Antiviral Cellular Therapy for Enhancing T-cell Reconstitution Before or After Hematopoietic Stem Cell Transplantation (ACES)

• ClinicalTrials.gov Identifier: NCT03475212
• Recruitment Status: Active, not recruiting
• First Posted: March 23, 2018
• Last Update Posted: March 3, 2022
• Sponsor: Michael Pulsipher, MD
• Information provided by (Responsible Party): Michael Pulsipher, MD, Children's Hospital Los Angeles

Tracking Information

• First Submitted Date: January 13, 2018
• First Posted Date: March 23, 2018
• Last Update Posted Date: March 3, 2022
• Actual Study Start Date: June 20, 2018
• Estimated Primary Completion Date: November 2022 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: April 27, 2018)

• Feasibility to identify suitable HLA matched VST products [ Time Frame: 30 days ]
  Feasibility will be defined as the ability of the investigators to identify suitable partially HLA- matched VST products from the VST bank at Children's National Medical Center for referred study subjects. The percentage of referred patients with potential partially-matched VST products identified will be recorded, as will timing between patient referral and treatment.
• Incidence of Treatment-Emergent Adverse Events [ Time Frame: 30 days ]
  The safety endpoint, dose-limiting toxicity (DLT), will be defined as acute GvHD grades III-IV or grades 3-5 infusion-related adverse events or grades 4-5 non-hematological adverse events related to the T cell product within 30 days of each VST dose and that are not due to the pre-existing infection or the original malignancy or pre-existing co-morbidities as defined by the NCI Common Terminology Criteria for Adverse Events (CTCAE), Version 4.03.
• Efficacy of VST at 30 days as measured by viral load [ Time Frame: 30 days ]
  Peripheral blood and, where relevant, stool and urine will be monitored for CMV, EBV, and/or adenovirus viral load. For patients with multiple viral infections, the response against the primary viral target will determine the classification. For the infection under treatment response in viral load will be assessed at 30 days after the first VST infusion

Original Primary Outcome Measures (submitted: March 16, 2018)

• Feasibility to identify suitable HLA matched VST products [ Time Frame: 30 days ]
  Feasibility will be defined as the ability of the investigators to identify suitable partially HLA- matched VST products from the VST bank at Children's National Medical Center for referred study subjects. The percentage of referred patients with potential partially-matched VST products identified will be recorded, as will timing between patient referral and treatment.
• Safety of administration of VSTs will be evaluated for 30 days for GVHD and for other toxicities. [ Time Frame: 30 days ]
  The safety endpoint, dose-limiting toxicity (DLT), will be defined as acute GvHD grades III-IV or grades 3-5 infusion-related adverse events or grades 4-5 non-hematological adverse events related to the T cell product within 30 days of each VST dose and that are not due to the pre-existing infection or the original malignancy or pre-existing co-morbidities as defined by the NCI Common Terminology Criteria for Adverse Events (CTCAE), Version 4.03.
• Efficacy of VST at 30 days as measured by viral load [ Time Frame: 30 days ]
  Peripheral blood and, where relevant, stool and urine will be monitored for CMV, EBV, and/or adenovirus viral load. For patients with multiple viral infections, the response against the primary viral target will determine the classification. For the infection under treatment response in viral load will be assessed at 30 days after the first VST infusion

• Current Secondary Outcome Measures: Not Provided
• Original Secondary Outcome Measures: Not Provided
• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Antiviral Cellular Therapy for Enhancing T-cell Reconstitution Before or After Hematopoietic Stem Cell Transplantation
• Official Title: Antiviral Cellular Therapy for Enhancing T-cell Reconstitution Before or After Hematopoietic Stem Cell Transplantation (ACES) PBMTC SUP1701
• Brief Summary: The purpose of this study is to evaluate whether virus-specific T cell lines (VSTs) are safe and can effectively control three viruses (EBV, CMV, and adenovirus) in patients who have had a stem cell transplant and also in patients that have a primary immunodeficiency disorder with no prior stem cell transplant.

Detailed Description

The primary purpose of the study is to evaluate whether most closely HLA-matched multivirus-specific T cell lines obtained from a bank of allogeneic virus-specific T cell lines (VSTs) have antiviral activity against three viruses: EBV, CMV and adenovirus.

