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.
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
