Clinical Trials /

Nivolumab in Epstein-Barr Virus (EBV)-Positive Lymphoproliferative Disorders and EBV-Positive Non-HodgkinLymphomas

NCT03258567

Description:

Background: The drug Nivolumab has been approved to treat some cancers. Researchers want to see if it can slow the growth of other cancers. They want to study its effects on cancers that may have not responded to chemotherapy or other treatments. Objectives: To see if Nivolumab slows the growth of some types of cancer or stops them from getting worse. To test the safety of the drug. Eligibility: People 12 and older who have Epstein-Barr Virus (EBV)-positive lymphoproliferative disorders or EBV-positive non-Hodgkin lymphomas with no standard therapy Design: Participants will be screened with: Medical history Physical exam Blood and urine tests CAT scan of the chest, abdomen, and pelvis Tumor and bone marrow biopsies (sample taken) Magnetic resonance imaging scan of the brain Lumbar puncture (also known as spinal tap) Positron emission tomography/computed tomography scan with a radioactive tracer Every 2 weeks, participants will get Nivolumab by vein over about 1 hour. They will also have: Physical exam Blood and pregnancy tests Review of side effects and medications During the study, participants will repeat most of the screening tests. They may also have other biopsies. After stopping treatment, participants will have a visit every 3 months for 1 year. Then they will have a visit every 6 months for years 2-5, and then once a year. They will have a physical exam and blood tests.

Related Conditions:
  • B-Cell Non-Hodgkin Lymphoma
  • Diffuse Large B-Cell Lymphoma
  • Lymphomatoid Granulomatosis
  • Lymphoproliferative Disorder
  • Non-Hodgkin Lymphoma
Recruiting Status:

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Nivolumab in Epstein-Barr Virus (EBV)-Positive Lymphoproliferative Disorders and EBV-Positive Non-HodgkinLymphomas
  • Official Title: Phase 2 Trial of Nivolumab in Epstein-Barr Virus (EBV)-Positive Lymphoproliferative Disorders and EBV-Positive Non-HodgkinLymphomas

Clinical Trial IDs

  • ORG STUDY ID: 170125
  • SECONDARY ID: 17-C-0125
  • NCT ID: NCT03258567

Conditions

  • Epstein-Barr Virus Infections
  • Lymphoma
  • Lymphoproliferative Disorder
  • Disorders, Lymphoproliferative

Interventions

DrugSynonymsArms
NivolumabA-Closed

Purpose

Background: The drug Nivolumab has been approved to treat some cancers. Researchers want to see if it can slow the growth of other cancers. They want to study its effects on cancers that may have not responded to chemotherapy or other treatments. Objectives: To see if Nivolumab slows the growth of some types of cancer or stops them from getting worse. To test the safety of the drug. Eligibility: People 12 and older who have Epstein-Barr Virus (EBV)-positive lymphoproliferative disorders or EBV-positive non-Hodgkin lymphomas with no standard therapy Design: Participants will be screened with: Medical history Physical exam Blood and urine tests CAT scan of the chest, abdomen, and pelvis Tumor and bone marrow biopsies (sample taken) Magnetic resonance imaging scan of the brain Lumbar puncture (also known as spinal tap) Positron emission tomography/computed tomography scan with a radioactive tracer Every 2 weeks, participants will get Nivolumab by vein over about 1 hour. They will also have: Physical exam Blood and pregnancy tests Review of side effects and medications During the study, participants will repeat most of the screening tests. They may also have other biopsies. After stopping treatment, participants will have a visit every 3 months for 1 year. Then they will have a visit every 6 months for years 2-5, and then once a year. They will have a physical exam and blood tests.

Detailed Description

      BACKGROUND:

        -  Epstein-Barr virus (EBV) is a chronic viral infection associated with a heterogeneous
           group of lymphoproliferative disorders (LPD) and non-Hodgkin lymphomas (NHL).

        -  The shared pathobiology of EBV-positive LPDs and NHLs includes a defect in host
           mechanisms of immune tolerance and immunosurveillance.

        -  Programmed death-1 (PD-1) is a surface protein present on T cells, B cells, and
           macrophages that serves a co-inhibitory role to negatively regulate immune responses

        -  PD-1 and its ligands, PD-L1 and PD-L2, are overexpressed in EBV-positive lymphomas and
           are markers of aggressive behavior.

        -  Blockade of the PD-1 pathway induces T-cell responses against tumor antigens in a
           variety of cancers, including Hodgkin lymphoma, that lead to clinical remissions.

        -  Nivolumab is a fully human IgG4 monoclonal anti-PD-1 receptor antibody with clinical
           activity in both indolent and lymphomas.

      OBJECTIVE:

      -To determine the best overall response rate of nivolumab in subjects with EBV-positive LPD
      and EBV-positive NHL

      ELIGIBLITY:

        -  Subjects must have a confirmed diagnosis of an EBV-positive B-cell LPD or an EBV-
           positive NHL confirmed by Laboratory of Pathology, NCI

             -  Cohort 1: LPD subjects may be previously untreated or relapsed from prior therapy

             -  Cohort 2: EBV-positive B-cell NHL subjects must have relapsed from previous
                treatment with an anthracycline and rituximab-based regimen or be considered not
                eligible for the same

        -  Adequate bone marrow function (unless disease-related) defined as:

             -  Absolute neutrophil count greater than or equal to 750/mcL

             -  Hemoglobin greater than 9g/dL (transfusion permitted)

             -  Platelet count greater than or equal to 50,000/mcL (transfusion not permitted)

        -  Age greater than or equal to 12 years

      <TAB>

      DESIGN:

        -  Phase II study of subjects with EBV-positive LPD and EBV-positive NHL, both relapsed and
           untreated.

        -  Subjects will be treated with nivolumab 480 mg IV every 4 weeks for up to 2 years if
           responding disease with clinical improvement and no unacceptable toxicity.

        -  All responding subjects (CR, PR, or SD with clinical benefit) who subsequently relapse
           or progress within 1 year after discontinuation of study drug are eligible for
           re-treatment.

        -  An optimal two-stage phase II trial design will be used to rule out a best overall
           response rate of 20% in each cohort. If fewer than 3 of the first 17 subjects respond,
           that cohort would accrue no more subjects.

        -  37 subjects with EBV-positive LPD and 37 subjects with EBV-positive NHL will be enrolled
           on this protocol.
    

Trial Arms

NameTypeDescriptionInterventions
A-ClosedExperimentalnivolumab 3mg/kg via IV infusion over approximately 60minutes every 2 weeks for up to 2 years (closed with Amendment C)
  • Nivolumab
BExperimentalNivolumab 480mg via IV infusion over approximately 30minutes every 4 weeks for up to 2 years
  • Nivolumab

Eligibility Criteria

        -  INCLUSION CRITERIA:

          -  Subjects must have histologically or cytologically confirmed EBV-positive LPD or an
             EBV-positive NHL confirmed by the Laboratory of Pathology, NCI.

               -  Cohort 1: EBV-positive B-cell LPD. Subjects may be previously untreated or
                  relapsed from prior therapy.

                    1. Lymphomatoid granulomatosis (LYG), grades I-II

                    2. Chronic active EBV disease (CAEBV)

                    3. EBV-positive post-transplantation lymphoproliferative disorder (PTLD) NOTE:
                       PTLD after solid organ transplantation is excluded. Patients who, at the
                       discretion of the investigator, need urgent therapy with standard agents
                       will not be eligible.

               -  Cohort 2: EBV-positive B-cell NHL subjects must have relapsed from previous
                  treatment with an anthracycline and rituximab-based regimen or be considered not
                  eligible for the same.

                    1. Lymphomatoid granulomatosis (LYG), grade III

                    2. EBV-positive immunodeficiency-associated diffuse large B-cell lymphoma
                       (DLBCL)

                    3. EBV-positive DLBCL

          -  Subjects must be at least 2 weeks from prior anti-lymphoma therapy (including
             radiation therapy)

          -  Subjects must be at least 100 days from prior stem cell transplant (autologous or
             allogeneic) or Donor Lymphocyte Infusion (DLI)

               -  Age greater than or equal to 12 years

               -  Patients greater than or equal to 12 and less than 18 years of age should weigh
                  at least 40 kilograms (kg); there is no weight requirement for adult subjects.

               -  NOTE: If a pediatric patient is identified for possible enrollment who weighs
                  less than 40 kg, the safety of the nivolumab dosing strategy used in this study
                  must be discussed with the PI and manufacturer to confirm safety, and this
                  discussion/approval for enrollment documented in the medical record prior to
                  declaring the pediatric patient eligible.

          -  Adequate performance status as follows:

               -  Patients greater than or equal to 16 years must have ECOG Performance Status 0-2
                  (Karnofsky greater than or equal to 60%)

               -  Pediatric patients less than 16 years must have Lansky play-performance of
                  60-100%

          -  Subjects must have measurable or evaluable disease.

          -  Subjects must have adequate organ and bone marrow reserve (unless disease-related) as
             defined below:

               -  absolute neutrophil count - greater than or equal to 750/mcL; greater than or
                  equal to 500/mcL if impairment is due to LPD/NHL

               -  platelets - greater than or equal to 50,000/mcL; greater than or equal to
                  25,000/mcL if impairment is due to LPD/NHL; (transfusions not permitted)

               -  Hemoglobin greater than or equal to 9g/dL (transfusion permitted)

               -  total bilirubin - < 3.0g/dl OR < 5.0g/dl if Gilbert s syndrome or disease
                  infiltration of the liver is present

               -  AST(SGOT)/ALT(SGPT) - less than or equal to 3 X institutional upper limit of
                  normal

               -  serum creatinine OR creatinine clearance - Adults: less than or equal to 1.5
                  mg/dL; Minors: serum Cr less than or equal to age-adjusted normal OR greater than
                  or equal to 40 ml/min/1.73m^2

          -  A formalin fixed tissue block or at least 15 slides of tumor sample (archival or
             fresh) must be available for performance of correlative studies. NOTE: Patient must be
             willing to have a pre-treatment tumor biopsy if adequate archival tissue is not
             available.