Reconstitution of anti-viral immunity by donor-derived VSTs has shown promise in preventing and treating infections associated with CMV, EBV and adenovirus post-transplant. However, the time required to prepare patient-specific products and lack of virus-specific memory T cells in cord blood and seronegative donors, limits their value. An alternative is to use banked partially HLA-matched allogeneic VSTs. A prior phase II study at Baylor College of Medicine using trivirus-specific VSTs generated using monocytes and EBV-transformed B cells gene-modified with a clinical grade adenoviral vector expressing CMV-pp65 to activate and expand specific T cells showed the feasibility, safety and activity of this approach for the treatment of refractory CMV, EBV and Adenovirus infections. More recent protocols utilizing synthetic viral peptide pools allow ex vivo expansion of T-cells targeting multiple viral antigens in 10-12 days without use of viral transduction.

The study will evaluate whether partially-HLA matched allogeneic multivirus-specific VSTs, activated using overlapping peptide libraries spanning immunogenic antigens from CMV, adenovirus and EBV, will be safe and produce anti-viral effects in immunodeficient recipients infected with one of more of the targeted viruses that are persistent despite conventional anti-viral therapy.

This study will evaluate safety and efficacy of partially-matched VST therapy in A) patients who have persistent viral infections in the post-HSCT period, and B) patients with primary immunodeficiency conditions who have persistent viral infections and have not undergone HSCT.

The study agent will be assessed for safety and antiviral activity.

• Study Type: Interventional
• Study Phase: Phase 1; Phase 2
• Study Design: Allocation: N/A; Intervention Model: Single Group Assignment; Masking: None (Open Label); Primary Purpose: Treatment

Condition

• Cytomegalovirus Infections
• Adenovirus Infection
• EBV Infection

Intervention

Biological: Virus Specific T-cell (VST) infusion

Patients will receive partially HLA-matched VSTs as a single infusion. Patients who have a partial response (>1 log decrease in viral load without clearance) or no response and do not have treatment-related dose-limiting toxicities are eligible to receive up to 3 additional doses from day 30 after the initial infusion and at 2 weekly intervals thereafter. The viral load of the virus (or viruses) that patients are initially treated for are monitored by viral PCR.

Study Arms

Experimental: Virus specific T cell lines (VSTs) against three viruses

The study will evaluate whether partially-HLA matched allogeneic multivirus-specific VSTs, activated using overlapping peptide libraries spanning immunogenic antigens from CMV, adenovirus and EBV, will be safe and produce anti-viral effects in immunodeficient recipients infected with one of more of the targeted viruses that are persistent despite conventional anti-viral therapy.

Intervention: Biological: Virus Specific T-cell (VST) infusion

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Active, not recruiting
• Estimated Enrollment (submitted: March 16, 2018): 60
• Original Estimated Enrollment: Same as current
• Estimated Study Completion Date: February 2023
• Estimated Primary Completion Date: November 2022 (Final data collection date for primary outcome measure)

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 cell 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.
  • Adenovirus: Treatment of persistent or relapsed adenovirus infection or disease despite standard therapy. Standard therapy is defined as antiviral therapy with cidofovir or brincidofovir.
  • EBV: Treatment of persistent or relapsed EBV infection despite standard therapy.

For EBV infection, standard therapy is defined as rituximab given at 375 mg/m2 in patients for 1-4 doses with a CD20+ tumor.

Additional Inclusion Criteria:

• 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.
• 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 ATG, Campath, Basiliximab or other immunosuppressive monoclonal antibodies targeting T-cells within 28 days of screening for enrollment.
• 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 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).

Sex/Gender

• Sexes Eligible for Study: All

• Ages: Child, Adult, Older Adult
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: United States

Administrative Information

• NCT Number: NCT03475212
• Other Study ID Numbers: PBMTC SUP1701
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

• IPD Sharing Statement: Not Provided
• Current Responsible Party: Michael Pulsipher, MD, Children's Hospital Los Angeles
• Original Responsible Party: Same as current
• Current Study Sponsor: Michael Pulsipher, MD
• Original Study Sponsor: Same as current
• Collaborators: Not Provided

Investigators

• Study Chair: Michael Pulsipher, MD; Children's Hospital Los Angeles
• Study Chair: Michael Keller, MD; Children's National Research Institute

• PRS Account: Children's Hospital Los Angeles
• Verification Date: March 2022