Trifluridine/Tipiracil Combined With Oxaliplatin and Bevacizumab Versus XELOX Plus Bevacizumab in mCRC (TOBACO)

Trifluridine/Tipiracil Combined With Oxaliplatin and Bevacizumab Versus XELOX Plus Bevacizumab in the First-line Treatment of Advanced Colorectal Cancer (TOBACO): a Randomized, Controlled, Phase II Study

This is a two-group, parallel, randomized, standard-control phase II study comparing the safety and efficacy of trifluridine/tipiracil combined with oxaliplatin and bevacizumab versus XELOX plus bevacizumab in the first-line treatment of advanced colorectal cancer. This study was conducted in the Department of Gastrointestinal Medical Oncology, Tianjin Medical University Cancer Institute and Hospital.

Patients with advanced colorectal cancer will be randomly assigned (1:1) to trifluridine/tipiracil combined with oxaliplatin and bevacizumab (experimental group) or XELOX plus bevacizumab (control group) after signing informed consent. In this study, 184 patients will be enrolled, 92 patients will receive trifluridine/tipiracil combined with oxaliplatin and bevacizumab and 92 patients will receive standard therapy.

In the experimental group, the treatment regimen is trifluridine/tipiracil 35mg/m2 orally taken on d1-5 and d8-12, oxaliplatin 85mg/m2 and bevacizumab 5mg/kg intravenously infused on d1 and d15 every 4 weeks, up to 6 cycles. Then patients will be given trifluridine/tipiracil and bevacizumab maintenance treatment. Patients enrolled in this group could acquire trifluridine/tipiracil free of charge.

The control group was XELOX plus bevacizumab regimen, bevacizumab 7.5mg/kg, d1 oxaliplatin 130mg/m2, d1, capecitabine 1000mg/m2, orally, bid (half an hour after breakfast and dinner), d1-14, every 3 weeks, up to 8 cycles. Then patients will be given capecitabine and bevacizumab maintenance treatment.

Patients received regular and periodic reviews, with imaging evaluations every 8 weeks. Safety will be evaluated by AE and laboratory tests. All patients were followed up every 3 months until death according to the plan.

Study Overview

• Status: Recruiting
• Conditions: Advanced Colorectal Cancer; First-line Treatment
• Intervention / Treatment: Drug: Trifluridine/Tipiracil

• Study Type: Interventional
• Enrollment (Anticipated): 184
• Phase: Phase 2

Contacts and Locations

Study Locations

• China
  • Tianjin, China
    • Recruiting
    • Tianjin Medical University Cancer Institute and Hospital
    • Contact: Yi Ba, MD; Phone Number: 022-23340123-1053; Email: bayi@tjmuch.com

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Signed the informed consent.
2. Age ≥18.
3. Colonic adenocarcinoma confirmed histologically or histopathologically.
4. No previous chemotherapy for advanced colorectal cancer, or patients who had received adjuvant chemotherapy after radical resection and relapsed 12 months after the completion of adjuvant chemotherapy.
5. ECOG physical status score is 0 or 1.
6. There are measurable metastatic lesions according to RECIST version 1.1.

7. Appropriate organ function according to the following laboratory test values obtained within 7 days prior to use on Day 1 of Cycle 1:

   1. Hemoglobin value ≥9.0g/dL.
   2. Absolute neutrophil count ≥1,500/mm3 (≥1.5*109/L).
   3. Platelet count ≥100,000/mm3 (≥100*109/L).
   4. Total serum bilirubin ≤1.5* upper normal limit (ULN).
   5. Aspartate aminotransferase (AST/SGOT) and alanine aminotransferase (ALT/SGPT) ≤2.5* upper limit of normal value (ULN). If the abnormal liver function is due to liver metastasis, AST and ALT should be ≤5*ULN.
   6. Serum creatinine ≤1.5 times * upper limit of normal (ULN) or creatinine clearance ≥50ml/min.
8. The results of urine or serum pregnancy test within 7 days prior to treatment were negative. Women who are likely to become pregnant and men must agree to take adequate contraceptive measures during the study period until 6 months after the end of medication.
9. Survival is expected to be at least 3 months.
10. Willing and able to follow research procedures and visit plans.

Exclusion Criteria:

1. Has a serious illness or medical condition, including but not limited to the following:

   1. There are other active malignant tumors at the same time, excluding those that have not occurred for more than 5 years or carcinoma in situ that can be cured by adequate treatment.
   2. Known presence of brain metastases or leptomeningeal metastases.
   3. Systemic active infection (i.e., infection causes body temperature ≥38℃).
   4. Clinically significant intestinal obstruction, pulmonary fibrosis, renal failure, liver failure, or symptomatic cerebrovascular disease.
   5. Uncontrolled diabetes.
   6. Severe/unstable angina, New York Heart Association (NYHA) grade III or IV symptomatic congestive heart failure.
   7. Gastrointestinal bleeding of clinical significance.
   8. Known presence of human immunodeficiency virus (HIV) or acquired routine immunodeficiency syndrome (AIDS) -associated disease, or active hepatitis B or C.
   9. There are psychiatric disorders that may increase the risk associated with participating in the study or taking the study drugs, or may interfere with the interpretation of the study results.

2. Any of the following treatments were received within a specific time frame before the study drug was taken:

   1. Major surgery in the previous 4 weeks. (Major surgery refers to laparotomy, thoracotomy, and laparoscopic resection of internal organs. On-off of abdomen was excluded)
   2. Radiotherapy with extended field within the previous 4 weeks or radiotherapy with limited field within the previous 2 weeks.
   3. Any investigational drugs within the previous 4 weeks.
3. Presence of neurotoxicity of CTCAE grade 2 or above caused by adjuvant therapy.
4. Pregnant or lactating women.
5. The researcher did not consider it appropriate to enter the study.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: experimental group; In the experimental group, the treatment regimen is trifluridine/tipiracil 35mg/m2 orally taken on d1-5 and d8-12, oxaliplatin 85mg/m2 and bevacizumab 5mg/kg intravenously infused on d1 and d15 every 4 weeks, up to 6 cycles. Then patients will be given trifluridine/tipiracil and bevacizumab maintenance treatment.	Drug: Trifluridine/Tipiracil; Trifluridine/tipiracil was approved in the third-line treatment of advanced colorectal cancer. Its efficacy in the first-line treatment was unknown.; Other Names: TAS-102
No Intervention: control group; The control group was XELOX plus bevacizumab regimen, bevacizumab 7.5mg/kg, d1 oxaliplatin 130mg/m2, d1, capecitabine 1000mg/m2, orally, bid (half an hour after breakfast and dinner), d1-14, every 3 weeks, up to 8 cycles. Then patients will be given capecitabine and bevacizumab maintenance treatment.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
ORR	the rate of patients with PR and CR	48 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
PFS	The time from the beginning of randomization to the time when the disease progresses or the patient dies from any cause.	48 months
OS	The time from the beginning of randomization to the time when the patient dies from any cause.	48 months

Collaborators and Investigators

• Sponsor: Tianjin Medical University Cancer Institute and Hospital

Study record dates

Study Major Dates

• Study Start (Actual): September 1, 2021
• Primary Completion (Anticipated): August 31, 2024
• Study Completion (Anticipated): August 31, 2025

Study Registration Dates

• First Submitted: September 23, 2021
• First Submitted That Met QC Criteria: October 11, 2021
• First Posted (Actual): October 14, 2021

Study Record Updates

• Last Update Posted (Actual): October 25, 2021
• Last Update Submitted That Met QC Criteria: October 15, 2021
• Last Verified: September 1, 2021

More Information

Terms related to this study

• Keywords: Trifluridine/tipiracil; first-line treatment; advanced colorectal cancer
• Additional Relevant MeSH Terms: Digestive System Diseases; Neoplasms; Neoplasms by Site; Gastrointestinal Neoplasms; Digestive System Neoplasms; Gastrointestinal Diseases; Colonic Diseases; Intestinal Diseases; Intestinal Neoplasms; Rectal Diseases; Colorectal Neoplasms; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Antiviral Agents; Antimetabolites; Trifluridine
• Other Study ID Numbers: TJMUCH-GI-CRC03

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No