CPI-613 and Fluorouracil in Treating Patients With Metastatic Colorectal Cancer That Cannot Be Removed by Surgery

PRIMARY OBJECTIVES:

I. To determine the maximum tolerated dose (MTD) of CPI-613 (6,8-bis[benzylthio]octanoic
acid), when used in combination with 5-FU (fluorouracil), in patients with non-resectable
metastatic colorectal cancer who have failed FOLFOX (leucovorin calcium, fluorouracil and
oxaliplatin), FOLFIRI (leucovorin calcium, fluorouracil, and irinotecan hydrochloride) and,
if Kirsten rat sarcoma viral oncogene homolog (KRAS) wild type, then a epidermal growth
factor receptor (EGFR) inhibitor-based regimen.

SECONDARY OBJECTIVES:

I. To assess the pharmacokinetic (PK), safety and efficacy of various doses of CPI-613, when
used in combination with 5-FU, in patients with non-resectable metastatic colorectal cancer.

OUTLINE: This is a dose-escalation study of 6,8-bis(benzylthio)octanoic acid.

Patients receive 6,8-bis(benzylthio)octanoic acid intravenously (IV) over 2 hours on days 1-4
and fluorouracil IV over 46 hours on days 2-4. Courses repeat every 2 weeks for 6 months in
the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up every 2 months for 3 years.

Inclusion Criteria:

- Histologically and cytologically confirmed metastatic colorectal adenocarcinoma
(colon, rectal or colorectal cancer) that is not resectable

- Have failed or have not tolerated FOLFOX, FOLFIRI and, if KRAS wild type, then a EGFR
inhibitor-based regimen

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

- 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

- At least 2 weeks must have elapsed from any prior surgery

- Granulocyte count >= 1500/mm^3

- White blood cell (WBC) >= 3500 cells/mm^3 or >= 3.5 bil/L

- Platelet count >= 100,000 cells/mm^3 or >= 100 bil/L

- Absolute neutrophil count (ANC) >= 1500 cells/mm^3 or >= 1.5 bil/L

- Hemoglobin >= 9 g/dL or >= 90 g/L

- Aspartate aminotransferase (AST/serum glutamic oxaloacetic transaminase [SGOT]) =< 3 x
upper normal limit (UNL), alanine aminotransferase (ALT/serum glutamate pyruvate
transaminase [SGPT]) =< 3 x UNL (=< 5 x UNL if liver metastases present)

- Bilirubin =< 1.5 x UNL

- Serum creatinine =< 1.5 mg/dL or 13 umol/L

- International normalized ratio or INR must be =< 1.5 unless on therapeutic blood
thinners

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

- Mentally competent, ability to understand and willingness to sign the informed consent
form

- At least one measurable lesion as assessed by computed tomography (CT) scan using
Response Evaluation Criteria in Solid Tumors (RECIST) criteria

Exclusion Criteria:

- Therapy with CPI-613 prior to participating in this trial

- Known hypersensitivity to 5-FU injection, poor nutritional state, known dipyrimidine
dehydrogenase deficiency, or taking sorivudine (such as Usevir, brovavir, etc.)

- History of hypersensitivity to active or inactive excipients of any component of
treatment

- Previous radiotherapy for central nervous system metastases

- Patients receiving any other standard or investigational treatment for their cancer,
or any other investigational agent for any indication, within the past 2 weeks prior
to initiation of treatment with study drugs

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

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

- History of abdominal fistula or gastrointestinal perforation =< 6 months prior to
treatment with study drugs

- Pregnant women, or women of child-bearing potential not using reliable means of
contraception

- Lactating females

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

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

- Unwilling or unable to follow protocol requirements

- Symptomatic heart disease including but not limited to symptomatic congestive heart
failure, symptomatic coronary artery disease, symptomatic angina pectoris, symptomatic
myocardial infarction or symptomatic congestive heart failure

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

- Evidence of active infection, or serious infection within the past month

- Patients with known human immunodeficiency virus (HIV) infection, hepatitis B, or
hepatitis C

- Patients who have received cancer immunotherapy of any type within the past 2 weeks
prior to initiation of CPI-613 treatment; steroid use for management of refractory
pain or for contrast induced allergy is allowed

- 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 the patient