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Whole-Brain Radiation Therapy With or Without Hippocampal Avoidance in Treating Patients With Limited Stage or Extensive Stage Small Cell Lung Cancer

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ClinicalTrials.gov Identifier: NCT02635009
Recruitment Status : Recruiting
First Posted : December 18, 2015
Last Update Posted : January 29, 2019
Sponsor:
Collaborators:
National Cancer Institute (NCI)
Radiation Therapy Oncology Group
Information provided by (Responsible Party):
NRG Oncology

Tracking Information
First Submitted Date  ICMJE December 16, 2015
First Posted Date  ICMJE December 18, 2015
Last Update Posted Date January 29, 2019
Study Start Date  ICMJE December 2015
Estimated Primary Completion Date April 2022   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: December 16, 2015)
  • HVLT-R delayed recall deterioration status, defined using the Reliable Change Index (RCI) (Phase III) [ Time Frame: 6 months from start of treatment ]
    Compared using Fisher's exact test at a significance level of 0.05.
  • Intracranial relapse rate (Phase II) [ Time Frame: 12 months ]
    It will be compared between arms using a binomial test of difference in proportions at a significance level of 0.1. If the rate of relapse in the HA-PCI arm is significantly greater than that of the PCI only arm, this study will not continue to the phase III portion.
Original Primary Outcome Measures  ICMJE Same as current
Change History Complete list of historical versions of study NCT02635009 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE
 (submitted: December 16, 2015)
  • Cost-effectiveness as measured by the EQ-5D (Phase III) [ Time Frame: Up to 3 years ]
    Quality-adjusted life years (QALY's) will be assessed as the area under the preference-weighted survival curve. Cost will be assessed using a societal perspective. The primary cost-effectiveness outcome will be the pooled incremental cost-per QALY ratio for HA-PCI versus standard PCI. The incremental cost per QALY ratio will be calculated as the total cost of the HA-PCI minus total cost of standard PCI which will be divided by the quality adjusted survival of the patients treated with HA-PCI minus the quality adjusted survival of patients receiving standard PCI.
  • Incidence of adverse events (AEs), as measured by the CTCAE v.4 (Phase III) [ Time Frame: Up to 3 years ]
    Counts of all AEs by grade will be provided by treatment arm. Counts and frequencies will be provided for the worst grade AE experienced by the patient by treatment arm.
  • Intracranial relapse rate (Phase III) [ Time Frame: Up to 12 months ]
    The occurrence of intracranial relapse will be defined as appearance of brain metastasis in brain. Cumulative incidence approach will be used to estimate the median time to intracranial relapse to account for the competing risk of death. Gray's test will be used to test for statistically significant difference in the distribution of intracranial relapse times. Cause-specific Cox proportional hazards regression model will be used to evaluate effect of stratification variables (age, stage, and planned concurrent memantine use) and other baseline characteristics, on time to intracranial relapse.
  • Overall survival (Phase III) [ Time Frame: From the date of randomization to the date of death, or, otherwise, the last follow-up date on which the patient was reported alive, assessed up to 3 years ]
    Estimated using the Kaplan-Meier method and differences between treatment arms will be tested using the log rank test. The Cox proportional hazard model will be performed with the stratification variables and other baseline characteristics as fixed variables to assess the treatment effect while adjusting for patient-specific risk factors.
  • Patient-reported HRQOL, as measured by the EORTC QLQ-C30 and BN20 (Phase III) [ Time Frame: Up to 24 months ]
    Correlation of changes in HRQOL domains measured by the EORTC QLQ-C30 and BN20 with changes in cognitive function will be assessed. Additionally cognitive function decline at 3, 6, 12, 18 and 24 months will also be assessed and compared using Fisher's exact test. Decline from baseline to each time point (3, 6, 12, 18, and 24 months from the start of treatment) in the following subscales will also be assessed and compared using Fisher's exact test: global QOL, physical functioning, role functioning, emotional functioning, and social functioning domains along with fatigue and pain items.
  • Preservation of neurocognitive function, as measured by neurocognitive decline for HVLT-R, COWA test, TMT Parts A and B, and Clinical Trial Battery Composite (CTB COMP) score (Phase III) [ Time Frame: Up to 24 months ]
    Standardized scores that adjust for age, education, and gender when necessary will be analyzed. For discrete time point analyses, the change from baseline to each follow-up time point (3, 6, 12, 18, and 24 months from the start of treatment) will be calculated and compared between treatment arms using a t-test or Wilcoxon-Mann- Whitney test, depending on the normality of the data. Neurocognitive decline using the RCI for the HVLT-R, COWA, and TMT also will be compared between treatment arms at each follow-up time point using Fisher's exact test.
  • Time to neurocognitive failure, where a failure is defined using the RCI criteria, as measured by HVLT-R, COWA test, and TMT Parts A and B (Phase III) [ Time Frame: Up to 3 years ]
    The cumulative incidence approach will be used to estimate the median time to neurocognitive failure to account for the competing risk of death. Gray's test will be used to test for statistically significant difference in the distribution of neurocognitive failure times. The cause-specific Cox proportional hazards regression model will be used to evaluate the effect of stratification variables (age, stage, and planned concurrent memantine use) and other baseline characteristics, on time to neurocognitive decline.
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures
 (submitted: December 16, 2015)
White matter injury and hippocampal volume on neurocognitive function [ Time Frame: Baseline to 6 months ]
The change from baseline to 6 months will be compared between arms using the t-test (or Wilcoxon test if not normally distributed) in the total score and the two subscale scores (agency and pathway). These scores will be correlated with the EORTC- QLQ-C30 total score using a Pearson correlation coefficient. A general linear model will be used to assess hopefulness, performed separately for the AHS total score and subscale scores, between treatment arms while adjusting for depression.
Original Other Pre-specified Outcome Measures Same as current
 
