A Phase I/II Study of Bexarotene in Combination With ZD1839 (IRESSA®) in the Treatment of Non-Small Cell Lung Cancer

Inclusion Criteria:- Patients must have histologically or cytologically confirmed NSCLC
which is stage IIIB with malignant pleural effusion or stage IV and have failed therapy
with at least a standard first line chemotherapy regimen, or be intolerant of standard
chemotherapy.

   - Patients may have non-measurable disease, or measurable disease, defined as at least
   one lesion that can be accurately measured in at least one dimension (longest diameter
   to be recorded) as >20 mm with conventional techniques or as >10 mm with spiral CT
   scan).

   - Patients with asymptomatic or treated brain metastases will be eligible if they last
   received therapy (including steroids) > 4 weeks from study entry and are felt to have
   a low likelihood of rapid deterioration from their brain metastases.

   - Patients must have had at least 1 prior systemic therapy for NSCLC, or have shown
   intolerance to chemotherapy. Patients may not have received prior therapy with
   bexarotene, ZD1839, or erlotinib (Tarceva).

   - At least 4 weeks must have elapsed from the time of major surgery and patients must
   have recovered from the effects of any significant procedure.

   - A three week interval must have elapsed from the last dose of chemotherapy (30 days
   for investigational therapy), prior to beginning protocol therapy (6 weeks if
   nitrosoureas or mitomycin C). Palliative radiotherapy to bony sites of disease is
   allowed while on trial and up to time of enrollment provided patient has no
   significant side effects from the radiotherapy.

   - Age >= 18 years.

   - Life expectancy > 2 months.

   - ECOG performance status 0-2.

   - Women of childbearing potential must have a negative pregnancy test (serum ß HCG with
   a sensitivity of at least 50 mlU/L) within 7 days prior to initiation of treatment and
   must have used 2 reliable forms of effective contraception used simultaneously or have
   been sexually abstinent for at least 4 weeks prior to the negative pregnancy test
   through entry in the study. Should a woman become pregnant or suspect she is pregnant
   while participating in this study, she should inform her treating physician
   immediately.

      - Retinoid class agents are known teratogens.

   - Female patients and male patients with female partners of childbearing potential must
   agree to sexual abstinence or to practice 2 reliable forms of effective contraception
   used simultaneously during the entire period of bexarotene capsule treatment and for
   at least 1 month after treatment is discontinued. Male patients must agree to use
   condoms if they have a female sexual partner who is, or may become, pregnant.

   - Patients must have normal organ and marrow function as defined below:

      - leukocytes >= 3,000/ul

      - absolute neutrophil count >= 1,500/ul

      - platelets >= 100,000/ul

      - total bilirubin within normal institutional limits

      - AST(SGOT)/ALT(SGPT) <= 2.5 X institutional upper limit of normal

      - creatinine within normal institutional limits OR calculated creatinine clearance
      >= 60 mL/min/1.73 m2 for patients with creatinine levels above institutional
      normal

      - triglycerides and cholesterol levels which are within normal limits or
      "normalized" with medication

   - Patients may take the following agents, but with caution due to interactions with P450
   metabolism: dexamethasone, protease inhibitors, ketoconazole and other azole
   antifungals, erythromycin and other macrolides antibiotics, grapefruit juice, other
   retinoid class drugs, beta-carotene compounds, and agents which enhance insulin
   secretion and sensitivity. They may not take phenytoin, carbamazepine, rifampicin,
   barbiturates, or St. John's Wort while on study.

   - Ability to understand and the willingness to sign a written informed consent document
   Exclusion Criteria:- Insulin dependent diabetes

   - Thyroid disease

   - Patients may not have had chemotherapy within 3 weeks (6 weeks for nitrosoureas or
   mitomycin C) prior to entering the study and must have recovered from adverse events
   due to agents administered more than 4 weeks earlier. Palliative radiotherapy is
   allowed to bony sites of disease.

   - Patients may not be receiving any other investigational agents or have received any
   within 30 days prior to day 1 of study.

   - Patients with known symptomatic brain metastases are excluded from this clinical trial
   because of their poor prognosis, those with treated, asymptomatic brain metastases are
   eligible proved they have not required any therapy including steroids for at least 4
   weeks.

   - Patients with a history of allergic reactions or sensitivity attributed to compounds
   of similar chemical or biologic composition to bexarotene and ZD1839 are excluded.

   - Patients with triglycerides or cholesterol levels which are not within normal limits
   or "normalized" with medication will be excluded.

   - Patients will be excluded for uncontrolled intercurrent illness including, but not
   limited to, ongoing or active infection, symptomatic congestive heart failure,
   unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations
   that would limit compliance with study requirements.

   - Patients with another active malignancy except for non-melanoma skin cancers are
   excluded.

   - Pregnant or breastfeeding women are excluded.

   - Patients with risk factors for pancreatitis are excluded such as a history of
   pancreatitis, significant alcohol consumption or other factors which are deemed to put
   them at high risk.

   - Patients taking systemic vitamin A in doses exceeding 15,000 IU/day within 14 days of
   study entry will be excluded.

   - Patients who are unwilling to minimize exposure to ultraviolet light (sunlight) while
   on bexarotene will be excluded.

   - Patients MAY NOT TAKE GEMFIBROZIL while on study due to interactions with bexarotene

   - Patients may not take phenytoin, carbamazepine, rifampicin, barbiturates, or St John's
   Wort while on the study.

   - Patients with any evidence of clinically active interstitial lung disease will be
   excluded (patients with chronic stable radiographic changes who are asymptomatic need
   not be excluded)