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

Condition(s) targeted: Colorectal Cancer

Intervention: cetuximab (Drug); irinotecan hydrochloride (Drug); sorafenib tosylate (Drug); anti-cytokine therapy (Procedure); antiangiogenesis therapy (Procedure); antibody therapy (Procedure); biological therapy (Procedure); chemotherapy (Procedure); drug resistance inhibition (Procedure); enzyme inhibitor therapy (Procedure); growth factor antagonist therapy (Procedure); monoclonal antibody therapy (Procedure)

Phase: Phase 1/Phase 2

Status: Recruiting

Sponsored by: Sidney Kimmel Comprehensive Cancer Center

Official(s) and/or principal investigator(s):
Wells Messersmith, MD, Principal Investigator, Affiliation: Sidney Kimmel Comprehensive Cancer Center

RATIONALE: 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.

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.

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: Interventional, Treatment

Primary outcome:

Toxicity of sorafenib as assessed by NCI CTCAE v3.0

Efficacy as assessed by PET scan and RECIST criteria

Pharmacokinetics

Pharmacodynamics

Detailed description: OBJECTIVES:

* 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.

* Determine the recommended phase II dose of sorafenib when combined with cetuximab and irinotecan in these patients.

* Correlate the clinical activity of this regimen, in terms of radiologic and positron emission tomography (PET) response, with baseline ERK expression in these patients.

* Determine the pharmacokinetics of this regimen in these patients.

* Correlate the pharmacodynamic effects of this regimen with baseline ERK expression in these patients.

* 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.

PROJECTED ACCRUAL: Approximately 9-48 patients (9-15 for the phase I portion and 18-33 for the phase II portion) will be accrued for this study within 2-16 months.

Minimum age: 18 Years. Gender(s): Both.

Criteria:

DISEASE CHARACTERISTICS:

* Histologically or cytologically confirmed colorectal cancer

- Advanced or metastatic disease

- Not amenable to potential curative resection

* Tumor must be amenable to sequential biopsies

* Must have evidence of disesase progression after first-line chemotherapy for advanced disease.

* Measurable disease, defined as ≥ 1 unidimensionally measurable target lesion ≥ 20 mm by conventional techniques OR ≥ 10 mm by spiral CT scan

- Previously irradiated lesions are not considered measurable disease

* No known brain metastases

PATIENT CHARACTERISTICS:

Age

* 18 and over

Performance status

* ECOG 0-2 OR

* Karnofsky 60-100%

Life expectancy

* More than 12 weeks

Hematopoietic

* WBC ≥ 3,000/mm^3

* Absolute neutrophil count ≥ 1,500/mm^3

* Platelet count ≥ 100,000/mm^3

* No evidence of bleeding diathesis

Hepatic

* Bilirubin normal

* AST and ALT ≤ 2. 5 times upper limit of normal

Renal

* Creatinine normal OR

* Creatinine clearance ≥ 60 mL/min

Cardiovascular

* No hypertension

* No symptomatic congestive heart failure

* No unstable angina pectoris

* No cardiac arrhythmia

Other

* Not pregnant or nursing

* Negative pregnancy test

* Fertile patients must use effective contraception

* 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

PRIOR CONCURRENT THERAPY:

Biologic therapy

* No prior cetuximab

* No concurrent prophylactic filgrastim (G-CSF), sargramostim (GM-CSF) or epoetin alfa

Chemotherapy

* See Disease Characteristics

* At least 4 weeks since prior chemotherapy (6 weeks for nitrosoureas or mitomycin) and recovered

* No other concurrent chemotherapy

Endocrine therapy

* Not specified

Radiotherapy

* See Disease Characteristics

* More than 4 weeks since prior radiotherapy and recovered

Surgery

* Not specified

Other

* 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 therapeutic anticoagulation

- Concurrent prophylactic anticoagulation (e. g., low-dose warfarin) for venous or arterial devices allowed provided requirements for PT, INR, or PTT are met

* No concurrent combination antiretroviral therapy for HIV-positive patients

* No other concurrent investigational agents

* No other concurrent anticancer therapy

Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, Maryland 21231-2410, United States; Recruiting
Clinical Trials Office - Sidney Kimmel Comprehensive Cancer Ce, Phone: 410-955-8804, Email: jhcccro@jhmi.edu

Clinical trial summary from the National Cancer Institute's PDQ® database

Starting date: September 2005
Last updated: June 4, 2007