Gefitinib in Treating Patients Who Are Undergoing Surgery and/or Radiation Therapy for Locally Advanced or Recurrent Squamous Cell Skin Cancer

Study Overview
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Brief Summary
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The goal of this clinical research study is to learn if giving Iressa (Gefitinib or ZD1839) with surgery and/or radiation will help to control squamous cell carcinoma of the skin. The safety of this treatment will also be studied

Detailed Description
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PRIMARY OBJECTIVES: I. Early progression rate (progression during ZD1839 induction). II. Feasibility of induction ZD1839 (for all patients) and concomitant ZD1839 with radiotherapy (for unresectable patients). III. Toxicities of induction ZD1839 (for all patients) and concomitant ZD1839 with radiotherapy (for unresectable patients). SECONDARY OBJECTIVES: I. Response: clinical responses to induction therapy. II. Failures: frequency and timing of local and distant failures. III. Biomarkers: biomarker levels in tumor and normal tissue. TERTIARY OBJECTIVES: I. For progressive disease responders, patients will be followed for locoregional and distant metastases data. II. Feasibility of maintenance ZD1839. III. Toxicities of maintenance ZD1839. OUTLINE: Patients are assigned to 1 of 2 groups. STRATUM I (initially resectable tumor): Patients undergo radiotherapy once daily (QD) 5 days a week for approximately 6-7 weeks. Patients also receive gefitinib orally (PO) QD for up to 12 months STRATUM II (initially unresectable tumor): Patients undergo radiotherapy QD 5 days a week for approximately 6-7 weeks. Patients also receive concurrent gefitinib PO QD for 6-7 weeks. Patients then undergo surgery. After surgery, patients receive gefitinib PO QD for up to 12 months. After completion of study treatment, patients are followed up for up to 5 years.

Official Title
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A Phase II Study of ZD1839 and Radiation in Patients With Squamous Cell Carcinoma of the Skin

Conditions
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Recurrent Skin Cancer, Squamous Cell Carcinoma of the Skin

Intervention / Treatment
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* Drug: Gefitinib
* Radiation: Radiotherapy
* Procedure: Conventional surgery
* Other: laboratory biomarker analysis


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Within 12 weeks (+/- 2 weeks) prior to study entry, patients must have histologically or cytologically confirmed squamous cell carcinoma (SCC) of skin that is either locally advanced or recurrent with measurable disease; if the biopsy was collected outside of MDACC, the MDACC Pathology Department must assess and confirm the SCC diagnosis Patients may have previous surgical intervention with residual or recurrent disease Eastern Cooperative Oncology Group (ECOG) performance status =< 2 (Karnofsky >= 60%) Leukocytes >= 3,000/mm^3 Absolute neutrophil count >= 1,500/mm^3 Platelets >= 100,000/mm*3 Total bilirubin within normal institutional limits aspartate aminotransferase (AST or SGOT) and alanine aminotransferase (ALT or SGPT) =< 2.5 * institutional upper limit of normal Creatinine within normal institutional limits OR; creatinine clearance >= 60 mL/min/1.73 m^2 for patients with creatinine levels above institutional normal Tumors must be at least 2 cms in size or have histological or cytological verification of muscle, bone, lymph node metastasis, or perineural involvement, as measured by the treating physician(s) or National principal investigator (PI) Negative serum pregnancy test for women of child-bearing potential (performed within 14 days, +/- 1 day, prior to start of treatment); women of child-bearing potential and men must agree to use adequate contraception prior to study entry and for the duration of study participation; should a woman become pregnant or suspect she is pregnant while participating in the study, she should inform her treating physician(s) immediately Ability to understand and the willingness to sign a written Informed Consent Document (ICD); in the event that non-English speaking participants are eligible for this study, a short form (if applicable) or an ICD in their language, will be utilized and completed in accordance with the MD Anderson's Policy For Consenting Non-English Speaking Participants Exclusion Criteria: Patients who have previous radiotherapy to the proposed site of skin cancer Patients with active cancers other than skin Patients currently receiving any other investigational agents at time of study enrollment; patients may have received investigational agents in the past; no washout time period is required Patients with a history of brain metastases must be excluded from this clinical study because of their poor prognosis and because they often develop progressive neurological dysfunction that would confound the evaluation of neurological and other adverse events History of allergic reactions attributed to compounds of similar chemical or biologic composition to ZD1839 Age less than 18 years Presence of uncontrolled intercurrent illness (co-morbid conditions) that would limit compliance with study requirements including , but not limited to, ongoing or active infection requiring parenteral antibiotics at time of study registration, symptomatic congestive heart failure (NYHA class II or greater), unstable angina pectoris or cardiac arrhythmia requiring maintenance medication Pregnant women are excluded from this study because ZD1839 is a signal transduction inhibitor agent with the potential for teratogenic or abortifacient effects; there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with ZD1839, breastfeeding should be discontinued if the mother is treated with ZD1839 Patients with known immune deficiency are at an increased risk when treated with marrow-suppressive therapy, HIV-positive patients receiving combination anti-retroviral therapy are excluded due to the possible pharmacokinetic interactions with ZD1839; appropriate studies will be undertaken in patients receiving combination anti-retroviral therapy when indicated CYP3A4 inducing agents; patients receiving the following CYP3A4 inducing agents will be excluded; these include: carbamazepine, ethosuximide, griseofulvin, modafinil, nafcillin, oxcarbazepine, Phenobarbital, phenylbutazone, phenytoin, rifampin, rifabutin, St. John's Wort, and sulfinpyrazone Patients with distant metastatic disease as determined by diagnostic imaging (i.e., chest x-rays) and/or hematologic assessments (i.e., liver enzymes)

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Stratum I (Gefitinib, Radiotherapy, Surgery)<br>Resectable Strata: Induction Gefitinib (60 days), Surgery followed 3-6 weeks later by daily Radiotherapy 5 days a week for approximately 6-7 weeks then after 4 weeks restart Maintenance Gefitinib for up to additional 12 months post radiation. Gefitinib Induction Phase starting dose 250 mg/day, possible doubling to 500 mg/day for no response Day 15; Maintenance dose post radiation starts at same dose level as last dosing of Induction Phase. | Drug: Gefitinib<br>* Oral Gefitinib induction therapy given daily for 2 months at 250 mg/day, once a day for 30 days (1 cycle = 30 days) with at least 2 cycles of treatment (60 days) given. After 2 months evaluate for clinical response (15 days) and resectability (60 days). If after 15 days with no tumor response, daily dose doubled (500 mg), and discontinuation if tumor progression.<br>* Other names: ZD 1839;Radiation: Radiotherapy<br>* Undergo radiation therapy treatments once a day Monday through Friday for about 7 weeks. Each treatment takes about 15 minutes.<br>* Other names: therapy, radiation;Other: laboratory biomarker analysis<br>* Correlative studies<br>|
| Experimental: Stratum II (Gefitinib, Radiotherapy/Surgery)<br>Unresectable Strata: Concomitant Radiation/Gefitinib and post-radiation (or post-surgery if surgery is indicated) Gefitinib. Daily Radiotherapy 5 days a week for approximately 6-7 weeks concurrent with Maintenance Gefitinib dose daily up to 12 months. Gefitinib Induction Phase starting dose 250 mg/day, possible doubling to 500 mg/day for no response Day 15; Maintenance dose post radiation starts at same dose level as last dosing of Induction Phase. | Drug: Gefitinib<br>* Oral Gefitinib induction therapy given daily for 2 months at 250 mg/day, once a day for 30 days (1 cycle = 30 days) with at least 2 cycles of treatment (60 days) given. After 2 months evaluate for clinical response (15 days) and resectability (60 days). If after 15 days with no tumor response, daily dose doubled (500 mg), and discontinuation if tumor progression.<br>* Other names: ZD 1839;Radiation: Radiotherapy<br>* Undergo radiation therapy treatments once a day Monday through Friday for about 7 weeks. Each treatment takes about 15 minutes.<br>* Other names: therapy, radiation;Procedure: Conventional surgery<br>* Undergo surgery<br>* Other names: surgery, conventional;Other: laboratory biomarker analysis<br>* Correlative studies<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Early Progression Rate | Number of participants out of total participants with progression following two 30 day courses of Gefitinib. Tumor response evaluated by Response Evaluation Criteria in Solid Tumors by physical exam, computed tomography (CT) or Magnetic Resonance Imaging (MRI). Progressive disease defined as determined as response to Gefitinib induction therapy: Progression: 25% increase in sum of products of all measurable lesions over smallest sum observed (over baseline if no decrease) using the same techniques, OR clear worsening of any evaluable disease, OR appearance of any new lesion/site, OR failure to return for evaluation due to death or deteriorating condition (unless clearly unrelated to this cancer). Participants restaged on days 15 and 60 of treatment. | Baseline to 60 days, up to 2 courses of induction therapy | 
| Number of Participants With Response Rate During Induction, Dose Escalation, and Concomitant With Radiation. | Completion Induction phase, participants are evaluated for clinical response and resectability. Resectable participants who had achieved at least stable disease and received surgery followed by radiation. Unresectable participants who had achieved at least stable disease received concomitant radiation/Gefitinib. | Up to 100 days | 
| Toxicity as Assessed by the National Cancer Institute (NCI) Common Toxicity Criteria Associated With Gefitinib Therapy: Expected Toxicities (Grade 1 - 3) | Severity and timing of toxicities evaluated according to NCI Common Terminology Criteria for Adverse Events (CTCAE), Version 3. Occurrences of late (post-radiation) toxicities that are radiation-related monitored and included. | Up to 5 years | 
| Toxicity as Assessed by the National Cancer Institute (NCI) Common Toxicity Criteria Associated With Gefitinib Therapy: UnExpected Toxicities (Grade 1 - 3) | Severity and timing of toxicities evaluated according to NCI Common Terminology Criteria for Adverse Events (CTCAE), Version 3. Occurrences of late (post-radiation) toxicities that are radiation-related monitored and included. | Up to 5 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Clinical Response According to Response Evaluation Criteria In Solid Tumors (RECIST) | Number participants with response defined by RECIST: Complete Response (CR): Disappearance all disease; No new lesions/non-evaluable disease; Responders on none/only maintenance doses of corticosteroids. Partial Response (PR): >/= 50% decrease under baseline in sum products perpendicular diameters of measurable lesions; No progression evaluable disease/new lesions; Responders on same/decreasing doses dexamethasone & stable/improved neurological exams. Stable/No Response (SD): Not qualify for CR, PR, or progression; requires minimum 12 weeks duration; Responders on same/decreasing doses dexamethasone & stable/improved neurological exams. Progression (PD): 25% increase in sum of products of all measurable lesions over smallest sum observed (over baseline if no decrease), OR clear worsening any evaluable disease, OR appearance any new lesion/site, OR failure to return due to death/deteriorating condition. All measurable/evaluable sites assessed using same baseline techniques. | Up to 5 years | 
| Frequency and Timing of Local and Distant Failures |  | From study entry to first documented local recurrence or last patient contact, assessed up to 5 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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squamous cell carcinoma of the skin, recurrent skin cancer, non-melanomatous skin cancer, Radiation, ZD1839, Iressa, Gefitinib