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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT00096265
Recruitment Status : Terminated
First Posted : November 9, 2004
Results First Posted : April 16, 2013
Last Update Posted : March 9, 2018
Sponsor:
Collaborator:
Radiation Therapy Oncology Group
Information provided by (Responsible Party):
National Cancer Institute (NCI)

Tracking Information
First Submitted Date  ICMJE November 9, 2004
First Posted Date  ICMJE November 9, 2004
Results First Submitted Date  ICMJE March 5, 2013
Results First Posted Date  ICMJE April 16, 2013
Last Update Posted Date March 9, 2018
Actual Study Start Date  ICMJE October 6, 2004
Actual Primary Completion Date June 14, 2011   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: January 11, 2018)
Overall Survival [ Time Frame: 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. ]
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.
Original Primary Outcome Measures  ICMJE Not Provided
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: January 11, 2018)
  • Rate of CNS Progression (One Year) [ Time Frame: From randomization to last follow-up, up to 48.1 months. Analysis occurs after all patients have been potentially followed for 9 months. ]
    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.
  • Quality-adjusted Survival as Measured by EuroQol 5-dimension Instrument [ Time Frame: From randomization to last follow-up, up to 48.1 months. Analysis occurs after all patients have been potentially followed for 9 months. ]
    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).
  • Change in Functional Assessment of Cancer Therapy-Brain (FACT-Br) Score at 3 Months [ Time Frame: From randomization to three 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.
  • Change in Performance Status at Six Months [ Time Frame: From randomization to 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.
  • Change in Steroid Dependence at Six Months [ Time Frame: From randomization to 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.
  • Cause of Death (Neurologic vs Other) [ Time Frame: From randomization to last follow-up, up to 48.1 months. Analysis occurs after all patients have been potentially followed for 9 months. ]
    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.
Original Secondary Outcome Measures  ICMJE Not Provided
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE 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  ICMJE 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
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.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 3
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE
  • Metastatic Malignant Neoplasm in the Brain
  • Recurrent Non-Small Cell Lung Carcinoma
  • Stage IV Non-Small Cell Lung Cancer AJCC v7
Intervention  ICMJE
  • Radiation: 3-Dimensional Conformal Radiation Therapy
    Patients undergo radiation therapy once daily for approximately 3 weeks
    Other Names:
    • 3-dimensional radiation therapy
    • 3D CONFORMAL RADIATION THERAPY
    • 3D CRT
    • 3D-CRT
    • Conformal Therapy
    • Radiation Conformal Therapy
  • Drug: Erlotinib Hydrochloride
    Given orally
    Other Names:
    • Cp-358,774
    • OSI-774
    • Tarceva
  • Radiation: Stereotactic Radiosurgery
    Patients undergo surgery after radiation therapy
    Other Names:
    • Stereotactic External Beam Irradiation
    • stereotactic external-beam radiation therapy
    • stereotactic radiation therapy
    • Stereotactic Radiotherapy
    • stereotaxic radiation therapy
    • stereotaxic radiosurgery
  • Drug: Temozolomide
    Given orally
    Other Names:
    • CCRG-81045
    • Imidazo[5,1-d]-1,2,3,5-tetrazine-8-carboxamide, 3, 4-dihydro-3-methyl-4-oxo-
    • M & B 39831
    • M and B 39831
    • Methazolastone
    • RP-46161
    • SCH 52365
    • Temcad
    • Temodal
    • Temodar
    • Temomedac
Study Arms  ICMJE
  • Active Comparator: 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.
    Interventions:
    • Radiation: 3-Dimensional Conformal Radiation Therapy
    • Radiation: Stereotactic Radiosurgery
  • Experimental: 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.
    Interventions:
    • Radiation: 3-Dimensional Conformal Radiation Therapy
    • Radiation: Stereotactic Radiosurgery
    • Drug: Temozolomide
  • Experimental: 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.
    Interventions:
    • Radiation: 3-Dimensional Conformal Radiation Therapy
    • Drug: Erlotinib Hydrochloride
    • Radiation: Stereotactic Radiosurgery
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Terminated
Actual Enrollment  ICMJE
 (submitted: May 5, 2014)
126
Original Enrollment  ICMJE Not Provided
Actual Study Completion Date  ICMJE April 1, 2012
Actual Primary Completion Date June 14, 2011   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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)
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Canada,   United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT00096265
Other Study ID Numbers  ICMJE NCI-2009-00720
NCI-2009-00720 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
CDR0000389490
RTOG 0320
RTOG 0320 ( Other Identifier: Radiation Therapy Oncology Group )
RTOG-0320 ( Other Identifier: CTEP )
U10CA021661 ( U.S. NIH Grant/Contract )
Has Data Monitoring Committee Not Provided
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Responsible Party National Cancer Institute (NCI)
Study Sponsor  ICMJE National Cancer Institute (NCI)
Collaborators  ICMJE Radiation Therapy Oncology Group
Investigators  ICMJE
Principal Investigator: Paul Sperduto Radiation Therapy Oncology Group
PRS Account National Cancer Institute (NCI)
Verification Date February 2018

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP