FOLFIRI Alone Versus FOLFIRI Plus Bevacizumab Versus FOLFIRI Plus E7820 as Second-Line Therapy in Patients With Locally Advanced or Metastatic Colorectal Cancer

An Open-Label, Multicenter, Randomized Phase Ib/II Study of FOLFIRI Alone Versus FOLFIRI Plus Bevacizumab Versus FOLFIRI Plus E7820 as Second-Line Therapy in Patients With Locally Advanced or Metastatic Colorectal Cancer

The purpose of the Phase Ib portion is to find out the highest dose of study drug that can safely be given when tested in a small group of subjects.

The purpose of the Phase II portion is to find out how safe the study drug is when taken at the highest dose in a larger group of subjects.

Study Overview

• Status: Terminated
• Conditions: Colorectal Cancer
• Intervention / Treatment: Drug: FOLFIRI; Drug: E7820; Drug: Bevacizumab

Detailed Description

The primary purpose for Phase 1b: to determine the maximum tolerated dose (MTD) of E7820 recommended for Phase 2 when administered in combination with the FOLFIRI regimen (irinotecan, leucovorin, and 5-fluorouracil [5-FU]) in participants with locally advanced or metastatic colorectal cancer (mCRC) who have failed first-line therapy. Phase 2: to evaluate the safety and tolerability of E7820 administered in combination with the FOLFIRI regimen, compared with FOLFIRI alone and FOLFIRI plus bevacizumab, in patients with locally advanced or mCRC who have failed first-line therapy.

• Study Type: Interventional
• Enrollment (Actual): 5
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• Australia
  • Merewether, Australia, 2305
    • Newcastle Private Hospital
  • New South Wales
    • Coffs Harbour, New South Wales, Australia, 2450
      • North Coast Cancer Institute
    • Hornsby, New South Wales, Australia, 2077
      • Sydney Haematology & Oncology Clinic
    • Waratah, New South Wales, Australia, 2298
      • Calvary Mater Newcastle
  • Queensland
    • Herston, Queensland, Australia, 4029
      • Royal Brisbane and Women's Hospital
  • South Australia
    • Hobart, South Australia, Australia, 7000
      • Royal Hobart Hospital
    • Woodville South, South Australia, Australia, 5011
      • Queen Elizabeth Hospital
  • Victoria
    • Box Hill, Victoria, Australia, 3128
      • Box Hill Hospital
    • Epping, Victoria, Australia, 3076
      • The Austin Hospital
• India
  • Ahmedabad, India, 380016
    • Gujarat Cancer & Research Institute
  • Bangalore, India, 560029
    • Kidwai Institute of Oncology
  • Bangalore, India, 560054
    • M. S. Ramaiah Memorial Hospital
  • Kolkata, India, 700106
    • Subodh Mitra Cancer Hospital and Research centre
  • Nashik, India, 422005
    • Shatabdi Hospital
  • Pune, India, 411013
    • Noble Hospital
  • Pune, India, 411004
    • Deenanath Mangeshkar Hospital and Research Center
  • Vellore, India, 632002
    • Christian Medical College
  • Madhya Pradesh
    • Bhopal, Madhya Pradesh, India, 462001
      • Jawaharlal Nehru Cancer Hospital and Research Centre
  • Rajasthan
    • Jaipur, Rajasthan, India, 302013
      • Searoc Cancer Hosptial
• Russian Federation
  • Moscow, Russian Federation, 129128
    • CCH #2 n.a. N. A. Semashko of LLC "Russian Railways"
  • St Petersburg, Russian Federation, 191104
    • City Mariinskaya Hospital
  • St Petersburg, Russian Federation, 197758
    • Scientific Research Oncology Institute named after N.N. Petr
  • Yaroslav, Russian Federation, 150054
    • Yaroslav Regional Clinical Oncology Hospital
• Ukraine
  • Dnipropetrovsk, Ukraine, 49102
    • Mun. Multifield Clin.Hosp.#4,Dept. of Chemotherapy, DSMU
  • Donetsk, Ukraine, 83092
    • Donetsk Regional Anticancer Centre
  • Kharkiv, Ukraine, 61001
    • City Clinical Hospital #2
  • Kharkiv, Ukraine, 61024
    • The St.Inst. "S.P.Grigoriev Med. Rad.Inst. of AMS of Ukr."
  • Uzhgorod, Ukraine, 88000
    • Uzhgorod Centr.City Cl.Hosp.,City Onc.Center, UNMU,Fac.of PG
• United States
  • Colorado
    • Denver, Colorado, United States, 80218
      • Rocky Mountain Cancer Center - Midtown
  • New Jersey
    • Berkeley Heights, New Jersey, United States, 07922
      • Summit Medical Group
    • Mount Holly, New Jersey, United States, 08060
      • Hematology Oncology Associates SJ P.A.
  • North Carolina
    • Chapel Hill, North Carolina, United States, 27599
      • University of North Carolina at Chapel Hill
  • Texas
    • Dallas, Texas, United States, 75246
      • University of Texas Southwestern Medical Center
  • Washington
    • Tacoma, Washington, United States, 98405
      • Northwest Medical Specialties, PLLC

Participation Criteria

Eligibility Criteria

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

Description

Inclusion Criteria:

Patients may be entered in the study only if they meet all of the following criteria:

1. Male or female patient greater than or equal to 18 years of age;
2. Histologically or cytologically confirmed nonresectable locally advanced or metastatic colorectal adenocarcinoma;
3. Patients must have failed a first-line chemotherapy regimen for nonresectable locally advanced or mCRC (first-line bevacizumab is allowed). Patients randomized to the Phase Ib portion can have up to 3 total prior regimens (including adjuvant therapy in addition to treatment for advanced disease);
4. At least 1 site of measurable disease by the Response Evaluation Criteria in Solid Tumors (RECIST version 1.1) criteria;
5. Life expectancy of > 3 months;
6. Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) 0 or 1;
7. Patients must have adequate renal function as evidenced by serum creatinine <2 mg/dL and creatinine clearance >50 mL/minute per the Cockcroft and Gault formula;
8. Patients must have adequate bone marrow function as evidenced by absolute neutrophil count (ANC) >1.5 x 109/L, platelets >100 x 109/L, hemoglobin >9.0 g/dL (a hemoglobin <9.0 g/dL at Screening is acceptable if it is corrected to >9 g/dL by growth factor or transfusion prior to first dose);
9. Patients must have adequate liver function as evidenced by bilirubin <1.5 times the upper limit of the normal range (ULN), and alkaline phosphatase, alanine aminotransferase (ALT), and aspartate aminotransferase (AST) <3 X ULN (in the case of liver metastases, <5 X ULN). If there are bone metastases, liver-specific alkaline phosphatase may be separated from the total and used to assess liver function instead of total alkaline phosphatase;
10. Blood pressure must be well-controlled (<140/90 mmHg at screening) with or without antihypertensive medication. Patients must have no history of hypertensive crisis or hypertensive encephalopathy;
11. Male or female patients of child-producing potential must agree to use double barrier contraception, oral contraceptives, or avoidance of pregnancy measures during the study and for 90 days after the last day of treatment;
12. Females of childbearing potential must have a negative serum pregnancy test;
13. Females may not be breastfeeding; and
14. Ability to understand and willingness to sign a written consent.

Exclusion Criteria:

Patients will not be entered in the study for any of the following reasons:

1. Received chemotherapy, targeted therapy, radiotherapy, surgery, immunotherapy, or treatment in another clinical study within the 30 days prior to commencing study treatment or have not recovered from side effects of all treatment-related toxicities to Grade <1, except for peripheral neuropathy (Grade 1 and Grade 2 are permitted) and alopecia;
2. Previously received irinotecan or irinotecan derivatives;
3. Previously received anti-alpha 2 integrin therapy;
4. History of other malignancies except: (1) adequately treated basal or squamous cell carcinoma of the skin; (2) curatively treated, a) in situ carcinoma of the uterine cervix, b) prostate cancer, or c) superficial bladder cancer; or (3) other curatively treated solid tumor with no evidence of disease for >5 years;
5. Presence of brain metastases, unless the patient has received adequate treatment at least 4 weeks prior to randomization, and is stable, asymptomatic, and off steroids for at least 4 weeks prior to randomization;
6. Are currently receiving any other anticancer treatment;
7. Palliative radiotherapy is not permitted throughout the study period;
8. Serious non-healing wound, ulcer, or active bone fracture;
9. Major surgical procedure, open biopsy or significant traumatic injury within 28 days prior to Day 1, or anticipation of need for a major surgical procedure during the course of the study;
10. Refractory nausea and vomiting, malabsorption, significant bowel resection, or any other medical condition that would preclude adequate absorption or result in the inability to take oral medication;
11. Significant cardiovascular impairment (history of congestive heart failure New York Heart Association [NYHA] Grade >2, unstable angina or myocardial infarction within the past 6 months, or serious cardiac arrhythmia);
12. Active hemoptysis (defined as bright red blood of
13. Current or recent use (within 7 days) of full-dose warfarin (except low-dose warfarin as required to maintain patency of preexisting, permanent indwelling IV catheters). For subjects receiving warfarin, International Normalization Ratio (INR) should be <1.5. Patients may have prophylactic use of low molecular weight heparin, however therapeutic use of heparin or low molecular weight heparin is not acceptable;
14. History of bleeding diathesis or coagulopathy;
15. Any history of cerebral vascular accident, transient ischemic attack or ≥ Grade 2 peripheral vascular disease, unless they have had no evidence of active disease for at least 6 months prior to randomization;
16. Abdominal fistula, gastrointestinal perforation, or intra-abdominal abscess within 6 months prior to Day 1, unless affected area has been removed surgically;
17. Patients with organ allografts requiring immunosuppression;
18. Known positive human immunodeficiency virus (HIV), known hepatitis B surface antigen, or active hepatitis C positive;
19. Patients with a history of allergic reactions attributed to compounds of similar chemical or biologic composition to bevacizumab, irinotecan, 5-FU, or leucovorin;
20. Hypersensitivity to sulfonamide derivatives; or
21. Have any medical condition that would interfere with the conduct of 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

