Radiation Therapy and Stereotactic Radiosurgery With or Without Temozolomide or Erlotinib in Treating Patients With Brain Metastases Secondary to Non-Small Cell Lung Cancer

Metastatic Malignant Neoplasm in the Brain Clinical Trial

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

Clinical Trial Details — Status: Terminated

Administrative data

• NCT number: NCT00096265
• Other study ID #: NCI-2009-00720
• Secondary ID: NCI-2009-00720CD
• Status: Terminated
• Phase: Phase 3
• First received: November 9, 2004
• Last updated: February 9, 2018
• Start date: October 6, 2004
• Est. completion date: April 1, 2012

Study information

• Verified date: February 2018
• Source: National Cancer Institute (NCI)
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Terminated
• Enrollment: 126
• Est. completion date: April 1, 2012
• Est. primary completion date: June 14, 2011
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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)

Related Conditions & MeSH terms

• Brain Neoplasms
• Carcinoma, Non-Small-Cell Lung
• Lung Neoplasms
• Metastatic Malignant Neoplasm in the Brain
• Neoplasms
• Neoplasms, Second Primary
• Recurrent Non-Small Cell Lung Carcinoma
• Stage IV Non-Small Cell Lung Cancer AJCC v7

Intervention

Radiation:
• 3-Dimensional Conformal Radiation Therapy
Patients undergo radiation therapy once daily for approximately 3 weeks

Drug:
• Erlotinib Hydrochloride
Given orally

Radiation:
• Stereotactic Radiosurgery
Patients undergo surgery after radiation therapy

