Phase I/II Clinical, Pharmacological, and Biological Study of BAY 43-9006 in Combination With Cetuximab and Irinotecan in Patients With Advanced Colorectal Cancer
Phase I/II Clinical, Pharmacological, and Biological Study of BAY 43-9006 in Combination With Cetuximab and Irinotecan in Patients With Advanced Colorectal Cancer
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
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.
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:
More than 7 days since prior and no concurrent administration of the following CYP3A4 inhibitors:
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