Irinotecan and Cetuximab With or Without Bevacizumab in Treating Patients With Metastatic Colorectal Cancer That Progressed During First-Line Therapy

Study Overview
=================
Brief Summary
-----------------
This randomized phase III trial is studying giving irinotecan and cetuximab together with bevacizumab to see how well it works compared with giving irinotecan and cetuximab alone in treating patients with metastatic colorectal cancer that progressed during first-line therapy. Drugs used in chemotherapy, such as irinotecan, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Monoclonal antibodies, such as cetuximab and bevacizumab, can block tumor growth in different ways. Some block the ability of tumor cells to grow and spread. Others find tumor cells and help kill them or carry tumor-killing substances to them. Bevacizumab may also stop the growth of tumor cells by blocking blood flow to the tumor. It is not yet known whether irinotecan and cetuximab are more effective with or without bevacizumab in treating metastatic colorectal cancer.

Detailed Description
-----------------
PRIMARY OBJECTIVES: I. Compare progression-free survival of patients with metastatic colorectal cancer that progressed on first-line therapy comprising bevacizumab and FOLFOX, OPTIMOX, or XELOX treated with irinotecan hydrochloride-based chemotherapy and cetuximab with vs without bevacizumab. II. Compare overall survival of patients treated with these regimens. III. Compare objective tumor response (confirmed and unconfirmed, complete and partial response) in patients with measurable disease treated with these regimens. IV. Compare the tolerability and safety profile of these regimens in these patients. OUTLINE: This is a multicenter, randomized study. Patients are stratified according to Zubrod performance status (0 vs 1 or 2), discontinuation of oxaliplatin during first-line therapy (yes vs no), planned concurrent chemotherapy (FOLFIRI vs single-agent irinotecan hydrochloride), and time from last dose of bevacizumab (14-42 days vs >= 43 days). All patients receive 1 of the following chemotherapy regimens: SINGLE AGENT IRINOTECAN HYDROCHLORIDE: Patients receive irinotecan hydrochloride intravenously (IV) over 90 minutes on day 1. Treatment repeats every 21 days in the absence of disease progression or unacceptable toxicity. FOLFIRI: Patients receive irinotecan hydrochloride IV over 90 minutes and leucovorin calcium IV over 2 hours on day 1 and fluorouracil IV continuously over 46-48 hours on days 1 and 2. Treatment repeats every 14 days in the absence of disease progression or unacceptable toxicity. Patients are then randomized to 1 of 3 treatment arms. ARM I: Patients receive single-agent irinotecan hydrochloride or FOLFIRI as outlined above and cetuximab IV over 1-2 hours on day 1. Courses repeat every 14-21 days (depending upon chemotherapy regimen) in the absence of disease progression or unacceptable toxicity. ARM II: Patients receive single-agent irinotecan hydrochloride or FOLFIRI as outlined above and cetuximab as in arm I. Patients also receive bevacizumab IV over 30 minutes on day 1. Courses repeat every 14-21 days (depending upon chemotherapy regimen) in the absence of disease progression or unacceptable toxicity. ARM III (closed to accrual as of 4/20/2009): Patients receive single-agent irinotecan hydrochloride or FOLFIRI as outlined above and cetuximab as in arm I. Patients also receive a higher dose of bevacizumab (higher than in arm II) IV over 30 minutes on day 1. Courses repeat every 14-21 days (depending upon chemotherapy regimen) in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed every 6 months for 2 years and then once a year for 3 years.

Official Title
-----------------
Phase III Trial of Irinotecan-Based Chemotherapy Plus Cetuximab (NSC-714692) or Bevacizumab (NSC-704865) as Second-Line Therapy for Patients With Metastatic Colorectal Cancer Who Have Progressed on Bevacizumab With Either FOLFOX, OPTIMOX or XELOX

Conditions
-----------------
Recurrent Colon Cancer, Recurrent Rectal Cancer, Stage IVA Colon Cancer, Stage IVA Rectal Cancer, Stage IVB Colon Cancer, Stage IVB Rectal Cancer

Intervention / Treatment
-----------------
* Drug: irinotecan hydrochloride
* Drug: leucovorin calcium
* Drug: fluorouracil
* Biological: cetuximab
* Biological: bevacizumab


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Patients must have metastatic colorectal cancer that has been histologically or cytologically confirmed; confirmation may be from either the primary tumor or a metastasis; patients must have wild type KRAS Patients must be registered within 28 days of documented disease progression on first line chemotherapy with bevacizumab plus either FOLFOX, OPTIMOX, or XELOX; this progression must have occurred within 90 days after the last dose of bevacizumab; patients who discontinued oxaliplatin, continued with 5-FU/LV or capecitabine and bevacizumab and then had subsequent progression while on fluoropyrimidine and bevacizumab are eligible; patients who discontinued bevacizumab due to adverse events in the first-line setting are not eligible Measurable or nonmeasurable disease At least 14 days must have elapsed since the last dose of first line chemotherapy and bevacizumab Patients must not have received prior treatment with irinotecan (either as adjuvant or metastatic treatment) Patients must have no history of prior treatment with cetuximab or other agents targeting VEGF or EGFR (except for bevacizumab) Prior radiotherapy is allowed, provided at least 28 days have elapsed since the last treatment; all adverse events related to radiation therapy must be resolved Prior surgery is allowed, provided at least 28 days have elapsed since any major surgery and patient has recovered from all effects Zubrod performance status 0-2 Absolute neutrophil count (ANC) >= 1,500/mm^3 Platelet count >= 100,000/mm^3 Hemoglobin >= 9 g/dL Total bilirubin =< 1.5 times upper limit of normal (ULN) Serum glutamic oxaloacetic transaminase (SGOT) or serum glutamic pyruvate transaminase (SGPT) =< 2.5 x IULN; if there are known liver metastases, SGOT or SGPT must be =< 5 x IULN; these results must be obtained within 28 days prior to registration Serum creatinine =< IULN or measured or estimated creatinine clearance >= 60 mL/min Patients must not have a history or known presence of brain metastasis Patients may be on full dose anticoagulation with warfarin provided that the patient has an acceptable International Normalized Ratio (INR) (between 2 and 3), obtained within 28 days prior to registration No clinically relevant bleeding diathesis or coagulopathy Patients must not have experienced nephrotic range proteinuria from prior bevacizumab therapy; urine protein must be screened by urine analysis for Urine Protein Creatinine (UPC) ratio; for UPC ratio > 0.5, 24-hour urine protein must be obtained and the level must be < 1,000 mg for patient enrollment; urine protein and creatinine used in calculating the UPC ratio must be obtained within 28 days prior to registration No uncontrolled high blood pressure (BP) (i.e., systolic BP > 150 mm Hg and diastolic BP > 90 mm Hg) No cardiovascular event within the past 6 months, including any of the following: Arterial thrombosis Unstable angina Myocardial infarction Cerebrovascular accident Patients must not have New York Heart Association (NYHA) >= Grade 2 congestive heart failure Patients must not have unstable symptomatic arrhythmia requiring medication; (patients with chronic, controlled arrhythmias such as atrial fibrillation or paroxysmal supraventricular tachycardia [PSVT] are eligible) No clinically significant peripheral vascular disease No serious or nonhealing active wound, ulcer, or bone fracture No history of gastrointestinal (GI) perforation while on prior bevacizumab No significant bleeding episodes (e.g., hemoptysis or upper or lower GI bleeding) within the past 6 months unless the source of bleeding has been resected No known hypersensitivity to bevacizumab or known potential hypersensitivity to cetuximab No other concurrent chemotherapy, hormonal therapy, radiotherapy, immunotherapy, or any other type of anticancer treatment Due to the possibility of harm to a fetus or nursing infant from this treatment regimen, patients must not be pregnant or nursing; women and men of reproductive potential must have agreed to use an effective contraceptive method No other malignancy within the past 5 years except for adequately treated basal or squamous cell skin cancer or cervical cancer in situ All patients must be informed of the investigational nature of this study and must sign and give written informed consent in accordance with institutional and federal guidelines At the time of patient registration, the treating institution's name and identification (ID) number must be provided to the Data Operations Center in Seattle in order to ensure that the current (within 365 days) date of institutional review board approval for this study has been entered into the data base

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm I (chemotherapy, cetuximab)<br>Patients receive single-agent irinotecan hydrochloride IV or FOLFIRI IV. They also receive cetuximab IV over 1-2 hours on day 1. Courses repeat every 14-21 days (depending upon chemotherapy regimen) in the absence of disease progression or unacceptable toxicity. | Drug: irinotecan hydrochloride<br>* Given IV<br>* Other names: U-101440E;Drug: leucovorin calcium<br>* Given IV<br>* Other names: LV;Drug: fluorouracil<br>* Given IV<br>* Other names: 5-FU;Biological: cetuximab<br>* Given IV<br>* Other names: monoclonal antibody C225;|
| Experimental: Arm II (chemotherapy, cetuximab, bevacizumab)<br>Patients receive single-agent irinotecan hydrochloride or FOLFIRI AND cetuximab as in arm I. Patients also receive bevacizumab IV over 30 minutes on day 1. Courses repeat every 14-21 days (depending upon chemotherapy regimen) in the absence of disease progression or unacceptable toxicity. | Drug: irinotecan hydrochloride<br>* Given IV<br>* Other names: U-101440E;Drug: leucovorin calcium<br>* Given IV<br>* Other names: LV;Drug: fluorouracil<br>* Given IV<br>* Other names: 5-FU;Biological: cetuximab<br>* Given IV<br>* Other names: monoclonal antibody C225;Biological: bevacizumab<br>* Given IV<br>* Other names: rhuMAb VEGF;|
| Experimental: Arm III (closed to accrual as of 4/20/2009)<br>Patients receive single-agent irinotecan hydrochloride or FOLFIRI AND cetuximab as in arm I. Patients also receive a higher dose of bevacizumab (higher than in arm II) IV over 30 minutes on day 1. Courses repeat every 14-21 days (depending upon chemotherapy regimen) in the absence of disease progression or unacceptable toxicity. | Drug: irinotecan hydrochloride<br>* Given IV<br>* Other names: U-101440E;Drug: leucovorin calcium<br>* Given IV<br>* Other names: LV;Drug: fluorouracil<br>* Given IV<br>* Other names: 5-FU;Biological: cetuximab<br>* Given IV<br>* Other names: monoclonal antibody C225;Biological: bevacizumab<br>* Given IV<br>* Other names: rhuMAb VEGF;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-free Survival (PFS) | PFS is measured from date of registration to first documentation of progression or symptomatic deterioration, or death due to any cause. Patients last known to be alive and progression free are censored at date of last contact. | Up to 5 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Survival | Time to death is from date of registration to date of death due to any cause. Patients last known to be alive are censored at date of last contact. | Up to 5 years | 
| Objective Tumor Response |  | Up to 5 years | 
| Toxicity | Number of patients with Grade 3 through 5 adverse events that are related to study drug. Only adverse events that are possibly, probably or definitely related to study drug are reported. | Up to 5 years |