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

Study Overview
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Brief Summary
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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
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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.

Official Title
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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

Conditions
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Metastatic Malignant Neoplasm in the Brain, Recurrent Non-Small Cell Lung Carcinoma, Stage IV Non-Small Cell Lung Cancer AJCC v7

Intervention / Treatment
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* Radiation: 3-Dimensional Conformal Radiation Therapy
* Drug: Erlotinib Hydrochloride
* Radiation: Stereotactic Radiosurgery
* Drug: Temozolomide


Participation Criteria
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Eligibility Criteria
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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)

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Arm I<br>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. | Radiation: 3-Dimensional Conformal Radiation Therapy<br>* Patients undergo radiation therapy once daily for approximately 3 weeks<br>* Other names: Radiation Conformal Therapy;Radiation: Stereotactic Radiosurgery<br>* Patients undergo surgery after radiation therapy<br>* Other names: stereotaxic radiosurgery;|
| Experimental: Arm II<br>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. | Radiation: 3-Dimensional Conformal Radiation Therapy<br>* Patients undergo radiation therapy once daily for approximately 3 weeks<br>* Other names: Radiation Conformal Therapy;Radiation: Stereotactic Radiosurgery<br>* Patients undergo surgery after radiation therapy<br>* Other names: stereotaxic radiosurgery;Drug: Temozolomide<br>* Given orally<br>* Other names: Temomedac;|
| Experimental: Arm III<br>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. | Radiation: 3-Dimensional Conformal Radiation Therapy<br>* Patients undergo radiation therapy once daily for approximately 3 weeks<br>* Other names: Radiation Conformal Therapy;Drug: Erlotinib Hydrochloride<br>* Given orally<br>* Other names: Tarceva;Radiation: Stereotactic Radiosurgery<br>* Patients undergo surgery after radiation therapy<br>* Other names: stereotaxic radiosurgery;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | 
| 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. | 
| 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. | 
| 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. | 
| 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. | 
| 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. |