<clinical_study>
  <!-- This xml conforms to an XML Schema at:
    https://clinicaltrials.gov/ct2/html/images/info/public.xsd -->
  <required_header>
    <download_date>ClinicalTrials.gov processed this data on September 20, 2023</download_date>
    <link_text>Link to the current ClinicalTrials.gov record.</link_text>
    <url>https://clinicaltrials.gov/ct2/show/NCT04485026</url>
  </required_header>
  <id_info>
    <org_study_id>IRB00068259</org_study_id>
    <secondary_id>P30CA012197</secondary_id>
    <secondary_id>WFBCCC62420</secondary_id>
    <nct_id>NCT04485026</nct_id>
  </id_info>
  <brief_title>Local Consolidative Radiotherapy for Oligoprogressive in Non-small Cell Lung Carcinoma</brief_title>
  <official_title>A Randomized Phase II Study of Local Consolidative Radiotherapy Versus Standard of Care Second Line Systemic Therapy in Patients With Oligoprogressive NSCLC on Immune Checkpoint Inhibitors</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Wake Forest University Health Sciences</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>National Cancer Institute (NCI)</agency>
      <agency_class>NIH</agency_class>
    </collaborator>
  </sponsors>
  <source>Wake Forest University Health Sciences</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
    <is_fda_regulated_drug>Yes</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
  </oversight_info>
  <brief_summary>
    <textblock>
      This is a randomized phase II study designed to evaluate the effect of local consolidative&#xD;
      radiation therapy (LCT) to all sites of oligoprogressive disease in patients with metastatic&#xD;
      non-small cell lung carcinoma who have progressed through first line systemic therapy&#xD;
      containing an immune checkpoint inhibitor (ICI).&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Primary Objective: To compare overall survival (OS) from the time of the time of&#xD;
      randomization between the treatment and control groups.&#xD;
&#xD;
      Secondary Objective(s)&#xD;
&#xD;
        -  To compare the extra-CNS PFS2 (EC-PFS2), defined as the time to extracranial disease&#xD;
           progression on second line systemic therapy or death from the first day of local&#xD;
           consolidative radiation therapy (treatment group) or from the start of second line&#xD;
           therapy (control group).&#xD;
&#xD;
        -  To evaluate time to initiation of second line systemic therapy or palliative care after&#xD;
           completion of local consolidative therapy in the treatment group&#xD;
&#xD;
        -  To compare the toxicities in the treatment and control groups;&#xD;
&#xD;
        -  To compare overall progression free survival from the time of the first day of local&#xD;
           consolidative radiation therapy for the treatment group and from the start of second&#xD;
           line therapy for the control group&#xD;
&#xD;
        -  To compare the pattern of next progression on second line therapy in the treatment group&#xD;
           vs the control group.&#xD;
&#xD;
        -  To evaluate local progression in lesions treated with local consolidative radiation&#xD;
           therapy.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Withdrawn</overall_status>
  <why_stopped>
    No enrollments, low patient population as well as a dramatic change in the insurance approval&#xD;
    processes for oligoprogressive state with eviCore saying they do not support SBRT in this&#xD;
    setting at all.&#xD;
  </why_stopped>
  <start_date type="Actual">November 4, 2020</start_date>
  <completion_date type="Anticipated">December 2025</completion_date>
  <primary_completion_date type="Anticipated">December 2023</primary_completion_date>
  <phase>Phase 2</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Randomized</allocation>
    <intervention_model>Parallel Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Overall Survival</measure>
    <time_frame>3 years</time_frame>
    <description>In each arm overall survival will be defined as the time from randomization to death from any cause. . Patients who are alive at the last follow up at the end of the study will be censored at the date of the last follow up appointment. A comparison of overall survival between the two groups will be made first using bivariate Kaplan-Meier method and then a multivariable Cox proportional hazards model. Participants who do not die during the course of observation will be right censored. Key covariates to be included in multivariable modeling include age, ECOG status, number of progressive treated sites (1 vs 2-4), and PD-L1 status (&gt;=50%; 1%-49%; &lt; 1%).</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Time to Progression Between Both Arms</measure>
    <time_frame>3 years</time_frame>
