Bevacizumab + Triplet Treatment for Untreated With Chemotherapy Metastatic Colorectal Cancer (BeTRI)

Phase II Trial of FOLFOXIRI + Bevacizumab in Patients With Untreated Metastatic Colorectal Cancer

The purpose of this study is to evaluate the efficacy and safety of fluorouracil (5-FU), levofolinate calcium (l-LV), oxaliplatin (L-OHP) and irinotecan hydrochloride hydrate (CPT-11) (FOLFOXIRI) plus bevacizumab in untreated metastatic colorectal cancer patients who harbor Uridine diphosphate (UDP)-glucuronosyl transferase 1A1 (UGT1A1) *1/*1, *1/*6 or *1/*28.

Study Overview

• Status: Completed
• Conditions: Metastatic Colorectal Cancer
• Intervention / Treatment: Drug: Oxaliplatin (L-OHP); Drug: Irinotecan hydrochloride hydrate (CPT-11); Drug: Continuous intravenous infusion of fluorouracil (CIV 5-FU); Drug: Levofolinate calcium (l-LV); Drug: Bevacizumab (Bmab)

• Study Type: Interventional
• Enrollment (Anticipated): 45
• Phase: Phase 2

Contacts and Locations

Study Locations

• Japan
  • Ehime-prefecture
    • Matsuyama-city, Ehime-prefecture, Japan, 790-8524
      • Matsuyama Red Cross Hospital
  • Kagawa-prefecture
    • Kita-gun, Miki-cho, Kagawa-prefecture, Japan, 761-0793
      • Kagawa University Hospital
  • Okayama-prefecture
    • Kurashiki-city, Okayama-prefecture, Japan, 701-0192
      • Kawasaki Medical School Hospital
    • Okayama-city, Okayama-prefecture, Japan, 700-8511
      • Okayama Saiseikai General Hospital
    • Okayama-city, Okayama-prefecture, Japan, 700-8558
      • Okayama University Hospital
    • Okayama-city, Okayama-prefecture, Japan, 702-8055
      • Okayama Rosai Hospital
  • Tokushima-prefecture
    • Komatsushima-city, Tokushima-prefecture, Japan, 773-8502
      • Tokushima Red Cross Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years to 66 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Histologically confirmed adenocarcinoma of the colon or rectum.
2. Unresectable or recurrent colorectal cancer patient.
3. One or more measurable lesion in RECIST ver.1.1 criteria.
4. No prior chemotherapy, immunotherapy, and radiotherapy.
5. Life expectancy at least 3 months.
6. Patients who harbor UGT1A1*1/*1, *1/*6 or *1/*28.
7. The Eastern Cooperative Oncology Group (ECOG) performance status of =<1.

8. Vital organ functions (listed below) are preserved within 14 days prior to entry.

   White blood cell count (WBC): >= 3,000 per cubic millimeter Neu: >= 1,500 per cubic millimeter Platelet count (PLT): >= 100,000 per cubic millimeter Aspartate aminotransferase (AST/GOT) and alanine aminotransferase (ALT/GPT): <= 100 IU/L, <= 150 IU/L in cases with liver metastasis T-bil: <= 1.5 mg/dL Serum creatinine: <= 1.50 mg/dL Proteinuria: <= 1+ Prothrombin time-international normalized ratio (PT-INR): < 1.5

9. Written informed consent.

Exclusion Criteria:

1. Vermiform appendix cancer and anal canal cancer.
2. Administration of blood products/ granulocyte-colony stimulating factor (G-CSF), and blood transfusion within 14 days prior to enrollment.
3. Synchronous multiple malignancy or metachronous multiple malignancy less than 5 years disease free interval.
4. Hepatitis B virus antigen (HBs-Ag)(+), or hepatitis C virus antibody (HCV-Ab)(+).
5. History of severe allergy.
6. Sensory alteration or paresthesia interfering with function.
7. Prior radiotherapy for ilium and abdomen.
8. Infectious disease.
9. Uncontrolled diarrhea.
10. Ileus or bowel obstruction.
11. Interstitial lung disease or pulmonary fibrosis.
12. Malignant coelomic fluid required drainage.
13. Administration of atazanavir sulfate.
14. Heart disease to be clinically problem.
15. Major surgical procedure or intestinal resection within 28 days prior to enrollment or colostomy within 14 days prior to enrollment.
16. Known brain metastasis or strongly suspected of brain metastasis.
17. History of a thromboembolic disease.
18. Receiving anti-platelet drugs.
19. Poorly controlled gastrointestinal ulcer.
20. History of intestinal perforation within the past 12 months.
21. Poorly controlled hypertension.
22. Poorly controlled diabetes mellitus.
23. Severe mental disorders.
24. Women who are pregnant or nursing, men and women who wish to conceive a child or with no intention to contraception.
25. Any other cases who are regarded as inadequate for study enrollment by investigators.