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: FOLFIRI; The FOLFIRI regimen consists of irinotecan at 180 mg/m2 (IV infusion) on Day 1 and Day 15 of each 28-day cycle, leucovorin at 200 mg/m2 (400 mg/m2 if using d,l-racemic mixture of leucovorin) by IV infusion on Days 1 and 15 of each cycle, and 5-FU at 400 mg/m2 as an IV bolus injection followed by a total of 2400 mg/m2 by CIV infusion over 46 hours over Days 1 and 2 via an ambulatory programmable pump (the use of an ambulatory pump is optional). The 5-FU IV bolus (400 mg/m2) and CIV infusion (2400 mg/m2) over 46 hours is repeated on Days 15 and 16 of each cycle.	Drug: FOLFIRI; FOLFIRI will be administered as IV infusion on Days 1 and 15 of each cycle, and 5-FU at 400 mg/m^2 as an IV bolus injection followed by a total of 2400 mg/m2 by CIV infusion over 46 hours over Days 1 and 2 via an ambulatory programmable pump. The 5-FU IV bolus (400 mg/m^2) and CIV infusion (2400 mg/m^2) over 46 hours is repeated on Days 15 and 16 of each cycle.; Other Names: leucovorin calcium (calcium folinate), 5-fluorouracil, and irinotecan
Experimental: E7820; E7820 is administered orally in tablet form once daily, every day of each 28-day treatment cycle. For the Phase Ib portion, the doses will be 40 mg/day, 70 mg/day, and 100 mg/day, and for the Phase II portion, the dose will be the MTD recommended Phase IB dose in combination with FOLFIRI, as determined during the Phase Ib portion of the study.	Drug: FOLFIRI; FOLFIRI will be administered as IV infusion on Days 1 and 15 of each cycle, and 5-FU at 400 mg/m^2 as an IV bolus injection followed by a total of 2400 mg/m2 by CIV infusion over 46 hours over Days 1 and 2 via an ambulatory programmable pump. The 5-FU IV bolus (400 mg/m^2) and CIV infusion (2400 mg/m^2) over 46 hours is repeated on Days 15 and 16 of each cycle.; Other Names: leucovorin calcium (calcium folinate), 5-fluorouracil, and irinotecan; Drug: E7820; E7820 will be administered orally in tablet form once daily, every day of each 28-day treatment cycle.
Experimental: FOLFIRI plus Bevacizumab; Bevacizumab at 5 mg/kg (IV infusion) on Days 1 and 15 of each 28-day treatment cycle	Drug: FOLFIRI; FOLFIRI will be administered as IV infusion on Days 1 and 15 of each cycle, and 5-FU at 400 mg/m^2 as an IV bolus injection followed by a total of 2400 mg/m2 by CIV infusion over 46 hours over Days 1 and 2 via an ambulatory programmable pump. The 5-FU IV bolus (400 mg/m^2) and CIV infusion (2400 mg/m^2) over 46 hours is repeated on Days 15 and 16 of each cycle.; Other Names: leucovorin calcium (calcium folinate), 5-fluorouracil, and irinotecan; Drug: Bevacizumab; Bevacizumab will be administered at 5 mg/kg (IV infusion) on Days 1 and 15 of each 28-day treatment cycle.; Other Names: Avastin

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Phase 1b: Number of Participants With Dose-limiting Toxicities (DLTs)	Dose-limiting toxicities were defined as clinically significant adverse events (AEs) occurring less than or equal to (<=) 28 days after commencing study treatment and considered by the investigator to be possibly or probably related to study treatment. Toxicity was evaluated according to National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0 (NCI CTCAE v.4.0).	Cycle 1 (each cycle length=28 days)
Phase 1b: Number of Participants With Any Treatment-emergent Adverse Events (TEAEs)	Adverse Events were defined as TEAEs if they started on or after the date and time of administration of the first dose of study drug during the study. An AE was defined as any untoward medical occurrence in a participant administered a pharmaceutical product, and which did not necessarily have a causal relationship with this treatment. Any change in hematology, clinical chemistry, urine values and regular measurement of vital signs which were deemed clinically significant by the investigator were recorded as TEAE.	From date of first dose up to 30 days after last dose of study treatment (up to 11.5 months)
Phase 1b: Number of Participants With Eastern Cooperative Oncology Group Performance Status (ECOG-PS)	ECOG-PS measured participant's performance status on 5 point scale: 0=Fully active/able to carry on all pre-disease activities without restriction; 1=restricted in physically strenuous activity, ambulatory/able to carry out light or sedentary work; 2=ambulatory (greater than[ >] 50 percent [%] of waking hours), capable of all self care, unable to carry out any work activities; 3=capable of only limited self care, confined to bed/chair >50% of waking hours; 4=completely disabled, cannot carry on any self care, totally confined to bed/chair; 5=dead.	From date of first dose up to 30 days after last dose of study treatment (up to 11.5 months)
Phase 1b: Number of Participants With Clinically Significant Changes in Physical Examinations	Physical examination included examination of the head, eyes, ears, nose, throat, neck, heart, chest, lungs, abdomen, extremities, skin, lymph nodes, and neurological status.	From date of first dose up to 30 days after last dose of study treatment (up to 11.5 months)
Phase 1b: Number of Participants With Clinically Significant Change From Baseline in Electrocardiograms (ECGs) Parameter	ECG was to be a complete standardized 12-lead recording. The ECGs were reviewed by the investigator or designee prior to study drug administration as part of the participant's standard of care.	From date of first dose up to 30 days after last dose of study treatment (up to 11.5 months)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Phase 2: Progression-Free Survival (PFS)	PFS was defined as the time from the date of randomization of a participant to the date of first documentation of PD or death (whichever occurred first) based on investigator assessments according to Response Evaluation Criteria in Solid Tumors (RECIST) version (v) 1.1. PD was defined as at least a 20% increase or 5 millimeter (mm) increase in the sum of diameters of target lesions (taking as reference the smallest sum on study) recorded since the treatment started or the appearance of 1 or more new lesions.	From the date of randomization to date of PD or death (whichever occurred first), up to 11 months
Phase 2: Time to Progression (TTP)	TTP was defined as time from the date of randomization of a participant until the date of first documented progression of such participant's disease based on investigator assessments according to RECIST v.1.1. PD was defined as at least a 20% increase or 5 mm increase in the sum of diameters of target lesions (taking as reference the smallest sum on study) recorded since the treatment started or the appearance of 1 or more new lesions.	From date randomization to date of PD or death, up to 11 months
Phase 2: Objective Response Rate (ORR)	ORR was defined as percentage of participants in the study whose best overall response was either CR or PR based on investigator assessments according to RECIST v1.1. A confirmatory scan was required after no less than 4 weeks and no later than 8 weeks, starting on the date that the response was first recorded. CR was defined as the disappearance of all target and non-target lesions (non-lymph nodes). All pathological lymph nodes (whether target or non-target) must have a reduction in their short axis to less than (<)10 mm. PR was defined as at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters.	From date of treatment start to until date of first PD or death (whichever occurred first), up to 11 months
Phase 2: Overall Survival (OS)	OS was defined as time from the date of randomization of a participant until the date of death of such participant, regardless of the actual cause of the participant's death.	From date of randomization to date of PD or death, up to 11 months

Collaborators and Investigators

• Sponsor: Eisai Inc.
• Collaborators: Quintiles, Inc.
• Investigators: Study Director: Harish Dave, Quintiles, Inc.

Study record dates

Study Major Dates

• Study Start (Actual): March 4, 2010
• Primary Completion (Actual): February 18, 2011
• Study Completion (Actual): February 18, 2011

Study Registration Dates

• First Submitted: May 21, 2010
• First Submitted That Met QC Criteria: May 28, 2010
• First Posted (Estimated): May 31, 2010

Study Record Updates

• Last Update Posted (Actual): November 7, 2023
• Last Update Submitted That Met QC Criteria: October 11, 2023
• Last Verified: July 1, 2012

More Information

Terms related to this study

• 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; Bevacizumab; Leucovorin; Irinotecan; Calcium; Levoleucovorin
• Other Study ID Numbers: E7820-701; 2009-016015-37 (EudraCT Number)