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

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.

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 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.