Phase I Study of Biweekly SIRB Regimen for Metastatic Colorectal Cancer

Study Overview
=================
Brief Summary
-----------------
Phase I Study of biweekly combination therapy with S-1, Irinotecan, and Bevacizumab as 1-line Chemotherapy in Patients With Advanced Colorectal Cancer.

Detailed Description
-----------------
In several clinical studies from Japan and South Korea, the combination regimen of S-1 and irinotecan has shown efficacy in the treatment of advanced colorectal cancer, and a Phase III study（TRICOLORE） showed that the combination therapy with S-1/irinotecan/bevacizumab (a 3-week regimen [SIRB] or 4-week regimen [IRIS/bevacizumab]) is not inferior to the oxaliplatin-based standard treatment (mFOLFOX6/bevacizumab or CapeOX/bevacizumab) in patients with metastatic colorectal cancer who had not previously received chemotherapy. Here, we design this phase I study to explore the Chinese population's tolerability and efficacy of Biweekly SIRB Regimen(S-1/irinotecan/bevacizumab) and to explore the recommended dose of irinotecan in this regimen.

Official Title
-----------------
Phase I Study of Combination Therapy With S-1, Irinotecan, and Bevacizumab as 1-line Chemotherapy in Patients With Advanced Colorectal Cancer.

Conditions
-----------------
Metastatic Colorectal Cancer

Intervention / Treatment
-----------------
* Drug: S-1
* Drug: Irinotecan
* Drug: Bevacizumab


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Histologically confirmed colorectal carcinoma with inoperable, locally advanced, or metastatic disease, not amenable to curative therapy Measurable disease or non-measurable but assessable disease according to the Response Evaluation Criteria in Solid Tumors (RECIST) Patients with no previous treatment (radiotherapy or chemotherapy). Patients who have received postoperative adjuvant chemotherapy are eligible if relapse is diagnosed more than 180 days after the end of such treatment. Age ≥20 years Life expectancy of at least 3 months ECOG PS of 0 or 1 Adequate function of major organs as defined below: Hemoglobin ≥9.0g/dL White blood cell count ≥3,500/mm3 Neutrophil count ≥1,500/mm3 Platelet count ≥100,000/mm3 AST and ALT ≤100 U/L (<200 U/L in patients with liver metastasis) Serum creatinine ≤1.2 mg/dL Creatinine clearance estimate by the Cockcroft-Gault method >50 mL/min (reduce initial dosage by one step if ≥50 but <80 mL/min) Able to take capsules orally. No electrocardiographic abnormalities within 28 days before enrollment that would clinically preclude the execution of the study, as judged by the investigator. Voluntary written informed consent. Exclusion Criteria: Serious drug hypersensitivity or a history of drug allergy Active double cancer Active infections (e.g., patients with pyrexia of 38℃ or higher) History of gastrointestinal perforation, intestinal tract paralysis, or ileus within 1 year. Uncontrolled hypertension Serious complications (e.g., pulmonary fibrosis, interstitial pneumonitis, heart failure, renal failure, hepatic failure, or poorly controlled diabetes) Moderate or severe ascites or pleural effusion requiring treatment Watery diarrhea Treatment with flucytosine or atazanavir sulfate Metastasis to the CNS Pregnant women, possibly pregnant women, women wishing to become pregnant, and nursing mothers. Men who are currently attempting to conceive children. Severe mental disorder Continuous treatment with steroids Urine dipstick for proteinuria should be <2+ Patient with a past history of thrombosis, cerebral infarction, myocardial infarction, or pulmonary embolism Major surgical procedure, open biopsy, or clinically significant traumatic injury within 4 weeks Long-term daily treatment with aspirin (>325 mg/day) History or evidence of inherited bleeding diathesis or coagulopathy with the risk of bleeding Judged ineligible for participation in the study by the investigator for safety reasons.

Ages Eligible for Study
-----------------
Minimum Age: 20 Years
Maximum Age: 75 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: SIRB2<br>Biweekly combination therapy with S-1, Irinotecan, and Bevacizumab | Drug: S-1<br>* - S-1 is administered orally on days 1 to 7 of a 14-day cycle. Patients are assigned on the basis of body surface area (BSA) to receive one of the following oral doses twice daily: 40 mg (BSA <1.25m2), 50 mg (BSA >1.25 to <1.50 m2), or 60 mg (BSA >1.50 m2).<br>* Other names: S1;Drug: Irinotecan<br>* - CPT-11 was administrated as a 90-min intravenous infusion on day 1 of a 14-day cycle. Five escalating dose levels of CPT-11 were prepared, at an initial dose of 75mg/m2/day (level 1), stepping up to 100 (level 2), 125 (level 3), 150 (level 4) or 175 (level 5) mg/m2/day.<br>* Other names: CPT-11;Drug: Bevacizumab<br>* - Bevacizumab (5 mg/kg) is administered by intravenous infusion over the course of 30 to 90 min on day 1 of each 2-week cycle.<br>* Other names: Avastin;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum tolerance dose | Maximum tolerance dose (MTD) is the dose of treatment in the cohort where there are 2 cases of DTL reported. | From enrollment to completion of study. Estimated about 12 months. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Dose limiting toxicity | Dose limiting toxicity (DLT) is referred to grade 3 non-hematological toxicity or grade 4 hematological toxicity according to NCI CTCAE 4.03 criteria. | From enrollment to completion of study. Estimated about 12 months. | 
| Objective response rate | Clinical response of treatment according to RESIST v1.1 criteria (ORR, objective response rate). | From enrollment to 6 months after treatment. | 
| Progression-free survival | The length of time from enrollment until the time of progression of disease (PFS, progression-free survival). | From enrollment to progression of disease. Estimated about 6 months. | 
| Overall survival | The length of time from enrollment until the time of death (OS, overall survival). | From enrollment to death of patients. Estimated about 1 year. |