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

NCT01133990 | Terminated Phase 1 Results

• 2 other identifiers: E7820-7012009-016015-37
• Study Type: interventional
• Target: 5
• Locations: 5 countries
• Sites: 34

Brief Summary

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.

Conditions

Colorectal Cancer

Outcome Measures

Primary Outcomes (5)

• 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 Outcomes (4)

• Phase 2: Progression-Free Survival (PFS)

  From the date of randomization to date of PD or death (whichever occurred first), up to 11 months

• Phase 2: Time to Progression (TTP)

  From date randomization to date of PD or death, up to 11 months

• Phase 2: Objective Response Rate (ORR)

  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)

  From date of randomization to date of PD or death, up to 11 months

Study Arms (3)

FOLFIRI

ACTIVE COMPARATOR

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

E7820

EXPERIMENTAL

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; Drug: E7820

FOLFIRI plus Bevacizumab

EXPERIMENTAL

Bevacizumab at 5 mg/kg (IV infusion) on Days 1 and 15 of each 28-day treatment cycle

Drug: FOLFIRI; Drug: Bevacizumab

Interventions

FOLFIRI DRUG

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.

Also known as: leucovorin calcium (calcium folinate), 5-fluorouracil, and irinotecan

E7820; FOLFIRI; FOLFIRI plus Bevacizumab

E7820 DRUG

E7820 will be administered orally in tablet form once daily, every day of each 28-day treatment cycle.

E7820

Bevacizumab DRUG

Bevacizumab will be administered at 5 mg/kg (IV infusion) on Days 1 and 15 of each 28-day treatment cycle.

Also known as: Avastin

FOLFIRI plus Bevacizumab

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Patients may be entered in the study only if they meet all of the following criteria:
• Male or female patient greater than or equal to 18 years of age;
• Histologically or cytologically confirmed nonresectable locally advanced or metastatic colorectal adenocarcinoma;
• 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);
• At least 1 site of measurable disease by the Response Evaluation Criteria in Solid Tumors (RECIST version 1.1) criteria;
• Life expectancy of \> 3 months;
• Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) 0 or 1;
• 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;
• 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);
• 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;
• 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;
• 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;
• Females of childbearing potential must have a negative serum pregnancy test;
• Females may not be breastfeeding; and
• Ability to understand and willingness to sign a written consent.

You may not qualify if:

• Patients will not be entered in the study for any of the following reasons:
• 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;
• Previously received irinotecan or irinotecan derivatives;
• Previously received anti-alpha 2 integrin therapy;
• 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;
• 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;
• Are currently receiving any other anticancer treatment;
• Palliative radiotherapy is not permitted throughout the study period;
• Serious non-healing wound, ulcer, or active bone fracture;
• 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;
• 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;
• 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);
• Active hemoptysis (defined as bright red blood of
• 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;
• History of bleeding diathesis or coagulopathy;

Sponsors & Collaborators

• Eisai Inc.: lead
• Quintiles, Inc.: collaborator

Study Sites (34)

Rocky Mountain Cancer Center - Midtown

Denver, Colorado, 80218, United States

Location

Summit Medical Group

Berkeley Heights, New Jersey, 07922, United States

Location

Hematology Oncology Associates SJ P.A.

Mount Holly, New Jersey, 08060, United States

Location

University of North Carolina at Chapel Hill

Chapel Hill, North Carolina, 27599, United States

Location

University of Texas Southwestern Medical Center

Dallas, Texas, 75246, United States

Location

Northwest Medical Specialties, PLLC

Tacoma, Washington, 98405, United States

Location

North Coast Cancer Institute

Coffs Harbour, New South Wales, 2450, Australia

Location

Sydney Haematology & Oncology Clinic

Hornsby, New South Wales, 2077, Australia

Location

Calvary Mater Newcastle

Waratah, New South Wales, 2298, Australia

Location

Royal Brisbane and Women's Hospital

Herston, Queensland, 4029, Australia

Location

Royal Hobart Hospital

Hobart, South Australia, 7000, Australia

Location

Queen Elizabeth Hospital

Woodville South, South Australia, 5011, Australia

Location

Box Hill Hospital

Box Hill, Victoria, 3128, Australia

Location

The Austin Hospital

Epping, Victoria, 3076, Australia

Location

Newcastle Private Hospital

Merewether, 2305, Australia

Location

Jawaharlal Nehru Cancer Hospital and Research Centre

Bhopal, Madhya Pradesh, 462001, India

Location

Searoc Cancer Hosptial

Jaipur, Rajasthan, 302013, India

Location

Gujarat Cancer & Research Institute

Ahmedabad, 380016, India

Location

Kidwai Institute of Oncology

Bangalore, 560029, India

Location

M. S. Ramaiah Memorial Hospital

Bangalore, 560054, India

Location

Subodh Mitra Cancer Hospital and Research centre

Kolkata, 700106, India

Location

Shatabdi Hospital

Nashik, 422005, India

Location

Deenanath Mangeshkar Hospital and Research Center

Pune, 411004, India

Location

Noble Hospital

Pune, 411013, India

Location

Christian Medical College

Vellore, 632002, India

Location

CCH #2 n.a. N. A. Semashko of LLC "Russian Railways"

Moscow, 129128, Russia

Location

City Mariinskaya Hospital

Saint Petersburg, 191104, Russia

Location

Scientific Research Oncology Institute named after N.N. Petr

Saint Petersburg, 197758, Russia

Location

Yaroslav Regional Clinical Oncology Hospital

Yaroslav, 150054, Russia

Location

Mun. Multifield Clin.Hosp.#4,Dept. of Chemotherapy, DSMU

Dnipropetrovsk, 49102, Ukraine

Location

Donetsk Regional Anticancer Centre

Donetsk, 83092, Ukraine

Location

City Clinical Hospital #2

Kharkiv, 61001, Ukraine

Location

The St.Inst. "S.P.Grigoriev Med. Rad.Inst. of AMS of Ukr."

Kharkiv, 61024, Ukraine

Location

Uzhgorod Centr.City Cl.Hosp.,City Onc.Center, UNMU,Fac.of PG

Uzhhorod, 88000, Ukraine

Location

MeSH Terms

Conditions

Colorectal Neoplasms

Interventions

IFL protocol; Leucovorin; Fluorouracil; Irinotecan; N-(3-cyano-4-methyl-1H-indol-7-yl)-3-cyanobenzene-sulfonamide; Bevacizumab

Condition Hierarchy (Ancestors)

Intestinal Neoplasms; Gastrointestinal Neoplasms; Digestive System Neoplasms; Neoplasms by Site; Neoplasms; Digestive System Diseases; Gastrointestinal Diseases; Colonic Diseases; Intestinal Diseases; Rectal Diseases

Intervention Hierarchy (Ancestors)

Formyltetrahydrofolates; Tetrahydrofolates; Folic Acid; Pterins; Pteridines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds; Coenzymes; Enzymes and Coenzymes; Uracil; Pyrimidinones; Pyrimidines; Heterocyclic Compounds, 1-Ring; Camptothecin; Alkaloids; Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins

Limitations and Caveats

The study was terminated early as the combination of E7820 and FOLFIRI was deemed to be not tolerable, hence no efficacy analysis was conducted.

Results Point of Contact

• Title: Eisai Medical Information
• Organization: Eisai Inc.

esi_oncmedinfo@eisai.com

1-888-274-2378

Study Officials

• Harish Dave

  Quintiles, Inc.

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: May 21, 2010
• First Posted: May 31, 2010
• Study Start: March 4, 2010
• Primary Completion: February 18, 2011
• Study Completion: February 18, 2011
• Last Updated: November 7, 2023
• Results First Posted: November 7, 2023

Record last verified: 2012-07

Locations

AU (9); RU (4); US (6); UA (5); IN (10)