Hematologic Malignancy
Conditions
Keywords
Hematopoietic Cell Transplant
Brief summary
This is a phase I, prospective clinical trial studying the safety and feasibility of providing early memory T-cell DLI. The primary objective is: \- To assess the safety and feasibility of early CD45RA-depleted DLI administration. The secondary objectives are * To assess the safety and feasibility of the addition of blinatumomab in the early post-transplant period in patients with CD19+ malignancy. * To measure and describe the pharmacokinetics of rabbit ATG in HCT recipients on this study.
Detailed description
The purpose of the study is to learn more about the effects (good and bad) of transplanting progenitor (blood making) cells and donor lymphocytes (white blood cells) donated by a partially matched family member that have been modified in a laboratory, to children and young adults with a high risk cancer that is in remission but is at high risk of relapse. This study builds upon what we have learned from recently completed studies and will be testing the safety and effects of the chemotherapy and the combination of two different types of blood cell infusions on the transplant recipient's disease and overall survival. In this study, participants with high-risk hematologic malignancies who lack an available suitable human leukocyte antigen (HLA) matched related/sibling donor (MSD) or matched unrelated donor (MUD), will undergo allogeneic hematopoietic cell transplantation (HCT) consisting of a TCRαβ-depleted haploidentical donor product with additional memory cell donor lymphocyte infusion (DLI) given in the early postHCT time period. Prior to the infusion of donor cells, a preparative regimen consisting of antibodies and chemotherapy will be given. The preparative regimen includes the following total dosages: ATG 5mg/kg (over days -12 to -10); Cyclophosphamide 60 mg/kg (day -9); Fludarabine 150 mg/m2 (over days -8 to -4); Thiotepa 10 mg/kg (divided in two doses on day -3); Melphalan 70 mg/m2 (over days -2 to -1). Following this regimen the TCRαβ-depleted haploidentical donor product will be given on day 0 (subsequent infusion given on day +1 if needed to achieve goal CD34+ cell dose. Approximately 2 weeks later the memory cell donor lymphocyte infusion (DLI) will be given at a dose previously determined to be safe and effective. Blinatumomab will be empirically added for patients with CD19+ malignancy and given at least four weeks after the memory cell DLI.
Interventions
DRUGThymoglobulin
IV
DRUGCyclophosphamide
IV
DRUGFludarabine
IV
DRUGThiotepa
IV
DRUGMelphalan
IV
DRUGMesna
IV
DRUGFilgrastim
IV
DRUGBlinatumomab
IV
DEVICECliniMACS
The mechanism of action of the CliniMACS Cell Selection System is based on magnetic-activated cell sorting (MACS). The CliniMACS device is a powerful tool for the isolation of many cell types from heterogeneous cell mixtures, (e.g. apheresis products). These can then be separated in a magnetic field using an immunomagnetic label specific for the cell type of interest.
Sponsors
St. Jude Children's Research Hospital
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
No minimum to 21 Years
Healthy volunteers
Yes
Inclusion criteria
Recipient: * Age less than or equal to 21 years * High risk hematologic malignancy whereas allogeneic transplantation is the current standard of care. This includes (but is not limited to): * High risk ALL in CR1 or CR2, * any ALL in CR3 or subsequent; * AML in high risk CR1 (AML diagnosis includes myeloid sarcoma), * any AML in CR2 or subsequent, * any therapy related AML; * MDS (primary or secondary), * NK cell, biphenotypic, or undifferentiated leukemia/lymphoma in CR1 or subsequent; * CML in accelerated phase, or in chronic phase with persistent molecular positivity or intolerance to tyrosine kinase inhibitor, or a history of blast crisis. * If prior CNS leukemia, it must be treated and in CNS CR * Left ventricular ejection fraction \> 40%, or shortening fraction ≥ 25% * Creatinine clearance (CrCl) or glomerular filtration rate (GFR) ≥ 50 ml/min/1.73m2 * Forced vital capacity (FVC) ≥ 50% of predicted value; or pulse oximetry ≥ 92% on room air if patient is unable to perform pulmonary function testing * Karnofsky or Lansky (age dependent) performance score ≥ 50 (See APPENDIX A) * Bilirubin ≤ 3 times the upper limit of normal for age * Alanine aminotransferase (ALT) or Aspartate aminotransferase (AST) ≤ 5 times the upper limit of normal for age Donor: * At least single haplotype matched (≥ 4 of 8) family member * At least 18 years of age * HIV negative * Regarding donation eligibility, is identified as either: * Completed the process of donor eligibility determination as outlined in 21 CFR 1271 and agency guidance; OR * Does not meet 21 CFR 1271 eligibility requirements, but has a declaration of urgent medical need completed by the principal investigator or physician sub-investigator per 21 CFR 1271
Exclusion criteria
Recipient: * Has a suitable HLA-identical sibling or suitable 12/12 (HLA-A, B, C, DRB1, DQB1, and DPB1) HLA-matched unrelated donor available in an appropriate time frame. * Any other active malignancy other than the one for which this HCT is indicated * Received a prior allogeneic HCT at any time * Received an autologous HCT within the previous 6 months * Pregnant, if female is of childbearing potential, negative test must be confirmed by serum or urine pregnancy test within 14 days prior to enrollment * Breast feeding * Any current uncontrolled bacterial, fungal or viral infection Donor: * Pregnant, negative test must be confirmed by serum or urine pregnancy test within 14 days prior to enrollment if female * If female, breast feeding
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of participants experiencing grade 3-4 GVHD and/or transplant related mortality (TRM). | Within 100 days post-transplant infusion | Safety will be measured by monitoring for the incidence of grade 3-4 GVHD as well as any transplant related mortality experience. Feasibility monitoring will include 1) failure to receive protocol directed DLI among the evaluable participants; and 2) the number of days from transplant infusion to DLI infusion among evaluable participants. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of participants experiencing safety issues or feasibility concerns related to blinatumomab administration. | Within 180 days post-transplant infusion | Safety and feasibility will be measured by monitoring for any early discontinuation of blinatumomab. |
| Describing pharmacokinetics of rabbit ATG in participants. | Within 14 days post-transplant infusion | Measuring concentration of rabbit ATG levels in participants at the specified time points within the protocol. |
Countries
United States
Contacts
CONTACTBrandon Triplett, MD
PRINCIPAL_INVESTIGATORBrandon Triplett, MD
St. Jude Children's Research Hospital
Outcome results
None listed