    <description>Investigators will compare progression after second line of therapy between both arms first using the bivariate Kaplan-Meier method and then a multivariable Cox proportional hazards model age, ECOG status, number of progressive treated sites (1 vs 2-4), and PD-L1 status (&gt;=50%; 1%-49%; &lt; 1%). RECIST version 1.1 criteria will be used to assess for progression.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Time to Second Line of Systemic Therapy or Palliative Care (Local Consolidative Radiation Therapy Arm Only)</measure>
    <time_frame>Up to 2 years after the completion of intervention</time_frame>
    <description>The time to the second line systemic therapy or palliative care will be defined as the time from the completion of local consolidation therapy to the first day of cycle 1 of a systemic therapy the patient has not yet received OR the date of hospice enrollment, whichever is sooner. Patients experiencing neither of these events will be censored at last follow up visit. Estimated median time to second line therapy (or palliative care) and corresponding 95% confidence interval as well as estimated proportion (and corresponding 95% confidence interval) of the treatment group who have started second-line therapy (or palliative care) by key time points including 6 months, 1 year, and 2 years after the end of local consolidative therapy.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Incidences of Toxicities</measure>
    <time_frame>Up to 3 years</time_frame>
    <description>Toxicities will be evaluated per Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. Toxicities between the two arms by comparing the proportions with grade 2 or higher, and grade 3 or higher, toxicities of any type at 3, 6, 12, 24 and 36 months following randomization using a chi-square test on the relevant 2x2 contingency table.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Progression Free Survival</measure>
    <time_frame>Up to 5 years</time_frame>
    <description>Progression free survival will be assessed by a modified RECIST version 1.1 criteria. If any individual target lesion meets RECIST v1.1 criteria - specifically an increase in the longest diameter (shortest diameter for lymph node lesions) of at least 20% and 5 mm absolute increase, the patient will be considered to have progression of disease. The criteria for determining pseudoprogression versus true progression and for mild progression while systemic therapy is held for the delivery of local consolidative radiation therapy in the treatment arm will be used for this outcome measure as well. Repeat oligoprogression will also be counted as progressive disease.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Time to Next Progression Following Local Consolidative Radiation Therapy or Second Line Systemic Therapy</measure>
    <time_frame>Up to 3 years</time_frame>
    <description>The pattern of next progression following local consolidation therapy (in treatment group) or second line systemic therapy (in control group) into one of three possible mutually exclusive and exhaustive categories: No progression, repeat oligoprogression or polyprogression, and will compare these patterns between the two groups using a chi-square analysis on the resulting 2x3 contingency table.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Proportion of Local of Lesions Treated with Local Consolidative Radiation Therapy That Progress</measure>
    <time_frame>Up to 5 years</time_frame>
    <description>Investigators will estimate proportion of lesions treated with local consolidative radiation therapy that experienced local progression (yes/no by study end) and construct a 95% confidence interval around this estimate.</description>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">0</enrollment>
  <condition>Non Small Cell Lung Cancer</condition>
  <condition>Oligoprogressive</condition>
  <arm_group>
    <arm_group_label>Local Consolidative Radiation Therapy Arm</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Definitive external beam radiation therapy will be delivered to all sites of progressive disease for all patients. The technique used to deliver radiation therapy will be determined by the treating radiation oncologist.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Standard of Care - Control Arm</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>Second line systemic therapy is at the discretion of the treating medical oncologist.</description>
  </arm_group>
  <intervention>
    <intervention_type>Radiation</intervention_type>
    <intervention_name>Local consolidative radiation therapy</intervention_name>
    <description>All local consolidative radiation therapy should be delivered using hypofractionated local consolidative radiation therapy (&gt;2 Gy per fraction). Exceptions may be approved on a case by case basis by the trial principal investigator. Three-dimensional conformal radiotherapy (3D-CRT), intensity modulated radiation therapy (IMRT), volumetric modulated arc therapy (VMAT), stereotactic body radiotherapy (SBRT), stereotactic radiosurgery (SRS), and proton beam therapy (PBT) are all acceptable.</description>
    <arm_group_label>Local Consolidative Radiation Therapy Arm</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Standard of care radiation therapy</intervention_name>
