of Sample 
Freezer ID: _____________   Shelf: ________________  Box:______________ 
Person Processing sample ____________________________Date__________ 
 

ICF_000.pdf: 
Official Title:An Open Label Study to Evaluate the Feasibility of 
CPI-613 Given With High Dose Cytarabine and Mitoxantrone in 
Patients With Relapsed or Refractory Acute Myeloid Leukemia 
(AML)
NCT02484391
IRB-Approved Date:  5/2/2019


Comprehensive Cancer Center of Wake Forest University 
CCCWFU 22215
Version: 06/04/18
Page 1 of 14
Section on Hematology and Oncology
AN OPEN LABEL STUDY TO EVALUATE THE FEASIBILITY OF CPI-613
GIVEN WITH HIGH DOSE CYTARABINE AND MITOXANTRONE IN
PATIENTS WITH RELAPSED OR REFRACTORY ACUTE MYELOID
LEUKEMIA (AML)
Informed Consent Form to Participate in Research
Bayard Powell, MD Principal Investigator
INTRODUCTION
You are invited to be in a research study. Research studies are designed to gain scientific 
knowledge that may help other people in the future. You are being asked to take part in this 
study because you have acute myeloid leukemia (AML) that has either returned after a period of 
remission, or is no longer responding to treatment. Your participation is voluntary. Please take 
your time in making your decision as to whether or not you wish to participate. Ask your study 
doctor or the study staff to explain any words or information contained in this informed consent 
document that you do not understand. You may also discuss the study with your friends and 
family.
WHY IS THIS STUDY BEING DONE?
Phase II studies are an early step in testing an investigational medication in humans. These 
studies look to see how many people complete the planned therapy and which of them has a 
response. It is the first step to determine if the experimental therapy can be tested in a larger trial.
The purpose of this study is to test whether the combination of an investigational drug called 
CPI-613 (“study drug”), given at a high or low dose, with two other chemotherapy drugs: 
cytarabine and mitoxantrone is effective in controlling your leukemia and how many patients 
complete all planned therapy. The study team has become aware that similar response rates with 
less side effects are possible at lower doses. Because of this the study team has revised the 
induction dose as well as added a low dose study group. Whether you receive the high or low 
dose of CPI-613 will be determined before you start treatment.  CPI-613 is thought to kill cancer 
cells by turning off their mitochondria. Mitochondria are used by cancer cells to produce energy 
and the building blocks needed to make more cancer cells. By shutting off these mitochondria, 
CPI-613 deprives the cancer cells of energy and other supplies that they need to survive and 
grow in your body. We want to find out what effects, good and/or bad, CPI-613 has on you and 
your cancer when given along with cytarabine and mitoxantrone. We also want to see if CPI-613 
when given alone as a maintenance therapy can prolong remission for those patients who 
respond to this treatment. 
An investigational drug is one that has not been approved by the U.S. Food and Drug 
Administration (FDA). CPI-613 is an investigational drug that has not been approved by the 
WFU School of Medicine 
Institutional Review Board 
IRB Number:IRB00033779
Meeting Date Approved 5/2/2019          
Version Valid Until: 5/1/2020


Comprehensive Cancer Center of Wake Forest University 
CCCWFU 22215
Version: 06/04/18                                                Page 2 of 14
FDA for any type of tumor or cancer, and it is currently being studied for the treatment of cancer.
HOW MANY PEOPLE WILL TAKE PART IN THE STUDY?
Approximately 67 people at Wake Forest Baptist Health will take part in this study. 
WHAT IS INVOLVED IN THE STUDY?
After your study doctor has answered all your questions about this study and you have given 
written consent by signing this form, several tests will be done to be sure you are able to enter 
this study. Many of the tests are the same as those you have had in the past to diagnose and treat 
your disease. Some of these same tests will also be done during the study to follow your 
progress.
This clinical research study consists of several parts induction, consolidation and maintenance. 
The first part is induction and is a two-week cycle. During the first week, treatment is given as 
follows: CPI-613 (given on days one through five), cytarabine (given on days three through 
five), and mitoxantrone (given on days three through five). The second week of the cycle is a rest 
week (no treatment). On day 14 you will have another bone marrow biopsy to see if your disease 
has responded (just like you would if you were not on the study). If you need another cycle of 
induction therapy you may receive either a repeat of the first round or a shorter 3 day cycle 
depending on what your doctor thinks. For those patients who respond to the treatment they may 
be treated with the next phase called consolidation. This treatment usually starts after patients 
have recovered from induction therapy and uses the shorter 3 day treatment. Patients can have up 
to 2 cycles of consolidation therapy as recommended by their doctor. After a patient has received 
all the consolidation therapy that they or their doctor wants them to get they can go onto 
maintenance therapy. In this phase of the study patients just get CPI-613 once a day for 5 days 
every month. This will continue until your AML progresses, your doctor thinks you should not 
get more therapy or you decide you want to withdraw from the study. 
Your participation in this study is divided into different visits:
Screening Visit (To see if you are eligible to participate in this study)
The following tests will be done during the Screening Visit. These tests may be completed over a 
four week period before receiving CPI-613. 

You will undergo a blood and bone marrow biopsy (if not already done by your doctor) 
to determine the extent of your cancer. 

Left Ventricular Ejection Fraction (by TTE, MUGA or cardiac MRI) sufficient to safely 
administer mitoxantrone as determined by the treating physician
The following tests may be completed within two weeks before receiving CPI-613.

The study doctor or study nurse will ask you about your medical history, and obtain a list 
of all medications that you are currently taking.

The study doctor or study nurse will examine you and determine your performance status.

A physical examination with your vital signs (heart rate, blood pressure, breathing rate, 
and body temperature), height, and body weight will be recorded.

Approximately 10 teaspoons of blood will be drawn for routine lab tests.

Approximately two teaspoons of blood will be drawn to evaluate potential heart muscle 
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damage.
The following test must be completed within one week before receiving CPI-613:

Pregnancy test for female subjects who can become pregnant. This must be done within 
one week of starting treatment. 
Evaluation / Procedures:
Day 1

You will be given CPI-613.

Your vital signs will be measured immediately after receiving CPI-613 and you may 
have a physical exam if needed. 
Day 2

Approximately 10 teaspoons of blood will be drawn for routine lab tests within 24 hours 
before receiving CPI-613. 

You will be given CPI-613.

You will be observed for one hour after receiving CPI-613. Your vital signs will be 
measured immediately after receiving CPI-613 and you may have a physical exam if 
needed. 
Days 3 and 4

Approximately 10 teaspoons of blood will be drawn for routine lab tests within 24 hours 
before receiving CPI-613. 

You will be given CPI-613.

You will be given mitoxantrone and cytarabine.

You will be observed for one hour after receiving CPI-613. Your vital signs will be 
measured immediately after receiving CPI-613 and you may have a physical exam if 
needed. 
Day 5

Prior to receiving treatment, you will undergo a blood test to determine how your cancer 
is doing

Approximately 10 teaspoons of blood will be drawn for routine lab tests within 24 hours 
before receiving CPI-613. 

You will be given CPI-613.

You will be given mitoxantrone and cytarabine.

You will have a physical exam

You will be observed for one hour after receiving CPI-613. Your vital signs will be 
measured immediately after receiving CPI-613 and you may have a physical exam if 
needed. One hour after completion of the CPI-613 infusion, you will have approximately 
two teaspoons of blood drawn to assess heart muscle damage.
Days 6, 7, and 8

Approximately 10 teaspoons of blood will be drawn for routine lab tests.
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
Approximately one teaspoon of blood will be drawn to monitor kidney function at 24, 48, 
and 72 hours after the last dose of CPI-613, mitoxantrone, and cytarabine (i.e., on days 6, 
7, and 8) 
Additional Evaluations and Procedures
Within 24 hours of every dose of CPI-613

Approximately one teaspoon of blood will be taken to monitor kidney function
Day 14 of cycle 1

You will undergo a bone marrow biopsy to evaluate your response to the therapy.

Note: If your study doctor determines that the treatment is beneficial to you, additional 
cycles may be given (see “How Long Will I Be In The Study?” below). In the event that 
you receive more than one cycle, a bone marrow biopsy and blood test to determine the 
extent of your cancer will be performed at the end of every other cycle (i.e., cycles 3, 5, 
7, etc.).
Maintenance Therapy
Patients who complete all planned consolidation therapy on this study may be treated with 
additional cycles of CPI-613 if their doctor feels this will be beneficial.  If you are eligible and 
agree to receive maintenance therapy with CPI-613, you will have the following tests and 
procedures completed. 
Day 1

Approximately 10 teaspoons of blood will be drawn for routine lab tests within 24 hours 
before receiving CPI-613. 

You will be given CPI-613.

Your vital signs will be measured immediately after receiving CPI-613 and you may 
have a physical exam if needed. 
Days 2-5

You will be given CPI-613.

You will be observed for one hour after receiving CPI-613. Your vital signs will be 
measured immediately after receiving CPI-613 and you may have a physical exam if 
needed. 

Approximately one teaspoon of blood will be drawn to monitor kidney function
Days 6 and 7

Rest days (no treatment)
You may receive maintenance therapy with CPI-613 until you are ready to have a stem cell 
transplant, your AML gets worse or you have an unacceptable side effect.  
Optional Sampling and Banking of Blood, Plasma, Urine and Bone Marrow Biopsy 
Samples
Optional blood samples (5 mL), urine (5-10 ml) as well as bone marrow via 
biopsy (if deemed appropriate by physician), will be obtained and “banked” for 
possible testing of biomarkers, predictors of biological responses, toxicity, 
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relationship between genotype and drug responses, etc. These samples will be 
obtained prior to treatment initiation, as well as prior to and following 
administration of CPI-613 during salvage Cycle 1.  The specific procedures are 
outlined below.
Optional blood, plasma samples and bone marrow via biopsy will be obtained 
within 2-4 weeks prior to the first dose.
Blood sample to be obtained prior to and following the dose of CPI-613 at 2, 4 6 
hours on days 1-5 and bone marrow sample to be obtained on day 14 of Cycle 1.
Urine samples will be collected from the first void after the first infusion of 
CPI-613 in the first induction cycle only.
HOW LONG WILL I BE IN THE STUDY?
You will be given CPI-613 five times a week for one week, followed by a week of rest. This two 
week period is considered “a cycle.” CPI-613 will be given over a two-hour infusion into your 
vein through a central venous catheter (a catheter that is put into a larger vein in your body and 
will remain in place for the duration of the treatment). The study plans on one or two cycles of 
induction therapy, up to two cycles of consolidation therapy and then maintenance therapy for as 
long as you are willing and your doctors feels is beneficial to you.
You can stop participating at any time. It is important to tell the study doctor if you are thinking 
about stopping so that any risks from CPI-613 can be evaluated by your study doctor. Another 
reason to tell your study doctor that you are thinking about stopping is to discuss what follow-up 
care and testing could be most helpful for you.
WHAT ARE THE RISKS OF THE STUDY?
Being in this study involves some risk to you. You should discuss the risk of being in this study 
with the study staff. 
Risks Related to CPI-613
The study drug is in the very early stages of development for use in humans. The main purpose 
of this study is to learn about the efficacy of the drug when given with mitoxantrone and 
cytarabine. Please carefully read the sections on risk and benefits below. Not all of the side 
effects are known at this time. If you choose to take part in this study, it is very important that 
you let the study team know of any symptoms you have.
Some potential risks associated with CPI-613 have been determined from previous animal 
studies. These side effects include vomiting and some temporary heart damage. CPI-613 has also 
caused inflammation around the area where the experimental drug is given, causing swelling, 
redness, and pain. To avoid this potential side effect, CPI-613 will be given to you through a 
central venous catheter. There may be other more severe side effects such as significant 
inflammation throughout your body. The study drug could cause changes in certain chemicals in 
your blood that could indicate liver problems. Significant side effects have also caused some 
deaths in test animals at dose levels that are higher than those to be used in this study. Many side 
effects may go away shortly after being given CPI-613 but in some cases, side effects may be 
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severe, long lasting, or may not go away. Although not yet reported in any human subjects, it 
remains possible that CPI-613 might cause your disease to progress or produce a fatal side effect. 
CPI-613 may also cause side effects that we have not yet seen and cannot predict.
The following describes events observed in patients who received one or more doses of CPI-613 
in clinical trials. These side effects may be related to CPI-613, related to other drugs 
administered or related to activity of the cancer being treated. 
COMMON, SOME MAY BE 
SERIOUS                                                                                          
In 100 cancer patients receiving CPI-613, more than 20 and up to 100 people may have 
experienced:

nausea.
OCCASIONAL, SOME MAY BE 
SERIOUS                                                                                                        
In 100 people receiving CPI-613, from 4 to 20 may have experienced:

vomiting

tiredness

taste changes

diarrhea

anemia

changes in liver function tests

reactions at the place where they received CPI-613

low sodium in the blood

high levels of hemoglobin (a part of red blood cells)
RARE AND SERIOUS
In 100 people receiving CPI-613, 3 or fewer may have experienced:

blockage of blood vessels

heart failure

heart attack

chest pain not related to the heart

death
In a study of patients with acute myeloid leukemia, who received CPI-613 combined with other 
chemotherapy, the most frequent (greater than 10%) side effects reported by people were: 

changes in liver function tests

changes in components of the blood

diarrhea

nausea

vomiting

tiredness
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
loss of appetite

alterations in coagulation tests

changes in kidney function

fever of unknown origin

sores on the gums
In previous animal studies, acute inflammation has been observed, however to date, no human 
subjects have experienced this side effect.
There may be other, more severe side effects, such as inflammation throughout your body. The 
study drug could cause changes in certain chemicals in your blood that could indicate liver 
problems. 
Pregnancy Risks
The effects of CPI-613 on a fetus are unknown.  You should not become pregnant or father a 
child while on this study.  If you are able to become pregnant or father a child, BOTH you and 
your partner must use effective birth control methods during the study period.  Effective birth 
control methods are outlined below.
Women subjects who have never been pregnant can use one of the following methods:

Abstinence

A barrier method (diaphragm, cervical cap, sponge, or condom with a spermicidal foam 
or jelly) plus hormonal birth control (oral, patch or injectable).

A barrier method (diaphragm, cervical cap, sponge, or condom with a spermicidal foam 
or jelly) plus an intrauterine device (IUD).
Women subjects who have previously been pregnant at least once can use one of the following 
methods:

Abstinence

A barrier method (diaphragm or condom with a spermicidal foam or jelly) plus hormonal 
birth control (oral, patch or injectable).

A barrier method (diaphragm or condom with a spermicidal foam or jelly) plus an 
intrauterine device (IUD).
Male subjects can use one of the following methods:

Abstinence

Condom with spermicide
For male subjects, you should also advise your partner to use an effective birth control method 
such as those outlined above for women subjects.  
If you suspect that you have become pregnant, you must notify the study doctor immediately.
Female subjects should avoid becoming pregnant for at least 10 weeks following completion of 
the study.  Male subjects should avoid fathering a child for at least 10 weeks following study 
completion.  
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Risks Related to Mitoxantrone
Some common side effects observed in patients taking mitoxantrone include:

