Gemcitabine and Carboplatin With or Without AZD2171 as First-Line Therapy in Treating Patients With Stage IIIB or Stage IV Non-Small Cell Lung Cancer

OBJECTIVES:

Primary

- Assess the objective tumor response rate in patients with stage IIIB or IV non-small
cell lung cancer treated with gemcitabine hydrochloride, carboplatin, and AZD2171 as
first-line therapy.

Secondary

- Compare the proportion of patients who are progression-free at 6 months after treatment
with gemcitabine hydrochloride and carboplatin with vs without AZD2171.

- Compare the duration of response for responding patients treated with these regimens.

- Compare the time-to-progression and time-to-treatment failure.

- Compare the 1-year overall survival.

- Compare the clinical toxicities.

- Assess the safety and tolerability of these regimens in these patients.

Tertiary

- Collect blood and tumor specimens for future evaluation of pharmacogenetic and
proteomic markers of tumor response and toxicity to therapy with these agents.

- Bank paraffin-embedded tissue blocks/slides and blood samples for future histochemistry
evaluation and DNA extraction.

OUTLINE: This is a randomized, multicenter study. Patients are stratified according to prior
adjuvant therapy (yes vs no) and ECOG performance status (0 vs 1). Patients are randomized
to 1 of 2 treatment arms.

- Arm I: Patients receive gemcitabine hydrochloride IV over 30 minutes on days 1 and 8,
carboplatin IV over 30 minutes on day 1, and oral AZD2171 once daily on days 1-21.
Treatment repeats every 21 days for up to 6 courses. Patients achieving stable disease,
partial response, or complete response after 6 courses of therapy receive AZD2171 alone
as above. Treatment with AZD2171 repeats every 21 days in the absence of disease
progression or unacceptable toxicity.

- Arm II: Patients receive gemcitabine and carboplatin as in arm I. Treatment repeats
every 21 days for up to 6 courses in the absence of disease progression or unacceptable
toxicity.

Patients undergo blood collection periodically during study for pharmacologic correlative
studies.

After completion of study treatment, patients are followed periodically for 5 years.

PROJECTED ACCRUAL: A total of 102 patients will be accrued for this study.

DISEASE CHARACTERISTICS:

- Histologically or cytologically confirmed non-small cell lung cancer (NSCLC)

- Squamous cell histology allowed

- No mixed histology with small cell component

- Stage IIIB (with pleural effusion) or stage IV disease

- Presence of peritoneal or pericardial effusion alone in the absence of cytologic
evidence is not allowed

- Measurable disease, defined as ≥ 1 lesion with longest diameter ≥ 2.0 cm by
conventional techniques OR ≥ 1.0 cm by spiral CT scan

- If the only site of measurable disease was previously irradiated, progressive
disease must be evident

- Ineligible for bevacizumab therapy

- No symptomatic, untreated, or uncontrolled CNS metastases

- CNS metastases treated with whole-brain radiation (WBRT) allowed 4 weeks after
completion of WBRT

PATIENT CHARACTERISTICS:

- ECOG performance status 0-1

- Life expectancy ≥ 12 weeks

- Absolute neutrophil count ≥ 1,500/mm^3

- Hemoglobin ≥ 9 g/dL

- Platelet count ≥ 100,000/mm^3

- Bilirubin ≤ 3 times upper limit of normal (ULN)

- ALT and AST ≤ 3 times ULN (5 times ULN if liver involvement)

- Alkaline phosphatase ≤ 5 times ULN

- Not pregnant or nursing

- Negative pregnancy test

- Fertile patients must use effective nonhormonal contraception

- No proteinuria ≥ 1+

- No uncontrolled blood pressure (BP), defined as systolic BP > 150 mm Hg and/or
diastolic BP > 100 mm Hg in spite of adequate antihypertensive therapy

- No impairment of gastrointestinal function or gastrointestinal disease that may
significantly alter the absorption of AZD2171 (e.g., ulcerative disease, uncontrolled
nausea, vomiting, or diarrhea, malabsorption syndrome, or small bowel resection)

- No seizure disorder

- No significant traumatic injury within 4 weeks prior to study entry

- No second primary malignancy except any of the following:

- Carcinoma in situ of the cervix

- Nonmelanoma skin cancer

- Prior malignancy diagnosed and definitively treated ≥ 5 years ago with no
subsequent evidence of recurrence

- History of low-grade (Gleason score ≤ 6) localized prostate cancer even if
diagnosed < 5 years prior to registration

- Treated stage I breast cancer ≤ 5 years prior to registration

- No uncontrolled intercurrent illness, including, but not limited to, any of the
following:

- Ongoing or active infection

- Significant pulmonary symptoms at baseline due to disease

- Symptomatic congestive heart failure

- Unstable angina pectoris

- Cardiac arrhythmia

- Psychiatric illness or social situation that would limit compliance with study
requirements

- Baseline hemoptysis

- Cavitating lesions

- No QTc prolongation > 500 msec or other significant ECG abnormality within the past
14 days

- No New York Heart Association class III or IV disease

PRIOR CONCURRENT THERAPY:

- See Disease Characteristics

- No prior chemotherapy for advanced lung cancer

- Neoadjuvant or adjuvant therapy for lung cancer within the past 12 months
allowed

- More than 12 months since prior immunotherapy and biologic therapy

- More than 4 weeks since prior radiotherapy (2 weeks for palliative radiotherapy to
skeletal metastases)

- At least 2 weeks since prior WBRT

- No radiotherapy to ≥ 25% of bone marrow

- No major surgery (i.e., laparotomy) or open biopsy within 4 weeks prior to study
entry (2 weeks for minor surgery)

- Insertion of a vascular access device not considered major or minor surgery

- No concurrent combination antiretroviral therapy for HIV-positive patients

- No concurrent grapefruit or grapefruit juice during AZD2171 treatment

- No concurrent drugs or biologics with proarrhythmic potential

- Concurrent palliative radiotherapy to nontarget sites (i.e., painful pre-existing
bony metastasis) allowed with AZD2171 (chemotherapy is held until completion of
radiotherapy)