ZD6474 in Treating Patients With Small Cell Lung Cancer

OBJECTIVES:

• Compare the progression-free survival of patients with previously treated small cell lung cancer (SCLC) treated with ZD6474 vs placebo.
• Compare the response rate of patients treated with these regimens (only patients who had measurable disease outside a prior radiation field at study entry).
• Compare the toxicity and tolerability of these regimens in these patients.
• Compare the pharmacokinetics of these regimens in these patients.
• Correlate outcome and response with vascular endothelial growth factor expression and microvessel density in patients treated with these regimens.
• Compare the quality of life of patients treated with these regimens.
• Provide a comprehensive tumor, plasma, and urine bank linked to a clinical database for further study of molecular markers in SCLC.

OUTLINE: This is a randomized, double-blind, placebo-controlled, multicenter study. Patients are stratified according to participating center, timing of prior radiotherapy (early [before day 1, course 4 of chemotherapy] vs late vs no prior radiotherapy), stage of disease at diagnosis (limited vs extensive), and response at study entry (complete vs partial). Patients are randomized to 1 of 2 treatment arms.

• Arm I: Patients receive oral ZD6474 daily.
• Arm II: Patients receive oral placebo daily. In both arms, courses repeat every 28 days for up to 2 years in the absence of disease progression or unacceptable toxicity.

Quality of life is assessed at baseline, every 4 weeks while on therapy, and then every 8 weeks until disease progression.

Patients are followed every 8 weeks until disease progression and then every 6 months thereafter.

PROJECTED ACCRUAL: A total of 100 patients (50 per treatment arm) will be accrued for this study.

DISEASE CHARACTERISTICS:

• Histologically or cytologically confirmed small cell carcinoma of the lung

• Small cell and variant histology allowed
• No mixed tumors (small and large cell)
• No neuroendocrine tumors of the lung
• Must have received at least 4 courses of first-line combination chemotherapy as part of an induction regimen

• No prior change in regimen due to disease progression
• Must have achieved a radiologically confirmed (i.e., CT scan, chest x-ray, or bone scan) complete response (CR) or partial response (PR) after prior chemotherapy with or without radiotherapy AND meets 1 of the following criteria:

• No more than 28 days since prior chemotherapy
• At least 7 and no more than 14 days since prior radiotherapy if administered after completion of prior chemotherapy*
• No CNS metastases

• Asymptomatic patients with CNS metastases who received prior therapeutic cranial irradiation and are on stable, decreasing, or no steroids are eligible
• No symptomatic lesions or evidence of necrosis or bleeding NOTE: *Randomization may take place up to 21 days after prior radiotherapy in the instance of severe esophagitis that precludes administration of oral medications

PATIENT CHARACTERISTICS:

Age

• Over 16

Performance status

• ECOG 0-2

Life expectancy

• At least 12 weeks

Hematopoietic

• Absolute granulocyte count at least 1,500/mm^3
• Platelet count at least 100,000/mm^3
• No history of bleeding diathesis

Hepatic

• Bilirubin less than 1.5 times upper limit of normal (ULN)
• ALT less than 2.5 times ULN

Renal

• Creatinine less than 1.5 times ULN
• Calcium normal

Cardiovascular

• No prior ventricular arrhythmia that was symptomatic or required treatment (CTC grade 3), including any of the following:

• Multifocal premature ventricular contractions
• Bigeminy
• Trigeminy
• Ventricular tachycardia
• No prior QT prolongation with any medication
• No congenital long QT syndrome
• No QT and QTc (with Bazett's correction) that is unmeasurable or is 460 msec or higher on screening ECG
• No significant cardiac event, including symptomatic heart failure or angina, within the past 3 months or any cardiac disease that increases the risk for ventricular arrhythmia
• No ongoing chronic atrial fibrillation
• LVEF at least 45% by MUGA for patients with significant cardiac history (myocardial infarction, severe hypertension, or arrhythmia) OR who received prior doxorubicin greater than 450 mg/m^2

Other

• Not pregnant or nursing
• Negative pregnancy test
• Fertile patients must use effective contraception
• Potassium normal
• Magnesium normal
• No serious active infection
• No recent major bleeding
• No other concurrent serious underlying medical condition that would preclude study participation
• Willing and able to complete quality of life questionnaires in English or French

PRIOR CONCURRENT THERAPY:

Biologic therapy

• No prior signal transduction inhibitors
• No prior angiogenesis inhibitors
• No concurrent anticancer biologic therapy or immunotherapy

Chemotherapy

• See Disease Characteristics
• Recovered from prior chemotherapy

Endocrine therapy

• Not specified

Radiotherapy

• See Disease Characteristics
• Recovered from prior radiotherapy
• No concurrent anticancer radiotherapy

• Concurrent low-dose, nonmyelosuppressive palliative radiotherapy allowed

Surgery

• More than 2 weeks since prior major surgery

Other

• More than 4 weeks since prior investigational drugs
• No prior epidermal growth factor receptor inhibitors
• No prior vascular endothelial growth factor receptor inhibitors
• No concurrent CYP3A4 inhibitors or inducers, including any of the following:

• Verapamil
• Rifampin
• Phenytoin
• Carbamazepine
• Barbiturates
• Hypericum perforatum (St. John's wort)
• No concurrent medication that affects QT/QTc and/or induces torsades de pointes
• No other concurrent anticancer cytotoxic therapy
• No other concurrent investigational drugs during and for 30 days after study participation
• No concurrent oral bisphosphonates (e.g., clodronate)

• Concurrent IV bisphosphonates allowed
• No concurrent 5HT_3 antagonists