CPI-613 in Combination With Modified FOLFIRINOX in Locally Advanced Pancreatic Cancer

The objective of this study is to determine if CPI-613 increases overall survival (OS) when
used in combination with modified FOLFIRINOX (mFOLFIRINOX), in participants with locally
advanced pancreatic cancer and to assess the safety of CPI-613 + mFOLFIRINOX combination in
participants with locally advanced pancreatic cancer. The study team would like to collect
tissue specimens for future correlative studies and aim to estimate median progression free
survival (PFS) and the percent resected when CPI-613 is used in combination with mFOLFIRINOX,
in participants with locally advanced pancreatic cancer.

This is a single-armed study of participants with locally advanced pancreatic cancer,
evaluating combination CPI-613 with modified FOLFIRINOX. Participants will be accrued at
University Hospitals Cleveland Medical Center over 24 months with data analysis, and
concluded 12 months after last accrual. Approximately 33 subjects will be enrolled in this
trial, and the total duration of therapy is 6 months. All participants will be followed until
death or 3 years from the completion of the study. The study team expects to complete accrual
in 24 months, and will analyze data 12 months after accrual completion. The study will be
completed 12 months after accrual completion.

Inclusion Criteria:

- Subjects must have histologically or cytologically confirmed pancreatic
adenocarcinoma.

- Subjects must have locally advanced (including unresectable or borderline resectable)
pancreatic cancer based on CT imaging as determined by the PI

- Eastern Cooperative Oncology Group (ECOG) Performance status being 01 within 1 week of
planned start of therapy [See Appendix I].

- Subjects must have normal organ and marrow function as defined below < 2 weeks must
be:

- Adequate hematologic (granulocyte count ≥1500/mm3; white blood cell [WBC] ≥3500
cells/mm3; platelet count ≥100,000 cells/mm3; absolute neutrophil count [ANC] ≥1500
cells/mm3; and hemoglobin ≥9 g/dL).

- Adequate hepatic function (aspartate aminotransferase [AST/SGOT] ≤3x upper normal
limit [UNL], alanine aminotransferase [ALT/SGPT] ≤3x UNL, bilirubin ≤1.5x UNL).

- Adequate renal function (serum creatinine ≤2.0 mg/dL or 177 µmol/L).

- Adequate coagulation ("International Normalized Ratio" or INR must be <1.5) unless on
therapeutic blood thinners.

- Expected survival ≥3 months in the view of the PI or investigators.

- Women of child-bearing potential (i.e., women who are pre-menopausal or not surgically
sterile) must use accepted contraceptive methods (abstinence, intrauterine device
[IUD], oral contraceptive or double barrier device) during the study, and must have a
negative serum or urine pregnancy test within 1 week prior to treatment initiation.

- Fertile men must practice effective contraceptive methods during the study, unless
documentation of infertility exists.

- No evidence of clinically significant active infection and no serious infection within
the past month.

- Subjects must have the ability to understand and the willingness to sign a written
informed consent document.

Exclusion Criteria:

The presence of any of the following will exclude a subject from study enrollment.

- Subjects under the age of 18 or older than 80 years of age.

- Subjects with endocrine or acinar pancreatic carcinoma.

- Subjects with resectable pancreatic cancer.

- Subjects with metastatic pancreatic cancer based on imaging.

- Subjects who have received prior surgical or medical treatment for pancreatic cancer.

- Subjects receiving any other standard or investigational treatment for their cancer
with a primary goal of improving survival within the past 2 weeks prior to initiation
of CPI-613 treatment.

- Pregnant women or breast feeding women, or women of child-bearing potential not using
reliable means of contraception are excluded from this study because the teratogenic
or abortifacient effects of CPI-613 is unknown. Because there is an unknown, but
potential risk for adverse events in nursing infants secondary to treatment of the
mother with CPI-613, breastfeeding should be discontinued if the mother is treated
with CPI-613. These potential risks may also apply to other agents used in this study.

- Fertile men unwilling to practice contraceptive methods during the study period.

- Subjects with a life expectancy less than 3 months.

- Subjects with a serious medical illness that would potentially increase subjects' risk
for toxicity

- Subjects with any active uncontrolled bleeding, and any patients with a bleeding
diathesis (e.g., active peptic ulcer disease).

- Subjects with a history of myocardial infarction that is <3 months prior to
registration.

- Subjects with uncontrolled intercurrent illness including, but not limited to ongoing
or active infection, symptomatic congestive heart failure or coronary artery disease,
unstable angina pectoris, cardiac arrhythmia, symptomatic myocardial infarction or
psychiatric illness/social situations that would limit compliance with study
requirements.

- Subjects who are known to be HIV-positive and on combination antiretroviral therapy
are ineligible because of the potential for pharmacokinetic interactions with CPI-613.