Conditions: Adult Primary Cholangiocellular Carcinoma Advanced Adult Primary Liver Cancer Cholangiocarcinoma of the Extrahepatic Bile Duct Cholangiocarcinoma of the Gallbladder Localized Unresectable Adult Primary Liver Cancer Metastatic Extrahepatic Bile Duct Cancer Recurrent Adult Primary Liver Cancer Recurrent Extrahepatic Bile Duct Cancer Unresectable Extrahepatic Bile Duct Cancer
Allocation: NON_RANDOMIZED | Intervention model: SEQUENTIAL
Enrollment: 17
Healthy volunteers: no

Brief summary:
This pilot clinical trial studies 6,8-bis(benzylthio)octanoic acid in treating patients with advanced or metastatic cholangiocarcinoma that cannot be removed by surgery. 6,8-Bis(benzylthio)octanoic acid may stop the growth of cholangiocarcinoma by blocking blood flow to the tumor

Detailed description:
PRIMARY OBJECTIVES:

I. To evaluate the safety and efficacy of CPI-613 (6,8-bis\[benzylthio\]octanoic acid) in patients with advanced unresectable cholangiocarcinoma who have failed available therapies.

OUTLINE:

Pre-cycle: Patients receive 6,8-bis(benzylthio)octanoic acid intravenously (IV) over 2 hours on days 1-5, 1 week prior to course 1.

Patients receive 6,8-bis(benzylthio)octanoic acid IV over 2 hours on days 1 and 4 of weeks 1-3. Treatment repeats every 4 weeks for up to 2 courses in the absence of disease progression or unacceptable toxicity. Patients responding to treatment may receive up to 4 more courses of treatment.

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

Arms:
arm 1: Participants will not be treated with CPI-613 during pre-Cycle 1 and will only be treated with 3 weeks on/1 week off at 2,300 mg/m² as a starting dose. If none of these 3 participants develop a dose-limiting toxicity through Cycle 1, the dose for the 3-weeks-on-1-week-off treatment cycles will be 3,000 mg/m² in all subsequent participants in this trial.

Patients receive 6,8-bis(benzylthio)octanoic acid IV over 2 hours on days 1 and 4 of weeks 1-3. Treatment repeats every 4 weeks for up to 2 courses in the absence of disease progression or unacceptable toxicity. Patients responding to treatment may receive up to 4 more courses of treatment. arm 2: Participants will received pre-cycle 1 week dose at 1200 mg/m² and dosing will escalate to 3,000 mg/m² for the three weeks on, one week off cycle.

Patients receive 6,8-bis(benzylthio)octanoic acid IV over 2 hours on days 1 and 4 of weeks 1-3. Treatment repeats every 4 weeks for up to 2 courses in the absence of disease progression or unacceptable toxicity. Patients responding to treatment may receive up to 4 more courses of treatment. arm 3: Participants will received pre-cycle 1 week dose at 600 mg/m² and dosing will escalate to 3,000 mg/m² for the three weeks on, one week off cycle.

Patients receive 6,8-bis(benzylthio)octanoic acid IV over 2 hours on days 1 and 4 of weeks 1-3. Treatment repeats every 4 weeks for up to 2 courses in the absence of disease progression or unacceptable toxicity. Patients responding to treatment may receive up to 4 more courses of treatment.

Interventions: intervention 1: 6,8-bis(benzylthio)octanoic acid
Intervention descriptions: intervention 1: Given IV

Protocol document:
Prot_SAP_000.pdf: 
Comprehensive Cancer Center of Wake Forest University 
A Pilot Study: Open-Label Clinical Trial of CPI-613 in Patients with Advanced Bile Duct 
Cancers 
CCCWFU # 59212 
 
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Principal Investigator: 
Caio Max S. Rocha Lima, MD 
 
 
 
 
Section on Hematology and Oncology 
Wake Forest School of Medicine 
 
 
 
 
Medical Center Boulevard 
 
 
 
 
Winston-Salem, NC 27157 
 
 
 
 
 
 
 
Co-Investigators: 
 
A. William Blackstock, MD 
 
 
 
 
Department of Radiation Oncology 
 
 
 
 
Wake Forest School of Medicine 
 
 
 
 
 
 
 
 
 
 
 
Biostatistician: 
 
Ralph B. D’Agostino, Jr, PhD 
 
 
 
 
Division of Public Health Sciences 
Comprehensive Cancer Center of Wake Forest University 
 
 
 
 
 
 
Research Nurse: 
 
Jennifer Ward Thoma, RN 
 
 
 
 
Comprehensive Cancer Center of Wake Forest University 
 
 
 
 
 
 
 
Data Manager: 
 
Claire E. Kimbrough 
 
 
 
 
Comprehensive Cancer Center of Wake Forest University 
 
 
 
 
 
 
 
Regulatory / Budget: 
Megan Brown 
 
 
 
 
Comprehensive Cancer Center of Wake Forest University 
 
 
 
 
 
 
Investigational Drug: 
CPI-613  
 
IND Number: 
 
117,500 
 
Drug Sponsor: 
 
Cornerstone Pharmaceuticals, Inc. 
 
Version Date:  
 
07.16.18 
 
 
 
 
02.28.18 
 
 
 
 
02.22.17 
 
 
 
 
02.16.16 
 
 
 
 
10.22.15 
 
 
 
 
06.16.15 


Comprehensive Cancer Center of Wake Forest University 
A Pilot Study: Open-Label Clinical Trial of CPI-613 in Patients with Advanced Bile Duct 
Cancers 
CCCWFU # 59212 
 
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04.23.15 
01.21.15 
 
 
 
 
11.14.14 
 
 
 
 
09.08.14 
 
 
 
 
07.24.14 
 
 
 
 
06.19.14 
05.20.14 
02.28.14 
 
 
 
 
08.16.13 
 
 
 
 
07.16.13 
04.23.13 
 
 
 
 
04.05.13 
 
 
 
 
02.08.13 
 
 
 
 
02.04.13 
 
 
 
 
12.19.12 
 
Proprietary and Confidential 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
SCHEMA 
 
Patients with histologically 
and cytologically proven 
bile duct cancer 


Comprehensive Cancer Center of Wake Forest University 
A Pilot Study: Open-Label Clinical Trial of CPI-613 in Patients with Advanced Bile Duct 
Cancers 
CCCWFU # 59212 
 
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 CT scan of chest, abdomen, and pelvis  
Treatment with 3 cycles of CPI-613  
(one cycle = 4 weeks) 
Progression of Disease 
Continue treatment for 2 additional 
cycles** 
Response 
Continue treatment for 3 additional 
cycles* 
Progression 
Discontinue treatment 
Response 
Continue up to a total of 12 cycles* (48 
weeks total duration); contrast CT scan of 
chest, abdomen and pelvis, after every 3rd 
cycle
Primary Objective 
To evaluate the safety and anti-cancer activities (assessed based on Response Rate) of CPI-613 in patients 
with advanced unresectable bile duct cancer who have failed available therapies. 
 
Secondary Outcome measures 
 
Progression-free survival 
 
Overall Survival 
 
Design 
Open-label single arm 
 
*   Maximum number of cycles allowed is 12, unless the investigator considers additional treatment can 
provide clinical benefit 
** Two additional cycles will not be given if the patient no longer meets eligibility criteria, has worsening 
of biliary function, or has symptomatic progression. 
Informed consent 
Contrast CT scan of chest, abdomen, and pelvis  
Pre-Cycle 1 treatment with CPI-613  


Comprehensive Cancer Center of Wake Forest University 
A Pilot Study: Open-Label Clinical Trial of CPI-613 in Patients with Advanced Bile Duct 
Cancers 
CCCWFU # 59212 
 
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Table of Contents 
1. BACKGROUND AND STUDY OBJECTIVES ..........................................................6 
2. STUDY DESIGN ............................................................................................................7 
2.1 
Study Objective ............................................................................................7 
2.2 
Outcome Measures.......................................................................................7 
2.3 
Open-Label Single-Arm Study Design ........................................................7 
3.0 PATIENT ELIGIBILITY CRITERIA ......................................................................7 
3.1 
Inclusion Criteria .........................................................................................7 
3.2 
Exclusion Criteria ........................................................................................8 
3.3 
Inclusion of Women and Minorities ............................................................9 
4.0 REGISTRATION PROCEDURES ............................................................................9 
5.0 STUDY PROCEDURES ...........................................................................................11 
5.1.1 Pre-Study Screening Tests .............................................................13 
5.1.2 Safety Assessment .........................................................................13 
5.1.3 Tumor Assessment .........................................................................13 
5.2 
Specifics of Tests Performed During the Study .........................................15 
5.2.1 ECOG Performance Status ............................................................15 
5.2.2 Clinical Chemistry, Hematology and Coagulation ........................16 
5.2.3 Analyses of Plasma CPI-613 Concentrations, Possibly Metabolite 
Concentrations, and Possibly Other Analyses ...............................17 
5.2.4 Optional Sampling and “Banking” of Blood and SerumSamples .19 
6.0 TREATMENT WITH CPI-613 ................................................................................21 
6.1 
Dose Levels, Dose Escalation, Sample Size and Justification of the Dose21 
6.1.1 Dose Levels, Dose Escalation and Sample Size ............................21 
6.1.2 Justification of the Dose.................................................................24 
6.2 
Dosing Delay and Dose Modification of CPI-613 in the Event of Adverse  Events
....................................................................................................................25 
6.3 
Duration of Treatment for Each Patient at Each Cohort ............................25 
7.0 STUDY DRUG - CPI-613 ..........................................................................................26 
7.1 
Description of CPI-613 Drug Product .......................................................26 


Comprehensive Cancer Center of Wake Forest University 
A Pilot Study: Open-Label Clinical Trial of CPI-613 in Patients with Advanced Bile Duct 
Cancers 
CCCWFU # 59212 
 
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7.2 
Handling of CPI-613 ..................................................................................26 
7.3 
Storage of CPI-613 ....................................................................................27 
7.4 
Intravenous (IV) Infusion Sets, Syringes and IV Bags to be Used for  
Administration of CPI-613 ........................................................................27 
7.5 
Reconstitution and Administration of CPI-613 .........................................28 
7.6 
Request for CPI-613 ..................................................................................29 
7.7 
Procurement of Investigational Drug .........................................................29 
7.8 
Disposal of CPI-613 ...................................................................................30 
7.9 
Calculation of the Amount of CPI-613 for Each Patient ...........................30 
7.10 
Concomitant Medications and Prophylactic Treatment .............................31 
8.0 ADVERSE EVENTS LIST AND REPORTING REQUIREMENTS ..................31 
8.1 
Adverse Event Characteristics ...................................................................31 
8.2 
STRC SAE Reporting Requirements .........................................................32 
8.3  
WFUHS IRB AE Reporting Requirements ...............................................33 
9.0 STATISTICAL CONSIDERATIONS .....................................................................34 
APPENDIX A – REGISTRATION GUIDELINES AND FORMS .............................40 
APPENDIX B  STRC SAE REPORTING GUIDELINES ..........................................47 
APPENDIX C – CCCWFU ADVERSE EVENT LOG ................................................51 
Appendix D – Efficacy Assessment Form ......................................................................52 
Appendix E – Withdrawal of Participation Form ........................................................53 
Appendix F - Post Study Bimonthly Telephone Follow Up Form ...............................54 
 
 
 


Comprehensive Cancer Center of Wake Forest University 
A Pilot Study: Open-Label Clinical Trial of CPI-613 in Patients with Advanced Bile Duct 
Cancers 
CCCWFU # 59212 
 
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1. BACKGROUND AND STUDY OBJECTIVES 
 
Biliary duct carcinoma is a rare but highly fatal malignancy. Estimated incidence of bile duct and 
gallbladder cancer approached 10,000 cases in 2009, with nearly 3,400 estimated deaths 
according to the American Cancer Society. 
 
Cholangiocarcinoma is an epithelial cancer of the biliary duct system that may originate in the 
liver and extrahepatic bile ducts, which may terminate at the ampulla of Vater.  Based on 
anatomical location, cholangiocarcinoma can be divided into 3 categories: (1) intrahepatic (20-
25%), occurring in the bile ducts residing within the liver; (2) extrahepatic or perihilar (also 
known as Klatskin tumour, 50%), occurring at the confluence of the right and left hepatic ducts; 
and (3) distal extrahepatic bile duct (20-25%), occurring beyond the liver.  More than 90% of 
cholangiocarcinoma are adenocarcinomas, with different histological variants including 
adenocarcinoma, papillary adenocarcinoma, intestinal-type adenocarcinoma, and mucinous 
adenocarcinoma. 
 
Conventional chemotherapy and radiation therapy have not been shown to be effective in 
prolonging long-term survival.  Although photodynamic therapy has been reported to be 
effective as a palliative treatment, it is not curative.  Radical surgery is the only potentially 
curative treatment modality.  However, in most cases, the tumors are well advanced at the time 
of diagnosis, which results in limited treatment options.  The impact of chemotherapy on survival 
remains controversial.  The overall survival for patients with cholangiocarcinoma is ~6 months. 
 
Gemcitabine, with or without cisplatin, is the first line chemotherapy.  However, the outcomes of 
this therapy are limited.  After gemcitabine/cisplatin therapy, there is essentially no known 
effective chemotherapy.  The poor response of cholangiocarcinoma to current therapy highlights 
the need for a safe and effective therapy. 
 
CPI-613 is a novel anti-cancer agent (Zachar et al. 2011).  CPI-613 selectively targets the altered 
form of mitochondrial energy metabolism in tumor cells, causing changes in mitochondrial 
enzyme activities and redox status which leads to apoptosis, necrosis and autophagy of tumor 
cells (Zachar et al. 2011).  The activities of CPI-613 involve the catalytic and regulatory 
functions of the altered form of the pyruvate dehydrogenase complex (PDC) and the α-
ketoglutarate dehydrogenase complex (KGDHC) found in tumor cells (Zachar et al. 2011).  CPI-
613 is also well-tolerated at doses up to 3,000 mg/m2, according to Phase 1 trials in patients with 
solid tumors and hematologic malignancies.  Although it has not been investigated in patients 
with cholangiocarcinoma, CPI-613 has exhibited anti-cancer activities against a variety of 
advanced cancers including different types of solid tumors (Lee et al. 2011 & 2012; Senzer et al. 
2012) and hematologic malignancies (Pardee et al, 2011a and b, & 2012).  Therefore, the anti-
cancer activities and safety of CPI-613 against advanced bile duct cancers are investigated in this 
study. Interestingly, after the first two cycles of treatment, the radiologic response by CAT scan 
or PET scan did not correlate well with the clinical response for various tumor types, and 
patients had increased survival despite pseudo-progression on their initial scan. One of the 
reasons is that CPI-613 seems to be producing an inflammatory and necrotic local effect that can 


Comprehensive Cancer Center of Wake Forest University 
A Pilot Study: Open-Label Clinical Trial of CPI-613 in Patients with Advanced Bile Duct 
Cancers 
CCCWFU # 59212 
 
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be read as pseudo-progression on a standard CT. For this reason, we will allow patients to 
continue for an additional two cycles even if the first treatment scan shows progression of 
disease by RECIST criteria. After 2 additional cycles, we expect to understand if the patient 
responded to therapy or not as the inflammatory/necrotic effect should have subsided.  Allowing 
2 additional treatment cycles with Disease Progression according to RECIST cannot take place if 
any of the following conditions occur: 
 
- the patient no longer meets eligibility criteria set at the start of the protocol (see Section 3.) 
- worsening of biliary function when compared to baseline 
- the patient has symptomatic progression 
 
2. STUDY DESIGN 
 
2.1 
Study Objective 
 
The objective of this study is to evaluate the safety and efficacy of CPI-613 in patients 
with advanced unresectable bile duct cancers who have failed available therapies.   
 
2.2 
Outcome Measures 
 
The primary outcome measures are safety and anti-cancer activities (assessed based on 
Response Rate [RR]). 
 
 
The secondary outcome measures are: 
 
 
Progression-Free-Survival (PFS). 
 
Overall Survival (OS). 
 
2.3 
Open-Label Single-Arm Study Design 
 
This is an open-label study, and investigators and subjects are not blinded to the 
treatment. Also, the assignment of patients will not be randomized, since there is only a 
single arm in this study. 
 
3.0 PATIENT ELIGIBILITY CRITERIA 
 
3.1 
Inclusion Criteria 
 
Patients must meet all of the following inclusion criteria before enrollment: 
 
A. Histologically and cytologically proven bile duct cancer of any type (including 
intrahepatic cholangiocarcinomas, extrahepatic primary cholangiocarcinomas, hilar 
cholangiocarcinomas, cholangiocarcinomas located in the gall bladder or hepatic 
capsule effraction, and carcinoma of the Ampulla of Vater, etc.) that is not amenable 


Comprehensive Cancer Center of Wake Forest University 
A Pilot Study: Open-Label Clinical Trial of CPI-613 in Patients with Advanced Bile Duct 
Cancers 
CCCWFU # 59212 
 
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to surgery, radiation, or combined modality therapy with curative intent, and has 
failed or is not eligible for available chemotherapies such as gemcitabine with or 
without platinum. 
B. Local, locally-advanced, or metastatic disease documented as having shown 
progression on a scan (e.g., CT, MRI). 
C. Measurable tumor according to RECIST 1.1 criteria with at least one 
unidimensionally measurable target lesion. 
D. No evidence of biliary duct obstruction, unless obstruction is controlled by local 
treatment or, in whom the biliary tree can be decompressed by endoscopic or 
percutaneous stenting with subsequent reduction in bilirubin to below 1.5x Upper 
Level of Normal (ULN). 
E. No acute toxic effects from previous treatment superior to grade 1 at the start of the 
study. 
F. Eastern Cooperative Oncology Group (ECOG) performance status being 0-2. 
G. Expected survival >3 months. 
H. Male and female patients18 years of age and older. 
I. 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) during the study, and must 
have a negative serum or urine pregnancy test within 1 week prior to treatment 
initiation.  
J. Fertile men must practice effective contraceptive methods during the study, unless 
documentation of infertility exists. 
K. Laboratory values ≤2 weeks must be: 
 Adequate hematologic (granulocyte count ≥1500/mm3; white blood cell 
[WBC] 3500 cells/mm3 or 3.5 bil/L; platelet count 100,000 cells/mm3 or 
100 bil/L; absolute neutrophil count [ANC] ≥1500 cells/mm3 or 1.5 bil/L; 
and hemoglobin ≥9 g/dL or ≥90 g/L). 
 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 2.0 mg/dL or 177 µmol/L).   
 Adequate coagulation (“International Normalized Ratio or INR must be <1.5” 
unless on therapeutic blood thinners) 
L. No evidence of active infection and no serious infection within the past month. 
M. Mentally competent, ability to understand and willingness to sign the informed 
consent form. 
 
3.2 
Exclusion Criteria   
 
 
Patients with the following characteristics are excluded: 
 


Comprehensive Cancer Center of Wake Forest University 
A Pilot Study: Open-Label Clinical Trial of CPI-613 in Patients with Advanced Bile Duct 
Cancers 
CCCWFU # 59212 
 
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A. 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. 
B. Serious medical illness that would potentially increase patients’ risk for toxicity. 
C. Any active uncontrolled bleeding, and any patients with a bleeding diathesis (e.g., 
active peptic ulcer disease). 
D. Pregnant women, or women of child-bearing potential not using reliable means of 
contraception (because the teratogenic potential of CPI-613 is unknown). 
E. Lactating females.   
F. Fertile men unwilling to practice contraceptive methods during the study period. 
G. Life expectancy less than 3 months. 
H. Any condition or abnormality which may, in the opinion of the investigator, 
compromise the safety of patients. 
I. Unwilling or unable to follow protocol requirements. 
J. Dyspnea with moderate exertion.  
K. Patients with clinically significant pleural or pericardial effusions. 
L. Active heart disease including but not limited to symptomatic congestive heart 
failure, symptomatic coronary artery disease, symptomatic angina pectoris, 
symptomatic myocardial infarction,  or symptomatic congestive heart failure. Also 
patients with a history of myocardial infarction that is <1 year prior to registration, or 
patients with previous congestive heart failure (<1 year prior to registration) requiring 
pharmacologic support or with Left Ventricular Ejection Fraction <50%). 
M. A history of additional risk factors for torsade de pointes (e.g., heart failure, 
hypokalemia, family history of Long QT Syndrome) 
N. Evidence of active infection, or serious infection within the past month. 
O. Patients with known HIV infection. 
P. Patients with baseline troponin levels greater than the institutional limit of normal. 
Q. Patients who have received cancer immunotherapy of any type within the past 2 
weeks prior to initiation of CPI-613 treatment. 
R. Requirement for immediate palliative treatment of any kind including surgery. 
S. Patients that have received a chemotherapy regimen with stem cell support in the 
previous 6 months. 
T. Prior illicit drug addiction. 
U. Any condition or abnormality which may, in the opinion of the investigator, 
compromise the safety of the patient. 
 
3.3 
Inclusion of Women and Minorities 
 
Both men and women and members of all races and ethnic groups are eligible for 
participation in this trial. 
 
4.0 REGISTRATION PROCEDURES   
 
All patients entered on any CCCWFU trial, whether treatment, companion, or cancer control 


Comprehensive Cancer Center of Wake Forest University 
A Pilot Study: Open-Label Clinical Trial of CPI-613 in Patients with Advanced Bile Duct 
Cancers 
CCCWFU # 59212 
 
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trial, must be registered with the CCCWFU Protocol Registrar or entered into the Oncology 
Research Information System (ORIS) Screening Log 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: 
 
1. Complete the Eligibility Checklist (Appendix A) 
2. Complete the Protocol Registration Form (Appendix A) 
3. 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. 
 
4. 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. 
 
To complete the registration process, the Registrar will: 
 assign a patient study number 
 register the patient on the study 
 
 


Comprehensive Cancer Center of Wake Forest University 
A Pilot Study: Open-Label Clinical Trial of CPI-613 in Patients with Advanced Bile Duct Cancers 
CCCWFU # 59212 
 
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5.0 STUDY PROCEDURES 
Table 5-1 (below) provides an overview of the study procedures for the pre-study screen and pre-cycle 1 treatment period. The specifics are described 
in subsequent sections. 
Table 5-1:  Study Procedures for Pre-Study Screen and Pre-Cycle 1 Treatment Period 
 
Assessments 
 
Pre-Study Screen8 
Pre-Cycle 1 treatment 
(Given Only Once for Each Patient) 
Days 1-5 
Days 6-7 
CPI-6131 
 
 
 
Medical history 
 
 
 
Pregnancy test for women of child-bearing potential 
 
 
 
Evaluation of symptoms and vital signs 
3 
4 
 
ECOG performance status and survival 
 
 
 
Clinical chemistry, hematology and coagulation2 
 
5 
 
Cardiac:  Troponin I  
 
5 
 
Cardiac:  ECG 
 
5 
 
CT w/ contrast (chest/abdomen/pelvis) 
 
 
 
CA-19-9 
 
 
 
Plasma CPI-613 concentrations, possibly metabolite concentrations, and 
possibly other analyses6 
 
7 
 
Optional blood and serum samples 9 
 
 
 
Adverse event evaluation 
 
 
 
ECOG = Eastern Cooperative Oncology Group; hr = hour; min = minute. 
1 CPI-613 is given as a 2-hr IV infusion via a central venous catheter.  
2 Specific chemistries are listed in section 5.2.2. Renal function will be assessed utilizing the Cockcroft-Gault formula.  Coagulation (PT/PTT) will only be 
assessed at screening. 
3 Other than evaluation of symptoms and vital signs, height and weight, physical exam, and medications are also determined during pre-study medical screening. 
4  Perform on Days 1 and 4 only. 
5 Perform on Days 1 and 5 only. 
6 Obtained according to the following schedule: pre-dose (~5 min before dosing), and at 0.5, 1, 1.5, 2, and 4 hrs post-dose of CPI-613. 
7  Day 1 only 
8 Pre-study screening tests, which are also enrollment evaluations, must be performed according the following time frames: 
Within 4 weeks:  tumor assessment (CT w/ contrast), CA-19-9 
Within 2 weeks:  medical history, physical exam, vital signs, height, weight, ECG, ECOG, evaluation of symptoms and medications, clinical chemistry, 
hematology, coagulation, and troponin  
Within 1 week:  pregnancy test for women of child-bearing potential, pre-study labs and ECG obtained before enrollment may be used for Day 1 
9 Optional blood and serum samples are for possible testing of biomarkers, predictors of biological responses, toxicity, genotype vs. drug response relationship, 
etc. 


