Clinical Trials /

Nivolumab and Radiation Therapy With or Without Ipilimumab in Treating Patients With Brain Metastases From Non-small Cell Lung Cancer

NCT02696993

Description:

This phase I/II trial studies the side effects and best dose of nivolumab when giving together with stereotactic radiosurgery or whole brain radiotherapy with or without ipilimumab and to see how well they work in treating patients with non-small cell lung cancer that has spread to the brain. Monoclonal antibodies, such as nivolumab and ipilimumab, 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. Radiation therapy, such as whole-brain radiotherapy, uses high energy x-rays to kill tumor cells and shrink tumors. Giving nivolumab together with stereotactic radiosurgery or whole brain radiotherapy with or without ipilimumab may work better in treating patients with non-small cell lung cancer that has spread to the brain.

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

Recruiting

Phase:

Phase 1/Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Nivolumab and Radiation Therapy With or Without Ipilimumab in Treating Patients With Brain Metastases From Non-small Cell Lung Cancer
  • Official Title: Phase I/II Trial of Nivolumab With Radiation or Nivolumab and Ipilimumab With Radiation for the Treatment of Intracranial Metastases From Non-Small Cell Lung Cancer

Clinical Trial IDs

  • ORG STUDY ID: 2015-0883
  • SECONDARY ID: NCI-2016-00661
  • SECONDARY ID: 2015-0883
  • SECONDARY ID: P30CA016672
  • NCT ID: NCT02696993

Conditions

  • Metastatic Malignant Neoplasm in the Brain
  • Stage IV Non-Small Cell Lung Cancer AJCC v7

Interventions

DrugSynonymsArms
IpilimumabAnti-Cytotoxic T-Lymphocyte-Associated Antigen-4 Monoclonal Antibody, BMS-734016, MDX-010, MDX-CTLA4, YervoyGroup C (nivolumab, ipilimumab, SRS)
NivolumabBMS-936558, MDX-1106, NIVO, ONO-4538, OpdivoGroup A (nivolumab, SRS)

Purpose

This phase I/II trial studies the side effects and best dose of nivolumab when giving together with stereotactic radiosurgery or whole brain radiotherapy with or without ipilimumab and to see how well they work in treating patients with non-small cell lung cancer that has spread to the brain. Monoclonal antibodies, such as nivolumab and ipilimumab, 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. Radiation therapy, such as whole-brain radiotherapy, uses high energy x-rays to kill tumor cells and shrink tumors. Giving nivolumab together with stereotactic radiosurgery or whole brain radiotherapy with or without ipilimumab may work better in treating patients with non-small cell lung cancer that has spread to the brain.

Detailed Description

      PRIMARY OBJECTIVES:

      I. To determine the recommended phase 2 dose (RP2D) of nivolumab with intracranial radiation
      and ipilimumab in combination with nivolumab and intracranial radiation in non-small cell
      lung cancer (NSCLC) with brain metastasis. (Phase I) II. To determine the RP2D of nivolumab
      in combination with stereotactic radiosurgery (SRS). (Phase I) III. To determine the RP2D of
      nivolumab in combination with whole brain radiation therapy (WBRT). (Phase I) IV. To
      determine the RP2D of ipilimumab in combination with nivolumab and SRS. (Phase I) V. To
      determine the RP2D of ipilimumab in combination with nivolumab and WBRT. (Phase I) VI. To
      estimate the 4-month intracranial progression free survival overall and within each treatment
      group; nivolumab and SRS; nivolumab and WBRT; nivolumab + ipilimumab and SRS; nivolumab +
      ipilimumab and WBRT. (Phase II)

      SECONDARY OBJECTIVES:

      I. To assess the potential neurocognitive changes in all treatment groups using the Hopkins
      Verbal Learning Revised (HVLT-R) total recall test. (Phase II) II. To estimate the rate of
      extracranial progression overall and within each treatment group. (Phase II) III. To estimate
      overall survival overall and within each treatment group. (Phase II) IV. To estimate the
      objective response rate of extracranial disease among all groups and within each treatment
      group. (Phase II) V. To estimate the duration of treatment response extracranially in
      patients who achieve an objective response. (Phase II) VI. To estimate steroid requirements
      in patients overall and within each treatment group. (Phase II)

      OUTLINE: This is a phase I, dose-escalation study of nivolumab followed by a phase II study.
      Patients are assigned to 1 of 4 groups.

