Clinical trial NCT00096265: Radiation Therapy and Stereotactic Radiosurgery With or Without Temozolomide or Erlotinib in Treating Patients With Brain Metastases Secondary to Non-Small Cell Lung Cancer
Official title: A Phase III Trial Comparing Whole Brain Radiation and Stereotactic Radiosurgery Alone Versus With Temozolomide or Erlotinib in Patients With Non-Small Cell Lung Cancer and 1-3 Brain Metastases
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE3
Conditions: Metastatic Malignant Neoplasm in the Brain
Recurrent Non-Small Cell Lung Carcinoma
Stage IV Non-Small Cell Lung Cancer AJCC v7
Lead sponsor: National Cancer Institute (NCI)
Sponsor class: NIH
Collaborators: name: Radiation Therapy Oncology Group
First posted: 2004-11-09
Enrollment: 126
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: This randomized phase III trial is studying whole-brain radiation therapy and stereotactic radiosurgery with or without temozolomide or erlotinib to see how well they work compared to whole-brain radiation therapy and stereotactic radiosurgery in treating patients with brain metastases secondary to non-small cell lung cancer. Radiation therapy uses high-energy x-rays to kill tumor cells. Stereotactic radiosurgery may be able to deliver x-rays directly to the tumor and cause less damage to normal tissue. Drugs used in chemotherapy, such as temozolomide, work in different ways to stop tumor cells from dividing so they stop growing or die. Erlotinib may stop the growth of tumor cells by blocking the enzymes necessary for their growth and by blocking blood flow to the tumor. It is not yet known whether radiation therapy and stereotactic radiosurgery are more effective with or without temozolomide or erlotinib in treating brain metastases.

Detailed description: PRIMARY OBJECTIVES:

I. Compare survival in patients with non-small cell lung cancer and brain metastases treated with whole brain radiotherapy and stereotactic radiosurgery with vs without temozolomide or erlotinib.

SECONDARY OBJECTIVES:

I. Compare time to CNS progression in patients treated with these regimens. II. Compare quality-adjusted survival in patients treated with these regimens. III. Compare 3-month quality of life in patients treated with these regimens. IV. Compare the 6-month performance status of patients treated with these regimens.

V. Compare 6-month steroid dependence in patients treated with these regimens. VI. Compare cause of death (neurologic vs other) in patients treated with these regimens.

VII. Determine the effects of non-protocol chemotherapy in these patients.

OUTLINE: This is a randomized, multicenter study. Patients are stratified according to age and the presence of extracranial metastases (\< 65 years old AND no extracranial metastases vs ≥ 65 years old OR extracranial metastases), number of metastases (1 vs 2 or 3), and extent of extracranial disease (none vs present). Patients are randomized to 1 of 3 treatment arms.

ARM I: Patients undergo whole brain radiotherapy (WBRT) once daily on days 1-5, 8-12, and 15-19. Within 14 days after completion of WBRT, patients undergo stereotactic radiosurgery.

ARM II: Patients undergo WBRT and stereotactic radiosurgery as in arm I. Beginning on the first day of WBRT, patients receive oral temozolomide once daily on days 1-21. Beginning 4 weeks after completion of WBRT, patients may receive oral temozolomide alone once daily on days 1-5. Treatment with temozolomide repeats every 28 days for up to 6 courses in the absence of disease progression or unacceptable toxicity.

ARM III: Patients undergo WBRT and stereotactic radiosurgery as in arm I. Beginning on the first day of WBRT, patients receive oral erlotinib once daily for up to 6 months.

In all arms, patients with recurrent brain metastases may undergo additional stereotactic radiosurgery.

Quality of life is assessed at baseline and at 3, 6, 9, 12, 18, and 24 months.

Patients are followed every 3 months for 2 years, every 6 months for 2 years, and then annually thereafter.

Eligibility criteria: Inclusion Criteria:

* Histologically confirmed non-small cell lung cancer
* One to 3 intraparenchymal brain metastases by contrast-enhanced MRI, meeting the following criteria:

  * Well circumscribed tumor(s)
  * Maximum diameter ≤ 4.0 cm

    * If multiple lesions are present and one lesion is at the maximum diameter, the other lesions must not exceed 3.0 cm in maximum diameter
  * No metastases within 10 mm of the optic apparatus such that a portion of the optic nerve or chiasm would be included in the high-dose stereotactic radiosurgery boost field
  * No metastases in the brainstem, midbrain, pons, or medulla
* No prior complete resection of all known brain metastases

  * Subtotal resection allowed provided residual disease is ≤ 4.0 cm in maximum diameter
* No clinical or radiographic evidence of progression (other than study lesion\[s\]) within the past month

  * Patients with brain metastases at initial presentation do not require 1 month of scans documenting stable disease
* Stable extracranial metastases allowed

  * No known or pre-existing liver metastases
* No leptomeningeal metastases by MRI or cerebrospinal fluid evaluation
* Synchronous brain metastases at initial diagnosis allowed
* Performance status - Zubrod 0-1
* Hemoglobin ≥ 8 g/dL
* Absolute neutrophil count ≥ 1,000/mm\^3
* Platelet count ≥ 100,000/mm\^3
* AST \< 2 times upper limit of normal (ULN)
* Alkaline phosphatase \< 2 times ULN unless due to elevated bone metastases
* Total bilirubin normal
* Lactic dehydrogenase \< 2 times ULN
* Creatinine \< 1.5 times ULN
* No clinically active interstitial lung disease

  * Chronic stable asymptomatic radiographic changes allowed
* Not pregnant or nursing
* Negative pregnancy test
* Fertile patients must use effective contraception
* HIV negative
* Neurologic function status 0-2
* No other major medical illness or psychiatric impairment that would preclude study participation
* No history of allergic reaction attributed to compounds of similar chemical or biologic composition to erlotinib or temozolomide
* No concurrent immunotherapy
* No concurrent biologic therapy, excluding growth factors and epoetin alfa
* No prior temozolomide or erlotinib
* No other concurrent chemotherapy during study radiotherapy

  * Other concurrent chemotherapy allowed after study radiotherapy, except for the following:

    * Temozolomide or erlotinib (arm I only)
    * Erlotinib (arm II only)
    * Temozolomide (arm III only)
* No prior cranial radiotherapy
* No concurrent intensity-modulated radiotherapy
* Concurrent radiotherapy to painful bone lesions allowed

  * No concurrent radiotherapy to more than 15% of bone marrow
* No other concurrent therapy for brain metastases unless a recurrence is detected
* More than 30 days since prior investigational drugs
* No concurrent enzyme-inducing antiepileptic drugs including, but not limited to, any of the following (for patients randomized to receive erlotinib):

  * Phenytoin
  * Carbamazepine
  * Rifampin
  * Phenobarbital
  * Primidone
  * Oxcarbazepine
* No other concurrent investigational drugs
* No concurrent Hypericum perforatum (St. John's wort)
* No drugs that alter gastric pH (e.g., proton pump inhibitors or H2 antagonists) within 4 hours after erlotinib administration (arm III patients only)

Primary outcomes:
measure: Overall Survival
timeFrame: From randomization to date of death or last follow-up, up to 48.1 months. Analysis occurs after all patients have been potentially followed for 9 months.
Secondary outcomes:
measure: Rate of CNS Progression (One Year)
timeFrame: From randomization to last follow-up, up to 48.1 months. Analysis occurs after all patients have been potentially followed for 9 months.
measure: Quality-adjusted Survival as Measured by EuroQol 5-dimension Instrument
timeFrame: From randomization to last follow-up, up to 48.1 months. Analysis occurs after all patients have been potentially followed for 9 months.
measure: Change in Functional Assessment of Cancer Therapy-Brain (FACT-Br) Score at 3 Months
timeFrame: From randomization to three months.
measure: Change in Performance Status at Six Months
timeFrame: From randomization to six months.
measure: Change in Steroid Dependence at Six Months
timeFrame: From randomization to six months.
measure: Cause of Death (Neurologic vs Other)
timeFrame: From randomization to last follow-up, up to 48.1 months. Analysis occurs after all patients have been potentially followed for 9 months.
Other outcomes:
Locations:
city: Scottsdale
country: United States
facility: Arizona Oncology Services Foundation
state: Arizona
city: Scottsdale
country: United States
facility: Scottsdale Health Care-Osborn
state: Arizona
city: Burbank
country: United States
facility: Providence Saint Joseph Medical Center/Disney Family Cancer Center
state: California
city: Los Angeles
country: United States
facility: Kaiser Permanente Los Angeles Medical Center
state: California
city: Pomona
country: United States
facility: Pomona Valley Hospital Medical Center
state: California
city: Grand Junction
country: United States
facility: Saint Mary's Hospital and Regional Medical Center
state: Colorado
city: Newark
country: United States
facility: Christiana Care Health System-Christiana Hospital
state: Delaware
city: Jacksonville Beach
country: United States
facility: Integrated Community Oncology Network-Florida Cancer Center Beaches
state: Florida
city: Jacksonville
country: United States
facility: Baptist MD Anderson Cancer Center
state: Florida
city: Jacksonville
country: United States
facility: Integrated Community Oncology Network-Southside Cancer Center
state: Florida
city: Jacksonville
country: United States
facility: Baptist Medical Center South
state: Florida
city: Miami
country: United States
facility: University of Miami Miller School of Medicine-Sylvester Cancer Center
state: Florida
city: Orange Park
country: United States
facility: 21st Century Oncology-Orange Park
state: Florida
city: Orlando
country: United States
facility: UF Cancer Center at Orlando Health
state: Florida
city: Palatka
country: United States
facility: 21st Century Oncology-Palatka
state: Florida
city: Panama City
country: United States
facility: Bay Medical Center
state: Florida
city: Saint Augustine
country: United States
facility: Integrated Community Oncology Network-Flager Cancer Center
state: Florida
city: Tallahassee
country: United States
facility: Tallahassee Memorial HealthCare
state: Florida
city: Columbus
country: United States
facility: John B Amos Cancer Center
state: Georgia
city: Boise
country: United States
facility: Saint Alphonsus Cancer Care Center-Boise
state: Idaho
city: Arlington Heights
country: United States
facility: Northwest Community Hospital
state: Illinois
city: Chicago
country: United States
facility: Northwestern University
state: Illinois
city: Harvey
country: United States
facility: Ingalls Memorial Hospital
state: Illinois
city: Springfield
country: United States
facility: Saint John's Hospital
state: Illinois
city: Fort Wayne
country: United States
facility: Parkview Hospital Randallia
state: Indiana
city: Hammond
country: United States
facility: Franciscan Saint Margaret Health-Hammond Campus
state: Indiana
city: Indianapolis
country: United States
facility: IU Health Methodist Hospital
state: Indiana
city: Dubuque
country: United States
facility: Finley Hospital
state: Iowa
city: Louisville
country: United States
facility: Norton Suburban Hospital and Medical Campus
state: Kentucky
city: Baltimore
country: United States
facility: University of Maryland/Greenebaum Cancer Center
state: Maryland
city: Baltimore
country: United States
facility: Saint Agnes Hospital
state: Maryland
city: Boston
country: United States
facility: Massachusetts General Hospital Cancer Center
state: Massachusetts
city: Ann Arbor
country: United States
facility: University of Michigan Comprehensive Cancer Center
state: Michigan
city: Detroit
country: United States
facility: Wayne State University/Karmanos Cancer Institute
state: Michigan
city: Kalamazoo
country: United States
facility: West Michigan Cancer Center
state: Michigan
city: Burnsville
country: United States
facility: Fairview Ridges Hospital
state: Minnesota
city: Coon Rapids
country: United States
facility: Mercy Hospital
state: Minnesota
city: Edina
country: United States
facility: Fairview-Southdale Hospital
state: Minnesota
city: Fridley
country: United States
facility: Unity Hospital
state: Minnesota
city: Minneapolis
country: United States
facility: Abbott-Northwestern Hospital
state: Minnesota
city: Minneapolis
country: United States
facility: University of Minnesota/Masonic Cancer Center
state: Minnesota
city: Robbinsdale
country: United States
facility: North Memorial Medical Health Center
state: Minnesota
city: Saint Cloud
country: United States
facility: Coborn Cancer Center at Saint Cloud Hospital
state: Minnesota
city: Saint Cloud
country: United States
facility: Saint Cloud Hospital
state: Minnesota
city: Saint Louis Park
country: United States
facility: Metro Minnesota Community Oncology Research Consortium
state: Minnesota
city: Saint Louis Park
country: United States
facility: Park Nicollet Clinic - Saint Louis Park
state: Minnesota
city: Saint Paul
country: United States
facility: United Hospital
state: Minnesota
city: Waconia
country: United States
facility: Ridgeview Medical Center
state: Minnesota
city: Saint Louis
country: United States
facility: Saint Louis University Hospital
state: Missouri
city: Las Vegas
country: United States
facility: Nevada Cancer Research Foundation CCOP
state: Nevada
city: Reno
country: United States
facility: Renown Regional Medical Center
state: Nevada
city: New Brunswick
country: United States
facility: Rutgers Cancer Institute of New Jersey-Robert Wood Johnson University Hospital
state: New Jersey
city: Red Bank
country: United States
facility: Riverview Medical Center/Booker Cancer Center
state: New Jersey
city: Sparta
country: United States
facility: Sparta Cancer Treatment Center
state: New Jersey
city: Rochester
country: United States
facility: University of Rochester
state: New York
city: Asheville
country: United States
facility: Mission Hospital-Memorial Campus
state: North Carolina
city: Akron
country: United States
facility: Summa Akron City Hospital/Cooper Cancer Center
state: Ohio
city: Cleveland
country: United States
facility: Cleveland Clinic Foundation
state: Ohio
city: Tulsa
country: United States
facility: Natalie Warren Bryant Cancer Center at Saint Francis
state: Oklahoma
city: Drexel Hill
country: United States
facility: Delaware County Memorial Hospital
state: Pennsylvania
city: Philadelphia
country: United States
facility: Radiation Therapy Oncology Group
state: Pennsylvania
city: Philadelphia
country: United States
facility: Thomas Jefferson University Hospital
state: Pennsylvania
city: Philadelphia
country: United States
facility: Fox Chase Cancer Center
state: Pennsylvania
city: West Reading
country: United States
facility: Reading Hospital
state: Pennsylvania
city: Charleston
country: United States
facility: Medical University of South Carolina
state: South Carolina
city: Knoxville
country: United States
facility: Thompson Cancer Survival Center
state: Tennessee
city: Arlington
country: United States
facility: Arlington Cancer Center
state: Texas
city: Dallas
country: United States
facility: UT Southwestern/Simmons Cancer Center-Dallas
state: Texas
city: Galveston
country: United States
facility: University of Texas Medical Branch
state: Texas
city: Houston
country: United States
facility: M D Anderson Cancer Center
state: Texas
city: Murray
country: United States
facility: Intermountain Medical Center
state: Utah
city: Ogden
country: United States
facility: McKay-Dee Hospital Center
state: Utah
city: Salt Lake City
country: United States
facility: Huntsman Cancer Institute/University of Utah
state: Utah
city: Salt Lake City
country: United States
facility: LDS Hospital
state: Utah
city: Norfolk
country: United States
facility: Sentara Norfolk General Hospital
state: Virginia
city: Richmond
country: United States
facility: Virginia Commonwealth University/Massey Cancer Center
state: Virginia
city: Seattle
country: United States
facility: Virginia Mason Medical Center
state: Washington
city: Madison
country: United States
facility: University of Wisconsin Hospital and Clinics
state: Wisconsin
city: Milwaukee
country: United States
facility: Froedtert and the Medical College of Wisconsin
state: Wisconsin
city: Racine
country: United States
facility: Wheaton Franciscan Cancer Care - All Saints
state: Wisconsin
city: Winnipeg
country: Canada
facility: CancerCare Manitoba
state: Manitoba
city: Ottawa
country: Canada
facility: Ottawa Hospital-Civic Campus
state: Ontario
city: Montreal
country: Canada
facility: McGill University Department of Oncology
state: Quebec
Study officials:
affiliation: Radiation Therapy Oncology Group
name: Paul Sperduto
role: PRINCIPAL_INVESTIGATOR
References: