XCHT for Irinotecan-Induced Gut Toxicities (Randomized Controlled Trial)

Study Overview
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Brief Summary
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Randomized double-blind placebo-controlled trial (RCT) study, to determine the impact of XCHT on irinotecan-induced severe delayed-onset diarrhea (SDOD), and to determine the feasibility of using plasma raloxifene-4'-glucuronide as a probe for intestinal UGT activity.

Detailed Description
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A total of 98 patients, who are planning to recieve at least 3 cycles of FOLFIRI/mXELIRI chemotherapy, will be randomly assigned, at a 1:1 ratio, to XCHT group or placebo group, using a central randomization system. Patients will be administered with XCHT/placebo (9 g, qd, po) for 5 days each cycle of chemotherapy for 3 cycles. The XCHT/placebo administration begins 3 days before chemotherapy in each cycle, that is the chemotherapy begins on the 4th day of XCHT/placebo administration. Plasma will be collected for pharmacokinetic testing (using raloxifene 60mg po as probe), on the day before chemotherapy, that is on the 3rd day of XCHT/placebo administration in each cycle. The purpose of this study includes 1) to determine the safety and efficacy of XCHT for prevention of irinotecan-induced diarrhea; 2) to determine the PK profile of SN-38, SN-38G, raloxifene, raloxifene-glucuronide, and XCHT components; and 3) to validate the use of raloxifene-4'G as a probe for irinotecan-induced diarrhea.

Official Title
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Mechanistic and Pharmacokinetic Studies of Classical Chinese Formula Xiao Chai Hu Tang (XCHT) Against Irinotecan-Induced Gut Toxicities(Clinical Study Part:Randomized Controlled Trial)

Conditions
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Xiao Chai Hu Tang, Irinotecan-induced Diarrhea

Intervention / Treatment
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* Drug: Xiao Chai Hu Tang (XCHT)
* Drug: Placebo
* Drug: FOLFIRI/mXELIRI regimen
* Other: Raloxifene


