Clinical trial NCT00524017: Cetuximab in Treating Patients With Precancerous Lesions of the Upper Aerodigestive Tract
Official title: Phase II Study of Single-Agent Cetuximab for Treatment of High-Risk Pre-malignant Upper Aerodigestive Lesions
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Head and Neck Cancer
Precancerous Condition
Keywords: hypopharyngeal cancer
laryngeal cancer
lip and oral cavity cancer
nasopharyngeal cancer
oropharyngeal cancer
paranasal sinus and nasal cavity cancer
salivary gland cancer
precancerous condition
Lead sponsor: Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
Sponsor class: OTHER
Collaborators: name: National Cancer Institute (NCI)
First posted: 2007-09-03
Enrollment: 35
Sex: ALL
Minimum age (years): 18
Maximum age (years): 120
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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.

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.

Eligibility criteria: 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)

Primary outcomes:
measure: Number of Participants With Objective Response Based on Histologic Grade
timeFrame: 8 weeks
Secondary outcomes:
measure: Number of Participants With Objective Response Based on Clinical Assessment
timeFrame: 8 weeks
measure: Status of Epidermal Growth Factor Receptor (EGFR) Pathway Components and Molecular Alterations in Pre-treatment Biopsies
timeFrame: Baseline (pre-treatment)
measure: Status of EGFR Pathway Components and Molecular Alterations in Post-treatment Biopsies
timeFrame: At 8 weeks post-treatment
measure: Survival
timeFrame: Up to year 5 years post-treatment
measure: Lesion Recurrence
timeFrame: Up to year 5 years post-treatment
Other outcomes:
Locations:
city: San Francisco
country: United States
facility: UCSF Helen Diller Family Comprehensive Cancer Center
state: California
city: Chicago
country: United States
facility: University of Chicago Cancer Research Center
state: Illinois
city: Lexington
country: United States
facility: Lucille P. Markey Cancer Center at University of Kentucky
state: Kentucky
city: Baltimore
country: United States
facility: Greenebaum Cancer Center at University of Maryland Medical Center
state: Maryland
city: Baltimore
country: United States
facility: Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
state: Maryland
city: Ann Arbor
country: United States
facility: University of Michigan Comprehensive Cancer Center
state: Michigan
city: New York
country: United States
facility: NYU Cancer Institute at New York University Medical Center
state: New York
city: Pittsburgh
country: United States
facility: UPMC Cancer Centers
state: Pennsylvania
city: Charleston
country: United States
facility: Hollings Cancer Center at Medical University of South Carolina
state: South Carolina
city: Vancouver
country: Canada
facility: British Columbia Cancer Agency - Vancouver Cancer Centre
state: British Columbia
Study officials:
affiliation: Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
name: Joseph Califano, MD
role: STUDY_CHAIR
References: