A Study of Niclosamide in Patients With Resectable Colon Cancer

Niclosamide is a drug traditionally used in parasitic infections that has recently been shown
to regulated the Wnt signaling pathway in cells at the level of the Frizzled receptor.

The Wnt pathway is critical for embryogenesis, differentiation of progenitor cells, and
supports proliferation of neoplastic tissue. In cancer, activation of the Wnt pathway leads
to increased transcription of genes important for growth, proliferation, differentiation,
apoptosis, genetic stability, migration, and angiogenesis. The Wnt pathway has particular
importance in colorectal cancer.

The purpose of this study is to obtain safety data along with pharmacokinetic data and
information on the changes in the WNT pathway signalling following niclosamide administration
in humans. This phase I study will support future studies in patients with more advanced
cancer and other cancers with dysregulation of the Wnt pathway.

Inclusion Criteria:

- Histologically confirmed diagnosis of colon adenocarcinoma with a plan to undergo
surgical resection no sooner than 7 days from the projected date of study drug
initiation. Patients with rectal cancer not receiving pre-operative chemoradiotherapy
are also eligible.

- Karnofsky performance status greater than or equal to 70%

- Age ≥ 18 years.

- Adequate hematologic function, with ANC > 1500/microliter, hemoglobin ≥ 9 g/dL (may
transfuse or use erythropoietin to achieve this level), platelets ≥
100,000/microliter; INR <1.5, PTT <1.5X ULN

- Adequate renal and hepatic function, with serum creatinine < 1.5 mg/dL, bilirubin <
1.5 mg/dL (except for Gilbert's syndrome which will allow bilirubin ≤ 2.0 mg/dL), ALT
and AST ≤ 2.5 x upper limit of normal.

- Ability to understand and provide signed informed consent that fulfills Institutional
Review Board's guidelines.

- Ability to return to Duke University Medical Center for adequate follow-up, as
required by this protocol.

Exclusion Criteria:

- Patients with concurrent cytotoxic chemotherapy or radiation therapy are excluded

- Known active brain or leptomeningeal metastases (defined as symptomatic metastases) or
continued requirement for glucocorticoids for brain or leptomeningeal metastases.
Treated, asymptomatic metastases are permitted provided the patient has been off
steroids for at least 1 month prior to day 1 of study drug.

- Patients with serious intercurrent chronic or acute illness, such as cardiac disease
(NYHA class III or IV), hepatic disease, or other illness considered by the Principal
Investigator as unwarranted high risk for investigational drug treatment.

- Patients with a medical or psychological impediment to probable compliance with the
protocol should be excluded.

- Concurrent (or within the last 5 years) second malignancy other than non melanoma skin
cancer, cervical carcinoma in situ, controlled superficial bladder cancer, or other
carcinoma in situ that has been treated.

- Presence of a known active acute or chronic infection including: a urinary tract
infection, HIV or viral hepatitis.

- Patients with prior use of niclosamide or allergies to niclosamide will be excluded
from the protocol.

- Concomitant use of strong CYP3A4, CYP 1A2 , or CYP2C9 substrates (See
http://medicine.iupui.edu/clinpharm/ddis/main-table).

- Pregnant and nursing women should be excluded from the protocol since this research
may have unknown and harmful effects on an unborn child or on young children. If the
patient is sexually active, the patient must agree to use a medically acceptable form
of birth control while receiving treatment and for a period of 12 months following the
last dose of niclosamide. It is not known whether the treatment used in this study
could affect the sperm and could potentially harm a child that may be fathered while
on this study.

- Patients with complete bowel obstruction or who are at high risk for GI perforation or
severe hemorrhage. Patients with inflammatory bowel disease.