Clinical Trials /

Rituximab and LMP-Specific T-Cells in Treating Pediatric Solid Organ Recipients With EBV-Positive, CD20-Positive Post-Transplant Lymphoproliferative Disorder

NCT02900976

Description:

This pilot phase II trial studies how well rituximab and latent membrane protein (LMP)-specific T-cells work in treating pediatric solid organ recipients with Epstein-Barr virus-positive, cluster of differentiation (CD)20-positive post-transplant lymphoproliferative disorder. Immunotherapy with monoclonal antibodies, such as rituximab, may induce changes in the body's immune system and may interfere with the ability of tumor cells to grow and spread. LMP-specific T-cells are special immune system cells trained to recognize proteins found on post-transplant lymphoproliferative disorder tumor cells if they are infected with Epstein-Barr virus. Giving rituximab and LMP-specific T-cells may work better in treating pediatric organ recipients with post-transplant lymphoproliferative disorder than rituximab alone.

Related Conditions:
  • Lymphoproliferative Disorder
Recruiting Status:

Suspended

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Rituximab and LMP-Specific T-Cells in Treating Pediatric Solid Organ Recipients With EBV-Positive Cluster of Differentiation(CD) 20-Positive Post-Transplant Lymphoproliferative Disorder
  • Official Title: A Pilot Study of Rituximab (RTX) and Third Party Latent Membrane Protein (LMP)-Specific Cytotoxic T-Lymphocytes in Pediatric Solid Organ Recipients (SOT) With EBV-Positive CD20-Positive Post-Transplant Lymphoproliferative Disease (PTLD)

Clinical Trial IDs

  • ORG STUDY ID: ANHL1522
  • SECONDARY ID: NCI-2016-01110
  • SECONDARY ID: ANHL1522
  • SECONDARY ID: ANHL1522
  • SECONDARY ID: U10CA180886
  • NCT ID: NCT02900976

Conditions

  • Epstein-Barr Virus-Related Post-Transplant Lymphoproliferative Disorder
  • Monomorphic Post-Transplant Lymphoproliferative Disorder
  • Polymorphic Post-Transplant Lymphoproliferative Disorder

Interventions

DrugSynonymsArms
Allogeneic LMP1/LMP2-Specific Cytotoxic T-LymphocytesArm II (LMP-TC)
RituximabABP 798, BI 695500, C2B8 Monoclonal Antibody, Chimeric Anti-CD20 Antibody, CT-P10, IDEC-102, IDEC-C2B8, IDEC-C2B8 Monoclonal Antibody, MabThera, Monoclonal Antibody IDEC-C2B8, PF-05280586, Rituxan, Rituximab Biosimilar ABP 798, Rituximab Biosimilar BI 695500, Rituximab Biosimilar CT-P10, Rituximab Biosimilar PF-05280586, Rituximab Biosimilar RTXM83, RTXM83Arm I (RTX)

Purpose

This pilot clinical trial studies how rituximab and latent membrane protein (LMP)-specific T-cells work in treating pediatric solid organ recipients with Epstein-Barr virus-positive, cluster of differentiation (CD)20-positive post-transplant lymphoproliferative disorder. Monoclonal antibodies, such as rituximab may block tumor growth in different ways by targeting certain cells. LMP-specific T-cells are special immune system cells trained to recognize proteins found on post-transplant lymphoproliferative disorder tumor cells if they are infected with Epstein-Barr virus. Giving rituximab and LMP-specific T-cells may be better in treating pediatric organ recipients with post-transplant lymphoproliferative disorder than rituximab alone.

Detailed Description

      PRIMARY OBJECTIVES:

      I. To determine the feasibility of treating pediatric and young adult solid organ transplant
      recipients with newly diagnosed or recurrent Epstein-Barr virus (EBV)-positive CD20-positive
      post-transplant lymphoproliferative disease (PTLD) with a novel T cell therapeutic,
      allogeneic Latent Membrane Protein(LMP)1/LMP2-specific cytotoxic T-lymphocytes (third party
      latent membrane protein [LMP]-specific T cells), in a cooperative group setting.

      SECONDARY OBJECTIVES:

      I. To determine the percentage of eligible patients for whom a suitable LMP-specific T cell
      product derived from a third party LMP-specific T cell bank is available.

      II. To estimate the response rate (RR) to three doses of rituximab (RTX) as single agent in
      children and young adults with EBV-positive CD20-positive PTLD after solid organ
      transplantation (SOT).

      III. To estimate the 2-year event-free survival (EFS) of children and young adults with
      EBV-positive CD20-positive PTLD after SOT treated with RTX with/without LMP-specific T
      cells.