Comprehensive Cancer Center of Wake Forest University 
A Pilot Study: Open-Label Clinical Trial of CPI-613 in Patients with Advanced Bile Duct Cancers 
CCCWFU # 59212 
 
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Table 5-2 (below) provides an overview of the study procedures for all treatment cycles and the follow-up period. The specifics are described in 
subsequent sections. 
Table 5-2:  Study Procedures for All Treatment Cycles and Follow-Up Period 
 
 
 
 
Assessments 
Cycles 1 and 2 
(Each cycle is 4 weeks) 
Cycles 3 through 12 
(Each cycle is 4 weeks) 
 
Follow-Up 
Week  
1 
Week  
2  
Week  
3 
Week  
4 
Week  
1 
Week  
2 
Week  
3 
Week  
4 
Every 2 months 
until death 
D1 D4 D1 D4 D1 D4 D3,4,or 5 D1 D4 D1 D4 D1 D4 D3, 4, or 5 
 
CPI-6131 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Evaluation of symptoms and vital signs 
2 
 
2 
 
2 
 
 
2 
 
2 
 
2 
 
 
 
ECOG performance status and survival 
2 
 
2 
 
2 
 
 
2 
 
2 
 
2 
 
 
 
Clinical chemistry, hematology 2,3,9 
2 
 
 
 
 
 
 
2 
 
 
 
 
 
 
 
Cardiac:  Troponin I and ECG9 
2 
 
 
 
 
 
 
2 
 
 
 
 
 
 
 
CT w/ contrast (chest/abdomen/pelvis) 
 
 
 
 
 
 
 
 
 
 
 
 
 
4 
 
CA-19-9 
 
 
 
 
 
 
 
 
 
 
 
 
 
4 
 
Plasma CPI-613 concentrations, possibly 
metabolite concentrations, and possibly other 
analyses 6 
8 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Optional blood and serum samples10 
 
 
 
 
 
 
 
 
 
 
 
 
 
4 
 
Phone contact 
7 
ECOG = Eastern Cooperative Oncology Group; hr = hour; min = minute; D1 = day 1; D4 = day 4. 
1 CPI-613 is given as a 2-hr IV infusion via a central venous catheter.  Treatment with CPI-613 may be adjusted +/- 1 day. 
2 These tests are performed with results available for review within 24 hrs before administration of the anti-tumor agents.   
3 Specific chemistries are listed in section 5.2.2. Renal function will be assessed utilizing the Cockcroft-Gault formula.  
4 Performed at the following time points: during week 4 (preferably Wednesday or later) of cycle 3 for all patients.  For patients without progression, 
perform during week 4 of cycles 6, 9, and 12.  In patients where progression was detected from the cycle 3 scan, perform during week 4 of cycle 5.  
If patient remains on study after cycle 5, perform every 3 months thereafter. 
6   Plasma samples will be obtained pre-dose (~5 min before dosing), and at 0.5, 1, 1.5, 2, and 4 hrs post-dose of CPI-613. 
7   Survival and post-study cancer treatment will be monitored bimonthly via telephone contact after the patients are taken off the trial. 
8  Cycle 1 only 
9  Within 1 week:  pre-study labs and ECG obtained before enrollment may be used for Day 1 
10 Optional blood and serum samples are for possible testing of biomarkers, predictors of biological responses, toxicity, genotype vs. drug response 
relationship, etc. 
 


Comprehensive Cancer Center of Wake Forest University 
A Pilot Study: Open-Label Clinical Trial of CPI-613 in Patients with Advanced Bile Duct 
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CCCWFU # 59212 
 
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5.1 
Pre-Study Screening Tests and Safety Assessment 
 
5.1.1 Pre-Study Screening Tests 
 
Pre-study screening tests, which are also enrollment evaluations, must be 
performed according the following time frames: 
 
Within 4 weeks:  tumor assessments based on contrast CT of chest, abdomen, and 
pelvis, and optional blood and serum samples. 
 
Within 2 weeks:  medical history, physical exam, vital signs, height, weight, 
ECG, ECOG, evaluation of symptoms and medications, clinical chemistry, 
hematology, coagulation, and troponin I. 
 
Within 1 week:  pregnancy test for women of child-bearing potential. 
 
5.1.2 Safety Assessment 
 
The safety of CPI-613 will be assessed from the first dose to 1 month after last 
dose of CPI-613.  The assessment will be based on: 
 
- 
evaluation of symptoms 
- 
vital signs 
- 
ECOG performance status and survival 
- 
clinical chemistry 
- 
renal function 
- 
hematology 
- 
coagulation 
- 
cardiac safety assessments via troponin I and ECG 
 
The specifics of the safety tests are described in Section 5.2.  All safety 
assessment tests are performed during screening (performed within 2 weeks prior 
to treatment with CPI-613 during Pre-Cycle 1), on Day 5 during Pre-Cycle 1, and 
prior to each treatment cycle with results available for review within 24 hrs before 
administration the anti-tumor agents. Chemistries, hematology, and renal function 
will also be performed on Days 1 and 4 of each treatment week during the first 2 
cycles.  ECOG performance status and survival will be assessed on Day 1 of each 
treatment week. 
 
 
5.1.3 Tumor Assessment 
 
Tumor response to treatment will assessed at baseline, and initially after the time 
frame encompassing the pre-cycle 1 treatment and the first three cycles  using 


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contrast CT of the chest, abdomen and pelvis  as well as serum levels of tumor 
marker CA-19-9 and performance status. Should the principal investigator 
determine that tumor progression has occurred the patient will be removed from 
the study. Should the principal investigator determine that the patient has stable 
disease or has had a favorable response, those patients will continue treatment 
with CPI-613 for an additional three cycles (approximately three months). At that 
time, patients will then undergo re-imaging contrast CT, CA-19-9 and 
performance status.  
 
According to the Response Evaluation Criteria in Solid Tumors (RECIST), the 
efficacy of treatment for solid tumors is determined by the tumor size. RECIST 
criteria are the golden standard to evaluate the tumor. In this study RECIST 
criteria will be used to evaluate response. However, there is a pseudoprogression 
phenomenon described with the use of CPI-613 in Phase I solid tumor studies 
(Lee et al. 2012). 
 
It is felt that if CPI-613-induces necrosis of the tumor lesion there may be some 
radiographic evidence for increasing size. CPI-613 induces tumor necrosis due to 
its mechanism of action – selectively targeting the altered form of mitochondrial 
energy metabolism in tumor cells, causing changes in mitochondrial enzyme 
activities and redox status, which leads to apoptosis, necrosis, and autophagy of 
tumor cells (2,3,7,17,18).  
 
For the purposes of this study, pseudoprogression will be defined and considered 
in patients who meet RECIST criteria of progression. It will be the treating 
physician’s discretion to continue treatment in this situation if the patient is 
deemed to be getting clinical palliative benefit. In these patients, the study drug 
can be given for another two cycles prior to making definitive determination of 
progression or response.  
. 
Assessment of tumor response will be the responsibility of the principal 
investigator and should be based on radiologic findings (i.e., contrast CT of the 
chest, abdomen, and pelvis, and MRI of the abdomen), CA-19-9 and performance 
status. 
 
OS will be monitored bimonthly via telephone contact after treatment termination. 
(Note:  During the bimonthly post-study telephone contact, information related to 
cancer treatment received after the study will also be collected). OS and PFS will 
be calculated from the first day of treatment. The duration of OS will be measured 
until the date of death or censored at follow-up. The duration of response 
(evaluated by PFS) will be measured from the date a first objective response is 
documented until the first sign of progression assessed by MRI and CT. 
 
**NOTE:  Tumor necrosis alone should not be criteria for determining 


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progression. 
 
Safety and RR of CPI-613 are the primary endpoints, whereas PFS and OS are 
secondary endpoints.  
 
Pseudoprogression will be ruled out by allowing patients to receive the study drug 
for another 2 cycles after the first response assessment before making definitive 
assessment of progression or response. However, patients will not be allowed to 
continue treatment with CPI-613 at the time of “pseudo-progression” if any of the 
following criteria are met: 
 
a. The patient does not meet eligibility criteria set at the start of the protocol. 
b. Biliary function worsens. 
c. The patient has symptomatic progression. 
 
OS will be determined from the first dose of CPI-613 to death, assessed up to 3 
years after the first dose of CPI-613. Post-study survival, medical and cancer 
treatment information will be collected bimonthly via telephone contact after 
treatment termination. 
 
RR is defined as % of patients who experienced a Complete Response (CR) or 
Partial Response (PR).  CR and PR are based on Response Evaluation Criteria in 
Solid Tumor (RECIST) Version 1.1 Eisenhauer et al. 2009). The best response 
recorded from the start of the treatment until Disease Progression (DP) will be 
considered. 
 
PFS will be determined from the first dose of CPI-613 to DP or death due to any 
cause, assessed up to 3 years after the first dose of CPI-613. 
 
5.2 
Specifics of Tests Performed During the Study 
 
Described below are the specifics of the tests performed in this study. 
 
5.2.1 ECOG Performance Status 
 
The ECOG Performance Status scales (Oken et al 1982) will be used to assess 
how a patient's disease is progressing and assess how the disease affects the daily 
living abilities of the patient.  These scales are listed in Table 5.2.1-1 (below).  
The higher the ECOG score, the worse the prognosis. 
 
 
 
 
 


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Table 5.2.1-1:  Scales Used in ECOG Performance Status 
Grade 
ECOG 
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 
 
5.2.2 Clinical Chemistry, Hematology and Coagulation 
 
Clinical chemistry assessed includes: 
 
glucose 
BUN 
creatinine 
AST/serum glutamic-oxaloacetic transaminase 
(SGOT) 
total protein 
ALT/serum glutamic-pyruvic transaminase (SGPT) 
albumin 
alkaline phosphatase (ALP) 
Na+ 
total bilirubin 
K+ 
 
Cl- 
 
Mg 
 
Ca+2 
 
PO4 
 
CO2 
 
 
Hematology includes: 
 
complete blood count 
hemoglobin 
differential count 
hematocrit 
platelet count 
 
 
Coagulation includes: 
 
Prothrombin 
time 
Partial thromboplastin time 
 
 
 
Cardiac assessment includes: 
 
 
 
Troponin I 
 
 
 
ECG 
 


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5.2.3 Analyses of Plasma CPI-613 Concentrations, Possibly Metabolite 
Concentrations, and Possibly Other Analyses 
 
Plasma samples for the determination of CPI-613 concentrations, possibly 
metabolite concentrations and possibly other analyses will be obtained before and 
at various times after dosing of CPI-613 on Day 1 of Pre-Cycle 1 & Day 1 of 
Cycle 1 at the following time points:  ~5 min before dosing, and at 0.5, 1, 1.5, 2, 
and 4 hrs post-dose of CPI-613. 
 
Blood (4 mL for each sample) should be obtained from a peripheral vein, and not 
from a central venous catheter. The blood samples should be collected in 4-mL 
lavender top collection tubes containing K2-EDTA anticoagulant. The procedures 
for obtaining plasma samples are described in subsequent sections. 
 
The specific procedures for collecting the blood samples are: 
Sample Collection: 
 
1. Collect 4 mL of blood into K2-EDTA plasma tubes. 
2. Blood samples should be processed within 30 minutes of collection and 
kept on ice or in an ice block until processing. 
3. Turn the filled tube upside down and then return it to the upright position.  
Do this 8-10 times.  Do not shake or vortex the tube.  You can also place 
the tubes on a mechanical shaker for 10 minutes to ensure full mixing. 
4. The samples are then immediately centrifuged (< 1300x g for 10 minutes). 
There should be ~2 mL of plasma from each 4 mL blood sample. 
5. The plasma fraction should then be transferred in approximately equal 
fractions using a disposable pipette to two 1.8-mL Nunc cryovial 
(provided by Cornerstone) and immediately frozen. The total time from 
collection to freezing should not exceed 60 minutes.  The recommended 
temperature for sample storage is -80°C (or lower). 
 
Sample Tube Labeling 
 
Each sample vial should be marked with a unique identifier, to be provided by 
Cornerstone. The unique identifier include the date and time of collection, 
dose, and subject number.  A separate document (the “PK Sample Collection 
Log”) should then identify the number as it pertains to dosage, date, time of 
collection, etc. 
 
Sample Tube Shipment 
 
When all samples from each patient have been collected, they should be 
shipped to Cornerstone Pharmaceuticals, Inc., to the attention of Asela Boteju. 


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Sample vials should be kept frozen during shipment through the use of dry 
ice.  Boxes should contain 30-40% of the box volume in dry ice, or enough to 
keep the samples frozen for at least three days.  Dry ice pellets, as opposed to 
a single slab of dry ice, are preferred and should surround the sample. 
 
Samples should be shipped via priority overnight courier Monday, Tuesday or 
Wednesday to ensure arrival before the end of the business week.  Do not ship 
during a holiday week or when severe weather is expected that may delay the 
shipment either at the final destination or transfer points. 
 
Ensure that the total package weight does not exceed 27.2 kg (60 pounds).  
Notify the contract lab via email on the morning of the shipment day.  The 
contract labs and the email addresses are: 
 
Lab: 
Cornerstone Pharmaceuticals, Inc. 
Email Address: 
Asela@cornerstonepharma.com 
 
Documentation Accompanying Shipment 
 
Each shipment should contain the following information on a document 
separate from the sample vials (the PK Sample Collection Log).  The 
document should be placed in an envelope taped to the outside of the 
Styrofoam container but inside the outer cardboard box. 
 
