The Efficacy of Bevacizumab Combined With m-FOLFOXIRI in Borderline Resectable Colorectal Liver Metastases (CBL)

Study to Investigate Efficacy of Bevacizumab Combined With Modified-FOLFOXIRI in Patients With Borderline Resectable Colorectal Liver Metastases

This single-arm study will evaluate the resection rate of liver metastases in patients with metastatic colorectal cancer and borderline unresectable liver metastases receiving treatment with bevacizumab in combination with modified-FOLFOXIRI as first line treatment. Patients will receive bevacizumab (5 mg/kg) plus modified-FOLFOXIRI (irinotecan 150 mg/m2, oxaliplatin 85 mg/m2, leucovorin 200 mg/m2, and fluorouracil 2400 mg/m2 as a 46-h continuous infusion) every 14 days as neoadjuvant chemotherapy regimen. This study treatment will continue until surgery, disease progression, unacceptable toxicity, or patient refusal.

Study Overview

• Status: Unknown
• Conditions: Colorectal Cancer
• Intervention / Treatment: Drug: bevacizumab; Drug: Oxaliplatin; Drug: Irinotecan; Drug: Leucovorin; Drug: 5-FU

Detailed Description

This is a phase II study to investigate the efficacy of biweekly bevacizumab in combination with modified-FOLFOXIRI regimen, as first-line chemotherapy in patients with borderline resectable colorectal liver metastases. Borderline resectable liver metastases are considered to have poor-risk diseases infeasible for upfront resection, but own the potential for resection after down-staging. The primary purpose of the study is to determine the resection rate of liver metastases in patients receiving this combination regimen. The secondary objectives are to determine the response rate, progression free survival, overall survival, and safety profiles.

Eligible patients will receive a triplet chemotherapy consisting of bevacizumab (5 mg/kg) plus modified-FOLFOXIRI (irinotecan 150 mg/m2, oxaliplatin 85 mg/m2, leucovorin 200 mg/m2, and fluorouracil 2400 mg/m2 as a 46-h continuous infusion) every 14 days as a cycle. Resectability of primary tumor and liver metastases will be assessed after five cycles of combination treatment with feasible image exams. Patients with progressive disease will be discontinued in this study. For patients feasible for tumor resection, the modified triplet chemotherapy without bevacizumab combination will be continued for one other cycle for patients before surgery. If patients don't reach both the feasibility of tumor resection and progressive disease, another four cycles of bevacizumab combined with modified-FOLFOXIRI could be continued by investigator's judgement. Reassessment of resectability for primary tumor and liver metastases will be conducted using feasible image exams after a total of 9 cycles of combination treatment in these patients. Similarly, the triplet chemotherapy without bevacizumab combination will be continued for the other one cycle before surgery for these patients feasible for tumor resection after reassessment. Bevacizumab should be stopped at least 4 weeks before the planned day of surgery. Short-course radiotherapy will be allowed before surgery for patients with rectal cancer. All patients will be discontinued in this study after tumor resection. Treatment will also be discontinued if the patient requests or the investigator decides that therapy should be withdrawn. Further tumor treatment after treatment discontinuation will be decided based on investigator's judgement with the best knowledge.

• Study Type: Interventional
• Enrollment (Anticipated): 40
• Phase: Phase 2

Contacts and Locations

Study Locations

• Taiwan
  • Tainan, Taiwan
    • Recruiting
    • National Cheng-Kung University Hospital
    • Contact: Jean Yang
    • Principal Investigator: Shang Hung Chen

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 20 years to 75 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Histologically proven diagnosis of colorectal cancer.
2. Borderline resectable liver metastases of colorectal cancer considered to have poor-risk disease not deemed to be suitable for upfront resection if they had one or more of the following features assessed by a local multidisciplinary team: more than four metastases, any liver lesion with diameter >5 cm, location and distribution of metastatic disease within the liver unsuitable for resection with clear margins (e.g. involvement of both lobes of liver, invasion of intrahepatic vascular structures), extent of liver involvement precluding resection with adequate post-resection residual liver parenchyma volume for viable liver function in the immediate postoperative period, and inability to retain adequate vascular inflow and outflow to maintain viable liver function.
3. At least one measurable lesion according to RECIST criteria.
4. Age 20-75 years.
5. ECOG performance < 1 if age < 70 years, ECOG PS = 0 if age = 70-75 years.
6. Life expectancy of at least 12 weeks.
7. Neutrophils ≥1.5 x 109/L, Platelets≥ 100 x 109/L, Hgb ≥10 g/dl.
8. Total bilirubin ≤1.5 time the upper-normal limits (UNL) of the Institutional normal values and ASAT (SGOT) and/or ALAT (SGPT) ≤5 x UNL, alkaline phosphatase ≤5 x UNL.
9. Serum creatinine≤ 1.5 x UNL.
10. Patients discovered to have proteinuria on urinalysis at baseline, should undergo a 24-hour urine collection and must demonstrate ≤1 g of protein/24 hr.
11. Written informed consent.