Anemia

Low white blood cells

Low platelets

Serious infections

Nausea

Hair loss

Menstrual irregularities (female patients)

Upper respiratory infection

Urinary tract infection

Irregular heart rhythm

Inflammation of the mucus membranes lining the mouth

Diarrhea

Constipation

Back pain

Sinusitis

Headache
Risks Related to Cytarabine
Some common side effects observed in patients taking cytarabine include:

Anemia

Low white blood cells

Low platelets

Serious infections

Nausea

Vomiting

Diarrhea

Stomach pain

Loss of appetite

Inflammation of the mucus membranes lining the mouth

Hair loss

Muscle or joint pain

Tiredness

Sore or red eyes

Anemia

Low levels of white blood cells

Increased risk of infection

Weight loss

Decreased liver function

Fever

Increased risk of bleeding
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Rarely, cytarabine has been associated with sepsis (whole-body infection and inflammation), 
pneumonia, difficulty urinating, decreased kidney function, nerve damage, sores in the throat, 
chest pain, inflammation of the lining that surrounds the heart, pancreatitis (inflammation of the 
pancreas), jaundice (temporary yellowing of the skin and eyes), eye infection, dizziness, 
shortness of breath, and headache.
Other Risks
It is possible that you could experience an allergic reaction to CPI-613 or to any combination of 
the drugs used in this study.  An allergic reaction can be mild, or it can be serious, leading to 
shock with loss of consciousness, or it can be life-threatening.
Certain drugs, when taken together with the study drug, may increase side effects.  It is possible 
that CPI-613 could increase the side effects of cytarabine or mitoxantrone. It is important that 
you inform your study doctor of any prescription, over-the-counter, or alternative medications 
you are taking while in this study.
Drawing blood may cause pain, bruising, lightheadedness, or, on rare occasions, infection.
Risks of a central venous catheter may include pain, bleeding, infection, and damage to lungs or 
other tissue.
Your condition may not get better or may become worse during this study.
If you have questions about risks and side effects, ask your study doctor.  You should talk to 
your study doctor about any side effects that you have while taking part in this study.  The 
study doctor will take steps to try to treat any side effects, if they appear.  If the study drug 
causes severe side effects or if your disease worsens, the study drug will be discontinued.  In that 
case, your study doctor will discuss treatment options with you.
 
Taking part in this research study may involve providing information that you consider 
confidential or private.  Efforts, such as coding research records, keeping research records secure 
and allowing only authorized people to have access to research records, will be made to keep 
your information safe.
ARE THERE BENEFITS TO TAKING PART IN THE STUDY?
If you agree to take part in this study, there may or may not be direct benefit to you. We hope the 
information learned from this study will benefit other people in the future. The benefits of 
participating in this study may be: improvement in your cancer.  
WHAT OTHER CHOICES ARE THERE?
You do not have to be in this study to receive treatment. You should talk to your doctor about all 
the choices you have. Instead of being in this study, you have these options:

Other chemotherapies 

Comfort care, which is an option if you decide that you do not want any more active 
treatment for your cancer. Comfort care includes pain medication and other types of 
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support. It aims to maintain your comfort and dignity rather than cure disease. Usually 
this care can be provided at home. If you think you might prefer comfort care, please 
discuss this with your family, friends, and your doctor.
SAMPLES FOR FUTURE STUDIES
The researchers would like your permission to use blood, plasma and/or bone marrow samples 
collected for the study for future health research related to the purposes of the CCCWFU-22215 
study.
My blood/tissue samples and related information may be kept in a Biobank for use in future 
health research.
YES ____
NO ____
Your blood/tissue samples will be stored de-identified, which means that no identifying 
information will be stored with it. Researchers will not know the name, date of birth, medical 
record number, social security number, etc., of the person who donated the sample.
The research that may be performed with your blood/tissue sample is not designed to help you 
specifically. There is no personal benefit to you from taking part in this aspect of the research 
study. It might help people who have diseases at some point in the future, but it is not known if 
this will happen. The results of the research performed with your blood will not be given to you 
or your doctor. The results will not be put in your medical record. The research using your 
blood/tissue sample will not affect your care.
Your blood/tissue sample will be used only for research and will not be sold. The findings from 
this research may result in the future development of products that are of commercial value. 
There are no plans to share any of the profits with you which may occur as a result of the 
research.
What About My Health Information?
In this research study, any new information we collect from you about your health or behaviors 
is considered Protected Health Information. The information we will collect for this research 
study includes: your health history, how you respond to study procedures, laboratory and other 
test results, and physical examinations.
If this research study involves the diagnosis or treatment of a medical condition, then Protected 
Health Information collected from you during this study will be placed in your medical record, 
and may be used to help treat you, arrange payment for your care, or assist with Medical Center 
operations. 
We will make every effort to keep your Protected Health Information private. We will store 
records of your Protected Health Information in a cabinet in a locked office or on a password 
protected computer. Only the following people or organizations will be granted access to your 
Protected Health Information:
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1) The study investigator and his/her staff, or others at Wake Forest University Health 
Sciences who oversee research
2) Other people or laboratories providing services for this research project on behalf of 
Wake Forest University Health Sciences and Wake Forest University Baptist Medical 
Center 
3) The U.S. Food and Drug Administration (FDA); Rafael Pharmaceuticals, Inc. 
If required by law or court order, we might also have to share your Protected Health Information 
with a judge, law enforcement officer, government agencies, or others. If your Protected Health 
Information is shared with any of these groups it may no longer be protected by federal or state 
law.
Any Protected Health Information collected from you in this study that is maintained in the 
research records will be kept for an indeterminate period of time. This authorization does not 
expire. Any research information entered into your medical record will be kept for as long as 
your medical record is kept by the Medical Center. You will not be able to obtain a copy of your 
Protected Health Information in the research records until all activities in the study are 
completely finished. 
You can tell Dr. Bayard Powell that you want to take away your permission to use and share 
your Protected Health Information at any time by sending a letter to this address:
Bayard Powell, MD
However, if you take away permission to use your Protected Health Information you will not be 
able to be in the study any longer. We will stop collecting any more information about you, but 
any information we have already collected can still be used for the purposes of the research 
study.
By signing this form you give us permission to use your Protected Health Information for this 
study.
If you choose to participate in this study, your medical record at Wake Forest University Baptist 
Medical Center will indicate that you are enrolled in a clinical trial.  Information about the 
research and any medications or devices you are being given as a participant may also be 
included in your medical record.  This part of the medical record will only be available to people 
who have authorized access to your medical record.  If you are not a patient at this Medical 
Center, a medical record will be created for you anyway to ensure that this important information 
is available to doctors in case of an emergency.
A description of this clinical trial will be available on http://www.ClinicalTrials.gov, as required 
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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 this Web site at any time. 
Laboratory test results and other medical reports created as a result of your participation in the 
research study may be entered into the computer systems of Wake Forest University Health 
Sciences and North Carolina Baptist Hospital.  These will be kept secure, with access to this 
information limited to individuals with proper authority, but who may not be directly involved 
with this research study.
A North Carolina Baptist Hospital (NCBH) medical record will be created for all study 
participants. Information about your participation in the study will be placed in the NCBH 
medical record, along with any routine medical test results that were obtained at NCBH as part 
of this study. 
WHAT ARE THE COSTS?
Taking part in this study may lead to added costs to you or your insurance company. We will 
give you an estimate of what the added cost may be based on your particular situation and 
insurance coverage.
 
