Clinical Trials /

Pembrolizumab and Stereotactic Radiosurgery for Melanoma or Non-Small Cell Lung Cancer Brain Metastases

NCT02858869

Description:

This pilot trial studies the side effects of giving pembrolizumab together with stereotactic radiosurgery to treat patients with melanoma or non-small cell lung cancer that has spread to the brain. Monoclonal antibodies, such as pembrolizumab, may interfere with the ability of tumor cells to grow and spread. Stereotactic radiosurgery is a specialized radiation therapy that delivers a single, high dose of radiation directly to the tumor and may cause less damage to normal tissue. Giving pembrolizumab together with stereotactic radiosurgery may be a better treatment for patients with melanoma or non-small cell lung cancer that has spread to the brain.

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

Recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: Pembrolizumab and Stereotactic Radiosurgery for Melanoma or Non-Small Cell Lung Cancer Brain Metastases
  • Official Title: Pilot Study of Pembrolizumab and Stereotactic Radio-Surgery (SRS) for Patients With Melanoma or Non-Small Cell Lung Cancer (NSCLC) Brain Metastases (BM)

Clinical Trial IDs

  • ORG STUDY ID: IRB00086461
  • SECONDARY ID: NCI-2016-00718
  • SECONDARY ID: RAD3179-16
  • NCT ID: NCT02858869

Conditions

  • Metastatic Malignant Neoplasm in the Brain
  • Metastatic Melanoma
  • Mucosal Melanoma
  • Ocular Melanoma
  • Stage IV Non-Small Cell Lung Cancer
  • Stage IV Skin Melanoma
  • Melanoma of Unknown Primary

Interventions

DrugSynonymsArms
PembrolizumabKeytruda, Lambrolizumab, MK-3475, SCH 900475Arm A (pembrolizumab, SRS 6 Gy, CLOSED):

Purpose

This pilot trial studies the side effects of giving pembrolizumab together with stereotactic radiosurgery to treat patients with melanoma or non-small cell lung cancer that has spread to the brain. Monoclonal antibodies, such as pembrolizumab, may interfere with the ability of tumor cells to grow and spread. Stereotactic radiosurgery is a specialized radiation therapy that delivers a single, high dose of radiation directly to the tumor and may cause less damage to normal tissue. Giving pembrolizumab together with stereotactic radiosurgery may be a better treatment for patients with melanoma or non-small cell lung cancer that has spread to the brain.

Detailed Description

      PRIMARY OBJECTIVE:

      I. To determine the safety of three different stereotactic radiosurgery (SRS) radiation arms
      in combination with pembrolizumab for melanoma and non-small cell lung cancer (NSCLC) brain
      metastasis (BM) patients.

      SECONDARY OBJECTIVES:

      I. To evaluate intracranial outcomes - control of the treated lesion in the brain with SRS+
      pembrolizumab (i.e. local control), development of additional sites of disease in the brain
      that were not initially treated with SRS (i.e. anywhere intra-cranial failure), intra-cranial
      progression free survival (local control of the area that received SRS and anywhere
      intra-cranial failure), extra-cranial disease response (overall progression free survival),
      rate of leptomeningeal dissemination, and overall survival.

      II. To determine the overall response rate and overall survival of combination SRS and
      pembrolizumab compared to SRS alone (historical control).

      III. To determine the overall response rate and overall survival of combination SRS and
      pembrolizumab compared to pembrolizumab alone (historical control).

      IV. To evaluate treatment response at un-irradiated and extra-cranial sites (i.e. the
      abscopal effect) with all three arms.

      V. To compare differences in potential immune biomarkers, pretreatment, during treatment, and
      post treatment.

      OUTLINE: Patients are assigned to 1 of 3 arms.

      ARM A (SRS 6 Gy, CLOSED): Patients receive pembrolizumab intravenously (IV) over 30 minutes
      on day 1. Courses repeat every 3 weeks (Q3W) for at least 2 years in the absence of disease
      progression or unacceptable toxicity. Patients undergo 5 SRS fractions between days 2-15 of
      course 1.

      ARM B (SRS 9 Gy): Patients receive pembrolizumab IV as in Arm A. Patients undergo 3 SRS
      fractions between days 2-15 of course 1.

