Cetuximab in Treating Patients With Advanced Solid Tumors

A Phase I Study of the Safety and Tolerability of Four Doses of Cetuximab (C225) in Patients With Advanced Solid Tumors

RATIONALE: 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.

PURPOSE: This phase I trial is studying the side effects and best dose of cetuximab in treating patients with advanced solid tumors.

Study Overview

• Status: Completed
• Conditions: Unspecified Adult Solid Tumor, Protocol Specific
• Intervention / Treatment: Biological: cetuximab; Genetic: molecular diagnostic method; Other: immunologic technique; Other: laboratory biomarker analysis

Detailed Description

OBJECTIVES:

Primary

• Determine the maximum tolerated dose of cetuximab in patients with advanced solid tumors.

Secondary

• Evaluate the safety and tolerability of this drug in these patients.
• Develop a detailed scale for assessment of rash in these patients.
• Investigate potential predictors of response using correlative studies on patient tissue, buccal mucosa, and blood samples.
• Obtain preliminary efficacy data and evaluate the relationship of efficacy to grade of rash.
• Correlate downstream markers (e.g., pMAPK, pAKT, and Ki-67) and the presence of epidermal growth factor receptor (EGFR) polymorphisms with clinical response and/or survival.
• Examine the levels of downstream marker proteins in buccal cells obtained pre- and post-treatment.
• Correlate basal p27 expression levels with response and/or survival.
• Determine if the presence of a K-RAS mutation influences response or survival outcome.
• Correlate the presence or absence of mutant K-RAS tumor DNA shed into patient plasma with response and/or outcome.
• Correlate levels of cytokines and chemokines with rash and clinical response.

OUTLINE: This is an open-label, dose-escalation study.

Patients receive cetuximab IV over 90 minutes once weekly for 4 weeks. Treatment repeats every 4 weeks for up to 12 courses in the absence of disease progression or unacceptable toxicity.

Cohorts of 3-6 patients receive escalating doses of cetuximab 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.

Patients undergo blood and buccal mucosa collection at baseline and prior to courses 2 and 3 of treatment for molecular correlative studies. Archival tumor tissue specimens are also used for molecular correlative studies. Immunologic correlative studies are performed using patient blood samples.

After completion of study treatment, patients are followed periodically for survival.

PROJECTED ACCRUAL: A total of 20 patients will be accrued for this study.

• Study Type: Interventional
• Enrollment (Actual): 27
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • California
    • Sacramento, California, United States, 95817
      • University of California Davis Cancer Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Signed written informed consent
• Histologically or cytologically proven advanced solid tumors not curable by surgery, radiation therapy or standard chemo-, immuno-, or hormonal therapy. A specific primary cancer need not have been identified (i.e., unknown primary is eligible).
• Patients must have received at least one prior regimen (chemotherapy and/or radiation) for metastatic disease. There is no limit to the number of prior therapies.
• Any prior chemotherapy must have been completed at least 4 weeks prior to start of study therapy. Previous radiation therapy must have been completed at least 2 weeks prior to start of study therapy. All side effects of prior therapy must be resolved prior to the start of study therapy.
• Patients with ZUBROD performance status 0-2 (see Appendix 1).
• Patients must have measurable disease or evaluable disease.
• Patients must have an estimated survival of at least 3 months.
• Patients with asymptomatic treated brain metastasis (surgical resection or radiotherapy) may be included if they are neurologically stable and have been off steroids for at least 4 weeks.
• Patients >/= 18 years of age.
• Patients of reproductive potential must agree to use an effective contraceptive method while on treatment and for 3 months afterward as the effects of cetuximab on the unborn fetus are unknown.
• Patients must have adequate hematologic function defined as: ANC >/= 1,500/mm3, platelets >/= 100,000/mm3.
• Patients must have adequate hepatic function defined as SGOT </= 3 x institutional UNL and serum bilirubin </= 2.0 mg/dL.
• Patients must have adequate renal function defined as a serum creatinine level </= 1.6 mg/dL or a calculated creatinine clearance of >/= 40 ml/min.

Exclusion Criteria:

• Female patients cannot be pregnant or breastfeeding as the effects of cetuximab on the unborn fetus are unknown. Documentation of a negative pregnancy test prior to treatment is required for all women of reproductive potential.
• Uncontrolled intercurrent illness including but not limited to ongoing infection or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situation that would limit compliance with study requirements.
• Patients with symptomatic brain metastasis or still requiring steroids.
• Patients who have received prior cetuximab therapy, prior therapy with any other drug that targets the EGF receptor (including, but not limited to, Iressa, Tarceva, Herceptin, CI1033, etc.), or prior therapy with a monoclonal antibody.
• Patients who have received prior chemotherapy within 4 weeks or radiation therapy within 2 weeks prior to the start of study therapy.
• Prior hypersensitivity reaction to chimerized or murine monoclonal antibody therapy.
• Patients may not receive any other chemotherapy, radiation therapy, or biologic therapy while on study.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: Phase I dose escalation study

Biological: cetuximab; Dose level 0: cetuximab 400 mg/m2 week 1, 250 mg/m2 weekly; Dose level 1: cetuximab 400 mg/m2 week 1, 300 mg/m2 weekly; Dose level 2: cetuximab 400 mg/m2 week 1, 350 mg/m2 weekly; Dose level 3: cetuximab 400 mg/m2 week 1, 400 mg/m2 weekly; Other Names: Erbitux; IMC-C225; Genetic: molecular diagnostic method; Tissue and Blood Specimens; IHC Methodology; IHC Scoring; K-RAS Mutation Analysis; Other: immunologic technique; Peripheral Blood Mononuclear Cells (PBMC); Other: laboratory biomarker analysis; Cetuximab Pharmacodynamics

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Maximum tolerated dose of cetuximab	December 2007

Secondary Outcome Measures

Outcome Measure	Time Frame
Safety and tolerability of cetuximab	December 2007
Potential predictors of response using correlative studies	December 2007
Correlation of efficacy of cetuximab with grade of skin rash	December 2007
Development of a detailed scale for assessing skin rash	December 2007

Collaborators and Investigators

• Sponsor: University of California, Davis
• Collaborators: National Cancer Institute (NCI)
• Investigators: Study Chair: Angela Davies, MD, University of California, Davis

Study record dates

Study Major Dates

• Study Start: December 1, 2004
• Primary Completion (Actual): November 1, 2007
• Study Completion (Actual): December 1, 2007

Study Registration Dates

• First Submitted: September 13, 2006
• First Submitted That Met QC Criteria: September 13, 2006
• First Posted (Estimate): September 15, 2006

Study Record Updates

• Last Update Posted (Estimate): March 29, 2010
• Last Update Submitted That Met QC Criteria: March 25, 2010
• Last Verified: March 1, 2010

More Information

Terms related to this study

• Keywords: unspecified adult solid tumor, protocol specific
• Additional Relevant MeSH Terms: Neoplasms; Antineoplastic Agents; Antineoplastic Agents, Immunological; Cetuximab
• Other Study ID Numbers: CDR0000506089; P30CA093373 (U.S. NIH Grant/Contract); UCDCC-165 (Other Identifier: University of California, Davis - Cancer Center); BMS-CA225027 (Other Grant/Funding Number: Bristol-Myers Squibb); 200412499 (Other Identifier: University of California, Davis - IRB); IMCL-8420 (Other Grant/Funding Number: Imclone Systems, Inc.)