Clinical trial NCT00066313: ZD6474 in Treating Patients With Small Cell Lung Cancer
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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Lung Cancer
Keywords: extensive stage small cell lung cancer
limited stage small cell lung cancer
Lead sponsor: Sanofi
Sponsor class: INDUSTRY
First posted: 2003-08-07
Sex: ALL
Minimum age (years): 16
Maximum age (years): 120
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Primary purpose: TREATMENT

Brief summary: 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.

Detailed description: 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.

Eligibility 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

Primary outcomes:
measure: Progression-free survival
Secondary outcomes:
measure: Overall Survival
measure: Response rates
measure: Toxicity and safety
measure: Pharmacokinetics
measure: Quality of life (QOL) as measured by EORTC QLQ-C30 and QLQ-LC13
Other outcomes:
Locations:
city: Calgary
country: Canada
facility: Tom Baker Cancer Centre - Calgary
state: Alberta
city: Edmonton
country: Canada
facility: Cross Cancer Institute at University of Alberta
state: Alberta
city: Kelowna
country: Canada
facility: British Columbia Cancer Agency - Centre for the Southern Interior
state: British Columbia
city: Surrey
country: Canada
facility: Fraser/Valley Cancer Centre at British Columbia Cancer Agency
state: British Columbia
city: Vancouver
country: Canada
facility: British Columbia Cancer Agency - Vancouver Cancer Centre
state: British Columbia
city: Moncton
country: Canada
facility: Moncton Hospital
state: New Brunswick
city: Saint John
country: Canada
facility: Saint John Regional Hospital
state: New Brunswick
city: Hamilton
country: Canada
facility: Margaret and Charles Juravinski Cancer Centre
state: Ontario
city: Kingston
country: Canada
facility: Cancer Centre of Southeastern Ontario at Kingston General Hospital
state: Ontario
city: Ottawa
country: Canada
facility: Ottawa Hospital Regional Cancer Centre - General Campus
state: Ontario
city: St. Catharines
country: Canada
facility: St. Catharines General Hospital at Niagara Health System
state: Ontario
city: Thunder Bay
country: Canada
facility: Northwestern Ontario Regional Cancer Care at Thunder Bay Regional Health Sciences Centre
state: Ontario
city: Toronto
country: Canada
facility: Toronto East General Hospital
state: Ontario
city: Toronto
country: Canada
facility: Toronto Sunnybrook Regional Cancer Centre at Sunnybrook and Women's College Health Sciences Centre
state: Ontario
city: Toronto
country: Canada
facility: Mount Sinai Hospital - Toronto
state: Ontario
city: Toronto
country: Canada
facility: Princess Margaret Hospital
state: Ontario
city: Windsor
country: Canada
facility: Windsor Regional Cancer Centre at Windsor Regional Hospital
state: Ontario
city: Montreal
country: Canada
facility: Hopital Notre- Dame du CHUM
state: Quebec
city: Montreal
country: Canada
facility: McGill Cancer Centre at McGill University
state: Quebec
city: Ste-Foy
country: Canada
facility: L'Hopital Laval
state: Quebec
city: Saskatoon
country: Canada
facility: Saskatoon Cancer Centre at the University of Saskatchewan
state: Saskatchewan
Study officials:
affiliation: Sanofi
name: Clinical Sciences & Operations
role: STUDY_DIRECTOR
References:
citation: Arnold AM, Seymour L, Smylie M, Ding K, Ung Y, Findlay B, Lee CW, Djurfeldt M, Whitehead M, Ellis P, Goss G, Chan A, Meharchand J, Alam Y, Gregg R, Butts C, Langmuir P, Shepherd F; National Cancer Institute of Canada Clinical Trials Group Study BR.20. 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. 2007 Sep 20;25(27):4278-84. doi: 10.1200/JCO.2007.12.3083.
citation: 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.