A team of University of Arizona Cancer Center chemoprevention investigators led by Drs. Sherry Chow and David Alberts received $8.4 million of funding from the National Cancer Institute, Division of Cancer Prevention since 2003 to conduct multiple early phase clinical trials of chemopreventive agents. The University of Arizona Cancer Center team is one of only six institutions nationwide selected for this competitive award program. A UA Phase I/II Cancer Chemoprevention Consortium office staffed with clinical coordinators, research assistants and data management staff is established to provide administrative and clinical support for all aspects of the development and implementation of trials funded through this mechanism. This funding mechanism also offers early phase cancer prevention trial training and research opportunities to University of Arizona Cancer Center faculty members.
The ongoing and planned consortium trials encompass the clinical development of potential chemopreventive agents for breast, cervix, prostate, melanoma, and esophageal cancer prevention. These trials also help evaluate intermediate clinical biomarkers of carcinogenesis or chemopreventive mechanisms. The study agents for the consortium trials have been agents identified by NCI, DCP or agents developed or proposed by University of Arizona Cancer Center investigators. Through the conduct and planning of these trials, the consortium has formed alliances with outside institutions and involved new UA medical subspecialists to enhance the patient recruitment capability and areas of specialty.
The following is a list of trials initiated through this program:
Phase Ib Sulindac Study for Women at Risk for Breast Cancer
Protocol PI: Patricia Thompson, PhD
The objective of this early phase trial is to assess the partitioning of sulindac and its metabolites to the breast and to assess the drug effect biomarkers in the breast after six weeks of sulindac intervention. This trial has successfully completed accrual of women at high risk for breast cancer and a manuscript is under review. Design of a follow-up Phase II sulindac trial is in the work.
Phase II Trial of Polyphenon E for Cervical Cancer Prevention
Protocol PI: Francisco A. Garcia, MD
The objective of this Phase II trial is to evaluate the efficacy of an enriched and defined green tea catechin preparation, Polyphenon E, for regression of persistent low grade cervical intraepithelial neoplasia, and to assess the toxicity of this agent in women with HPV infection and persistent disease. The study team, led by Dr. Garcia, is actively accruing study participants and has expanded to include investigators from Maricopa Integrated Health System and The Southern Pines Women's Health Center, P.C . It is anticipated that this trial will help define the utility of Polyphenon E in women with persistent low grade cervical intraepithelial neoplasia. Clinical specimens collected from this trial could also be used for future translational research in cervical cancer prevention.
Phase Ib Study of Polyphenon E in a Pre-prostatectomy Prostate Cancer Cohort
Protocol PI: Frederick R. Ahmann, MD
The objective of this early phase trial is to determine the bioavailability of green tea catechins in prostate tissue following 3-6 weeks of Polyphenon E intervention and to assess the effect of Polyphenon E intervention on tissue/blood biomarkers associated with prostate cancer development and progression. The study team, led by Dr. Ahmann, is actively accruing study participants and has expanded to establish a network of local and Phoenix urologists to help with patient recruitment. This established network will greatly benefit future prevention trials in the same patient cohort.
Clinical Study of Resveratrol on Drug and Carcinogen Metabolizing Enzymes
Protocol PI: H-H Sherry Chow, PhD
Resveratrol has been shown to exhibit cancer preventive activities in preclinical studies. Modulation of Phase I and Phase II enzymes has been suggested to be one of the mechanisms responsible for the cancer preventive effect of resveratrol. A clinical study has been conducted to determine the effect of pharmacological doses of resveratrol on drug and carcinogen metabolizing enzymes. This trial has been successfully completed and a manuscript is under review. The study shows that large pharmacological doses of resveratrol affect drug and carcinogen metabolizing enzymes. The data suggest that resveratrol administered at this dose level may modulate carcinogen activation, and potentially detoxification, but may lead to adverse drug-drug interactions. Further clinical development of large pharmacological doses of resveratrol needs to consider the potential drug-drug interactions. Design of a follow-up trial is in the work.
Phase Ib Trial of Sulindac in Individuals at Increased Risk for Melanoma
Protocol PI: Clara Curiel, MD
Despite extensive efforts at primary prevention, including promotion of sun protection behaviors, melanoma rates continue to rise. The increasing incidence of melanoma and its poor prognosis in advanced stages suggest that other prevention measures need to be investigated. Chemoprevention of melanoma has been an area that has only been explored to a limited extent. The study team, led by Dr. Curiel, proposes to conduct a pilot clinical study to evaluate the potential of NSAIDs for melanoma prevention in high risk individuals. The objective of this trial is to determine whether oral sulindac intervention can result in extensive distribution of sulindac and sulindac metabolites to target tissue and lead to favorable changes in surrogate endpoint biomarkers in atypical nevi. The study is actively accruing study participants locally and at Stanford University.
Clinical Study of Ursodeoxycholic Acid in Barrett's Patients with Low Grade Dysplasia
Protocol PI: Bhaskar Banerjee, MD
Barrett's esophagus is most often diagnosed in people who have long-term gastroesophageal reflux disease (GERD) — a chronic regurgitation of acid from the stomach into the lower esophagus. Only a small percentage of people with GERD will develop Barrett's esophagus. A diagnosis of Barrett's esophagus can be concerning because it increases the risk of developing esophageal cancer. Although the risk of esophageal cancer is small, monitoring and treatment of Barrett's esophagus focuses on periodic exams to find precancerous esophagus cells. The objective of this project is to see if a drug could help prevent progression in Barrett’s esophagus. The drug is called ursodeoxycholic acid (UDCA). UDCA is a natural bile acid found in humans in small quantities. It is used to treat or prevent certain kinds of gallstones or to treat certain types of liver disease. This research will examine the potential of UDCA to prevent esophageal cancer. The study is actively accruing study participants locally (Southern Arizona VA Health Care System (Dr. Habib), UMC/UPH (Drs. Banerjee and Trowers), and at University of North Carolina (Dr. Shaheen).
Phase I Dose-Finding Trial of Letrozole in Postmenopausal Women at High Risk for Breast Cancer
Protocol PI: Ana Maria Lopez, MD, MPH
Research has shown that higher estrogen levels in postmenopausal women may increase the risk of breast cancer. Letrozole is approved by the Food and Drug Administration (FDA) to treat certain breast cancers or to keep certain breast cancers from coming back in postmenopausal women. It decreases the amount of estrogen produced by the body. The study team, led by Dr. Lopez, will compare several doses of letrozole including the one used for women with breast cancer and several lower doses. The objective of this study is to determine whether lower doses of letrozole can be used to lower estrogen levels and whether lower doses would have fewer side effects than the standard dose in postmenopausal women who have some risk factor for breast cancer. The study is actively accruing study participants locally and at Mayo Clinic Rochester.
Phase II Study of Metformin in a Pre-prostatectomy Prostate Cancer Cohort
Protocol PI: Mike Nguyen, MD, MPH
Prostate cancer is the most common cancer affecting men. Recent studies have shown that treatment with metformin may substantially reduce the risk for development of cancer, including prostate cancer. This study will evaluate metformin’s prostate tissue bioavailability and bioactivity and will meaningfully add to the current body of knowledge regarding metformin’s role in prostate cancer prevention. Information from the trial will enable future informed research and will therefore have an important impact in furthering chemoprevention science in this area. The study team, led by Dr. Nguyen, is actively accruing study participants at the University of Arizona.
Pilot Study on the Bioactivity of Vitamin D in the Skin after Oral Supplementation
Protocol PI: Clara Curiel, MD
The overall objective of this project is to determine the potential of high dose, orally supplemented vitamin D in preventing skin cancer in people who have sun damaged skin and low blood levels of Vitamin D. The researchers will determine if Vitamin D can be detected in skin areas usually protected from the sun as well as in areas that are exposed to the sun following high-dose Vitamin D supplementation; and whether improvement in the nature of the skin cells’ ability to prevent skin cancer will occur. Dr. Curiel is actively accruing study participants at the University of Arizona.