Clinical Trials /

Pembrolizumab and Stereotactic Body Radiation Therapy or Non-Stereotactic Wide-Field Radiation Therapy in Treating Patients With Non-small Cell Lung Cancer

NCT02444741

Description:

This randomized phase I/II trial studies the side effects and best dose of pembrolizumab when given together with stereotactic body radiation therapy or non-stereotactic wide-field radiation therapy (conventional radiation therapy) and to see how well they work in treating patients with non-small cell lung cancer. Immunotherapy with monoclonal antibodies, such as pembrolizumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Radiation therapy uses high-energy x-rays to kill tumor cells and shrink tumors. Stereotactic body radiation therapy uses special equipment to position a patient and deliver radiation to tumors with high precision. This method can kill tumor cells with fewer doses over a shorter period and cause less damage to normal tissue. Giving pembrolizumab together with radiation therapy may kill more tumor cells.

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

Recruiting

Phase:

Phase 1/Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Pembrolizumab and Stereotactic Body Radiation Therapy or Non-Stereotactic Wide-Field Radiation Therapy in Treating Patients With Non-small Cell Lung Cancer
  • Official Title: Phase I/II Trial of MK-3475 and Hypofractionated Stereotactic Radiation Therapy in Patients With NSCLC

Clinical Trial IDs

  • ORG STUDY ID: 2014-1020
  • SECONDARY ID: NCI-2015-01505
  • SECONDARY ID: 2014-1020
  • SECONDARY ID: P30CA016672
  • NCT ID: NCT02444741

Conditions

  • Lung Non-Small Cell Carcinoma
  • Metastatic Lung Non-Small Cell Carcinoma
  • Stage IV Lung Non-Small Cell Cancer AJCC v7

Interventions

DrugSynonymsArms
PembrolizumabKeytruda, Lambrolizumab, MK-3475, SCH 900475Group I, Phase I (pembrolizumab + SBRT)

Purpose

This randomized phase I/II trial studies the side effects and best dose of pembrolizumab when given together with stereotactic body radiation therapy or non-stereotactic wide-field radiation therapy (conventional radiation therapy) and to see how well they work in treating patients with non-small cell lung cancer. Immunotherapy with monoclonal antibodies, such as pembrolizumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Radiation therapy uses high-energy x-rays to kill tumor cells and shrink tumors. Stereotactic body radiation therapy uses special equipment to position a patient and deliver radiation to tumors with high precision. This method can kill tumor cells with fewer doses over a shorter period and cause less damage to normal tissue. Giving pembrolizumab together with radiation therapy may kill more tumor cells.

Detailed Description

      PRIMARY OBJECTIVES:

      I. To evaluate the safety and toxicity profile of intravenous MK-3475 (pembrolizumab)
      administered in combination with stereotactic body radiation therapy (SBRT) targeting 1-4
      liver or thoracic lesion(s) in patients with metastatic non-small cell lung cancer (NSCLC).
      (Phase I) II. To evaluate the safety and toxicity profile of intravenous MK-3475 administered
      in combination with non-stereotactic wide-field radiation therapy (WFRT) targeting 1-4 liver
      or thoracic lesion(s) in patients with metastatic NSCLC. (Phase I) III. To determine the
      maximum tolerated dose (MTD) and dose limiting toxicities (DLTs) of MK-3475 and SBRT
      combination therapy. (Phase I) IV. To determine the MTD and DLTs of MK-3475 and WFRT
      combination therapy. (Phase I) V. To determine the rate of out-of-field objective responses
      (either complete response [CR] or partial response [PR]) of the non-irradiated disease sites.
      (Phase II)

      SECONDARY OBJECTIVES:

      I. To determine whether the addition of radiation therapy (XRT) to MK-3475 can improve the
      progression free survival (PFS) rate compared to MK-3475 alone. (Phase II)

      OUTLINE: This is a phase I, dose-escalation study of pembrolizumab followed by a phase II
      study.

      PHASE I: Patients are assigned to 1 of 2 treatment groups.

      GROUP I: Patients who exhibit a lung lesion of size and location amenable to SBRT receive
      pembrolizumab intravenously (IV) over 30 minutes on day 1. Patients also receive SBRT in 4
      fractions daily on days 2-5 or either intensity modulated radiation therapy (IMRT), proton
      beam radiation therapy (PBRT), or 3 dimensional conformation radiation therapy (3D-CRT) in 15
      fractions total concurrent with pembrolizumab administration on days 1-19. Treatment repeats
      every 21 days for up to 16 courses in the absence of disease progression or unacceptable
      toxicity.

      GROUP II: Patients who exhibit a lung lesion of size or location not amenable to SBRT, but
      amenable to WFRT receive pembrolizumab as in Group I and either IMRT, PBRT, or 3D-CRT in 15
      fractions total concurrent with pembrolizumab administration.

      PHASE II: Patients for whom SBRT is recommended are randomized to Group 1 or 2, patients for
      whom conventional radiation therapy is recommended are randomized to Group 3 or 4, and
      patients with lesions amenable to SBRT or WFRT are assigned to Group 5.

      GROUP I: Patients who exhibit a lung lesion with size and location amenable to SBRT receive
      pembrolizumab IV on day 1 and SBRT on days 44-47 or IMRT, PBT, or 3D-CRT on days 43-61.
      Treatment with pembrolizumab repeats every 21 days for up to 16 courses in the absence of
      disease progression or unacceptable toxicity.

      GROUP II: Patients who exhibit a lung lesion with size and location amenable to SBRT receive
      pembrolizumab IV as in Group I without XRT. At the first planned efficacy evaluation (5
      weeks), patients exhibiting progressive disease (PD) are treated with SBRT concurrent with
      the remaining cycles of pembrolizumab. In the event that lesion size has progressed to the
      point where the attending physician no longer considers SBRT safe, then the patient will be
      salvaged with IMRT, PBRT, or 3D-CRT and analyzed as part of the fourth treatment group.

      GROUP III: Patients who exhibit a lung lesion with size and location not amenable to SBRT,
      but amenable to WFRT receive pembrolizumab IV as in Group I and IMRT, PBRT, or 3D-CRT on days
      43-61.

      GROUP IV: Patients who exhibit a lung lesion with size and location not amenable to SBRT, but
      amenable to WFRT receive pembrolizumab IV as in Group I without XRT. The decision on when to
      start XRT will be assessed first at week 5 (after the second dose of pembrolizumab). If a
      patient has PD based on immune response related criteria (irRC) then XRT will be delivered
      after the third dose of pembrolizumab, while patients with stable disease (SD) or PR will not
      start XRT and will continue to be followed. These patients will then have follow up computed
      tomography (CT) scans 5 weeks after course 3 three and then approximately every 3 months for
      the remainder of the trial; any patient at this point with PD will then have XRT delivered
      with the sixth dose of pembrolizumab.

      GROUP V: Patients with lesions amenable to SBRT or WFRT receive pembrolizumab IV as in Group
      I. Patients also receive either IMRT, PBRT, or 3D-CRT in 15 fractions to the primary lesions
      and low dose radiation therapy to other lesions on days 43-61 or SBRT in 4 fractions to
      primary lesions and low dose radiation therapy to other lesions on days 44-47.

      After completion of study treatment, patients are followed up at 30 days and then every 12
      weeks.
    

Trial Arms

NameTypeDescriptionInterventions
Group I, Phase I (pembrolizumab + SBRT)ExperimentalPatients who exhibit a lung lesion of size and location amenable to SBRT receive pembrolizumab IV over 30 minutes on day 1. Patients also receive SBRT in 4 fractions daily on days 2-5 or either IMRT, PBRT, or 3D-CRT in 15 fractions total concurrent with pembrolizumab administration on days 1-19. Treatment repeats every 21 days for up to 16 courses in the absence of disease progression or unacceptable toxicity.
  • Pembrolizumab
Group I, Phase II (pembrolizumab + SBRT)ExperimentalPatients who exhibit a lung lesion with size and location amenable to SBRT receive pembrolizumab IV on day 1 and SBRT on days 44-47 or IMRT, PBT, or 3D-CRT on days 43-61. Treatment with pembrolizumab repeats every 21 days for up to 16 courses in the absence of disease progression or unacceptable toxicity.
  • Pembrolizumab
Group II, Phase I (pembrolizumab + IMRT, PBRT or 3D-CRT)ExperimentalPatients who exhibit a lung lesion of size or location not amenable to SBRT, but amenable to WFRT receive pembrolizumab as in Group I and either IMRT, PBRT, or 3D-CRT in 15 fractions total on days 1-19 concurrent with pembrolizumab administration.
  • Pembrolizumab
Group II, Phase II (pembrolizumab + XRT upon PD)ExperimentalPatients who exhibit a lung lesion with size and location amenable to SBRT receive pembrolizumab IV as in Group I without XRT. At the first planned efficacy evaluation (5 weeks), patients exhibiting PD are treated with SBRT concurrent with the remaining cycles of pembrolizumab. In the event that lesion size has progressed to the point where the attending physician no longer considers SBRT safe, then the patient will be salvaged with IMRT, PBRT, or 3D-CRT and analyzed as part of the fourth treatment group.
  • Pembrolizumab
Group III, Phase II (pembrolizumab + IMRT, PBRT, or 3D-CRT)ExperimentalPatients who exhibit a lung lesion with size and location not amenable to SBRT, but amenable to WFRT receive pembrolizumab IV as in Group I and IMRT, PBRT, or 3D-CRT on days 43-61.
  • Pembrolizumab
Group IV, Phase II (pembrolizumab + XRT upon PD)ExperimentalPatients who exhibit a lung lesion with size and location not amenable to SBRT, but amenable to WFRT receive pembrolizumab IV as in Group I without XRT. The decision on when to start XRT will be assessed first at week 5 (after the second dose of pembrolizumab). If a patient has PD based on irRC then XRT will be delivered after the third dose of pembrolizumab, while patients with SD or PR will not start XRT and will continue to be followed. These patients will then have follow up CT scans 5 weeks after course 3 and then approximately every 3 months for the remainder of the trial; any patient at this point with PD will then have XRT delivered with the sixth dose of pembrolizumab.
  • Pembrolizumab
Group V, Phase II (low dose radiation therapy)ExperimentalPatients with lesions amenable to SBRT or WFRT receive pembrolizumab IV as in Group I. Patients also receive either IMRT, PBRT, or 3D-CRT in 15 fractions to the primary lesions and low dose radiation therapy to other lesions on days 43-61 or SBRT in 4 fractions to primary lesions and low dose radiation therapy to other lesions on days 44-47.
  • Pembrolizumab

Eligibility Criteria

        Inclusion Criteria:

          -  Pathologically confirmed non-small lung cancer

          -  Stage IV metastatic disease (only during the phase II)

          -  At least one thoracic or liver lesion amenable to radiation, for group 5 we need one
             area that can safely receive SBRT or WFRT, not restricted to lung or liver sites

          -  At least one additional non-contiguous lesion to the irradiated lesion amenable to
             radiographic evaluation

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

          -  Have measurable disease based on immune related response criteria (irRC) criteria

          -  Have a performance status of 0 or 1 on the Eastern Cooperative Oncology Group (ECOG)
             performance scale

          -  Patients with brain metastasis will be included as long as they are free of neurologic
             symptoms related to metastatic brain lesions and who do not require or receive
             systemic corticosteroid therapy in the 14 days prior to beginning MK-3475 therapy

          -  Absolute neutrophil count (ANC) >= 1,500 /mcL (performed within 28 days prior to study
             registration up to the first dose of study drug)

          -  Platelets >= 100,000 /mcL (performed within 28 days prior to study registration up to
             the first dose of study drug)

          -  Hemoglobin >= 9 g/dL or >= 5.6 mmol/L (performed within 28 days prior to study
             registration up to the first dose of study drug)

          -  Serum creatinine or measured or calculated creatinine clearance (glomerular filtration
             rate [GFR] can also be used in place of creatinine or calculated creatinine clearance
             [CrCl]) =< 1.5 X upper limit of normal (ULN) or >= 60 mL/min for subject with
             creatinine levels > 1.5 X institutional ULN (creatinine clearance should be calculated
             per institutional standard) (performed within 28 days prior to study registration up
             to the first dose of study drug)

          -  Serum total bilirubin =< 1.5 X ULN or direct bilirubin =< ULN for subjects with total
             bilirubin levels > 1.5 ULN (performed within 28 days prior to study registration up to
             the first dose of study drug)

          -  Aspartate aminotransferase (AST) serum glutamic-oxaloacetic transaminase (SGOT) and
             alanine aminotransferase (ALT) serum glutamic-pyruvic transaminase (SGPT) =< 2.5 X ULN
             or =< 5 X ULN for subjects with liver metastases (performed within 28 days prior to
             study registration up to the first dose of study drug)

          -  International normalized ratio (INR) =< 1.5 X ULN unless subject is receiving
             anticoagulant therapy as long as prothrombin time (PT) or partial prothrombin time
             (PTT) is within therapeutic range of intended use of anticoagulants (performed within
             28 days prior to study registration up to the first dose of study drug)

          -  Prothrombin time =< 1.5 X ULN unless subject is receiving anticoagulant therapy as
             long as PT or PTT is within therapeutic range of intended use of anticoagulants
             (performed within 28 days prior to study registration up to the first dose of study
             drug)

