RATIONALE: ZD6474 may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. ZD6474 may also stop the growth of small cell lung cancer by blocking blood flow to the tumor.

PURPOSE: This randomized phase II trial is studying how well ZD6474 works compared to placebo in treating patients with small cell lung cancer that has responded to previous chemotherapy with or without radiation therapy.

Condition	Treatment or Intervention	Phase
extensive stage small cell lung cancer limited stage small cell lung cancer	Drug: ZD6474  Procedure: adjuvant therapy  Procedure: anti-cytokine therapy  Procedure: antiangiogenesis therapy  Procedure: biological response modifier therapy  Procedure: enzyme inhibitor therapy  Procedure: growth factor antagonist therapy  Procedure: protein tyrosine kinase inhibitor therapy	Phase II

Further Study Details: 

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 120 patients (60 per treatment arm) will be accrued for this study.

Ages Eligible for Study:  16 Years and above,  Genders Eligible for Study:  Both

Criteria

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

Canada, Alberta
      Cross Cancer Institute, Edmonton,  Alberta,  T6G 1Z2,  Canada; Recruiting
      Tom Baker Cancer Centre - Calgary, Calgary,  Alberta,  T2N 4N2,  Canada; Recruiting
Canada, British Columbia
      British Columbia Cancer Agency - Centre for the Southern Interior, Kelowna,  British Columbia,  V1Y 5L3,  Canada; Recruiting
      British Columbia Cancer Agency, Vancouver,  British Columbia,  V5Z 4E6,  Canada; Recruiting
      Fraser Valley Cancer Centre at Surrey Memorial Hospital, Surrey,  British Columbia,  V3V 1Z2,  Canada; Recruiting
Canada, New Brunswick
      Moncton Hospital, Moncton,  New Brunswick,  E1C 6ZB,  Canada; Recruiting
      Saint John Regional Hospital, Saint John,  New Brunswick,  E2L 4L2,  Canada; Recruiting
Canada, Ontario
      Cancer Care Ontario - Windsor Regional Cancer Centre, Windsor,  Ontario,  N8W 2X3,  Canada; Recruiting
      Cancer Centre of Southeastern Ontario, Kingston,  Ontario,  K7L 5P9,  Canada; Recruiting
      Hotel Dieu Health Sciences Hospital - Niagara, St. Catharines,  Ontario,  L2R 5K3,  Canada; Recruiting
      Margaret and Charles Juravinski Cancer Centre, Hamilton,  Ontario,  L8V 5C2,  Canada; Recruiting
      Mount Sinai Hospital - Toronto, Toronto,  Ontario,  M5G 1X5,  Canada; Recruiting
      Ottawa Regional Cancer Centre at Ottawa Hospital - General Campus, Ottawa,  Ontario,  K1H 8L6,  Canada; Recruiting
      Princess Margaret Hospital, Toronto,  Ontario,  M5G 2M9,  Canada; Recruiting
      Regional Cancer Care at Thunder Bay Regional Health Sciences Centre, Thunder Bay,  Ontario,  P7B 6V4,  Canada; Recruiting
      Toronto East General Hospital, Toronto,  Ontario,  M4C 3E7,  Canada; Recruiting
      Toronto Sunnybrook Regional Cancer Centre, Toronto,  Ontario,  M4N 3M5,  Canada; Recruiting
Canada, Quebec
      Hopital Notre- Dame du CHUM, Montreal,  Quebec,  H2L 4M1,  Canada; Recruiting
      L'Hopital Laval, Ste Foy,  Quebec,  G1V 4G5,  Canada; Recruiting
      McGill Cancer Centre, Montreal,  Quebec,  H2W 1S6,  Canada; Recruiting
Canada, Saskatchewan
      Saskatoon Cancer Centre, Saskatoon,  Saskatchewan,  S7N 4H4,  Canada; Recruiting

Study chairs or principal investigators

Andrew M. Arnold, MD,  Study Chair,  Margaret and Charles Juravinski Cancer Centre   

Study ID Numbers:  CDR0000315518; CAN-NCIC-BR20; ZENECA-6474IL/0005; NCT00066313
Record last reviewed:  December 2004
Last Updated:  April 4, 2005
Record first received:  August 6, 2003
ClinicalTrials.gov Identifier:  NCT00066313
Health Authority: United States: Federal Government
ClinicalTrials.gov processed this record on 2005-04-08