WILL YOU BE PAID FOR PARTICIPATING?
The investigational study drug, CPI-613, is being provided to you at no cost from the 
pharmaceutical company (Rafael Pharmaceuticals, Inc.). Parking validation will be provided for 
study-related visits.
WHO IS SPONSORING THIS STUDY?
This study is being sponsored by Wake Forest University Health Science.  Rafael 
Pharmaceuticals, Inc. is providing the investigational drug (CPI-613) to Wake Forest University 
Health Sciences to help conduct this study. Dr. Timothy Pardee, a Co-investigator on this study, 
has a relationship with Rafael Pharmaceuticals and receives compensation, separate from this 
study, for consulting services.  Rafael has also provided some lab materials for Dr. Pardee’s 
research. Dr. Powell and the other researchers do not, however, hold a direct financial interest in 
Rafael Pharmaceuticals, Inc. or the product being studied. 
WHAT HAPPENS IF YOU EXPERIENCE AN INJURY OR ILLNESS AS A 
RESULT OF PARTICIPATING IN THIS STUDY?
Should you experience a physical injury or illness as a direct result of your participation in this 
study, Wake Forest University School of Medicine maintains limited research insurance 
coverage for the usual and customary medical fees for reasonable and necessary treatment of 
such injuries or illnesses. To the extent research insurance coverage is available under this policy 
the reasonable costs of these necessary medical services will be paid, up to a maximum of 
$25,000. Wake Forest University Baptist Medical Center holds the insurance policy for this 
coverage. It provides a maximum of $25,000 coverage for each claim and is limited to a total of 
$250,000 for all claims in any one year. The Wake Forest University School of Medicine, and 
the North Carolina Baptist Hospitals, Incorporated do not assume responsibility to pay for these 
medical services or to provide any other compensation for such injury or illness. Additional 
information may be obtained from the Medical Center’s Director of Risk and Insurance 
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Management, at 
.
If you are injured, the insurer may require information such as your name, social security 
number, and date of birth in order to pay for your care.  This is because the insurer is required by 
law to report any payments made to cover the care of any persons who are members of a 
government insurance plan to the Department of Health and Human Services.
You do not give up any legal rights as a research participant by signing this consent form. For 
more information on medical treatment for research related injuries or to report a study related 
illness, adverse event, or injury you should call Dr. Bayard Powell at 
.
WHAT ARE MY RIGHTS AS A RESEARCH STUDY PARTICIPANT?
Taking part in this study is voluntary. You may choose not to take part or you may leave the 
study at any time. Refusing to participate or leaving the study will not result in any penalty or 
loss of benefits to which you are entitled. If you decide to stop participating in the study we 
encourage you to talk to the investigators or study staff first to learn about any potential health or 
safety consequences. The investigators also have the right to stop your participation in the study 
at any time. This could be because it is in your best interest, you do not follow the study rules, 
the study is stopped, you do not later consent to any future changes that may be made to the 
study plan, or your become pregnant. 
You will be given any new information we become aware of that would affect your willingness 
to continue to participate in the study.
WHOM DO I CALL IF I HAVE QUESTIONS OR PROBLEMS?
For questions about the study or in the event of a research-related injury, contact the study 
investigator, Dr. Bayard Powell at 
.
The Institutional Review Board (IRB) is a group of people who review the research to protect 
your rights. If you have a question about your rights as a research participant, or you would like 
to discuss problems or concerns, have questions or want to offer input, or you want to obtain 
additional information, you should contact the Chairman of the IRB at 
.
You will be given a copy of this signed consent form. 
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SIGNATURES
I agree to take part in this study. I authorize the use and disclosure of my health information as 
described in this consent and authorization form.  If I have not already received a copy of the 
Privacy Notice, I may request one or one will be made available to me.  I have had a chance to 
ask questions about being in this study and have those questions answered.   By signing this 
consent and authorization form, I am not releasing or agreeing to release the investigator, the 
sponsor, the institution or its agents from liability for negligence.
Subject Name (Printed):_____________________________
Subject Signature: _________________________________ Date: ________Time:_______ am pm 
Person Obtaining Consent (Printed):___________________________
Person Obtaining Consent:___________________________ Date:_________ Time:________ am pm
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