Sorafenib, Cetuximab, and Irinotecan in Treating Patients With Advanced or Metastatic Colorectal Cancer

Study Overview
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Brief Summary
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This phase I/II trial is studying the side effects and best dose of sorafenib when given together with cetuximab and irinotecan and to see how well they work in treating patients with advanced or metastatic colorectal cancer. Sorafenib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Monoclonal antibodies, such as cetuximab, 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. Sorafenib and cetuximab may also stop tumor growth by blocking blood flow to the tumor. Drugs used in chemotherapy, such as irinotecan, work in different ways to kill tumor cells, either by killing the cells or by stopping them from dividing. Giving sorafenib together with cetuximab and irinotecan may kill more tumor cells

Detailed Description
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OBJECTIVES: I. Determine the toxicity spectrum and dose-limiting toxic effects of sorafenib when combined with cetuximab and irinotecan in patients with advanced or metastatic colorectal cancer. II. Determine the recommended phase II dose of sorafenib when combined with cetuximab and irinotecan in these patients. III. Correlate the clinical activity of this regimen, in terms of radiologic and positron emission tomography (PET) response, with baseline extracellular signal-regulated kinase (ERK) expression as well as Kirsten rat sarcoma (KRAS), BRAF, and other genetic properties of tumors in these patients. IV. Determine the pharmacokinetics of this regimen in these patients. V. Correlate the pharmacodynamic effects of this regimen with baseline ERK expression as well as KRAS, BRAF, and other genetic properties of tumors in these patients. VI. Correlate the pharmacodynamic effects of this regimen on mitogen-activated protein kinase (MAPK) status in peripheral blood mononuclear cells and on normal skin and oral mucosa with clinical parameters in these patients. OUTLINE: This is a phase I dose-escalation study of sorafenib followed by a multicenter phase II study. PHASE I: COURSE 1 (56 days): Patients receive oral sorafenib once or twice daily on days 1-56, cetuximab IV over 1-2 hours on days 1, 8,15, 22, 29, 36, 43, and 50, and irinotecan IV over 90 minutes on days 15, 22, 29, and 36. COURSE 2 AND ALL SUBSEQUENT COURSES (42 days): Patients receive oral sorafenib once or twice daily on days 1-42, cetuximab IV over 1-2 hours on days 1, 8, 15, 22, 29, and 36, and irinotecan IV over 90 minutes on days 1, 8, 15, and 22. Courses repeat every 42 days in the absence of disease progression or unacceptable toxicity. Cohorts of 3-6 patients receive escalating doses of sorafenib until the maximum tolerated dose (MTD) is determined. The MTD is defined as the dose preceding that at which 2 of 3 or 2 of 6 patients experience dose-limiting toxicity. At least 6 patients are treated at the MTD. PHASE II: Patients receive sorafenib at the MTD determined in phase I, cetuximab, and irinotecan as in phase I. After completion of study treatment, patients are followed at 30 days. *NOTE: This trial was intended to be Phase I/II, but the trial never continued to the Phase II portion.

Official Title
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Phase I/II Clinical, Pharmacological, and Biological Study of BAY 43-9006 in Combination With Cetuximab and Irinotecan in Patients With Advanced Colorectal Cancer

Conditions
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Recurrent Colon Cancer, Recurrent Rectal Cancer, Stage III Colon Cancer, Stage III Rectal Cancer, Stage IV Colon Cancer, Stage IV Rectal Cancer

Intervention / Treatment
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* Drug: sorafenib tosylate
* Drug: cetuximab
* Drug: irinotecan hydrochloride


