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

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 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.