    <description>Standard of care palliative radiotherapy to symptomatic lesions is permissible. The dose to symptomatic lesions should not exceed 30 Gy in 10 fractions. Brain metastases will be treated with standard of care CNS therapy throughout the study. This may include (but is not limited to) stereotactic radiosurgery, neurosurgical intervention, whole brain radiotherapy</description>
    <arm_group_label>Standard of Care - Control Arm</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Histologically confirmed diagnosis of non-small cell lung cancer.&#xD;
&#xD;
          -  Have completed at least 4 cycles of a first line systemic therapy regimen for&#xD;
             metastatic disease that includes a PD-1 axis targeted agent prior to progression.&#xD;
             (Patients may be on maintenance/consolidation anti PD-1 axis therapy or have completed&#xD;
             maintenance anti PD-1 axis therapy within the last 3 months at the time of&#xD;
             progression).&#xD;
&#xD;
          -  Initial response of stable disease (SD), partial response (PR) or complete response&#xD;
             (CR) in at least one lesion prior to progression as defined by RECIST v1.1 criteria.&#xD;
&#xD;
          -  Oligoprogressive disease in 4 or fewer lesions (Progression of the primary tumor&#xD;
             and/or regional lymph nodes will be counted as one lesion)&#xD;
&#xD;
          -  CNS lesions will not count towards the 4 or fewer progressive lesions if they are all&#xD;
             able to be treated with stereotactic radiosurgery.&#xD;
&#xD;
          -  Progression by RECIST v1.1 criteria or by PET/CT criteria will be considered&#xD;
             progressive disease. Both are not required to determine progressive disease.&#xD;
&#xD;
        Progression for study entry will be defined as by a modified RECIST v1.1 criteria,&#xD;
        including: Development of a new lesion; increase in the longest diameter (shortest diameter&#xD;
        for lymph node lesions) of any individual lesion by 20% above nadir and a minimal increase&#xD;
        of 5 mm.&#xD;
&#xD;
          -  In cases of PET/CT, the criteria for progression of PET/CT are: Any individual FDG&#xD;
             avid lesion with an uptake greater than twice that of the surrounding tissue on the&#xD;
             attenuation corrected image. Any individual FDG avid lesion with greater than 30%&#xD;
             increase in 18F-FDG SUV peak, with greater than 0.8 SUV units increase in tumor SUV&#xD;
             from the nadir or the pre-enrollment PET/CT in pattern typical of tumor and not of&#xD;
             infection/treatment effect per the treating investigator. Visible increase in the&#xD;
             extent of 18F-FDG uptake of any lesion by 20% in the longest diameter and an absolute&#xD;
             increase of at least 5mm that is not consistent with treatment effect and/or infection&#xD;
             per the treating investigator. No more than the following number of progressing&#xD;
             lesions in any one organ (including any lesions previously treated with radiation&#xD;
             therapy). Less than or equal to four (4) lung lesions (including primary and&#xD;
             mediastinal lymph nodes as one lesion). Less than or equal to three (3) liver lesions.&#xD;
             Less than or equal to three (3) cumulative vertebral lesions&#xD;
&#xD;
          -  At least one non-progressing lesion, which may not have undergone prior definitive&#xD;
             local therapy.&#xD;
&#xD;
          -  All progressive lesions must be amenable to definitive radiation therapy as determined&#xD;
             by the treating radiation oncologist.&#xD;
&#xD;
          -  Age of 18 years or greater.&#xD;
&#xD;
          -  ECOG Performance Status of 0-2.&#xD;
&#xD;
          -  Negative serum or urine pregnancy test within 2 weeks of the date of enrollment&#xD;
&#xD;
          -  for women of child-bearing potential.&#xD;
&#xD;
          -  Ability to understand and the willingness to sign an IRB-approved informed consent&#xD;
             document (either directly or via a legally authorized representative).&#xD;
&#xD;
          -  If EGFR and/or ALK status is unknown, the patient is eligible.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Inability to safely treat all progressive lesions with definitive radiation therapy as&#xD;
             determined by the treating radiation oncologist&#xD;
&#xD;
          -  Patients may not be receiving any other investigational anti-cancer agents.&#xD;
&#xD;
          -  Progressive disease in the CNS only.&#xD;
&#xD;
          -  Known targetable EGFR mutation or EML4-ALK fusion.&#xD;
&#xD;
          -  Progressive cutaneous metastases.&#xD;
&#xD;
          -  Progressive disease involving the esophagus, stomach, or intestines.&#xD;
&#xD;
          -  Malignant pleural or pericardial effusion at the time of oligoprogression.&#xD;
&#xD;
