Adoptive Cord Blood Immunotherapy for EBV, CMV, BKV and Adenovirus Reactivation/Infection or Prophylaxis

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ClinicalTrials.gov Identifier: NCT03594981

Recruitment Status : Recruiting

First Posted : July 23, 2018

Last Update Posted : February 3, 2023

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View this study on Beta.ClinicalTrials.gov

Sponsor:

Collaborator:

M.D. Anderson Cancer Center

Information provided by (Responsible Party):

Catherine Bollard, Children's National Research Institute

Study Description

Brief Summary:

This Phase I-II dose-finding trial to determine the optimal dose of intravenous (IV) injection dose of donor-derived cytotoxic T lymphocytes (CTLs) specific for CMV, EBV, BKV and Adenovirus. A maximum of 36 patients will be treated in up to 18 cohorts each of size 2, with the first cohort treated at the lowest dose level 1, all successive doses chosen by the EffTox method, and no untried dose level skipped when escalating.

The scientific goal of the trial is to determine an optimal IV-CTL cell dose level among the three doses 1.0x107cells/m2, 2 x107cells/m2 and 5x107cells/m2., hereafter dose levels 1, 2, 3. Dose-finding will be done using the sequentially adaptive EffTox trade-off-based design of Thall et al.

Condition or disease	Intervention/treatment	Phase
Viral Infection	Biological: CMV/AdV /EBV/BKV specific T cells	Phase 1 Phase 2

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Detailed Description:

CMV/AdV /EBV/BKV specific T cells will be thawed and given or thawed and diluted into a total volume of 10 mL of Plasmalyte A by slow intravenous injection over 1-2 minutes. This is a traditional Phase I dose escalation study of a single infusion of CMV/AdV/EBV/BKV-specific CTLs to patients at risk for CMV and EBV reactivation and Adenoviral and BK virus infection after umbilical cord blood transplantation. Three dose levels will be explored. The lowest dose level will be 1x107cells/m2 and the highest will be 5x107/m2. There will be 2-6 patients at each dose level (depending on toxicity) following the scheme below. The decision on whether it is safe to escalate to next dose level or not will be made after at least two patients in each dose level have finished their 45-days toxicity follow up. If the first two patients have not finished their 45 days follow-up, up to 2 additional incoming patients can be enrolled at the current dose level. In addition, we will give the option of administering 2 additional doses (at the same dose level), 28 days after the first infusion of the same dose, in subjects who have a partial response after one dose or who have received other therapy that may affect the persistence or function of the infused CTL in vivo. If there are no toxicities and immunological efficacy is not seen at any dose, then the doses will be further escalated after additional local and federal approval.

Dose Levels and Dosing Schedule

Dose Level CTL Dose Given from Day +30 post SCT

1x107/m2
2.0x107/m2
5x107/m2

Escalation of Multi-virus-specific CTL infusions

CMV/AdV/EBV/BKV CTL will be given from day +30 either as prophylaxis or treatment for CMV, EBV, BK and/or adenovirus infection. If the patient has viral reactivation or evidence of CMV/EBV/AdV/BKV disease (e.g. pneumonitis, gastroenteritis and/or retinitis or Post Transplant Lymphoproliferative Disorder (PTLD) or hemorrhagic cystitis the CTL can be given with concurrent antiviral pharmacotherapy.

A dose escalation scheme utilizing cohorts of two patients will be used

Each cohort of 2 patients will be treated and observed for 45 days for toxicity, dose escalation, and GvHD. The algorithm described in Section 9 will be used to determine the dose for each cohort. If 1x107CTL/m2 results in unacceptable toxicity or efficacy, the study will be closed to accrual.

The Optimal Dose of Infused CMV/AdV/EBV/BKV-Specific CTL

After all patients in the trial have been evaluated, the optimal dose of infused CMV/AdV/EBV-specific CTL will be determined by the algorithm using the sequentially adaptive EffTox trade-off-based design of Thall et al.

Study Design

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Study Type :	Interventional (Clinical Trial)
Estimated Enrollment :	36 participants
Allocation:	N/A
Intervention Model:	Single Group Assignment
Masking:	None (Open Label)
Primary Purpose:	Treatment
Official Title:	Adoptive Cord Blood ImmunotHerapy Using Expanded Cord Blood T Cells for EBV, CMV, BKV and Adenovirus Reactivation/Infection or ProphylaxiS
Actual Study Start Date :	January 24, 2018
Estimated Primary Completion Date :	July 2024
Estimated Study Completion Date :	November 2025

Arms and Interventions

Arm	Intervention/treatment
Experimental: CMV/AdV /EBV/BKV specific T cells CMV/AdV /EBV/BKV specific T cells will be thawed and transferred to a syringe given by slow intravenous injection over 1-2 minutes. Three dose levels will be explored. The lowest dose level will be 1x107cells/m2 and the highest will be 5x107/m2.	Biological: CMV/AdV /EBV/BKV specific T cells Each cohort of 2 patients will be treated and observed for 45 days for toxicity, dose escalation, and GvHD. The algorithm of sequentially adaptive EffTox trade-off-based design of Thall et al will be used to determine the dose for each cohort. If 1x107CTL/m2 results in unacceptable toxicity or efficacy, the study will be closed to accrual.

