Erlotinib With or Without Fulvestrant in Treating Patients With Stage IIIB or Stage IV Non-Small Cell Lung Cancer

OBJECTIVES:

Primary

- Compare objective tumor response in patients stage IIIB or IV non-small cell lung cancer
treated with erlotinib hydrochloride with vs without fulvestrant.

Secondary

- Correlate response rate with ER and EGF receptor expression in patients treated with
these regimens.

- Correlate measurement of ER-α, ER-β, EGF/HER-1 receptor and HER-2/neu receptor with
clinical response in patients treated with these regimens.

- Correlate erlotinib hydrochloride resistance with ER and HER receptor expression in
patients treated with these regimens.

OUTLINE: This is a randomized, open-label, multicenter study. Patients are stratified
according to performance status, gender, and participating center. Patients are randomized to
1 of 2 treatment arms.

- Arm I: Patients receive oral erlotinib hydrochloride once daily on days 1-28. Courses
repeat every 28 days.

- Arm II: Patients receive erlotinib hydrochloride as in arm I and fulvestrant
intramuscularly on days 1, 15, and 29, and then every 28 days thereafter.

In both arms, treatment continues in the absence of disease progression or unacceptable
toxicity.

After completion of study treatment, patients are followed for 30 days and then every 2
months until disease progression.

PROJECTED ACCRUAL: A total of 102 patients (34 in arm I and 68 in arm II) will be accrued for
this study.

Inclusion criteria:

- adults over the age of 18 capable of giving informed consent.

- Histologically confirmed non-small cell lung cancer

- Stage IIIB or IV NSCLC

- Tumor tissue block available.

- ECOG performance status of 0, 1 or 2.

- Measurable disease by RECIST criteria defined as ≥ 1 target lesion that has not been
irradiated. New lesions that have developed in a previously irradiated field may be
used as sites of measurable disease provided all other criteria are met.

- Meets 1 of the following criteria:

- Progressive disease after ≥ 1 prior standard chemotherapy regimen

- Refused chemotherapy

- Unable to receive standard chemotherapy

- women of childbearing age must have negative pregnancy test by urine or serum prior to
initiation of treatment. men and women of childbearing potential must consent to using
adequate contraception throughout treatment and for 3 months following surgery.

Exclusion criteria:

- Renal insufficiency (serum creatinine >2mg/dl)

- Liver insufficiency (serum total bilirubin >1.5X ULN, or serum transaminases > 2.5X
the ULN or %X ULN if hepatic metastases).

- hematologic abnormality platelets< 100,000 ANC <1,500/mm3

- THerapeutic anticoagulation will be allowed, but patients receiving fulvestrant while
on therapeutic anticoagulation will have the fulvestrant dose divided into twice as
many syringes to minimize the volume of intramuscular injection in these patients. In
patients receiving low molecular weight heparin or fondaparinux, these medications
should be held for 12 hours before and after fulvestrant injection if possible.

- Active CNS metastases.

- New York Heart Association class III or IV cardiac disease

- myocardial infarction within the past 12 months

- symptomatic ventricular arrhythmia

- symptomatic conduction abnormality

- evidence of clinically active interstitial lung disease

- Patients with asymptomatic chronic stable radiographic changes are eligible

- pregnant or nursing or inadequate contraception

- hypersensitivity to erlotinib hydrochloride or fulvestrant or to any of their
excipients

- comorbid disease or medical condition that would preclude study treatment or
compliance

- malignancy within the past 3 years except nonmelanoma skin cancer or carcinoma in situ
of the cervix

- chemotherapy or non-cytotoxic investigational agents within 4 weeks of initiating
treatment.

- major surgery within 4 weeks of initiating therapy. Minor surgery within 7 days of
initiating therapy.

- anticancer antiestrogen therapy. Concurrent stable-dose steroids allowed

- concomitant radiation therapy to the lungs. Radiation therapy to non-target lesions
will be allowed as long as it is completed 1 week prior to initiation of treatment.

- prior anticancer epidermal growth factor receptor inhibitors

- concurrent CYP3A4 inducers, including any of the following:

- Phenytoin

- Carbamazepine

- Rifampin

- Barbiturates

- Hypericum perforatum (St. John's wort)