TIP-003 - EVALUATING THE IMPACT OF XIAO-CHAI-HU-TANG ON PHARMACOKINETIC BEHAVIORS OF IRINOTECAN, RALOXIFENE AND THEIR METABOLITES IN HUMANS: A RUN-IN SAFETY STUDY.

Z. Zheng¹, R. Sun², R. Singh², L. Zhu³, Y. Zhu⁴, Z. Liu³, H. Zhang⁴, M. Hu²; ¹University of Houston, Houston, TX, United States, ²University of Houston, ³Guangzhou University of Chinese Medicine, ⁴Guangdong Provincial Hospital of Chinese Medicine.

Background: Irinotecan (CPT-11) is used as a standard first-line treatment for metastatic colorectal cancer and various solid tumors. However, it leads to severe delayed-onset diarrhea (SDOD) in up to 40% of patients, significantly reducing patient’s quality of life. Our preclinical research has demonstrated that a traditional herbal formulation Xiao-Chai-Hu-Tang (XCHT) showed efficacy against SDOD in mice and rats. Therefore, this study aims to assess safety and its impact on pharmacokinetic (PK) behavior of irinotecan when co-administering irinotecan, raloxifene and XCHT. Additionally, the potential of using raloxifene and raloxifene-glucuronide ratio as probes for assessing intestinal Uridine 5′-diphospho-glucronosyltrasferase (UGT) activity will be evaluated.

Methods: This study consists of two cohorts with 24 patients (NCT04926545). Cohort A has enrolled 6 naïve postmenopausal female patients who have not undergone irinotecan treatment previously. In this group, patients have been given 4 rounds different combinations of irinotecan, raloxifene and XCHT to determine (1) the safety of co-administering XCHT, raloxifene, and FOLFIRI (folinic acid+5- fluorouracil+irinotecan); (2) the impact of XCHT on irinotecan’s PK behaviors; (3) the impact of XCHT on raloxifene’s PK behaviors. Cohort B aims to evaluate the safety of co-administering irinotecan, XCHT and raloxifene in both male and female patients who have previously been treated with irinotecan and experienced at least one episode of diarrhea with a severity of ≥ grade 2. 18 patients in cohort B will receive 3 rounds of FOLFIRI chemotherapy along with XCHT and raloxifene.

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Design: 1) Our approach focuses on reducing intestinal exposure to SN-38 by XCHT, without affecting SN-38 systemic exposure, which is critical for its anti-tumor efficacy; 2) We will comprehensively evaluate the impact of multiple rounds of FOLFIRI on PK profile of irinotecan and its metabolites in patients, which has not been reported before; 3) We will assess the safety of co-administering of herbal medicine with raloxifene and irinotecan; 4) We will evaluate the impact of herb-drug interactions on PK behavior of raloxifene and irinotecan, an aspect often be overlooked.