Cetuximab in Treating Patients With Precancerous Lesions of the Upper Aerodigestive Tract

Phase II Study of Single-Agent Cetuximab for Treatment of High-Risk Pre-malignant Upper Aerodigestive Lesions

RATIONALE: Monoclonal antibodies, such as cetuximab, can block abnormal cell growth in different ways. Some block the ability of abnormal cells to grow and spread. Others find abnormal cells and help kill them or carry cell-killing substances to them.

PURPOSE: This randomized phase II trial is studying how well cetuximab works in treating patients with precancerous lesions of the upper aerodigestive tract.

Study Overview

• Status: Completed
• Conditions: Head and Neck Cancer; Precancerous Condition
• Intervention / Treatment: Biological: cetuximab

Detailed Description

OBJECTIVES:

Primary

• To determine the histologic response rate in patients with high-risk, premalignant lesions of the upper aerodigestive tract treated with cetuximab.

Secondary

• To determine the clinical response rate in these patients.
• To determine if patterns of epidermal growth factor receptor (EGFR) component expression are altered in these patients.
• To determine the change in status of genetic alterations, including loss of heterozygosity, in these patients.

OUTLINE: This is a multicenter study. Patients are stratified by lesion type [diffuse dysplasia vs recurrent dysplasia vs dysplastic lesions with 3p or 9p loss of heterozygosity (LOH)]. Patients are randomized to 1 of 2 arms.

• Arm I (treatment): Patients receive cetuximab IV over 1-2 hours on days 1, 8, 15, 22, 29, 36, 43, and 50 in the absence of disease progression or unacceptable toxicity.
• Arm II (control): Patients receive regular follow-up care. Patients have the option of receiving cetuximab after completion of the study.

In both arms, patients with persistent or recurrent high-grade dysplasia or dysplastic lesions with 3p or 9p LOH undergo surgical resection, if feasible, after week 8.

Tumor biopsy samples are obtained at baseline* and after week 8 for histologic and biomarker correlative studies. Tissue samples are analyzed by histopathology to determine histologic changes in post-treatment lesions and by immuno-histochemistry (IHC) to measure expression and activation of EGFR signaling pathway components. LOH studies are also performed.

NOTE: *Paraffin-embedded tissue from the original diagnostic biopsy may be used for baseline assessment, if the diagnostic biopsy was performed within 3 months prior to study entry.

After completion of study therapy, patients are followed at approximately 1 month, every 3 months for 2 years, and then every 6 months for up to 5 years as per routine standard of care.

• Study Type: Interventional
• Enrollment (Actual): 35
• Phase: Phase 2

Contacts and Locations

Study Locations

• Canada
  • British Columbia
    • Vancouver, British Columbia, Canada, V5Z 4E6
      • British Columbia Cancer Agency - Vancouver Cancer Centre
• United States
  • California
    • San Francisco, California, United States, 94115
      • UCSF Helen Diller Family Comprehensive Cancer Center
  • Illinois
    • Chicago, Illinois, United States, 60637-1470
      • University of Chicago Cancer Research Center
  • Kentucky
    • Lexington, Kentucky, United States, 40536-0093
      • Lucille P. Markey Cancer Center at University of Kentucky
  • Maryland
    • Baltimore, Maryland, United States, 21231-2410
      • Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
    • Baltimore, Maryland, United States, 21201
      • Greenebaum Cancer Center at University of Maryland Medical Center
  • Michigan
    • Ann Arbor, Michigan, United States, 48109-0942
      • University of Michigan Comprehensive Cancer Center
  • New York
    • New York, New York, United States, 10010
      • NYU Cancer Institute at New York University Medical Center
  • Pennsylvania
    • Pittsburgh, Pennsylvania, United States, 15232
      • UPMC Cancer Centers
  • South Carolina
    • Charleston, South Carolina, United States, 29425
      • Hollings Cancer Center at Medical University of South Carolina

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 120 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

DISEASE CHARACTERISTICS:

• Histologically confirmed high-risk, premalignant lesions of the upper aerodigestive tract, meeting one of the following criteria:

  • Unresectable, diffuse high-grade dysplasia, defined as moderate or severe dysplasia that is not assessable by physical examination and/or that cannot be excised by standard surgical techniques
  • previously treated HNSCC with persistent or recurrent high grade dysplasia with no evidence of head and neck malignancy for three months prior to enrollment or who have successfully completed therapy for head and neck malignancy more than 3 months prior to enrollment.
  • Dysplastic lesions with 3p or 9p loss of heterozygosity