Drug:
• Temozolomide
Given orally

Locations

Country	Name	City	State
Canada	McGill University Department of Oncology	Montreal	Quebec
Canada	Ottawa Hospital-Civic Campus	Ottawa	Ontario
Canada	CancerCare Manitoba	Winnipeg	Manitoba
United States	Summa Akron City Hospital/Cooper Cancer Center	Akron	Ohio
United States	University of Michigan Comprehensive Cancer Center	Ann Arbor	Michigan
United States	Arlington Cancer Center	Arlington	Texas
United States	Northwest Community Hospital	Arlington Heights	Illinois
United States	Mission Hospital-Memorial Campus	Asheville	North Carolina
United States	Saint Agnes Hospital	Baltimore	Maryland
United States	University of Maryland/Greenebaum Cancer Center	Baltimore	Maryland
United States	Saint Alphonsus Cancer Care Center-Boise	Boise	Idaho
United States	Massachusetts General Hospital Cancer Center	Boston	Massachusetts
United States	Providence Saint Joseph Medical Center/Disney Family Cancer Center	Burbank	California
United States	Fairview Ridges Hospital	Burnsville	Minnesota
United States	Medical University of South Carolina	Charleston	South Carolina
United States	Northwestern University	Chicago	Illinois
United States	Cleveland Clinic Foundation	Cleveland	Ohio
United States	John B Amos Cancer Center	Columbus	Georgia
United States	Mercy Hospital	Coon Rapids	Minnesota
United States	UT Southwestern/Simmons Cancer Center-Dallas	Dallas	Texas
United States	Wayne State University/Karmanos Cancer Institute	Detroit	Michigan
United States	Delaware County Memorial Hospital	Drexel Hill	Pennsylvania
United States	Finley Hospital	Dubuque	Iowa
United States	Fairview-Southdale Hospital	Edina	Minnesota
United States	Parkview Hospital Randallia	Fort Wayne	Indiana
United States	Unity Hospital	Fridley	Minnesota
United States	University of Texas Medical Branch	Galveston	Texas
United States	Saint Mary's Hospital and Regional Medical Center	Grand Junction	Colorado
United States	Franciscan Saint Margaret Health-Hammond Campus	Hammond	Indiana
United States	Ingalls Memorial Hospital	Harvey	Illinois
United States	M D Anderson Cancer Center	Houston	Texas
United States	IU Health Methodist Hospital	Indianapolis	Indiana
United States	Baptist MD Anderson Cancer Center	Jacksonville	Florida
United States	Baptist Medical Center South	Jacksonville	Florida
United States	Integrated Community Oncology Network-Southside Cancer Center	Jacksonville	Florida
United States	Integrated Community Oncology Network-Florida Cancer Center Beaches	Jacksonville Beach	Florida
United States	West Michigan Cancer Center	Kalamazoo	Michigan
United States	Thompson Cancer Survival Center	Knoxville	Tennessee
United States	Nevada Cancer Research Foundation CCOP	Las Vegas	Nevada
United States	Kaiser Permanente Los Angeles Medical Center	Los Angeles	California
United States	Norton Suburban Hospital and Medical Campus	Louisville	Kentucky
United States	University of Wisconsin Hospital and Clinics	Madison	Wisconsin
United States	University of Miami Miller School of Medicine-Sylvester Cancer Center	Miami	Florida
United States	Froedtert and the Medical College of Wisconsin	Milwaukee	Wisconsin
United States	Abbott-Northwestern Hospital	Minneapolis	Minnesota
United States	University of Minnesota/Masonic Cancer Center	Minneapolis	Minnesota
United States	Intermountain Medical Center	Murray	Utah
United States	Rutgers Cancer Institute of New Jersey-Robert Wood Johnson University Hospital	New Brunswick	New Jersey
United States	Christiana Care Health System-Christiana Hospital	Newark	Delaware
United States	Sentara Norfolk General Hospital	Norfolk	Virginia
United States	McKay-Dee Hospital Center	Ogden	Utah
United States	21st Century Oncology-Orange Park	Orange Park	Florida
United States	UF Cancer Center at Orlando Health	Orlando	Florida
United States	21st Century Oncology-Palatka	Palatka	Florida
United States	Bay Medical Center	Panama City	Florida
United States	Fox Chase Cancer Center	Philadelphia	Pennsylvania
United States	Radiation Therapy Oncology Group	Philadelphia	Pennsylvania
United States	Thomas Jefferson University Hospital	Philadelphia	Pennsylvania
United States	Pomona Valley Hospital Medical Center	Pomona	California
United States	Wheaton Franciscan Cancer Care - All Saints	Racine	Wisconsin
United States	Riverview Medical Center/Booker Cancer Center	Red Bank	New Jersey
United States	Renown Regional Medical Center	Reno	Nevada
United States	Virginia Commonwealth University/Massey Cancer Center	Richmond	Virginia
United States	North Memorial Medical Health Center	Robbinsdale	Minnesota
United States	University of Rochester	Rochester	New York
United States	Integrated Community Oncology Network-Flager Cancer Center	Saint Augustine	Florida
United States	Coborn Cancer Center at Saint Cloud Hospital	Saint Cloud	Minnesota
United States	Saint Cloud Hospital	Saint Cloud	Minnesota
United States	Saint Louis University Hospital	Saint Louis	Missouri
United States	Metro Minnesota Community Oncology Research Consortium	Saint Louis Park	Minnesota
United States	Park Nicollet Clinic - Saint Louis Park	Saint Louis Park	Minnesota
United States	United Hospital	Saint Paul	Minnesota
United States	Huntsman Cancer Institute/University of Utah	Salt Lake City	Utah
United States	LDS Hospital	Salt Lake City	Utah
United States	Arizona Oncology Services Foundation	Scottsdale	Arizona
United States	Scottsdale Health Care-Osborn	Scottsdale	Arizona
United States	Virginia Mason Medical Center	Seattle	Washington
United States	Sparta Cancer Treatment Center	Sparta	New Jersey
United States	Saint John's Hospital	Springfield	Illinois
United States	Tallahassee Memorial HealthCare	Tallahassee	Florida
United States	Natalie Warren Bryant Cancer Center at Saint Francis	Tulsa	Oklahoma
United States	Ridgeview Medical Center	Waconia	Minnesota
United States	Reading Hospital	West Reading	Pennsylvania

Sponsors (2)

Lead Sponsor	Collaborator
National Cancer Institute (NCI)	Radiation Therapy Oncology Group

