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

• Sponsor: Eisai Inc. (Industry)
• Overall Status: Completed
• CT.gov ID: NCT01347645
• Collaborator: PharmaBio Development Inc. (Industry)
• Enrollment: 82
• Locations: 38
• Arms: 2
• Actual Duration (Months): 57.7
• Patients Per Site: 2.2
• Patients Per Site Per Month: 0

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Colon Cancer; Rectal Cancer	Drug: FOLFIRI; Drug: E7820	Phase 1/Phase 2

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.

Study Design

• Study Type: Interventional
• Actual Enrollment: 82 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (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
• Actual Study Start Date: Sep 1, 2011
• Actual Primary Completion Date: Jun 22, 2015
• Actual Study Completion Date: Jun 22, 2016

Arms and Interventions

Arm	Intervention/Treatment
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).

Outcome Measures

Primary Outcome Measures

1. Safety parameter: adverse events [Participants will be followed for the duration of the study, an expected average of 18 months]

   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.

2. Safety Parameter: Concomitant medications [Participants will be followed for the duration of the study, an expected average of 18 months]

   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.

3. Safety parameter: lab tests [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]

   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.

4. Safety parameter: ECGs [Assessed at Day 1 of each treatment cycle after termination of drug administration, an expected average of 3 years]

   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

1. Efficacy parameter: Time to progression (TTP) [Assessed until disease progression or death, an expected average of 18 months]

   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.

2. Efficacy parameter: Overall survival (OS [Assessed until disease progression or death, an expected average of 3 years]

   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.

3. Efficacy parameter: Overall response rate (ORR) [Assessed until disease progression or death, an expected average of 18 months]

   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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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

Locations

	Site	City	State	Country	Postal Code
1		Birmingham	Alabama	United States	35294
2		West Palm Beach	Florida	United States	33401
3		Atlanta	Georgia	United States	30341
4		Ann Arbor	Michigan	United States	48109
5		Berkeley Heights	New Jersey	United States	7922
6		Bismarck	North Dakota	United States	58501
7		Ciudad Autonoma de Buenos Aires	Buenos Aires	Argentina
8		La Rioja	La Rioha	Argentina
9		Rosario	Santa Fe	Argentina
10		Cordoba		Argentina
11		Coffs Harbour	New South Wales	Australia	2450
12		Concord	New South Wales	Australia	2139
13		Townsville	Queensland	Australia	4814
14		Elizabeth Vale	South Australia	Australia	5112
15		Kurralta Park	South Australia	Australia	5035
16		Woodville South	South Australia	Australia	5011
17		Carlton	Victoria	Australia	3053
18		Clayton	Victoria	Australia	3168
19		Epping	Victoria	Australia	3076
20		Frankston	Victoria	Australia	3199
21		Wodonga	Victoria	Australia	3690
22		Belo Horizonte	Minas Gerais	Brazil
23		Novo Hamburgo	Rio Grande Do Sul	Brazil
24		Passo Fundo	Rio Grande Do Sul	Brazil
25		Port Alegre	Rio Grande Do Sul	Brazil
26		Porto Alegre	Rio Grande Do Sul	Brazil
27		Jau	Sao Paulo	Brazil
28		Rio de Janeiro		Brazil
29		Arkhangelsk		Russian Federation	163045
30		Chelyabinsk		Russian Federation	454087
31		Moscow		Russian Federation	115478
32		Sochi		Russian Federation	354057
33		St. Petersburg		Russian Federation	195067
34		St. Petersburg		Russian Federation	197758
35		Dnipropetrovsk		Ukraine	49102
36		Kharkiv		Ukraine	61024
37		Kharkiv		Ukraine	61037
38		Uzhgorod		Ukraine	88000

Sponsors and Collaborators

• Eisai Inc.
• PharmaBio Development Inc.

Investigators

• Study Director: Harish Dave, Quintiles, Inc.

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Eisai Inc.
• ClinicalTrials.gov Identifier: NCT01347645
• Other Study ID Numbers: E7820-702; 2011-001762-18
• First Posted: May 4, 2011
• Last Update Posted: Aug 28, 2017
• Last Verified: Aug 1, 2017

• Keywords provided by Eisai Inc.: locally advanced; metastatic colon; rectal cancer
• Additional relevant MeSH terms: Rectal Neoplasms

Study Results

No Results Posted as of Aug 28, 2017