Safety and Effectiveness Study of CPI-613 and/or Gemcitabine to Treat Metastatic Pancreatic Cancer

Data from dose-escalated Phase I trials indicate that CPI-613 is safe and effective against
metastatic pancreatic cancer (Lee et al. 2012; Retter et al. 2012). Accordingly, this Phase
II trial is conducted to assess the safety and efficacy of CPI-613 in patients with
metastatic pancreatic cancer.

Primary Outcome Measure:

- Overall Survival (OS)

Secondary Outcome Measures:

- Changes in CA 19-9

- Quality of Life (QOL) assessment

- Progression-Free Survival (PFS)

- Safety

Inclusion Criteria:

- Histologically and cytologically confirmed, measurable metastatic pancreatic
adenocarcinoma

- Eastern Cooperative Oncology Group (ECOG) performance status being 0-2

- Expected survival >2 months

- 18 years of age or older of both genders

- 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. (Note: Pregnant patients are excluded because the effects of CPI-613 on a
fetus are unknown.)

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

- At least 2 weeks must have elapsed from any prior surgery or hormonal therapy. Must
have fully recovered from the acute toxicities of any prior treatment with any
anti-cancer drugs, radiotherapy or other anti-cancer modalities (returned to baseline
status as noted before most recent treatment). Patients with persisting, stable
chronic toxicities from prior treatment ≤Grade 1 are eligible, but must be documented
as such.

- Laboratory values ≤2 weeks must be:

- Adequate hematologic (white blood cell [WBC] ≥3500 cells/mm3 or ≥3.5 bil/L;
platelet count ≥150,000 cells/mm3 or ≥150 bil/L; absolute neutrophil count [ANC]
≥1500 cells/mm3 or ≥1.5 bil/L; and hemoglobin (Hgb) ≥9 g/dL or ≥90 g/L).

- Adequate hepatic function (aspartate aminotransferase [AST/SGOT] ≤3x upper
normal limit [UNL], alanine aminotransferase [ALT/SGPT] ≤3x UNL (≤5x UNL if
liver metastases present), bilirubin ≤1.5x UNL).

- Adequate renal function (serum creatinine ≤2.0 mg/dL or 177 μmol/L, and blood
urea nitrogen [BUN] ≤25 mg/dL).

- Adequate coagulation ("International Normalized Ratio or INR must be <1.5"),
unless treated with anticoagulants.

- No evidence of active infection and no serious infection within the past month; no
systemic fungal, bacterial, viral or other infection not controlled (defined as
exhibiting ongoing signs/symptoms related to the infection and without improvement,
despite appropriate antibiotics or other treatment.

- Consent to participating the study by signed informed consent form

Exclusion Criteria:

- Serious medical illness that would potentially increase patients' risk for toxicity

- Any active uncontrolled bleeding or patients with a bleeding diathesis (e.g., active
peptic ulcer disease)

- Patients with active central nervous system (CNS) or epidural tumor

- Lactating females (Note: Lactating females are excluded because the effects of
CPI-613 on a nursing child are unknown)

- Life expectancy less than 2 months

- Unwilling or unable to follow protocol requirements

- Dyspnea with minimal to moderate exertion, or patients with pleural, pericardial, or
peritoneal effusions

- Active heart disease including but not limited to symptomatic congestive heart
failure, symptomatic coronary artery disease, symptomatic angina pectoris,
symptomatic myocardial infarction, arrhythmias requiring medication, or symptomatic
congestive heart failure. Also patients with a history of myocardial infarction that
is <1 year prior to registration, or patients with previous congestive heart failure
(<1 year prior to registration) requiring pharmacologic support or with Left
Ventricular Ejection Fraction <50%).

- A marked baseline prolongation of QT/QTc interval (e.g., repeated exhibition of a QTc
interval >470 ms.); a history of additional risk factors for torsade de pointes
(e.g., heart failure, hypokalemia, family history of Long QT Syndrome).

- Requirement for immediate palliative treatment of any kind including surgery

- Any condition or abnormality which may, in the opinion of the investigator,
compromise the safety of patients