Clinical trial NCT02900976: 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)
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE2
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
Lead sponsor: Children's Oncology Group
Sponsor class: NETWORK
Collaborators: name: National Cancer Institute (NCI)
First posted: 2016-09-15
Enrollment: 18
Sex: ALL
Maximum age (years): 29
Standard ages: CHILD
ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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.

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

Primary outcomes:
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
timeFrame: Day 8 of the first LMP-TC cycle (cycle = 42 days)
Secondary outcomes:
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
timeFrame: Day 1 of the first LMP-TC cycle (cycle = 42 days)
measure: Progression-free Survival
timeFrame: 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
measure: Event-free Survival (EFS)
timeFrame: 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
measure: Overall Survival (OS)
timeFrame: 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
measure: Response Rate (RR) to Rituximab
timeFrame: Up to week 3
measure: Response Rate (RR) to LMP-specific T Cells
timeFrame: Up to week 6
measure: Absence of Epstein-Barr Virus Viremia
timeFrame: Up to 12 months
measure: Incidence of Adverse Events
timeFrame: Up to 12 months
Other outcomes:
Locations:
city: Birmingham
country: United States
facility: Children's Hospital of Alabama
state: Alabama
city: Phoenix
country: United States
facility: Phoenix Childrens Hospital
state: Arizona
city: Loma Linda
country: United States
facility: Loma Linda University Medical Center
state: California
city: Los Angeles
country: United States
facility: Children's Hospital Los Angeles
state: California
city: Los Angeles
country: United States
facility: Mattel Children's Hospital UCLA
state: California
city: Palo Alto
country: United States
facility: Lucile Packard Children's Hospital Stanford University
state: California
city: San Francisco
country: United States
facility: UCSF Medical Center-Mission Bay
state: California
city: Aurora
country: United States
facility: Children's Hospital Colorado
state: Colorado
city: Washington
country: United States
facility: Children's National Medical Center
state: District of Columbia
city: Gainesville
country: United States
facility: University of Florida Health Science Center - Gainesville
state: Florida
city: Miami
country: United States
facility: University of Miami Miller School of Medicine-Sylvester Cancer Center
state: Florida
city: Atlanta
country: United States
facility: Children's Healthcare of Atlanta - Arthur M Blank Hospital
state: Georgia
city: Indianapolis
country: United States
facility: Riley Hospital for Children
state: Indiana
city: Iowa City
country: United States
facility: University of Iowa/Holden Comprehensive Cancer Center
state: Iowa
city: Baltimore
country: United States
facility: Johns Hopkins University/Sidney Kimmel Cancer Center
state: Maryland
city: Ann Arbor
country: United States
facility: C S Mott Children's Hospital
state: Michigan
city: Minneapolis
country: United States
facility: University of Minnesota/Masonic Cancer Center
state: Minnesota
city: Rochester
country: United States
facility: Mayo Clinic in Rochester
state: Minnesota
city: Jackson
country: United States
facility: University of Mississippi Medical Center
state: Mississippi
city: Kansas City
country: United States
facility: Children's Mercy Hospitals and Clinics
state: Missouri
city: Saint Louis
country: United States
facility: Washington University School of Medicine
state: Missouri
city: Omaha
country: United States
facility: University of Nebraska Medical Center
state: Nebraska
city: Hackensack
country: United States
facility: Hackensack University Medical Center
state: New Jersey
city: New York
country: United States
facility: NYP/Columbia University Medical Center/Herbert Irving Comprehensive Cancer Center
state: New York
city: Rochester
country: United States
facility: University of Rochester
state: New York
city: Chapel Hill
country: United States
facility: UNC Lineberger Comprehensive Cancer Center
state: North Carolina
city: Durham
country: United States
facility: Duke University Medical Center
state: North Carolina
city: Cincinnati
country: United States
facility: Cincinnati Children's Hospital Medical Center
state: Ohio
city: Cleveland
country: United States
facility: Cleveland Clinic Foundation
state: Ohio
city: Oklahoma City
country: United States
facility: University of Oklahoma Health Sciences Center
state: Oklahoma
city: Philadelphia
country: United States
facility: Children's Hospital of Philadelphia
state: Pennsylvania
city: Pittsburgh
country: United States
facility: Children's Hospital of Pittsburgh of UPMC
state: Pennsylvania
city: Nashville
country: United States
facility: Vanderbilt University/Ingram Cancer Center
state: Tennessee
city: Dallas
country: United States
facility: UT Southwestern/Simmons Cancer Center-Dallas
state: Texas
city: Houston
country: United States
facility: Baylor College of Medicine/Dan L Duncan Comprehensive Cancer Center
state: Texas
city: Salt Lake City
country: United States
facility: Primary Children's Hospital
state: Utah
city: Seattle
country: United States
facility: Seattle Children's Hospital
state: Washington
city: Milwaukee
country: United States
facility: Children's Hospital of Wisconsin
state: Wisconsin
Study officials:
affiliation: Children's Oncology Group
name: Birte Wistinghausen
role: PRINCIPAL_INVESTIGATOR
References: