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T-Lymphocytes for Prevention or Treatment of Viral Infections Following Hematopoietic Stem Cell Transplantation (NATS)

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ClinicalTrials.gov Identifier: NCT03180216
Recruitment Status : Recruiting
First Posted : June 8, 2017
Last Update Posted : January 18, 2020
Sponsor:
Information provided by (Responsible Party):
Michael Keller, Children's National Research Institute

Tracking Information
First Submitted Date  ICMJE May 1, 2017
First Posted Date  ICMJE June 8, 2017
Last Update Posted Date January 18, 2020
Actual Study Start Date  ICMJE February 15, 2017
Estimated Primary Completion Date July 2020   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: June 15, 2017)
  • Incidence of acute GvHD (grade III-IV) [ Time Frame: Within 45 days of the last VSTs dose ]
    Number of patients with acute GvHD grades III-IV within 45 days of the last dose of VSTs
  • Incidence of adverse events as per CTCAE common criteria guidelines. [ Time Frame: Within 45 days of the last VSTs dose ]
    2) Grades 3-5 infusion-related adverse events within 45 days of the last dose of VSTs, or 3) Grades 4-5 non-hematological adverse events within 45 days of the last VSTs dose based on a standardized clinical assessment form.
Original Primary Outcome Measures  ICMJE
 (submitted: June 6, 2017)
Safety: Incidence of acute GvHD (grade III-IV) or other adverse events within 45 days. [ Time Frame: Within 45 days of the last VSTs dose ]
  1. Number of patients with acute GvHD grades III-IV within 45 days of the last dose of VSTs, or
  2. Grades 3-5 infusion-related adverse events within 45 days of the last dose of VSTs, or
  3. Grades 4-5 non-hematological adverse events within 45 days of the last VSTs dose based on a standardized clinical assessment form.
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: December 31, 2018)
  • Antiviral response [ Time Frame: 1 year ]
    Peripheral blood and, where relevant, stool and urine will be monitored for viral load by PCR assay. The response in viral load will be defined as follows: Complete response: Clearance of targeted virus by PCR assay. Partial response: Decrease in viral load of >= 1 log from baseline Mixed response: Decrease in viral load of >= 1 logarithm from baseline for one targeted infection and an increase or no change in viral load for a second infection. Stable disease: Changes insufficient to qualify as partial response or progression Progression: Increase in viral load in body fluids of >= 1 log from baseline or dissemination to other sites of disease.
  • Antiviral Immunity [ Time Frame: 1 year ]
    Reconstitution of Antiviral Immunity: Patient peripheral blood mononuclear cells will be assessed for the presence of virus-reactive T cells using ELIspot and flow cytometry using the MACS Gamma capture kit to assess the percentage of peripheral blood T-cells specific for the targeted virus(es).
Original Secondary Outcome Measures  ICMJE
 (submitted: June 6, 2017)
  • Antiviral Activity: incidence of clearance or improvement of the targeted viral infection(s) [ Time Frame: 2 years ]
    Antiviral Activity: Peripheral blood and, where relevant, stool and urine will be monitored for viral load. The response in viral load will be defined as follows: Complete response: Clearance of targeted virus from blood or other measured body fluids by PCR assay. Partial response: Decrease in viral load of >= 1 log in body fluids from baseline with improvement in clinical signs and symptoms. Mixed response: Decrease in viral load of >= 1 logarithm from baseline for one targeted infection and an increase or no change in viral load for a second infection. Stable disease: Changes insufficient to qualify as partial response or progression Progression: Increase in viral load in body fluids of >= 1 log from baseline or dissemination to other sites of disease.
  • Reconstitution of Antiviral Immunity: detection of T-cells specific for the targeted virus(es). [ Time Frame: 2 years ]
    Reconstitution of Antiviral Immunity: Patient peripheral blood mononuclear cells will be assessed for the presence of virus-reactive T cells using ELIspot and flow cytometry using the MACS Gamma capture kit to assess the percentage of peripheral blood T-cells specific for the targeted virus(es).
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE T-Lymphocytes for Prevention or Treatment of Viral Infections Following Hematopoietic Stem Cell Transplantation
Official Title  ICMJE Novel Antigens Targeted by ex Vivo Expanded T-Lymphocytes for Prevention or Treatment of Viral Infections Following Hematopoietic Stem Cell Transplantation
Brief Summary

This Phase I dose-escalation trial is designed to evaluate the safety of rapidly generated multivirus-specific T-cell products with antiviral activity against CMV, EBV, adenovirus, HHV6, BK virus, JC virus, and human parainfluenza-3 (HPIV3), derived from eligible HSCT donors.

In this trial, the investigators will utilize a rapid generation protocol for broad spectrum multivirus-specific T cells for infusion to recipients of allogeneic hematopoietic stem cell transplant (HSCT), who are at risk of developing EBV, CMV, adenovirus, HHV6, BKV and/or HPIV3, or with PCR/culture confirmed infection(s). These cells will be derived from HSCT donors, and the study agent will be assessed at each dose for evidence of dose-limiting toxicities (DLT).

This study will have two arms: Arm A will include patients who receive prophylactic treatment, and Arm B will include patients who receive VSTs for one or more active infections with targeted viruses. Determination of the study arm will be determined by the patient's clinical status. Study arms will each be analyzed for safety endpoints and secondary endpoints.

Detailed Description

Viral infections are normally controlled by T-cell immunity and are a cause of significant morbidity and mortality during the period of immune recovery after hematopoietic stem cell transplantation (HSCT). Risk for infection is impacted by the degree of tissue mismatch between donor and recipient and the immune status of the donor, including the degree and length of immunosuppression following transplantation. Reactivation of latent viruses such as cytomegalovirus (CMV), Epstein-Barr virus (EBV), and Human Herpesvirus 6B (HHV6) are common and often cause symptomatic disease. Reactivations of the polyomaviruses BK virus and JC virus are also common and frequently cause renal disease including hemorrhagic cystitis and less commonly neurologic disease (pervasive multifocal leukoencephalopathy). Respiratory viruses such as adenovirus and human parainfluenza also frequently cause infection. Antiviral pharmacologic agents are only effective against some of these viruses; their use is costly, and associated with significant toxicities and the outgrowth of drug-resistant mutants. As delay in recovery of virus-specific cellular immune response is clearly associated with viral reactivation and disease in these patients, cellular immunotherapy to restore viral-specific immunity is an attractive option that has already been successfully used to target several of these viruses.

To broaden the specificity of single T cells lines to include the three most common viral pathogens of stem cell recipients, the investigators reactivated CMV and adenovirus-specific T cells by using mononuclear cells transduced with a recombinant adenoviral vector encoding the CMV antigen pp65 (Ad5f35CMVpp65). Subsequent stimulations with EBV-LCL transduced with the same vector both reactivated EBV-specific T cells and maintained the expansion of the activated adenovirus and CMV-specific T cells. This method reliably produced T cells with cytotoxic function specific for all three viruses, which the investigators infused into 14 stem cell recipients in a Phase I prophylaxis study. The investigators observed recovery of immunity to CMV and EBV in all patients but an increase in adenovirus-specific T cells was only seen in patients who had evidence of adenovirus infection pre-infusion. A follow-up study in which the frequency of adenovirus-specific T cells was increased in the infused T cells produced similar results, thus highlighting the importance of endogenous antigen to promote the expansion of infused T cells in vivo. Nevertheless, all patients in both clinical trials with pre-infusion CMV, adenovirus or EBV infection or reactivation were able to clear the infection, including one patient with severe adenoviral pneumonia requiring ventilatory support. T cells recognizing multiple antigens can therefore produce clinically relevant effects against all three viruses.

Recent studies have extended the number of targeted viruses, and included HHV6B, BK virus, and Varicella-zoster virus (VZV). In a recent study, 11 patients were treated with VST targeting 5-viruses (CMV, EBV, Adv, HHV6B, BKV) which were generated using a rapid protocol with overlapping peptides encompassing 12 viral protein. VST infusion resulted in a 94% antiviral response rate in these patients (complete or partial responses against CMV=3/3, EBV=5/5, Adv=1/1, HHV6B=2/2, BKV=6/7). Two of the patients who received 5-virus VST developed transplant-associated microangiopathy, which was deemed secondary to HSCT and unrelated to VST infusion. One of these patients developed grade II skin GVHD, which improved with topical therapy. In another recent study, ten adult patients were prophylactically treated with VST specific for CMV, EBV, Adv, and Varicella (VZV). These VSTs were generated using donor-derived dendritic cells which were infected with either Ad5f35-pp65 or with varivax vaccine, and were then pooled and used to stimulate donor PBMCs. All ten patients were protected against EBV, Adv, and VZV. Six patients developed CMV reactivation, but only one required antiviral therapy. Of these 10 patients, 7 developed acute or chronic GVHD, though compared to a non-treated group at the same institution, the rate of GVHD did not differ significantly. Thus, it has been possible to target an extended panel of viruses with a single VST product.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 1
Study Design  ICMJE Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE
  • Viral Infections
  • Bone Marrow Transplant Infection
Intervention  ICMJE Biological: Virus Specific T cells (VSTs)

Pediatric and adult patients following any type of allogeneic transplant (HSCT) will receive VSTs as prophylaxis or treatment of reactivation or infection with CMV, adenovirus, EBV, HHV6, BK virus, JC virus, and/or HPIV3). The goal of this cell infusion will be to initiate an immune response against viral infections after HSCT.

