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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


Phase 1/Phase 2
18 Years
N/A
Not Enrolling
Both
Recurrent Colon Cancer, Recurrent Rectal Cancer, Stage III Colon Cancer, Stage III Rectal Cancer, Stage IV Colon Cancer, Stage IV Rectal Cancer

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Trial Information

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


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 ERK expression as well as 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 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.


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

- ECOG 0-2 OR Karnofsky 60-100%

- Life expectancy of more than 12 weeks

- 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
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

- AST and ALT ≤ 2.5 times upper limit of normal

Type of Study:

Interventional

Study Design:

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

Outcome Measure:

Toxicity spectrum and dose-limiting toxicities of sorafenib in combination with cetuximab and irinotecan as assessed by NCI CTCAE v 3.0

Outcome Time Frame:

Up to 30 days

Safety Issue:

Yes

Principal Investigator

Wells Messersmith

Investigator Role:

Principal Investigator

Investigator Affiliation:

University of Colorado at Denver Health Sciences Center

Authority:

United States: Food and Drug Administration

Study ID:

NCI-2009-00110

NCT ID:

NCT00134069

Start Date:

June 2005

Completion Date:

December 2011

Related Keywords:

  • Recurrent Colon Cancer
  • Recurrent Rectal Cancer
  • Stage III Colon Cancer
  • Stage III Rectal Cancer
  • Stage IV Colon Cancer
  • Stage IV Rectal Cancer
  • Colonic Neoplasms
  • Rectal Neoplasms
  • Colorectal Neoplasms

Name

Location

Johns Hopkins UniversityBaltimore, Maryland  21205
University of Colorado at Denver Health Sciences CenterDenver, Colorado  80045