Phase II year
2017
(last award dollars: 2019)
Phase II Amount
$1,999,248
Capecitabine is a widely prescribed and orally available prodrug of the chemotherapeutic agent 5-fluorouracil (5-FU). The principle dose-schedule limiting toxicity associated with its use is Hand-Foot syndrome (HFS), and occurs in 60-70% of patients receiving capecitabine. HFS manifests in the hands and feet of patients, and rapidly progresses to painful peeling, blistering, and bleeding that commonly require narcotics. There is no approved treatment to prevent or treat HFS, and management typically involves disruptions in capecitabine dosing regimens, which can diminish the efficacy of the drug in its approved indications. There remains a significant need to develop a treatment for HFS that would permit uninterrupted capecitabine therapy at optimal dosing regimens and improve quality of life for patients. Product and Long-Term Goal: Nanometics (d.b.a PHD Biosciences [PHD]) is developing an 0.1% uracil topical cream (UTC) to prevent HFS, which has successfully completed a Phase 1-2 clinical trial in 18 patients. Technical Innovation: Uracil is an endogenous metabolite and competitive substrate to enzymes that catabolize capecitabine to the toxic metabolites responsible for HFS. When administered topically to the hands and feet of patients as UTC, uracil is absorbed by diffusion and inhibits local cutaneous toxicity without impacting the systemic anti-cancer activity of 5-FU. Phase I SBIR Equivalent Outcomes: In a randomized, double-blind placebo controlled Phase 1-2 clinical study in metastatic breast cancer patients receiving capecitabine, the risk of >=Grade 2 HFS, a severity that is associated with pain and impairment of daily activities, was lower in the UTC treated group (44%) than the placebo group (78%). The UTC group also had a tripling of time to >=Grade 2 HFS relative to placebo (treatment group hazard ratio = 0.33, p = 0.09), and an excellent safety profile with no adverse events. Direct Phase II Objectives: Demonstrate the safety and efficacy of UTC in 25 metastatic breast cancer patients (mBC) being treated with capecitabine. Expected Outcomes: Concurrent treatment with UTC among women with mBC treated with capecitabine will delay a meaningfully detrimental increase in patient-reported pain associated with the development of HFS. Commercial Application: UTC will be commercialized as a topical treatment for capecitabine patients.
Public Health Relevance Statement: Hand-foot syndrome (HFS) is the principle dose limiting toxicity of the widely prescribed chemotherapeutic capecitabine and occurs in 60-70% of capecitabine users. Currently there is no treatment for HFS, which can be a debilitating condition that forces physicians to disrupt dosing regimens; potentially diminishing the efficacy of capecitabine in its approved indications. This project seeks to complete a phase 2 clinical trial of a 0.1% uracil topical cream to prevent HFS in metastatic breast cancer patients being treated with capecitabine.
Project Terms: Adverse event; attenuation; Basal Cell; Biological Sciences; Biotechnology; Breast Cancer Patient; Bulla; capecitabine; Cell Proliferation; chemotherapeutic agent; chemotherapy; clinical development; Clinical Research; Clinical Trials; clinically relevant; commercial application; commercialization; Coupled; Cream; Cutaneous; cytotoxic; Development; Diffusion; Dose; Dose-Limiting; Double-Blind Method; drug efficacy; Edema; Effectiveness; Enzymes; Erythema; Evaluation; Fluorouracil; foot; Funding; Futility; Goals; Hand; hazard; Hemorrhage; Hour; Impairment; improved; Incidence; innovation; keratinocyte; Knowledge; Malignant Neoplasms; meetings; Metabolic; Metastatic breast cancer; Multicenter Studies; Names; Narcotics; Outcome; Pain; Painless; Palmar-plantar erythrodysesthesia syndrome; Patients; Pharmacologic Substance; Phase; Phase II Clinical Trials; Physicians; Placebo Control; Placebos; prevent; Prevention; Prodrugs; Quality of life; Randomized; Recruitment Activity; Regimen; Reporting; Risk; Safety; Schedule; Severities; Small Business Innovation Research Grant; Staging; standard of care; success; technological innovation; Therapeutic; Thymidine Phosphorylase; Time; Topical application; Toxic effect; treatment group; treatment response; tumor; United States National Institutes of Health; Uracil; Woman
