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

2018-07-26 12:30:16 | BioPortfolio

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.

Description

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. To implement the design's model using the latest EffTox version 4.0.12 program, doses will coded numerically to be 1, 2, 3.

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

1. 1x107/m2

2. 2.0x107/m2

3. 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

At each dose level, two to six patients will be treated and observed for 45 days for toxicity, dose escalation and for GvHD. If one of the initial cohort of two patients experience Dose Limiting Toxicity (DLT), then four additional patients will be treated at this dose level. If two or more the six patients experience DLT, then this dose level will be considered unacceptable toxicity and the number of infused CTL will be de-escalated unless we are at the initial dosing levels. If 1x107CTL/m2 results in unacceptable toxicity, the study will be closed to accrual.

The MTD of infused CMV/AdV/EBV/BKV-specific CTL

The MTD of infused CMV/AdV/EBV-specific CTL will be that number at which DLT is observed in at most one of six patients and the next higher dose presents unacceptably toxic, as defined above. If the highest number of CTL safely infused is 5x107/m2 per dose, then no MTD exists among these dosing levels. Note: at least six patients must be treated at the 5x107/m2 dose level.

Study Design

Conditions

CMV, EBV, BK Virus and Adenovirus Infection After Cord Blood Transplant

Intervention

CMV/AdV /EBV/BKV specific T cells

Location

Childrens National Medical Center
Washington
District of Columbia
United States
20010

Status

Recruiting

Source

Children's Research Institute

Results (where available)

View Results

Links

Published on BioPortfolio: 2018-07-26T12:30:16-0400

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