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TETRAVI Multivirus CTL for Treatment of EBV, CMV, Adenovirus, and BK Infections Post Allogeneic SCT. (TETRAVI)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details. Identifier: NCT04013802
Recruitment Status : Recruiting
First Posted : July 10, 2019
Last Update Posted : March 10, 2021
The Methodist Hospital Research Institute
Information provided by (Responsible Party):
John Craddock, Baylor College of Medicine

Brief Summary:

The purpose of this study is to use VSTs (virus-specific T cells) from a donor that is a partial HLA (human leukocyte antigen) match with the patient to treat viral infections after an allogeneic hematopoietic stem cell transplant (HSCT).

The patient must have had a myeloablative or non-myeloablative allogeneic HSCT using either bone marrow, single/double umbilical cord blood, or peripheral blood stem cells (PBSC). After a transplant, while the immune system grows back, the patient is at risk for infection. Some viruses can stay in the body for life and are normally controlled by a healthy immune system, but if the immune system is weakened, like after a transplant, they can cause life threatening infections. He/she must have had an infection with one or more of the following viruses -Epstein Barr virus (EBV), cytomegalovirus (CMV), adenovirus (AdV), Human polyomavirus type I (BKV), and human polyomavirus type II (JCV)- that has persisted or recurred despite standard therapy.

In this study, the investigators want to use white blood cells that have been trained to treat viral infections. In an earlier study the investigators showed that treatment with such specially trained T cells has been successful when the cells are made from the transplant donor. However as it takes 1-2 months to make the cells, that approach is not practical for patients who already have an infection. In a subsequent study, the investigators were able to create multivirus-specific T cells (VSTs) from the blood of healthy donors and created a bank of these cells. The investigators then successfully used these banked cells to treat virus infections after a stem cell transplant. In this study the investigators have further modified their production method to decrease the potential side effects and the investigators want to find out if they can use these banked VSTs to fight infections caused by the viruses mentioned above.

Condition or disease Intervention/treatment Phase
Viral Infection Biological: HLA-matched VSTs Phase 1

Detailed Description:

The virus-specific T cells (VSTs) given to the patient will be thawed and injected into their intravenous line. To prevent an allergic reaction if the patient had a prior reaction to blood products like blood transfusions or platelets, prior to receiving the VSTs he/she may be given diphenhydramine (Benadryl) and acetaminophen (Tylenol). The patient will remain in the clinic for at least one hour after the infusion.

All participants on this study will be infused with the same number (dose) of cells. If the patient has persistent infection after the first dose, the investigators would discuss this with the patient and allow them to receive up to four more treatments if there were no complications with prior infusions. These additional treatments might be with cells from the same donor, or if the investigators feel that there is another donor whose cells might be better for the patient, the investigators would use cells from a different donor. This second product will be administered at the same dose level 14 days after the patient's initial infusion, and any additional infusions should be at least 14 days apart. After each VST infusion, the patient will be monitored as described above.

After the patient receives the cells the patient's transplant doctor will monitor the levels of the virus the subject is infected with in their blood.

The patient will continue to be followed by their doctor(s) after the injection. They will be seen in the clinic by research staff for follow up every week for 6 weeks. To learn more about the way the VSTs are working in the patient's body, up to an extra 30-40 ml (6-8 teaspoons) of blood may be taken before the infusion and then at 2, 4, and 6 weeks. Blood should come from the central intravenous line, and should not require extra needle sticks.

Any leftover samples of blood may be used to help future research. The specimens may be kept for a long time. These specimens and information about the patient's circumstances may be shared with other cancer researchers. Although there will be a record identifying under what circumstances these specimens were obtained, under all circumstances the patient's identity will be kept confidential.

Study Duration : The patient will be on the study for approximately 42 days after the patient's infusion. If the patient receives additional doses of the T cells as described above, the patient will be followed for 42 days after their last dose of T-cells.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 47 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Administration of Most Closely HLA-matched Multivirus-specific Cytotoxic T-Lymphocytes for the Treatment of EBV, CMV, Adenovirus, and BK Virus Infections Post Allogeneic Stem Cell Transplant
Actual Study Start Date : March 8, 2021
Estimated Primary Completion Date : May 1, 2024
Estimated Study Completion Date : May 1, 2024

Arm Intervention/treatment
Experimental: HLA-matched VSTs

Partially HLA-matched VSTs will be thawed and given by intravenous injection. Patients will receive 2 x 107 partially HLA-matched VSTs/m2 as a single infusion. In the rare case where insufficient banked cell product is available, a lower number of cells may be infused with agreement of the principal investigator, patient and/or guardian and the treatment team

Additional doses may be from the same donor or a different donor based on available cell lines and patient/disease factors. Decision to switch to a different donor can be made by the principal investigator based on factors that include sequential treatment of different viral infections, concerns for immune escape of the targeted virus and/or availability of a better matched or otherwise superior VST line. Additional treatments will only be given following the agreement of the patient, treating physician, and investigator. This process can be repeated as needed.