Descriptive Information
Brief Title  ICMJE Whole-Brain Radiation Therapy With or Without Hippocampal Avoidance in Treating Patients With Limited Stage or Extensive Stage Small Cell Lung Cancer
Official Title  ICMJE Randomized Phase II/III Trial of Prophylactic Cranial Irradiation With or Without Hippocampal Avoidance for Small Cell Lung Cancer
Brief Summary This randomized phase II/III trial studies how well whole-brain radiation therapy works and compares it with or without hippocampal avoidance in treating patients with small cell lung cancer that is found in one lung, the tissues between the lungs, and nearby lymph nodes only (limited stage) or has spread outside of the lung in which it began or to other parts of the body (extensive stage). Radiation therapy uses high energy x-rays to kill tumor cells and shrink tumors. The hippocampus is part of the brain that is important for memory. Avoiding the hippocampus during whole-brain radiation could decrease the chance of side effects on memory and thinking. It is not yet known whether giving whole-brain radiation therapy is more effective with or without hippocampal avoidance in treating patients with small cell lung cancer.
Detailed Description

PRIMARY OBJECTIVES:

I. Determine whether the 12-month intracranial relapse rate following hippocampal avoidance (HA)-prophylactic cranial irradiation (PCI) is non-inferior compared to the rate following PCI for patients with small cell lung cancer (SCLC). (Randomized Phase II Component [Non-Inferiority]) II. Determine whether HA-PCI reduces the likelihood of 6-month deterioration from baseline in Hopkins Verbal Learning Test (HVLT)-Revised (R) delayed recall compared to PCI for patients with SCLC. (Phase III Component [Efficacy])

SECONDARY OBJECTIVES:

I. Compare time to cognitive failure, as measured by a battery of tests (HVLT-R, Controlled Oral Word Association [COWA] test, and Trail Making Test [TMT] parts A and B), after PCI versus HA-PCI in SCLC.

II. Compare time to cognitive failure as separately measured by each test (HVLT-R for Total Recall and Delayed Recognition, COWA test, and TMT parts A and B), after PCI versus HA-PCI for SCLC.

III. Compare patient-reported cognitive functioning and other quality of life domains (assessed by the European Organization for Research and Treatment of Cancer [EORTC] Quality of Life Questionnaire [QLQ]-Core [C]30 and BN20) between PCI versus HA-PCI for patients with SCLC.

IV. Compare overall survival after PCI versus HA-PCI for patients with SCLC. V. Compare 12-month intracranial relapse rate (at completion of phase III) and time to intracranial relapse after PCI versus HA-PCI for patients with SCLC.

