ZD6474, Carboplatin, and Paclitaxel in Treating Patients With Stage IIIB, Stage IV, or Recurrent Non-Small Cell Lung Cancer

OBJECTIVES:

Primary

- Determine the appropriate and tolerable dose of ZD6474 when given in combination with
paclitaxel and carboplatin in patients with previously untreated stage IIIB or IV or
recurrent non-small cell lung cancer. (Part I)

- Compare the efficacy of ZD6474 vs paclitaxel and carboplatin vs ZD6474 in combination
with paclitaxel and carboplatin, in terms of time to progression, in these patients.
(Part II)

Secondary

- Compare the pharmacokinetics of these regimens in these patients. (Part I)

- Compare the objective tumor response rate (complete response [CR] and partial response
[PR]) in patients treated with these regimens. (Part II)

- Compare disease control rates (CR, PR, and stable disease) in patients treated with
these regimens. (Part II)

- Compare the safety and tolerability of these regimens in these patients. (Part II)

- Compare the quality of life, symptom improvement, and WHO performance status of
patients treated with these regimens. (Part II)

- Compare the overall survival of patients treated with these regimens. (Part II)

- Compare the changes in plasma exposure of these regimens in these patients. (Part II)

- Correlate plasma exposure with safety and biological activity of these regimens in
these patients. (Part II)

OUTLINE: This is a 2-part, randomized, single-blind, open-label, multicenter study.

- Part 1 (safety run-in phase): Patients receive paclitaxel IV over 60-90 minutes* and
carboplatin IV over 30-60 minutes on day 1. Patients also receive oral ZD6474 once
daily on days 1-21*. Treatment repeats every 21 days for 6 courses. Patients achieving
a partial response (PR), complete response (CR), or stable disease (SD) after 6 courses
of therapy receive oral ZD6474 alone once daily in the absence of disease progression
or unacceptable toxicity.

NOTE: *During course 1, patients receive paclitaxel over 3 hours and ZD6474 on days 2-21.

A cohort of 10 patients receives ZD6474 at dose level 1. If it is determined that there are
no safety concerns with the administration of ZD6474 at dose level 1, a second cohort of 10
patients receives ZD6474 at dose level 2. Once the appropriate and tolerable dose is
determined, additional patients are accrued and entered into part 2 of the study.

- Part 2 (randomized phase): Patients are randomized to 1 of 3 treatment arms.

- Arm I: Patients receive oral ZD6474 once daily at the appropriate and tolerable
dose determined in part 1.

- Arm II: Patients receive oral ZD6474 once daily on days 1-21 and paclitaxel and
carboplatin as in part 1. Treatment repeats every 21 days for 6 courses. Patients
achieving a PR, CR, or SD after 6 courses of therapy receive oral ZD6474 alone
once daily.

- Arm III: Patients receive oral placebo once daily on days 1-21 and paclitaxel and
carboplatin as in part 1. Treatment repeats every 21 days for 6 courses. Patients
achieving a PR, CR, or SD after 6 courses of therapy receive oral placebo alone
once daily.

Treatment in all arms continues in the absence of disease progression or unacceptable
toxicity.

In both parts of the study, quality of life is assessed at baseline and on day 1 of each
course.

Patients are followed every six weeks for at least 2 years.

PROJECTED ACCRUAL: A total of 10-220 patients (10-20 for part I and 200 [100 for arm I, 50
for arm II, and 50 for arm III] for part II) will be accrued for this study.

DISEASE CHARACTERISTICS:

- Histologically or cytologically confirmed non-small cell lung cancer (NSCLC), meeting
1 of the following stage criteria:

- Stage IIIB with pleural effusion

- Stage IV

- Previously resected stage I-III disease that has relapsed in the non-resected
metastatic site

- Measurable disease

- At least 1 lesion ≥ 10 mm by spiral CT scan OR ≥ 20 mm by conventional
techniques

- Considered suitable for first-line treatment with paclitaxel, carboplatin, and ZD6474

- No mixed small cell and non-small cell histology

- No brain metastasis or spinal cord compression unless both of the following are true:

- Treated at least 4 weeks ago

- Stable without steroids for 1 week

PATIENT CHARACTERISTICS:

Age

- 18 and over

Performance status

- WHO 0-1

Life expectancy

- More than 12 weeks

Hematopoietic

- Neutrophil count ≥ 1,500/mm^3

- Platelet count ≥ 100,000/mm^3

Hepatic

- Bilirubin ≤ 1.5 times upper limit of normal (ULN)

- AST or ALT ≤ 2.5 times ULN (5.0 times ULN if liver metastases are present)

- Alkaline phosphatase ≤ 2.5 times ULN

Renal

- Creatinine clearance ≥ 30 mL/min

- Calcium (ionized or adjusted for albumin) normal* NOTE: *Supplementation allowed

Cardiovascular

- LVEF ≥ 45% by MUGA or echocardiogram*

- No significant cardiac event, including symptomatic heart failure or symptomatic
angina within the past 3 months

- No congenital long QT syndrome

- No QT with Bazett's correction unmeasurable or ≥ 460 msec by ECG

- No superior vena cava syndrome

- No cardiac disease that would increase the risk of ventricular arrhythmia

- No uncontrolled hypertension (i.e., systolic blood pressure (BP) > 160 mm Hg OR
diastolic BP > 100 mm Hg)

- No history of QT interval prolongation while taking other medication unless approved
by the investigator

- No history of chronic atrial fibrillation

- No clinically significant symptomatic arrhythmia (e.g., multifocal pre-ventricular
contractions, bigeminy, trigeminy, or ventricular tachycardia) requiring treatment

- No symptomatic sustained ventricular tachycardia NOTE: *For patients with prior
anthracycline therapy (total dose > 450 mg/m2), significant cardiovascular disease,
or chest irradiation

Pulmonary

- No clinically significant hemoptysis within the past 3 months

Other

- Not pregnant or nursing

- Negative pregnancy test

- Fertile patients must use effective contraception

- Potassium ≥ 3.5 mEq/L*

- Magnesium normal*

- No active skin disease (e.g., acne, psoriasis, or eczema)

- No active gastrointestinal disease that would preclude absorption of ZD6474 or
tolerating diarrhea

- No other malignancy within the past 5 years except basal cell carcinoma or carcinoma
in situ of the cervix

- No other condition that would preclude study participation or compliance NOTE:
*Supplementation allowed

PRIOR CONCURRENT THERAPY:

Biologic therapy

- No prior biologic therapy

- No concurrent biologic response modifiers, including cytokines

Chemotherapy

- See Disease Characteristics

- No prior chemotherapy

Endocrine therapy

- See Disease Characteristics

- No concurrent hormonal therapy

Radiotherapy

- No prior radiotherapy

- Prior radiotherapy to the brain or palliative radiotherapy for bone metastasis
allowed

- No concurrent radiotherapy

Surgery

- See Disease Characteristics

Other

- No prior adjuvant or neoadjuvant therapy

- More than 30 days since prior participation in an investigational trial

- More than 2 weeks since prior and no concurrent administration of the following:

- Potent inhibitors of CYP3A4, including any of the following:

- Ketoconazole

- Itraconazole

- Felbamate

- Fluoxetine

- Fluvoxamine

- Lansoprazole

- Amiodarone

- Azithromycin

- Ciprofloxacin

- Clarithromycin

- Cimetidine

- Diltiazem

- Erythromycin

- Fluconazole

- Nefazodone

- Dolasetron

- Ritonavir

- Verapamil

- Grapefruit juice

- Seville oranges

- Potent inducers of CYP3A4, including any of the following:

- Rifampin

- Phenytoin

- Carbamazepine

- Barbiturates

- Hypericum perforatum (St. John's wort)

- Therapeutic doses of warfarin for an INR ≥ 2

- Concurrent low-dose warfarin for catheter clot prophylaxis allowed

- Medications that prolong QTc interval or induce Torsades de Pointes

- Medications that cause sustained elevations in gastric pH (pH ≥ 5)

- No blood donation during and for 3 months after study participation

- No other concurrent cytotoxic agents

- No other concurrent cancer therapy or investigational agents