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. Rituximab is a monoclonal antibody that may interfere with the ability of cancer 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:

Active, not recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Rituximab and LMP-Specific T-Cells in Treating Pediatric Solid Organ Recipients With EBV-Positive, CD20-Positive Post-Transplant Lymphoproliferative Disorder
  • Official Title: A Pilot Study of Rituximab (RTX) and Third Party Latent Membrane Protein (LMP)-Specific Cytotoxic T-Lymphocytes (LMP-TC) 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: ANHL1522
  • SECONDARY ID: U10CA180886
  • NCT ID: NCT02900976

Conditions

  • EBV-Related Post-Transplant Lymphoproliferative Disorder
  • Monomorphic Post-Transplant Lymphoproliferative Disorder
  • Polymorphic Post-Transplant Lymphoproliferative Disorder
  • Recurrent Monomorphic Post-Transplant Lymphoproliferative Disorder
  • Recurrent Polymorphic Post-Transplant Lymphoproliferative Disorder
  • Refractory Monomorphic Post-Transplant Lymphoproliferative Disorder
  • Refractory 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 ABBS, Rituximab Biosimilar ABP 798, Rituximab Biosimilar BI 695500, Rituximab Biosimilar CT-P10, Rituximab Biosimilar GB241, Rituximab Biosimilar IBI301, Rituximab Biosimilar JHL1101, Rituximab Biosimilar PF-05280586, Rituximab Biosimilar RTXM83, Rituximab Biosimilar SAIT101, Rituximab Biosimilar SIBP-02, rituximab biosimilar TQB2303, rituximab-abbs, RTXM83, TruximaArm I (RTX)

Purpose

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. Rituximab is a monoclonal antibody that may interfere with the ability of cancer 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.

Detailed Description

      PRIMARY OBJECTIVE:

      I. To determine the feasibility of treating pediatric and young adult solid organ transplant
      recipients who have newly diagnosed, relapsed or refractory Epstein-Barr virus (EBV)-positive
      CD20-positive post-transplant lymphoproliferative disease (PTLD) with a novel T-cell
      therapeutic, allogeneic LMP1/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 newly diagnosed or relapsed 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 newly
      diagnosed, refractory or relapsed EBV-positive CD20-positive PTLD after SOT treated with RTX
      and/or LMP-specific T cells.

      IV. To estimate overall survival (OS) of children and young adults with newly diagnosed,
      refractory or relapsed EBV-positive CD20-positive PTLD after SOT treated with RTX and/or
      LMP-specific T cells.

      V. To estimate the RR to LMP-specific T cells of newly diagnosed (without complete response
      to course RTX1), refractory, and relapsed children and young adults with EBV-positive
      CD20-positive PTLD.

      VI. To estimate progression-free survival (PFS) of children and young adults with newly
      diagnosed, refractory or relapsed EBV-positive CD20-positive PTLD after SOT treated with RTX
      and/or LMP-specific T cells.

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

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

      EXPLORATORY 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 (Cohorts A and B): Patients receive rituximab or biosimilar intravenously (IV) on
      days 1, 8, 15. Cycle 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, Cohorts A): Patients with newly diagnosed PTLD who achieve a complete response
      (CR) after induction receive additional rituximab or biosimilar as in induction.

      ARM II (LMP-TC, Cohorts A, B, C): Patients with newly diagnosed PTLD who do not achieve a CR
      to induction, all relapsed patients after induction, and all patients with refractory disease
      who received rituximab or biosimilar within 90 days according to institutional guidelines,
      receive allogeneic LMP1/LMP2-specific cytotoxic T-lymphocytes IV over 1- 2 minutes on days 0
      and 7. Cycle continues for up to 42 days in the absence of disease progression or
      unacceptable toxicity. Patients with PR or SD after first cycle of cycle 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 complete response (CR) after induction receive additional rituximab or biosimilar as in induction.
  • Rituximab
Arm II (LMP-TC)ExperimentalPatients with newly diagnosed PTLD who do not achieve a CR to induction, all relapsed patients after induction, and all patients with refractory disease who received rituximab or biosimilar within 90 days according to institutional guidelines, receive allogeneic LMP1/LMP2-specific cytotoxic T-lymphocytes IV over 1- 2 minutes on days 0 and 7. Cycle continues for up to 42 days in the absence of disease progression or unacceptable toxicity. Patients with PR or SD after first cycle of cycle allogeneic LMP1/LMP2-specific cytotoxic T-lymphocytes receive an additional cycle.
  • Allogeneic LMP1/LMP2-Specific Cytotoxic T-Lymphocytes
  • Rituximab

Eligibility Criteria

        Inclusion Criteria:

          -  Patient must have a history of solid organ transplantation

          -  Patients must have biopsy-proven newly diagnosed, relapsed or refractory 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 evaluable disease at study entry either by imaging or by serial
             endoscopic biopsies.

               -  Note: a measurable node must have an LDi (longest diameter) greater than 1.5 cm;
                  a measurable extranodal lesion should have an LDi greater than 1.0 cm; all tumor
                  measurements must be recorded in millimeters (or decimal fractions of
                  centimeters)

          -  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

          -  Myelosuppressive chemotherapy: must not have received within 2 weeks of entry onto
             this study

          -  COHORT A and B: Patient must not have received therapy with anti-CD20 monoclonal
             antibodies within 90 days of entry onto this study

          -  COHORT C: Patient must have received rituximab at 375 mg/m^2 weekly for at least 3
             doses within the last 90 days prior to study enrollment

          -  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

          -  COHORT C: HLA typing is available and will be submitted at the time of enrollment.

        Exclusion Criteria:

          -  Burkitt morphology

          -  Central nervous system (CNS) involvement; CNS status must be confirmed by lumbar
             puncture

               -  Note: lumbar puncture can be performed at the time of diagnosis and does not need
                  to be repeated unless there is a change in neurological status or it was
                  performed more than 14 days prior to study entry

          -  Bone marrow involvement (> 25%)

               -  Note: bone marrow aspiration/biopsy can be performed at the time of diagnosis and
                  does not need to be repeated unless there is a change in peripheral blood counts
                  or it was performed more than 14 days prior to study entry

          -  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

          -  Any documented donor-derived PTLD

          -  Hepatitis B or C serologies 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 since there is no available information regarding
             human fetal or teratogenic toxicities

          -  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 and for 12 months following completion of study therapy.

          -  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 latent membrane protein-specific T-cells (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 8 of the first LMP-TC cycle (cycle = 42 days)
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:Percentage of patients successfully matched to a latent membrane protein (LMP)-specific T cell product derived from a third party LMP-specific T cell bank
Time Frame:Day 1 of the first LMP-TC cycle (cycle = 42 days)
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:Progression-free survival
Time Frame:Time to first occurrence of progression or death (events) or loss to follow-up or survival to analysis date (non-events), assessed 12 months from enrollment of the last patient on the study
Safety Issue:
Description:Will be assessed using Kaplan-Meier estimates, for all patients combined and separately for each cohort.
Measure:Event-free survival (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 12 months from enrollment of the last patient on the study
Safety Issue:
Description:Will be assessed using Kaplan-Meier estimates, for all patients combined and separately for each cohort.
Measure:Overall survival (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 12 months from enrollment of the last patient on the study
Safety Issue:
Description:Will be assessed using Kaplan-Meier estimates, for all patients combined and separately for each cohort.
Measure:Response rate (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. Will be evaluated in Cohorts A and B only (combined and separately).
Measure:Response rate (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. Will be evaluated in all Cohorts combined and in each Cohort separately.
Measure:Absence of Epstein-Barr virus viremia
Time Frame:Up to 12 months
Safety Issue:
Description:Will be correlated with response rate (RR), event-free survival (EFS) and overall survival (OS). Using the log-rank test for EFS and OS and the exact conditional test of proportions (Fisher's exact test for RR, both for all patients combined and stratified by cohort.
Measure:Incidence of adverse events
Time Frame:Up to 12 months
Safety Issue:
Description:Will be assessed by National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0. Toxicities will be described using descriptive statistics. Toxicity monitoring and analysis will be performed based on "as treated".

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Active, not recruiting
Lead Sponsor:Children's Oncology Group

Last Updated

April 8, 2021