VI. Evaluate adverse events according to Common Terminology Criteria for Adverse Events (CTCAE) criteria.

VII. Correlate changes in health-related quality of life (HRQOL) domains with changes in cognitive testing outcomes following PCI versus HA-PCI for patients with SCLC.

VIII. Assess cost-effectiveness of HA-PCI (intensity modulated radiation therapy [IMRT]) and PCI (3-dimensional conformal radiation therapy [3DCRT]) using the EuroQual (EQ)-5-Dimensions (5D)-5L.

TERTIARY OBJECTIVES:

I. Collect serum, whole blood, and urine for future translational research analyses.

II. Evaluate baseline magnetic resonance (MR) imaging biomarkers of white matter injury and hippocampal volumetry as potential predictors of cognitive decline and differential benefit from HAPCI as compared to PCI.

OUTLINE: Patients are randomized to 1 of 2 treatment arms.

ARM I: Patients undergo PCI using 3DCRT daily for 2 weeks.

ARM II: Patients undergo PCI with HA using IMRT daily for 2 weeks.

After completion of study treatment, patients are followed every 3 months for 1 year, then every 6 months until 3 years and then annually until death.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Phase 3
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE
  • Extensive Stage Small Cell Lung Carcinoma
  • Limited Stage Small Cell Lung Carcinoma
Intervention  ICMJE
  • Radiation: 3-Dimensional Conformal Radiation Therapy
    Undergo PCI using 3DCRT
    Other Names:
    • 3-dimensional radiation therapy
    • 3D-CRT
    • Conformal Therapy
    • Radiation Conformal Therapy
  • Other: Cognitive Assessment
    Ancillary studies
  • Radiation: Intensity-Modulated Radiation Therapy
    Undergo PCI with HA using IMRT
    Other Names:
    • IMRT
    • Intensity Modulated RT
    • Intensity-Modulated Radiotherapy
  • Other: Laboratory Biomarker Analysis
    Correlative studies
  • Other: Quality-of-Life Assessment
    Ancillary studies
    Other Name: Quality of Life Assessment
Study Arms  ICMJE
  • Active Comparator: Arm I (PCI using 3DCRT)
    Patients undergo PCI using 3DCRT daily for 2 weeks.
    Interventions:
    • Radiation: 3-Dimensional Conformal Radiation Therapy
    • Other: Cognitive Assessment
    • Other: Laboratory Biomarker Analysis
    • Other: Quality-of-Life Assessment
  • Experimental: Arm II (PCI with HA using IMRT)
    Patients undergo PCI with HA using IMRT daily for 2 weeks.
    Interventions:
    • Other: Cognitive Assessment
    • Radiation: Intensity-Modulated Radiation Therapy
    • Other: Laboratory Biomarker Analysis
    • Other: Quality-of-Life Assessment
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 Recruiting
Estimated Enrollment  ICMJE
 (submitted: December 16, 2015)
304
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE April 2027
Estimated Primary Completion Date April 2022   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  • PRIOR TO STEP 1 REGISTRATION
  • Histologic proof or unequivocal cytologic proof (fine needle aspiration, biopsy or two positive sputa) of SCLC within 250 days prior to Step 1 registration
  • Patients must have a three-dimensional (3D), T1-weighted, spoiled gradient (SPGR), magnetization-prepared rapid gradient echo (MP-RAGE), or turbo field echo (TFE) MRI scan without and with gadolinium contrast-enhanced T1-weighted axial, coronal, and sagittal sequence acquisitions and standard T2-weighted axial and coronal fluid attenuation inversion recovery (FLAIR) sequence acquisitions within 28 days of Step 1 registration; to yield acceptable image quality, the pre-contrast-enhanced should have a resolution of 1 x 1 x 1.2 mm and should follow the protocols established by the Alzheimer's Disease Neuroimaging Initiative (ADNI); performance of this sequence at a 3 Tesla field strength is recommended; sites may contact the Imaging Co-Chair, Dr. Tammie Benzinger, for further information or assistance if needed; to yield acceptable image quality, the gadolinium contrast-enhanced T1-weighted scan should use the smallest possible axial slice thickness not exceeding 1.5 mm; the associated coronal and sagittal sequences can be up to 2.5 mm in slice thickness; this imaging is considered standard of care
  • Note: The MRI study as part of response assessment following chemotherapy can be used for this purpose, but the appropriate sequences must be obtained; this sequence cannot be obtained prior to chemotherapy and is mandatory irrespective of randomization to the experimental or control arm of this study
  • Patients must sign a study-specific informed consent prior to study entry
  • PRIOR TO STEP 2 REGISTRATION
  • The following baseline neurocognitive assessments must be completed within 14 days prior to Step 2 registration: HVLT-R, TMT, and COWA; the neurocognitive assessments will be uploaded into the National Surgical Adjuvant Breast and Bowel Project, Radiation Therapy Oncology Group, and Gynecologic Oncology Group (NRG) Oncology RAVE system for evaluation by Dr. Wefel; once the upload is complete, a notification will be sent to the site to proceed to Step 2; note: completed baseline neurocognitive assessments can be uploaded at the time of Step 1 registration
  • Patients must have a baseline raw score greater than 2 on the HVLT-R delayed recall
  • Prior to chemotherapy or thoracic radiotherapy, patients must be defined as limited-stage or extensive-stage SCLC after clinical staging evaluation involving the following:

    • History/physical examination;
    • Computed tomography (CT) of the chest and abdomen with contrast (does not have to be done if the patient has had a positron emission tomography (PET)/CT scan within 8 weeks prior to initiating chemotherapy or thoracic radiotherapy)
    • MRI of the brain
    • For patients without evidence of extensive-stage SCLC on chest and abdomen CT and brain MRI, a PET/CT or bone scan is required to confirm limited-stage SCLC
  • Patients must be registered on study no earlier than 1 week and no later than 8 weeks after completing chemotherapy (+/- thoracic radiotherapy)
  • After chemotherapy, patients must be restaged using the same diagnostic work-up as required pre-chemotherapy; repeat PET/CT or bone scan is not required; patients must have:

    • No central nervous system (CNS) metastases
    • Radiographic partial or complete response to chemotherapy in at least one disease site using Response Evaluation Criteria in Solid Tumors (RECIST) criteria
    • No progression in any site
  • Zubrod performance status 0-2
  • Women of childbearing potential and male participants must practice adequate contraception
  • Women of childbearing potential must have a negative qualitative serum pregnancy test =< 2 weeks prior to study entry
  • Patients who are primary English or French speakers are eligible

Exclusion Criteria:

  • Prior radiotherapy to the head or neck (except for T1 glottic cancer), resulting in overlap of radiation fields
  • Radiographic evidence of CNS metastases
  • Radiographic evidence of hydrocephalus
  • Planned concurrent chemotherapy or anti-tumor agent during PCI
  • Concomitant invasive malignancy or invasive malignancy within the past five years other than non-melanomatous skin cancer; history of in situ carcinoma (e.g. ductal carcinoma in situ of breast, in situ carcinoma of the cervix, vulva or larynx) is permitted
  • Contraindication to MR imaging, such as implanted metal devices or foreign bodies or severe claustrophobia
  • Severe, active comorbidity, defined as follows:

    • Unstable angina and/or congestive heart failure requiring hospitalization within the last 6 months
    • Transmural myocardial infarction within the last 6 months
    • Acute bacterial or fungal infection requiring intravenous antibiotics at the time of registration
    • Hepatic insufficiency resulting in clinical jaundice and/or coagulation defects
    • Chronic obstructive pulmonary disease exacerbation or other respiratory illness requiring hospitalization or precluding study therapy at the time of registration
    • Uncontrolled, clinically significant cardiac arrhythmias
  • Women of childbearing potential and male participants who are sexually active and not willing/able to use medically acceptable forms of contraception
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Listed Location Countries  ICMJE Canada,   United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT02635009
Other Study ID Numbers  ICMJE NRG-CC003
NCI-2015-01548 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
NRG-CC003 ( Other Identifier: NRG Oncology )
NRG-CC003 ( Other Identifier: DCP )
UG1CA189867 ( U.S. NIH Grant/Contract )
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Responsible Party NRG Oncology
Study Sponsor  ICMJE NRG Oncology
Collaborators  ICMJE
  • National Cancer Institute (NCI)
  • Radiation Therapy Oncology Group
Investigators  ICMJE
Principal Investigator: Vinai Gondi NRG Oncology
PRS Account NRG Oncology
Verification Date January 2019

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