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FOLFOXIRI With or Without Bevacizumab as First-line Treatment for Unresectable Liver-only Metastatic Colorectal Cancer Patients With RAS Mutation-type

NCT02350530

Description:

BACKGROUND: For patients with liver-limited metastatic colorectal cancer (mCRC), complete resection of liver metastases is the only potentially curative treatment. The current goal of medical treatment for colorectal cancer with initially unresectable liver metastases is to maximize the rate of secondary resection and prolong overall survival (OS). A strong correlation was found between response rate and secondary resection rate of metastases, and the triple drugs combination of infusional 5-fluorouracil/leucovorin (5-FU/LV), irinotecan, and oxaliplatin (FOLFOXIRI) was recommended can be used in selected patients with potentially resectable metastases in order to improve response rate and make resection more possible. The addition of a anti-VEGFs monoclonal antibody such as bevacizumab to chemotherapy has been shown to increase response rate, resection rate and improve OS in the first-line treatment of mCRC patients. The efficacy and safety of bevacizumab in addition to triplet drugs were previously tested in OLIVIA trial, the resection rate of liver metastases of 49% was reported, and the response rate was 81%; most common grade 3-4 adverse events was neutropenia. On the basis of such promising results, we conducted the present randomized study to explore whether FOLFOXIRI plus bevacizumab compared with FOLFOXIRI alone as first-line treatment could improve radical resectability in patients with RAS mutation-type, unresectable liver-only metastatic colorectal cancer. OBJECTIVE: The primary objective of the FOBULM study is to evaluate the efficacy of FOLFOXIRI plus bevacizumab compared to FOLFOXIRI alone in patients with initially unresectable liver-limited RAS mutation-type mCRC. Secondary objectives are safety and tolerability of the treatment, efficacy in terms of objective response rate (ORR), OS, progression free survival (PFS), quality of life and an assessment of biomarkers for predictive response and prognosis.

Related Conditions:
  • Colorectal Adenocarcinoma
Recruiting Status:

Unknown status

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: FOLFOXIRI With or Without Bevacizumab as First-line Treatment for Unresectable Liver-only Metastatic Colorectal Cancer Patients With RAS Mutation-type
  • Official Title: A Phase II Study to Evaluate the Surgical Conversion Rate in Patients With RAS Mutation-type Receiving FOLFOXIRI +/- Bevacizumab for Unresectable Colorectal Liver-Limited Metastases

Clinical Trial IDs

  • ORG STUDY ID: GIHSYSU09
  • NCT ID: NCT02350530

Conditions

  • Metastatic Colorectal Cancer

Interventions

DrugSynonymsArms
FOLFOXIRI + BevacizumabBevacizumab, Irinotecan, Oxaliplatin, 5-FluorouracilA (FOLFOXIRI + Bevacizumab)
FOLFOXIRIIrinotecan, Oxaliplatin, 5-FluorouracilB (FOLFOXIRI)

Purpose

BACKGROUND: For patients with liver-limited metastatic colorectal cancer (mCRC), complete resection of liver metastases is the only potentially curative treatment. The current goal of medical treatment for colorectal cancer with initially unresectable liver metastases is to maximize the rate of secondary resection and prolong overall survival (OS). A strong correlation was found between response rate and secondary resection rate of metastases, and the triple drugs combination of infusional 5-fluorouracil/leucovorin (5-FU/LV), irinotecan, and oxaliplatin (FOLFOXIRI) was recommended can be used in selected patients with potentially resectable metastases in order to improve response rate and make resection more possible. The addition of a anti-VEGFs monoclonal antibody such as bevacizumab to chemotherapy has been shown to increase response rate, resection rate and improve OS in the first-line treatment of mCRC patients. The efficacy and safety of bevacizumab in addition to triplet drugs were previously tested in OLIVIA trial, the resection rate of liver metastases of 49% was reported, and the response rate was 81%; most common grade 3-4 adverse events was neutropenia. On the basis of such promising results, we conducted the present randomized study to explore whether FOLFOXIRI plus bevacizumab compared with FOLFOXIRI alone as first-line treatment could improve radical resectability in patients with RAS mutation-type, unresectable liver-only metastatic colorectal cancer. OBJECTIVE: The primary objective of the FOBULM study is to evaluate the efficacy of FOLFOXIRI plus bevacizumab compared to FOLFOXIRI alone in patients with initially unresectable liver-limited RAS mutation-type mCRC. Secondary objectives are safety and tolerability of the treatment, efficacy in terms of objective response rate (ORR), OS, progression free survival (PFS), quality of life and an assessment of biomarkers for predictive response and prognosis.

Detailed Description

      OVERVIEW OF TRIAL DESIGN

      This FOCULM trial is a a two-arm, multicenter, open labelled, prospective, randomized phase
      II studies. Eligible patients with initially unresectable liver-limited mCRC will be
      randomised 1:1 to receive either FOLFOXIRI plus bevacizumab or FOLFOXIRI alone.
    

Trial Arms

NameTypeDescriptionInterventions
A (FOLFOXIRI + Bevacizumab)ExperimentalFOLFOXIRI + Bevacizumab
  • FOLFOXIRI + Bevacizumab
B (FOLFOXIRI)Active ComparatorFOLFOXIRI
  • FOLFOXIRI

Eligibility Criteria

        Inclusion Criteria:

          1. Willing and able to provide written informed consent

          2. Histological or cytological documentation of adenocarcinoma of the colon or rectum.

          3. Male or female subjects > 18 years < 70 of age.

          4. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.

          5. There must be documentation by CT scan, MRI, or intraoperative palpation that the
             patient has evidence of metastases confined to the liver.

          6. The liver metastases must have been assessed by multidisciplinary team including
             hepatic surgeon approved to participate in the study to be unresectable based on at
             least one of the four criteria: 1. All of the liver metastases can not be completed
             resected with negative margins; 2. No ability to preservation of two contiguous
             hepatic segments; 3. No ability to preservation of adequate vascular inflow and
             outflow as well as biliary drainage; 4. Complete resection would require greater than
             70% of the liver parenchyma to be removed.

          7. The colorectal primary tumor or metastatic tumor must be determined to be KRAS (exon 2
             at codon 12 and 13; exon 3 at codon 59 and 61; exon 4 at codon 117 and 146) or NRAS
             (exon 2 at codon 12 and 13; exon 3 at codon 59 and 61; exon 4 at codon 117 and 146)
             mutation-type.

          8. Primary tumor and regional nodes were resected with clear surgical margins or;
             unresected primary tumor with plan to radical resect the primary tumor.

          9. No previous any systemic anticancer therapy for metastatic disease (adjuvant
             chemotherapy for non-metastatic disease is allowed if terminated more than 6 months
             ago).

         10. Adequate bone marrow, hepatic and renal function as assessed by the following
             laboratory requirements conducted within 7 days of starting study treatment:
             Hemoglobin (Hb) ≥ 90g/ L, absolute neutrophil count (ANC) ≥ 1.5×109/ L, platelet count
             ≥ 100×109/ L; Total bilirubin ≤ 1.5×the upper limit of normal (ULN), alanine
             aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 5 ×ULN; Serum creatinine
             ≤1.5×the ULN.

        Exclusion Criteria:

          1. Any evidence of extrahepatic metastases, lymph node (including portal lymph nodes)
             metastases and primary tumor recurrence.

          2. Previous hepatic resection and/or ablation, hepatic arterial infusion therapy,
             radiation therapy to the liver.

          3. Previous or concurrent cancer that is distinct in primary site or histology from
             colorectal cancer within 5 years prior to randomization.

          4. Significant cardiovascular disease including unstable angina or myocardial infarction
             within 6 months before initiating study treatment.

          5. Heart failure grade III/IV (NYHA-classification).

          6. Unresolved toxicity higher than CTCAE v.4.0 Grade 1 attributed to any prior
             therapy/procedure.

          7. Subjects with known allergy to the study drugs or to any of its excipients.

          8. Current or recent (within 4 weeks prior to starting study treatment) treatment of
             another investigational drug or participation in another investigational study.

          9. Breast- feeding or pregnant women

         10. Lack of effective contraception.
      
Maximum Eligible Age:70 Years
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:The conversion rate of liver metastases
Time Frame:8 months
Safety Issue:
Description:Defined as the proportion of patients who had a curative liver treatment following protocol treatment, i.e., liver metastases that can be radical resected with or without ablation with no postoperative evidence of residual malignant disease.

Secondary Outcome Measures

Measure:Toxicity assessed using the NCI common toxicity criteria, version 4.0.
Time Frame:8 months
Safety Issue:
Description:The grade of toxicity will be assessed using the NCI common toxicity criteria, version 4.0.
Measure:Response rate
Time Frame:8 months
Safety Issue:
Description:CR + PR rate will be assessed according to the RECIST version 1.1 guidelines.
Measure:Overall survival time
Time Frame:5 years
Safety Issue:
Description:Estimated from the date of randomization to death from any cause.
Measure:Progression free survival
Time Frame:2 years
Safety Issue:
Description:Time measured from the day of randomization to the date of first documented progression, or death from any cause.
Measure:Quality of life (QLQ C30)
Time Frame:Every 2 weeks after the first treatment until 6 months
Safety Issue:
Description:Scores according to EORTC QLQ-C30 scoring manual

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Sun Yat-sen University

Trial Keywords

  • Colorectal cancer
  • Metastatic colorectal cancer
  • Liver metastases
  • Liver resection
  • Liver ablation
  • Conversion therapy
  • FOLFOXIRI
  • Oxaliplatin
  • Irinotecan
  • Fluorouracil
  • Bevacizumab
  • RAS mutation

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