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

Phase 2

Completed

Conditions: Recurrent Skin Cancer
Squamous Cell Carcinoma of the Skin

Interventions: Drug: Gefitinib
Radiation: Radiotherapy
Other: laboratory biomarker analysis
Procedure: Conventional surgery

Registration Number: NCT00126555

Lead Sponsor: National Cancer Institute (NCI)

Brief Summary: 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: 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.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 23

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)

Study & Design

Study Type: INTERVENTIONAL

Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Stratum I (Gefitinib, Radiotherapy, Surgery)	laboratory biomarker analysis	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.
Stratum I (Gefitinib, Radiotherapy, Surgery)	Gefitinib	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.
Stratum I (Gefitinib, Radiotherapy, Surgery)	Radiotherapy	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.
Stratum II (Gefitinib, Radiotherapy/Surgery)	Radiotherapy	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.
Stratum II (Gefitinib, Radiotherapy/Surgery)	laboratory biomarker analysis	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.
Stratum II (Gefitinib, Radiotherapy/Surgery)	Conventional surgery	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.
Stratum II (Gefitinib, Radiotherapy/Surgery)	Gefitinib	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.

Primary Outcome Measures

Name	Time	Method
Number of Participants With Response Rate During Induction, Dose Escalation, and Concomitant With Radiation.	Up to 100 days	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.
Toxicity as Assessed by the National Cancer Institute (NCI) Common Toxicity Criteria Associated With Gefitinib Therapy: Expected Toxicities (Grade 1 - 3)	Up to 5 years	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.
Toxicity as Assessed by the National Cancer Institute (NCI) Common Toxicity Criteria Associated With Gefitinib Therapy: UnExpected Toxicities (Grade 1 - 3)	Up to 5 years	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.
Early Progression Rate	Baseline to 60 days, up to 2 courses of induction therapy	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.

Secondary Outcome Measures

Name	Time	Method
Clinical Response According to Response Evaluation Criteria In Solid Tumors (RECIST)	Up to 5 years	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.
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