Irinotecan Plus E7820 Versus FOLFIRI in Second-Line Therapy in Patients With Locally Advanced or Metastatic Colon or Rectal Cancer

This study is ongoing, but not recruiting participants.
Sponsor:
Collaborator:
PharmaBio Development Inc.
Information provided by (Responsible Party):
Eisai Inc.
ClinicalTrials.gov Identifier:
NCT01347645
First received: April 28, 2011
Last updated: July 17, 2014
Last verified: July 2014
  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
Colon Cancer
Rectal Cancer
Drug: FOLFIRI
Drug: E7820
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 Irinotecan Plus E7820 Versus FOLFIRI in Second-Line Therapy in Patients With Locally Advanced or Metastatic Colon or Rectal Cancer

Resource links provided by NLM:


Further study details as provided by Eisai Inc.:

Primary Outcome Measures:
  • Safety parameter: adverse events [ Time Frame: Participants will be followed for the duration of the study, an expected average of 18 months ] [ Designated as safety issue: Yes ]

    Phase Ib: to determine the maximum tolerated dose (MTD) of E7820 recommended for Phase II when administered in combination with Irinotecan in patients with locally advanced or metastatic colorectal cancer (mCRC) who have failed first-line therapy;

    • Phase II: to evaluate the safety and tolerability of E7820 administered in combination with Irinotecan compared with FOLFIRI alone, in patients with locally advanced or metastatic colorectal cancer (mCRC)who have failed first-line therapy.

  • Safety Parameter: Concomitant medications [ Time Frame: Participants will be followed for the duration of the study, an expected average of 18 months ] [ Designated as safety issue: Yes ]

    Phase Ib: to determine the maximum tolerated dose (MTD) of E7820 recommended for Phase II when administered in combination with Irinotecan in patients with locally advanced or metastatic colorectal cancer (mCRC) who have failed first-line therapy;

    • Phase II: to evaluate the safety and tolerability of E7820 administered in combination with Irinotecan, compared with FOLFIRI alone, in patients with locally advanced or mCRC who have failed first-line therapy.

  • Safety parameter: lab tests [ Time Frame: Assessed at Day 1 of each treatment cycle for the duration of the study and after termination of drug administration, an expected average of 6 months ] [ Designated as safety issue: Yes ]

    Phase Ib: to determine the maximum tolerated dose (MTD) of E7820 recommended for Phase II when administered in combination with Irinotecan in patients with locally advanced or metastatic colorectal cancer (mCRC) who have failed first-line therapy;

    • Phase II: to evaluate the safety and tolerability of E7820 administered in combination with Irinotecan, compared with FOLFIRI alone, in patients with locally advanced or mCRC who have failed first-line therapy.

  • Safety parameter: ECGs [ Time Frame: Assessed at Day 1 of each treatment cycle after termination of drug administration, an expected average of 3 years ] [ Designated as safety issue: Yes ]
    • Description: Phase Ib: to determine the maximum tolerated dose (MTD) of E7820 recommended for Phase II when administered in combination with Irinotecan in patients with locally advanced or metastatic colorectal cancer (mCRC) who have failed first-line therapy;
    • Phase II: to evaluate the safety and tolerability of E7820 administered in combination with Irinotecan, compared with FOLFIRI alone, in patients with locally advanced or mCRC who have failed first-line therapy.


Secondary Outcome Measures:
  • Efficacy parameter: Time to progression (TTP) [ Time Frame: Assessed until disease progression or death, an expected average of 18 months ] [ Designated as safety issue: No ]
    • Phase Ib: to determine the maximum tolerated dose (MTD) of E7820 recommended for Phase II when administered in combination with Irinotecan in patients with locally advanced or metastatic colorectal cancer (mCRC) who have failed first-line therapy;
    • Phase II: to evaluate the safety and tolerability of E7820 administered in combination with Irinotecan, compared with FOLFIRI alone, in patients with locally advanced or metastatic colorectal cancer(mCRC) who have failed first-line therapy.

  • Efficacy parameter: Overall survival (OS [ Time Frame: Assessed until disease progression or death, an expected average of 3 years ] [ Designated as safety issue: No ]
    • Phase Ib: to determine the maximum tolerated dose (MTD) of E7820 recommended for Phase II when administered in combination with the FOLFIRI regimen (irinotecan, leucovorin, and 5-fluorouracil [5-FU]) in patients with locally advanced or metastatic colorectal cancer (mCRC) who have failed first-line therapy;
    • Phase II: to evaluate the safety and tolerability of E7820 administered in combination with the FOLFIRI regimen, compared with FOLFIRI alone, in patients with locally advanced or mCRC who have failed first-line therapy.

  • Efficacy parameter: Overall response rate (ORR) [ Time Frame: Assessed until disease progression or death, an expected average of 18 months ] [ Designated as safety issue: No ]
    • Phase Ib: to determine the maximum tolerated dose (MTD) of E7820 recommended for Phase II when administered in combination with Irinotecan in patients with locally advanced or metastatic colorectal cancer (mCRC) who have failed first-line therapy;
    • Phase II: to evaluate the safety and tolerability of E7820 administered in combination with Irinotecan, compared with FOLFIRI alone, in patients with locally advanced or metastatic colorectal cancer (mCRC) who have failed first-line therapy.


Estimated Enrollment: 95
Study Start Date: October 2011
Estimated Study Completion Date: September 2014
Estimated Primary Completion Date: September 2014 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Active Comparator: 1
Experimental Irinotecan plus E7820
Drug: E7820

Test product: dose and mode of administration:

E7820 is administered orally in tablet form once daily, every day of each 14-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 Pase II portion, the dose will be the MTD in combination with Irinotecan, as determined during the Phase ib portion of the study.

The irinotecan regimen consists of an irinotecan dose of 180 mg/m2 by IV infusion once every 2 weeks (Day 1 of each 14-day cycle).

Active Comparator: 2
FOLFIRI alone
Drug: FOLFIRI
Comparator dose and mode of administration The FOLFIRI regimen consists of irinotecan at 180 mg/m2 (IV infusion) on Day 1 of each 14-day cycle, leucovorin at 200 mg/m2 (400 mg/m2 if using d,l-racemic mixture of leucovorin) by IV infusion on Day 1 of each cycle, and 5-FU at 400 mg/m2 as an IV bolus injection followed by a total of 2400 mg/m2 by continuous IV infusion over 46 hours over Days 1 and 2 via an ambulatory programmable pump (the use of an ambulatory pump is optional).

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 2-arm design. Approximately 95 patients with measurable, nonresectable locally advanced or metastatic colorectal adenocarcinoma, who have failed first-line chemotherapy, will be enrolled in the study (approximately 12 to 15 patients in the Phase Ib portion and 80 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 12 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 12 cycles, patients 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 12 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 5-FU-based therapies, including but not limited to FOLFOX, FOLFOX 4, mFOLFOX6, CapeOX, single-agent capecitabine, infusional 5-FU, or other chemotherapies. Bevacizumab, cetuximab, panitumumab, and EGFR inhibitors are allowed. Prior treatment with irinotecan or FOLFIRI is not allowed for Phase II). For Phase Ib only, up to 3 prior therapies are allowed (including non-irinotecan containing therapies and adjuvant therapy);
  4. At least 1 site of measurable disease by the Response Evaluation Criteria in Solid Tumors (RECIST version 1.1) criteria;
  5. Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) of less than or equal to 2;
  6. Patients must have adequate renal function as evidenced by serum creatinine less than 2 mg/dL and creatinine clearance greater than 50 mL/minute per the Cockcroft and Gault formula;
  7. Patients must have adequate bone marrow function as evidenced by absolute neutrophil count (ANC) greater than or equal to 1.5 x 109/L, platelets greater than100 x 109/L, hemoglobin greater than or equal to 9.0 g/dL (a hemoglobin less than 9.0 g/dL at Screening is acceptable if it is corrected to greater than or equal to 9 g/dL by growth factor or transfusion prior to the first dose);
  8. Patients must have adequate liver function as evidenced by bilirubin less than or equal to 1.5 times the upper limit of the normal range (ULN), and alkaline phosphatase, alanine aminotransferase (ALT), and aspartate aminotransferase (AST) less than or equal to 3 X ULN (in the case of liver metastases, less than or equal to 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;
  9. For patients with hypertension, it must be well controlled. If a patient presents with poorly controlled hypertension, defined as a mean systolic blood pressure greater than or equal to140 mm Hg or mean diastolic blood pressure greater than or equal to 90 mm Hg,antihypertensive medication(s) should be initiated or adjusted with a goal to control the blood pressure less than 140/90 mm Hg. Blood pressure must be reassessed on 2 occasions, consecutively, that are separated by a minimum of 24 hours;
  10. 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;
  11. Females of childbearing potential must have a negative serum pregnancy test at Screening;
  12. Females may not be breastfeeding; Ability to understand and willingness to sign a written informed consent.

Exclusion Criteria:

  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 less than or equal to 1, except for peripheral neuropathy (Grade 1 and Grade 2 are permitted) and alopecia;
  2. Previously received irinotecan or irinotecan derivatives in Phase II (irinotecan-containing regimens are allowed in Phase Ib);
  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 in situ carcinoma of the uterine cervix; or (3) other curatively treated solid tumor with no evidence of disease for greater than or equal to 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. Serious non-healing wound, ulcer, or active bone fracture;
  8. 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;
  9. 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;
  10. Significant cardiovascular impairment (history of congestive heart failure New York Heart Association [NYHA] Grade greater than 2, unstable angina or myocardial infarction within the past 6 months, or serious cardiac arrhythmia);
  11. Active hemoptysis (defined as bright red blood of 1/2 teaspoon or more) within the 30 days prior to study entry;
  12. Current or recent use (within 7 days) of full-dose warfarin (except low-dose warfarin as required to maintain patency of pre-existing, permanent indwelling IV catheters). For patients receiving warfarin, International Normalization Ratio (INR) should be less than 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;
  13. History of bleeding diathesis or coagulopathy;
  14. Any history of cerebral vascular accident, transient ischemic attack, or Grade greater than or equal to 2 peripheral vascular disease, unless they have had no evidence of active disease for at least 6 months prior to randomization;
  15. Abdominal fistula, gastrointestinal perforation, or intra-abdominal abscess within 6 months prior to Day 1, unless affected area has been removed surgically;
  16. Patients with organ allografts requiring immunosuppression;
  17. Known positive human immunodeficiency virus (HIV), known hepatitis B surface antigen, or active hepatitis C positive;
  18. Patients with a history of allergic reactions attributed to compounds of similar chemical or biologic composition to irinotecan, 5-FU, or leucovorin;
  19. Hypersensitivity to sulfonamide derivatives;
  20. Have any medical condition that would interfere with the conduct of the study.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01347645

  Show 38 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: NCT01347645     History of Changes
Other Study ID Numbers: E7820-702, 2011-001762-18
Study First Received: April 28, 2011
Last Updated: July 17, 2014
Health Authority: United States: Food and Drug Administration

Keywords provided by Eisai Inc.:
locally advanced
metastatic colon
rectal cancer

Additional relevant MeSH terms:
Colonic Neoplasms
Rectal Neoplasms
Colorectal Neoplasms
Intestinal Neoplasms
Gastrointestinal Neoplasms
Digestive System Neoplasms
Neoplasms by Site
Neoplasms
Digestive System Diseases
Gastrointestinal Diseases
Colonic Diseases
Intestinal Diseases
Rectal Diseases
Irinotecan
Antineoplastic Agents, Phytogenic
Antineoplastic Agents
Therapeutic Uses
Pharmacologic Actions
Radiation-Sensitizing Agents
Physiological Effects of Drugs
Topoisomerase I Inhibitors
Topoisomerase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action

ClinicalTrials.gov processed this record on July 22, 2014