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A Randomized Two Arm Phase II Trial of Pembrolizumab Alone or Sequentially Following Single Fraction Non-ablative Radiation to One of the Target Lesions, in Previously Treated Patients With Stage IV NSCLC

NCT02658097

Description:

This study looks at patients with advanced lung cancer. Participants in this study will be randomized into two groups. The first group will have radiation plus a drug (pembrolizumab). The second group will have only the drug (pembrolizumab). Tumors of participants will be measured to see if the addition of radiation changes the growth of the tumor compared to the drug alone.

Related Conditions:
  • Non-Small Cell Lung Carcinoma
Recruiting Status:

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: A Randomized Two Arm Phase II Trial of Pembrolizumab Alone or Sequentially Following Single Fraction Non-ablative Radiation to One of the Target Lesions, in Previously Treated Patients With Stage IV NSCLC
  • Official Title: A Phase II Trial of Pembrolizumab Sequentially Following Single Fraction Non-ablative Radiation to One of the Target Lesions, in Previously Treated Patients With Stage IV NSCLC

Clinical Trial IDs

  • ORG STUDY ID: CASE1516
  • NCT ID: NCT02658097

Conditions

  • Stage IV Non-Small Cell Lung Cancer

Interventions

DrugSynonymsArms
PembrolizumabSingle Fraction Radiation Therapy (SFRT) + pembrolizumab

Purpose

This study looks at patients with advanced lung cancer. Participants in this study will be randomized into two groups. The first group will have radiation plus a drug (pembrolizumab). The second group will have only the drug (pembrolizumab). Tumors of participants will be measured to see if the addition of radiation changes the growth of the tumor compared to the drug alone.

Detailed Description

      This is a Phase 2 randomized two arm phase II trial of pembrolizumab alone or sequentially
      following focal radiation to one of the target lesions, in previously treated patients with
      stage IV Non-Small Cell Lung Cancer (NSCLC). The primary goal of this trial is to compare the
      efficacy of focal radiation (RT) to an index lesion as a way of enhancing the anti-tumor
      immune response to pembrolizumab to that of pembrolizumab alone. The primary efficacy
      endpoint is overall RECIST-defined response outside the radiation field. To accomplish this
      goal 66 patients will be randomized 2:1 (stratified by histology (squamous versus
      non-squamous) and refractory versus non-refractory disease) to radiation plus pembrolizumab
      or pembrolizumab only, respectively.

      Primary Objective: To determine the tumor responses outside the radiation field (abscopal
      effect) after radiation followed by pembrolizumab in metastatic NSCLC.

      Secondary Objectives:

        1. To determine the progression-free and overall survival in patients with NSCLC receiving
           pembrolizumab, who receive Single Fraction Radiation Therapy (SFRT)

        2. To determine the safety and toxicity of the combination of SFRT and pembrolizumab

        3. To examine potential predictive biomarkers in tumor samples and peripheral blood in
           patients treated with pembrolizumab and SFRT

        4. To determine the local control of SFRT in the radiated lesion, when SFRT is given with
           pembrolizumab

        5. To evaluate the induction of a T-cell response in patients with metastatic NSCLC treated
           with radiation and the effect of radiation
    

Trial Arms

NameTypeDescriptionInterventions
Single Fraction Radiation Therapy (SFRT) + pembrolizumabExperimental200mg Pembrolizumab by IV infusion on day 1 of each 3 week cycle. 8Gy will be given in a single fraction on the first day of treatment
  • Pembrolizumab
PembrolizumabActive Comparator200mg Pembrolizumab by IV infusion on day 1 of each 3 week cycle.
  • Pembrolizumab

Eligibility Criteria

        Inclusion Criteria:

          -  Be willing and able to provide written informed consent/assent for the trial.

          -  Have measurable disease based on RECIST 1.1.

          -  Be willing to provide tissue from a newly obtained core or excisional biopsy of a
             tumor lesion. Newly-obtained is defined as a specimen obtained up to 6 weeks (42 days)
             prior to initiation of treatment on Day 1. Subjects for whom newly-obtained samples
             cannot be provided (e.g. inaccessible or subject safety concern) may submit an
             archived specimen only upon agreement from the Sponsor and primary investigator.

          -  Have a performance status of ≤1 ECOG Performance Scale.

          -  Demonstrate adequate organ function

               -  Absolute neutrophil count (ANC) ≥ 1,500/mcL

               -  Platelets ≥ 100,000/mcL

               -  Hemoglobin ≥ 9g/dL

               -  Serum creatinine or measured ≤1.5 times the upper limit of normal (ULN) or
                  measured or calculated creatinine clearance ≥ 60 mL/min for subjects with
                  creatinine levels >1.5 times the institutional ULN

               -  Serum total bilirubin ≤ 1.5 X ULN or direct bilirubin ≤ ULN for subjects with
                  total bilirubin levels > 1.5 ULN

               -  AST (SGOT) and ALT (SGPT) ≤ 2.5 times ULN or ≤ 5 times ULN for subjects with
                  liver metastases

               -  Albumin ≥ 2.5 mg/dL

          -  Have one measurable lesion of at least 1 cm outside the planned radiation field
             (defined as not receiving direct beam from any of the treatment portals).

          -  Female subject of childbearing potential should have a negative urine or serum
             pregnancy within 72 hours prior to receiving the first dose of study medication. If
             the urine test is positive or cannot be confirmed as negative, a serum pregnancy test
             will be required.

          -  Female subjects of childbearing potential must be willing to use an adequate method of
             contraception - Contraception, for the course of the study through 120 days after the
             last dose of study medication.

        Note: Abstinence is acceptable if this is the usual lifestyle and preferred contraception
        for the subject

          -  Male subjects of childbearing potential must agree to use an adequate method of
             contraception- Contraception, starting with the first dose of study therapy through
             120 days after the last dose of study therapy.

        Note: Abstinence is acceptable if this is the usual lifestyle and preferred contraception
        for the subject.

        Exclusion Criteria:

          -  Is currently participating and receiving study therapy or has participated in a study
             of an investigational agent and received study therapy or used an investigational
             device within 4 weeks of the first dose of treatment.

          -  Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy or any
             other form of immunosuppressive therapy within 7 days prior to the first dose of trial
             treatment.

          -  Has a known history of active TB (Bacillus Tuberculosis)

          -  Hypersensitivity to pembrolizumab or any of its excipients.

          -  Has had a prior anti-cancer monoclonal antibody (mAb) within 4 weeks prior to study
             Day 1 or who has not recovered (i.e., ≤ Grade 1 or at baseline) from adverse events
             due to agents administered more than 4 weeks earlier.

          -  Has had prior chemotherapy, targeted small molecule therapy, or radiation therapy
             within 2 weeks prior to study Day 1 or who has not recovered (i.e., ≤ Grade 1 or at
             baseline) from adverse events due to a previously administered agent.

               -  Note: Subjects with ≤ Grade 2 neuropathy are an exception to this criterion and
                  may qualify for the study.

               -  Note: If subject received major surgery, they must have recovered adequately from
                  the toxicity and/or complications from the intervention prior to starting
                  therapy.

          -  Patient who have previously received radiation overlapping with the current planned
             radiation treatment fields are ineligible. Overlap is defined as any tissue falling
             within the direct path of both prior and current planned radiation fields.

          -  Has a known additional malignancy that is progressing or requires active treatment.
             Exceptions include basal cell carcinoma of the skin or squamous cell carcinoma of the
             skin that has undergone potentially curative therapy or in situ cervical cancer.

          -  Patients with active central nervous system (CNS) metastases and/or carcinomatous
             meningitis. Subjects with previously treated brain metastases may participate provided
             they are clinically stable for at least 4 weeks and, have no evidence of new or
             enlarging brain metastases and also are off steroids 3 days prior to dosing with study
             medication. Stable brain metastases by this definition should be established prior to
             the first dose of pembrolizumab.