          -  Thoracentesis/thoracoscopic biopsy for a stable or asymptomatic pleural effusion is&#xD;
             not required unless the effusion is hypermetabolic on PET/CT or if there are active&#xD;
             pleural based metastatic lesions at the time of oligoprogression.&#xD;
&#xD;
          -  Effusions that are too small for thoracentesis/pericardiocentesis are considered&#xD;
             resolved for the purposes of trial eligibility.&#xD;
&#xD;
          -  Pregnant women are excluded from this study because radiation therapy has known&#xD;
             potential for teratogenic or abortifacient effects.&#xD;
&#xD;
          -  Uncontrolled intercurrent illness including, but not limited to ongoing or active&#xD;
             infection requiring intravenous antibiotics, symptomatic congestive heart failure,&#xD;
             unstable angina pectoris, unstable cardiac arrhythmia, or psychiatric illness/social&#xD;
             situations that would limit compliance with study requirements as determined by the&#xD;
             treating physician.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Michael Farris, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Wake Forest University Health Sciences</affiliation>
  </overall_official>
  <removed_countries>
    <country>United States</country>
  </removed_countries>
  <verification_date>April 2022</verification_date>
  <study_first_submitted>July 20, 2020</study_first_submitted>
  <study_first_submitted_qc>July 20, 2020</study_first_submitted_qc>
  <study_first_posted type="Actual">July 24, 2020</study_first_posted>
  <last_update_submitted>April 27, 2022</last_update_submitted>
  <last_update_submitted_qc>April 27, 2022</last_update_submitted_qc>
  <last_update_posted type="Actual">May 4, 2022</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Carcinoma, Non-Small-Cell Lung</mesh_term>
  </condition_browse>
  <patient_data>
    <sharing_ipd>No</sharing_ipd>
  </patient_data>
  <!-- Results have not yet been posted for this study                                          -->
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT04485026
org study id: IRB00068259
secondary id: P30CA012197
secondary id: WFBCCC62420
nct id: NCT04485026
lead sponsor: 
collaborator: 
has dmc: Yes
is fda regulated drug: Yes
is fda regulated device: No
This is a randomized phase II study designed to evaluate the effect of local consolidative
      radiation therapy (LCT) to all sites of oligoprogressive disease in patients with metastatic
      non-small cell lung carcinoma who have progressed through first line systemic therapy
      containing an immune checkpoint inhibitor (ICI).
Primary Objective: To compare overall survival (OS) from the time of the time of
      randomization between the treatment and control groups.

      Secondary Objective(s)

        -  To compare the extra-CNS PFS2 (EC-PFS2), defined as the time to extracranial disease
           progression on second line systemic therapy or death from the first day of local
           consolidative radiation therapy (treatment group) or from the start of second line
           therapy (control group).

        -  To evaluate time to initiation of second line systemic therapy or palliative care after
           completion of local consolidative therapy in the treatment group

        -  To compare the toxicities in the treatment and control groups;

        -  To compare overall progression free survival from the time of the first day of local
           consolidative radiation therapy for the treatment group and from the start of second
           line therapy for the control group

        -  To compare the pattern of next progression on second line therapy in the treatment group
           vs the control group.

        -  To evaluate local progression in lesions treated with local consolidative radiation
           therapy.
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Overall Survival
time frame: 3 years
description: In each arm overall survival will be defined as the time from randomization to death from any cause. . Patients who are alive at the last follow up at the end of the study will be censored at the date of the last follow up appointment. A comparison of overall survival between the two groups will be made first using bivariate Kaplan-Meier method and then a multivariable Cox proportional hazards model. Participants who do not die during the course of observation will be right censored. Key covariates to be included in multivariable modeling include age, ECOG status, number of progressive treated sites (1 vs 2-4), and PD-L1 status (>=50%; 1%-49%; < 1%).
measure: Time to Progression Between Both Arms
time frame: 3 years
description: Investigators will compare progression after second line of therapy between both arms first using the bivariate Kaplan-Meier method and then a multivariable Cox proportional hazards model age, ECOG status, number of progressive treated sites (1 vs 2-4), and PD-L1 status (>=50%; 1%-49%; < 1%). RECIST version 1.1 criteria will be used to assess for progression.
measure: Time to Second Line of Systemic Therapy or Palliative Care (Local Consolidative Radiation Therapy Arm Only)
time frame: Up to 2 years after the completion of intervention
description: The time to the second line systemic therapy or palliative care will be defined as the time from the completion of local consolidation therapy to the first day of cycle 1 of a systemic therapy the patient has not yet received OR the date of hospice enrollment, whichever is sooner. Patients experiencing neither of these events will be censored at last follow up visit. Estimated median time to second line therapy (or palliative care) and corresponding 95% confidence interval as well as estimated proportion (and corresponding 95% confidence interval) of the treatment group who have started second-line therapy (or palliative care) by key time points including 6 months, 1 year, and 2 years after the end of local consolidative therapy.
measure: Incidences of Toxicities
time frame: Up to 3 years
description: Toxicities will be evaluated per Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. Toxicities between the two arms by comparing the proportions with grade 2 or higher, and grade 3 or higher, toxicities of any type at 3, 6, 12, 24 and 36 months following randomization using a chi-square test on the relevant 2x2 contingency table.
measure: Progression Free Survival
time frame: Up to 5 years
description: Progression free survival will be assessed by a modified RECIST version 1.1 criteria. If any individual target lesion meets RECIST v1.1 criteria - specifically an increase in the longest diameter (shortest diameter for lymph node lesions) of at least 20% and 5 mm absolute increase, the patient will be considered to have progression of disease. The criteria for determining pseudoprogression versus true progression and for mild progression while systemic therapy is held for the delivery of local consolidative radiation therapy in the treatment arm will be used for this outcome measure as well. Repeat oligoprogression will also be counted as progressive disease.
measure: Time to Next Progression Following Local Consolidative Radiation Therapy or Second Line Systemic Therapy
time frame: Up to 3 years
description: The pattern of next progression following local consolidation therapy (in treatment group) or second line systemic therapy (in control group) into one of three possible mutually exclusive and exhaustive categories: No progression, repeat oligoprogression or polyprogression, and will compare these patterns between the two groups using a chi-square analysis on the resulting 2x3 contingency table.
measure: Proportion of Local of Lesions Treated with Local Consolidative Radiation Therapy That Progress
time frame: Up to 5 years
description: Investigators will estimate proportion of lesions treated with local consolidative radiation therapy that experienced local progression (yes/no by study end) and construct a 95% confidence interval around this estimate.
arm group label: Local Consolidative Radiation Therapy Arm
arm group type: Experimental
description: Definitive external beam radiation therapy will be delivered to all sites of progressive disease for all patients. The technique used to deliver radiation therapy will be determined by the treating radiation oncologist.
arm group label: Standard of Care - Control Arm
arm group type: Active Comparator
description: Second line systemic therapy is at the discretion of the treating medical oncologist.
intervention type: Radiation
intervention name: Local consolidative radiation therapy
description: All local consolidative radiation therapy should be delivered using hypofractionated local consolidative radiation therapy (>2 Gy per fraction). Exceptions may be approved on a case by case basis by the trial principal investigator. Three-dimensional conformal radiotherapy (3D-CRT), intensity modulated radiation therapy (IMRT), volumetric modulated arc therapy (VMAT), stereotactic body radiotherapy (SBRT), stereotactic radiosurgery (SRS), and proton beam therapy (PBT) are all acceptable.
arm group label: Local Consolidative Radiation Therapy Arm
intervention type: Drug
intervention name: Standard of care radiation therapy
description: Standard of care palliative radiotherapy to symptomatic lesions is permissible. The dose to symptomatic lesions should not exceed 30 Gy in 10 fractions. Brain metastases will be treated with standard of care CNS therapy throughout the study. This may include (but is not limited to) stereotactic radiosurgery, neurosurgical intervention, whole brain radiotherapy
arm group label: Standard of Care - Control Arm
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Michael Farris, MD
role: Principal Investigator
affiliation: Wake Forest University Health Sciences
country: United States
responsible party type: Sponsor
mesh term: Carcinoma, Non-Small-Cell Lung
sharing ipd: No