Radiation Therapy Combined With Either Gefitinib or Temozolomide in Pats With NSCLC and Brain Metastases

Whole Brain Radiotherapy in Combination With Gefitinib (Iressa) or Temozolomide (Temodal) for Brain Metastases From Non-Small Lung Cancer (NSCLC) A Randomized Phase II Trial

RATIONALE: Radiation therapy uses high-energy x-rays to kill tumor cells. Gefitinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Drugs used in chemotherapy, such as temozolomide, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Giving radiation therapy together with either gefitinib or temozolomide may kill more tumor cells.

PURPOSE: This randomized phase II trial is studying how well giving radiation therapy together with either gefitinib or temozolomide works in treating patients with non-small cell lung cancer and brain metastases.

Study Overview

• Status: Completed
• Conditions: Lung Cancer; Metastatic Cancer
• Intervention / Treatment: Drug: gefitinib; Radiation: radiation therapy; Drug: temozolomide

Detailed Description

OBJECTIVES:

Primary

• Compare the efficacy of whole-brain radiotherapy combined with either gefitinib or temozolomide, in terms of overall survival, in patients with non-small cell lung cancer and brain metastases.

Secondary

• Compare the tolerability and toxicity of these regimens in these patients.
• Compare the time to neurological disease progression, time to extracranial disease progression, and time to overall disease progression, in patients treated with these regimens.
• Compare adverse events in patients treated with these regimens.
• Compare cognitive function and quality of life of patients treated with these regimens.

OUTLINE: This is a randomized, open-label, parallel-group, multicenter study. Patients are stratified according to extracranial disease (yes vs no), number of brain metastases (1-3 vs ≥ 4), prior chemotherapy (yes vs no), WHO performance status (0-1 vs 2), and participating center. Patients are randomized to 1 of 2 treatment arms.

• Arm I: Patients undergo whole-brain radiotherapy (WBRT) once daily on days 1-5 and 8-12 and receive oral gefitinib once daily on days 1-28. Gefitinib treatment repeats every 28 days in the absence of disease progression or unacceptable toxicity.
• Arm II: Patients undergo WBRT as in arm I and receive oral temozolomide once daily on days 1-21. Temozolomide treatment repeats every 28 days in the absence of disease progression or unacceptable toxicity.

Quality of life is assessed at baseline and on day 1 of courses 2, 3, and 5.

After completion of study therapy, patients are followed every 3 months.

PROJECTED ACCRUAL: A total of 30-86 patients (15-43 per treatment arm) will be accrued for this study within 3 years.

• Study Type: Interventional
• Enrollment (Actual): 59
• Phase: Phase 2

Contacts and Locations

Study Locations

• Switzerland
  • Bellinzona, Switzerland, CH-6500
    • Oncology Institute of Southern Switzerland
  • Chur, Switzerland, CH-7000
    • Kantonsspital Graubuenden
  • Lausanne, Switzerland, CH-1011
    • Centre Hospitalier Universitaire Vaudois

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

DISEASE CHARACTERISTICS:

• Histologically or cytologically confirmed non-small cell lung cancer AND newly diagnosed brain metastases meeting 1 of the following criteria:

  • Multiple brain metastases
  • Single brain metastasis not amenable to potentially curative treatment
• No advanced extracranial disease severely compromising vital functions and performance

PATIENT CHARACTERISTICS:

Age

• 18 and over

Performance status

• WHO 0-2

Life expectancy

• Not specified

Hematopoietic

• Hemoglobin > 10 g/dL
• Absolute neutrophil count > 1,500/mm^3
• Platelet count > 100,000/mm^3

Hepatic

• Bilirubin ≤ 1.5 times upper limit of normal (ULN)
• AST and ALT ≤ 2.5 times ULN
• Alkaline phosphatase ≤ 2.5 times ULN (5 times ULN in the presence of documented bone metastases)
• No unstable or uncompensated hepatic disease that would preclude study participation

Renal

• Creatinine clearance ≥ 40 mL/min
• No unstable or uncompensated renal disease that would preclude study participation

Cardiovascular

• No myocardial infarction within the past 3 months
• No unstable or uncompensated cardiac disease that would preclude study participation

Pulmonary

• No clinically active interstitial lung disease

  • Patients with chronic stable radiographic changes who are asymptomatic eligible
• No other unstable or uncompensated respiratory disease that would preclude study participation

Other

• Not pregnant or nursing
• Negative pregnancy test
• Fertile patients must use effective contraception during and for 12 months after completion of study treatment
• No nausea, vomiting, inability to swallow whole tablets/capsules, or malabsorption syndrome that would preclude oral medication ingestion or absorption
• No psychiatric disorder that would preclude giving informed consent or study compliance
• No active infection
• No uncontrolled diabetes mellitus
• No other medical condition that would preclude study participation

PRIOR CONCURRENT THERAPY:

Biologic therapy

• Not specified

Chemotherapy

• No prior temozolomide

Endocrine therapy

• Concurrent corticosteroids allowed provided dose has been stable or decreasing for ≥ 4 days before study entry

Radiotherapy

• No prior brain irradiation

Surgery

• Not specified

Other

• No prior gefitinib or erlotinib
• More than 30 days since prior investigational clinical trial participation
• No other concurrent experimental drugs
• No other concurrent anticancer therapy

• No concurrent treatment with any of the following:

  • Phenytoin
  • Carbamazepine
  • Rifampin
  • Barbiturates
  • Hypericum perforatum (St. John's wort)
  • Other enzyme-inducing anti-epileptic drugs or tuberculostatic treatments
  • Any drug that contraindicates administration with study drugs

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: NONE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
ACTIVE_COMPARATOR: Arm I; Patients undergo whole-brain radiotherapy (WBRT) once daily on days 1-5 and 8-12 and receive oral gefitinib once daily on days 1-28. Gefitinib treatment repeats every 28 days in the absence of disease progression or unacceptable toxicity	Drug: gefitinib; Once daily during days 1-28; Radiation: radiation therapy; Whole brain radiotherapy
ACTIVE_COMPARATOR: Arm II; Patients undergo WBRT as in arm I and receive oral temozolomide once daily on days 1-21. Temozolomide treatment repeats every 28 days in the absence of disease progression or unacceptable toxicity	Radiation: radiation therapy; Whole brain radiotherapy; Drug: temozolomide; Once daily on days 1-21

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Overall survival	life-long

Secondary Outcome Measures

Outcome Measure	Time Frame
Time to progression	28 days
Time to neurological progression	28 days
Time to extracranial disease progression	28 days
Adverse events as measured at completion of study treatment	28 days

Collaborators and Investigators

• Sponsor: Swiss Group for Clinical Cancer Research
• Investigators: Study Chair: Gianfranco Pesce, MD, Istituto Oncologico della Svizzera Italiana - Ospedale San Giovanni; Principal Investigator: Roger Stupp, MD, Centre Hospitalier Universitaire Vaudois

Publications and helpful links

General Publications

• Pesce GA, Klingbiel D, Ribi K, Zouhair A, von Moos R, Schlaeppi M, Caspar CB, Fischer N, Anchisi S, Peters S, Cathomas R, Bernhard J, Kotrubczik NM, D'Addario G, Pilop C, Weber DC, Bodis S, Pless M, Mayer M, Stupp R. Outcome, quality of life and cognitive function of patients with brain metastases from non-small cell lung cancer treated with whole brain radiotherapy combined with gefitinib or temozolomide. A randomised phase II trial of the Swiss Group for Clinical Cancer Research (SAKK 70/03). Eur J Cancer. 2012 Feb;48(3):377-84. doi: 10.1016/j.ejca.2011.10.016. Epub 2011 Nov 15.

Study record dates

Study Major Dates

• Study Start: May 1, 2005
• Primary Completion (ACTUAL): April 1, 2009
• Study Completion (ACTUAL): November 1, 2010

Study Registration Dates

• First Submitted: October 12, 2005
• First Submitted That Met QC Criteria: October 12, 2005
• First Posted (ESTIMATE): October 13, 2005

Study Record Updates

• Last Update Posted (ESTIMATE): June 5, 2012
• Last Update Submitted That Met QC Criteria: June 4, 2012
• Last Verified: June 1, 2012

More Information

Terms related to this study

• Keywords: recurrent non-small cell lung cancer; stage IV non-small cell lung cancer; tumors metastatic to brain
• Additional Relevant MeSH Terms: Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Respiratory Tract Diseases; Neoplasms; Lung Diseases; Neoplasms by Site; Respiratory Tract Neoplasms; Thoracic Neoplasms; Central Nervous System Neoplasms; Nervous System Neoplasms; Lung Neoplasms; Brain Neoplasms; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antineoplastic Agents; Antineoplastic Agents, Alkylating; Alkylating Agents; Protein Kinase Inhibitors; Temozolomide; Gefitinib
• Other Study ID Numbers: SAKK 70/03; EU-20526