A Phase I/II Study of XELOXIRI and Bevacizumab as First-line Treatment in Metastatic Colorectal Cancer

Study Overview
=================
Brief Summary
-----------------
The phase I/II study was designed to evaluate if the regimen of Irinotecan, Oxaliplatin, Capecitabine (XELOXIRI) and Bevacizumab is a superior first-line option for patients with metastatic colorectal cancer(mCRC) in terms of safety and efficacy.

Detailed Description
-----------------
Recent studies have shown that the triplet-drug regimen FOLFOXIRI (irinotecan/oxaliplatin/fluorouracil) can further improves survival benefit for patients with metastatic colorectal cancer(mCRC) compared to standard two-drug regimens in first-line therapy, especially when combined with bevacizumab. However, the increased toxicities of FOLFOXIRI limited its usage. Capecitabine demonstrates a superior efficacy and safety than fluorouracil, so we designed this trial to evaluate if the XELOXIRI plus bevacizumab can be a better alternative to FOLFOXIRI plus bevacizumab. The phase I study is to determine the safety and the recommended phase II dose (RP2D) of XELOXIRI plus Bevacizumab. In the phase II study, we aim to determine the efficacy of the regimen as first-line therapy for mCRC and explore potential molecular biomarkers (genomes, circulating tumor cell) for toxicity forecasting or efficacy monitoring.

Official Title
-----------------
A Phase I/II Study of Irinotecan, Oxaliplatin, Capecitabine (XELOXIRI) and Bevacizumab as a First-line Therapy for Patients With Metastatic Colorectal Cancer

Conditions
-----------------
Metastatic Cancer, Colorectal Cancer, Colorectal Adenocarcinoma

Intervention / Treatment
-----------------
* Drug: XELOXIRI/Bevacizumab


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Patients with histologically confirmed metastatic colorectal adenocarcinoma; Age 18-80 years old; Eastern Cooperation Oncology Group (ECOG) performance score(<2); At least one measurable lesion for disease assessment according to RECIST version 1.1; Able to take oral medications; Previous fluoropyrimidine-based adjuvant or neoadjuvant chemotherapy was allowed only when it ended ≥ 6 months before study enrollment; No previous therapy for mCRC; Adequate organ functions as assessed by the following laboratory requirements: Leukocytes≥3.0x109/L, absolute neutrophil count≥1.5x109/L, platelet count≥100x109/L, hemoglobin≥9g/dL; serum bilirubin≤1.5x the upper limit of normal(ULN);Alanine aminotransferase(ALT) and aspartate aminotransferase(AST)≤3x ULN; serum creatinine≤1.5x ULN; calculated creatinine clearance or 24 hour creatinine clearance ≥60ml/min. An expected survival of at least 3 months; Willingly provide written informed consent to study procedures. Exclusion Criteria: Patients with dysphagia, active peptic ulcer, intestinal obstruction, active gastrointestinal bleeding, peptic perforation, malabsorption syndrome or uncontrolled intestinal inflammatory diseases; With a history of extensive enterotomy or pelvic radiation therapy; Suffering from grade 2 or higher symptomatic peripheral neuropathy according to National Cancer Institute Common Toxicity (NCI-CTC) criteria; Uncontrolled central nervous system metastasis, disseminated intravascular coagulation or active infection; With concurrent cancer distinct from colorectal adenocarcinoma except cured skin basal cell carcinoma and cervical carcinoma in situ; Undergone a major operation, open biopsy or major traumatic injury within 28 days before study enrollment or have potential to receive major operation during the trial; Received central venous access device within 2 days before study enrollment; Any kind of concurrent cardiac disease with clinical meanings, such as cardiovascular accident, myocardial infarction, thromboembolism or hemorrhage within 6 months before enrollment, congestive heart failure ≤New York Heart Association (NYHA) class 2 or uncontrolled hypertension. With positive urine protein and 24-hour urinary protein content>1g; Have a tendency of bleeding or clotting; With nasty open wounds, ulcers or fractures; Current or recent treatment of anticoagulants, antiplatelet agent or nonsteroidal anti-inflammatory drugs, while aspirin of daily dose less than 325mg is allowed. With any illness or medical conditions that may jeopardize the patient's compliance or interfere the analyses or judgements of study results; Pregnancy or lactation at the time of study entry; With fertility but refuse to contraception.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 70 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: XELOXIRI/Bevacizumab<br>drugs: Irinotecan, Oxaliplatin, Capecitabine, Bevacizumab bevacizumab 5mg/kg on day1, irinotecan 150mg/m2 or 165mg/m2 on day1, oxaliplatin 85mg/m2 on day1 and capecitabine 1000mg/m2 twice a day on day1-7, administered every 2 week for 12 cycles, after 12 cycles, administer bevacizumab 5mg/kg on day 1 and capecitabine 1000mg/m2 twice a day on day1-7 as maintenance therapy. | Drug: XELOXIRI/Bevacizumab<br>* bevacizumab 5mg/kg on day1, irinotecan 150mg/m2 or 165mg/m2 on day1, oxaliplatin 85mg/m2 on day1 and capecitabine 1000mg/m2 twice a day on day1-7 repeated every 2 week for 12 cycles, after 12 cycles, bevacizumab 5mg/kg on day 1 and capecitabine 1000mg/m2 twice a day on day1-7 as maintenance therapy repeated every 2 week<br>* Other names: Irinotecan, Oxaliplatin, Capecitabine, Bevacizumab;|

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

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| dose-limited toxicity (DLT) | dose limited toxicities are evaluated in the phase I study according to CTCAE v5.0 and reviewed through the phase I study completion | up to 1 year | 
| maximum tolerated dose (MTD) | MTD is determined according to the DLT in the phase I study | up to 1 year | 
| recommended phase 2 dose (RP2D) | RP2D is determined according to DLT and MTD in the phase 1 study | up to 1 year | 
| objective response rate (ORR) | ORR is defined as the proportion of patients achieving complete response or partial response | up to 2 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Adverse events (AEs) | Adverse events assessments are computed and categorized according to the Common Toxicity Criteria of the National Cancer Institute, version 5.0 | though study completion, an average of 2 years | 
| progression-free survival (PFS) | PFS is defined as the time from randomization to the earliest evidence of disease progression (per RECIST v1.1), or death from any cause | though study completion, an average of 2 years | 
| overall survival (OS) | OS is defined as the time from randomized to death from any cause or to last contact | up to 5 years | 
| disease control rate (DCR) | DCR is defined as the proportion of patients achieving complete response, partial response or having stable disease | up to 2 years | 
| duration of response (DOR) | DOR is defined as the length from the first response occured to disease progression | though study completion, an average of 2 years | 
| time to response (TTR) | TTR is defined as the length from randomization to the first response occured. | up to 2 years | 
| the surgical resection rate of patients with liver-only metastases | the percentage of patients with liver-only metastases undergoing surgical resections during the trial therapy | up to 2 years | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
XELOXIRI, metastatic colorectal cancer, metastatic colorectal adenocarcinoma, bevacizumab