          -  Activated partial thromboplastin time (aPTT) =< 1.5 X ULN unless subject is receiving
             anticoagulant therapy as long as PT or PTT is within therapeutic range of intended use
             of anticoagulants (performed within 28 days prior to study registration up to the
             first dose of study drug)

          -  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 should be willing to use 2 methods of birth
             control or be surgically sterile, or abstain from heterosexual activity for the course
             of the study through 120 days after the last dose of study medication; subjects of
             childbearing potential are those who have not been surgically sterilized or have not
             been free from menses for > 1 year

          -  Male subjects should agree to use an adequate method of contraception starting with
             the first dose of study therapy through 120 days after the last dose of study therapy

          -  We will allow XRT prior to study entry to other sites, with no washout period, allowed
             prior to study entry as long as at least one measurable sites of disease is kept
             unirradiated

        Exclusion Criteria:

          -  Is currently participating in or has participated in a study of an investigational
             agent (except glutamine) or using an investigational device within 4 weeks of the
             first dose of treatment or 5 half lives, whichever is shorter

          -  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; unless the steroid therapy is for physiological replacement

          -  Has a diagnosis of active scleroderma, lupus, or other autoimmune disease which by the
             opinion of the treating radiation oncologist precludes safe radiation therapy

          -  Has had prior radiation therapy to all available thoracic and liver lesions such that
             additional radiation therapy is unsafe by the opinion of the treating radiation
             oncologist

          -  Has had a prior monoclonal antibody within 4 weeks or 5 half-lives, which ever is
             shorter, 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 or targeted small molecule 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

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

          -  Has known active central nervous system (CNS) metastases and/or carcinomatous
             meningitis; subjects with previously treated brain metastases may participate provided
             they are stable (without evidence of progression by imaging for at least four weeks
             prior to the first dose of trial treatment and any neurologic symptoms have returned
             to baseline), have no evidence of new or enlarging brain metastases, and are not using
             steroids for at least 7 days prior to trial treatment

          -  Has an active autoimmune disease requiring systemic treatment within the past 3 months
             or a documented history of clinically severe autoimmune disease, or a syndrome that
             requires systemic steroids or immunosuppressive agents; subjects with vitiligo or
             resolved childhood asthma/atopy would be an exception to this rule; subjects that
             require intermittent use of bronchodilators or local steroid injections would not be
             excluded from the study; subjects with hypothyroidism stable on hormone replacement or
             Sjogren's syndrome will not be excluded from the study

          -  Has evidence of interstitial lung disease or active, non-infectious pneumonitis

          -  Has an active infection requiring systemic therapy or hospital admission

          -  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 a known history of human immunodeficiency virus (HIV) (HIV 1/2 antibodies)

          -  Has known active hepatitis B (e.g., hepatitis B virus HBsAg surface protein antigen
             [HBsAg] reactive) or hepatitis C (e.g., hepatitis C virus [HCV] ribonucleic acid [RNA]
             [qualitative] is detected)

          -  Has received a live vaccine within 30 days prior to the first dose of trial treatment

          -  Symptomatic brain metastasis

          -  Has experienced a dose limiting toxicity on treatment with either prior radiation or
             anti programmed cell death 1 (PD-1) or programmed cell death 1 ligand 1 (PD-L1)
             inhibitor therapy
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Disease response, according to immune related response criteria (Phase I/II)
Time Frame:Beginning 3 months after initiation of treatment
Safety Issue:
Description:Treatment success will be defined as radiographic complete response or partial response measured using Pearson chi-squared or Fisher exact tests.

Secondary Outcome Measures

Measure:Progression-free survival (Phase II)
Time Frame:From the time of enrollment to first evidence of progressive disease, assessed at 3 months after treatment initiation
Safety Issue:
Description:Analysis conducted using Kaplan-Meier method. At the discretion of the investigators, multivariate Cox regression will be done to adjust for (among other factors): number of metastatic disease sites, number of prior treatments, primary cancer histology, age, pre-treatment Karnofsky performance scale, and Royal Marsden score.
Measure:Overall survival
Time Frame:Receipt of the first pembrolizumab dose to death, assessed up to 5 years
Safety Issue:
Description:Analysis conducted using Kaplan-Meier method, with comparisons regarding overall survival made via the log-rank test. At the discretion of the investigators, multivariate Cox regression will be done to adjust for (among other factors): number of metastatic disease sites, number of prior treatments, primary cancer histology, age, pre-treatment Karnofsky performance scale, and Royal Marsden score.

Details

Phase:Phase 1/Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:M.D. Anderson Cancer Center

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