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: Trial of Nivolumab With Radiation or Nivolumab and Ipilimumab With Radiation for the Treatment of Intracranial 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
  • NCT ID: NCT02696993

Conditions

  • Metastatic Brain Cancer

Interventions

DrugSynonymsArms
NivolumabBMS-936558, OpdivoNivolumab + Stereotactic Radiosurgery (SRS)
IpilimumabYervoy, BMS-734016, MDX010Nivolumab + Ipilimumab and Stereotactic Radiosurgery (SRS)

Purpose

There are 2 parts to this research study: Part 1 (dose escalation) and Part 2 (dose expansion). The goal of Part 1 of this clinical research study is to find the highest tolerable dose of nivolumab that can be given either with radiation therapy alone or in combination with radiation and ipilimumab, in patients with NSCLC. The goal of Part 2 of this study is to learn if the dose of nivolumab found in Part 1 when given with radiation therapy and ipilimumab can help to control the disease.

Detailed Description

      Study Groups and Therapy:

      If you are found to be eligible to take part in this study, you will be assigned to a study
      part (to learn which dose level of nivolumab you will receive) and to 1 of 2 study arms (to
      learn which treatment combination you will receive). This is done because no one knows if
      one study part is the same, better, or worse than the other.

        -  If you are enrolled in Arm A, you will receive nivolumab by vein over about 1 hour
           every 2 weeks and radiation therapy.

        -  If you are enrolled in Arm B, you will receive ipilimumab by vein over about 90 minutes
           every 6 weeks, nivolumab by vein over about 1 hour every 2 weeks, and radiation
           therapy.

      The study doctor will decide which type of radiation therapy (either stereotactic
      radiosurgery [SRS] or whole brain radiation therapy [WBRT]) you will receive. If you receive
      SRS therapy, you will receive it 1 time. If you receive WBRT therapy, you will receive it 1
      time each day for 10 days.

      If you are enrolled in Part 1 of the study, the dose of nivolumab you receive will depend on
      when you join this study. The first group of participants will receive the highest dose of
      nivolumab. If intolerable side effects are seen, the next group of participants will receive
      a lower dose.

      If you are enrolled in Part 2 of the study, the dose of nivolumab you receive will depend on
      the results seen in Part 1. The study doctor will tell you the dose of nivolumab you will
      receive.

      All participants will receive the same dose of ipilimumab and radiation therapy.

      Study Visits:

      Right before your first treatment and then over 2 weeks (+/- 3 days) after that:

        -  You will have a physical exam.

        -  Blood (about 1 tablespoon) will be drawn for routine tests.

      About 1 month after you have received radiation:

        -  You will have an MRI, CT, or PET/CT scan to check the status of the disease.

        -  You will complete the neurocognitive exam.

      Length of Study:

      You may continue to receive the study drug(s) unless the disease gets worse, if you have
      intolerable side effects, or if you are unable to follow study directions. You will only
      receive radiation therapy during the beginning of the study, either 1 time or for up to 10
      days.

      If the disease appears to be getting worse or the tumors appear to be getting larger, you
      may still be able to receive the study drug if you and your doctor decide it is in your best
      interest. Sometimes the disease appears to get worse but the study drug is actually working.

      However, there are risks of continuing to receive the study drug(s) because the disease may
      actually be getting worse. You are still at risk for side effects due to the study drug(s).
      This could also delay starting other treatments. The disease may get worse to the point that
      you are no longer able to receive other treatments. The study doctor will discuss this
      option with you.

      Your participation on the study will be over after you have completed follow-up.

      Follow-Up:

      About 30 days after your last dose of study drug(s), you will have a physical exam.

      Long-Term Follow-Up:

      Every 12 weeks for up to 1 year:

        -  You will have a physical exam.

        -  Blood (about 1 tablespoon) will be drawn for routine tests.

        -  You will have an MRI, CT, or PET/CT scan to check the status of the disease.

        -  You will complete the neurocognitive exam.

      If the follow-up is done at another hospital, the information about your medical history,
      physical exam, routine blood tests, and imaging scans will be sent to MD Anderson for
      review. If you cannot come to MD Anderson for your follow up visits, the study team may call
      you every 12 weeks to ask how you are doing. Each call should last about 10 minutes.

      This is an investigational study. Both WBRT and SRS radiation are FDA approved for local
      control of metastatic and primary tumors. Nivolumab is FDA approved and commercially
      available for the treatment of melanoma and NSCLC. Ipilimumab is FDA approved and
      commercially available for the treatment of melanoma. It is considered investigational to
      use radiation therapy, nivolumab, and ipilimumab to treat NSCLC. The study doctor can
      explain how the study drugs are designed to work.

      Up to 80 participants will take part in this study. All will be enrolled at MD Anderson.
    

