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

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
National Cancer Institute (NCI)
ClinicalTrials.gov Identifier:
NCT00134069
First received: August 22, 2005
Last updated: April 15, 2014
Last verified: April 2014
  Purpose

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


Condition Intervention Phase
Recurrent Colon Cancer
Recurrent Rectal Cancer
Stage III Colon Cancer
Stage III Rectal Cancer
Stage IV Colon Cancer
Stage IV Rectal Cancer
Drug: sorafenib tosylate
Drug: cetuximab
Drug: irinotecan hydrochloride
Phase 1

Study Type: Interventional
Study Design: Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
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

Resource links provided by NLM:


Further study details as provided by National Cancer Institute (NCI):

Primary Outcome Measures:
  • 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 ] [ Designated as safety issue: Yes ]
  • Recommended dose for phase II evaluation of the combination of sorafenib, cetuximab and irinotecan [ Time Frame: 56 days ] [ Designated as safety issue: No ]
  • Clinical activity of the combination of sorafenib, cetuximab and irinotecan in terms of radiological response [ Time Frame: Up to 30 days ] [ Designated as safety issue: No ]
  • 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 ] [ Designated as safety issue: No ]
  • Pharmacodynamics of the combination of irinotecan when given in combination with sorafenib and cetuximab in tumor tissues [ Time Frame: Up to 30 days ] [ Designated as safety issue: No ]

Enrollment: 48
Study Start Date: June 2005
Study Completion Date: December 2011
Primary Completion Date: September 2010 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: 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.
Drug: sorafenib tosylate
Given orally
Other Names:
  • BAY 43-9006
  • BAY 43-9006 Tosylate Salt
  • BAY 54-9085
  • Nexavar
  • SFN
Drug: cetuximab
Given IV
Other Names:
  • C225
  • C225 monoclonal antibody
  • IMC-C225
  • MOAB C225
  • monoclonal antibody C225
Drug: irinotecan hydrochloride
Given IV
Other Names:
  • Campto
  • Camptosar
  • CPT-11
  • irinotecan
  • U-101440E

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

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
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
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00134069

Locations
United States, Colorado
University of Colorado at Denver Health Sciences Center
Aurora, Colorado, United States, 80045
United States, Maryland
Johns Hopkins University
Baltimore, Maryland, United States, 21287-8936
Sponsors and Collaborators
Investigators
Principal Investigator: Wells Messersmith University of Colorado at Denver Health Sciences Center
  More Information

No publications provided

Responsible Party: National Cancer Institute (NCI)
ClinicalTrials.gov Identifier: NCT00134069     History of Changes
Other Study ID Numbers: NCI-2009-00110, 07-0571, R21CA117125, U01CA070095
Study First Received: August 22, 2005
Last Updated: April 15, 2014
Health Authority: United States: Food and Drug Administration

Additional relevant MeSH terms:
Colonic Neoplasms
Colorectal Neoplasms
Rectal Neoplasms
Colonic Diseases
Digestive System Diseases
Digestive System Neoplasms
Gastrointestinal Diseases
Gastrointestinal Neoplasms
Intestinal Diseases
Intestinal Neoplasms
Neoplasms
Neoplasms by Site
Rectal Diseases
Antibodies
Antibodies, Monoclonal
Cetuximab
Irinotecan
Sorafenib
Antineoplastic Agents
Antineoplastic Agents, Phytogenic
Enzyme Inhibitors
Immunologic Factors
Molecular Mechanisms of Pharmacological Action
Pharmacologic Actions
Physiological Effects of Drugs
Protein Kinase Inhibitors
Radiation-Sensitizing Agents
Therapeutic Uses
Topoisomerase I Inhibitors
Topoisomerase Inhibitors

ClinicalTrials.gov processed this record on October 21, 2014