Participation Criteria
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Eligibility Criteria
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Inclusion criteria: Malignant tumor confirmed by histology or cytology; Age ≥ 18 years old, ≤ 75 years old; ECOG score of the patient ≤ 2 points; Patients who have diarrhea worse than grade 2 due to irinotecan chemotherapy (the last dose of irinotecan is administered within 1 month); Patients who plan to receive 3 cycles of FOLFIRI/mXELIRI chemotherapy; Normal organ functions which can meet the requirements for systemic chemotherapy: Normal bone marrow function: 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; AST & ALT ≤ 5 × ULN if abnormal hepatic functions are caused by a potentially malignant tumor. Patients who can understand and complete the questionnaires in the case report form; Patients who can understand and sign the informed consent form, is well compliant, and can be followed up. Exclusion Criteria: Patients with diagnosed depression, obsession or/and schizophrenia; Patients with diagnosed inflammatory bowel diseases (including Crohn's disease, ulcerative colitis) Patient with active tuberculosis and other uncontrolled infections; Patient who has previously received radiotherapy on the abdominal cavity or pelvic cavity; Pregnant or lactating women; Patient who previously had or is now having thromboembolic events.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: XCHT group<br>Patients will be administered with XCHT (9 g, qd, po) for 5 days each cycle of FOLFIRI/mXELIRI chemotherapy for 3 cycles. The XCHT administration begins 3 days before chemotherapy in each cycle, that is the chemotherapy begins on the 4th day of XCHT administration. Plasma will be collected for pharmacokinetic testing (using raloxifene 60mg po as probe), on the day before chemotherapy, that is on the 3rd day of XCHT administration in each cycle. | Drug: Xiao Chai Hu Tang (XCHT)<br>* XCHT 9g, po qd, 3 days before each cycle of chemotherapy for 5 days, for 3 cycles of chemotherapy.<br>* Other names: Xiao Chai Hu Tang granules from Nin Jiom Medicine Manufactory (Hong Kong) Ltd;Drug: FOLFIRI/mXELIRI regimen<br>* Patients will receive 3 cycles of FOLFIRI/mXELIRI chemotherapy. FOLFIRI regimen:irinotecan (180 mg/m2) intravenous (IV) for over 90 minutes on Day 1. Folinic acid (400 mg/m2) IV over 2 hours on Day 1. 5-fluorouracil (5-FU) IV bolus (400 mg/m2) over 5 minutes on Day 1, followed by 5-FU (2400 mg/m2) IV continuously for 46-48 hours. Every 2 weeks. mXELIRI regimen:irinotecan (200 mg/m2) intravenous (IV) for over 90 minutes on Day 1. Capecitabine (800 mg/m²) PO bid on day 1-14. Every 3 weeks.<br>Other: Raloxifene<br>* Raloxifene 60mg po, used as probe for pharmacokinetic testing, on Day 3 (the day before chemotherapy), for 3 cycles of chemotherapy.<br>|
| Placebo Comparator: Placebo group<br>Patients will be administered with placebo (9 g, qd, po) for 5 days each cycle of FOLFIRI/mXELIRI chemotherapy for 3 cycles. The placebo administration begins 3 days before chemotherapy in each cycle, that is the chemotherapy begins on the 4th day of placebo administration. Plasma will be collected for pharmacokinetic testing (using raloxifene 60mg po as probe), on the day before chemotherapy, that is on the 3rd day of placebo administration in each cycle. | Drug: Placebo<br>* Placebo 9g, po qd, 3 days before each cycle of chemotherapy for 5 days, for 3 cycles of chemotherapy.<br>* Other names: Placebo provided by Nin Jiom Medicine Manufactory (Hong Kong) Ltd;Drug: FOLFIRI/mXELIRI regimen<br>* Patients will receive 3 cycles of FOLFIRI/mXELIRI chemotherapy. FOLFIRI regimen:irinotecan (180 mg/m2) intravenous (IV) for over 90 minutes on Day 1. Folinic acid (400 mg/m2) IV over 2 hours on Day 1. 5-fluorouracil (5-FU) IV bolus (400 mg/m2) over 5 minutes on Day 1, followed by 5-FU (2400 mg/m2) IV continuously for 46-48 hours. Every 2 weeks. mXELIRI regimen:irinotecan (200 mg/m2) intravenous (IV) for over 90 minutes on Day 1. Capecitabine (800 mg/m²) PO bid on day 1-14. Every 3 weeks.<br>Other: Raloxifene<br>* Raloxifene 60mg po, used as probe for pharmacokinetic testing, on Day 3 (the day before chemotherapy), for 3 cycles of chemotherapy.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of diarrhea (grade ≥2) | The diarrhea severity will be evaluated following standard criteria in NCI-CTC AE 5.0 Grade 2 is defined as Stool is increased by 4-6 times each day relative to baseline; discharge from stoma moderately increased. | Through study completion, an average of 2 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of diarrhea (grade ≥3) | The diarrhea severity will be evaluated following standard criteria in NCI-CTC AE 5.0 | Through study completion, an average of 2 months | 
| Incidence of other chemo-related adverse effects | Other adverse reactions will be evaluated following standard criteria in NCI-CTC AE 5.0 | Through study completion, an average of 2 months | 
| Occult blood test for stool | Occult blood test for stool, reported as negative, weak positive, and positive. | Through study completion, an average of 2 months | 
| PK parameters(Cmax) | Cmax ,if with complete data, in each cycle of Cmax for XCHT and their metabolites (14 compounds) and intestinal UGT enzyme probe (raloxifene and metabolites) | The blood samples (2.0 ml) will be collected at 4 points for each cycle(hour 0, hour 1, hour 2, hour 4 after raloxifene administration) | 
| PK parameters(AUC) | AUC 0-24hr, if with complete data, in each cycle of AUC0-24hr for XCHT and their metabolites (14 compounds) and intestinal UGT enzyme probe (raloxifene and metabolites) | The blood samples (2.0 ml) will be collected at 4 points for each cycle(hour 0, hour 1, hour 2, hour 4 after raloxifene administration) | 
| PK parameters(T1/2) | T1/2, if with complete data, in each cycle of T1/2 for XCHT and their metabolites (14 compounds) and intestinal UGT enzyme probe (raloxifene and metabolites) | The blood samples (2.0 ml) will be collected at 4 points for each cycle(hour 0, hour 1, hour 2, hour 4 after raloxifene administration) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Malignant tumor, Irinotecan-induced diarrhea, Xiao Chai Hu Tang, Classical Chinese Formula, pharmacokinetic mechanism