      GROUP A: Patients receive nivolumab intravenously (IV) over 90 minutes every 2 weeks in the
      absence of disease progression or unacceptable toxicity. Patients undergo SRS once the day
      after nivolumab administration.

      GROUP B: Patients then receive nivolumab as in Group A. Patients undergo WBRT once daily for
      10 days.

      GROUP C: Patients receive nivolumab as in Group A and ipilimumab IV over 90 minutes every 6
      weeks in the absence of disease progression or unacceptable toxicity. Patients undergo SRS
      once the day after nivolumab administration.

      GROUP D: Patients receive nivolumab as in Group A and ipilimumab as in Group C. Patients
      undergo WBRT once daily for 10 days.

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

Trial Arms

NameTypeDescriptionInterventions
Group A (nivolumab, SRS)ExperimentalPatients receive nivolumab IV over 90 minutes every 2 weeks in the absence of disease progression or unacceptable toxicity. Patients undergo SRS once the day after nivolumab administration.
  • Nivolumab
Group B (nivolumab, WBRT)ExperimentalPatients then receive nivolumab as in Group A. Patients undergo WBRT once daily for 10 days.
  • Nivolumab
Group C (nivolumab, ipilimumab, SRS)ExperimentalPatients receive nivolumab as in Group A and ipilimumab IV over 90 minutes every 6 weeks in the absence of disease progression or unacceptable toxicity. Patients undergo SRS once the day after nivolumab administration.
  • Ipilimumab
  • Nivolumab
Group D (nivolumab, ipilimumab, WBRT)ExperimentalGROUP D: Patients receive nivolumab as in Group A and ipilimumab as in Group C. Patients undergo WBRT once daily for 10 days.
  • Ipilimumab
  • Nivolumab

Eligibility Criteria

        Inclusion Criteria:

          -  Pathologically confirmed non-small lung cancer

          -  Stage IV metastatic disease with intracranial disease visible with magnetic resonance
             image (MRI)

          -  At least one brain lesion size >= 0.3 cm in the longest axis amenable to radiation
             therapy (either via SRS or WBRT)

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

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

          -  Absolute neutrophil count (ANC) >= 1,000 /mcL (performed 28 days prior to study
             registration up to the first dose of study drug)

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

          -  Hemoglobin >= 9 g/dL or >= 5.6 mmol/L (performed 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 creatinine clearance [CrCl]) =<
             1.5 X upper limit of normal (ULN) or >= 40 mL/min CrCl using the Cockroft-Gault
             formula (performed 28 days prior to study registration up to the first dose of study
             drug)

          -  Serum total bilirubin =< 1.5 X ULN (except for subjects with Gilbert syndrome, who may
             have total bilirubin < 3.0 mg/dl) or direct bilirubin =< ULN for subjects with total
             bilirubin levels > 1.5 x ULN (performed 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 glutamate pyruvate transaminase (SGPT)]) =< 3 X
             ULN or =< 5 X ULN for subjects with the liver metastases (performed 28 days prior to
             study registration up to the first dose of study drug)

          -  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 (performed 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 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 24 hours of study enrollment up to administration of the dose of
             study drug; 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 31 weeks 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 31 weeks after the last dose of study therapy

          -  We will allow prior radiation to other sites, with no washout period, prior to study
             entry as long as the high dose regions of the prior and proposed radiation fields do
             not overlap; in patients where the prior high dose area would overlap with the high
             dose area of the intended radiation, a 4 month washout period will be required; the
             safety of such treatment will be at discretion of the treating radiation oncologist

          -  Prior central nervous system (CNS) radiation is allowed as long as cumulative
             radiation doses do not exceed tolerance of critical structures as judged by the
             treating radiation oncologist

        Exclusion Criteria:

