Antiviral Cellular Therapy (Virus Specific T-Cells) for the Treatment of Epstein-Barr Virus, Cytomegalovirus, or Adenovirus Infections in Patients Who Have Undergone a Stem Cell Transplant or Patients with Primary Immunodeficiency Disorder

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Status: Active

Description

This phase I / II trial studies the side effects of virus specific T-cells and to see how well they work in treating Epstein-Barr virus, cytomegalovirus, or adenovirus infections in patients who have undergone a stem cell transplant or patients with primary immunodeficiency disorder. Virus specific T-cells are blood cells from a separate donor that have been grown in a special way that may help to control Epstein-Barr virus, cytomegalovirus, and adenovirus infections in patients who have undergone a stem cell transplant or patients with primary immunodeficiency disorder.

Eligibility Criteria

Inclusion Criteria

  • Patients who have received any type of allogeneic transplant or who have a primary immunodeficiency disorder will be eligible if they have CMV, adenovirus, and/or EBV infection/disease with failure of treatment after 7 days of standard therapy OR if unable to tolerate standard therapy
  • Patients must meet one of the following criteria: * Recipient of prior myeloablative or non-myeloablative allogeneic hematopoietic stem cell transplant using either bone marrow or peripheral blood stem cells or single or double cord blood within the previous 18 months OR * Have a diagnosed primary immunodeficiency disorder (as defined by clinical and laboratory evaluations) and not undergone HSCT
  • Treatment of the following persistent or relapsed infections despite standard therapy * CMV: Treatment of persistent or relapsed CMV disease or infection after standard therapy. For CMV infection, standard therapy is defined as antiviral therapy with ganciclovir, foscarnet or cidofovir for at least 14 days ** CMV disease: defined as: *** Demonstration of CMV by biopsy specimen, culture, or molecular testing (polymerase chain reaction [PCR], antigenemia) from visceral sites of disease *** Detection of CMV by culture or direct fluorescent antibody stain, or PCR in bronchoalveolar lavage fluid in the presence of new or changing pulmonary infiltrates or respiratory disease *** Findings consistent with CMV retinitis on ophthalmologic examination ** CMV infection: defined as the presence of CMV positivity as detected by PCR from at least ONE site such as stool or blood or urine or nasopharynx ** Failure of antiviral therapy: defined as a rise or a fall of less than 1 log in viral load in peripheral blood or any site of disease (as measured by PCR compared with baseline levels taken immediately prior to initiation of antiviral therapy) after at least 14 days of antiviral therapy, or inability to tolerate standard antiviral therapy due to toxicities. If antiviral medications have recently been changed, patients must be on the same antiviral medication for at least 7 days prior to enrollment on trial * Adenovirus: Treatment of persistent or relapsed adenovirus infection or disease despite standard therapy. Standard therapy is defined as antiviral therapy with cidofovir or brincidofovir ** Adenovirus infection: defined as the presence of adenoviral positivity as detected by PCR or culture from ONE site such as stool or blood or urine or nasopharynx ** Adenovirus disease: defined as the presence of adenoviral positivity as detected by PCR, direct fluorescent antibody staining (DFA) or culture from two or more sites such as stool or blood or urine or nasopharynx ** Failure of therapy: defined as either an increase, or a fall of less than 1 log in viral load in peripheral blood or any site of disease (as measured by PCR compared with baseline levels taken immediately prior to initiation of antiviral therapy) after at least 14 days of antiviral therapy, or failure of therapy if patient cannot tolerate cidofovir or brincidofovir therapy due to toxicities including poor renal function. If patients have been switched from cidofovir to brincidofovir or vice versa, they must consistently be on the same medication for at least 7 days prior to enrollment on trial * EBV: Treatment of persistent or relapsed EBV infection despite standard therapy. For EBV infection, standard therapy is defined as rituximab given at 375 mg/m^2 in patients for 1-4 doses with a CD20 positive (+) tumor. Only B-cell lymphoproliferative disease would be eligible for treatment under this trial, as T/natural killer (NK) severe chronic active EBV (SCAEBV) has not been amenable to third party VSTs in prior studies ** EBV infection: defined as *** Biopsy proven B-cell lymphoma with EBV genomes detected in tumor cells by immunocytochemistry or in situ PCR *** Clinical or imaging findings consistent with EBV B-cell lymphoma and/or elevated EBV viral load in peripheral blood ** Failure of therapy is defined as *** Increase, or less than 50% decrease in overall disease burden of EBV-post-transplant lymphoproliferative disorder (PTLD) at sites of disease by imaging measurements (in comparison with last imaging prior to rituximab therapy) after at least 14 days following the 1st dose of rituximab *** Increase, or a fall of less than 1 log, in EBV viral load in peripheral blood or any site of disease (as measured by PCR compared with baseline levels taken immediately prior to initiation of antiviral therapy) after at least 14 days following the 1st dose of rituximab * Inability to tolerate standard antiviral therapy is defined as: ** History of allergic reaction to antiviral medication ** Pre-existing liver or kidney disease (grade III – IV) that would preclude safe use of antiviral therapy ** Adverse reaction to antiviral medication (i.e. hepatitis, renal insufficiency, cytopenias, other organ disease not attributable to viral infection) ** Very young infants (< 6 months of age) may proceed if otherwise eligible without failing antiviral therapy as there is no standard in very young infants
  • Patients with simultaneous infections with CMV, EBV and/or adenovirus infections are eligible if one or more infection(s) is persistent or relapsed despite standard therapy as defined above. Patients with multiple infections with one or more reactivation and one or more controlled infection are eligible to enroll. For patients with multiple persistent viral infections, the patients would be enrolled onto the primary stratum (CMV or adenovirus). For patients with both CMV and adenovirus infections, the patient would be recruited to whichever strata has fewer subjects
  • Clinical status at enrollment that allows tapering of steroids to equal or less than 0.5 mg/kg/day prednisone (or equivalent) prior to infusion of the VST doses
  • Negative pregnancy test in female patients if applicable (childbearing potential who have received a reduced intensity conditioning regimen)
  • Written informed consent and/or signed assent line from patient, parent or guardian