      ARM C (SRS 18-21 Gy): Patients receive pembrolizumab IV as in Arm A. Patients undergo 1 SRS
      fraction between days 2-3 of course 1.

      After completion of study treatment, patients are followed up at 30 days, then every 12 weeks
      for up to 1 year.
    

Trial Arms

NameTypeDescriptionInterventions
Arm A (pembrolizumab, SRS 6 Gy, CLOSED):ExperimentalPatients receive 200 mg pembrolizumab IV over 30 minutes on day 1. Courses repeat Q3W for at least 2 years in the absence of disease progression or unacceptable toxicity. Patients undergo 5 SRS fractions between days 2-15 of course 1.
  • Pembrolizumab
Arm B (pembrolizumab, SRS 9 Gy)ExperimentalPatients receive pembrolizumab IV as in Arm A. Patients undergo 3 SRS fractions between days 2-15 of course 1.
  • Pembrolizumab
Arm C (pembrolizumab, SRS 18-21 Gy)ExperimentalPatients receive pembrolizumab IV as in Arm A. Patients undergo 1 SRS fraction between days 2-3 of course 1.
  • Pembrolizumab

Eligibility Criteria

        Inclusion Criteria:

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

          -  Eastern Cooperative Oncology Group (ECOG) performance scale (PS) of 0-1; Karnofsky
             performance status ≥ 70%

          -  Patients must have histological diagnosis of melanoma or non-small cell lung cancer
             (biopsy will be done per standard of care, if needed to prove metastatic melanoma
             and/or NSCLC as well as for clinically relevant mutation analysis); additional biopsy
             will be per standard of care

          -  Patients can be treated either in first line or in the refractory setting; programmed
             death-ligand 1 (PD-L1) positivity is not required for enrollment

          -  All melanoma patients may be tested for proto-oncogene B-Raf (BRAF) as part of routine
             standard of care, but is not a requirement for the trial; all NSCLC patients may be
             tested for with epidermal growth factor receptor (EGFR) and anaplastic lymphoma kinase
             (ALK) as part of standard of care, but is not a requirement of the trial

          -  Having gotten prior programmed cell death protein 1 (PD1) therapy is allowed for,
             especially if they have previously progressed on it; progression may include
             extra-cranial as well as intra-cranial progression; after progressing on PD1 therapy,
             intervening chemotherapy and/or targeted therapy (BRAF inhibitors [BRAFi], etc) is
             allowed; if they are on intervening chemotherapy and/or targeted therapy (BRAFi, etc),
             they have to have progression intra-cranially and/or extra-cranially and must be off
             intervening therapy for at least 2 weeks

          -  Patient must be asymptomatic at time of getting SRS (day 0) on trial; prednisone < 10
             mg/day for at least 7 days prior to treatment is allowed

          -  Patients with ocular, mucosal and unknown primary melanoma will also be eligible

          -  Patients with 1-10 untreated brain metastases at time of initial brain metastases
             diagnosis (surgery to one of the brain lesions and/or biopsy of a lesion for
             diagnostic purposes and/or for standard of care purposes is acceptable)

          -  Largest brain metastases volume measures less than 14.15 cc³

          -  Prior radiation to the primary and/or regional radiotherapy for melanoma and/or NSCLC
             is acceptable

          -  Baseline labs as within standard of care (complete blood count [CBC], basic metabolic
             panel [BMP], lactate dehydrogenase [LDH], erythrocyte sedimentation rate [ESR], etc)
             are required within 14 days of enrollment

          -  Have measurable disease based on Response Evaluation Criteria in Solid Tumors (RECIST)
             1.1

          -  Patients must have at least 14 days to recover from all prior treatment, including
             surgery, chemotherapy, immunotherapies, prior to enrollment on this protocol

          -  Demonstrate adequate organ function, all screening labs should be performed within 14
             days of treatment initiation

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

               -  Platelets ≥ 100,000/microliters (mcL)

               -  Hemoglobin ≥ 9 g/dL or ≥ 5.6 mmol/L without transfusion or erythropoietin (EPO)
                  dependency (within 7 days of assessment)

               -  Serum creatinine ≤ 1.5 X upper limit of normal (ULN) OR measured or calculated
                  creatinine clearance (glomerular filtration rate [GFR] can also be used in place
                  of creatinine or creatinine clearance [CrCl]) ≥ 60 mL/min for subject with
                  creatinine levels > 1.5 X institutional ULN (creatinine clearance should be
                  calculated per institutional standard)

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

               -  Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT])
                  and alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT])
                  ≤ 2.5 X ULN OR ≤ 5 X ULN for subjects with liver metastases

               -  Albumin ≥ 2.5 mg/dL

               -  International normalized ratio (INR) or prothrombin time (PT) ≤ 1.5 X ULN unless
                  subject is receiving anticoagulant therapy as long as PT or partial
                  thromboplastin time (PTT) is within therapeutic range of intended use of
                  anticoagulants

               -  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

          -  Female subject of childbearing potential should have a negative urine or serum
             pregnancy within 2 weeks 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

               -  Abstinence is acceptable, if this is the usual life style and preferred
                  contraception for the patient

        Exclusion Criteria:

          -  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

          -  If they have brain metastases located in the brain stem (including midbrain, pons, or
             medulla)

          -  Inability to undergo magnetic resonance imaging (MRI) evaluation for treatment
             planning and follow-up

          -  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 recipients

          -  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

          -  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

          -  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 (e.g., thyroxine, insulin, or physiologic corticosteroid
             replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a
             form of systemic treatment

          -  Has known history of (non-infectious) pneumonitis that required steroids or current
             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 a known history of human immunodeficiency virus (HIV) (HIV 1/2 antibodies)

          -  Has known active hepatitis B (e.g., hepatitis B specific 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 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:Proportion of dose limiting toxicities defined as Radiation Therapy Oncology Group grade 3 central nervous system toxicities which are irreversible severe neurological symptoms requiring medications
Time Frame:3 months after first pembrolizumab dose
Safety Issue:
Description:Proportion of acute toxicity for each arm will be reported, and 95% confidence intervals will be estimated using the Clopper-Pearson method.

Secondary Outcome Measures

Measure:Frequency and absolute cell counts for pre and post treatment serum immune biomarkers
Time Frame:Baseline to up to 3 years
Safety Issue:
Description:Descriptive statistics for the frequency and absolute cell counts for the major lymphocyte populations (cluster of differentiation [CD]3, CD4, CD8, CD19) T cells and monocytes (CD14) along with other markers listed above will be estimated and compared between the three different radiation arms.
Measure:Overall response (intra-cranial and extra-cranial) assessed using RECIST and immune RECIST Criteria
Time Frame:At week 12 and 3 months after completing the first cycle of pembrolizumab and SRS (i.e C1D2-3)
Safety Issue:
Description:Response will be measured for all metastatic sites and at un-irradiated sites (i.e. the abscopal effect). Response rates will be reported along with 95% confidence intervals will be estimated using the Clopper-Pearson method.
Measure:Overall survival
Time Frame:From first treatment on cycle 1, day 1 to the earlier of date of death and/or last follow up, assessed up to 3 years
Safety Issue:
Description:Estimated using the Kaplan-Meier product-limit method.
Measure:Rate of anywhere intra-cranial failure (also called distant brain failure, DBR)
Time Frame:From the first treatment on cycle 1, day 1 to the earlier of the recurrence event and/or last follow up/death, assessed up to 3 years
Safety Issue:
Description:Estimated using cumulative incidence methodology, with death considered a competing risk.
Measure:Rate of leptomeningeal disease
Time Frame:From the first treatment on cycle 1, day 1 to the earlier of the recurrence event and/or last follow up/death, assessed up to 3 years
Safety Issue:
Description:Estimated using cumulative incidence methodology, with death considered a competing risk.
Measure:Rate of local recurrence
Time Frame:From the first treatment on cycle 1, day 1 to the earlier of the recurrence event and/or last follow up/death, assessed up to 3 years
Safety Issue:
Description:Estimated using cumulative incidence methodology, with death considered a competing risk.
Measure:Rate of symptomatic radiation necrosis defined as evidence of necrosis on MRI images (radiographic evidence or radionecrosis) and a patient having neurological symptoms attributed to the location where the radiosurgery was done (symptomatic)
Time Frame:Up to 12 months after first pembrolizumab dose
Safety Issue:
Description:Proportion late toxicity for each arm will be reported, and 95% confidence intervals will be estimated using the Clopper-Pearson method.

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Emory University

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