          -  Is currently participating in or has participated in a study of an investigational
             agent 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 severe active scleroderma, lupus, other rheumatologic or autoimmune
             disease within the past 3 months; patients with a documented history of clinically
             severe autoimmune disease or a syndrome requiring systemic steroids or
             immunosuppressive agents will not be allowed on this study; subjects with vitiligo or
             resolved childhood asthma/atopy are an exception to this rule; subjects that require
             intermittent use of bronchodilators or local steroid injections are not excluded from
             the study; subjects with hypothyroidism stable on hormone replacement are not excluded
             from this study

          -  Has had a prior monoclonal antibody within 4 weeks or 5 half-lives, whichever 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

          -  For the nivolumab only arm patients who received anti PD1 or anti PD-L1 therapies will
             be excluded, for ipilimumab and nivolumab arms patients who received anti PD1 or anti
             PD L1 therapies will be eligible

          -  Has had prior chemotherapy or targeted small molecule therapy within 3 weeks prior to
             administration of the study drug or who has not recovered (i.e., =< grade 1 or at
             baseline) from adverse events due to a previously administered agent; *Note: Subjects
             with permanent =< grade 2 toxicities (e.g. neuropathy) or toxicities corrected through
             routine medical management (e.g. thyroid replacement for hypothyroidism), 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; *Note: Subjects with =<
             grade 2 amylase or lipase elevations abnormalities that have no corresponding clinical
             manifestations (e.g. manifestation of pancreatitis), are an exception to this
             criterion and may qualify for the study

          -  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, indolent lymphomas, or in situ cervical cancer that has undergone potentially
             curative therapy

          -  Has known carcinomatous meningitis (also known as leptomeningeal disease)

          -  Has an active infection requiring intravenous systemic therapy or hospital admission

          -  Has a history or current evidence of any condition, therapy, or laboratory
             abnormality, including psychiatric or substance abuse disorder, 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

          -  Is pregnant or breastfeeding, or expecting to conceive or father children within the
             projected duration of the trial, starting with the screening visit through 31 weeks
             after the last dose of trial treatment

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

          -  Patients should be excluded if they are positive test for hepatitis B virus surface
             antigen (HBV sAg) or hepatitis C virus ribonucleic acid (hepatitis C virus [HCV]
             antibody) indicating acute or chronic infection

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

          -  Has experienced grade 4 toxicity on treatment with prior radiation

          -  Has experienced grade 3-4 intracranial toxicity (hypophysitis or CNS toxicity) with
             either prior intracranial radiation, anti programmed cell death-1 (PD-1), or cytotoxic
             t-lymphocyte-associated protein 4 (CTLA-4) inhibitor therapy

          -  Is taking > 4mg/day of dexamethasone or its equivalent at the start of immunotherapy
             or has required > 4mg/day of dexamethasone or its equivalent for 3 consecutive days
             within 1 week of starting treatment

          -  Patients whose tumor exhibit activating EGFR mutation, ALK or ROS translocation and
             have a standard of care molecular targeted therapy available for these mutations, will
             be excluded from this study; patients who progressed or could not tolerate these
             standard of care molecular targeted agents are eligible for this study; adenocarcinoma
             patients may be consented prior to the EGFR and ALK status being known, but EGFR and
             ALK status must be determined prior to initiating therapy

          -  Allergies and adverse drug reaction to the following: history of allergy to study drug
             components; history of severe hypersensitivity reaction to any monoclonal antibody

          -  Previous CNS surgery within 2 weeks of treatment, with the exception of biopsy

          -  Unable or unwilling to tolerate an intracranial MRI
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Recommended phase 2 dose (RP2D) of nivolumab defined as the probability of > 15% intracranial or > 30% extracranial dose limiting toxicities (DLT) (Phase I)
Time Frame:Up to 6 weeks
Safety Issue:
Description:Assessed using a Bayesian model.

Secondary Outcome Measures

Measure:Neurocognitive changes assessed by the Hopkins Verbal Learning Revised (HVLT-R) total recall test (Phase II)
Time Frame:1 month after radiation to 3 years
Safety Issue:
Description:General descriptive statistics will be computed.

Details

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

Last Updated

December 23, 2019