A Research Pilot Study in Healthy Volunteers to Evaluate Biomarkers for Novel Anticancer Treatments

Many physiological processes in normal growth, development, injury, and repair are critical
for tumor growth and progression. Usually these processes are deregulated, allowing for the
potential of tumor selectivity in targeting many of these processes. In many cases, altered
host stromal tissues themselves are critical for many of steps in cancer progression.
Stromal endothelial cells and fibroblasts produce many tumor growth factors, which act in
paracrine loops. In addition, components of the host tissue matrix and plasma proteins also
help promote or inhibit tumor growth. These topics have been extensively reviewed.

A large number of targeted therapies for cancer are also in various stages of clinical
development. Due to the likely minimal toxicity and only modest single agent activity of
these agents, determining the optimal dose and schedule for these agents will depend upon
the identification of biomarkers that can demonstrate proof of target inhibition and/or
characterize the downstream consequences of this inhibition.

Despite often robust and durable clinical responses, essentially all patients treated with
bevacizumab progress, implying primary or acquired resistance, or both. Treatment related
changes in VEGF ligands and receptors have been reported in response to anti-VEGF therapy in
preclinical models. Treatment related changes have also been noted for many additional
angiogenic factors, including PDGF, bFGF, and IGF, all of which have been shown to
potentially mediate sensitivity and resistance to anti-VEGF therapy. Despite the known
importance of numerous angiogenic factors in both preclinical models and in patients, there
have not yet been a broad and systematic evaluation of either baseline or treatment related
changes of multiple angiogenic factors in response to bevacizumab. Similar information is
also lacking for essentially all targeted therapies.

Biomarkers to better understand the mechanisms of action, primary and acquired resistance,
and toxicity of these agents are urgently needed. The topic has been extensively reviewed
and is considered a priority by the NCI. The need for such biomarkers is critical given the
increasing number of permutations of targeted therapeutics and the need for biomarkers to
guide patient and treatment selection both in clinical trials and in general use of
anti-cancer therapy. Assay optimization and defining expected values of each marker or
panel of markers is critical before use of such assays in large therapeutic clinical trials
designed to target specific patient populations. In addition, understanding the biology and
regulation of biomarkers related to tumor growth and tumor angiogenesis is also important.
Most candidate biomarkers are themselves cellular growth factors, and are involved in not
only tumor promotion and growth, but also in normal growth and development and in normal and
abnormal tissues responses to injury. The primary purpose of the proposed project is to
help refine new biomarkers and new and evolving technologies to assess them.

Inclusion Criteria:

LOCAL (Raleigh-Durham, Chapel Hill) candidates only!!!

- Age >18 years.

- Ability to understand and the willingness to sign a written informed consent
document.

Exclusion Criteria:

- Subjects may not have major medical or other conditions that might affect the study
assays: major surgery or trauma in the past six months, known current pregnancy,
diabetes, history of coagulation abnormalities.

- Subjects may not be receiving any investigational agents.

- Subjects may not be taking medications that are likely to significantly affect wound
healing or clotting (eg steroids, anti-coagulants, hormonal contraceptives), aspirin
> 325mg/d or other NSAID > once per day, birth control pills or other hormonal
contraceptives.

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

- HIV-positive patients and patients on combination antiretroviral therapy are
ineligible because of the potential for alterations in normal wound healing
responses. In addition, subjects who currently have a malignancy or have had
malignant disease in the past 5 years are not eligible.