Outcome Measures

Primary Outcome Measures :

Number of participants with investigational product-related adverse events as assessed by CTCAE v4.03 [ Time Frame: 45 days for toxicity ]
The study will determine the optimal dose of intravenous injection of donor-derived cytotoxic T lymphocytes (CTLs) specific for CMV, EBV, Adenovirus and BK virus( BKV) given to patients with or at risk for CMV, EBV, BK virus and adenovirus infection after cord blood transplant. The safety will be assessed by investigational product-related adverse events as per CTCAE v4.03.

Secondary Outcome Measures :

Impact of CMV/AdV /EBV/BKV specific T cells will be measured by existence of cells in the system. [ Time Frame: 12 months ]
To evaluate the impact of CTLs on CMV/AdV /EBV/BKV -specific T-lymphocyte immune reconstitution. The impact will be evaluated by the number of months/years of cell survival.

Eligibility Criteria

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

Criteria

Inclusion Criteria:

Inclusion Criteria at the Time of Procurement

Pediatric and adult patients (there are no lower and upper age limits for patients) with malignant or nonmalignant diseases who are candidates for transplant.
Patients must have a CB unit (or units) matched with the patient at 4, 5, or 6/6 HLA class I (serological) and II (molecular) antigens. The unit selected for CTL expansion must be either:
1. be cryopreserved in two fractions, with a minimum of 2.5x107 total nucleated cells (TNC) per kg pre-thaw in the fraction which will be used for the primary transplant. The remaining fraction will be used to generate the CTLs to give at day 30 or beyond as described below. OR
2. be cryopreserved with a cell dose that totals > 3x10e7 TNC per kg pre thaw. On thaw, 20% of the total volume will be used for CTL manufacture to give at day 30 or beyond and the remaining 80% will be used for the primary transplant.
3. For recipients of double CBT, if possible both CB units should be cryopreserved in two fractions and T-cells will be made from both units if possible.

Inclusion Criteria at the Time of CTL Infusion

Recipients of at least one unmanipulated cord blood unit as described above (i.e. from a HLA matched or mismatched unrelated donor) transplant at risk for or with CMV/Adenoviral/BKV and/or EBV infection or reactivation.
Lansky/Karnofsky scores ≥60
Absolute neutrophil count (ANC) greater than 500/u
No evidence of GVHD > Grade II at time of enrollment
Life expectancy > 30 days
Absence of severe renal disease (Creatinine < 3x normal for age)
Absence of severe hepatic disease. Direct bilirubin must be < 3 mg/dl and AST < 5x upper limit of normal
Patient must be at least 30 days post transplant to be eligible to receive CTL
Written informed consent and/or signed assent line from patient, parent or guardian

Exclusion Criteria:

Exclusion Criteria at the Time of Procurement

Pregnant or lactating
Patients with active central nervous system disease
Patients with Karnofsky performance status <70%
Patients with grade 3 or 4 or primary myelofibrosis
Patients with suitable related donors Exclusion Criteria at the Time of CTL Infusion
Pregnant or lactating
Patient on Fi02 of >60%
Unable to wean steroids to ≤0.5 mg/kg/day prednisone or equivalent
Patients with Grade 3 hyperbilirubinemia
Patients with other uncontrolled infections (except CMV and/or adenovirus and/or EBVemia and/or BK viruria/viremia). 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 attributable to sepsis or new symptoms, 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 less than 50% donor chimerism in either peripheral blood or bone marrow or patients with relapse of original disease
Patients who have received investigational (IND) product within 28 days of screening for CTL infusion under this study

Contacts and Locations

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 ClinicalTrials.gov identifier (NCT number): NCT03594981

Contacts

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Contact: Allistair Abraham, MD	202-476-5772	AAbraham@childrensnational.org
Contact: Fahmida Hoq, MBBS, MS	202-476-334	fhoq@childrensnational.org

Locations

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United States, District of Columbia
Children's National Health System	Recruiting
Washington, District of Columbia, United States, 20010
Contact: Fahmida Hoq, MBBS, MS 202-476-3634 fhoq@childrensnational.org
Principal Investigator: Allistair Abraham, MD
United States, Texas
M.D. Anderson Cancer Center (MDACC)	Recruiting
Houston, Texas, United States, 77030
Contact: Amanda Olson, MD
Principal Investigator: Amanda Olson, MD

Sponsors and Collaborators

Catherine Bollard

M.D. Anderson Cancer Center

More Information

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Responsible Party:	Catherine Bollard, Director, Center for Cancer and Immunology/ Center for Emerging Technologies in Immune Cell Therapies (CETI), Children's National Research Institute
ClinicalTrials.gov Identifier:	NCT03594981
Other Study ID Numbers:	CHEERS
First Posted:	July 23, 2018 Key Record Dates
Last Update Posted:	February 3, 2023
Last Verified:	February 2023
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

Additional relevant MeSH terms:

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Infections Communicable Diseases Virus Diseases Disease Attributes Pathologic Processes

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