Phase I/II Clinical, Pharmacological, and Biological Study of BAY 43-9006 in Combination With Cetuximab and Irinotecan in Patients With Advanced Colorectal Cancer
Overview
- Phase
- Phase 1
- Intervention
- sorafenib tosylate
- Conditions
- Recurrent Colon Cancer
- Sponsor
- National Cancer Institute (NCI)
- Enrollment
- 48
- Locations
- 2
- Primary Endpoint
- 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
- Status
- Completed
- Last Updated
- 12 years ago
Overview
Brief Summary
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
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.
Investigators
Eligibility Criteria
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
Exclusion Criteria
- Not provided
Arms & Interventions
Treatment (sorafenib, irinotecan, cetuximab)
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.
Intervention: sorafenib tosylate
Treatment (sorafenib, irinotecan, cetuximab)
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.
Intervention: cetuximab
Treatment (sorafenib, irinotecan, cetuximab)
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.
Intervention: irinotecan hydrochloride
Outcomes
Primary Outcomes
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
Time Frame: Up to 30 days
Clinical activity of the combination of sorafenib, cetuximab and irinotecan in terms of radiological response
Time Frame: 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
Time Frame: Up to 30 days
Pharmacodynamics of the combination of irinotecan when given in combination with sorafenib and cetuximab in tumor tissues
Time Frame: Up to 30 days
Recommended dose for phase II evaluation of the combination of sorafenib, cetuximab and irinotecan
Time Frame: 56 days