Development of Novel Herbal Therapy for Prevention of Irinotecan-induced Severe Delayed Onset Diarrhea

PROJECT SUMMARY / ABSTRACT Cancer is the second leading cause of death in the United States. According to American Cancer Society statistics, about 1.76 million new patients are expected to be diagnosed with cancer and about 600,000 people are expected to die due to cancer in the United States in 2019. Approximately 6-10% of the total cancer patients are diagnosed with stage IV/metastatic cancer, while 30-50% develop metastasis during disease progression. Through the advent of new and effective drugs for cancer treatment, 5-year survival rate for cancer has improved to about 67%, however treatment of refractory/recurrent disease in metastatic cancer patients remains a critical challenge. Among the various cancer drugs available for metastatic cancer treatment, irinotecan is often the drug of last resort for the refractory diseases. Recent clinical studies have indicated that high-dose irinotecan therapy can be successfully used in patients with refractory diseases, even in irinotecan-refractory patients, improving life expectancy of cancer patients. However, irinotecan treatment is currently limiting due to severe and sometimes life-threatening dose-limiting site effects (i.e. neutropenia and severe delayed onset diarrhea). Chemotherapy-induced neutropenia (low white blood cells) is effectively managed with prophylactic antibiotics and human G-CSF (granulocyte colony stimulating factor) agents in clinics. However, in about 15% of patients on standard of care irinotecan therapy, diarrhea is unmanageable with current drugs such as loperamide, requiring hospitalization and even cessation of therapy. Moreover, most current treatments only provide symptomatic relief but do not prevent the increasing damage to gut function and integrity, resulting with consecutive cycles of irinotecan therapy. Based on recent preliminary data from our collaborator’s lab, Sanarentero is proposing to develop a new herbal product (SE_H1) which can prevent the irinotecan-induced diarrheal toxicity and gut damage. This will help improve the quality of life, reduce the cost of treatment by reducing incidences of hospitalization, and increase the life expectancy of metastatic cancer patients with refractory/recurrent diseases, by allowing continuation of treatment and high-dose irinotecan therapy. The specific aims of this Phase I SBIR proposal are to 1) develop a standardized novel proprietary herbal formula using Caco-2 cells; 2) establish the in vivo efficacy of the proprietary herbal formula for SDOD prevention; and 3) standardize CMC (Chemistry, Manufacturing, and Controls) of SE_H1 for Phase II studies. Success of this project will generate a well-characterized, standardized, safe and efficacious proprietary herbal product for prevention of irinotecan-induced severe delayed onset diarrhea. It will also provide us with proof-of concept evidence of efficacy and safety in a preclinical model, therefore derisking the product for further development in phase II SBIR proposal.PROJECT NARRATIVE The proposed research aims to develop well-characterized, standardized, safe and efficacious proprietary herbal product to prevent severe delayed onset diarrhea, the dose-limiting side effect of irinotecan in cancer patients. The herbal product is targeted to reduce the treatment cost due to hospitalization for diarrheal management and improve the quality of life of the cancer patients on irinotecan standard therapy. Additionally, the availability of this product in clinics is expected to increase the overall life expectancy of metastatic cancer patients with refractory/ recurrent diseases by allowing the use of high-dose irinotecan therapy by preventing the dose-limiting side effects.