          -  The toxicity profile of nivolumab in patients with disease involvement of the central
             nervous system (CNS) is unknown. For this reason, we will introduce early stopping
             rules.

          -  The effects of nivolumab on the developing human fetus are unknown. For this reason,
             the following measures apply:

               -  Women of childbearing potential (WOCBP) must have a negative serum or urine
                  pregnancy test (minimum sensitivity 25 IU/L or equivalent units of HCG) during
                  screening and within 48 hours prior to the first dose of nivolumab.

               -  WOCBP and men who are sexually active with WOCBP must use adequate contraception
                  (e.g., hormonal or 2 barrier methods with a failure rate of less than 1% per year
                  or abstinence) prior to study entry and throughout study drug administration.
                  WOCBP receiving nivolumab will be instructed to adhere to contraception for a
                  period of 23 weeks after the last dose of investigational product. Men receiving
                  nivolumab and who are sexually active with WOCBP will be instructed to adhere to
                  contraception for a period of 31 weeks after the last dose of investigational
                  product.

               -  Women who are not of childbearing potential (i.e., who are postmenopausal or
                  surgically sterile as well as azoospermic men do not require contraception.

               -  WOCBP is defined as any female who has experienced menarche and who has not
                  undergone successful surgical sterilization (hysterectomy, bilateral tubal
                  ligation, or bilateral ophorectomy), and who is not postmenopausal. Post
                  menopause is defined as:

                    1. Amenorrhea greater than or equal to 12 consecutive months without another
                       cause, and a documented serum follicle stimulating hormone (FSH) level > 35
                       mIU/mL or

                    2. Women with irregular menstrual periods and a documented serum follicle
                       stimulating hormone (FSH) level > 35 mIU/mL or NOTE: FSH level testing is
                       not required for women greater than or equal to 62 years old with amenorrhea
                       of greater than or equal to 1 year

                    3. Women on hormone replacement therapy (HRT)

          -  Pregnant women are excluded from this study because nivolumab is an IgG monoclonal
             antibody with the potential for teratogenic or abortifacient effects.

          -  Because there is an unknown but potential risk for adverse events in nursing infants
             secondary to treatment of the mother with nivolumab, breastfeeding should be
             discontinued if the mother is treated with nivolumab.

          -  Ability of subject or Legally Authorized Representative (LAR) to understand and sign
             the written informed consent document.

        EXCLUSION CRITERIA:

          -  Subjects who are receiving any other investigational agents.

          -  History of allergic reactions attributed to compounds of similar chemical or biologic
             composition to nivolumab.

          -  Subjects with second malignancies requiring active systemic therapy are excluded.
             Subjects with second malignancies not requiring active systemic therapy or
             premalignant conditions such as monoclonal B-cell lymphocytosis (MBL) or monoclonal
             gammopathy of undetermined significance (MGUS) may be eligible.

          -  Subjects with any condition or autoimmune disease that requires systemic
             corticosteroids (> 10 mg daily prednisone equivalents) or immunosuppressive
             medications within 14 days of study drug administration. Inhaled or topical steroids
             are permitted.

          -  Subjects with active graft-vs-host disease (GVHD) requiring steroids or other
             immunosuppressive agents; history of greater than or equal to grade II acute GVHD or
             extensive chronic GVHD.

          -  Subjects who have had solid organ transplant.

          -  Prior therapy with an anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CD137 or anti CTLA-4
             antibody.

          -  Non-oncology vaccine therapies for prevention of infectious disease within 4 weeks of
             study drug administration.

          -  A serious uncontrolled medical condition requiring therapy.

          -  Seizures disorder not controlled by anti-seizure medications.

          -  Subjects with CNS involvement may be included on the study as long as they have not
             had any seizure activity in past 4 weeks.

          -  Hepatitis B virus surface antigen positive.

          -  Active Hepatitis C infection with a positive PCR; subjects who are Hepatitis C
             antibody positive and PCR negative may be eligible. In these cases the subjects will
             be monitored via HCV PCR throughout the study.

          -  History of anaphylactic reaction to monoclonal antibody therapy.

          -  HIV positive subjects are excluded because the function of their T-cell immune
             responses is impaired.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:12 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:overall response rate of nivolumab in patients with EBV-positive LPDand EBV-positive NHL
Time Frame:one year
Safety Issue:
Description:number of patients who respond to the protocol therapy (CR, PR, SD)

Secondary Outcome Measures

Measure:toxicity profile of nivolumab in patients with EBV-LPD and EBVNHL
Time Frame:4 weeks
Safety Issue:
Description:number and type of AEs experienced
Measure:duration of remission for patients who respond to nivolumab
Time Frame:4 weeks
Safety Issue:
Description:number of months patients stay in remission
Measure:PFS of patients with EBV-LPD and EBV-NHL treated with nivolumab
Time Frame:annually
Safety Issue:
Description:number of patients who do not experience progressive disease
Measure:overall survival of patients with EBVLPD and EBV-NHL treated withnivolumab
Time Frame:annually
Safety Issue:
Description:number of patients that survive 5 years or more

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:National Cancer Institute (NCI)

Trial Keywords

  • Monoclonal Antibody

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