      IV. To estimate overall survival (OS) of children and young adults with EBV-positive
      CD20-positive PTLD after SOT treated with RTX with/without LMP-specific T cells.

      V. To estimate the RR to LMP-specific T cells of children and young adults with EBV-positive
      CD20-positive PTLD after SOT who have not had a complete response to RTX.

      VI. To estimate progression-free survival (PFS) of children and young adults with
      EBV-positive CD20-positive PTLD after SOT treated with RTX with/without LMP-specific T
      cells.

      VII. To describe the toxicity of third party LMP-specific T cells in children and young
      adults with EBV-positive CD20-positive PTLD after SOT treated with RTX and LMP-specific T
      cells.

      VIII. To validate that absence of EBV viremia correlates with RR, EFS and OS.

      TERTIARY OBJECTIVES:

      I. To determine whether third party LMP-specific T cells promote autologous immune
      reconstitution of EBV-specific T cells.

      II. To determine whether EBV viremia is inversely correlated with an increase in
      EBV-specific T cells in vivo.

      III. To determine whether plasma cytokine profile and changes in cytokines over time
      correlate with treatment response or toxicity (e.g. cytokine release syndrome).

      OUTLINE:

      INDUCTION: Patients receive rituximab intravenously (IV) on days 1, 8, 15. Course continues
      for up to 21 days in the absence of disease progression or unacceptable toxicity

      Patients are assigned to 1 of 2 arms.

      ARM I (RTX): Patients with newly diagnosed PTLD who achieve a complete response (CR) receive
      additional rituximab as in induction.

      ARM II (LMP-TC): Patients with newly diagnosed PTLD who achieve a partial response (PR),
      stable disease (SD), progressive disease (PD), or recurrent PTLD regardless of response
      after induction, receive allogeneic LMP1/LMP2-specific cytotoxic T-lymphocytes IV over 1- 2
      minutes on days 0 and 7. Course continues for up to 42 days in the absence of disease
      progression or unacceptable toxicity. Patients with PR or SD after first course of course
      allogeneic LMP1/LMP2-specific cytotoxic T-lymphocytes receive an additional course.

      After completion of study treatment, patients are followed up at 1, 2, 3, 6, 9, and 12
      months.
    

Trial Arms

NameTypeDescriptionInterventions
Arm I (RTX)ExperimentalPatients with newly diagnosed PTLD who achieve a CR receive additional rituximab as in induction.
    Arm II (LMP-TC)ExperimentalPatients with newly diagnosed PTLD who achieve a PR, SD, PD, response after induction, receive allogeneic LMP1/LMP2-specific cytotoxic T-lymphocytes IV over 1- 2 minutes on days 0 and 7. Course continues for up to 42 days in the absence of disease progression or unacceptable toxicity. Patients with PR or SD after first course of allogeneic LMP1/LMP2-specific cytotoxic T-lymphocytes receive an additional course..

      Eligibility Criteria

              Inclusion Criteria:
      
                -  Patient must have a history of solid organ transplantation
      
                -  Patients must have biopsy-proven newly diagnosed polymorphic or monomorphic PTLD
                   using the World Health Organization (WHO) classification and that is
      
                     -  CD20 positive
      
                     -  EBV positive by Epstein-Barr virus early ribonucleic acid (RNA) (EBER) in situ
                        hybridization (preferred) and/or LMP immunoperoxidase staining
      
                -  There must be measurable disease at study entry (the presence of at least one lesion
                   that can be accurately measured in at least one dimension with the longest diameter
                   at least 10 mm using computer tomography scanning)
      
                -  Patients must be considered medically refractory to decreased immunosuppression (50%
                   or greater reduction) for at least 1 week or there must be documentation in the
                   medical chart that decreased immunosuppression would be associated with an
                   unacceptable risk of rejection
      
                -  Patients must have a performance status corresponding to Eastern Cooperative Oncology
                   Group (ECOG) scores of 0 or 1
      
                     -  Use Karnofsky for patients > 16 years of age and Lansky for patients =< 16 years
                        of age
      
                -  Patients must have a life expectancy of >= 8 weeks
      
                -  Patients must have fully recovered from the acute toxic effects of all prior
                   chemotherapy, immunotherapy, or radiotherapy prior to entering this study
      
                -  Must not have received myelosuppressive chemotherapy within 2 weeks of entry onto
                   this study
      
                -  Must not have received therapy with anti-CD20 monoclonal antibodies within 90 days of
                   entry onto this study
      
                -  Must not have received any prior radiation to any sites of measurable disease
      
                -  Must not have received any prior stem cell transplant
      
                -  Must not have received investigational therapy within 30 days of entry onto this
                   study
      
                -  Must not have received prior EBV or LMP-specific T cells within 90 days of entry onto
                   this study
      
                -  Must not have received alemtuzumab or other anti-T-cell antibody therapy within 28
                   days of entry onto this study
      
              Exclusion Criteria:
      
                -  Burkitt morphology
      
                -  Any documented donor-derived PTLD
      
                -  Central nervous system (CNS) involvement
      
                -  Bone marrow involvement (> 25%)
      
                -  Fulminant PTLD defined as: fever > 38 degrees Celsius (C), hypotension, and evidence
                   of multi-organ involvement/failure including two or more of the following:
      
                     -  Bone marrow (including pancytopenia without any detectable B cell proliferation)
      
                     -  Liver (coagulopathy, transaminitis and/or hyperbilirubinemia)
      
                     -  Lungs (interstitial pneumonitis with or without pleural effusions)
      
                     -  Gastrointestinal hemorrhage
      
                -  Hepatitis B and C serologies that are consistent with past or current infections
                   because of the risk of reactivation with rituximab
      
                -  Severe and/or symptomatic refractory concurrent infection other than EBV
      
                -  Pregnant females are ineligible
      
                -  Lactating females are not eligible unless they have agreed not to breastfeed their
                   infants
      
                -  Female patients of childbearing potential are not eligible unless a negative
                   pregnancy test result has been obtained
      
                -  Sexually active patients of reproductive potential are not eligible unless they have
                   agreed to use an effective contraceptive method for the duration of their study
                   participation
      
                -  All patients and/or their parents or legal guardians must sign a written informed
                   consent
      
                -  All institutional, Food and Drug Administration (FDA), and National Cancer Institute
                   (NCI) requirements for human studies must be met
            
      Maximum Eligible Age:29 Years
      Minimum Eligible Age:N/A
      Eligible Gender:All
      Healthy Volunteers:No

      Primary Outcome Measures

      Measure:Percentage of patients assigned to Arm LMP-TC with successful LMP-specific T cell product match, were treated within two weeks of the expected start date, and received both weekly doses
      Time Frame:Day 42 of LMP-TC course 2
      Safety Issue:
      Description:An exact one-sided binomial 95% confidence interval will be used to get a lower bound for the actual rate of successful treatments.

      Secondary Outcome Measures

      Measure:Absence of EBV viremia
      Time Frame:Up to 12 months
      Safety Issue:
      Description:Will be correlated with RR, EFS and OS. Using the Log-Rank test for EFS and OS and the exact conditional test of proportions for RR.
      Measure:EFS
      Time Frame:Time to first occurrence of progression or death (events) or loss to follow-up or survival to analysis date (non-events), assessed up to 12 months
      Safety Issue:
      Description:Will be assessed using Kaplan-Meier estimates.
      Measure:Incidence of adverse events assessed by National Cancer Institute Common Terminology Criteria for Adverse Events
      Time Frame:Up to 12 months
      Safety Issue:
      Description:Toxicities will be described using descriptive statistics. Toxicity monitoring and analysis will be performed based on "as treated".
      Measure:OS
      Time Frame:Time to first occurrence of progression or death (events) or loss to follow-up or survival to analysis date (non-events), assessed up to 12 months
      Safety Issue:
      Description:Will be assessed using Kaplan-Meier estimates.
      Measure:Percentage of patients successfully matched to a LMP-specific T cell product derived from a third party LMP-specific T cell bank
      Time Frame:Day 42 of LMP-TC course 2
      Safety Issue:
      Description:Will be assessed using an exact one-sided binomial 95% confidence interval to get a lower bound for the actual rate.
      Measure:PFS
      Time Frame:Time to first occurrence of progression or death (events) or loss to follow-up or survival to analysis date (non-events), assessed up to 12 months
      Safety Issue:
      Description:Will be assessed using Kaplan-Meier estimates.
      Measure:RR to LMP-specific T cells
      Time Frame:Up to week 6
      Safety Issue:
      Description:Will be assessed using exact two-sided binomial 95% confidence intervals to get estimates of the response rate.
      Measure:RR to rituximab
      Time Frame:Up to week 3
      Safety Issue:
      Description:Will be assessed using exact two-sided binomial 95% confidence intervals to get estimates of the response rate.

      Details

      Phase:Phase 2
      Primary Purpose:Interventional
      Overall Status:Recruiting
      Lead Sponsor:Children's Oncology Group

      Trial Keywords

      • Organ Transplantation

      Last Updated

      March 8, 2017