Also, send an email to give Asela Botejuat Cornerstone Pharmaceuticals, Inc. 
notice that the shipment is coming.  The email should provide the protocol 
number, number of insulated boxes being shipped, a scan of the PK Sample 
Collection Logs of the patient samples being shipped, the name of the express 
courier including the tracking number and the method of shipment (preferably 
FedEx Priority Overnight), and expected date and time of arrival, plus the 
contact information of the person at Wake Forest University Health Sciences 
who is responsible for the shipment. 
Shipment Address 
Samples should be shipped to: 
 
Asela BotejuCornerstone Pharmaceuticals, Inc. 
1 Duncan Drive 
Cranbury, NJ 08512-3629 
Office Tel:  609-409-7050 ext. 212 
Mobile Tel: (609) 423-9804Fax: (609) 409-6035 
Email: Asela@cornerstonepharma.com 
 
CPI-613 and Metabolite Assays 
Plasma concentrations of CPI-613 and possibly metabolites will be assayed 


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using the validated Liquid Chromatography (LC)-Mass Spectroscopy/Mass 
Spectroscopy (LC/MS/MS) method (Cornerstone Study# VLD-002).  
Individual and mean plasma concentrations of CPI-613 and possibly 
metabolites for each patient will be tabulated at each time point and presented 
graphically. The following parameters will be estimated in all patients (as 
appropriate) from individual plasma concentration vs. time data: 
 
- the maximum observed concentration (Cmax) 
- area under the curve from time zero until the last measurable concentration 
(AUC0-t, calculated by the linear trapezoidal rule and extrapolated to 
infinity by acceptable methods) 
- area under the curve from time zero to infinity (AUC0-infinity) 
- Kel  (estimated by linear regression of the terminal elimination phase) 
- t1/2 
- Cl 
- Vd 
- Cend 
 
5.2.4 Optional Sampling and “Banking” of Blood and SerumSamples 
 
Optional blood and serum samples (10 mL and 8.5 mL, respectively) 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 (within 4 weeks prior to 1st 
dose), as well as prior to each restaging scan. 
 
Whole Blood Samples 
 
 Samples (10 mL each) will be collected into a green top sodium heparin 
Vacutainer® tube. 
 Invert the tube a minimum of 10 times to mix the anticoagulant (sodium 
heparin) completely, then place sample on crushed ice. 
 Label sample and store at refrigerated temperature (2-8°C). 
 Samples will be shipped on cold pack to the address shown at the bottom 
of this section within 24-48 hours. 
Serum Samples 
 
 Collect blood (8.5 mL each) in serum separator tube (10.0mL, with 
Polymer gel/Silica activator). 
 Gently invert the tube 8-10 times, and let tube sit in an upright position for 
at least 15-30 minutes at room temperature to allow the blood to clot. 
 Within 2 hours from time of collection while at room temperature, spin the 
tubes at 1000x g using a standard room temperature centrifuge for 10-15 


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minutes. 
 After centrifugation, pipette 1.0 mL aliquots of plasma into each of the 1.8 
mL-size polypropylene screw-capped cryovials. Expect to collect between 
3-5 cryovials each containing 1.0 mL aliquots of plasma. 
 Label the aliquots. 
 Quickly freeze the aliquots by placing them either on dry ice or in a –70°C 
freezer. Store the samples at –70°C or colder until shipment. 
 Samples will be shipped on dry ice to the address shown at the bottom of 
this section 
 
Shipment of Optional Samples 
 
All optional samples and specimens should be shipped to: 
 
Asela BotejuCornerstone Pharmaceuticals, Inc. 
1 Duncan Drive 
Cranbury, NJ 08512 
Tel:  (609) 409-7050 ext.215 
Fax: (609) 409-6035 
Email: Asela@cornerstonepharma.com 
 
 


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6.0 TREATMENT WITH CPI-613 
 
CPI-613 will be administered to patients as shown in Table 6-1 (below). Briefly, a treatment 
cycle is 4 weeks, with CPI-613 given on Days 1 and 4 of the first 3 weeks. CPI-613 will also be 
given for 5 consecutive days a week before the start of Cycle 1, and this Pre-Cycle 1 treatment 
will only be given once in each patient. During Pre-Cycle 1 and each treatment cycle, patients 
will be treated with CPI-613 at the same dose, unless dose modification is warranted (see Section 
6.2). 
Table 6-1:  Administration of CPI-613 in Patients with Advanced Cholangiocarcinoma 
Treatment Cycle 
Administration of CPI-613 
 
Week 
Day 
 
Pre- 
Cycle 1 
(1 week) 
1 
1 
2-hr IV infusion via a central venous catheter 
 
2 
2-hr IV infusion via a central venous catheter 
 
3 
2-hr IV infusion via a central venous catheter 
 
4 
2-hr IV infusion via a central venous catheter 
 
5 
2-hr IV infusion via a central venous catheter 
Cycle 1 
(4 weeks) 
1 
1 
2-hr IV infusion via a central venous catheter 
 
4 
2-hr IV infusion via a central venous catheter 
2 
1 
2-hr IV infusion via a central venous catheter 
 
4 
2-hr IV infusion via a central venous catheter 
3 
1 
2-hr IV infusion via a central venous catheter 
 
4 
2-hr IV infusion via a central venous catheter 
4 
 
 
Cycle 2 
(4 weeks) 
1 
1 
2-hr IV infusion via a central venous catheter 
 
4 
2-hr IV infusion via a central venous catheter 
2 
1 
2-hr IV infusion via a central venous catheter 
 
4 
2-hr IV infusion via a central venous catheter 
3 
1 
2-hr IV infusion via a central venous catheter 
 
4 
2-hr IV infusion via a central venous catheter 
4 
 
 
Etc. up to a total 
of 12 cyclesa 
 
 
 
hr = hour; IV = intravenous; min = minutes. 
a Additional cycles can be given if the investigator considers it beneficial to do so. 
 
6.1 
Dose Levels, Dose Escalation, Sample Size and Justification of the Dose 
 
6.1.1 Dose Levels, Dose Escalation and Sample Size 
 
The dose levels to be used in assessing the safety and anti-cancer activities of 
CPI-613 in 10 patients with advanced bile duct cancers will be determined from a 
dose-escalation scheme using cohorts of patients with advanced bile duct cancers, 
as described below. The dose-escalation scheme is based on the number of 
patients exhibiting dose-limiting toxicity (DLT), and DLT is defined as toxicity of 
Grade 3 or higher attributed as probably or definitely related to CPI-613. The 
DLT determining period for all cohorts in the dose-escalation scheme is through 
the first cycle. 
 


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Cohort 1:  The first 3 patients will not be treated with the 5 daily doses of CPI-
613 during the pre-Cycle 1 week, and will only be treated with 3-weeks-on-1-
week-off treatment cycles (see Table 6-1). The dose of CPI-613 will be 2,300 
mg/m2 (which is approximately three-quarters of the target dose). If none of 
these 3 patients develop a dose-limiting toxicity (DLT) through Cycle 1, the 
dose for the 3-weeks-on-1-week-off treatment cycles will be 3,000 mg/m2 in all 
subsequent patients in this trial.  However, if a DLT is observed in a patient 
(whether it is the 1st, 2nd or 3rd of the 3 intended patients), the number of patients 
in this cohort will be expanded to a maximum of 6 patients.  If no DLT is 
observed in another patient out of a maximum of 6 patients, the dose for the 3-
weeks-on-1-week-off treatment cycles will be 3,000 mg/m2 in all subsequent 
patients in this trial. However, once DLT is observed in 2 patients, no additional 
patients will be treated at 2,300 mg/m2 for the 3-weeks-on-1-week-off treatment 
cycles from that point on, even though the total number of patients in this cohort 
is as few as 2. The dose level of 2,300 mg/m2, which induces a DLT in 2 or 
more patients, is considered to be above the maximum tolerated dose (MTD) for 
the 3-weeks-on-1-week-off treatment cycles. In this case, all subsequent patients 
in this trial will be treated at 1,700 mg/m2 for the 3-weeks-on-1-week-off 
treatment cycles. 
 
Cohort 2:  In another 3 patients, the dose of CPI-613 for the 3-weeks-on-1-week-
off treatment cycles will be as determined from Cohort 1. These patients will 
also be treated with the 5 daily doses of CPI-613 during the pre-Cycle 1 week.  
The dose of CPI-613 for the pre-Cycle 1 week will be 1,200 mg/m2/day, which 
has previously been established to be the weekly MTD (see Section 6.1.2). If 
none of these 3 patients develop a DLT, the study can move onto Cohort 3. 
 
However, if a DLT is observed in a patient (whether it is the 1st, 2nd or 3rd of the 
3 intended patients), the number of patients in this cohort will be expanded to a 
maximum of 6 patients. If no DLT is observed in another patient out of a 
maximum of 6 patients, the study will move onto Sub-Cohort 2 (see below).  
However, if a DLT is observed in 2 patients, no additional patients will be 
treated at 1,200 mg/m2/day during the pre-Cycle 1 week even though the total 
number of patients at this cohort is as few as 2. The dose level of 1,200 
mg/m2/day during the pre-Cycle 1 week, which induces a DLT in 2 or more 
patients, is considered to be above the MTD for the pre-Cycle 1 week. In this 
case, the dose of CPI-613 for the pre-Cycle 1 week in subsequent patients in this 
trial will be 600 mg/m2/day (or 3,000 mg/m2/week, equivalent to the MTD 
when given as a single dose). 
 
Sub-Cohort 2:  Sub-Cohort 2 is activated only if 1 out of 6 patients exhibits 
DLT in Cohort 2. There are 3 patients in this sub-cohort, the dose of CPI-613 
for the 3-weeks-on-1-week-off treatment cycles will be as determined from 
Cohort 1. These patients will also be treated with the 5 daily doses of CPI-613 


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during the pre-Cycle 1 week. The dose of CPI-613 for the pre-Cycle 1 week 
will be 1,700 mg/m2/day. If none of these 3 patients develop a DLT, the study 
can move onto Cohort 3. However, if a DLT is observed in a patient (whether 
it is the first, second or third of the 3 intended patients), the number of patients 
in this cohort will be expanded to a maximum of 6 patients. If no DLT is 
observed in another patient out of a maximum of 6 patients, the study will 
move onto Cohort 3. However, if a DLT is observed in 2 patients, no 
additional patients will be treated at 1,700 mg/m2/day during the pre-Cycle 1 
week even though the total number of patients at this sub-cohort is as few as 
2. The dose level of 1,700 mg/m2/day during the pre-Cycle 1 week, which 
induces a DLT in 2 or more patients, is considered to be above the MTD for 
the pre-Cycle 1 week.  In this case, the dose of CPI-613 for the pre-Cycle 1 
week in subsequent patients in this trial will be 600 mg/m2/day (or 3,000 
mg/m2/week, equivalent to the MTD when given as a single dose). 
 
Cohort 3:  This cohort will be performed only if DLT is observed in Cohort 2, or 
DLT is observed in 1 or less patients in Sub-Cohort 2.  There are 3 patients in 
this cohort, and the dose of CPI-613 for the 3-weeks-on-1-week-off treatment 
cycles will be as determined from Cohort 1.  The dose for the 5 daily IV 
infusions during the pre-Cycle 1 week will be 2,300 mg/m2/day.  If none of 
these 3 patients develop a DLT, the study can move onto Cohort 4.  However, if 
a DLT is observed in a patient (whether it is the 1st, 2nd or 3rd of the 3 intended 
patients), the number of patients in this cohort will be expanded to a maximum 
of 6 patients.  If no DLT is observed in another patient out of a maximum of 6 
patients, the study will move onto Cohort 4.  However, if a DLT is observed in 
2 patients, no additional patients will be treated at 2,300 mg/m2/day during the 
pre-Cycle 1 week even though the total number of patients at this sub-cohort is 
as few as 2.  The dose level of 2,300 mg/m2/day during the pre-Cycle 1 week, 
which induces a DLT in 2 or more patients, is considered to be above the MTD 
for the pre-Cycle 1 week.  In this case, the dose of CPI-613 for the pre-Cycle 1 
week in subsequent patients in this trial will be 1,700 mg/m2/day. 
 
Cohort 4:  This cohort will be performed only if DLT is observed in 1 or less 
patients in Cohort 3.  There are 3 patients in this cohort, and the dose of CPI-
613 for the 3-weeks-on-1-week-off treatment cycles will be as determined from 
Cohort 1.  The dose for the 5 daily IV infusions during the pre-Cycle 1 week 
will be 3,000 mg/m2/day.  If none of these 3 patients develop a DLT, the study 
can move onto Cohort 5.  However, if a DLT is observed in a patient (whether it 
is the first, second or third of the 3 intended patients), the number of patients in 
this cohort will be expanded to a maximum of 6 patients.  If no DLT is observed 
in another patient out of a maximum of 6 patients, the study will move onto 
Cohort 5.  However, if a DLT is observed in 2 patients, no additional patients 
will be treated at 3,000 mg/m2/day during the pre-Cycle 1 week even though the 
total number of patients at this cohort is as few as 2.  The dose level of 3,000 


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mg/m2/day during the pre-Cycle 1 week, which induces a DLT in 2 or more 
patients, is considered to be above the MTD for the pre-Cycle 1 week.  In this 
case, the dose of CPI-613 for the pre-Cycle 1 week in subsequent patients in this 
trial will be 2,300 mg/m2/day 
 
Cohort 5:  This cohort is performed once the dose of CPI-613 for the 3-weeks-on-
1-week-off treatment cycles has been determined from Cohort 1, and once the 
dose of CPI-613 for the pre-Cycle 1 week has been determined from Cohort 2-
4.  There are 10 patients in this cohort.  These patients will be treated with CPI-
613 for 5 days during the pre-Cycle 1 week at doses as determined from 
Cohorts 2-4, and the dose of CPI-613 for the 3-weeks-on-1-week-off treatment 
cycles will be as determined from Cohort 1. 
 
6.1.2 Justification of the Dose 
 
Based on Phase I trials in patients with solid tumors and hematologic 
malignancies, 3,000 mg/m2 is the MTD, when CPI-613 is given as a single agent 
infused over 2 hours on Days 1 and 4 for 3 weeks of a 4-week treatment cycle.  
CPI-613 did not induce any significant adverse effects at or below MTD. 
Additionally, CPI-613 at or below 3,000 mg exhibits anti-tumor activities in 
patients with various types of solid and hematologic malignancies (Pardee et al, 
2011a and b, & 2012; Lee et al. 2011 & 2012; Senzer et al 2012). Because of the 
safety and efficacy against other cancers, 3,000 mg/m2 is the target dose for this 
pilot study. 
 
In this study, patients will be treated with CPI-613 for 5 consecutive days during 
pre-Cycle 1, prior to being treated with CPI-613 given 2x weekly for 3 weeks. A 
sub-MTD (2,300 mg/m2, approx. three-quarters of the MTD) will be used in the 
first 3 patients (in Cohort 1) who will be treated with the 4-week treatment cycles 
and without treatment during the pre-Cycle 1 week to ensure safety, before 
initiating the dose escalation procedure to determine the MTD. The maximum 
plasma concentration (Cmax) of CPI-613 associated with the dose level of 2,300 
mg/m2 is ~90 μM, which is significantly lower than the Cmax of ~200 μM 
associated with 3,000 mg/m2. Therefore, 2,300 mg/m2 is expected to be a safe 
starting dose. 
 
After determining the dose to be used in 3-weeks-on-1-week-off cycles, the safety 
of the dailyx5 treatment with CPI-613 during pre-Cycle 1 will be evaluated in a 
dose-escalated manner in Cohorts 2-4.   
 
 
 


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6.2 
Dosing Delay and Dose Modification of CPI-613 in the Event of Adverse 
 
Events 
 
For adverse events unrelated to serum creatinine elevation or reduction in renal function 
but are possibly related to CPI-613, the occurrence of Grade 1 toxicity does not generally 
require dose modification for subsequent doses for that patient.  However, if Grade 2 
toxicity (other than alopecia and nausea) probably related to CPI-613 develops, treatment 
is to be withheld and 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 occurs.  Grade 2 alopecia and nausea 
do not require withholding treatment or dose reduction.  If Grade 3 or 4 toxicity probably 
related to CPI-613 develops, dosing of CPI-613 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 with CPI-613 for a patient who has had CPI-613-related 
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 to 50% of the dose at 
which such Grade 3 or 4 toxicity occurs. 
 
For adverse events related to creatinine elevation or reduction in renal function that are 
possibly related to CPI-613, dosing of the patient will be withheld even if the severity 
level is Grade 2 or above.  Treatment can resume only after the toxicity has been reduced 
to Grade 1.  The dose level for subsequent doses for that patient will be reduced by 15% 
if the severity level is of Grade 1, by 25% for Grade 2 toxicity, and by 50% for Grade 3 
or 4 toxicity. 
 
Furthermore, if the toxicity possibly related to CPI-613 is acute renal failure and the 
severity level is Grade 3 or 4, further patient enrollment will be temporarily suspended in 
order to enable assessment of the following aspects of the trial and implementation of 
corrective measures or protocol amendment, and if necessary: 
 
- compliance of the study sites and investigators to the study protocol 
- evaluation of the appropriateness of the procedures for monitoring renal function 
 
6.3 
Duration of Treatment for Each Patient at Each Cohort 
 
Twelve cycles of treatment is recommended for patients who have a response, unless or 
until: 
 
- 
Patients exhibit progression of disease together with worsening of biliary 
function, no longer meeting eligibility criteria, or exhibiting symptomatic 
progression; or patients exhibit progression of disease which was confirmed after 
1 additional treatment cycles 
- 
Unacceptable toxicity from CPI-613 
- 
Patient withdrawal of consent 


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- 
Investigator’s discretion to withdraw patients from the study because continued 
participation in the study is not in the patient’s best interest. 
- 
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 
 
When terminating treatment during this trial, the investigator should make every effort to 
contact the patient and to perform a final evaluation.  Also, the reason(s) for withdrawal 
from the study must be recorded. 
 
All patients will be followed until death. 
 
Additional treatment cycles beyond the recommended 12 cycles can be given if the 
investigator considers it beneficial to do so. 
 
7.0 STUDY DRUG - CPI-613 
 
7.1 
Description of CPI-613 Drug Product 
 
CPI-613 is provided in 10-mL amber glass vials.  Each vial contains 10 mL of CPI-613 at 
a concentration 50 mg/mL, 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.   
 
7.2 
Handling of CPI-613 
 
CPI-613 is an investigational drug and its 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. 
 


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7.3 
Storage of CPI-613 
 
CPI-613 should be stored under refrigeration, at 2˚-8˚C (36˚-46˚F), except when being 
prepared for administration. 
 
7.4 
Intravenous (IV) Infusion Sets, Syringes and IV Bags to be Used for 
 
Administration of CPI-613 
 
CPI-613 must be administered IV by infusion, via an IV catheter with D5W running at a 
rate of about 125-150 mL/hr.  To avoid local reactions at and around the site of 
administration, CPI-613 should be administered via a central venous catheter.  
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 the IV sets, IV bags and syringes that do not contains DEHP and therefore 
can be used in the administration of CPI-613 are: 
 
Extension Set for Syringe Pump Use:  All extension sets from MED-RX do not contain 
DEHP. 
 
Syringes:  Kendall Monoject syringes, all mono-ject syringes are DEHP free. 
 
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 administer 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-free:  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 


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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. 
 Norm-Ject, polyethlyene barrel, polyethylene plunger, latex free (Henke Sass Wolf 
GMBH) syringes 
 Becton Dickinson syringes 
 Terumo syringes 
 Monoject syringes 
 Glass syringes 
 
7.5 
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, precipitate 
or coloration (other than colorless) 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 an IV catheter that is free flowing and free of air in 
the dead space of the IV catheter, 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).  To avoid local reactions at and around the site of administration, CPI-613 must be 
administered via a central venous catheter.   
 
CPI-613 must not be administered as a bolus, but by infusion, 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.  This is 
to 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. 
C. Confirmation that the IV line is free of dead air space. 
D. Dilute CPI-613 drug product with D5W, as instructed in the study protocol. 
E. Administer CPI-613 by infusion, not as a bolus. 
F. After administration of CPI-613, flush the IV line with ~10 mL of D5W to remove 


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residual CPI-613. 
G. To avoid local reactions at and around the site of administration, CPI-613 should be 
administered via a central venous catheter.   
 
7.6 
Request for CPI-613 
 
CPI-613 must be requested from Cornerstone 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.  Cornerstone 
policy requires that CPI-613 be shipped directly to the institution where the patient is to 
be treated.  Cornerstone does not permit the transfer of CPI-613 between institutions 
(unless with prior written approval from Cornerstone).  Requests must be submitted to 
Cornerstone by fax or email to the following address:  
 
Ms. Claudia Maturo 
Department of Regulatory and Clinical Affairs 
Cornerstone Pharmaceuticals, Inc. 
25 Health Sciences Drive 
Stony Brook, NY 11790 
Telephone: 631-444-6868 
Telefax: 631-444-6895 
Email:  claudia@cornerstonepharma.com 
 
The following information must be provided in the request of CPI-613 from 
Cornerstone: 
 
- 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 
 
7.7 
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. 
 
The investigator, or the designee, will be responsible for dispensing and accounting of 
CPI-613 provided by Cornerstone and for exercising accepted medical and pharmacy 
practices. 


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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 Cornerstone, or its designee, during periodic 
monitoring visits. 
 
7.8 
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 destroyed according to the policy of the 
institution.  The destruction of CPI-613, and the quantity destroyed, must be 
documented.  A copy of the Certificate of Destruction should be sent to: 
 
Ms. Claudia Maturo 
Department of Regulatory and Clinical Affairs 
Cornerstone Pharmaceuticals, Inc. 
25 Health Sciences Drive 
Stony Brook, NY 11790 
Telephone: 631-444-6868 
Telefax: 631-444-6895 
Email:  claudia@cornerstonepharma.com 
 
7.9 
Calculation of the Amount of CPI-613 for Each Patient 
 
The amount of CPI-613 at each dose level is based on the BSA of the patient. The BSA 
values will be calculated based on the height and body weight taken during screening and 
this BSA value is used throughout the study. This is unless there is a >10% change in the 
body weight from baseline during the study. At that point, BSA should be revised based 
on the new body weight and height. The new BSA values will be used from that point on 


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for the remainder of the study, unless there is another >10% change in body weight which 
will require another revision of the BSA. 
 
7.10 
Concomitant Medications and Prophylactic Treatment 
 
Patients cannot receive any standard or investigational treatment (except CPI-613) for 
their cancer, or any other investigational drugs for any indications, while on this study.  
All otherwise permitted concomitant medications (including trade and generic names, 
dosage and dosing schedule) must be recorded. 
 
Prophylactic treatment for drug-related symptoms is not planned, or it will interfere with 
the assessment of the toxicity of the investigational product. However, following the 
evaluation of the causal relationship of the symptom(s) to the study drug and the 
information has been documented, the investigator may prescribe supportive treatment.  
Supportive treatment may include anti-emetic, anti-diarrhea, anti-pyretic, anti-allergic, 
anti-hypertensive medications, analgesics, antibiotics, allopurinol, and others such as 
blood products and bone marrow growth factors.  Patients may use erythropoietin for 
chronic anemia.  Also, the hemoglobin should be maintained ≥9 g/dL or ≥90 g/L during 
the course of the study.  The treating physician may utilize erythropoietic factors, or 
blood or platelet transfusions at their discretion. 
 
8.0 ADVERSE EVENTS LIST AND REPORTING REQUIREMENTS 
 
8.1 
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. 
 
List of Adverse Events to be Reported: 


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*Abdominal pain 
Alkaline phosphatase 
ALT (SGPT) 
Anorexia 
AST (SGOT) 
Bilirubin (hyperbilirubinemia) 
Calcium (hypercalcemia, hypocalcemia) 
*Creatinine 
*Diarrhea 
Flushing 
Hemoglobin (anemia) 
*Injection site Reaction 
Leukocytes 
Lymphopenia 
*Nausea 
Neutrophils (neutropenia) 
Platelets (thrombocytopenia) 
Potassium 
Sodium 
*Vomiting 
 
All grade 3, 4, 5 adverse events should be reported on flowsheets and in ORIS regardless 
of whether they are on this list. 
 
Asterisk (*) denotes expected Adverse Events. 
 
All Serious Adverse Events (SAEs) which are Possibly, Probably or Definitively Related 
to CPI-613, and Unexpected are required to be reported to Cornerstone Pharmaceuticals 
via the provided SAE Reporting Form within 7 days.  All completed forms must be sent 
to Claudia Moore at Cornerstone.  Cornerstone will submit any applicable SAEs to the 
FDA.   
 
 
SAE reports must be submitted to Cornerstone by fax or email to the following address: 
 
Department of Regulatory and Clinical Affairs 
Cornerstone Pharmaceuticals, Inc. 
25 Health Sciences Drive 
Stony Brook, NY 11790 
Telephone: 631-444-6868 
Telefax: 631-794-2319 
      Email: claudiamoore2001@yahoo.com 
 
8.2 
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 


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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.  
 
8.3  
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 
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 


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safety, rights or welfare of research subjects. 
 
9.0 STATISTICAL CONSIDERATIONS 
 
This is a pilot study with the primary goal to be able to determine initial estimates of RR, and 
secondary goals to determine PFS and OS. Data from this trial will also provide additional data 
concerning the safety profile of the CPI-613 therapy. Since there is some uncertainty about what 
dose to examine for the 10 patients in this pilot study we propose the following pre-defined dose 
escalation scheme in order to determine the appropriate dose to provide to 10 patients with 
advanced bile duct cancers. This scheme has been discussed/proposed by the FDA and it is very 
specific and is described below. The dose-escalation scheme is based on the number of patients 
exhibiting dose-limiting toxicity (DLT), and DLT is defined as toxicity of Grade 3 or higher.  
The DLT determining period for all cohorts in the dose-escalation scheme is through the first 
cycle. Note – this section is redundant with section 6.1 but is included for completeness. 
 
Cohort 1:  The first 3 patients will not be treated with the 5 daily doses of CPI-613 during the 
pre-Cycle 1 week, and will only be treated with 3-weeks-on-1-week-off treatment cycles (see 
Table 6-1). The dose of CPI-613 will be 2,300 mg/m2 (which is approximately three-quarters of 
the target dose). If none of these 3 patients develop a dose-limiting toxicity (DLT) through Cycle 
1, the dose for the 3-weeks-on-1-week-off treatment cycles will be 3,000 mg/m2 in all 
subsequent patients in this trial. However, if a DLT is observed in a patient (whether it is the 1st, 
2nd or 3rd of the 3 intended patients), the number of patients in this cohort will be expanded to a 
maximum of 6 patients. If no DLT is observed in another patient out of a maximum of 6 patients, 
the dose for the 3-weeks-on-1-week-off treatment cycles will be 3,000 mg/m2 in all subsequent 
patients in this trial. However, once DLT is observed in 2 patients, no additional patients will be 
treated at 2,300 mg/m2 for the 3-weeks-on-1-week-off treatment cycles from that point on, even 
though the total number of patients in this cohort is as few as 2. The dose level of 2,300 mg/m2, 
which induces a DLT in 2 or more patients, is considered to be above the maximum tolerated 
dose (MTD) for the 3-weeks-on-1-week-off treatment cycles. In this case, all subsequent patients 
in this trial will be treated at 1,700 mg/m2 for the 3-weeks-on-1-week-off treatment cycles. 
 
Cohort 2:  In another 3 patients, the dose of CPI-613 for the 3-weeks-on-1-week-off treatment 
cycles will be as determined from Cohort 1. These patients will also be treated with the 5 daily 
doses of CPI-613 during the pre-Cycle 1 week.  The dose of CPI-613 for the pre-Cycle 1 week 
will be 1,200 mg/m2/day, which has previously been established to be the weekly MTD (see 
Section 6.1.2). If none of these 3 patients develop a DLT, the study can move onto Cohort 3. 
 
However, if a DLT is observed in a patient (whether it is the 1st, 2nd or 3rd of the 3 intended 
patients), the number of patients in this cohort will be expanded to a maximum of 6 patients.  If 
no DLT is observed in another patient out of a maximum of 6 patients, the study will move onto 
Sub-Cohort 2 (see below).  However, if a DLT is observed in 2 patients, no additional patients 
will be treated at 1,200 mg/m2/day during the pre-Cycle 1 week even though the total number of 
patients at this cohort is as few as 2.  The dose level of 1,200 mg/m2/day during the pre-Cycle 1 
week, which induces a DLT in 2 or more patients, is considered to be above the MTD for the 


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pre-Cycle 1 week.  In this case, the dose of CPI-613 for the pre-Cycle 1 week in subsequent 
patients in this trial will be 600 mg/m2/day (or 3,000 mg/m2/week, equivalent to the MTD when 
given as a single dose). 
 
Sub-Cohort 2:  Sub-Cohort 2 is activated only if 1 out of 6 patients exhibits DLT in Cohort 2.  
There are 3 patients in this sub-cohort, the dose of CPI-613 for the 3-weeks-on-1-week-off 
treatment cycles will be as determined from Cohort 1.  These patients will also be treated with 
the 5 daily doses of CPI-613 during the pre-Cycle 1 week.  The dose of CPI-613 for the pre-
Cycle 1 week will be 1,700 mg/m2/day.  If none of these 3 patients develop a DLT, the study can 
move onto Cohort 3.  However, if a DLT is observed in a patient (whether it is the first, second 
or third of the 3 intended patients), the number of patients in this cohort will be expanded to a 
maximum of 6 patients.  If no DLT is observed in another patient out of a maximum of 6 
patients, the study will move onto Cohort 3.  However, if a DLT is observed in 2 patients, no 
additional patients will be treated at 1,700 mg/m2/day during the pre-Cycle 1 week even though 
the total number of patients at this sub-cohort is as few as 2.  The dose level of 1,700 mg/m2/day 
during the pre-Cycle 1 week, which induces a DLT in 2 or more patients, is considered to be 
above the MTD for the pre-Cycle 1 week.  In this case, the dose of CPI-613 for the pre-Cycle 1 
week in subsequent patients in this trial will be 600 mg/m2/day (or 3,000 mg/m2/week, 
equivalent to the MTD when given as a single dose). 
 
Cohort 3:  This cohort will be performed only if DLT is observed in Cohort 2, or DLT is 
observed in 1 or less patients in Sub-Cohort 2.  There are 3 patients in this cohort, and the dose 
of CPI-613 for the 3-weeks-on-1-week-off treatment cycles will be as determined from Cohort 1.  
The dose for the 5 daily IV infusions during the pre-Cycle 1 week will be 2,300 mg/m2/day.  If 
none of these 3 patients develop a DLT, the study can move onto Cohort 4.  However, if a DLT 
is observed in a patient (whether it is the 1st, 2nd or 3rd of the 3 intended patients), the number of 
patients in this cohort will be expanded to a maximum of 6 patients.  If no DLT is observed in 
another patient out of a maximum of 6 patients, the study will move onto Cohort 4.  However, if 
a DLT is observed in 2 patients, no additional patients will be treated at 2,300 mg/m2/day during 
the pre-Cycle 1 week even though the total number of patients at this sub-cohort is as few as 2.  
The dose level of 2,300 mg/m2/day during the pre-Cycle 1 week, which induces a DLT in 2 or 
more patients, is considered to be above the MTD for the pre-Cycle 1 week.  In this case, the 
dose of CPI-613 for the pre-Cycle 1 week in subsequent patients in this trial will be 1,700 
mg/m2/day. 
 
Cohort 4:  This cohort will be performed only if DLT is observed in 1 or less patients in Cohort 
3.  There are 3 patients in this cohort, and the dose of CPI-613 for the 3-weeks-on-1-week-off 
treatment cycles will be as determined from Cohort 1.  The dose for the 5 daily IV infusions 
during the pre-Cycle 1 week will be 3,000 mg/m2/day.  If none of these 3 patients develop a 
DLT, the study can move onto Cohort 5.  However, if a DLT is observed in a patient (whether it 
is the first, second or third of the 3 intended patients), the number of patients in this cohort will 
be expanded to a maximum of 6 patients.  If no DLT is observed in another patient out of a 
maximum of 6 patients, the study will move onto Cohort 5.  However, if a DLT is observed in 2 
patients, no additional patients will be treated at 3,000 mg/m2/day during the pre-Cycle 1 week 


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even though the total number of patients at this cohort is as few as 2.  The dose level of 3,000 
mg/m2/day during the pre-Cycle 1 week, which induces a DLT in 2 or more patients, is 
considered to be above the MTD for the pre-Cycle 1 week.  In this case, the dose of CPI-613 for 
the pre-Cycle 1 week in subsequent patients in this trial will be 2,300 mg/m2/day 
 
Cohort 5:  This cohort is performed once the dose of CPI-613 for the 3-weeks-on-1-week-off 
treatment cycles has been determined from Cohort 1, and once the dose of CPI-613 for the pre-
Cycle 1 week has been determined from Cohort 2-4.  There are 10 patients in this cohort.  These 
patients will be treated with CPI-613 for 5 days during the pre-Cycle 1 week at doses as 
determined from Cohorts 2-4, and the dose of CPI-613 for the 3-weeks-on-1-week-off treatment 
cycles will be as determined from Cohort 1. 
As can be seen by the above scheme there are several possible scenarios that could occur in order 
to determine the dose for the 10 patients to be evaluated in the pilot trial. Once the above 
procedure is completed we will then enroll 10 patients at the determined dose. 
Accrual Rate 
We anticipate accruing one patient per month for this protocol. Since the dose escalation 
procedure described above may involve a variable number of patients (at least 6 but possibly 
more) we cannot be certain the entire length of accrual for this protocol.  However, we do 
anticipate that the total number of patients in this protocol will be between 16-40 (with 16-22 
being the most likely range). Thus, we anticipate that we will reach the target sample size of 10 
patients treated at MTD within two years. A minimum of 16 patients to a maximum of 40 
patients will be accrued to the study, with the first 6-30 being evaluated for toxicity in a dose-
escalated manner for determining the MTD, and the remaining 10 used in the analytic sample. 
 
Proposed Analyses 
The analyses for this protocol will be primarily descriptive. With a sample size of 10 treated at 
MTD, we do not expect to see statistically significant effects for the outcomes of interest, 
however this data will provide useful preliminary data on the overall safety and efficacy of CPI-
613 and provide useful data to predict the variability and likely effect sizes for these outcomes.   
 
For the time-to-event outcomes we will estimate survival curves for OS and PFS using Kaplan-
Meier techniques. In addition, we will estimate the 6 month and 1-year OS and PFS rates for 
these participants. For response rate we will present the proportion of patients who are CR, PR, 
SD or PD. In addition, we will estimate the proportion of responders as the percent of patients 
who are CR or PR. For this rate we will also include a 95% confidence interval. 
 
We will also examine toxicities for these 10 patients by looking at each toxicity identified earlier 
in the protocol by grade.   
 
Sample Size Considerations 
Since this is a pilot study we do not anticipate having statistical power to detect specific effects, 
however with this sample size we will be able to estimate the response rate using a 2-sided 95% 
confidence interval with an interval that will extend no more than 0.31 from the observed 


Comprehensive Cancer Center of Wake Forest University 
A Pilot Study: Open-Label Clinical Trial of CPI-613 in Patients with Advanced Bile Duct 
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CCCWFU # 59212 
 
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response rate.  


Comprehensive Cancer Center of Wake Forest University 
A Pilot Study: Open-Label Clinical Trial of CPI-613 in Patients with Advanced Bile Duct 
Cancers 
CCCWFU # 59212 
 
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10.0 REFERENCES 
 
 
1. Eisenhauer EA, Therasse P, et al. 2009.  New response evaluation criteria in solid 
tumours:  Revised RECIST guideline (version 1.1).  European Journal of Cancer.  
45:228-247. 
 
2. Lee K, Khaira D, Rodriguez R, Maturo C, O’Donnell K, Shorr R.  Long-Term Stable 
Disease of Stage IV Pancreatic Neuroendocrine Tumors and Without Significant Adverse 
Effect by CPI-613, an Investigational Novel Anti-Cancer Agent.  Case Study and Case 
Report, 1(3):137-145, 2011. 
 
3. Lee K, Maturo C, Luddy J, Rodriguez R, Shorr R. Pseudo-progression of metastatic 
pancreatic cancer assessed by imaging studies - a case report.  Case Study and Case 
Report 2(3): 95-101,2012. 
 
4. Pardee TS, DeFord-Watts LM, Peronto E, Levitan DA, Hurd DD, Kridel S.  Altered lipid 
and mitochondrial metabolism are viable targets in acute leukemia.  American Society of 
Hematology (ASH).  Abstract# 3618.  53rd Annual Meeting and Exposition, 2011a. 
 
5. Pardee TS, Levitan DA, Hurd DD.  Altered mitochondrial metabolism as a target in acute 
myeloid leukemia.  J Clin Oncol 29: 2011b (suppl; abstr 6590) 
 
6. Pardee TS, DeFord-Watts LM, Peronto E, Levitan DA, Hurd DD, Kridel S, Harrelson R, 
Manuel M, Lyerly S, Powell BL.  Evaluation of the first-in-class antimitochondrial 
metabolism agent CPI-613 in hematologic malignancies.  J Clin Oncol 30: 2012 (suppl; 
abstr 6524) 
 
7. Senzer N, Bedell C, Maturo C, Luddy J, Shorr R, Lee K. CPI-613, an investigational 
novel anti-cancer agent, provides long-term stable disease without significant adverse 
effects in a patient with stage IV relapsed hepatocellular carcinoma. Case Study and Case 
report 2012; 2(2): 38-45,2012. 
 
8. Study COM-001.  2006.  Compatibility Testing of CPI-613 Drug Product - Infusion Sets. 
 
9. Study COM-002. Bhasin R. 2008. Compatibility Testing of CPI-613 Drug Product 
Dosing Solutions with Different Types of Syringes. 
 
10. 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. 
 
11. Study NCL-027.  Seng J.  2006.  Escalating Dose Toxicology Study of Intravenously 
Administered CPI-613 to Miniature Pigs. 


Comprehensive Cancer Center of Wake Forest University 
A Pilot Study: Open-Label Clinical Trial of CPI-613 in Patients with Advanced Bile Duct 
Cancers 
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12. Study NCL-030.  Seng J.  2006.  An Acute Toxicity Study of CPI-613 Administered Via 
the Intravenous (Slow Bolus) Route to Mice. 
 
13. 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. 
 
14. Study PHO-001 (Covance Study# 7769-101).  Potts B.  2007.  Photostability Testing of 
CPI-613 Drug Product. 
 
15. Study STA-010.  Bhasin R. 2007.  Stability of CPI-613 Injection dosing solutions after 
Dilution with 5% Dextrose (D5W). 
 
16. 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. 
 
17. Zachar Z, Marecek J, Maturo Claudia, Gupta S, Stuart S, Howell K, Schauble A, Lem J, 
Piramzadian A, Karnik S, Lee K, Rodriguez R, Shorr R, Bingham PM:  Non-redox-active 
lipoate derivates disrupt cancer cell mitochondrial metabolism and are potent anti-cancer 
agents in vivo.  J Mol Med 19 July 2011 Online. DOI 10.1007/s00109-011-0785-8. 
 
18. Retter AS, Maturo C, Hoffman K, Luddy J, Shorr R, Lee K. Translational assessment of 
the efficacy of CPI-613 against pancreatic cancer in animal models versus patients with 
stage IV disease. J Clin Oncol. 2012 ;30(suppl) :3075. 
 
 
 


Comprehensive Cancer Center of Wake Forest University 
A Pilot Study: Open-Label Clinical Trial of CPI-613 in Patients with Advanced Bile Duct 
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CCCWFU # 59212 
 
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APPENDIX A – REGISTRATION GUIDELINES AND FORMS 
 
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 registered with the CCCWFU Protocol Registrar or entered into ORIS Screening 
Log 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: 
1. Complete the Eligibility Checklist (attached) 
2. Complete the Protocol Registration Form (attached) 
3. 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. 
4. 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. 
 
 


Comprehensive Cancer Center of Wake Forest University 
A Pilot Study: Open-Label Clinical Trial of CPI-613 in Patients with Advanced Bile Duct 
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CCCWFU # 59212 
 
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CCCWFU # 59212                                       Eligibility Checklist                                              
Yes No N/A Inclusion Criteria (All responses must be YES in order to enter study) 
Eligibility 
Confirmation 
(registrar) 
 
 
 
1. 
Does the patient have histologically and cytologically proven 
cholangiocarcinoma of any type (including intrahepatic 
chlangiocarcinoma, extrahepatic primary cholangiocarcinoma, hilar 
cholangiocarcinomas, cholangiocarcinomas located in the gall bladder 
or hepatic capsule effraction, and carcinoma of the Ampulla of Vater, 
etc.) that is not amenable to surgery, radiation, or combined modality 
therapy with curative intent, and has failed or is not eligible for 
available chemotherapies such as gemcitabine with or without 
platinum? 
 
 
 
 
2. 
Does the patient have local, locally-advanced, or metastatic 
disease documented as having shown progression on a scan (e.g., CT, 
MRI)? 
 
 
 
 
3. 
Does the patient have measurable tumor according to RECIST 1.1 
criteria with at least one unidimensionally measurable target lesion? 
 
 
 
 
4. 
Does the patient have no evidence of biliary duct obstruction, 
unless obstruction is controlled by local treatment or, in whom the 
biliary tree can be decompressed by endoscopic or percutaneous 
stenting with subsequent reduction in bilirubin to below 1.5x Upper 
Level of Normal (ULN)? 
 
 
 
 
5. 
Is the patient free from acute toxic effects from previous treatment 
superior to grade 1 at the start of the study? 
 
 
 
 
6. 
Does the patient have an ECOG performance status of 0 to 2? 
 
 
 
 
7. 
Is the patient’s expected survival greater than 3 months? 
 
 
 
 
8. 
Is the patient a male or female age 18 years and older?  
 
 
 
 
9. 
If the patient is a woman of child-bearing potential (i.e., pre-
menopausal or not surgically sterile), does she agree to use accepted 
contraceptive methods (abstinence, intrauterine device [IUD], oral 
contraceptive or double barrier device) during the study, and agree to 
have a negative serum or urine pregnancy test within 1 week prior to 
treatment initiation? 
 
 
 
 
10. If the patient is a fertile man, does he agree to practice effective 
contraceptive methods during the study, unless documentation of 
infertility exists? 
 


Comprehensive Cancer Center of Wake Forest University 
A Pilot Study: Open-Label Clinical Trial of CPI-613 in Patients with Advanced Bile Duct 
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CCCWFU # 59212 
 
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CCCWFU # 59212                                       Eligibility Checklist                                              
 
 
 
11. Does the patient have documentation (≤2 weeks) of the following 
laboratory values?: 
 Adequate hematologic (granulocyte count ≥1500/mm3; white 
blood cell [WBC] 3500 cells/mm3 or 3.5 bil/L; platelet count 
100,000 cells/mm3 or 100 bil/L; absolute neutrophil count 
[ANC] ≥1500 cells/mm3 or 1.5 bil/L; and hemoglobin ≥9 g/dL 
or ≥90 g/L). 
 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 2.0 mg/dL or 177 
µmol/L).   
 Adequate coagulation (“International Normalized Ratio or INR 
must be <1.5” unless on therapeutic blood thinners) 
 
 
 
 
12. Is the patient free from evidence of active infection and no serious 
infection within the past month? 
 
 
 
 
13. Is the patient mentally competent, able to understand and willing 
to sign the informed consent document?  
 
 
Yes No N/A Exclusion Criteria (All responses must be NO in order to enter study) 
 
 
 
 
1. Is the patient receiving any other standard or investigational 
treatment for their cancer, or have they received any other 
investigational agent for any indication within the past 2 weeks prior 
to initiation of CPI-613 treatment? 
 
 
 
 
2. Does the patient have a serious medical illness that would potentially 
increase his or her risk for toxicity? 
 
 
 
 
3. Does the patient have any active uncontrolled bleeding, or a 
bleeding diathesis (e.g., active peptic ulcer disease)? 
 
 
 
 
4. Is the patient a pregnant woman, or a woman of child-bearing 
potential who is not using reliable means of contraception? 
 
 
 
 
5. Is the patient a lactating female? 
 
 
 
 
6. Is the patient a fertile man who is unwilling to practice contraceptive 
methods during the study period? 
 
 
 
 
7. Is the patient’s life expectancy less than 3 months? 
 
 
 
 
8. Does the patient have any condition or abnormality which may, in 
the opinion of the investigator, compromise his or her safety? 
 
 
 
 
9. Is the patient unwilling or unable to follow protocol requirements? 
 
 
 
 
10. Does the patient experience dyspnea with moderate exertion?  
 
 
 
 
11. Does the patient have clinically significant pleural or pericardial 
effusions? 
 


Comprehensive Cancer Center of Wake Forest University 
A Pilot Study: Open-Label Clinical Trial of CPI-613 in Patients with Advanced Bile Duct 
Cancers 
CCCWFU # 59212 
 
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CCCWFU # 59212                                       Eligibility Checklist                                              
 
 
 
12. Does the patient have active heart disease including but not limited 
to symptomatic congestive heart failure, symptomatic coronary 
artery disease, symptomatic angina pectoris, symptomatic 
myocardial infarction, or symptomatic congestive heart failure?   
 
 
 
 
13. Does the patient have a history of myocardial infarction that is <1 
year prior to registration, or previous congestive heart failure (<1 
year prior to registration) requiring pharmacologic support or with 
Left Ventricular Ejection Fraction <50%)? 
 
 
 
 
14. Does the patient have a history of additional risk factors for torsade 
de pointes (e.g., heart failure, hypokalemia, family history of Long 
QT Syndrome)? 
 
 
 
 
15. Does the patient have evidence of active infection, or serious 
infection within the past month? 
 
 
 
 
16. Does the patient have known HIV infection? 
 
 
 
 
17. Does the patient have baseline troponin levels greater than the 
institutional limit of normal? 
 
 
 
 
18. Will the patient have received cancer immunotherapy of any type 
within the past 2 weeks prior to initiation of CPI-613 treatment? 
 
 
 
 
19. Does the patient require immediate palliative treatment of any kind, 
including surgery? 
 
 
 
 
20. Has the patient received a chemotherapy regimen with stem cell 
support in the previous 6 months? 
 
 
 
 
21. Does the patient have a history of prior illicit drug addiction? 
 
 
 
 
22. Does the patient have any condition or abnormality which may, in 
the opinion of the investigator, compromise his or her safety? 
 
 
 
Signature: ___________________________________ Date: _________________ 
 
Please send source documentation with Eligibility Form.  
 
 


Comprehensive Cancer Center of Wake Forest University 
A Pilot Study: Open-Label Clinical Trial of CPI-613 in Patients with Advanced Bile Duct 
Cancers 
CCCWFU # 59212 
 
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CCCWFU # 59212  
 
 Protocol Registration Form                                 
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 
 PAIFIC ISLANDER                 NATIVE AMERICAN 
Height:   ___ ___.___ inches 
Weight: ___ ___ ___.___lbs.(actual) 
Surface Area: ___ ___.___m2   
 
Zip Code:  ___ ___ ___ ___ ___ 
Primary Diagnosis: _____________________________________________________________ 
Date of Diagnosis: ___ ___ /___ ___/___ ___ 
 
Performance Status : __________ 
Stage of Disease: ______________ 
 
CURRENT DISEASE STATUS AT REGISTRATION: _____________________________________________ 
Prior Therapies/ 
 
Start / End Date of 
Best Response 
Date of  
 
Date of  
 
Duration of  
Protocol # if applicable 
Prior Therapy 
(PROG, TE, STAB, 
Best Response 
Relapse 
 
Best Response 
 
 
 
 
 
,NE, CR, PR, NE) 
 
 
 
 
(in Months) 
 
#1 ___________________ 
_______/________ 
_______________ 
_____________ 
______________ 
________________ 
 
#2 ___________________ 
_______/________ 
_______________ 
_____________ 
______________ 
________________ 
 
#3 ___________________ 
_______/________ 
_______________ 
_____________ 
______________ 
________________ 
 
#4 ___________________ 
_______/________ 
_______________ 
_____________ 
______________ 
________________ 
 
Protocol Registrar can be contact by calling 336-713-6767 between 8:30 AM and 4:00 PM, 
Monday – Friday. 
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. 
PROTOCOL INFORMATION 
Date of Registration: 
___ ___ / ___ ___ / ___ ___ 
MD Name (last) : 
______________________       
Date protocol treatment started: 
___ ___ / ___ ___ / ___ ___ 
Informed written consent: 
(consent must be signed prior to registration) 
 YES 
  NO 
 
Date Consent Signed: 
___ ___ / ___ ___ / ___ ___ 
 
PID # (to be assigned by ORIS): 
___ ___ ___ ___ ___ ___ ___ ___ 
 


Comprehensive Cancer Center of Wake Forest University 
A Pilot Study: Open-Label Clinical Trial of CPI-613 in Patients with Advanced Bile Duct 
Cancers 
CCCWFU # 59212 
 
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CCCWFU # 59212  Eligibility Source Documentation Checklist                    
(to be submitted with Protocol Registration Form) 
Source Documents Needed 
 or 
N/A 
1 
Pathology report confirming histologically and cytologically proven 
cholangiocarcinoma of any type 
 
2 
Lab report documenting all initial required lab values 
 
3 
Radiologic documentation that patient has local, locally-advanced, or metastatic 
disease that has shown progression 
 
4 
Documentation of measurable tumor according to RECIST 1.1 criteria with at 
least one unidimensionally measurable target lesion 
 
5 
Documentation that the patient is free of evidence of biliary duct obstruction 
(unless obstruction is controlled by local treatment) OR documentation that 
patinent’s biliary tree can be decompressed by endoscopic or percutaneous 
stenting with subsequent bilirubin to below 1.5x ULN 
 
6 
Documentation that the patient is free from acute toxic effects from previous 
treatment superior to grade 1 
 
7 
Documentation of ECOG performance status of 0, 1 or 2 
 
8 
Documentation of expected survival > 3 months 
 
9 
Most recent H&P documenting patient is 18 – 80 years of age 
 
10 
For female patients of childbearing potential, documentation that patient agrees to 
use accepted contraceptive methods during the study and to have a negative serum 
or urine pregnancy test within 1 week prior to initiation of treatment 
 
11 
For male patients, documentation of infertility OR for fertile men, documentation 
that patient agrees to practice effective contraceptive methods during the study 
 
12 
Lab report performed (< 2 weeks) documenting the following values: 
 Granulocyte count ≥1500/mm3 
 White blood cell 3500 cells/mm3 or 3.5 bil/L 
 Platelet count 100,000 cells/mm3 or 100 bil/L 
 Absolute neutrophil count ≥1500 cells/mm3 or 1.5 bil/L 
 Hemoglobin ≥9 g/dL or ≥90 g/L 
 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 
 Serum creatinine 2.0 mg/dL or 177 µmol/L 
 International Normalized Ratio or INR must be <1.5 unless on therapeutic 
blood thinners 
 
13 
Documentation that the patient is free from evidence of active infection and has 
had no serious infection within the past month 
 
14 
Documentation that the patient is mentally competent 
 
15 
Copy of signed consent form 
 
16 
Documentation that the patient is not currently receiving any other standard or 
 


Comprehensive Cancer Center of Wake Forest University 
A Pilot Study: Open-Label Clinical Trial of CPI-613 in Patients with Advanced Bile Duct 
Cancers 
CCCWFU # 59212 
 
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Source Documents Needed 
 or 
N/A 
investigational treatment for their cancer, and has not received any other 
investigational agent for any indication within the past 2 weeks prior to initiation 
of treatment with CPI-613 
17 
Documentation that the patient does not have a serious medical illness, condition, 
or abnormality that would potentially increase his or her risk for toxicity or 
compromise his or her safety 
 
18 
Documentation that the patient does not have evidence of active uncontrolled 
bleeding or a bleeding diathesis 
 
19 
Documentation that the patient is not pregnant, lactating, or (if a woman of 
childbearing potential) using a reliable means of contraception 
 
20 
Documentation that the patient is not unwilling or unable to follow protocol 
requirements 
 
21 
Documentation that the patient does not experience dyspnea with moderate 
exertion 
 
22 
Documentation that the patient does not have clinically significant pleural or 
pericardial effusions 
 
23 
Documentation that the patient does not have active heart disease including but 
not limited to: symptomatic congestive heart failure, symptomatic coronary artery 
disease, symptomatic angina pectoris, symptomatic myocardial infarction, or 
symptomatic congestive heart failure  
 
24 
Documentation that the patient does not have a history of myocardial infarction 
that is <1 year prior to registration, or previous congestive heart failure (<1 year 
prior to registration) requiring pharmacologic support or with Left Ventricular 
Ejection Fraction <50%) 
 
25 
Documentation that the patient does not have a history of additional risk factors 
for torsade de pointes (e.g., heart failure, hypokalemia, family history of Long QT 
Syndrome) 
 
26 
Documentation that the patient’s albumin is <2.5 g/dL or <25 g/L 
 
27 
Documentation that the patient does not have known HIV infection 
 
28 
Documentation that the patient does not have baseline troponin levels greater than 
the institutional limit of normal 
 
29 
Documentation that the patient has not received cancer immunotherapy of any 
type within the past 2 weeks prior to initiation of treatment with CPI-613 
 
30 
Documentation that the patient does not require immediate palliative treatment of 
any kind, including surgery 
 
 
31 
Documentation that the patient has not received a chemotherapy regimen with 
stem cell support in the previous 6 months 
 
32 
Documentation that the patient does not have a history of prior illicit drug 
addiction 
 
 


Comprehensive Cancer Center of Wake Forest University 
A Pilot Study: Open-Label Clinical Trial of CPI-613 in Patients with Advanced Bile Duct 
Cancers 
CCCWFU # 59212 
 
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APPENDIX B  STRC SAE REPORTING GUIDELINES 
 
Mandatory Safety and Toxicity Review Committee (STRC; Previously CROC) 
Serious Adverse Event (SAE) Notification Procedure 
 
Mandatory STRC SAE Reporting Requirements – Revised 6/05/2012 
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 summary IV reporting guidelines, CCCWFU Institutional 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 studies, as 
defined above. STRC currently requires that unexpected grade 4 and all grade 5 SAEs 
on these trials be reported to them for review. All Clinical Research Management (CRM) 
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, 
followed by informing the entire committee via the required email notification. 
THESE REPORTING REQUIREMENTS APPLY TO EVERYONE WORKING WITH 
CANCER CENTER INSTITUTIONAL PROTOCOLS. 
What is considered an SAE under this mandatory procedure? 
Any unexpected grade 4 event not including routinely experienced events per protocol 
(e.g. myelosuppression) and all grade 5 events (death during protocol intervention) 
should be reported. The patient is considered “on-treatment” as defined in the protocol, 
which can extend days/weeks/months past the last date of actual protocol intervention.  
 
 


Comprehensive Cancer Center of Wake Forest University 
A Pilot Study: Open-Label Clinical Trial of CPI-613 in Patients with Advanced Bile Duct 
Cancers 
CCCWFU # 59212 
 
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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 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 the event applies to 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.) 
3. Ensure that you document that the appropriate persons on the STRC has been 
contacted. 
 
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 


Comprehensive Cancer Center of Wake Forest University 
A Pilot Study: Open-Label Clinical Trial of CPI-613 in Patients with Advanced Bile Duct 
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CCCWFU # 59212 
 
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4. Follow up with/update the clinical member of STRC regarding any new 
developments or information obtained during the course of the SAE investigation 
and reporting process. 
Elements needed to complete the electronic STRC form: 
1. ORIS Patient ID (PID) 
2. Name of STRC Clinician notified/Date/Time/Comments. 
3. Grade of event. 
4. Is this related to protocol intervention or treatment? 
5. Is suspension of the protocol needed? 
6. Is any change to consent or protocol needed? 
7. Was the nature or severity of the event unexpected? 
8. Date of the event. 
9. Brief description of the event using approved CTC version terminology. 
10.  Date of last study dose before event. 
11. Relevant tests/labs. 
12. Most importantly make sure that the Investigator assigns attribution to the 
reported event (grade) using the appropriate CTCAE version for the protocol. 
 
The Clinical Members of STRC to Notify by Phone or Page: 
 
Bayard Powell, MD – Director-at-Large, CCCWFU; Chair, PRC; Section Head, 
Hematology/Oncology 
Glenn Lesser, MD – Hematology Oncology  
Kathryn Greven, MD – Vice Chair – Radiation Oncology 
Marissa Howard-McNatt, MD – General Surgery  
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 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. 
 
 


Comprehensive Cancer Center of Wake Forest University 
A Pilot Study: Open-Label Clinical Trial of CPI-613 in Patients with Advanced Bile Duct 
Cancers 
CCCWFU # 59212 
 
- 50 of 54 - 
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 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. 
 
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. 
 
 
 
 
 
 
 


Comprehensive Cancer Center of Wake Forest University 
A Pilot Study: Open-Label Clinical Trial of CPI-613 in Patients with Advanced Bile Duct Cancers 
CCCWFU # 59212 
 
51 
 
APPENDIX C – CCCWFU ADVERSE EVENT LOG
Adverse 
Event 
Description 
Cycle of 
Toxicity 
Onset 
Start 
Date 
 
Stop 
Date 
 
AE Type 
Grade (1-5) 
per CTC v. 4.0 
 
 
Attribution 
 
 
 
Dose 
Limiting  
Toxicity 
Serious 
 
 
 
Action Taken 
 
 
 
 
 
 
 
Expected 
Unexpected 
Mild/1 
Moderate/2 
Severe/3 
Life-   
threatening/4 
Death/5 
Related 
Probably 
Possible 
Unlikely 
Unrelated 
 
Yes 
No 
No 
Hospitalization 
Disability 
Birth Defect  
Life-threatening 
Death 
Other: _______ 
None 
Therapy Withheld 
Therapy D/C 
Therapy Adjusted 
Other: _______ 
N/A 
 
 
 
 
Expected 
Unexpected 
Mild/1 
Moderate/2 
Severe/3 
Life-   
threatening/4 
Death/5 
Related 
Probably 
Possible 
Unlikely 
Unrelated 
 
Yes 
No 
No 
Hospitalization 
Disability 
Birth Defect  
Life-threatening 
Death 
Other: _______ 
None 
Therapy Withheld 
Therapy D/C 
Therapy Adjusted 
Other: _______ 
N/A 
 
 
 
 
Expected 
Unexpected 
Mild/1 
Moderate/2 
Severe/3 
Life-   
threatening/4 
Death/5 
Related 
Probably 
Possible 
Unlikely 
Unrelated 
 
Yes 
No 
No 
Hospitalization 
Disability 
Birth Defect  
Life-threatening 
Death 
Other: _______ 
None 
Therapy Withheld 
Therapy D/C 
Therapy Adjusted 
Other: _______ 
N/A 
 
 
 
 
Expected 
Unexpected 
Mild/1 
Moderate/2 
Severe/3 
Life-   
threatening/4 
Death/5 
Related 
Probably 
Possible 
Unlikely 
Unrelated 
 
Yes 
No 
No 
Hospitalization 
Disability 
Birth Defect  
Life-threatening 
Death 
Other: _______ 
None 
Therapy Withheld 
Therapy D/C 
Therapy Adjusted 
Other: _______ 
N/A 


Comprehensive Cancer Center of Wake Forest University 
A Pilot Study: Open-Label Clinical Trial of CPI-613 in Patients with Advanced Bile Duct 
Cancers 
CCCWFU # 59212 
 
52 
 
Appendix D – Efficacy Assessment Form 
ORIS PID: _______________________  
Date Completed: ____ / ____ / ____ 
 
Visit Type:   
 Pre-Study         
 Cycle 1 Visit      
 Cycle 2 Visit     
 Cycle 3 Visit       
 Cycle 4 Visit     
 Cycle 5 Visit     
 Cycle 6 Visit       
 Cycle 7 Visit     
 Cycle 8 Visit      
 Cycle 9 Visit 
 Cycle 10 Visit   
 Cycle 11 Visit    
 Cycle 12 Visit    
 
 Other (Specify: __________________________________________________________ ) 
ECOG Performance Status (Date Performed: ____ / ____ / ____): 
  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. 
 
Date of CT (Chest/abdomen/pelvis): ____ / ____ / ____  
CT (Chest/abdomen/pelvis) Result: 
 Stable disease 
 Mixed response 
 Pseudo-progression (for 1st CT only) 
 Partial response 
 Progression of disease 
 
Were new lesions identified on CT (Chest/abdomen/pelvis)?   
 Yes   
 No 
Were the new lesions confirmed by biopsy?  
 Yes   
 No   
 NA 
Has this subject progressed? (As determined by the Principal Investigator)  
 Yes   
 No 
Was tissue obtained for research purposes?  
 Yes   
 No 
 
COMMENTS:  ________________________________________________________________ 
_____________________________________________________________________________ 
_____________________________________________________________________________ 


Comprehensive Cancer Center of Wake Forest University 
A Pilot Study: Open-Label Clinical Trial of CPI-613 in Patients with Advanced Bile Duct 
Cancers 
CCCWFU # 59212 
 
53 
 
Appendix E – Withdrawal of Participation Form 
 
ORIS PID _______________________ 
 
 
Date Completed ____ / ____ / ____ 
 
Name of person completing form __________________________ 
Did the subject meet eligibility criteria for study enrollment?   Yes 
   No 
 
Was the subject withdrawn from the study?   Yes 
   No 
 
 
Reasons for withdrawal: (Check all that apply and provide additional information) 
 Patient exhibited progression of disease 
 
 Patient exhibited progression of disease together with worsening of biliary function 
 
 Exhibiting symptomatic progression 
 Patient exhibit progression of disease which was confirmed after 2 additional treatment      
cycles 
 Unacceptable toxicity from CPI-613 
 Patient withdrawal of consent 
 
 For just the primary intervention (CPI-613 administration only) 
 
 For all components of the research study (including follow up in the medical record) 
 Investigator’s discretion to withdraw patient from the study because continued participation in the 
study is not in the patient’s best interest 
 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 clinical sponsor 
 
COMMENTS:  ________________________________________________________________ 
_____________________________________________________________________________ 
_____________________________________________________________________________ 


Comprehensive Cancer Center of Wake Forest University 
A Pilot Study: Open-Label Clinical Trial of CPI-613 in Patients with Advanced Bile Duct 
Cancers 
CCCWFU # 59212 
 
54 
 
Appendix F - Post Study Bimonthly Telephone Follow Up Form 
 
ORIS PID _______________________ 
Date of Bimonthly Telephone Call ____ / ____ / ____ 
Name of person completing form __________________________ 
What was the result of the telephone call? 
 Call was unanswered 
 Spoke directly with the subject 
 Spoke to a family member 
 Left a message 
Comments: 
_____________________________________________________________________________________
____________________________________________________________________________________ 
Is this subject still living? Yes 
   No 
   Unknown 
 
If the subject has expired, list date of death: ____ / ____ / ____ 
 
Is the subject currently receiving or has received since coming off the 59212 study systemic 
chemotherapeutic cancer treatment?  Yes 
   No 
  
Type of cancer treatment being received (including the dose, dosing schedule and duration, if 
applicable and if known): 
__________________________________________________________________________________ 
Is the subject receiving radiation for cancer treatment?  Yes 
   No 
 
Type of radiation treatment being received: 
__________________________________________________________________________________ 
ECOG Performance Status: 
  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. 
COMMENTS:  ________________________________________________________________ 
_____________________________________________________________________________ 
_____________________________________________________________________________