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histologically or cytologically confirmed colorectal cancer (advanced or metastatic disease not amenable to potential curative resection) Archival tumor (blocks and/or slides) must be available for patients who decline tumor biopsies Tumor must be amenable to sequential biopsies for patients willing to undergo tumor biopsy Must have evidence of disease progression after first-line chemotherapy for advanced disease Previously irradiated lesions are not considered measurable disease Measurable disease, defined as >= 1 unidimensionally measurable target lesion >= 20 mm by conventional techniques OR >= 10 mm by spiral CT scan No known brain metastases Eastern Cooperative Oncology Group (ECOG) 0-2 OR Karnofsky 60-100% Life expectancy of more than 12 weeks white blood cell count (WBC) >= 3,000/mm^3 Bilirubin normal Creatinine normal OR creatinine clearance >= 60 mL/min No hypertension No symptomatic congestive heart failure No unstable angina pectoris No cardiac arrhythmia Not pregnant or nursing Able to swallow oral medication Willing to undergo 2 sequential tumor and skin biopsies No ongoing or active infection No history of allergic reaction attributed to compounds of similar chemical or biologic composition to study drugs No psychiatric illness or social situation that would preclude study compliance No other uncontrolled illness No prior cetuximab No concurrent prophylactic filgrastim (G-CSF), sargramostim (GM-CSF) or epoetin alfa At least 4 weeks since prior chemotherapy (6 weeks for nitrosoureas or mitomycin) and recovered No other concurrent chemotherapy More than 4 weeks since prior radiotherapy and recovered No prior sorafenib No other prior therapy targeted against MAPK More than 14 days since prior and no concurrent administration of the following cytochrome P450 3A4 (CYP3A4) inducers: Rifampin Rifabutin Hypericum perforatum (St. John's wort) Phenytoin Carbamazepine Phenobarbital More than 7 days since prior and no concurrent administration of the following CYP3A4 inhibitors: Amiodarone Clarithromycin Diltiazem Erythromycin Grapefruit juice Indinavir Saquinavir Lopinavir in combination with ritonavir Fosamprenavir Ritonavir Atazanavir Nelfinavir Itraconazole Ketoconazole Nefazodone No concurrent combination antiretroviral therapy for HIV-positive patients No other concurrent investigational agents No other concurrent anticancer therapy Negative pregnancy test Fertile patients must use effective contraception Absolute neutrophil count >=1,500/mm^3 Platelet count ≥ 100,000/mm^3 No evidence of bleeding diathesis Aspartate aminotransferase (AST) and Alanine Aminotransferase (ALT) ≤ 2.5 times upper limit of normal

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment (sorafenib, irinotecan, cetuximab)<br>Patients will receive sorafenib by mouth once or twice a day and a 1- to 2-hour infusion of cetuximab once a week for 8 weeks. They will also receive a 1½-hour infusion of irinotecan once a week in weeks 3-6. Patients will then receive sorafenib by mouth once or twice a day and a 1- to 2-hour infusion of cetuximab once a week for 6 weeks. They will also receive a 1½-hour infusion of irinotecan once a week in weeks 1-4. Treatment may repeat every 6 weeks for as long as benefit is shown. | Drug: sorafenib tosylate<br>* Given orally<br>* Other names: SFN;Drug: cetuximab<br>* Given IV<br>* Other names: monoclonal antibody C225;Drug: irinotecan hydrochloride<br>* Given IV<br>* Other names: U-101440E;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Toxicity spectrum and dose-limiting toxicities of sorafenib in combination with cetuximab and irinotecan as assessed by NCI Common Toxicity Criteria for Adverse Effects (CTCAE) v 3.0 |  | Up to 30 days | 
| Recommended dose for phase II evaluation of the combination of sorafenib, cetuximab and irinotecan |  | 56 days | 
| Clinical activity of the combination of sorafenib, cetuximab and irinotecan in terms of radiological response |  | Up to 30 days | 
| Pharmacokinetics of sorafenib, cetuximab, and irinotecan when given in combination or when given in combination with cetuximab alone and with cetuximab and irinotecan |  | Up to 30 days | 
| Pharmacodynamics of the combination of irinotecan when given in combination with sorafenib and cetuximab in tumor tissues |  | Up to 30 days |