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

This study has been completed.
Sponsor:
Collaborator:
PharmaBio Development Inc.
Information provided by (Responsible Party):
Eisai Inc.
ClinicalTrials.gov Identifier:
NCT01133990
First received: May 21, 2010
Last updated: May 21, 2013
Last verified: July 2012
  Purpose

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.


Condition Intervention Phase
Colorectal Cancer
Drug: FOLIRI
Drug: FOLIRI plus E7820
Drug: FOLFIRI plus Bevacizumab
Phase 1
Phase 2

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: 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

Resource links provided by NLM:


Further study details as provided by Eisai Inc.:

Primary Outcome Measures:
  • Safety Parameter: Adverse Events [ Time Frame: Until study termination; 3 years ] [ Designated as safety issue: Yes ]
    Phase 1B: To determine the MTD of E7820 in combination with FOLFIRI as determined by occurrence of dose-limiting toxicity at 3 ascending dose levels of E7820. Phase II: Safety and tolerability of E7820 at the MTD determined in Phase Ib in combination with FOLFIRI as measured by rate of adverse events by body system and grade.

  • Safety Parameter: Concomitant Meds [ Time Frame: Until study termination; 3 years ] [ Designated as safety issue: Yes ]
    Phase 1B: To determine the MTD of E7820 in combination with FOLFIRI as determined by occurrence of dose-limiting toxicity at 3 ascending dose levels of E7820. Phase II: Safety and tolerability of E7820 at the MTD determined in Phase Ib in combination with FOLFIRI as measured by rate of adverse events by body system and grade.

  • Safety Parameter: Lab tests [ Time Frame: Days 1 and 28 of every cycle until study termination; 3 years ] [ Designated as safety issue: Yes ]
    Phase 1B: To determine the MTD of E7820 in combination with FOLFIRI as determined by occurrence of dose-limiting toxicity at 3 ascending dose levels of E7820. Phase II: Safety and tolerability of E7820 at the MTD determined in Phase Ib in combination with FOLFIRI as measured by rate of adverse events by body system and grade.

  • Safety Parameter: ECGs [ Time Frame: Day 1 and 30 days after termination of therapy; 3 years ] [ Designated as safety issue: Yes ]
    Phase 1B: To determine the MTD of E7820 in combination with FOLFIRI as determined by occurrence of dose-limiting toxicity at 3 ascending dose levels of E7820. Phase II: Safety and tolerability of E7820 at the MTD determined in Phase Ib in combination with FOLFIRI as measured by rate of adverse events by body system and grade.


Secondary Outcome Measures:
  • Efficacy Parameter [ Time Frame: Time Frame: Progression-Free Survival (PFS) - Until disease progression or death for 3 years ] [ Designated as safety issue: No ]
    Phase 1B: To determine the MTD of E7820 in combination with FOLFIRI as determined by occurrence of dose-limiting toxicity at 3 ascending dose levels of E7820. Phase II: Safety and tolerability of E7820 at the MTD determined in Phase Ib in combination with FOLFIRI as measured by rate of adverse events by body system and grade.

  • Efficacy Parameter [ Time Frame: Time Frame: Time to progression (TTP) - Until disease progression or death for 3 years ] [ Designated as safety issue: No ]
    Phase 1B: To determine the MTD of E7820 in combination with FOLFIRI as determined by occurrence of dose-limiting toxicity at 3 ascending dose levels of E7820. Phase II: Safety and tolerability of E7820 at the MTD determined in Phase Ib in combination with FOLFIRI as measured by rate of adverse events by body system and grade.

  • Efficacy Parameter [ Time Frame: Time Frame: Objective Response Rate (ORR) - Until disease progression or death for 3 years ] [ Designated as safety issue: No ]
    Phase 1B: To determine the MTD of E7820 in combination with FOLFIRI as determined by occurrence of dose-limiting toxicity at 3 ascending dose levels of E7820. Phase II: Safety and tolerability of E7820 at the MTD determined in Phase Ib in combination with FOLFIRI as measured by rate of adverse events by body system and grade.

  • Efficacy Parameter [ Time Frame: Time Frame: Overall Survival (OS) - Until disease progression or death for 3 years ] [ Designated as safety issue: No ]
    Phase 1B: To determine the MTD of E7820 in combination with FOLFIRI as determined by occurrence of dose-limiting toxicity at 3 ascending dose levels of E7820. Phase II: Safety and tolerability of E7820 at the MTD determined in Phase Ib in combination with FOLFIRI as measured by rate of adverse events by body system and grade.


Enrollment: 5
Study Start Date: April 2010
Study Completion Date: January 2011
Primary Completion Date: January 2011 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Active Comparator: FOLIRI Drug: FOLIRI
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.
Other Name: leucovorin calcium (calcium folinate), 5-fluorouracil, and irinotecan
Experimental: E7820
FOLFIRI Alone Versus FOLFIRI Plus Bevacizumab Versus FOLFIRI Plus E7820
Drug: FOLIRI plus 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.
Experimental: FOLFIRI plus Bevacizumab Drug: FOLFIRI plus Bevacizumab
Bevacizumab at 5 mg/kg (IV infusion) on Days 1 and 15 of each 28-day treatment cycle
Other Name: Avastin

Detailed Description:

This open-label, multicenter, randomized study will consist of a Phase Ib portion: a safety run-in period with 3 ascending doses of E7820; and a Phase II portion: a randomized 3-arm design. Approximately 135 patients with measurable, nonresectable locally advanced or metastatic colorectal adenocarcinoma, who have failed first-line chemotherapy, will be enrolled in the study (approximately 15 patients in the Phase Ib portion and 120 patients in the Phase II portion). Patients will only participate in either the Phase Ib or the Phase II portion of the study. Patients will receive up to a planned total of 6 cycles of study treatment unless there is occurrence of progressive disease, unacceptable toxicity, withdrawal of consent, withdrawal by the Investigator, lost to follow-up, or death, whichever occurs first. After 6 cycles, patients in Arm 3 (FOLFIRI + E7820) who demonstrate clinical benefit may continue single agent E7820 for long as clinical benefit is sustained and the treatment is well tolerated. If the treating physician does not feel comfortable discontinuing chemotherapy after 6 cycles, further chemotherapy may be considered following discussion with the medical monitor and sponsor.

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

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.
  Contacts and Locations
Please refer to this study by its ClinicalTrials.gov identifier: NCT01133990

  Show 34 Study Locations
Sponsors and Collaborators
Eisai Inc.
PharmaBio Development Inc.
Investigators
Study Director: Harish Dave Quintiles
  More Information

No publications provided

Responsible Party: Eisai Inc.
ClinicalTrials.gov Identifier: NCT01133990     History of Changes
Other Study ID Numbers: E7820-701, 2009-016015-37
Study First Received: May 21, 2010
Last Updated: May 21, 2013
Health Authority: United States: Food and Drug Administration
Russia: Ministry of Health of the Russian Federation
Ukraine: State Pharmacological Center - Ministry of Health
India: Drugs Controller General of India
Australia: Department of Health and Ageing Therapeutic Goods Administration

Additional relevant MeSH terms:
Colorectal Neoplasms
Intestinal Neoplasms
Gastrointestinal Neoplasms
Digestive System Neoplasms
Neoplasms by Site
Neoplasms
Digestive System Diseases
Gastrointestinal Diseases
Colonic Diseases
Intestinal Diseases
Rectal Diseases
Fluorouracil
Irinotecan
Bevacizumab
Leucovorin
Levoleucovorin
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Pharmacologic Actions
Antimetabolites, Antineoplastic
Antineoplastic Agents
Therapeutic Uses
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Vitamin B Complex
Vitamins
Micronutrients
Growth Substances
Antidotes

ClinicalTrials.gov processed this record on April 14, 2014