VSTs will be generated using clinical grade overlapping peptides (Pepmixes) to directly stimulate PBMCs, growth promoting cytokines and the G-Rex culture device optimized for T cell expansion. Donor T-cells will be stimulated with overlapping peptide libraries encompassing pp65 and IE-1 (CMV), Hexon and Penton (Adenovirus), LMP2 and EBNA-1 (EBV), LgT and VP1 (BK virus), U54 and U90 (HHV6B), and Mat and NP (HPIV3).

Study Arms  ICMJE Experimental: Prophylactic and treatment

Virus Specific T cells (VSTs) for prophylactic and treatment of active viral infection(s) after HSCT.

3 different dose levels starting with 1 x 10E7 /m2 (a T cell number more than an order of magnitude lower than that administered at the time of an unmanipulated marrow infusion), followed by 2 x 10E7/m2 and a final dose 5 x 10E7 VSTs/m2

Intervention: Biological: Virus Specific T cells (VSTs)
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: June 6, 2017)
32
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE August 2021
Estimated Primary Completion Date July 2020   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

Recipient Inclusion Criteria at the time of VST infusion

  1. Prior myeoloablative or non-myeloablative allogeneic hematopoietic stem cell transplant using either bone marrow or peripheral blood stem cells no earlier than 5 days prior to the date of VST infusion, AND
  2. Prophylaxis for patients at risk of CMV, adenovirus, EBV, HHV6, BK virus, JC virus, and/or HPIV3 infection, OR
  3. Treatment of reactivation or active infection which is defined for each virus as below
  4. Treatment may be given to eligible patients with a single or multiple infections. Patients with multiple infections with one or more reactivation and one or more controlled infection are eligible to enroll.
  5. Clinical status at enrollment to allow tapering of steroids to less than 0.5 mg/kg/day prednisone or equivalent.
  6. Karnofsky/Lansky score of ≥ 50
  7. Bilirubin <2x upper limit normal
  8. AST < 5 x upper limit normal
  9. Serum creatinine < 2 x upper limit normal

12. Hgb >8.0 g/dL(level can be achieved with transfusion)

13. Pulse oximetry of > 90% on room air

14. Available multivirus-specific T cells (VSTs)

15. Negative pregnancy test in female patients if applicable (childbearing potential who have received a reduced intensity conditioning regimen).

16. Written informed consent and/or signed assent line from patient, parent or guardian.

Exclusion Criteria:

Recipient Exclusion criteria at the time of VST infusion:

  1. Patients receiving ATG, Campath, Basiliximab, or other immunosuppressive T cell monoclonal antibodies within 28 days of screening for enrollment. In patients who have received these therapies as part of their conditioning regimens, 28 days must have elapsed since the final dose before VST may be given.
  2. Patients with other uncontrolled infections. 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 worsening clinical symptoms, physical findings, vital sign abnormalities (including hemodynamic instability), and/or microbiologic or radiographic findings attributable to infection. Persisting fever without other signs /symptoms or laboratory evidence will not be interpreted as progressing infection.

  3. Patients who have received donor lymphocyte infusion (DLI) or other cellular therapies (with the exception of the allogeneic cells relating to the transplantation) within 28 days.
  4. Patients with active acute GVHD grades II-IV.
  5. Active and uncontrolled relapse of malignancy
  6. Patients with Grade >3 hyperbilirubinemia
  7. Patients who have received investigational (IND) product within 28 days of screening for enrollment under this study
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE Child, Adult, Older Adult
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Michael Keller, MD 202-476-5843 MKeller@childrensnational.org
Contact: Fahmida Hoq, MBBS, MS 202-476-2634 fhoq@cnmc.org
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03180216
Other Study ID Numbers  ICMJE Pro00008637
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  ICMJE
Plan to Share IPD: Yes
Responsible Party Michael Keller, Children's National Research Institute
Study Sponsor  ICMJE Children's National Research Institute
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Principal Investigator: Michael D Keller, MD Children's National Research Institute
PRS Account Children's National Research Institute
Verification Date January 2020

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP