A Multi-Center Randomized Phase IB/II Study of Gemcitabine and Cisplatin With or Without CPI-613 as First Line Therapy for Patients With Advanced Unresectable Biliary Tract Cancer (BilT-04)
Phase: PHASE1
Conditions: Biliary Tract Cancer
Sponsor: University of Michigan Rogel Cancer Center

ID: UMCC 
2019.116 
 Gemcitabine and Cisplatin With or Without CPI-613 as 
First Line Therapy for Patients With Advanced 
Unresectable Biliary Tract Cancer (BilT-04) 
 NCT04203160 

Page 1 of 54 
UMCC 2019.116 
A Multi-Center Randomized Phase IB/II Study of Gemcitabine and Cisplatin With 
or Without CPI-613 as First Line Therapy for Patients with Advanced Unresectable 
Biliary Tract Cancer (BilT-04) 
Principal/Sponsor-Investigator: 
Vaibhav Sahai, MBBS, MS 
Division of Hematology/Oncology 
Department of Internal Medicine 
University of Michigan 
C412 Med Inn Building 
1500 E. Medical Center Drive  
Ann Arbor, MI 48109 
Phone: 734-936-4991 
Fax: 734-936-4940  
Email: vsahai@med.umich.edu  
Coordinating Center: 
University of Michigan 
Biostatistician: 
Kent Griffith, MPH, MS 
University of Michigan 
Center for Cancer Biostatistics 
School of Public Health 
Email: kentg@med.umich.edu  
Study Drug: 
CPI-613® (Devimistat) 
Initial Version: 
12/06/2019 
Amended: 
08/17/2020 
02/04/2021 
04/12/2021 
09/20/2021 
09/14/2022 
NOTE: To effectively manage restrictions put in place during public health or civil emergency or restrictions 
(i.e., COVID-19 pandemic), changes to protocol-required items are to be made to minimize or eliminate 
immediate hazards or to protect the life and well-being of research participants (e.g., to limit exposure to 
infectious pathogens). These changes are listed in Appendix III of the protocol (Contingency Operations 
Plan) 

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TABLE OF CONTENTS 
STUDY SYNOPSIS .............................................................................................. 6 
1.0 BACKGROUND AND RATIONALE ............................................................... 9 
1.1 
Biliary Tract Cancer - Disease Overview ......................................................................... 9 
1.2 
Introduction to CPI-613 and its Role in BTC ................................................................... 9 
1.3 
Role of Chemotherapy in Conjunction with CPI-613 ....................................................... 9 
1.4 
Rationale ........................................................................................................................ 10 
1.5 
Correlative Studies ........................................................................................................ 10 
2.0 STUDY OBJECTIVES .................................................................................. 10 
2.1 
Primary Objectives ......................................................................................................... 11 
2.2 
Secondary Objectives .................................................................................................... 11 
2.3 
Exploratory Objectives ................................................................................................... 11 
2.4 
Endpoints Assessment .................................................................................................. 11 
3.0 PATIENT ELIGIBILITY ................................................................................. 11 
3.1 
Eligibility Criteria ............................................................................................................ 11 
4.0 SUBJECT SCREENING AND ENROLLMENT PROCEDURES .................. 13 
5.0 TREATMENT PLAN ..................................................................................... 14 
5.1 
Treatment Dosage and Administration .......................................................................... 14 
5.2 
Toxicities and Dosing Delays/Dose Modifications ......................................................... 16 
5.3 
Concomitant Medications/Treatments ........................................................................... 20 
5.4 
Other Modalities or Procedures ..................................................................................... 20 
5.5 
Duration of Therapy ....................................................................................................... 20 
5.6 
Off Treatment Criteria .................................................................................................... 20 
5.7 
Duration of Follow-Up .................................................................................................... 21 

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5.8 
Off Study Criteria ........................................................................................................... 21 
5.9 
Patient Replacement ..................................................................................................... 21 
6.0 STUDY PROCEDURES ................................................................................ 21 
6.1 
Screening/Baseline Procedures .................................................................................... 21 
6.2 
Time and Events Table/Schedule of Events/Study Calendar........................................ 22 
7.0 MEASUREMENT OF EFFECT ..................................................................... 24 
7.1 
Antitumor Effect- Solid Tumors ...................................................................................... 24 
7.2 
Safety/Tolerability .......................................................................................................... 28 
8.0 ADVERSE AND OTHER REPORTABLE EVENTS ...................................... 28 
8.1 
Adverse Event Reporting Requirements ....................................................................... 28 
8.2 
Definitions ...................................................................................................................... 29 
8.3 
Adverse Event Characteristics ...................................................................................... 30 
8.4 
Serious Adverse Event Reporting Guidelines ............................................................... 30 
8.5 
Routine Reporting .......................................................................................................... 31 
8.6 
Reporting of Pregnancy ................................................................................................. 31 
8.7 
Reporting of Unanticipated Problems ............................................................................ 31 
8.8 
Safety Report Reconciliation ......................................................................................... 32 
9.0 DRUG INFORMATION ................................................................................. 32 
9.1 
Gemcitabine ................................................................................................................... 32 
9.2 
Cisplatin ......................................................................................................................... 34 
9.3 
CPI-613 .......................................................................................................................... 36 
10.0 CORRELATIVES/TRANSLATIONAL STUDIES ........................................ 39 
10.1 Tissue Collection ........................................................................................................... 40 
10.2 Blood Collection ............................................................................................................. 40 
10.3 Centralized Imaging ....................................................................................................... 40 
10.4 Specimen Banking ......................................................................................................... 40 

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11.0 STATISTICAL CONSIDERATIONS............................................................ 40 
11.1 Study Design/Study Endpoints ...................................................................................... 40 
11.2 Phase 1B ....................................................................................................................... 41 
11.3 Phase 2 .......................................................................................................................... 43 
11.4 Data Analyses Plans...................................................................................................... 45 
12.0 ADMINISTRATIVE PROCEDURES............................................................ 45 
12.1 Ethics and Good Clinical Practice ................................................................................. 45 
12.2 Data Management ......................................................................................................... 45 
12.3 Record Retention ........................................................................................................... 46 
13.0 DATA AND SAFETY MONITORING .......................................................... 46 
14.0 QUALITY ASSURANCE AND AUDITS ...................................................... 47 
15.0 CLINICAL MONITORING PROCEDURES ................................................. 47 
16.0 REFERENCES ............................................................................................ 49 
17.0 APPENDICES ............................................................................................. 50 
Appendix I 
     ECOG Performance Status ........................................................................... 51 
Appendix II 
Investigator’s Statement ................................................................................. 52 
Appendix III 
Contingency Operations Plan ........................................................................ 53 

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ABBREVIATIONS: 
 
AE 
Adverse Event 
ALT 
Alanine Aminotransferase 
ALC 
Absolute Lymphocyte Count 
AST 
Aspartate Aminotransferase 
BUN 
Blood Urea Nitrogen 
BTC 
Biliary Tract Cancer 
CBC 
Complete Blood Count 
CMP 
Comprehensive Metabolic Panel 
CR 
Complete Response 
CT 
Computed Tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
CTSU 
Clinical Trials Support Unit 
DLT 
Dose Limiting Toxicity 
DSMC 
Data and Safety Monitoring Committee 
H&P 
History & Physical Exam 
HRPP 
Human Research Protections Program 
IND 
Investigational New Drug 
IRB 
Institutional Review Board 
IV (or iv) 
Intravenously 
MSC 
Multi-Site Coordinator 
MTD 
Maximum Tolerated Dose 
NCI 
National Cancer Institute 
ORR 
Overall Response Rate 
OS 
Overall Survival 
PBMCs 
Peripheral Blood Mononuclear Cells 
PD 
Progressive Disease 
PFS 
Progression Free Survival 
PI 
Principal Investigator 
p.o. 
per os/by mouth/orally 
PR 
Partial Response 
PRC 
Protocol Review Committee 
SAE 
Serious Adverse Event 
SD 
Stable Disease 
UaP 
Unanticipated Problem 
WBC 
White Blood Cells 
 
 
 

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STUDY SCHEMA 
 
 
 
 
 
Figure 1. Study Schema 
STUDY SYNOPSIS 
Title 
A Multi-Center Randomized Phase IB/II Study of Gemcitabine and Cisplatin With 
or Without CPI-613 as First Line Therapy for Patients with Advanced 
Unresectable Biliary Tract Cancer 
Phase 
Phase IB/II 
Methodology 
Phase IB – Single arm (TiTE-CRM) 
Phase II – Randomized 2:1, open-label 
Study Duration 
4 years 
Study Center(s) 
Multi-Center 
Objectives 
Primary objectives: 
1. Phase IB – Determine the maximum tolerated dose/recommended phase 2 
dose for gemcitabine and cisplatin with CPI-613 
2. Phase II – Determine the overall response rate in patients with advanced BTC 
treated with gemcitabine and cisplatin with or without CPI-613. 
 
Secondary objectives: 
1. Evaluate the median PFS and OS of patients with advanced BTC. 
2. Evaluate the safety of CPI-613 in combination with gemcitabine and cisplatin 
in this patient population. 
 
Exploratory objectives: 
1. To explore predictors of biomarker response and mechanisms of resistance 
based on the exploratory analysis of tissue obtained through serial biopsies 
and blood. 
a) Immunohistochemical staining for PDK, PDH, KGDH, SOD2 and CD79a 
b) Whole exome genomic and transcriptomic (RNAseq) analysis for tumor 
biology at baseline and progression. 
c) Blood collection, including serum, plasma and serum for future biomarker 
analysis, including ctDNA. 
Number of 
Subjects 
68-78 
 
Phase II Arm A (N=32-38) 
Gemcitabine + Cisplatin + 
CPI-613 
Phase II Arm B (N=16-20) 
Gemcitabine + Cisplatin  
Locally Advanced 
Unresectable or  
Metastatic Biliary 
Tract Cancer 
With No Prior 
Systemic Therapy  
(N=68-78) 
Phase IB (N=20) 
Gemcitabine + Cisplatin 
+ CPI-613 
RR 
2 
1 

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Eligibility Criteria 
1. Patients must have a pathologically or cytologically confirmed carcinoma 
(except neuroendocrine) of the biliary tract (intra-hepatic, extra-hepatic (hilar, 
distal) or gallbladder) that is not eligible for curative resection, transplantation, 
or ablative therapies. Tumors of mixed cholangiocarcinoma/hepatocellular 
carcinoma histology are excluded. 
2. Patients must not have received prior systemic treatment (chemotherapy or 
targeted therapy) for advanced BTC. Prior peri-operative chemotherapy is 
permitted provided it was completed > 6 months from enrollment.  
3. Prior radiation, chemoembolization, radioembolization or other local ablative 
therapies or hepatic resection is permitted if completed ≥ 4 weeks prior to 
enrollment AND if patient has recovered to ≤ grade 1 toxicity. Extrahepatic 
palliative radiation is permitted if completed ≥ 2 weeks prior to enrollment AND 
if patient has recovered to ≤ grade 1 toxicity. 
4. Patients must have radiographically measurable disease (as per 
RECISTv1.1) in at least one site not previously treated with radiation or liver 
directed therapy (including bland, chemo- or radio-embolization, or ablation) 
either within the liver or in a metastatic site. 
5. Must be ≥ 18 years of age 
6. Must have an ECOG performance status of 0-1 
7. Ability to understand and willingness to sign IRB-approved informed consent 
8. Willing to provide archived tissue, if available, from a previous diagnostic 
biopsy or surgery 
9. Must be able to tolerate CT and/or MRI with contrast 
10. Must have adequate organ function obtained ≤2 weeks prior to enrollment 
(absolute neutrophil count >1500/mm3, hemoglobin >9 g/dL, platelets 
>100,000/mm3, serum creatinine < 1.5 x upper limit normal (ULN), creatinine 
clearance ≥ 50 mL/min, albumin >3.0 g/dL, AST/ALT <3.0 x ULN (<5 x ULN if 
liver tumor or metastasis), total bilirubin < 1.5 x upper limit normal, INR < 1.5 
upper limit normal) 
11. Must not have prior history of brain metastasis (unless previously treated, 
asymptomatic and stable for at least 3 months), or organ transplantation. 
12. Must not have undergone a major surgical procedure < 4 weeks prior to 
enrollment. 
13. Must not have an active second malignancy other than in situ cancer or 
localized prostate cancer (Gleason score <8). Patients with a history of other 
malignancy are eligible provided primary treatment of that cancer was 
completed > 1 year prior to enrollment and the patient is free of clinical or 
radiologic evidence of recurrent or progressive malignancy. 
14. Must have no ongoing active, uncontrolled infections (afebrile for > 48 hours 
off antibiotics). 
15. Must not have a psychiatric illness, other significant medical illness, or social 
situation which, in the investigator’s opinion, would limit compliance or ability 
to comply with study requirements. 
16. Women must not be pregnant or breastfeeding since study drugs may harm 
the fetus or child. All females of childbearing potential (not surgically sterilized 
and between menarche and 1-year post menopause) must have a negative 
screening pregnancy test. 
17. Women of child-bearing potential and men must agree to use 2 methods of 
adequate contraception (hormonal plus barrier or 2 barrier forms) OR 
abstinence prior to study entry, for the duration of study participation, and for 
6 months (for men and women) following completion of study therapy.  
18. Must not have active heart disease including symptomatic heart failure (NYHA 
class 3 or 4), unstable angina pectoris, uncontrolled cardiac arrhythmia or 
interstitial lung disease. 
19. Prisoners or subjects who are involuntarily incarcerated, or compulsorily 
detained for treatment of either a psychiatric or physical (e.g. infectious 

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disease) illness would be excluded. 
20. Must not have prolonged QTcF interval >480 msec 
21. Patients with known hypersensitivity to cisplatin, gemcitabine or CPI-613, or 
its inactive components would be excluded. 
Study Product(s), 
Dose, Route, 
Regimen 
Phase IB and Phase II Arm A (days 1, 8 Q21 days):  
Gemcitabine 1000 mg/m2 IV 
Cisplatin 25 mg/m2 IV  
CPI-613 at dose level or RP2D IV  
 
Phase II Arm B (days 1, 8 Q21 days):  
Gemcitabine 1000 mg/m2 IV  
Cisplatin 25 mg/m2 IV  
Duration of 
Administration 
Patients may be treated on study for no longer than 2 years. 
 
Arm A: The patient may continue gemcitabine, cisplatin and CPI-613 in 
absence of disease progression or unacceptable toxicity.  
 
Arm B: The patient may continue gemcitabine and cisplatin in absence of disease 
progression or unacceptable toxicity. 
Statistical 
Methodology 
This protocol will enroll patients with locally advanced, unresectable or metastatic 
BTC to receive Gemcitabine, Cisplatin and CPI-613 in a limited Phase 1b study 
to confirm the safety profile of the combination therapy and the recommended 
Phase 2 dose (RP2D) using TiTE-CRM methodology. The primary endpoint for 
the phase IB portion is the occurrence/lack thereof of dose-limiting toxicity during 
the first 21-day cycle of combination therapy. After determining the combination 
RP2D, 48-58 additional evaluable patients will be enrolled in the phase 2 portion 
of the study and randomized 2:1 to treatment arms A (combination regimen at 
RP2D) and B (Gemcitabine and Cisplatin alone), respectively, using a Bayesian 
approach for the control arm. We will stratify the randomization by locally 
advanced versus metastatic disease. The primary endpoint for the phase 2 study 
is the ORR (PR+CR) per RECIST v1.1 criteria during active study treatment. 
Secondary endpoints include safety, PFS and OS. In practice, the 16-20 evaluable 
patients randomized to standard of care arm will suggest whether the historical 
ORR of 21% is reasonable for our current patient population. The ORR estimated 
and 95% confidence interval for the control group may suggest altering the 
historical null ORR value for comparison.   
 
 
 

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1.0 
BACKGROUND AND RATIONALE 
1.1 
Biliary Tract Cancer - Disease Overview 
Biliary tract cancer (BTC) develops as a result of malignant transformation of the biliary 
tract mucosa and is anatomically classified as intra-hepatic, extra-hepatic (hilar and distal) 
and gall bladder adenocarcinoma. BTC accounts for 10-15% of all primary liver cancer 
cases worldwide, and its incidence is rising (Shaib and El-Serag 2004).  Advanced BTCs 
are aggressive tumors with median survival time from diagnosis of less than 12 months 
(Valle, Wasan et al. 2010), and five-year overall survival (OS) of ~5% despite therapy 
(Nathan, Pawlik et al. 2007). The options for systemic chemotherapy for patients with 
advanced BTC remains limited with only a few meaningful improvements made over the 
past few decades. Valle et al randomly assigned 410 patients with locally advanced or 
metastatic BTC to receive gemcitabine with or without cisplatin in the phase III ABC-02 trial 
(Valle, Wasan et al. 2010). Patients on the gemcitabine cisplatin arm demonstrated an 
improvement in OS (11.7 versus 8.1 months; hazard ratio (HR), 0.64; 95% CI, 0.52 to 0.80; 
p<0.001) as compared to the gemcitabine alone arm. The objective response rate was 
26.1% in the cisplatin and gemcitabine combination arm. The following clinically relevant 
grade 3 and 4 adverse events were noted in the gemcitabine/cisplatin arm: neutropenia 
(25.3%), anemia (7.6%), thrombocytopenia (15.7%), abnormal liver function (16.7%), 
fatigue (18.7%), nausea (4%), vomiting (5.1%), impaired renal function (1.5%), infection 
(18.2%), deep vein thrombosis (2%), and thromboembolic event (3.5%). This result 
established the gemcitabine 1000 mg/m2 and cisplatin 25 mg/m2 combination as a standard 
first line regimen for patients with advanced BTC. 
1.2 
Introduction to CPI-613 and its Role in BTC 
CPI-613 is a stable analog of normally transient, acylated catalytic intermediates of lipoic 
acid (lipoate), an essential co-factor for 2 enzyme complexes, pyruvate dehydrogenase 
(PDH) and a-ketoglutarate dehydrogenase (KGDH) central to the tricarboxylic acid (TCA) 
or Kreb’s cycle (Zachar, Marecek et al. 2011). These lipoic intermediates are monitored by 
regulatory systems to control flux through these 2 enzymes. Regulatory systems controlling 
this flux are significantly modified during anabolic reprogramming in cancer making them 
more susceptible to CPI-613. Additionally, tumor cells take up CPI-613 preferentially, 
apparently through upregulated vitamin and fatty acid transporters which limits toxicity to 
normal cells (Stuart, Schauble et al. 2014). CPI-613 selectively inactivates these two 
enzymes, thereby collapsing mitochondrial metabolism of the tumor cells. This collapse of 
mitochondrial metabolism leads, in turn, to redundant activation of apoptotic and necrotic 
cell death pathways (Zachar, Marecek et al. 2011). 
 
To date, 23 studies have been done with CPI-613 including 16 completed trials and 7 
ongoing trials. Two of these trials are phase 3 trials in metastatic pancreatic 
adenocarcinoma (NCT03504423) and acute myeloid leukemia (NCT03504410). Over 800 
subjects have received one or more doses of CPI-613 in these clinical studies. 
1.3 
Role of Chemotherapy in Conjunction with CPI-613 
A total of 40 patients with advanced pancreatic cancer of which 14 patients received CPI-
613 as a single agent on 3 trials (CPI-613-002, CL-CPI-613-023, CCCWFU57113), 6 
patients received CPI-613 in combination with gemcitabine on the CL-CPI-613-004 trial, 
and 20 received CPI-613 in combination with modified FOLFIRINOX (mFOLFIRINOX) on 
the CCWFU57112 trial.  
 
The phase 1 dose escalation CCWFU57112 trial of CPI-613 in combination with 
mFOLFIRINOX chemotherapy was conducted in patients with metastatic pancreatic 
adenocarcinoma with no prior treatment. A total of 20 patients, ages 48-72, were dosed 
with CPI-613 plus mFOLFIRINOX of which 18 were evaluable. The 2 patients who 
experienced DLTs were not evaluable as they did not have follow-up radiology 

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assessments per RECIST v1.1. Overall, 17% of patients achieved a complete response 
(CR), 44% achieved a partial response (PR), 17% achieved stable disease (SD), and 22% 
had progressive disease (PD). The overall response rate (ORR=CR+PR) was 61%. Median 
overall survival (OS) was 19.7 months, median progression free survival (PFS) 9.9 months, 
and duration of response (DOR) 12.6 months (Alistar, Morris et al. 2017). Based on these 
data, an international phase 3 clinical trial is being conducted in this patient population. 
 
For the 18 patients given the maximum tolerated dose, the most common grade 3–4 non-
hematological adverse events were hyperglycemia (ten [55%] patients), hypokalemia (six 
[33%]), peripheral sensory neuropathy (five [28%]), diarrhea (five [28%]), and abdominal 
pain (four [22%]). The most common grade 3–4 hematological adverse events were 
neutropenia (five [28%] of 18 patients), lymphopenia (five [28%]), anemia (four [22%], and 
thrombocytopenia in three [17%]). Sensory neuropathy (all grade 1–3) was recorded in 17 
(94%) of the 18 patients and was managed with dose de-escalation or discontinuation per 
standard of care. No patients died while on active treatment; 11 study participants died, 
with cause of death as terminal pancreatic cancer (Alistar, Morris et al. 2017). 
1.4 
Rationale 
Patients with advanced, unresectable or metastatic BTC have a poor prognosis despite 
systemic chemotherapy with gemcitabine and cisplatin. CPI-613 is an inhibitor of pyruvate 
dehydrogenase (PDH) and a-ketoglutarate dehydrogenase (KGDH) central to the Kreb’s 
cycle. This selective inhibition leads to the collapse of mitochondrial metabolism and 
activation of apoptotic and necrotic cell death pathways. CPI-613 has shown significant 
efficacy (ORR 61%, median OS 19.7 months) compared to historical data (ORR 32%, 
median OS 11.1 months) when given in combination with mFOLFIRINOX in patients with 
metastatic pancreatic cancer (Conroy, Desseigne et al. 2011, Alistar, Morris et al. 2017).  
 
Therefore, we hypothesize that CPI-613, a mitochondrial inhibitor, in combination with 
gemcitabine and cisplatin will improve the overall response, progression-free and overall 
survival in this population without increasing toxicity. These results are expected to have an 
important positive impact because they will provide a strong evidence-guided 
understanding of BTC microenvironment and identification of potential biomarkers of 
response (and resistance) to inform a phase III clinical trial in BTC.  
1.5 
Correlative Studies 
We will study the BTC tumor microenvironment through the use of pre-treatment tissue (all 
sites) and post-treatment (optional for patients enrolled at all sites) tumor biopsies. In 
addition, blood will be collected as detailed in the schedule of events/study calendar. 
Identification of important biologic subsets of BTC patients that may have clinical efficacy 
from this drug combination will be the overarching goal of these translational studies along 
with developing biologic insights for future therapeutic development. Biologic markers and 
RNA expression will be examined in the context of tumor biology, and therapeutic efficacy.  
 
2.0 
STUDY OBJECTIVES 

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2.1 
Primary Objectives 
2.1.1 
Phase Ib: Determine the maximum tolerated dose (MTD)/recommended phase 2 
dose (RP2D) for gemcitabine and cisplatin with CPI-613  
2.1.2 
Phase II: Determine the overall response rate in patients with advanced BTC 
treated with gemcitabine and cisplatin with or without CPI-613. 
2.2 
Secondary Objectives  
2.2.1 
Evaluate the median PFS and OS of patients with advanced BTC. 
2.2.2 
Evaluate the safety of CPI-613 in combination with gemcitabine and cisplatin in 
this patient population. 
2.3 
Exploratory Objectives 
2.3.1 
To explore predictors of biomarker response and mechanisms of resistance 
based on the exploratory analysis of tumor tissue obtained through serial 
biopsies and blood. 
a) Immunohistochemical staining for PDK, PDH, KGDH, SOD2 and CD79a 
b) Whole exome genomic and transcriptomic (RNAseq) analysis for tumor 
biology at baseline and progression  
c) Blood collection, including serum, plasma and serum for future biomarker 
analysis, including ctDNA. 
2.4 
Endpoints Assessment 
2.4.1 
Primary Endpoint Assessment: Overall response rate (ORR) will be determined 
as per the RECISTv1.1 criteria. 
 
2.4.2 
Secondary Endpoint Assessment: The progression-free survival (PFS) will be 
defined as time from date of treatment to date of radiological or clinical 
progression (leading to withdrawal from the study), or death from any cause, 
whichever comes first. Follow-up time will be censored at the date of last disease 
evaluation. Overall survival (OS) will be defined from the date of treatment to 
either date of death or censoring. Adverse events and reportable serious events 
are defined by the study protocol (NCI Common Toxicity Criteria for Adverse 
Events (CTCAE) v5.0). 
 
3.0 
PATIENT ELIGIBILITY 
Subjects must meet all of the eligibility criteria to be enrolled to the study. Study treatment may 
not begin until a subject is enrolled. 
 
3.1 
Eligibility Criteria 
 
3.1.1 
Patients must have a pathologically or cytologically confirmed carcinoma 
(except neuroendocrine) of the biliary tract (intra-hepatic, extra-hepatic (hilar, 
distal) or gallbladder) that is not eligible for curative resection, 
transplantation, or ablative therapies. Tumors of mixed 
cholangiocarcinoma/hepatocellular carcinoma histology are excluded. 
 

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3.1.2 
Patients may not have received prior systemic treatment (chemotherapy or 
targeted therapy) for advanced BTC. Prior peri-operative chemotherapy is 
permitted provided it was completed > 6 months from enrollment. 
 
3.1.3 
Patients may have received prior radiation, chemoembolization, 
radioembolization or other local ablative therapies or hepatic resection if 
completed ≥ 4 weeks prior to enrollment AND if patient has recovered to ≤ grade 
1 toxicity. Extrahepatic palliative radiation is permitted if completed ≥ 2 weeks 
prior to enrollment AND if patient has recovered to ≤ grade 1 toxicity 
 
3.1.4 
Patients must have radiographically measurable disease (as per RECISTv1.1) in 
at least one site not previously treated with radiation or liver directed therapy 
(including bland, chemo- or radio-embolization, or ablation) either within the liver 
or in a metastatic site.  
 
3.1.5 
Must be ≥ 18 years of age. 
 
3.1.6 
Must have an ECOG performance status of 0-1. 
 
3.1.7 
Ability to understand and willingness to sign IRB-approved informed consent. 
 
3.1.8 
Willing to provide archived tissue, if available, from a previous diagnostic biopsy 
or surgery. 
 
3.1.9 
Must be able to tolerate CT and/or MRI with contrast.  
 
3.1.10 Adequate organ function obtained ≤ 2 weeks prior to enrollment:  
 
absolute neutrophil count 
≥ 1500/mm3 
hemoglobin 
≥ 9 g/dL 
platelets 
≥ 100,000/mm3 
serum creatinine 
≤ 1.5 x ULN 
creatinine clearance 
≥ 50 mL/min 
albumin 
≥ 3.0 g/dL 
AST/ALT  
≤ 3.0 x ULN (≤5 x ULN if liver tumor or 
metastasis) 
total bilirubin 
≤ 1.5 x ULN 
INR 
≤ 1.5 x ULN 
 
3.1.11 Must not have prior history of brain metastasis (unless previously treated, 
asymptomatic and stable for at least 3 months), or organ transplantation. 
 
3.1.12 Must not have undergone a major surgical procedure < 4 weeks prior to 
enrollment. 
 
3.1.13 Must not have an active second malignancy other than in situ cancer or localized 
prostate cancer (Gleason score <8). Patients with a history of other malignancy 
are eligible provided primary treatment of that cancer was completed > 1 year 
prior to enrollment and the patient is free of clinical or radiologic evidence of 
recurrent or progressive malignancy. 
 
3.1.14 Must have no ongoing active, uncontrolled infections (afebrile for > 48 hours off 
antibiotics) 
 

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3.1.15 Must not have a psychiatric illness, other significant medical illness, or social 
situation which, in the investigator’s opinion, would limit compliance or ability to 
comply with study requirements. 
 
3.1.16 Women must not be pregnant or breastfeeding since study drugs may harm the 
fetus or child. All females of childbearing potential (not surgically sterilized and 
between menarche and 1 year post menopause) must have a negative screening 
pregnancy test. 
 
3.1.17 Women of child-bearing potential and men must agree to use 2 methods of 
adequate contraception (hormonal plus barrier or 2 barrier forms) OR abstinence 
prior to study entry, for the duration of study participation and for 6 months (for 
men and women) following completion of study therapy.  
 
3.1.18 Must not have active heart disease including symptomatic heart failure (NYHA 
class 3 or 4), unstable angina pectoris, uncontrolled cardiac arrhythmia or 
interstitial lung disease. 
 
3.1.19 Prisoners or subjects who are involuntarily incarcerated, or compulsorily detained 
for treatment of either a psychiatric or physical (e.g. infectious disease) illness 
would be excluded. 
 
3.1.20 Must not have prolonged QTcF interval >480 msec 
 
3.1.21 Patients with known hypersensitivity to cisplatin, gemcitabine or CPI-613, or its 
inactive components would be excluded. 
4.0 
SUBJECT SCREENING AND ENROLLMENT PROCEDURES 
Patient enrollment and randomization for this trial will be centrally managed by the Oncology 
Clinical Trials Support Unit (i.e. the Coordinating Center) of The University of Michigan Rogel 
Cancer Center as described below: 
 
A potential study subject who has been screened for the trial and who has signed the Informed 
Consent document will be initially documented by the participating site on the Screening and 
Enrollment Log provided by the Coordinating Center. 
 
It is the responsibility of the local site investigator to determine patient eligibility prior to submitting 
patient enrollment request to the Coordinating Center. After patient eligibility has been 
determined, a copy of the completed Eligibility Worksheet together with all the pertinent de-
identified source documents will be submitted by the requesting site to the Coordinating Center, 
by email to CTSU-Oncology-Multisite@med.umich.edu.    
 
A Multi-Site Coordinator (MSC) of the Coordinating Center, who acts as the registrar, will review 
the submitted documents and process the enrollment. Sites should inform the Multi-Site 
Coordinator of a potential enrollment by 5 p.m. on the day prior to enrollment.  Same day 
enrollments cannot be guaranteed.   
 
The registrar will send an email to the requesting site registrar to confirm patient enrollment and 
randomization and to provide the study identification number and randomization number assigned 
to the patient. In addition, a copy of the completed Eligibility Worksheet signed and dated by the 
registrar will be sent back to the requesting site registrar. 
 
Patients found to be ineligible for participation after being consented will be considered screen 
failures, and documented as such in the Screening and Enrollment Log. These patients will not 
have study identification number assigned to them, and will not receive study treatment. 
 

Protocol UMCC 2019.116 
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5.0 
TREATMENT PLAN 
5.1 
Treatment Dosage and Administration 
Protocol treatment must start within 14 calendar days of enrollment otherwise the patient 
will be taken off study. Re-screening is allowed. 
5.1.1 
Phase IB 
5.1.1.1 
Dose Levels 
 
Table 1. Phase IB Treatment Plan (Q21 days) 
Dose 
Level 
CPI-613 
Gemcitabine 
Cisplatin 
3 
2,000 mg/m2 
1000 mg/m2 
25 mg/m2 
2 
1,500 mg/m2 
1000 mg/m2 
25 mg/m2 
1* 
1,000 mg/m2 
1000 mg/m2 
25 mg/m2 
-1 
500 mg/m2 
800 mg/m2 
25 mg/m2 
 
 
*starting dose level 
 
The starting dose level of 1000 mg/m2 is based on the use of 500 mg/m2 dose in 
combination with FOLFIRINOX chemotherapy backbone for pancreatic cancer 
(NCT03699319), and use of 1500 mg/m2 dose in combination with gemcitabine and nab-
paclitaxel chemotherapy backbone for pancreatic cancer (NCT03435289). 
5.1.1.2 
Treatment Plan 
 
Table 2. Phase IB – Regimen Description 
Agent 
Prophylaxis 
Dose 
Route1 
Schedule2 
Cycle 
Length 
CPI-613 
Palonosetron 
0.25 mg IV + 
dexamethasone 
12 mg PO/IV + 
fosaprepitant 150 
mg IV,  
OR  
per  
institutional policy 
Per Dose 
Level 
IV over 120 (range 
110 – 150) 
minutes before 
gemcitabine3 
Days 1 
and 8 
3 
weeks 
(21 
days)  
Gemcitabine 
Per Dose 
Level 
IV over 25 – 40 
minutes after CPI-
613 
Days 1 
and 8 
Cisplatin 
Per Dose 
Level 
IV over 25 – 65 
minutes after 
gemcitabine 
Day 1  
and 8 
1Infusion times may follow institutional policy for gemcitabine and cisplatin and/or be extended as 
needed for safety (e.g. infusion reaction occurs). These instances should be documented in the 
patient medical records.  
2As per section 5.5, patients may not be treated on study for longer than 2 years. 
3 This rate is for all dose levels. 
 

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5.1.1.3 
Dose Limiting Toxicities (DLTs)  
A DLT will be any of the following occurring during the first 3 weeks of therapy, 
including cycle 2 day 1, attributed (possibly, probably, or definitely) to the drug 
combination following day 1 treatment and occurring in the 22-day interval as assessed 
using the NCI CTCAE v5.0. 
 
a. Grade 4 or greater hematological toxicity with the exception of uncomplicated grade 
4 leukopenia/ neutropenia lasting <7 days) 
b. Grade 3 or higher thrombocytopenia with bleeding 
c. Grade 3 or greater febrile neutropenia. 
d. Grade 3 or greater non-hematological toxicity with the following exceptions:  
i. 
Grade 3 nausea, vomiting, or diarrhea < 72 hours with adequate antiemetic 
and other supportive care measures,  
ii. 
Grade 3 fatigue < 1 week,  
iii. 
Grade 3 or higher electrolyte abnormality that lasts <24 to 72 hours, is not 
clinically complicated, and resolves spontaneously or responds to 
conventional medical interventions, 
iv. 
Grade 3 or higher amylase or lipase that is not associated with symptoms or 
clinical manifestations of pancreatitis.  
e. Any death not clearly due to the underlying disease or extraneous causes. 
f. 
Toxicities meeting Hy’s law criteria 
g. Grade 2, treatment related non-hematological toxicity which prevents Cycle 1 day 8 
or Cycle 2 day 1 dosing of one or more of the study agents. 
h. Patients stopping treatment early due to or secondary to toxicity 
 
With completion of cycle 1, and following DLT determination (yes vs. no) on cycle 2 day 
1, cycle 2 may begin. All DLTs must be reported to the Coordinating Center within 24 
hours of first awareness of the event. Events should be reported using the Coordinating 
Center’s DLT form as available in the study database 
5.1.2 
Phase II Arm A 
 
Table 3. Phase II Arm A – Regimen Description 
Agent 
Prophylaxis 
Dose 
Route1 
Schedule2 
Cycle 
Length 
CPI-613 
Palonosetron 
0.25 mg IV + 
dexamethasone 
12 mg PO/IV + 
fosaprepitant 
150 mg IV,  
OR  
per  
institutional 
policy 
RP2D mg/m2 
IV over 120 
(range 110 – 
150) minutes 
before 
gemcitabine3 
Days 1 
and 8 
3 
weeks 
(21 
days)  
Gemcitabine 
1000 mg/m2 per 
commercial 
package insert 
IV over 25 – 
40 minutes 
after CPI-613 
Days 1 
and 8 
Cisplatin 
25 mg/m2 per 
commercial 
package insert 
IV over 25 – 
65 minutes 
after 
gemcitabine 
Day 1  
and 8 
1 Infusion times may follow institutional policy for gemcitabine and cisplatin and/or be extended as 
needed for safety (e.g. infusion reaction occurs). These instances should be documented in the 
patient medical records. 
2 As per section 5.5, patients may not be treated on study for longer than 2 years. 
3 This rate is for all dose levels. RP2D for CPI-613 was determined to be 2000 mg/m2. 
 

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5.1.3 
Phase II Arm B 
 
Table 4. Phase II Arm B – Regimen Description 
Agent 
Prophylaxis 
Dose 
Route1 
Schedule2 
Cycle 
Length 
Gemcitabine 
Palonosetron 
0.25 mg IV + 
dexamethasone 
12 mg PO/IV + 
fosaprepitant 
150 mg IV,  
OR  
per  
institutional 
policy 
1000 mg/m2 per 
commercial 
package insert 
IV over 25 – 
40 minutes 
before 
cisplatin 
Days 1 
and 8 
3 weeks 
(21 
days)  
Cisplatin 
25 mg/m2 per 
commercial 
package insert 
IV over 25 – 
65 minutes 
after 
gemcitabine 
Days 1  
and 8 
1 Infusion times may follow institutional policy and/or be extended as needed for safety (e.g. 
infusion reaction occurs). These instances should be documented in the patient medical records. 
2 As per section 5.5, patients may not be treated on study for longer than 2 years. 
 
5.2 
Toxicities and Dosing Delays/Dose Modifications 
Any patient who receives treatment on this protocol will be evaluable for toxicity. Each 
patient will be assessed for the development of toxicity according to the Time and Events 
Table (Section 6.2). Toxicity will be assessed according to the NCI Common Terminology 
Criteria for Adverse Events (CTCAE), version 5.0. Dose adjustments should be made 
according to the system showing the greatest degree of toxicity.  
 
Table 5: Dose Modifications 
Gemcitabine 
Current Dose 
Percentage Decrease 
Modified Dose 
1000 mg/m2 
20% 
800 mg/m2 
800 mg/m2 
20% 
640 mg/m2 
640 mg/m2 
100% 
Discontinue 
Cisplatin 
25 mg/m2 
20% 
20 mg/m2 
20 mg/m2 
20% 
16 mg/m2 
16 mg/m2 
100% 
Discontinue 
CPI-613 
2000 mg/m2 
25% 
1500 mg/m2 
1500 mg/m2 
33% 
1000 mg/m2 
1000 mg/m2 
50% 
500 mg/m2 
500 mg/m2 
100% 
Discontinue 
 

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5.2.1 
All dose reductions will be permanent unless otherwise noted or approved by the 
Sponsor-Investigator. 
5.2.2 
If more than one toxicity occurs requiring dose reduction, the dose administered 
should be based on the most severe toxicity. 
5.2.3 
Treatment delay of more than 28 days from last intended therapy will result in  
discontinuation from trial, unless otherwise agreed and documented between the 
treating investigator and the sponsor-investigator and the delay is not due to 
toxicity attributable to study treatment. 
5.2.4 
If one of the drugs is discontinued due to toxicity attributed to that agent, the 
patient will be allowed to continue a modified regimen with the remaining study 
arm agent/s. However, monotherapy with cisplatin is not permitted, though 
monotherapy with gemcitabine is allowed. Additionally, if both gemcitabine and 
cisplatin are held on day 1 or day 8, then also hold CPI-613. If both gemcitabine 
and cisplatin are discontinued, then CPI-613 should also be discontinued. 
5.2.5 
Investigators should consider dose re-calculation of gemcitabine, cisplatin, and/or 
CPI-613 with change in BSA as per standard of care/institutional guidelines. 
However, a change in BSA by 10% or more requires a dose re-calculation. 
5.2.6 
If a patient experiences neutropenic fever at any point in the treatment cycle, 
chemotherapy will be delayed until ANC > 1,000 and antibiotic treatment of the 
event is completed. When treatment resumes, proceed with one dose level 
reduction as per Table 2 for one or more agents. 
5.2.7 
Doses will not be modified for cholangitis attributable to biliary obstruction/stent 
occlusion unless this occurs in the setting of > grade 3 neutropenia. 
5.2.8 
Laboratory abnormalities that are not clinically relevant (i.e., lymphopenia) do not 
require modification of dosing. 
5.2.9 
Missed Dose: If the regimen held or missed was to be given on Day 1 then that 
next cycle will not be considered to start until the day the first dose is actually 
administered. Held doses of either or all drugs on Day 8 will be considered 
omitted. 
 

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TABLE 6. Day 1 Dose Modifications for Hematologic Toxicity 
Hematologic Toxicity1 
Dose Adjustment 
ANC1 ≥ 1000/mm3 
AND 
Platelets ≥ 75,000/mm3 
Treat as scheduled 
ANC1 < 1000/mm3 
OR/AND 
Platelets < 75,000/mm3 
Hold all protocol treatment up to a maximum of 28 days until ANC ≥ 1000/mm3 AND platelets 
≥ 75,000/mm3 then resume at next lower dose level for either OR both gemcitabine and cisplatin as 
detailed in Table 52. If not resolved, then discontinue all treatment. 
1Note: Growth factors may be added for low ANC BEFORE a dose reduction is instituted for subsequent cycles at the treating physician’s 
discretion. Investigators may consider dose reduction for gemcitabine and/or cisplatin and/or CPI-613 for grade 3 or higher anemia. 
 
 
Table 7: Day 8 Dose Modifications for Hematologic Toxicity 
Hematologic Toxicity 
Dose Adjustment for  
Gemcitabine 
Dose Adjustment for  
Cisplatin 
Dose Adjustment for 
CPI-613 
ANC1 >1000/mm3 
AND 
Platelets ≥ 75,000/mm3 
No change in dose 
No change in dose 
No change in dose 
ANC1 500-999/mm3 
OR 
Platelets 50,000-74,999/mm3 
Decrease Day 8 dose by 1 dose 
level for this cycle 
2Consider decrease in Day 1 & 8 
dose by 1 dose level for 
subsequent cycles 
Decrease Day 8 dose by 1 dose 
level for this cycle 
2Consider decrease in Day 1 & 8 
dose by 1 dose level for 
subsequent cycles 
Decrease Day 8 dose by 1 dose 
level for this cycle 
2Consider decrease in Day 1 & 8 
dose by 1 dose level for 
subsequent cycles 
ANC1 <500/mm3 
OR 
Platelets <50,000/mm3 
Hold Day 8 treatment 
Decrease Day 1 & 8 by 1 dose level 
for subsequent cycles1,2 
Hold Day 8 treatment 
Decrease in Day 1 & 8 dose by 1 
dose level for subsequent cycles1,2 
Hold Day 8 treatment 
Decrease in Day 1 & 8 dose by 1 
dose level for subsequent cycles1 
1Note: Growth factors may be added for low ANC BEFORE a dose reduction is instituted for subsequent cycles at the treating physician’s 
discretion. Investigators may consider dose reduction for gemcitabine and/or cisplatin and/or CPI-613 for grade 3 or higher anemia. 
2Note: Dose level reduction may be for one or more agents as per investigator discretion when toxicity is at least possible attributed to the agent 
 
 

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Table 8: Dose Modifications for Non-Hematologic Toxicity 
Non-Hematologic Toxicity 
Dose Adjustment for  
Gemcitabine 
Dose Adjustment for  
Cisplatin 
Dose Adjustment for  
CPI-613 
Alopecia, venous 
thromboembolism 
No modification to doses 
Grade >3 Nausea and 
vomiting (ongoing after 
maximal anti-emetic 
therapy) 
No change in dose 
Consider dose reduction to next dose 
level or discontinuation of cisplatin 
Hold CPI-613 until resolved to Grade 
1 or baseline, and then consider dose 
reduction to next dose level. 
Grade >3 Diarrhea (at least 
possibly attributed after 
negative infectious work-up 
AND maximal supportive 
therapy) 
No change in dose 
Consider dose reduction to next dose 
level 
Hold CPI-613 until resolved to Grade 
1 or baseline, and then consider dose 
reduction to next dose level. 
Grade >2 
Hyperbilirubinemia 
Hold all protocol treatment up to a maximum of 28 days until toxicity resolves to Grade ≤ 1 or baseline, then may 
resume at same doses as before or next dose level for one or more agents. If not resolved, then discontinue all 
treatment. Doses will not be modified for cholangitis attributable to biliary obstruction/stent occlusion unless this 
occurs in the setting of >grade 3 neutropenia 
Grade >3 possibly 
attributable to cytotoxic 
treatment 
Hold all protocol treatment up to a maximum of 28 days until toxicity resolves to Grade ≤ 1 or baseline, then 
resume at next dose level for one or more agents. 
>Grade 3 Peripheral 
neuropathy 
No change in dose 
 
Hold cisplatin up to a maximum of 28 
days until toxicity resolves to Grade ≤ 
2, then consider dose reduction to 
next dose level. 
No change in dose 
>Grade 2 Creatinine 
increase (>1.5 x baseline or 
ULN whichever is higher) 
No change in dose 
Hold cisplatin, assess hydration and 
general medical status of the patient. 
Cisplatin may be resumed if 
creatinine improves to <1.5 x ULN or 
baseline with one dose level 
reduction. 
Hold CPI-613, assess hydration and 
general medical status of the-patient. 
CPI-613 may be resumed if creatinine 
improves to <1.5 x ULN or baseline 
with one dose level reduction. 
 
Note: Laboratory abnormalities that are not clinically relevant (i.e., lymphopenia) do not require modification of dosing. All dose adjustments for 
toxicity will be described in the clinical record.

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5.3 
Concomitant Medications/Treatments 
The following concomitant medications or treatments are not permitted while the patient 
is currently receiving therapy on the protocol: 
• 
Other investigational agents 
• 
Concurrent radiation unless given for palliation during which study therapy must 
be held. 
 
The following concomitant medications may require additional monitoring during cisplatin 
therapy: 
• 
Plasma levels of anticonvulsant agents (valproic acid, phenytoin, and 
carbamazepine) may become sub-therapeutic and should be monitored. 
• 
Concomitant use with aminoglycosides, tacrolimus, and amphotericin B increase 
risk of nephrotoxicity.  
• 
Concomitant use with loop diuretics and aminoglycosides increase risk of 
ototoxicity.  
• 
Concurrent use with lithium may result in reduced lithium plasma concentration. 
• 
Concurrent use with warfarin may result in increased INR.  
• 
Concurrent use with thioctic acid (alpha-lipoic acid) may result in decreased 
cisplatin effectiveness and should be avoided. 
5.4 
Other Modalities or Procedures 
None 
5.5 
Duration of Therapy 
Treatment may continue for a total of 2 years or until one of the following criteria apply: 
• 
Disease progression as defined in Section 7.0 
• 
Inter-current illness that prevents further administration of treatment 
• 
Unacceptable adverse event(s) 
• 
Sexually active subjects who refuse to use medically accepted barrier 
methods of contraception (e.g., male condom, female condom) during the 
course of the study and for 6 months after discontinuation of study treatment 
• 
Patient who becomes pregnant or is breastfeeding 
• 
Patient who cannot tolerate the minimum protocol-specified dose of study 
treatment 
• 
Request by regulatory agencies for termination of treatment of an individual 
subject or all subjects under the protocol 
• 
Significant noncompliance with the protocol schedule in the opinion of the 
investigator 
• 
Patient voluntarily withdraws from treatment OR 
• 
General or specific changes in the patient’s condition render the patient 
unacceptable for further treatment in the judgment of the investigator 
5.6 
Off Treatment Criteria  
Patients will be removed from protocol therapy when any of the criteria listed in Section 
5.5 apply. Document in the source the reason for ending protocol therapy and the date 
the patient was removed from treatment. All patients who discontinue treatment should 
comply with protocol specific follow-up procedures as outlined in Section 5.8. The only 
exception to this requirement is when a subject withdraws consent for all study 
procedures or loses the ability to consent freely. 

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5.7 
Duration of Follow-Up 
After treatment discontinuation, follow-up for survival and initiation of any other anti-
cancer therapies will be documented every 3 months via telephone or office visit 
documentation for up to 2 years from treatment discontinuation or until death, whichever 
comes first, or 3 years after first date of treatment initiation for those that remain on 
treatment. Patients removed from treatment for unacceptable adverse events will also be 
followed more closely until resolution or stabilization of the adverse event.  
5.8 
Off Study Criteria 
Patients can be taken off study at any time at their own request, or they may be 
withdrawn at the discretion of the investigator for safety, behavioral or administrative 
reasons. The reason(s) for discontinuation from study will be documented and may 
include: 
5.8.1 
Patient withdraws consent (termination of treatment and follow-up);  
5.8.2 
Loss of ability to freely provide consent through imprisonment or involuntary 
incarceration for treatment; 
5.8.3 
Termination of the study by the Sponsor, the University of Michigan, or the FDA; 
5.8.4 
Patient completes protocol treatment and follow-up criteria; 
5.9 
Patient Replacement 
 
Patients enrolled in the study will be considered non-evaluable under the following case 
scenarios and replaced by additional patients: 
 
1. Patients who received no investigational therapy. 
 
2. Patients who were discontinued or withdrew consent for study therapy prior to first 
response evaluation. 
 
3. Patients meeting off study criteria 5.8.1 and 5.8.2.  
 
6.0 
STUDY PROCEDURES 
6.1 
Screening/Baseline Procedures 
Assessments performed exclusively to determine eligibility for this study will be 
done only after obtaining informed consent. Assessments performed for clinical 
indications (not exclusively to determine study eligibility) may be used for 
baseline values even if the studies were done before informed consent was 
obtained. 
 
 
 
 

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6.2 
Time and Events Table/Schedule of Events/Study Calendar 
Table 9. Study Calendar 
Procedures 
Screening1 
Phase IB or II Arm A 
Phase II Arm B 
EOT 
Visit8 
Follow-Up 
Q3 months 
+/- 1 week9 
Cycle 113 
Cycle X13 
Cycle 
113 
Cycle X13 
Day 1 
Day 1 
Day 8 
Day 1 
Day 1 
Day 8 
Informed Consent 
X 
 
 
 
 
 
 
 
 
History, Physical 
Examination 
X 
X 
X 
 
X 
X 
 
X 
 
Weight, BSA 
X 
X 
X 
 
X 
X 
 
X 
 
Vital Signs 
X 
X 
X 
X 
X 
X 
X 
X 
 
Performance Status 
X 
X 
X 
 
X 
X 
 
X 
 
Toxicity Evaluations 
 
X 
X 
C1D812 
X 
X 
 
X 
 
Scans with Tumor 
Measurements 
X 
 
X5 
 
 
X5 
 
 
 
CBC with differential 
X 
X 
X 
X 
X 
X 
X 
 
 
CMP2 
X 
X 
X 
X 
X 
X 
X 
 
 
HbA1c 
X 
 
X11 
 
 
X11 
 
 
 
CA 19-9, CEA 
 
X 
X10 
 
X 
X10 
 
X 
 
PT, PTT 
X 
 
 
 
 
 
 
 
 
Pregnancy Test3 
X 
 
 
 
 
 
 
 
 
Concomitant 
Medication Review 
X 
X 
X 
 
X 
X 
 
 
 
ECG 
X 
 
 
 
 
 
 
 
 
Research Blood4 
 
X 
X 
 
X 
X 
 
X 
 
Tissue6 
X 
 
 
 
 
 
 
X 
 
Study Drug 
Administration7 
 
X 
X 
X 
X 
X 
X 
 
 
Survival Follow-up 
 
 
 
 
 
 
 
 
X 
 
1. All screening procedures to be completed within 2 weeks of enrollment, except imaging which should be ≤ 4 weeks. Protocol 
treatment is to begin <14 days of enrollment. 
2. Comprehensive metabolic panel includes BUN/creatinine, sodium, potassium, chloride, glucose, calcium, alkaline phosphatase, 
albumin, AST, ALT, total bilirubin and total protein. 

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3. Required for females of childbearing potential. Serum or urine pregnancy test per site investigator discretion. 
4. Cycle 1 Day 1 specimens will be collected prior to administration of initial dose, and Cycle X Day 1 specimens will be collected on 
Cycle 4 Day 1 prior to drug administration. Refer to the lab manual for sample collection and processing details. 
5. MRI or CT (abdomen with or without pelvis) with contrast along with CT chest with or without contrast will be assessed every 8 + 1 
weeks starting from C1D1. Imaging assessment of scans at the site should be completed by either a radiologist or an imaging 
core, and not by the oncologist nor via abstraction of data from the subjective/clinical radiology report. 
6. Pre-treatment, diagnostic pathology specimens obtained in the course of standard biopsy or surgery. Procurement of tissue is 
mandatory for enrollment, however, all biopsies are optional. If tissue from initial biopsy is not available, a repeat biopsy is NOT 
required and patient will be eligible for enrollment. Refer to the lab manual for sample collection and processing details.  
7. See Section 5.1 for details. Study drug administration with associated labs will have a window of + 3 days. 
8. End of treatment (EOT) visit should be completed within 30 days of last treatment. And if possible, end of treatment biopsy should 
be collected for patients enrolled on Phase IB or II Arm A only prior to start of subsequent therapy. 
9. Patients will be followed every 3 months via telephone or office visit documentation for up to 2 years from treatment discontinuation 
or until death, whichever comes first, or 3 years after first date of treatment initiation for those that remain on treatment. 
10. Check CA 19-9 (preferred) and/or CEA every 6 +/- 1 weeks prior to infusion, if elevated at baseline. May be delayed if infusion is not 
scheduled within the window. 
11. Check HbA1c every 12 +/ - 1 weeks prior to infusion. May be delayed if infusion is not scheduled within the window. 
12. Mandatory for cycle 1 day 8 only; rest per institutional guidelines 
13. A ± 1-day window will be allowed for all treatment visits and associated labs, unless otherwise specified. However, every effort must 
be made to follow the schedule outlined in the table above. 
 

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7.0 
MEASUREMENT OF EFFECT 
7.1 
Antitumor Effect- Solid Tumors 
 
 
Objective response assessment will be determined by review of CT or MR scans 
of the chest, abdomen with or without pelvis using RECIST v1.1 every 8 weeks 
+/- 1 week while patients are on treatment (Eisenhauer, Therasse et al. 2009). 
7.1.1 
Definitions 
Evaluable for toxicity. All patients will be evaluable for toxicity from the time of 
their first treatment with study drug. 
 
Evaluable for phase IB primary endpoint, MTD/RP2D. All patients that receive at 
least one dose of study therapy will be considered evaluable. Patients enrolled to 
therapy but that never receive study therapy will be replaced. See Section 5.9. 
 
Evaluable for phase II primary endpoint, overall response rate. All enrolled 
patients who received at least 1 cycle(s) of therapy, and had their disease re-
evaluated will be considered evaluable for response. These patients will have 
their response classified according to the definitions stated below. (Note: Patients 
who exhibit objective disease progression prior to the end of cycle 1 will also be 
considered evaluable.) 
7.1.2 
Disease Parameters 
Measurable disease. Measurable lesions are defined as those that can be 
accurately measured in at least one dimension (longest diameter in the plane of 
measurement is to be recorded) with a minimum size of: 
 
• 
10 mm by CT scan (irrespective of scanner type) for studies with a slice 
thickness of <5mm or twice the slice thickness or MRI 
• 
10 mm caliper measurement by clinical exam (lesions which cannot be 
accurately measured with calipers should be recorded as non-
measurable)          
• 
20 mm by chest X-ray (if clearly defined and surrounded by aerated lung) 
                           
All tumor measurements must be recorded in millimeters (or decimal fractions of   
centimeters). 
 
Malignant lymph nodes: To be considered pathologically enlarged and 
measurable, a lymph node must be ≥15mm in short axis when assessed by CT 
scan (CT scan slice thickness recommended to be no greater than 5 mm). At 
baseline and in follow-up, only the short axis will be measured and followed. 
 
Note: Tumor lesions that are situated in a previously irradiated area will only be 
considered measurable, if they have had subsequent progression by at least 5 
mm.  
 
Non-measurable disease. All other lesions (or sites of disease), including small 
lesions (longest diameter <10 mm using CT scan), are considered non-
measurable disease. Bone lesions without measurable soft tissue component, 
leptomeningeal disease, ascites, pleural/pericardial effusions, lymphangitis 
cutis/pulmonitis, inflammatory breast disease, abdominal masses (not followed 
by CT or MRI), and cystic lesions are all non-measurable. 
 

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Target lesions. All measurable lesions up to a maximum of 2 lesions per organ 
and 5 lesions in total should be identified as target lesions and recorded and 
measured at baseline. Target lesions should be selected on the basis of their 
size (non-nodal lesions with the longest diameter), be representative of all 
involved organ(s), but in addition should be those that lend themselves to 
reproducible repeated measurements. 
 
Lymph nodes merit special mention since they are normal anatomical structures 
that may be visible by imaging even if not involved by tumor. Pathological nodes 
that are defined as measurable and may be identified as target lesions must 
meet the criterion of a short axis of ≥15 mm by CT scan. Only the short axis of 
these nodes will contribute to the baseline sum. The short axis of the node is the 
diameter normally used by radiologists to judge if a node is involved by solid 
tumor. Nodal size is normally reported as two dimensions in the plane in which 
the image is obtained (for CT scan this is almost always the axial plane; for MRI 
the plane of acquisition may be axial, sagittal or coronal). The smaller of these 
measures is the short axis. For example, an abdominal node which is reported as 
being 20 mm x 30 mm has a short axis of 20 mm and qualifies as a malignant, 
measurable node. In this example, 20 mm should be recorded as the nodal 
measurement. All other pathological nodes (those with short axis ≥10mm but <15 
mm) should be considered non-target lesions. Nodes that have a short axis 
<10mm are considered non-pathological and should not be recorded or followed. 
A sum of the diameters (longest for non-nodal lesions, short axis for nodal 
lesions) for all target lesions will be calculated and reported as the baseline sum 
of diameters. If lymph nodes are to be included in the sum, then as noted above, 
only the short axis is added into the sum. The baseline sum of diameters will be 
used as reference to further characterize any objective tumor regression in the 
measurable dimension of the disease.  
 
Non-target lesions. All other lesions (or sites of disease) including pathological 
lymph nodes should be identified as non-target lesions and should also be 
recorded at baseline. Measurements are not required, and these lesions should 
be followed as ‘present’, ‘absent’, or in rare cases ‘unequivocal progression’ 
(more details to follow). In addition, it is possible to record multiple non-target 
lesions involving the same organ as a single item on the case record form (e.g. 
‘multiple enlarged pelvic lymph nodes’ or ‘multiple liver metastases’). 
7.1.3 
Guidelines for Evaluation of Measurable Disease 
All measurements should be recorded in metric notation, using calipers if 
clinically assessed. All baseline evaluations should be performed as close as 
possible to the treatment start date and never more than 4 weeks before the 
beginning of the treatment. 
 
The same method of assessment and the same technique should be used to 
characterize each identified and reported lesion at baseline and during 
subsequent follow-up studies. Imaging-based evaluation should always be done 
rather than clinical examination unless the lesion(s) being followed cannot be 
imaged but are assessable by clinical exam. 
 
Clinical lesions: Clinical lesions will only be considered measurable when they 
are superficial and >10 mm diameter as assessed using calipers (e.g. skin 
nodules). For the case of skin lesions, documentation by color photography 
including a ruler to estimate the size of the lesion is suggested. As noted above, 
when lesions can be evaluated by both clinical exam and imaging, imaging 
evaluation should be undertaken since it is more objective and may also be 
reviewed at the end of the study. 

Protocol UMCC 2019.116 
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CT, MRI: CT is the best currently available and reproducible method to measure 
lesions selected for response assessment. This guideline has defined 
measurability of lesions on CT scan based on the assumption that CT slice 
thickness is 5mm or less. When CT scans have slice thickness greater than 5 
mm, the minimum size for a measurable lesion should be twice the slice 
thickness. MRI is also acceptable in certain situations (e.g. for body scans). 
 
Ultrasound: Ultrasound is not useful in assessment of lesion size and should not 
be used as a method of measurement. Ultrasound examinations cannot be 
reproduced in their entirety for independent review at a later date and, because 
they are operator dependent, it cannot be guaranteed that the same technique 
and measurements will be taken from one assessment to the next. If new lesions 
are identified by ultrasound in the course of the study, confirmation by CT or MRI 
is advised. If there is concern about radiation exposure at CT, MRI may be used 
instead of CT in selected instances. 
 
Endoscopy, laparoscopy: The utilization of these techniques for objective tumor 
evaluation is not advised. However, they can be useful to confirm complete 
pathological response when biopsies are obtained or to determine relapse in 
trials where recurrence following complete response or surgical resection is an 
endpoint. 
 
Tumor markers: Tumor markers alone cannot be used to assess objective tumor 
response.  
 
7.1.4 
Response Criteria 
7.1.4.1 Evaluation of Target Lesions 
Complete Response (CR): Disappearance of all target lesions, 
determined by two separate observations conducted not less than 4 
weeks apart. There can be no appearance of new lesions. 
 
Partial Response (PR): At least a 30% decrease in the sum of the 
longest diameter (LD) of target lesions, taking as reference the baseline 
sum LD. There can be no appearance of new lesions. 
 
Progressive Disease (PD): At least a 20% increase in the sum of the LD 
of target lesions (with a minimum absolute increase of 5 mm), taking as 
reference the smallest sum LD recorded since the treatment started, or 
the appearance of one or more new lesions. 
 
Stable Disease (SD): Neither sufficient shrinkage to qualify for PR (taking 
as reference the baseline sum LD) nor sufficient increase to qualify for 
PD (taking as reference the smallest sum LD since the treatment 
started). 
 
7.1.4.2 Evaluation of Non-Target Lesions 
Complete Response (CR): Disappearance of all non-target lesions. All 
lymph nodes should be non-pathological in size (<10 mm short axis) 
 
Non-CR/Non-PD: Persistence of one or more non-target lesion(s) 

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Progressive Disease (PD): Appearance of one or more new lesions 
and/or unequivocal progression of existing non-target lesions. 
 
Although a clear progression on non-target lesions in absence of stable 
target lesions is exceptional, the opinion of the treating physician should 
prevail in such circumstances.  
7.1.4.3 Evaluation of Best Overall Response 
The best overall response is the best response recorded from the start of 
the treatment until disease progression/recurrence (taking as reference 
for progressive disease the smallest measurements recorded since the 
treatment started). The patient's best response assignment will depend 
on the achievement of both measurement and confirmation criteria. 
 
 
 
 
 
 
 
Table 10. Response Evaluation as per RECISTv1.1 
Target 
Lesions 
Non-Target 
Lesions 
New 
Lesions 
Overall 
Response per 
RECISTv1.1 
Confirmed Response 
for this Category 
Requires: 
CR 
CR 
No 
CR 
>4 wks. confirmation 
CR 
CR 
Non-CR/PD 
No 
PR 
>4 wks. confirmation 
PR 
CR 
Non-CR/PD 
No 
SD 
CR 
Non-CR/PD 
No 
SD 
Documented at least 
once >4 wks. from 
baseline 
PD 
Any 
Any 
PD 
>4 wks. confirmation 
Any 
PD* 
Any 
Any 
Any 
Yes 
* 
Only in exceptional circumstances, unequivocal progression in non-target 
lesions may be accepted as disease progression. 
 
Note: Patients with a global deterioration of health status requiring 
discontinuation of treatment without objective evidence of disease progression 
at that time should be reported as “symptomatic deterioration”. Every effort 
should be made to document the objective progression even after 
discontinuation of treatment. 
          
 
             NA=not applicable 
 
Note: If subjects respond to treatment and are able to have their disease 
resected, the patient’s response will be assessed prior to the surgery. 
 
7.1.5 
Duration of Response 
Duration of overall response: The duration of overall response is measured from 
the time measurement criteria are met for CR or PR (whichever is first recorded) 
until the first date that recurrent or progressive disease is objectively documented 
(taking as reference for progressive disease the smallest measurements 
recorded since the treatment started). 
 

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Duration of stable disease: Stable disease is measured from the start of the 
treatment until the criteria for progression are met, taking as reference the 
smallest measurements recorded since the treatment started.  
7.2 Safety/Tolerability 
Analyses will be performed for all patients having received at least one dose of study 
drug. The study will use the CTCAE version 5.0 for reporting of adverse events 
(http://ctep.cancer.gov/reporting/ctc.html).  
 
8.0 
ADVERSE AND OTHER REPORTABLE EVENTS 
8.1 
Adverse Event Reporting Requirements 
Adverse event (AE) monitoring and reporting is a routine part of every clinical trial and is 
done to ensure the safety of subjects enrolled in the studies as well as those who will 
enroll in future studies using similar agents. Data on adverse events will be collected from 
the time of the initial study treatment administration through 30 days after the last dose of 
study treatment. Any serious adverse event that occurs more than 30 days after the last 
study treatment and is considered related to the study treatment or intervention must also 
be reported. Serious Adverse Events (SAEs) will continue to be followed until: 
• 
Resolution or the symptoms or signs that constitute the serious adverse event 
return to baseline; 
• 
There is satisfactory explanation other than the study treatment for the changes 
observed; or  
• 
Death. 
The investigator is responsible for the detection, documentation, grading and assignment 
of attribution of events meeting the criteria and definition of an AE or SAE. The definitions 
of AEs and SAEs are given below. It is the responsibility of the principal investigator to 
ensure that all staff involved in the trial is familiar with the content of this section. 
Any medical condition or laboratory abnormality with an onset date before initial study 
treatment administration is considered to be pre-existing in nature. Any known pre-
existing conditions that are ongoing at time of study entry should be considered medical 
history. 
All events meeting the criteria and definition of an AE or SAE, as defined in Section 8.3, 
occurring from the initial study treatment administration through 30 days following the last 
dose of the study treatment must be recorded as an adverse event in the patient’s source 
documents and on the CRF regardless of frequency, severity (grade) or assessed 
relationship to the study treatment or intervention. However, with regards to laboratory 
and vital sign abnormalities, only those which require protocol treatment to be modified or 
treatment to be rendered should be reported as AEs. 
In addition to new events, any increase in the frequency or severity (i.e., toxicity grade) of 
a pre-existing condition that occurs after the patient begins study treatment is also 
considered an adverse event. However, anticipated fluctuations of pre-existing 
conditions, including the disease under study, that don’t represent a clinically significant 
exacerbation or worsening, need not be reported as AEs.  

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8.2 
Definitions 
8.2.1 Adverse Event 
An adverse event (AE) is any untoward medical occurrence in a patient receiving 
study treatment and which does not necessarily have a causal relationship with 
this treatment. An AE can be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease temporally associated with the 
use of an experimental intervention, whether or not related to the intervention.  
 
• 
Diagnostic and therapeutic non-invasive and invasive (i.e., surgical) 
procedures will not be reported as adverse events. However, the medical 
condition for which the procedure was performed must be reported if it 
meets the definition of an adverse event unless it is a pre-existing (prior 
to protocol treatment) condition. 
8.2.2 Serious Adverse Event 
An adverse event is considered “serious” if, in the view of either the investigator 
or sponsor-investigator, it results in any of the following outcomes: 
  
• 
Death 
If death results from (progression of) the disease, the disease should be 
reported as event (SAE) itself. 
• 
A life-threatening adverse event 
An adverse event is considered ‘life-threatening’ if, in the view of either 
the investigator [or sponsor], its occurrence places the patient or subject 
at immediate risk of death. It does not include an adverse event that, had 
it occurred in a more severe form, might have caused death.  
• 
Inpatient hospitalization or prolongation of existing hospitalization for > 
24 hours 
• 
A persistent or significant incapacity or substantial disruption of the ability 
to conduct normal life functions 
• 
A congenital anomaly/birth defect 
• 
Important medical event: Any event that may not result in death, be life-
threatening, or require hospitalization may be considered serious when, 
based upon appropriate medical judgment, they may jeopardize the 
patient and may require medical or surgical intervention to prevent one of 
the outcomes listed in this definition of “Serious Adverse Event”. 
Examples of such medical events include allergic bronchospasm 
requiring intensive treatment in an emergency room or at home; 
convulsions that do not result in inpatient hospitalization or the 
development of drug dependency or drug abuse.  
 
Previously planned (prior to signing the informed consent form) surgeries should 
not be reported as SAEs unless the underlying medical condition has worsened 
during the course of the study. Preplanned hospitalizations or procedures for 
preexisting conditions that are already recorded in the patient’s medical history at 
the time of study enrollment should not be considered SAEs. Hospitalization or 
prolongation of hospitalization without a precipitating clinical AE (for example, for 
the administration of study therapy or other protocol-required procedure) should 
not be considered SAEs. However, if the preexisting condition worsened during 
the course of the study, it should be reported as an SAE. 
 
8.2.3 Expected Adverse Events 
An adverse event (AE) is considered “expected” if: 

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• 
For approved and marketed drugs or devices, those adverse events are 
described in the approved Package Insert (Label).  
• 
For investigational new drugs or devices, those adverse events are 
described in the CPI-613 Investigator’s Brochure.  
• 
In clinical research studies, information on expected adverse events is 
also summarized in the protocol and in the consent document.  See 
section 9.1 for the list of expected adverse events related to the drug 
under study. 
8.2.4 Unexpected Adverse Event 
An adverse event (AE) is considered “unexpected” if it is not described in the 
Package Insert, CPI-613 Investigator’s Brochure, in published medical literature, 
in the protocol, or in the informed consent document.  
8.3 
Adverse Event Characteristics 
8.3.1 CTCAE Term 
(AE description) and grade: The descriptions and grading scales found in the NCI 
Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 will be 
utilized for AE reporting. All appropriate treatment areas should have access to a 
copy of the CTCAE version 5.0. A copy of the CTCAE version 5.0 can be down 
loaded from the CTEP web site. (http://ctep.cancer.gov) 
8.3.2 Attribution of the AE 
The investigator or co-investigator is responsible for assignment of attribution. 
RELATED 
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. 
UNRELATED 
Unlikely – The AE is doubtfully related to the study treatment. 
Unrelated – The AE is clearly NOT related to the study 
treatment/intervention. 
8.4 
Serious Adverse Event Reporting Guidelines  
8.4.1 Reporting procedures for multi-site trials 
All serious adverse events (SAEs) and unanticipated problems (UPs), regardless 
of causality to study drug, will be reported to the Principal Investigator and also to 
the Coordinating Center.  All SAEs and UPs must be reported to the Coordinating 
Center within 24 hours of first awareness of the event.  Events should be reported 
using the Coordinating Center’s SAE form as available in the study database.  A 
copy of the SAE form as available in the study database should be sent to the 
Coordinating Center via fax at 734-232-0744 or via email to CTSU-Oncology-
Multisite@med.umich.edu within 24 hours of the site’s knowledge of the event.  
 
Follow-up information must also be reported within 24 hours of receipt of the 
information by the investigator. 
 
All SAEs and UPs will be reported to the IRB per current institutional standards. 
 
The Coordinating Center will disseminate information regarding SAEs and UPs to 
the participating sites within 5 days of review of the information by the Coordinating 
Center’s Principal Investigator (or designee in the event of extended absence) only 

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in the case that the event(s) is believed to be related (i.e., possibly, probably, or 
definitely) to the study drug. The Coordinating Center will be responsible for 
reporting of events to the FDA and supporters, as appropriate (outlined below). 
8.4.2 
Reporting procedures to Cornerstone Pharmaceuticals 
All Serious Adverse Events (SAEs) occurring from the initial study treatment 
administration through 30 days following the last dose of the study treatment will 
be reported by the Coordinating Center to Cornerstone Pharmaceuticals. Any 
SAEs occurring after 30 days following the last dose of the study treatment that 
are believed to be related to study drug will also be reported to Cornerstone 
Pharmaceuticals.  
The Coordinating Center will send the initial completed SAE Form within 24 
hours of receipt via email to SAEIntake@labcorp.com and  
safety@cornerstonepharma.com. 
If only limited information is initially available or an ongoing SAE changes in its 
intensity or relationship to the study drug, or if new information becomes 
available, a follow-up report will be generated and sent to 
SAEIntake@labcorp.com and safety@cornerstonepharma.com. 
Reporting procedures to FDA 
In this trial, serious, unexpected adverse events believed to be definitely, 
probably or possibly related to the study treatment will be reported to the Food 
and Drug Administration via the MedWatch 3500A Form. The MICHR IND/IDE 
Assistance Program (MIAP) (University of Michigan) will assist the IND Sponsor 
in reporting SAEs to the FDA that meet the reporting requirements in 21 CFR 
312.32. This reporting could include the initial report and follow-up reports when 
appropriate for the event. SAEs not meeting the expedited reporting 
requirements will be submitted to the FDA with the IND Annual Report.  
8.5 
Routine Reporting 
All other adverse events- such as those that are expected, or are unlikely or definitely not 
related to the study participation- are to be reported annually as part of regular data 
submission. 
8.6 
Reporting of Pregnancy 
Pregnancies that occur during study participation or within 6 months of last study dose 
should be reported to the Coordinating Center via e-mail at CTSU-Oncology-
Multisite@med.umich.edu immediately upon site’s knowledge of the event.  
8.7 
Reporting of Unanticipated Problems 
There are types of incidents, experiences and outcomes that occur during the conduct of 
human subjects research that represent unanticipated problems but are not considered 
adverse events. For example, some unanticipated problems involve social or economic 
harm instead of the physical or psychological harm associated with adverse events. In 
other cases, unanticipated problems place subjects or others at increased risk of harm, 
but no harm occurs. 
 
Upon becoming aware of any incident, experience, or outcome (not related to an adverse 
event) that may represent an unanticipated problem, the investigator should assess 
whether the incident, experience, or outcome represents an unanticipated problem. The 
incident, experience or outcomes is considered unanticipated if it meets all of the 
following criteria: 
 

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1. Unexpected (in terms of nature, severity, or frequency); 
2. Related or possibly related to participation in the research; and 
3. Suggests that the research places subjects or others at a greater risk of harm 
than was previously known or recognized. 
If the investigator determines that the incident, experience, or outcome represents an 
unanticipated problem, the investigator must report it to the IRB within 14 calendar days 
of the study team becoming aware of the problem. 
8.8 
Safety Report Reconciliation  
The Sponsor will reconcile the clinical database SAE reports transmitted to Cornerstone 
Pharmaceuticals. Frequency of reconciliation should be every 3 months and prior to the 
database lock or final data summary. Cornerstone Pharmaceuticals will email, upon 
request from the Investigator, the GPV&E reconciliation report. The data elements listed 
on the GPV&E reconciliation report will be used for identification purposes. If the 
Investigator determines a report was not transmitted to Cornerstone Pharmaceuticals, the 
report should be sent immediately.   
 
9.0 
DRUG INFORMATION 
9.1 
Gemcitabine 
9.1.1 
Other Names 
 
 
Gemzar® 
9.1.2 
Classification 
Gemcitabine (difluorodeoxycytidine) is a pyrimidine antimetabolite, which is an 
analogue of deoxycytidine. It was initially synthesized as a potential antiviral drug 
but selected for anticancer development because of its activity in in-vivo and in 
vitro tumors. Gemcitabine is approved for the treatment of patients with BTC and 
will be obtained commercially. 
9.1.3 
Mechanism of Action 
Gemcitabine kills cells undergoing DNA synthesis and blocks the progression of 
cells through the G1/S-phase boundary. Gemcitabine is metabolized by 
nucleoside kinases to diphosphate (dFdCDP) and triphosphate (dFdCTP) 
nucleosides. Gemcitabine diphosphate inhibits ribonucleotide reductase, an 
enzyme responsible for catalyzing the reactions that generate deoxynucleoside 
triphosphates for DNA synthesis, resulting in reductions in deoxynucleotide 
concentrations, including dCTP. Gemcitabine triphosphate competes with dCTP 
for incorporation into DNA. The reduction in the intracellular concentration of 
dCTP by the action of the diphosphate enhances the incorporation of 
gemcitabine triphosphate into DNA (self-potentiation). After the gemcitabine 
nucleotide is incorporated into DNA, only one additional nucleotide is added to 
the growing DNA strands, which eventually results in the initiation of apoptotic 
cell death. 
9.1.4 
Pharmacokinetics 
1. Distribution: Gemcitabine plasma protein binding is negligible. The volume of 
distribution is increased with the infusion length. In a pharmacokinetics study 
of patients with various solid tumors, the volume of distribution of 
gemcitabine was 50 L/m2 following infusions lasting <70 minutes. For long 
infusions (70 to 285 minutes), the volume of distribution rose to 370 L/ m2. 

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2. Metabolism: Gemcitabine is metabolized intracellularly to form active 
gemcitabine di- and tri-phosphates. The gemcitabine di- and triphosphates 
do not appear to circulate in plasma in measurable amounts. Gemcitabine is 
metabolized by the liver to form the inactive uracil derivative, 2'-deoxy-2',2'-
difluorouridine (dFdU). The inactive metabolite does not appear to 
accumulate with weekly dosing; however, it is excreted by the kidneys and 
may accumulate in patients with decreased renal function. 
 
3. Elimination: Following a single 1,000 mg/m2 over 30 min [14C]-gemcitabine 
infusion, 92% to 98% of the dose was recovered within 1 week after 
gemcitabine administration. Urinary excretion of the parent drug and the 
dFdU metabolite accounted for 99% of the excreted dose, and less than 1% 
of the dose was excreted in feces. The renal clearance of gemcitabine is less 
than 10%; therefore, the parent drug appears to be almost completely 
metabolized to the inactive dFdU. 
 
Clearance of gemcitabine is affected by age and gender and is lower in 
women and the elderly. Differences in either clearance or volume of 
distribution based on patient characteristics or the duration of infusion result 
in changes in half-life and plasma concentrations. Studies showed that 
gemcitabine half-life for short infusions ranged from 42 to 94 minutes, for 
long infusions it varied from 245 to 638 minutes, depending on age and 
gender, reflecting a greatly increased volume of distribution with longer 
infusions. The terminal phase half-life for the active metabolite, gemcitabine 
triphosphate, in mononuclear cells ranges from 1.7-19.4 hours. 
9.1.5 
Storage, Preparation and Stability 
Refer to the current FDA-approved package insert for storage, stability and 
special handling information. 
9.1.6 
Dosing and Administration 
See Section 5.1 
9.1.7 
Availability 
Gemcitabine is commercially available and will not be supplied. Refer to the 
current FDA-approved package insert for the most comprehensive and up to date 
information. 
9.1.8 
Handling and Disposal 
Handling and disposal of gemcitabine should be per institutional guidelines for 
the handling and disposal of biologic and cytotoxic agents. Recommended safety 
measures for preparation and handling of gemcitabine include laboratory coats 
and gloves. 
9.1.9 
Adverse Effects 
1. Side Effects: Refer to the current FDA-approved package insert for the most 
comprehensive and up to date information on adverse reactions. Adverse 
effects reported in >20% to 100% of subjects treated with gemcitabine 
include: myelosuppression including anemia, leukopenia, neutropenia, and 
thrombocytopenia, increased liver function tests (AST, ALT and/or alkaline 
phosphatase), proteinuria, hematuria, nausea, vomiting, low grade fever, flu-
like symptoms, fatigue, rash and dyspnea. Adverse effects reported in 4% to 
20% of subjects include: diarrhea, constipation, bleeding, infection, alopecia, 

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stomatitis, somnolence, paresthesia, blood or platelet transfusions, 
peripheral edema, infection, and injection site reaction. Adverse effects 
reported in 3% or less of subjects include: anaphylaxis, posterior reversible 
encephalopathy syndrome (PRES), arrhythmias, supraventricular 
arrhythmias, congestive heart failure, myocardial infarction, desquamation 
and bullous skin eruptions, gangrene, sepsis, cerebrovascular accident, 
hepatic failure, adult respiratory distress syndrome (ARDS), anaphylaxis, 
renal failure, pulmonary fibrosis, pulmonary edema, bronchospasm, and 
interstitial pneumonitis. Grade 3 and 4 adverse events in combination with 
cisplatin for BTC from the phase trial are as listed in Table 2 of the 
publication (Valle, Wasan et al. 2010).  
 
2. Pregnancy and Lactation: Category D. Gemcitabine may cause fetal harm 
when administered to a pregnant woman. This agent has produced 
teratogenic effects in mice and rabbits when administered at a dose of < 2 
mg/m2. Adverse effects included decreased fetal viability, weight and 
morphologic defects. There is no data on gemcitabine administration during 
human pregnancy, and it is not currently known if metabolites are excreted in 
human milk. However, many drugs are excreted in human milk, and there is 
a potential for adverse effects in nursing infants. Therefore, the use of 
gemcitabine should be avoided in pregnant or nursing women because of the 
potential hazard to the fetus or infant. 
 
3. Drug Interactions: Per gemcitabine package insert, no formal drug interaction 
studies have been performed to date. When gemcitabine was administered 
with cisplatin there was minimal or no effect on the pharmacokinetics of the 
studied drugs. 
9.2 
Cisplatin 
9.2.1 
Other Names 
CDDP, Platinol®, NSC-119875 
9.2.2 
Classification 
Cisplatin is an alkylating agent, which inhibits DNA synthesis by producing cross-
linking of parent DNA strands (cell-cycle phase-nonspecific). Cisplatin is 
approved for the treatment of patients with BTC and will be obtained 
commercially. 
9.2.3 
Mechanism of Action 
 
 
Cisplatin (cis-diamminedichloroplatinum) is a heavy metal complex containing a 
central platinum atom surrounded by two chloride atoms and two ammonia 
molecules in the cis position. It is water soluble and acts as a bifunctional 
alkylating agent with cell cycle nonspecific characteristics. The intra-strand cross-
links, in particular with guanine and cytosine, change DNA conformation and 
inhibit DNA synthesis leading to the cytotoxic and anti-tumor effects of cisplatin. 
Although cisplatin seems to act as an alkylating agent, there are data to indicate 
that its mode and sites of action are different from those of nitrogen mustard and 
the standard alkylating agents and that cisplatin does not exhibit cross-resistance 
with other alkylating agents or nitrosoureas. 
9.2.4 
Pharmacokinetics 
1. Absorption: Following rapid IV injection of cisplatin over up to one hour, peak 
plasma drug and platinum concentrations occur immediately. When cisplatin 
is administered by IV infusion over 6 or 24 hours, plasma concentrations of 

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total platinum increase gradually during the infusion and peak immediately 
following the end of the infusion. 
 
2. Distribution: Following intravenous dosing, cisplatin distributes rapidly into 
tissues, with highest concentrations in the liver, prostate and kidney. Plasma 
levels of cisplatin decay in a biphasic mode with an initial half-life of 25 to 49 
minutes, and a secondary phase ranging from 58 to 73 hours. This prolonged 
phase is due to protein binding, which exceeds 90%. Cisplatin penetrates 
poorly into the CNS. 
 
3. Metabolism: Cisplatin is non-enzymatically transformed to one or more 
metabolites that are extensively protein bound and have minimal cytotoxic 
activity. The non-protein bound (unchanged) fraction is cytotoxic. 
 
4. Elimination: Urinary excretion is incomplete. Following bolus injection or 
infusion over a dose range of 40-140 mg/m2 varying in length from 1-24 
hours, from 10 to about 40% of the administered platinum is excreted in the 
urine in 24 hours. Renal clearance of free platinum exceeds the glomerular 
filtration rate, indicating that cisplatin or other platinum containing molecules 
are actively secreted by the kidneys. Renal clearance of free platinum is 
nonlinear and variable, and is dependent on dose, urine flow rate, and 
individual variability in the extent of active secretion and possible tubular 
reabsorption. 
9.2.5 
Storage, Preparation and Stability 
Refer to the current FDA-approved package insert for storage, stability and 
special handling information. 
9.2.6 
Dose and Administration 
 
 
See Section 5.1 
9.2.7 
Availability 
Cisplatin is commercially available and will not be supplied. Refer to the current 
FDA-approved package insert for the most comprehensive and up to date 
information. 
9.2.8 
Handling and Disposal 
Handling and disposal of cisplatin should be per institutional guidelines for the 
handling and disposal of biologic and cytotoxic agents. Recommended safety 
measures for preparation and handling of gemcitabine include laboratory coats 
and gloves. 
9.2.9 
Adverse Effects 
1. Side Effects: Refer to the current FDA-approved package insert for the most 
comprehensive and up to date information on adverse reactions. Adverse 
effects reported in >20% to 100% of subjects treated with cisplatin include: 
nausea, vomiting, fatigue, myelosuppression with anemia, leucopenia, 
thrombocytopenia, nephrotoxicity (acute renal failure and chronic renal 
insufficiency), hyperglycemia, and alopecia. Adverse effects reported in 4% 
to 20% of subjects include: fever, stomatitis, electrolyte disorders such as 
hypocalcemia and hypomagnesemia, injection site reaction, increased liver 
function tests (AST, ALT and/or alkaline phosphatase), infection, headache, 
bleeding, hypotension, dysgeusia, diarrhea, hypersensitivity reaction, 
vestibular dysfunction, peripheral neuropathy, blurred vision or altered color 

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perception, and ototoxicity. Adverse effects reported in 3% or less of subjects 
include: rash, febrile neutropenia, sepsis, autonomic neuropathy, reversible 
posterior leukoencephalopathy syndrome (PRES), muscle cramps, 
secondary malignancy and seizure. Other published literature suggests risk 
of thromboembolic events (Seng, Liu et al. 2012). 
 
2. Pregnancy and Lactation: Category D. Cisplatin can cause fetal harm when 
administered to a pregnant woman. In mice, cisplatin is teratogenic and 
embryotoxic. This drug has been found to be excreted in human milk and 
because of the potential for serious adverse reactions in nursing infants, 
patients receiving cisplatin should not breast feed. 
 
3. Drug Interactions: During cisplatin therapy, plasma levels of anticonvulsant 
agents (valproic acid, phenytoin, and carbamazepine) may become sub-
therapeutic and should be monitored. Concomitant use with 
aminoglycosides, tacrolimus, and amphotericin B increase risk of 
nephrotoxicity. Concomitant use with loop diuretics and aminoglycosides 
increase risk of ototoxicity. Concurrent use with lithium may result in reduced 
lithium plasma concentration. Concurrent use with warfarin may result in 
increased INR. Concurrent use with thioctic acid may result in decreased 
cisplatin effectiveness and should be avoided. 
9.3 
CPI-613 
9.3.1 
Other Names 
CPI-613® (devimistat) also known as 6,8-bis(benzylthio)-octanoic acid. It’s 
chemical name is 6,8 bis(benzylsulfanyl) octanoic acid. It is a white to off white 
crystalline powder with slight sulphurous odor. Its empirical molecular formula is 
C22H28S2O2 and the molecular weight is 388.6. 
9.3.2 
Classification 
CPI-613 is the first of a novel class of tumor-specific anti-mitochondrial 
metabolism inhibitors. 
9.3.3 
Mechanism of Action 
CPI-613 is a stable analog of normally transient, acylated catalytic intermediates 
of lipoic acid (lipoate), an essential co-factor for 2 enzyme complexes, pyruvate 
dehydrogenase (PDH) and a-ketoglutarate dehydrogenase (KGDH) central to the 
tricarboxylic acid (TCA) or Kreb’s cycle. These lipoic intermediates are monitored 
by regulatory systems to control flux through these 2 enzymes. Regulatory 
systems controlling this flux are significantly modified during anabolic 
reprogramming in cancer making them more susceptible to CPI-613. Additionally, 
tumor cells take up CPI-613 preferentially, apparently through upregulated 
vitamin and fatty acid transporters. CPI-613 selectively inactivates these two 
enzymes, thereby collapsing mitochondrial metabolism of the tumor cells. This 
collapse of mitochondrial metabolism leads, in turn, to redundant activation of 
apoptotic and necrotic cell death pathways. 
9.3.4 
Pharmacokinetics 
1. Distribution: The elimination T1/2 from 0-8 hours post-administration of CPI-
613 at 3000 mg/m2 (the highest dose tested) was ~1 hr., Vd was ~5 L/kg, 
and CL was ~5 L/hr/kg. The results from 1st and 6th (last) dose of CPI-613 
were similar, indicating that repeated dosing does not result in a change in 
the T1/2 and CL and Vd values and there was no evidence of accumulation 
on multiple dosing during the dosing interval. CPI-613 is rapidly and 

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extensively converted to its principal metabolite CPI-2850 which is produced 
predominantly in tumors by beta oxidation of the parent drug. This 
conversion has been observed in patients dosed with CPI-613 as a single 
agent and when dosed in combination with FOLFIRINOX. Both CPI-613 and 
CPI 2850 exhibit extensive and high affinity binding to serum albumin 
(greater than 99.7%). 
 
2. Elimination: CPI-613 and its metabolites are eliminated from the body 
through the gut and urine. In a 26 patient phase I study, a relatively rapid 
decline in plasma levels occurred during the first 8-10 hours post-
administration followed by low plasma CPI-613 values that persisted for 
several days. The concentration-time curves associated with all dose levels 
of CPI-613 were triphasic. The α-phase occurred during the first 6-8 hours 
post-administration and was associated with a relatively rapid decline in the 
mean plasma CPI-613 concentrations with a half-life of ~1.3 hrs. and mean 
residence time of ~1.8 hours. The β-phase occurred from 6-8 hours to 24 
hours post-administration and was associated with a modest increase in the 
mean plasma CPI-613 values, from ~0.5 to 4 μM when averaged across all 
dose levels. The γ or final phase started from 24 hours until 72 hours post-
administration and was associated with a very slow decline in mean plasma 
CPI-613 values, consistent with the high plasma protein binding properties of 
CPI-613. CPI-613 could not be detected in the plasma prior to administering 
the 1st dose, but the baseline plasma CPI-613 values associated with Dose 
6 had an overall average value of ~3 μM. The amount of CPI-613 present in 
the plasma prior to the 6th dose was only ~10% of the Cmax value of ~45 
μM induced by the MTD (2,940 mg/m2 given over 2 hours) of CPI-613. The 
small residual CPI-613 in the plasma did not have any significant drug 
accumulation effects, as reflected by the concentration-time curves 
associated with Dose 1 being comparable to that of the 6th (last) dose of 
Cycle 1. 
9.3.5 
Storage, Preparation and Stability 
CPI-613 injection is a sterile, nonpyrogenic, clear, colorless to light yellow 
solution suitable for intravenous (IV) administration. CPI-613 injection is supplied 
in 10-mL USP type-I amber glass vial with 20 mm grey butyl stopper and royal 
blue flip off seal. Each mL contains: 50 mg of CPI-613 and 150 mg of 
Triethanolamine (TEA). CPI-613 injection is a concentrate and must be diluted 
with 5% dextrose (D5W) injection before use. CPI-613 injection is not compatible 
with saline solution. 
 
CPI-613 injection must be stored in a refrigerator, 2°- 8°C (36° to 46°F) and 
protected from light. After dilution, the CPI-613 injection is chemically and 
physically stable for upto 24 hours at room temperature with normal light 
exposure. If CPI-613 injection is to be transferred from one storage area to 
another, or is to be prepared for dosing, care must be taken to maintain 
appropriate product temperature. CPI-613 injection slightly photosensitive when 
exposed to intense light. Therefore, after removal of CPI-613 drug product from 
the amber vials, CPI-613 injection should be administered to patients without 
unnecessary delay to minimize excessive exposure to light or covered to protect 
from light. 
 
The contents of CPI-613 injection must be visually inspected prior to dilution to 
confirm that the contents are clear and colorless to light yellow. If not, it should 
not be used. CPI-613 injection must be diluted from 50 mg/mL to 12.5 mg/mL 
with 5% dextrose (D5W) prior to administration. The diluted drug product should 
be visually inspected for clarity. If haziness or precipitate is observed, do not use 

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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 injection has been found to 
be stable for 24 hours with normal light exposure. 
9.3.6 
Dose and Administration 
See Section 5.1 for dosage. 
 
CPI-613 must be administered intravenously, via a central venous 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. 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. 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. To avoid local reactions at and around the site of 
administration, CPI-613 must be administered via a central venous catheter. 
 
Diluted CPI-613 MUST be administered as by IV infusion and not as bolus via a 
central venous catheter over 2 hours via an infusion pump. This is to minimize 
potential acute toxicity of CPI-613. 
 
The following precautions must be taken when administering CPI-613: 
1. Confirmation of the placement of the IV line to ensure a lack of leakage of CPI- 
613 into the perivascular space to avoid local reactions at and around the site of 
administration 
2. Confirmation that the IV line is free flowing 
3. Confirmation that the IV line is free of dead air space 
4. Dilute CPI-613® (devimistat) drug product with D5W (12.5 mg/mL) and infuse 
over 120 (110-150) minutes. Administer D5W concurrently at the rate of 125 
mL/hr.  
5. Administer CPI-613 by infusion, not as a bolus 
6. After administration of CPI-613, flush the IV line with ~10 mL of D5W to 
remove residual CPI-613. 
 
Leaching of Diethylhexyl Phthalate (DEHP) by CPI-613: 
CPI-613 can cause leaching of DEHP from IV infusion sets and IV bags. 
Therefore, DEHP-containing IV infusion sets, IV bags or syringes SHOULD NOT 
be used in mixing or administration of CPI-613. 
 
CPI-613 drug product is slightly photosensitive. 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. 
9.3.7 
Availability 
Cornerstone Pharmaceuticals will provide the study drug through a distribution 
depot. 
9.3.8 
Handling and Disposal 
CPI-613 is an investigational drug and the toxicity in humans is not fully 
understood. All necessary precautions in handling potentially toxic chemicals 
must be strictly adhered to. Gloves and protective clothing must be worn when 
handling CPI-613. Avoid contact by all modes of exposure. If the solution 
contacts the skin, it must be washed immediately and thoroughly with soap and 
water. If the solution comes in contact with mucous membranes, the membranes 

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must be flushed thoroughly with water. Spills should be picked up with chemo 
spill kit. CPI-613 drug product is slightly photosensitive. 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. 
 
Each study site must ensure that the study drug is not used beyond expiration•  
 
During the study, store the used CPI-613 vials (which must be separate from the 
unused CPI-613 vials) at controlled room temperature (20°C-25°C) in an access-
limited area. Alternatively, destroy the used CPI-613 vials according to 
institutional guidelines and in compliance with applicable environmental 
guidelines or return the used and empty vials to depot. Drug destruction must be 
adequately documented. At the end of the study, deface the label (both used and 
unused vials) with a permanent marking pen. Destroy used CPI-613 vials 
according to institutional guidelines and in compliance with applicable 
environmental guidelines. Drug destruction must be adequately documented. All 
unused CPI-613 vials must be returned or destroyed according to institutional 
guidelines. 
9.3.9 
Adverse Effects 
1. Adverse Effects: In a phase I open-label, single arm clinical trial of CPI-613 in 
patients with metastatic and locally advanced pancreatic adenocarcinoma 
and poor performance status (CCCWFU57113), 9 patients were dosed with 
CPI-613 alone. The safety of CPI-613 was evaluated in 6 patients. A total of 
124 toxicities were reported of which 18 were considered Grade 3 or above 
(15%). In another phase 1 study of CPI-613 with modified FOLFIRINOX 20 
patients were enrolled and included in the safety evaluation. A total of 674 
treatment related and not related AEs were reported by the 20 patients, of 
which 114 were considered grade 3 or higher. For the 18 patients given the 
maximum tolerated dose, the most common non-hematological grade 3–4 
adverse events were hypokalemia (n=6, 33%), diarrhea (n=5, 28%), 
abdominal pain (n=4, 22%), hyperglycemia (n=10, 55%), and peripheral 
sensory neuropathy (n=5, 28%) patients. The most common grade 3–4 
hematological adverse events were neutropenia (n=5, 28%), lymphopenia 
(n=5, 28%), anemia (n=4, 22%), and thrombocytopenia (n=3, 17%). No 
patients died while on active treatment; 11 study participants died, with cause 
of death as terminal pancreatic cancer. 
 
2. Pregnancy and Lactation: Category D. No data are available. 
 
3. Drug Interactions: CPI-613 at levels of 30-50 μM have been found to inhibit a 
variety of liver S9 fraction enzymes including certain cytochrome P450 
isozymes (NCL-044). Plasma levels of CPI-613 and its principal bioactive 
metabolite CPI 2850 have been observed to be 100 μM or substantially 
greater, even to > 300 μM. Thus, the potential exists for drug-drug 
interactions. At concentrations above 30 μM CPI-613 inhibits the activity of 
various cytochrome P450 isozymes responsible for oxidation and 
glucuronidation and other possible drug conjugation and transport 
phenomena. Based on data provided in the Investigator’s Brochure (Edition 
1.3), the drug-drug interactions potential between CPI-631 and co-
medications (either substrates, inhibitors or inducers of CYP450 enzymes) 
are expected to be low. 
10.0 
CORRELATIVES/TRANSLATIONAL STUDIES 

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We will study the BTC tumor microenvironment through the use of pre-treatment tissue collection 
(at all sites) and post-treatment tissue collection (optional); refer to the lab manual for sample 
collection and processing details. Identification of important biologic subsets of BTC patients that 
may have clinical efficacy from CPI-613 will be the overarching goal of this translational science. 
Tissue (core biopsy, surgical excision) may be examined by whole exome analysis, RNA seq and 
histologically by immunohistochemistry (IHC). Biologic markers and RNA expression (using 
genomic analysis conducted on available/submitted tissue, as well as previously completed 
genomic analysis reports for enrolled patients from all sites, if available) will be examined in the 
context of patient efficacy.  
10.1 Tissue Collection 
Tissue will be collected at the time points specified in section 6.2 Study Calendar. Please 
refer to the lab manual for sample collection and processing details.  
10.2 Blood Collection 
Blood samples will be collected at the time points specified in section 6.2 Study Calendar. 
Please refer to the lab manual for sample collection and processing details.  
10.3 Centralized Imaging 
All CT scans will be coded using trial patient and site IDs and shipped or electronically 
uploaded for banking and exploratory endpoint assessment. Please see the lab manual for 
details regarding shipping address and/or information for electronic upload. 
10.4 Specimen Banking 
Patient samples collected for this study will be retained at University of Michigan. 
Specimens will be stored indefinitely or until they are used up. If future use is denied or 
withdrawn by the patient, best efforts will be made to stop any additional studies and to 
destroy the specimens. 
 
Specimens being stored long-term for potential use not outlined in the protocol are subject 
to University Policy Governing Tissue Sample Collection, Ownership, Usage, and 
Disposition within all UMMS Research Repositories. 
 
11.0 
STATISTICAL CONSIDERATIONS 
11.1 Study Design/Study Endpoints 
This protocol will enroll patients with advanced, unresectable BTC to receive Gemcitabine, 
Cisplatin and CPI-613 in a limited Phase 1b study to confirm the safety profile of the 
combination therapy and the recommended Phase 2 dose (RP2D). The primary endpoint 
for the phase 1b portion is the occurrence/lack thereof of dose-limiting toxicity (defined in 
Section 5.1.1.3) during the first 21-day cycle of combination therapy. After determining the 
combination RP2D additional patients will be enrolled in the phase 2 portion of the study 
and randomized 2:1 to treatment arms A (combination regimen at RP2D) and B 
(Gemcitabine and Cisplatin alone), respectively. We will stratify the randomization by locally 
advanced versus metastatic disease. The primary endpoint for the phase 2 study is the 
ORR (PR+CR) per RECIST v1.1 criteria during active study treatment. Secondary 
endpoints include PFS and OS. The statistical comparison will not be between treatment 
groups; rather between the experimental treatment arm (A) and historical ORR levels. We 
will use the estimated ORR for the limited-sized control arm (B) to confirm the control arm 
has similar response rate as the historical ORR value.  

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11.2 Phase 1B 
We will implement a limited phase 1b trial to assure that the dose levels suggested for this 
combination are safe. Because toxicity across the combined agents is expected to be 
mildly additive and not synergistic, and in light of the poor prognosis for these patients, we 
are willing to tolerate up to but not exceeding 35% DLT toxicity proportion during the first 
cycle (21-days) of therapy. To investigate this, we will enroll up to 20 patients with dose 
allocation using the Time-to-Event (TiTE) (Cheung and Chappell 2000) (O'Quigley, Pepe et 
al. 1990). This method assumes a model for the time to occurrence of toxic responses as a 
function of the dose. The time-to-event modification allows information from all patients 
treated (even those with only partial observation) to contribute information for calculating 
the dose-toxicity relationship. This method is flexible with regard to the number of patients 
treated at each dose level, patients may be continuously recruited without recruitment 
pauses subject to the trial’s explicit accrual rules, given patients are assigned to a dose 
level deemed safe at the time of her/his enrollment. The dose toxicity relationship is 
estimated using all toxicity data observed when each new patient is scheduled to begin 
treatment. Population for estimation: Every patient enrolled and receiving at least one dose 
of CPI-613 will be considered evaluable for estimation of the probability of DLT. If a patient 
withdraws for any reason during the first cycle of therapy, not primarily or secondarily 
associated with toxicity, that patient’s follow-up will be used in the ongoing estimation of the 
probability of toxicity; however, such a patient would be replaced when calculating the 
maximum trial size.  Patients stopping treatment early due to or secondary to toxicity will be 
considered to have had a DLT event (as defined in section 5.1.1.3).  
 
DLT target rate to determine MTD/RP2D. The highest probability of DLT at a dose level 
acceptable during the first cycle of therapy is 35%. The dose level with estimated 
probability closest to, but not exceeding the DLT target rate will be considered the RP2D.  
 
Criterion for dose escalation. The dose level will be assigned to each new patient according 
to the estimates from the TiTE-CRM algorithm. Whenever a patient presents for enrollment 
on this trial, the probability of DLT will be estimated for each dose level, based upon the 
initial expectations and the incidence of DLT events in patients already treated on trial 
weighted by the percentage of the acute DLT observation period observed. The level that 
has an estimated toxicity closest to the target rate for DLT will be assigned, subject to the 
following:  
 
The dose level cannot be escalated until at least 2 patients have been observed for the 
entire DLT observation period (22 days).  
Patient 1 and 2 will be assigned to receive dose level 1.  
Dose escalation is restricted to one dose level between consecutively treated patients.  
Dose de-escalation is not restricted and may be reduced by more than one level between 
consecutively treated patients.  
If at enrollment the TiTE-CRM algorithm estimates all dose levels (-1, 1, 2, and 3) to have 
probability of DLT above our target level (35%), the trial will close, declaring all available 
dose levels too toxic for treatment. The trial may seek to remain open after initiating a 
protocol amendment to alter dose levels to be less toxic. 
 
Patients will be recruited and treated on this trial as naturally available. Accrual is estimated 
to be approximately 2 patients per month. The operating characteristics of this Phase 1B 
trial were evaluated through simulation using estimate for the true probability of DLT at 
each dose level under 3 scenarios (n=1,000 simulated trials per scenario).  In the first 
scenario, the true probability of DLT at each dose level is as we had expected a posteriori; 
the second scenario we have moderately underestimated the true probabilities of DLT for 
higher dose levels; the third scenario the additive effect of CPI-613 upon the observed 
toxicity from the chemotherapy regimen is negligible and not dose dependent.  The dose 
level nearest to but not exceeding our target rate is bolded for each scenario. 
 

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Table 11. Operating Characteristics of the Phase 1B Trial 
Dose 
Level 
Expected 
Probability of DLT 
Simulation 
scenario #1 
Simulation 
Scenario #2 
Simulation 
Scenario #3 
-1 
0.20 
0.20 
0.20 
0.20 
1 
0.25 
0.25 
0.30 
0.21 
2 
0.30 
0.30 
0.40 
0.22 
3 
0.35 
0.35 
0.50 
0.23 
 
 
The figure below illustrates (top left) the mean number of patients per trial experiencing a 
DLT per dose level per simulated scenario; (top right) the mean number of patient per trial 
treated per dose level per simulated scenario; (bottom left) percent of simulated trials per 
simulated scenario that had 0-2, 3-5, 6-8, and 9-11 patients in total experiencing DLT 
events; (bottom right) the percent of simulated trials per simulated scenario that picked 
dose level -1, 1, 2, or 3 as the MTD or that declared all level too toxicity and stopped the 
trial early. 
 
Reviewing the operating characteristics suggest that when the true probability of DLT is as 
expected (simulation scenario #1), the trial design will treat nearly 10 patients at the target 
level dose and selects that dose correctly as the MTD/RP2D dose in over 70% of simulated 
trials. Similarly, if toxicity is not increased by adding CPI-613 to standard of care 
chemotherapy (simulation scenario #3), the design treats nearly 12 patients at the target 
level dose and selects that dose as the MTD/RP2D in approximately 80% of simulated 
trials. In the event that we have underestimated toxicity a posteriori and the probability of 
DLT increases more sharply with increasing dose of CPI-613, the design will pick a dose at 
or below the target level in the majority of simulated trials more likely to pick lower dose 
levels or stop early. 

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Figure 2. Simulated Scenario of Mean Number of Patients Experiencing a  
DLT per Dose Level 
 
11.3 
Phase 2 
Upon completion of the 20 patient Phase 1b portion of the trial, an MTD/RP2D will have 
been determined or all dose levels for the combination deemed excessively toxic. After the 
MTD/RP2D is determined, additional patients will be enrolled and randomized in a 2 (Arm 
A: CPI-613+Gemcitabine+Cisplatin) to 1 (Arm B: Gemcitabine+Cisplatin) manner during the 
phase 2 portion of this trial to assess efficacy as measured by the ORR. Historical data at 
the time of trial inception suggested the ORR for Arm B in this patient population was 
approximately 25% (N=42/161) per phase 3 ABC-02 trial (Valle, Wasan et al. 2010). We 
suggested that the combination therapy at the MTD/RP2D would be successful by 

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increasing the ORR to 43%. Since the trial’s inception, data from the phase 3 TOPAZ-1 trial 
treating similar patient population with either placebo or durvalumab in combination with 
gemcitabine plus cisplatin, has demonstrated a response rate of 18.7% (N=64) in 342 
patients on the placebo (Gemcitabine + Cisplatin only) arm.  As the placebo arm of TOPAZ-
1 is consistent with this trial’s Arm B we suggest a more accurate null hypothesis 
comparison for the ORR of Arm A (CPI-613+Gemcitabine+Cisplatin) would be to combine 
the ABC-02 and TOPAZ-1 data, suggesting a 21.1% ORR for the control group.  With 50 
patients receiving the combination therapy at the MTD/RP2D  this trial will have >90% 
power to detect such a difference significantly using a two sided comparison to the point 
estimate 21.1%.  With minimal acceptable power- 80% and using a two-sided comparison - 
we can detect a 38% alternative versus a 21.1% null value, with 5% type 1 error. 
The operating characteristics presented above for the Phase 1B portion of the trial suggest 
that 10-12 patients will have been treated at the MTD/RP2D and those patients will be 
included in the Phase 2 efficacy assessment. Therefore, the Phase 2 portion of the trial will 
randomize approximately 48 to 58 patients in order to assure 50 patients in the CPI-613 
treated group. Approximately 16 to 20 patients will be assigned to Arm B/standard of care 
regimen. 
The comparison of interest will be between the observed ORR in those receiving 
combination therapy versus the historical estimate. Patients randomized to Arm B will help 
suggest whether the historical estimate for ORR is a reasonable null hypothesis for 
comparison. If the ORR estimated for the control group is higher than the historical value, it 
may suggest increasing the null hypothesis value for comparison. In order to operationalize 
this comparison, we will implement a Bayesian approach to estimate the probability of ORR 
(CR+PR) for the control patients.  Given that the historical estimates published by Valle, 
et.al 2010 is ~25% for the 162 patients treated in that phase 3 trial and is ~19% for the 342 
patient treated in the TOPAZ-1 chemotherapy only arm, we will formalize that probability 
using a beta distribution b (106,397), which is a unimodal distribution, with mean 0.21 with 
precision proportional to the sample size, 503.  We will then collect binary outcome data for 
the control patients (yes/no ORR) which allows the posterior distribution (prior data + trial’s 
experience for control patients) to be described also as a beta distribution.  If after adding 
the trial’s control data it is suggested that the probability that the ORR is greater than 21% 
is more than 0.7 (70%), we will increase the estimate for the null hypothesis in the primary 
outcome comparison to be the probability estimated from the mean of the posterior 
distribution.  The following table lists the number of control patients with an overall 
response based upon the number of control patients treated (may range from 16 to 20) for 
biologically reasonable ORR rates above 21%. 
 
Table 12. Operating Characteristics of the Control Arm in Phase 2 
Number of Control 
Cases Randomized 
and Treated 
Number of Control 
Cases with an OR 
Null Hypothesis value for the Probability of 
ORR for control patients used to compare to 
experimental treatment 
16 
9 
0.22031 
16 
10 
0.22222 
16 
11 
0.22414 
17 
9 
0.21989 
17 
10 
0.22180 
17 
11 
0.22371 
18 
9 
0.21947 
18 
10 
0.22137 
18 
11 
0.22328 
18 
12 
0.22519 
19 
10 
0.22095 

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19 
11 
0.22286 
19 
12 
0.22476 
19 
13 
0.22667 
20 
10 
0.22053 
20 
11 
0.22243 
20 
12 
0.22433 
20 
13 
0.22624 
 
11.4 Data Analyses Plans 
We will report the estimate probability of DLT with 95% Bayesian Credible Intervals for 
each dose level as estimated by the TiTE-CRM algorithm at the completion of the Phase 1.  
The probability of DLT will be updated using the experience of the Phase 2 patients at the 
MTD/RP2D as well. 
 
We will record ORR as a yes/no outcome for each patient for the period of active study 
treatment and report the estimate and exact 95% binomial confidence intervals. Patients 
will be considered evaluable for ORR if the patient has at least the first scan, to be taken 8 
weeks +/- 1 week following D1C1 or if the patient is taken off study treatment prior to first 
scan due to toxicity or clinical progression or by physician discretion secondary to toxicity or 
intolerability.  If the patient is taken off treatment prior to first scan due for any other reason 
(patient revocation of consent, incarceration, pregnancy, etc.) then the patients will be 
replaced for assessment of the primary outcome.  We will estimate PFS and OS using the 
product-limit method of Kaplan and Meier, for the response evaluable and total population 
(any patient receiving study therapy) Follow-up time will be defined as time from date of 
first study treatment until the date of radiological or clinical progression (leading to 
withdrawal from the study), or death from any cause, whichever comes first for PFS and for 
only death from any cause for OS. For patients without events, we will censor the follow-up 
time at the date of last disease evaluation at the time of analysis. We will report estimates 
for the median and 75th percentiles with 95% confidence intervals. We will summarize 
additional safety data (e.g., laboratory safety parameters, vital signs, concomitant 
medications and new physical examination findings) descriptively by reporting counts and 
percentages, with exact binomial confidence intervals where appropriate. ORR will be 
determined as per the RECISTv1.1 guidelines. We will report adverse events per the NCI 
CTCAE v5.0. 
12.0 
ADMINISTRATIVE PROCEDURES 
12.1 Ethics and Good Clinical Practice 
This study must be carried out in compliance with the protocol and be consistent with Good 
Clinical Practice (GCP), as defined by the International Conference on Harmonization 
(ICH), WHO and any local directives. 
 
The protocol, any amendments, and the subject informed consent will receive Institutional 
Review Board/Independent Ethics Committee (IRB/IEC) approval/favorable opinion before 
initiation of the study.  
12.2 Data Management 
All information will be recorded locally and entered into Case Report Forms (CRFs) on the 
web-based electronic data capture (EDC) system of the University of Michigan. Online 
access will be provided to each site by the Coordinating Center.  
 
CRFs will be reviewed and source verified by the MSC during annual monitoring visits and 
prior to and between visits. Discrepant, unusual and incomplete data will be queried by the 

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MSC. The investigator or study coordinator will be responsible for providing resolutions to 
the data queries, as appropriate. The investigator must ensure that all data queries are 
dealt with promptly.  
 
The data submission schedule is as follows:  
• At the time of enrollment  
o 
Subject entry into the EDC 
o 
Subject Status 
o 
Demographics 
• During study participation 
o 
All data should be entered online within 10 business days of data acquisition. 
[Information on dose limiting toxicity events must be entered within one 
business day.] Information on Serious Adverse Events must be entered 
within the reporting timeframe specified in Section 8.5 of the protocol.  
  
All study information should be recorded in an appropriate source document (e.g. clinic 
chart). 
12.3 Record Retention 
The Investigators must retain all study records and source documents for the maximum 
period required by applicable regulations and guidelines, or institution procedures, 
whichever is longer. 
 
13.0 
DATA AND SAFETY MONITORING 
This study will be monitored in accordance with the NCI approved University of Michigan Rogel 
Cancer Center Data and Safety Monitoring Plan, with oversight by the Rogel Cancer Center Data 
and Safety Monitoring Committee (DSMC). 
 
The Sponsor-Investigator (S-I)/Study Principal Investigator will provide ongoing monitoring of data 
and patient safety in this trial and conduct regular data review with participating sites. 
 
The Sponsor-Investigator (S-I)/Study Principal Investigator and/or the Project Manager/Delegate 
will review data and patient safety issues with participating sites per a defined [phase I: monthly 
/ phase II: quarterly] meeting cadence. Depending on the protocol activity, the meeting cadence 
may be more frequent. This data review meeting may be achieved via a teleconference or 
another similar mechanism to discuss matters related to: 
 
 Enrollment rate relative to expectations, characteristics of participants 
 Safety of study participants (SAE reporting, unanticipated problems) 
 Adherence to protocol (protocol deviations) 
 Completeness, validity and integrity of study data 
 Retention of study participants 
 
Participating sites are required to ensure all pertinent data for the review period are available in 
the database at the time of the discussion. 
 
Participating sites unable to participate in the data review meeting are required to provide written 
confirmation that their site has reviewed the relevant data and patient safety issues for the review 
period and their site’s data are in alignment with the data reported in the database. Written 
confirmation is to be provided to the Project Manager/Delegate within the timeline requested to 
retain compliance with monitoring timelines. 
 
Documentation of the teleconference or alternate mechanism utilized to review items above is to 
be retained in the Trial Master File.  

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The Project Manager/Delegate is responsible for collating the data from all participating sites and 
completing the Protocol Specific Data and Safety Monitoring Report (DSMR) form to document 
the data review meeting discussion.  
 
The DSMR will be signed by the Sponsor-Investigator (S-I)/Study Principal Investigator or 
designated Co-Investigator and submitted to the DSMC on a [phase I: monthly / phase II: 
quarterly] basis for independent review.  
14.0 
QUALITY ASSURANCE AND AUDITS 
The Data and Safety Monitoring Committee can request a ‘for cause’ quality assurance audit of 
the trial if the committee identifies a need for a more rigorous evaluation of study-related issues.  
 
A regulatory authority (e.g. FDA) may also wish to conduct an inspection of the study, during its 
conduct or even after its completion. If an inspection has been requested by a regulatory 
authority, the site investigator must immediately inform the Coordinating Center that such a 
request has been made. 
15.0 
CLINICAL MONITORING PROCEDURES 
Clinical studies coordinated by The University of Michigan Rogel Cancer Center must be 
conducted in accordance with the ethical principles that are consistent with Good Clinical 
Practices (GCP) and in compliance with other applicable regulatory requirements. 
 
This study will be monitored by a representative of the Coordinating Center of the Rogel Cancer 
Center. Monitoring visits will be made during the conduct of the study and at study close-out. 
 
Prior to subject recruitment, a participating site will undergo site initiation meeting to be conducted 
by the Coordinating Center. This will be done as an actual site visit; teleconference, 
videoconference, or web-based meeting after the site has been given access to the study 
database and assembled a study reference binder. The site’s principal investigator and his study 
staff should make every effort in attending the site initiation meeting. Study–related questions or 
issues identified during the site initiation meeting will be followed-up by the appropriate Rogel 
Cancer Center personnel until they have been answered and resolved. 
 
Monitoring of this study will include both ‘Centralized Monitoring’, the review of source documents 
at the Coordinating Center and ‘On-site Monitoring’, an actual site visit. The first ‘Centralized’ visit 
should occur after the first subject enrolled completes [first treatment cycle/course]. The study site 
will send the de-identified source documents to the Coordinating Center for monitoring.  
‘Centralized’ monitoring may be requested by the Coordinating Center if an amendment requires 
changes to the protocol procedures. The site will send in pertinent de-identified source 
documents, as defined by the Coordinating Center for monitoring.  
 
The first annual ‘On-site’ monitoring visit should occur after the first five study participants are 
enrolled or twelve months after a study opens, whichever occurs first. The annual visit may be 
conducted as a ‘Centralized’ visit if less than three subjects have enrolled at the study site.  The 
type of visit is at the discretion of the Coordinating Center. At a minimum, a routine monitoring 
visit will be done at least once a year, or once during the course of the study if the study duration 
is less than 12 months. The purpose of these visits is to verify: 
 
 
Adherence to the protocol 
 
Completeness and accuracy of study data and samples collected 
 
Proper storage, dispensing and inventory of study medication 
 
Compliance with regulations 
 

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During a monitoring visit to a site, access to relevant hospital and clinical records must be given 
by the site investigator to the Coordinating Center representative conducting the monitoring visit 
to verify consistency of data collected on the CRFs with the original source data.  While most 
patient cases will be selected from patients accrued since the previous monitoring visit, any 
patient case has the potential for review.  At least one or more unannounced cases will be 
reviewed, if the total accruals warrant selection of unannounced cases.  
 
The Coordinating Center expects the relevant investigational staff to be available to facilitate the 
conduct of the visit, that source documents are available at the time of the visit, and that a 
suitable environment will be provided for review of study-related documents. Any issues identified 
during these visits will be communicated to the site and are expected to be resolved by the site in 
a timely manner. For review of study-related documents at the Coordinating Center, the site will 
be required to ship or fax documents to be reviewed.   
 
Participating site will also undergo a site close-out upon completion, termination or cancellation of 
a study to ensure fulfillment of study obligations during the conduct of the study, and that the site 
Investigator is aware of his/her ongoing responsibilities. In general, a site close-out is conducted 
during a site visit; however, site close-out can occur without a site visit. 
 
 

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16.0 
REFERENCES 
Alistar, A., B. B. Morris, R. Desnoyer, H. D. Klepin, K. Hosseinzadeh, C. Clark, A. Cameron, J. Leyendecker, 
R. D'Agostino, Jr., U. Topaloglu, L. W. Boteju, A. R. Boteju, R. Shorr, Z. Zachar, P. M. Bingham, T. Ahmed, 
S. Crane, R. Shah, J. J. Migliano, T. S. Pardee, L. Miller, G. Hawkins, G. Jin, W. Zhang and B. Pasche 
(2017). "Safety and tolerability of the first-in-class agent CPI-613 in combination with modified FOLFIRINOX 
in patients with metastatic pancreatic cancer: a single-centre, open-label, dose-escalation, phase 1 trial." 
Lancet Oncol 18(6): 770-778. 
Cheung, Y. K. and R. Chappell (2000). "Sequential designs for phase I clinical trials with late-onset 
toxicities." Biometrics 56(4): 1177-1182. 
Conroy, T., F. Desseigne, M. Ychou, O. Bouche, R. Guimbaud, Y. Becouarn, A. Adenis, J. L. Raoul, S. 
Gourgou-Bourgade, C. de la Fouchardiere, J. Bennouna, J. B. Bachet, F. Khemissa-Akouz, D. Pere-Verge, 
C. Delbaldo, E. Assenat, B. Chauffert, P. Michel, C. Montoto-Grillot, M. Ducreux, U. Groupe Tumeurs 
Digestives of and P. Intergroup (2011). "FOLFIRINOX versus gemcitabine for metastatic pancreatic 
cancer." N Engl J Med 364(19): 1817-1825. 
Eisenhauer, E. A., P. Therasse, J. Bogaerts, L. H. Schwartz, D. Sargent, R. Ford, J. Dancey, S. Arbuck, S. 
Gwyther, M. Mooney, L. Rubinstein, L. Shankar, L. Dodd, R. Kaplan, D. Lacombe and J. Verweij (2009). 
"New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1)." Eur J Cancer 
45(2): 228-247. 
Nathan, H., T. M. Pawlik, C. L. Wolfgang, M. A. Choti, J. L. Cameron and R. D. Schulick (2007). "Trends in 
survival after surgery for cholangiocarcinoma: A 30-Year population-based SEER database analysis." 
Journal of Gastrointestinal Surgery 11: 1488-1497. 
O'Quigley, J., M. Pepe and L. Fisher (1990). "Continual reassessment method: a practical design for phase 
1 clinical trials in cancer." Biometrics 46(1): 33-48. 
Seng, S., Z. Liu, S. K. Chiu, T. Proverbs-Singh, G. Sonpavde, T. K. Choueiri, C. K. Tsao, M. Yu, N. M. 
Hahn, W. K. Oh and M. D. Galsky (2012). "Risk of venous thromboembolism in patients with cancer treated 
with Cisplatin: a systematic review and meta-analysis." J Clin Oncol 30(35): 4416-4426. 
Shaib, Y. and H. B. El-Serag (2004). "The epidemiology of cholangiocarcinoma." Semin Liver Dis 24(2): 
115-125. 
Stuart, S. D., A. Schauble, S. Gupta, A. D. Kennedy, B. R. Keppler, P. M. Bingham and Z. Zachar (2014). 
"A strategically designed small molecule attacks alpha-ketoglutarate dehydrogenase in tumor cells through 
a redox process." Cancer Metab 2(1): 4. 
Valle, J., H. Wasan, D. H. Palmer, D. Cunningham, A. Anthoney, A. Maraveyas, S. Madhusudan, T. Iveson, 
S. Hughes, S. P. Pereira, M. Roughton, J. Bridgewater and A. B. C. T. Investigators (2010). "Cisplatin plus 
gemcitabine versus gemcitabine for biliary tract cancer." N Engl J Med 362(14): 1273-1281. 
Zachar, Z., J. Marecek, C. Maturo, S. Gupta, S. D. Stuart, K. Howell, A. Schauble, J. Lem, A. Piramzadian, 
S. Karnik, K. Lee, R. Rodriguez, R. Shorr and P. M. Bingham (2011). "Non-redox-active lipoate derivates 
disrupt cancer cell mitochondrial metabolism and are potent anticancer agents in vivo." J Mol Med (Berl) 
89(11): 1137-1148. 
 
 
 
 

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17.0 
APPENDICES 
 
Appendix I 
ECOG Performance Status 
Appendix II 
Investigator’s Statement 
Appendix III 
Contingency Operations Plan 
 
 
 
 

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Appendix I 
ECOG Performance Status 
 
 
Description 
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. 
Source: Eastern Cooperative Oncology Group 
 
 
 

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Appendix II 
Investigator’s Statement 
 
1. I have carefully read this protocol entitled “A Randomized Phase IB/II Study of Gemcitabine and 
Cisplatin With or Without CPI-613 as First Line Therapy for Patients with Advanced Unresectable 
Biliary Tract Cancer”, Version 4.1 dated 07/22/2022, and agree that it contains all the necessary 
information required to conduct the study. I agree to conduct the study as outlined in the protocol.  
 
2. I agree to conduct this study according to the moral, ethical and scientific principles governing 
clinical research as set out in the Declaration of Helsinki, the principles of Good Clinical Practice 
(GCP) as described in 21 Code of Federal Regulations (CFR) and any applicable local 
requirements.  
 
3. I understand that this trial and any subsequent changes to the trial will not be initiated without 
approval of the appropriate Institutional Review Board, and that all administrative requirements of 
the governing body of the institution will be complied with fully.  
 
4. Informed written consent will be obtained from all participating patients in accordance with 
institutional and Food and Drug Administration (FDA) requirements as specified in Title 21, CFR, 
Part 50.  
 
5. I understand that my signature on the electronic Case Report Form (eCRF) indicates that I have 
carefully reviewed each page and accept full responsibility for the contents thereof.  
 
6. I understand that the information presented in this study protocol is confidential, and I hereby 
assure that no information based on the conduct of the study will be released without prior consent 
from University of Michigan unless this requirement is superseded by the FDA. 
 
 
 
Site PI Name: 
 
________________________________________ 
 
Site Name:  
 
________________________________________ 
 
Signature of Site PI:  
________________________________________ 
 
Date of Signature:  
____________\______________\_____________ 
 
 

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Appendix III 
Contingency Operations Plan 
In the event of a public health or civil emergency or restrictions, clinical changes may be necessary to 
effectively manage the study. Should such an instance occur, the following adjustments may be applied by 
participating sites as required to minimize or eliminate immediate hazards or to protect the life and well-
being of research participants (e.g., to limit exposure to infectious pathogens) and may be implemented 
without IRB acknowledgement/approval but are to be reported afterwards, as required.  
1. Infectious Diseases Testing:  
a. Should testing be available/required for a public health or civil emergency, it is not currently 
being added to the protocol as part of the screening requirements, but may be done as part of 
the clinical assessment, as needed during the course of the event/restrictions. 
b. During the course of the study, Infectious Diseases tests/results will be recorded in the subject’s 
source documents but will only be added as an Adverse/Serious Adverse Event in the eCRF 
should the test yield a positive result.  
c. The Sponsor-Investigator or designee is to be immediately informed in the event that a trial 
participant exhibits or reports symptoms consistent with the infectious diseases (whether or not 
confirmed by a positive test result). Depending on the investigational product being 
administered and the patient’s clinical presentation, dosing may be withheld, until such time as 
symptoms resolve. This decision should be made by the site Principal Investigator, determining 
what is the best course of action for the patient, in consultation with the Sponsor-Investigator. 
In some cases, the site PI and/or Sponsor-Investigator may request a participant be retested 
before dosing of the investigational product is resumed. 
 
2. Study Visit Schedule: 
a. For individual instances where assessments cannot be made and/or data are not able to be 
collected, the reasons for failing to obtain the data should be documented (e.g., identifying the 
specific limitation imposed by the event/restriction leading to the inability to perform the 
protocol-specified assessment) and recorded as a protocol deviation, as required. 
b. Ongoing participants who are unable or unwilling to attend protocol-specified trial visits and 
procedures, may continue in the trial if the site PI in consultation with the Sponsor-Investigator 
deems it appropriate and for as long as the patient continues to consent to participation and 
where patient safety can be monitored. 
c. Where participants cannot be seen at the site or by home visit, the use of telemedicine and 
adaptation of schedule of assessments can be implemented, where feasible to ensure patient 
safety.  
d. Adjustments to the protocol imaging visit window (8 ± 1 week) are permitted by the Sponsor-
Investigator if on-schedule visits are not possible due to the national emergency/restrictions. 
 
3. Laboratory Assessments: 
It may be possible that lab closure is required as a contingency measure during the course of a public 
health or civil emergency or restrictions. Should that occur: 
a. Correlative samples will not be collected unless the participating site lab facilities has 
appropriate storage capacity/capabilities to do so. If the participating site does not have lab 
storage capacity/capabilities, research bloods samples are not to be drawn. Operations will 
continue per usual once they are provided approval from the UM Coordinating Center that it is 
safe for labs to re-open 
i. Pre-Treatment and End of Treatment (EOT) biopsy samples will be obtained, if 
applicable/possible, and will be retained at site until further notification. 
ii. Cycle 1 Day 1, Cycle 4 Day 1 and End of Treatment blood samples will be obtained if 
possible and will be processed and shipped per the study lab manual.  If the research 

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lab closes and is unavailable to accept samples, this will be communicated out to the 
study team. 
b. Patients will be allowed to have safety labs (routine standard of care labs) drawn at a local 
lab and results will be reviewed by the study team. 
 
4. Study Medications: 
a. Adjustments for alternate drug administration will be permitted by the Supporters (Cornerstone 
Pharmaceuticals) and Sponsor-Investigator. Ongoing participants who are unable or unwilling 
to attend protocol-specified trial visits and procedures, may continue in the trial if the site PI in 
consultation with the Sponsor-Investigator deems it appropriate and for as long as the patient 
continues to consent to participation and where patient safety can be monitored.  
b. The patient may remain on study without receiving drug for more than 28 days if the drug(s) 
are held due to the national emergency/restrictions. 
c. If a patient does not receive investigational regimen consecutively for 4 weeks from last 
intended dose between consecutive CT scans due to the national emergency/restrictions, then 
the patient may continue on treatment despite progression on CT scan.