XCHT for Irinotecan-Induced Gut Toxicities (Run-in Study)

Run-in safety study, to determine the safety of co-administration of irinotecan, raloxifene, and Xiao Chai Hu Tang (XCHT), and to optimize the blood collection time points for pharmacokinetic (PK) study for another randomized control trial.

There will be two cohorts with a total of 24 patients in this study. Cohort A will enroll 6 naïve postmenopausal female patients who have never received irinotecan treatment before. Patients in this group will have 4 rounds of studies following different protocol to determine (1) the impact of XCHT on raloxifene PK (Round 0, co-administration of XCHT and raloxifene); (2) the impact of XCHT on irinotecan PK (Round 1, co-administration of XCHT and standard FOLFIRI); (3) the safety of co- administration of XCHT, raloxifene, and FOLFIRI and evaluation of raloxifene as a probe for XCHT treatment to prevent irinotecan-induced severe delayed-onset diarrhea (Round 2 and 3, co-administration of XCHT, raloxifene, and standard FOLFIRI). The reason to recruit postmenopausal women is that these patients usually take raloxifene to prevent osteoporosis and the risk of raloxifene is expected to be limited.

Cohort B will recruit 18 patients who were treated with irinotecan previously and have at least one diarrhea episode with a severity of ≥grade 2. The reason we propose to recruit patients who had diarrhea induced by irinotecan is that these patients are supposed to be sensitive to irinotecan so that we can determine the PK changes and safety. Patients in this group will have 3 rounds of FOLFIRI chemotherapy to determine (1) the impact of FOLFIRI on raloxifene PK (Round 1, co-administration of FOLFIRI with raloxifene); (2) the complete PK profile of SN-38, SN-38G, raloxifene, raloxifene-glucuronide, and XCHT components (Round 2, co- administration of FOLFIRI with XCHT and raloxifene); and (3) the safety of co-administration of XCHT, raloxifene, and FOLFIRI in sensitive patients and evaluation of raloxifene as a probe for XCHT treatment to prevent irinotecan-induced diarrhea (Round 3, co-administration of XCHT, raloxifene and standard FOLFIRI).

Eligibility Criteria:
Cohort A: Naïve (no irinotecan treatment before) postmenopausal female cancer patients.

Inclusion criteria:

1. Malignant tumor confirmed by histology or cytology;
2. Postmenopausal women, after bilateral oophorectomy; age \> 60 years old, or age \< 60 years old with menopause for more than 1 year;
3. Age ≥ 18 years old, ≤ 75 years old;
4. ECOG score of the patient ≤ 2 points;
5. Never been treated with irinotecan;
6. Plan to receive at least 3 rounds of FOLFIRI chemotherapy determined by physicians;
7. Normal organ functions can meet the requirements for systemic chemotherapy:

   * Reserve functions of normal bone marrow: absolute neutrophil count (ANC) ≥ 1.5×109/L, PLT ≥ 100×109/L, hemoglobin ≥ 90 g/L;
   * Normal renal functions: serum creatinine ≤ 1.5 mg/dl (133 μmol/L) and/or creatinine clearance ≥ 60 ml/min;
   * Normal hepatic functions: total serum bilirubin level ≤ 1.5 times of the upper limit of normal value (ULN), serum aspartate aminotransferase (AST) \& alanine aminotransferase (ALT) ≤ 2.5 × ULN; If abnormal hepatic functions are caused by a potentially malignant tumor, and AST ＆ ALT ≤ 5 × ULN;
8. Patient is willing to participate and cooperate to complete the questions in the case report form;
9. Patient can understand and sign the informed consent form, is well compliant, and can be followed up.

Cohort B: cancer patients who experienced irinotecan -induced diarrhea (grade \>2)

Inclusion criteria:

1. Malignant tumor confirmed by histology or cytology;
2. Age ≥ 18 years old, ≤ 75 years old;
3. ECOG score of the patient ≤ 2 points;
4. Patients who have diarrhea worse than grade 2 due to irinotecan chemotherapy (the last dose of irinotecan is administered within 1 month);
5. Patients who plan to receive 3 rounds of FOLFIRI chemotherapy;
6. Normal organ functions can meet the requirements for systemic chemotherapy:

   * Reserve functions of normal bone marrow: absolute neutrophil count (ANC) ≥ 1.5×109/L, PLT ≥ 100×109/L, hemoglobin ≥ 90g/L;
   * Normal renal functions: serum creatinine ≤ 1.5mg/dl (133μmol/L) and/or creatinine clearance ≥ 60ml/min;
   * Normal hepatic functions: total serum bilirubin level ≤ 1.5 times of the upper limit of normal value (ULN), serum aspartate aminotransferase (AST) \& alanine aminotransferase (ALT) ≤ 2.5 × ULN; If abnormal hepatic functions are caused by a potentially malignant tumor, and AST ＆ ALT ≤ 5 × ULN;
7. Patient is willing to participate and cooperate to complete the questions in the case report form;
8. Patients can understand and sign the informed consent form, is well compliant, and can be followed up.

Exclusion Criteria:

1. Patients with diagnosed depression, obsession or/and schizophrenia;
2. Patients with diagnosed inflammatory bowel diseases (including Crohn's disease, ulcerative colitis)
3. Patient with active tuberculosis and other uncontrolled infections;
4. Patient has previously received radiotherapy on the abdominal cavity and pelvic cavity;
5. Pregnant or lactating women;
6. Patient previously had or is now having thromboembolic (blood clotting) events.