Sorafenib, Cetuximab, and Irinotecan in Treating Patients With Advanced or Metastatic Colorectal Cancer
Information source: National Cancer Institute (NCI)
ClinicalTrials.gov processed this data on August 23, 2015 Link to the current ClinicalTrials.gov record.
Condition(s) targeted: Recurrent Colon Cancer; Recurrent Rectal Cancer; Stage III Colon Cancer; Stage III Rectal Cancer; Stage IV Colon Cancer; Stage IV Rectal Cancer
Intervention: sorafenib tosylate (Drug); cetuximab (Drug); irinotecan hydrochloride (Drug)
Phase: Phase 1
Status: Completed
Sponsored by: National Cancer Institute (NCI) Official(s) and/or principal investigator(s): Wells Messersmith, Principal Investigator, Affiliation: University of Colorado at Denver Health Sciences Center
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
Clinical Details
Official title: Phase I/II Clinical, Pharmacological, and Biological Study of BAY 43-9006 in Combination With Cetuximab and Irinotecan in Patients With Advanced Colorectal Cancer
Study design: Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment
Primary outcome: 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 3.0Recommended dose for phase II evaluation of the combination of sorafenib, cetuximab and irinotecan Clinical activity of the combination of sorafenib, cetuximab and irinotecan in terms of radiological response Pharmacokinetics of sorafenib, cetuximab, and irinotecan when given in combination or when given in combination with cetuximab alone and with cetuximab and irinotecan Pharmacodynamics of the combination of irinotecan when given in combination with sorafenib and cetuximab in tumor tissues
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.
Eligibility
Minimum age: 18 Years.
Maximum age: N/A.
Gender(s): Both.
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
- 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
Locations and Contacts
University of Colorado at Denver Health Sciences Center, Aurora, Colorado 80045, United States
Johns Hopkins University, Baltimore, Maryland 21287-8936, United States
Additional Information
Starting date: June 2005
Last updated: April 15, 2014
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