Exclusion Criteria:

1. Prior neoadjuvant or adjuvant chemotherapy completed <6 months.
2. Prior chemotherapy for metastatic disease.
3. Any extrahepatic metastases.
4. History or evidence upon physical examination of CNS disease unless adequately treated (e.g., seizure not controlled with standard medical therapy or history of stroke).
5. Serious, non-healing wound, ulcer, or bone fracture.
6. Evidence of bleeding diathesis or coagulopathy.
7. Uncontrolled hypertension.
8. Clinically significant (i.e. active) cardiovascular disease for example cerebrovascular accidents (≤6 months), myocardial infarction (≤ 6 months), unstable angina, New York Heart Association (NYHA) grade II or greater congestive heart failure, serious cardiac arrhythmia requiring medication.
9. Current or recent (within 10 days prior to study treatment start) ongoing treatment with anticoagulants for therapeutic purposes.
10. Chronic daily treatment with aspirin .
11. Patients with known allergy to Chinese hamster ovary cell proteins, or any of the components of the study medications.
12. Other co-existing malignancies or malignancies diagnosed within the last 5 years with the exception of sin basal cell carcinoma or cervical cancer in situ.
13. Major surgical procedure, open biopsy, or significant traumatic injury within 28 days prior to study treatment start, or anticipation of the need for major surgical procedure during the course of the study.
14. Other severe systemic diseases without stable medical control.
15. Pregnant or lactating women.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: bevacizumab+mFOLFOXIRI	Drug: bevacizumab; 5mg/kg iv day 1 every 2 weeks; Drug: Oxaliplatin; 85mg/m2 2-hour iv infusion, day 1 every 2 weeks; Drug: Irinotecan; 150mg/m2 1.5-hour iv infusion, day 1 every 2 weeks; Drug: Leucovorin; 200mg/m2 2-hour iv infusion, day 1 every 2 weeks; Drug: 5-FU; 2400mg/m2 46-hour continuous iv infusion, day 1 every 2 weeks

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Resection rate of liver metastases	The percentage of the number of subjects with R0 and R1 resection after treatment.	6 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Tumor response rate	The percentage of the number of subjects with tumor response after combination treatment evaluated using the RECIST criteria version 1.1.	6 months
Progression free survival	Time duration measured from the day of registration until the first observation of disease progression based on image exam findings or investigator clinical judgement.	5 years
Overall survival	Time duration between the day of registration and the date of death or the last date the patient was known to be alive.	5 years
Percentage of adverse effects related to combination treatment	The percentage of subjects with adverse effects related to combination treatment evaluated using the CTCAE criteria version 4.03.	5 years

Collaborators and Investigators

• Sponsor: National Cheng-Kung University Hospital
• Investigators: Principal Investigator: Shang Hung Chen, National Health Research Institutes, Taiwan

Study record dates

Study Major Dates

• Study Start (Actual): January 8, 2019
• Primary Completion (Anticipated): October 30, 2020
• Study Completion (Anticipated): October 30, 2020

Study Registration Dates

• First Submitted: October 12, 2018
• First Submitted That Met QC Criteria: October 16, 2018
• First Posted (Actual): October 18, 2018

Study Record Updates

• Last Update Posted (Actual): March 13, 2019
• Last Update Submitted That Met QC Criteria: March 12, 2019
• Last Verified: March 1, 2019

More Information

Terms related to this study

• Keywords: bevacizumab; FOLFOXIRI; colorectal liver metastases
• Additional Relevant MeSH Terms: Pathologic Processes; Neoplasms; Neoplastic Processes; Neoplasm Metastasis; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antineoplastic Agents; Protective Agents; Topoisomerase Inhibitors; Antineoplastic Agents, Immunological; Angiogenesis Inhibitors; Angiogenesis Modulating Agents; Growth Substances; Growth Inhibitors; Micronutrients; Vitamins; Topoisomerase I Inhibitors; Antidotes; Vitamin B Complex; Oxaliplatin; Bevacizumab; Leucovorin; Irinotecan
• Other Study ID Numbers: IIT-10

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