Alternate Title
Basic Trial Information
Objectives
Entry Criteria
Expected Enrollment
Outcomes
Outline
Published Results
Trial Contact Information
Registry Information

Alternate Title

ZD6474 in Treating Patients With Small Cell Lung Cancer

Basic Trial Information

Phase Type Status Age Sponsor Protocol IDs Phase II Treatment Closed Over 16 Other CAN-NCIC-BR20 ZENECA-6474IL/0005, NCT00066313, BR20

Objectives

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

Entry 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]

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 5HT₃ antagonists

Patient Characteristics:

Age

• Over 16

Performance status

• ECOG 0-2

Life expectancy

• At least 12 weeks

Hematopoietic

• Absolute granulocyte count at least 1,500/mm³
• Platelet count at least 100,000/mm³
• 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/m²

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

Expected Enrollment

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

Outcomes

Progression-free survival

Overall Survival
Response rates
Toxicity and safety
Pharmacokinetics
Quality of life (QOL) as measured by EORTC QLQ-C30 and QLQ-LC13

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.

Arnold AM, Seymour L, Smylie M, et al.: Phase II study of vandetanib or placebo in small-cell lung cancer patients after complete or partial response to induction chemotherapy with or without radiation therapy: National Cancer Institute of Canada Clinical Trials Group Study BR.20. J Clin Oncol 25 (27): 4278-84, 2007.[PUBMED Abstract]

Arnold AM, Smylie M, Ding K, et al.: Randomized phase II study of maintenance vandetanib (ZD6474) in small cell lung cancer (SCLC) patients who have a complete or partial response to induction therapy: NCIC CTG BR.20. [Abstract] J Clin Oncol 25 (Suppl 18): A-7522, 390s, 2007.

Trial Contact Information

Trial Lead Organizations

NCIC-Clinical Trials Group

Andrew Arnold, MD, Protocol chair		Ph: 905-387-9495 ext. 64602 Email: andrew.arnold@hrcc.on.ca

Registry Information
Official Title		A Phase II Study Of ZD6474 Or Placebo In Small Cell Lung Cancer Patients Who Have Complete Or Partial Response To Induction Chemotherapy +/- Radiation Therapy
Trial Start Date		2003-05-12
Registered in ClinicalTrials.gov		NCT00066313
Date Submitted to PDQ		2003-06-06
Information Last Verified		2006-04-14

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