Exclusion Criteria

  • Patients receiving anti-thymocyte globulin (ATG), Campath, basiliximab, brentuximab, tocilizumab or other immunosuppressive monoclonal antibodies impacting T-cells survival within 28 days of screening for enrollment or < 5 medication half-lives elapsed (whichever is shorter)
  • Patients who have received donor lymphocyte infusion (DLI) or other experimental cellular therapies within 28 days
  • Current therapy with ruxolitinib or other JAK inhibitors within the previous 3 days
  • Patients who have received immune checkpoint inhibitors with < 3 medication half-lives elapsed
  • Patients with other uncontrolled infections, defined as bacterial or fungal infections with clinical signs of worsening despite standard therapy. For bacterial infections, patients must be receiving definitive therapy and have no signs of progressing infection for 72 hours prior to enrollment. For fungal infections, patients must be receiving definitive systemic anti-fungal therapy and have no signs of progressing infection for 1 week prior to enrollment. Progressing infection is defined as hemodynamic instability, worsening physical signs, or radiographic findings attributable to infection. Persisting fever without other signs or symptoms will not be interpreted as progressing infection
  • Patients with active and uncontrolled relapse of malignancy (if applicable)

Locations & Contacts

Arizona

Phoenix
Phoenix Childrens Hospital
Status: Active
Contact: Roberta H. Adams
Email: radams@phoenixchildrens.com

California

Duarte
City of Hope Comprehensive Cancer Center
Status: Active
Contact: Nicole Amalia Karras
Email: nkarras@coh.org
Los Angeles
Children's Hospital Los Angeles
Status: Active
Contact: Nini Huynh
Phone: 323-361-2546
UCLA / Jonsson Comprehensive Cancer Center
Status: Active
Contact: Andres Vargas
Phone: 310-825-6708
Palo Alto
Lucile Packard Children's Hospital Stanford University
Status: Active
Contact: Rajni Agarwal-Hashmi
Email: rajnia@stanford.edu
San Francisco
UCSF Medical Center-Mount Zion
Status: Active
Contact: Kevin Magruder
Phone: 415-476-0554

Colorado

Aurora
Children's Hospital Colorado
Status: Active
Contact: Elizabeth Ann Chick
Phone: 720-777-5179

Connecticut

New Haven
Yale University
Status: Active
Contact: Linda Lee Eford
Phone: 203-785-4640

