A Study of FOLFOXIRI Plus Cetuximab vs. FOLFOXIRI Plus Bevacizumab (DEEPER)

A Randomized Phase II Study to Investigate the Deepness of Response of FOLFOXIRI Plus Cetuximab (Erbitux) Versus FOLFOXIRI Plus Bevacizumab as the First-line Therapy in Metastatic Colorectal Cancer Patients With RAS Wild-type Tumors: DEEPER

This study is to verify the advantage of FOLFOXIRI plus cetuximab over FOLFOXIRI plus bevacizumab as the first-line therapy in metastatic colorectal cancer patients with RAS wild-type tumors.

Study Overview

• Status: Unknown
• Conditions: Colorectal Cancer
• Intervention / Treatment: Drug: fluorouracil; Drug: Leucovorin; Drug: oxaliplatin; Biological: bevacizumab; Biological: cetuximab; Drug: irinotecan

Detailed Description

This study is to verify the advantage of FOLFOXIRI plus cetuximab over FOLFOXIRI plus bevacizumab as the first-line therapy in metastatic colorectal cancer patients with RAS wild-type tumors. In this study the investigators employed deepness of response as a primary endpoint.

• Study Type: Interventional
• Enrollment (Anticipated): 360
• Phase: Phase 2

Contacts and Locations

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 20 years and older (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Histologically confirmed colorectal cancer
• RAS wild-type
• Measurable lesion by RECIST (Ver.1.1)
• No past history of chemotherapy in the case of unresectable primary lesion/distant metastasis/lymph node metastasis.In the case of recurrence, no treatment for the first recurrence lesion after operation
• Eastern Cooperative Oncology Group (ECOG) Performance status 0-1.The case >=71 years is PS0.
• Life expectancy of more than 6 months

• Patients have enough organ function for study treatment within 14 days before enrollment;

  1. White blood cell (WBC)>=3,000/mm3, <12,000/mm3.
  2. Neu>=1,500/mm3.
  3. Platelet count (PLT) >=10.0x104/mm3.
  4. Hb>=9.0g/dL.
  5. Total Bilirubin<=1.5x Upper Limited Normal (ULN)
  6. aspartate aminotransferase (AST) <=2.5xULN.
  7. alanine aminotransferase (ALT) <=2.5xULN.
  8. Creatinine<=1.5xULN.
  9. Proteinuria<=1+.
  10. prothrombin time-international normalized ratio (PT-INR) <=1.5
• Must be able to swallow tablets
• Written informed consent

Exclusion Criteria:

• Synchronous multiple malignancy or metachronous multiple malignancy within 5 years disease free interval
• Lynch syndrome
• Brain metastases
• Infectious disease
• Interstitial lung disease or pulmonary fibrosis
• Comorbidity or history of serious heart failure
• History of thromboembolic events
• Cerebrovascular disease
• History of hemoptysis/hematemesis
• Uncontrolled hypertension (systolic BP>180mmHg, or diastolic BP>100mmHg)
• Sensory alteration or paresthesia interfering with function
• Large quantity of pleural, abdominal or cardiac effusion
• Severe comorbidity (renal failure, liver failure, hypertension, etc)
• Prior radiotherapy for primary and metastases leision
• Men/women who are unwilling to avoid pregnancy
• Women who are pregnant or breastfeeding
• Women with a positive pregnancy test
• History of severe allergy
• HBsAg positive or active viral hepatitis
• Administration of blood products/ Granulocyte-Colony Stimulating Factor (G-CSF), and blood transfusion within 14 days
• Surgical procedure or such as skin-open biopsy, trauma surgery, or other more intensive surgery within 28 days
• Systematic administration of antiplatelet drug or non steroid anti-inflammatory drugs (NSAIDs)
• Diathesis of bleeding (history of hemoptysis, including cavitation and/or necrosis in lung metastasis confirmed by imaging), coagulopathy
• History of gastrointestinal perforation within 1 year
• Unhealed traumatic bone fracture
• Uncontrolled diarrhea
• History of organ recipient
• Prior cetuximab/bevacizumab/Irinotecan/Oxaliplatin treatment (Adjuvant therapy by Oxaliplatin is excluded)
• Administration of atazanavir sulfate
• Jaundice
• Ileus or bowel obstruction
• Clinical diagnosis of Alzheimer's Disease
• Insulin dependent diabetes
• Thyroid disease
• 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: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: NONE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: FOLFOXIRI+Bmab; Patients in the FOLFOXIRI + Bmab group receive until 12 cycles of FOLFOXIRI plus bevacizumab, consisting of a 30-minute infusion of bevacizumab at a dose of 5 mg per kilogram, a 60-minute infusion of irinotecan at a dose of 150 mg per square meter, and a 120-minute infusion of oxaliplatin at a dose of 85 mg per square meter and a concomitant 120-minute infusion of leucovorin at a dose of 200 mg per square meter, followed by a 48-hour continuous infusion of fluorouracil to a total dose of 2400 mg per square meter. Cycles were repeated every 14 days. After 13 cycles, patients receive fluorouracil, leucovorin and bevacizumab every 14 days until disease progression.	Drug: fluorouracil; Other Names: 5-FU; 5-fluorouracil; Drug: Leucovorin; Other Names: Levofolinate; Drug: oxaliplatin; Other Names: eloxatin; Biological: bevacizumab; Drug: irinotecan; Other Names: CPT-11
Experimental: FOLFOXIRI+Cmab; Patients in the experimental group received until 12 cycles of FOLFOXIRI plus cetuximab, consisting of a 30-minute infusion of cetuximab first time at a dose of 400 mg per kilogram, after the second time at a dose of 250mg per kilogram, a 60-minute infusion of irinotecan at a dose of 150 mg per square meter, and a 120-minute infusion of oxaliplatin at a dose of 85 mg per square meter and a concomitant 120-minute infusion of leucovorin at a dose of 200 mg per square meter, followed by a 48-hour continuous infusion of fluorouracil to a total dose of 2400 mg per square meter. Cycles were repeated every 14 days. After 13 cycles, patients receive fluorouracil, leucovorin and cetuximab every 14 days until disease progression.	Drug: fluorouracil; Other Names: 5-FU; 5-fluorouracil; Drug: Leucovorin; Other Names: Levofolinate; Drug: oxaliplatin; Other Names: eloxatin; Biological: cetuximab; Drug: irinotecan; Other Names: CPT-11

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Best deepness of response	The maximum tumor shrinkage rates by Response Evaluation Criteria in Solid Tumors (RECIST) throughout the treatments	up to 2 years

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Overall survival		up to 2 years
Early tumor shrinkage	The rates of tumor shrinkage by RECIST at 8 weeks	at 8 weeks
Response rate		up to 2 years
Deepness of response	The tumor shrinkage rates by RECIST at 4 months	at 4 months
Progression free survival		up to 2 years
Rate of curatively resected metastatic lesion		up to 2 years
Number of adverse events		up to 2 years

Collaborators and Investigators

• Sponsor: Japan Clinical Cancer Research Organization
• Investigators: Study Director: Toshifusa Nakajima, MD, Japan Clinical Cancer Research Organization

Study record dates

Study Major Dates

• Study Start: August 1, 2015
• Primary Completion (Anticipated): December 1, 2017
• Study Completion (Anticipated): June 1, 2020

Study Registration Dates

• First Submitted: July 12, 2015
• First Submitted That Met QC Criteria: August 4, 2015
• First Posted (Estimate): August 5, 2015

Study Record Updates

• Last Update Posted (Estimate): August 5, 2015
• Last Update Submitted That Met QC Criteria: August 4, 2015
• Last Verified: August 1, 2015

More Information

Terms related to this study

• Keywords: FOLFOXIRI; Bmab; Cmab
• 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; Topoisomerase I Inhibitors; Antidotes; Vitamin B Complex; Fluorouracil; Oxaliplatin; Bevacizumab; Leucovorin; Irinotecan; Cetuximab
• Other Study ID Numbers: JACCRO CC-13