Trial Arms

NameTypeDescriptionInterventions
Nivolumab + Stereotactic Radiosurgery (SRS)ExperimentalPhase I: Nivolumab administered initially at 3 mg/kg by vein every 2 weeks. Stereotactic Radiosurgery (SRS) performed once, at dosage prescribed by treating physician. SRS performed optimally the day after the first administration of Nivolumab, but may occur within the first two weeks. Neurocognitive exam completed at baseline and 1 month after radiation treatment.
  • Nivolumab
Nivolumab + Whole Brain Radiation Therapy (WBRT)ExperimentalPhase I: Nivolumab administered initially at 3 mg/kg by vein every 2 weeks. WBRT delivered to the whole brain 5 days a week. Participants treated to a total dose of 30 Gy in 10 fractions. WBRT performed optimally the day after the first administration of nivolumab, but may occur within the first two weeks. Neurocognitive exam completed at baseline and 1 month after radiation treatment.
  • Nivolumab
Nivolumab + Ipilimumab and Stereotactic Radiosurgery (SRS)ExperimentalPhase II: Nivolumab administered by vein every two weeks at the maximum tolerated dose from Phase I. Ipilimumab 1 mg/kg by vein every 6 weeks. SRS performed optimally the day after the first administration of Ipilimumab , but may occur within the first two weeks. Neurocognitive exam completed at baseline and 1 month after radiation treatment.
  • Nivolumab
  • Ipilimumab
Nivolumab+Ipilimumab and Whole Brain Radiation Therapy (WBRT)ExperimentalPhase II: Nivolumab administered by vein every two weeks at the maximum tolerated dose from Phase I. Ipilimumab 1 mg/kg by vein every 6 weeks. WBRT delivered to the whole brain 5 days a week. Participants treated to a total dose of 30 Gy in 10 fractions. WBRT performed optimally the day after the first administration of nivolumab, but may occur within the first two weeks. Neurocognitive exam completed at baseline and 1 month after radiation treatment.
  • Nivolumab

Eligibility Criteria

        Inclusion Criteria:

          1. Pathologically confirmed non-small lung cancer.

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

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

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

          5. Be >/= 18 years of age on day of signing informed consent

          6. Have a performance status of 0 or 1 on the ECOG Performance Scale.

          7. Demonstrate adequate organ function as defined in the table below, all screening labs
             should be performed 28 days prior to study registration up to the first dose of study
             drug.

          8. Adequate Organ Function Laboratory Values: HEMATOLOGICAL=Absolute neutrophil count
             (ANC) >/=1,000 /mcL; Platelets >/= 100,000 /mcL; Hemoglobin >/= 9 g/dL or >/= 5.6
             mmol/L. RENAL=Serum creatinine or Measured or calculated creatinine clearance (GFR
             can also be used in place of creatinine or CrCl) </=1.5 X upper limit of normal (ULN)
             or >/= 40 mL/min CrCl using the Cockcroft-Gault Formula. HEPATIC=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; aspartate aminotransferase (AST (SGOT)) and alanine
             aminotransferase (ALT (SGPT)) </= 3 X ULN or </= 5 X ULN for subjects with the liver
             metastases

          9. Inclusion #8 (continued): COAGULATION=International Normalized Ratio (INR) or
             Prothrombin Time (PT) </= 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.
             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

         10. 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

         11. 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

         12. 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.

         13. 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.

         14. Prior 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:

          1. 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.

          2. 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.

          3. 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.

          4. 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.

          5. 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

          6. Has known carcinomatous meningitis (also known as leptomeningeal disease).

          7. Has an active infection requiring intravenous systemic therapy or hospital admission.

          8. 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.

          9. 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.

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

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

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

         13. Has experienced Grade 4 toxicity on treatment with prior radiation.

         14. 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.

         15. 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.

         16. Tumor exhibits epidermal growth factor receptor (EGFR) mutations or ALK
             re-arrangement that qualifies the patient for treatment with a systemic agent
             targeting these mutations.

         17. Allergies and adverse drug reaction to the following: History of allergy to study
             drug components; History of severe hypersensitivity reaction to any monoclonal
             antibody

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

         19. Unable or unwilling to tolerate an intracranial MRI.

         20. In the first 5 patients enrolled in treatment groups on part B of this study
             (receiving combination ipilimumab and nivolumab), patients may have had 1-0 prior
             lines of systemic therapy after being diagnosed with metastatic disease. This
             restriction will be lifted in all subsequent cohorts of patients treated on part B.
      
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 in Combination with Stereotactic Radiosurgery (SRS)
Time Frame:6 weeks
Safety Issue:
Description:If acceptable toxicity is observed in first 10 patients, this dose considered the RP2D.

Secondary Outcome Measures

Measure:Intracranial Progression Free Survival
Time Frame:4 months
Safety Issue:
Description:Progression free survival assessed by MRI, CT, or PET/CT scan.
Measure:Neurocognitive Changes
Time Frame:Every 12 weeks for up to 1 year
Safety Issue:
Description:Neurocognitive changes assessed using the Hopkins Verbal Learning Revised (HVLT-R) total recall test.

Details

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

Trial Keywords

  • Metastatic Brain Cancer
  • Non-small cell lung cancer with brain metastasis
  • NSCLC
  • Intracranial disease
  • Stereotactic radiosurgery
  • SRS
  • Whole brain radiation therapy
  • WBRT
  • Neurocognitive exam
  • Nivolumab
  • BMS-936558
  • Opdivo
  • Ipilimumab
  • Yervoy
  • BMS-734016
  • MDX010

Last Updated

February 14, 2017