          -  Has had prior chemotherapy, within 2 weeks prior to study treatment. Patients on
             targeted therapy (tyrosine kinase inhibitor) may go on the study after 5 days off
             therapy.

          -  Patients who have not recovered (i.e., ≤ Grade 2 or at baseline) from adverse events
             due to a previously administered agent.

             --Note: If subject received major surgery, they must have recovered adequately from
             the toxicity and/or complications from the intervention prior to starting therapy. Has
             active autoimmune disease that has required systemic treatment in the past 2 years
             (i.e. with use of disease modifying agents, corticosteroids or immunosuppressive
             drugs). Replacement therapy (eg., thyroxine, insulin, or physiologic corticosteroid
             replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a
             form of systemic treatment.

          -  Has history of (non-infectious) pneumonitis that required steroids, evidence of
             interstitial lung disease or active, non-infectious pneumonitis.

          -  Has an active infection requiring systemic therapy.

          -  Has a history or current evidence of any condition, therapy, or laboratory abnormality
             that might confound the results of the trial, interfere with the subject's
             participation for the full duration of the trial, or is not in the best interest of
             the subject to participate, in the opinion of the treating investigator.

          -  Has known psychiatric or substance abuse disorders that would interfere with
             cooperation with the requirements of the trial.

          -  Is pregnant or breastfeeding, or expecting to conceive or father children within the
             projected duration of the trial, starting with the pre-screening or screening visit
             through 120 days after the last dose of trial treatment.

          -  Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent.

          -  Has a known history of Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies).

          -  Has known active Hepatitis B (e.g., HBsAg reactive) or Hepatitis C.

          -  Has received a live vaccine within 30 days of planned start of study therapy.

               -  Note: Seasonal influenza vaccines for injection are generally inactivated flu
                  vaccines and are allowed; however intranasal influenza vaccines (e.g., Flu-Mist®)
                  are live attenuated vaccines, and are not allowed.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Number of patients with each response as measured by RECIST 1.1
Time Frame:From first visit to disease progression, up to 24 months after beginning treatment
Safety Issue:
Description:The Best Overall Response is the best response recorded from the start of the treatment until disease progression (taking as reference for progressive disease the smallest measurements recorded since the treatment started). The anti-tumor activity will be evaluated as an efficacy endpoints based on radiographic (CT or PET/CT). RECIST 1.1 will be applied for evaluation of tumor response.

Secondary Outcome Measures

Measure:Median time of progression free survival
Time Frame:From first visit to disease progression, up to 24 months after beginning treatment
Safety Issue:
Description:Progression free survival, PFS is defined as the time from initiation of study drug post-SFRT, until the first documented, confirmed progression of disease. PFS will also be measured and report from the initiation of study drug, pre-SFRT.
Measure:Median time of overall survival
Time Frame:From first visit to disease progression, up to 24 months after beginning treatment
Safety Issue:
Description:Overall Survival, OS will be measure from the initiation of study therapy
Measure:Number of patients with local control of disease with SFRT
Time Frame:From first visit to disease progression, up to 24 months after beginning treatment
Safety Issue:
Description:Local Control with SFRT: The target lesion selected for SFRT will be followed for local control. For the purpose of the study, local control will be defined as a complete response, partial response, or stable disease within the planning target volume.
Measure:Duration of local control of disease with SFRT
Time Frame:From first visit to disease progression, up to 24 months after beginning treatment
Safety Issue:
Description:Local Control with SFRT: The target lesion selected for SFRT will be followed for local control. For the purpose of the study, local control will be defined as a complete response, partial response, or stable disease within the planning target volume. The duration of local control will be measured from the time of SBRT treatment fraction.

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Case Comprehensive Cancer Center

Trial Keywords

  • Lung Cancer
  • pembrolizumab
  • focal radiation
  • RT

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