• Disease location amenable to endoscopic biopsy in an outpatient clinical setting or operative biopsy within the routine scheduling and practice of clinical care

  • No medical contraindication to biopsy of the target lesion
  • Pathology must be reviewed by the Johns Hopkins Hospital Department of Pathology

PATIENT CHARACTERISTICS:

• Eastern Cooperative Oncology Group (ECOG) performance status 0-1
• Absolute neutrophil count (ANC) > 1,000/mm³
• Platelet count > 75,000/mm³
• Creatinine clearance > 60 mL/min
• Total serum bilirubin < 1.5 mg/dL
• Not pregnant or nursing
• Negative pregnancy test
• Fertile patients must use effective contraception during and for 3 months after completion of study therapy
• No concurrent illness likely to preclude study therapy or surgical resection
• Patients with a history of a curatively treated malignancy are eligible provided they are disease-free and have a survival prognosis that exceeds 5 years

• No evidence of clinically active interstitial lung disease

  • Patients with chronic, stable radiographic changes who are asymptomatic are eligible
• No history or radiological evidence of pulmonary fibrosis
• No acute myocardial infarction within the past 3 months
• No uncontrolled angina, arrhythmia, or congestive heart failure
• No evidence of other severe or uncontrolled systemic disease (e.g., unstable or uncompensated respiratory, cardiac, hepatic, or renal disease)
• No evidence of any other significant clinical disorder or laboratory finding that would preclude study participation
• No known severe hypersensitivity to cetuximab or any of its excipients
• No prior hypersensitivity reaction to chimerized or murine monoclonal antibody therapy
• No severe abnormality of the cornea

PRIOR CONCURRENT THERAPY:

• See Disease Characteristics
• Recovered from prior oncologic or other major surgery or biopsy
• More than 30 days since prior non-approved or investigational drugs
• No prior chemotherapy, radiotherapy, or surgery for the premalignant lesions
• No prior EGFR-targeted agents (e.g., cetuximab, gefitinib, or erlotinib)

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Arm I (treatment); Patients receive cetuximab IV over 1-2 hours on days 1, 8, 15, 22, 29, 36, 43, and 50 in the absence of disease progression or unacceptable toxicity.	Biological: cetuximab; given IV
No Intervention: Arm II (control); Patients receive regular follow-up care

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants With Objective Response Based on Histologic Grade	Histologic downgrade by at least one grade of dysplasia (e.g Severe to Moderate).	8 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants With Objective Response Based on Clinical Assessment	Clinical visualization on whether lesion responded to treatment (i.e., direct visualization of the lesion combined with histologic grade)	8 weeks
Status of Epidermal Growth Factor Receptor (EGFR) Pathway Components and Molecular Alterations in Pre-treatment Biopsies		Baseline (pre-treatment)
Status of EGFR Pathway Components and Molecular Alterations in Post-treatment Biopsies		At 8 weeks post-treatment
Survival		Up to year 5 years post-treatment
Lesion Recurrence		Up to year 5 years post-treatment

Collaborators and Investigators

• Sponsor: Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
• Collaborators: National Cancer Institute (NCI)
• Investigators: Study Chair: Joseph Califano, MD, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

Study record dates

Study Major Dates

• Study Start: May 1, 2007
• Primary Completion (Actual): December 1, 2011
• Study Completion (Actual): December 1, 2011

Study Registration Dates

• First Submitted: August 31, 2007
• First Submitted That Met QC Criteria: August 31, 2007
• First Posted (Estimate): September 3, 2007

Study Record Updates

• Last Update Posted (Actual): March 12, 2020
• Last Update Submitted That Met QC Criteria: February 27, 2020
• Last Verified: February 1, 2020

More Information

Terms related to this study

• Keywords: precancerous condition; oropharyngeal cancer; laryngeal cancer; hypopharyngeal cancer; lip and oral cavity cancer; nasopharyngeal cancer; paranasal sinus and nasal cavity cancer; salivary gland cancer
• Additional Relevant MeSH Terms: Neoplasms; Precancerous Conditions; Antineoplastic Agents; Antineoplastic Agents, Immunological; Cetuximab
• Other Study ID Numbers: J0644 CDR0000562250; P30CA006973 (U.S. NIH Grant/Contract); P50CA096784 (U.S. NIH Grant/Contract); JHOC-J0644; JHOC-NA_00001757