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

Polymorphic Post-Transplant Lymphoproliferative Disorder Clinical Trial

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 Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT02900976
• Other study ID #: ANHL1522
• Secondary ID: NCI-2016-01110AN
• Status: Active, not recruiting
• Phase: Phase 2
• Start date: March 22, 2017
• Est. completion date: September 22, 2024

Study information

• Verified date: November 2023
• Source: Children's Oncology Group
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 18
• Est. completion date: September 22, 2024
• Est. primary completion date: March 31, 2021
• Accepts healthy volunteers: No
• Gender: All
• Age group: N/A to 29 Years

Eligibility

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

Related Conditions & MeSH terms

• EBV-Related Post-Transplant Lymphoproliferative Disorder
• Lymphoproliferative Disorders
• Monomorphic Post-Transplant Lymphoproliferative Disorder
• Polymorphic Post-Transplant Lymphoproliferative Disorder
• Recurrence
• Recurrent Monomorphic Post-Transplant Lymphoproliferative Disorder
• Recurrent Polymorphic Post-Transplant Lymphoproliferative Disorder
• Refractory Monomorphic Post-Transplant Lymphoproliferative Disorder
• Refractory Polymorphic Post-Transplant Lymphoproliferative Disorder

Intervention

Biological:
• Allogeneic LMP1/LMP2-Specific Cytotoxic T-Lymphocytes
Given IV
• Rituximab
Given IV

Locations

Country	Name	City	State
United States	C S Mott Children's Hospital	Ann Arbor	Michigan
United States	Children's Healthcare of Atlanta - Egleston	Atlanta	Georgia
United States	Children's Hospital Colorado	Aurora	Colorado
United States	Johns Hopkins University/Sidney Kimmel Cancer Center	Baltimore	Maryland
United States	Children's Hospital of Alabama	Birmingham	Alabama
United States	UNC Lineberger Comprehensive Cancer Center	Chapel Hill	North Carolina
United States	Cincinnati Children's Hospital Medical Center	Cincinnati	Ohio
United States	Cleveland Clinic Foundation	Cleveland	Ohio
United States	UT Southwestern/Simmons Cancer Center-Dallas	Dallas	Texas
United States	Duke University Medical Center	Durham	North Carolina
United States	University of Florida Health Science Center - Gainesville	Gainesville	Florida
United States	Hackensack University Medical Center	Hackensack	New Jersey
United States	Baylor College of Medicine/Dan L Duncan Comprehensive Cancer Center	Houston	Texas
United States	Riley Hospital for Children	Indianapolis	Indiana
United States	University of Iowa/Holden Comprehensive Cancer Center	Iowa City	Iowa
United States	University of Mississippi Medical Center	Jackson	Mississippi
United States	Children's Mercy Hospitals and Clinics	Kansas City	Missouri
United States	Loma Linda University Medical Center	Loma Linda	California
United States	Children's Hospital Los Angeles	Los Angeles	California
United States	Mattel Children's Hospital UCLA	Los Angeles	California
United States	University of Miami Miller School of Medicine-Sylvester Cancer Center	Miami	Florida
United States	Children's Hospital of Wisconsin	Milwaukee	Wisconsin
United States	University of Minnesota/Masonic Cancer Center	Minneapolis	Minnesota
United States	Vanderbilt University/Ingram Cancer Center	Nashville	Tennessee
United States	NYP/Columbia University Medical Center/Herbert Irving Comprehensive Cancer Center	New York	New York
United States	University of Oklahoma Health Sciences Center	Oklahoma City	Oklahoma
United States	University of Nebraska Medical Center	Omaha	Nebraska
United States	Lucile Packard Children's Hospital Stanford University	Palo Alto	California
United States	Children's Hospital of Philadelphia	Philadelphia	Pennsylvania
United States	Phoenix Childrens Hospital	Phoenix	Arizona
United States	Children's Hospital of Pittsburgh of UPMC	Pittsburgh	Pennsylvania
United States	Mayo Clinic in Rochester	Rochester	Minnesota
United States	University of Rochester	Rochester	New York
United States	Washington University School of Medicine	Saint Louis	Missouri
United States	Primary Children's Hospital	Salt Lake City	Utah
United States	UCSF Medical Center-Mission Bay	San Francisco	California
United States	Seattle Children's Hospital	Seattle	Washington
United States	Children's National Medical Center	Washington	District of Columbia

Sponsors (2)

Lead Sponsor	Collaborator
Children's Oncology Group	National Cancer Institute (NCI)

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	The percentage of patients assigned to Arm LMP-TC who had a suitable LMP-specific T-cell product, were treated within two weeks of the expected start date, and received both weekly doses in a cooperative multi-institutional setting. A statistical analysis was planned, but not performed because accrual was stopped early and the sample size required for the analysis was not reached.	Day 8 of the first LMP-TC cycle (cycle = 42 days)
Secondary	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	Will be assessed using an exact one-sided binomial 95% confidence interval to get a lower bound for the actual rate.	Day 1 of the first LMP-TC cycle (cycle = 42 days)
Secondary	Progression-free Survival	Will be assessed using Kaplan-Meier estimates, for all patients combined and separately for each cohort.	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
Secondary	Event-free Survival (EFS)	Will be assessed using Kaplan-Meier estimates, for all patients combined and separately for each cohort.	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
Secondary	Overall Survival (OS)	Will be assessed using Kaplan-Meier estimates, for all patients combined and separately for each cohort.	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
Secondary	Response Rate (RR) to Rituximab	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).	Up to week 3
Secondary	Response Rate (RR) to LMP-specific T Cells	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.	Up to week 6
Secondary	Absence of Epstein-Barr Virus Viremia	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.	Up to 12 months
Secondary	Incidence of Adverse Events	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".	Up to 12 months