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: Treatment Arm; Patients receive FOLFOXIRI plus bevacizumab [oxaliplatin (L-OHP): 85 mg/sq.m., irinotecan hydrochloride hydrate (CPT-11): 165 mg/sq.m., continuous intravenous infusion of fluorouracil (CIV 5-FU): 3,200 mg/sq.m., Levofolinate calcium (l-LV): 200 mg/sq.m., bevacizumab: 5 mg/kg]. The treatment will be repeated every 2 weeks, for up to 12 cycles, unless the disease progression, unacceptable toxicity, tumor resection or consent withdrawal.

Drug: Oxaliplatin (L-OHP); Drug: Irinotecan hydrochloride hydrate (CPT-11); Drug: Continuous intravenous infusion of fluorouracil (CIV 5-FU); Drug: Levofolinate calcium (l-LV); Drug: Bevacizumab (Bmab)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Response rate (RR) by response evaluation criteria in solid tumors (RECIST v1.1)	RR will be calculated as the ratio of the number of eligible patients who experienced a confirmed Complete response(CR) or Partial response(PR) by RECIST v1.1.	Up to 18 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Time to treatment failure (TTF)	TTF is defined as the time from date of starting treatment until date of treatment discontinuation, the first documented progression or death from any cause, whichever comes first.	Up to 18 months
Progression-free survival (PFS)	PFS is defined as the time from date of starting treatment until date of the first documented progression or death from any cause, whichever comes first.	Up to 3 years
Overall survival (OS)	OS is defined as the time from date of starting treatment until date of death from any cause.	Up to 3 years
R0 resection rate	R0 resection rate will be calculated as the ratio of the number of eligible patients who experienced a complete (R0) resection.	Up to 18 months
Relative dose intensity (RDI)	RDI will be calculated as the ratio of actual delivered dose intensity in comparison with planned dose intensity. Dose intensity (DI) is defined as the amount of drug delivered per unit time, expressed in mg/m2/week.	Up to 18 months
Incidence of adverse events		Up to 3 years

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Early tumor shrinkage (ETS) rates in 8 weeks after starting the treatment, evaluated by RECIST v1.1	ETS will be calculated as the ratio of the number of eligible patients who experienced a 20% or more tumor shrinkage at week 8 compared with baseline.	Baseline (week 0), week 8
Deepness of response (DoR)	DoR will be calculated as the median of the maximum tumor shrinkage rates.	Up to 3 years

Collaborators and Investigators

• Sponsor: Translational Research Center for Medical Innovation, Kobe, Hyogo, Japan
• Collaborators: Hiroshima Prefectural Hospital; National Hospital Organization Shikoku Cancer Center
• Investigators: Principal Investigator: Katsunori Shinozaki, MD, Ph.D., Hiroshima Prefectural Hospital; Principal Investigator: Tomohiro Nishina, MD, Ph.D., National Hospital Organization Shikoku Cancer Center

Study record dates

Study Major Dates

• Study Start (Actual): May 21, 2015
• Primary Completion (Actual): June 1, 2019
• Study Completion (Actual): June 1, 2019

Study Registration Dates

• First Submitted: June 25, 2015
• First Submitted That Met QC Criteria: July 9, 2015
• First Posted (Estimate): July 14, 2015

Study Record Updates

• Last Update Posted (Actual): June 17, 2020
• Last Update Submitted That Met QC Criteria: June 16, 2020
• Last Verified: June 1, 2020

More Information

Terms related to this study

• Keywords: oxaliplatin; bevacizumab; irinotecan; fluorouracil; hydrochloride hydrate; levofolinate calcium
• 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; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antimetabolites, Antineoplastic; Antimetabolites; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Protective Agents; Topoisomerase Inhibitors; Antineoplastic Agents, Immunological; Angiogenesis Inhibitors; Angiogenesis Modulating Agents; Growth Substances; Growth Inhibitors; Micronutrients; Vitamins; Calcium-Regulating Hormones and Agents; Topoisomerase I Inhibitors; Antidotes; Vitamin B Complex; Fluorouracil; Oxaliplatin; Bevacizumab; Leucovorin; Irinotecan; Calcium; Levoleucovorin
• Other Study ID Numbers: TRICC1414; UMIN000017102 (Other Identifier: UMIN-CTR)