Biological: HLA-matched VSTs

An alternative approach that bypasses the need to grow VSTs for individual patients is to bank closely HLA-matched allogeneic VSTs that could be available as an "off the shelf" product.

The HLA-matched VST product is to produce immune activity to CMV, Adv, BK virus and EBV in all recipients.

Most recently our group extended this "off the shelf" approach to five viruses using the T cell product manufactured in 10 days. The VSTs were administered to 38 patients with 45 infections in a phase II clinical trial. A single infusion produced a cumulative complete or partial response rate of 92% overall and the following rates by virus: 100% for BKV (n = 16), 94% for CMV (n = 17), 71% for AdV (n = 7), 100% for EBV (n = 2), and 67% for HHV-6 (human herpesvirus) (n = 3).

Primary Outcome Measures :
  1. Dose Limiting toxicity: (DLT) rate by CTCAE v5 [ Time Frame: 6 weeks ]
    Safety of HLA-matched VSTs: Safety including acute GVHD (Graft-versus-host disease) grades III-IV of the last dose of VSTs, secondary graft failure, or grades 3-5 non-hematological adverse events.

  2. Overall Response Rate: (The viral load of the virus (or viruses) by viral PRC (replication-competent retrovirus) within 42 days) [ Time Frame: 6 weeks ]
    Antiviral Responses: Antiviral responses within 42 days after the first dose of VSTs.

Information from the National Library of Medicine

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Ages Eligible for Study:   Child, Adult, Older Adult
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No

Inclusion Criteria:

  1. Patients has to have received a prior myeloablative or non-myeloablative allogeneic hematopoietic stem cell transplant using either bone marrow, single/double cord blood or PBSC
  2. Cells administered as:

    1. Treatment of relapsed or persistent reactivation or infection for EBV, CMV, adenovirus, and/or BK virus despite standard therapy. Multiple infections are eligible to enroll.
    2. Early treatment for single or multiple infections with EBV, CMV, adenovirus, and/or BK virus following treatment failure or in patients who are unable to tolerate standard therapy
    3. Treatment of JC virus infection
  3. Steroids less than or equal to 1.0 mg/kg/day methylprednisolone (or equivalent)
  4. Hgb ≥ 7.0 gm/dl
  5. Available VSTs must be partially HLA matched and verified
  6. Negative pregnancy test (if female of childbearing potential after reduced intensity conditioning)
  7. Patient or parent/guardian capable of providing informed consent.

Exclusion Criteria:

  1. Received ATG (anti-thymocyte globulin), Campath or other T cell immunosuppressive monoclonal antibodies in the last 28 days.
  2. Patients with other uncontrolled infections
  3. Patients who are less than 28 days removed from their allogeneic hematopoietic stem cell transplant or who have received donor lymphocyte infusions (DLI) within 28 days.
  4. Evidence of GVHD >= grade 2
  5. Active and uncontrolled relapse of malignancy
  6. Requirement for FiO2 (fraction of inspired oxygen) > 50% oxygen to maintain arterial oxygen saturation > 90%.Note: patients requiring oxygen at FiO2<=50% to maintain arterial oxygen saturation >90% are eligible to receive VSTs if the reason for this oxygen requirement is believed attributable to the virus being treated

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its identifier (NCT number): NCT04013802

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Contact: John Craddock, MD 832-824-1583
Contact: Kim Mooney-McGee 832-824-1589 Kimberly.Mcgee-Mooney@Bcm.Edu

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United States, Texas
Houston Methodist Hospital Recruiting
Houston, Texas, United States, 77003
Contact: George Carrum, MD    713-441-1450   
Principal Investigator: George Carrum, MD         
Texas Children's Hospital Recruiting
Houston, Texas, United States, 77030
Contact: John Craddock, MD    832-824-4723    John.Craddock@Bcm.Edu   
Principal Investigator: John Craddock, MD         
Sponsors and Collaborators
Baylor College of Medicine
The Methodist Hospital Research Institute
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Principal Investigator: John Craddock, MD Baylor College of Medicine
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Responsible Party: John Craddock, Associate Professor, Baylor College of Medicine Identifier: NCT04013802    
Other Study ID Numbers: H-44843 TETRAVI
First Posted: July 10, 2019    Key Record Dates
Last Update Posted: March 10, 2021
Last Verified: March 2021
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: No
Keywords provided by John Craddock, Baylor College of Medicine:
cytomegalovirus (CMV)
BK virus
Epstein-Barr virus (EBV)
Additional relevant MeSH terms:
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Communicable Diseases
Adenoviridae Infections
Virus Diseases
DNA Virus Infections