Countries where clinical trial is conducted

United States,  Canada, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Overall Survival	Survival time is defined as time from randomization to date of death from any cause and estimated by the Kaplan-Meier method. Patients last known to be alive are censored at date of last contact.	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	Rate of CNS Progression (One Year)	CNS progression is defined as any increase in perpendicular bi-dimensional tumor area for any of the 1-3 tracked brain metastases, by any amount, or the appearance of any new brain metastasis on a follow-up MRI (SRS planning scan will not be used to evaluate CNS progression). For lesions smaller than 1 cm in maximum diameter, a maximum increase of 50% in perpendicular bi-dimensional treatment area is necessary to score as progression. This caveat is included to account for potential variability in measurement, which is most susceptible to proportionate errors at smaller sizes. For greater than 1 cm lesions, the definition uses a 25% rule for change. Rates of CNS progression estimated by the cumulative incidence method, with death treated as a competing risk.	From randomization to last follow-up, up to 48.1 months. Analysis occurs after all patients have been potentially followed for 9 months.
Secondary	Quality-adjusted Survival as Measured by EuroQol 5-dimension Instrument	Quality-adjusted life years (QALY) incorporate the societal-based utilities of health states into expected life years for a health condition. The QALY model is QALY(h,y) where h is a health state and y is the years of life. Higher quality-adjusted life year values represent a better outcome. A patient's health state will be determined from the index score of the EQ-5D-5L patient questionnaire.The EQ-5D-5L is a 2-part self-assessment questionnaire, a 5-item index score and a visual analogue scale, but only the index score is used for quality-adjusted survival. The index score has 5 items (mobility, self care, usual activities, pain/discomfort, anxiety/depression) each with 5 problem levels (1-none to 5-extreme). The 5-item index score is transformed into a utility score between 0 (worst health state) and 1 (best health state).	From randomization to last follow-up, up to 48.1 months. Analysis occurs after all patients have been potentially followed for 9 months.
Secondary	Change in Functional Assessment of Cancer Therapy-Brain (FACT-Br) Score at 3 Months	The Functional Assessment of Cancer Therapy-Brain (FACT-Br) is a 19-item self-report instrument designed to measure multidimensional quality of life in patients with brain cancer. It is to be administered with the FACT-General. There are 5 responses options, with 0=Not a lot and 4=Very much. All items are added together to obtain a total score, which ranges from 0 to 76. Certain items must be reversed before it is added by subtracting the response from 4. It requires at least 50% of the items to be completed while the overall response rate of the FACT-Br including the FACT-G must be greater than 80%. If items are missing, the subscale scores can be prorated. A higher score indicates better QOL. A change of 5 points will be considered a minimal clinically meaningful change. Change from baseline at three months (3 month score - baseline score) will be categorized as improvement if increased, stable if no change, or deterioration if decreased.	From randomization to three months.
Secondary	Change in Performance Status at Six Months	Compared between two treatment arms using a two-group chi-squared test. Zubrod score will be collected at baseline and follow-up. The Zubrod performance score runs from 0 to 5, with 0 denoting perfect health and 5 death. Change from baseline is calculated as 6-month value - baseline value. Patients with a baseline score who have died by six months will be included in the analysis with a score of 5 at six months.	From randomization to six months.
Secondary	Change in Steroid Dependence at Six Months	Daily steroid dose will be collected at baseline and follow-up, as one of the following: 0-4 mg, >4 to = 8 mg, >8 to =12 mg, and >12 mg. Change from baseline at six months will be evaluated to have decreased, remained stable, or increased, based on these categories.	From randomization to six months.
Secondary	Cause of Death (Neurologic vs Other)	Patients were considered to have died neurologic deaths (coded as "Brain Metastases") if they had stable systemic disease and progressive neurologic disease consisting of expanding intracranial masses, CNS hemorrhages, hydrocephalus resulting in herniation or fulminant meningeal carcinomatosis.	From randomization to last follow-up, up to 48.1 months. Analysis occurs after all patients have been potentially followed for 9 months.