District of Columbia

Washington
Children's National Medical Center
Status: Active
Contact: Blachy Davila Saldana
Email: BJDAVILA@childrensnational.org

Georgia

Atlanta
Children's Healthcare of Atlanta - Egleston
Status: Active
Contact: Elizabeth O'Brien Stenger
Email: elizabeth.obrien.stenger@emory.edu

Illinois

Chicago
Lurie Children's Hospital-Chicago
Status: Active
Contact: Sonali Chaudhury
Email: SoChaudhury@luriechildrens.org

Indiana

Indianapolis
Riley Hospital for Children
Status: Active
Contact: Courtney Spiegel
Phone: 317-948-0581

Massachusetts

Boston
Boston Children's Hospital
Status: Active
Contact: Sung-Yun Pai
Email: Sung-Yun.Pai@childrens.harvard.edu
Floating Hospital for Children at Tufts Medical Center
Status: Active
Contact: Jaime Chisholm
Phone: 617-636-5535

Michigan

Grand Rapids
Helen DeVos Children's Hospital at Spectrum Health
Status: Active
Contact: Ulrich A. Duffner
Email: ulrich.duffner@spectrumhealth.org

Minnesota

Minneapolis
University of Minnesota / Masonic Cancer Center
Status: Active
Contact: Christen Layne Ebens
Email: ebens012@umn.edu

Missouri

Saint Louis
Saint Louis Children's Hospital
Status: Active
Contact: Lisa Murray
Phone: 314-454-6018

New York

New York
NYP / Columbia University Medical Center / Herbert Irving Comprehensive Cancer Center
Status: Active
Contact: Jean Veronica Sosna
Phone: 212-305-9138

North Carolina

Durham
Duke University Medical Center
Status: Active
Contact: Suhag H. Parikh
Email: suhag.parikh@duke.edu

Oregon

Portland
OHSU Knight Cancer Institute
Status: Active
Contact: Evan Brooke Shereck
Phone: 503-418-4397
Email: shereck@ohsu.edu

Pennsylvania

Philadelphia
Children's Hospital of Philadelphia
Status: Active
Contact: Barbara McGlynn
Phone: 215-590-1000

Tennessee

Memphis
St. Jude Children's Research Hospital
Status: Active
Contact: Ewelina Kinga Mamcarz
Email: Ewelina.Mamcarz@STJUDE.ORG

Texas

Dallas
UT Southwestern / Simmons Cancer Center-Dallas
Status: Active
Contact: Gevel Jackson
Phone: 214-456-7194
San Antonio
Methodist Children's Hospital of South Texas
Status: Active
Contact: Sherri L. Shade
Phone: 210-575-7268

Virginia

Richmond
Virginia Commonwealth University / Massey Cancer Center
Status: Active
Contact: Jenifer Chirico
Phone: 804-628-0829

Washington

Seattle
Fred Hutchinson Cancer Research Center
Status: Active
Contact: Ann E Dahlberg
Email: adahlber@fredhutch.org

Trial Objectives and Outline

PRIMARY OBJECTIVE:

I. To evaluate the feasibility, safety and anti-viral activity of partially human leukocyte antigen (HLA)-matched adenovirus (AdV)/cytomegalovirus (CMV)/Epstein-Barr virus (EBV)-specific allogeneic T-lymphocytes (virus specific T-cells [VSTs]) for treatment of persistent EBV, CMV, and/or adenovirus infections in patients who have undergone hematopoietic stem cell transplantation (HSCT), or in patients with primary immunodeficiency disorder (PID) who have not undergone HSCT.

OUTLINE:

Patients receive VSTs intravenously (IV) over 1-2 minutes. Patients who have a partial response, stable disease, receive medications which may affect the persistence or function of the infused VST, and have no treatment-related dose-limiting toxicities may receive up to 3 additional doses at 30 days post-infusion and a minimum of 2 weekly intervals thereafter in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up weekly for 6 weeks, then at 3, 6, and 12 months.

Trial Phase & Type

Trial Phase

Phase I/II

Trial Type

Treatment

Lead Organization

Lead Organization
Children's Hospital Los Angeles

Principal Investigator
Michael Allen Pulsipher

Trial IDs

Primary ID PBMTC SUP1701
Secondary IDs NCI-2019-05525
Clinicaltrials.gov ID NCT03475212