Hematologic Malignancies
Conditions
Keywords
allogeneic donor, Lymphocyte Infusion
Brief summary
This study is being done to assess the safety and determine the maximum tolerable dose (MTD) of TCRαβ+/CD19+-depleted Donor Lymphocyte Infusion (αβT/B dep-DLI) after allogeneic stem cell transplant (allo-SCT) in highrisk patients with hematologic malignancies.
Detailed description
Primary Objectives * To assess safety of prophylactic TCRαβ+/CD19+ depleted donor lymphocyte infusion (αβT/B dep-DLI) after allogeneic stem cell transplant (allo-SCT) in high-risk patients with hematologic malignancies * To determine the maximum tolerated dose (MTD) or maximum administered dose (MAD) of αβT/B dep-DLI Secondary Objectives * To assess the feasibility of αβT/B dep-DLI * To assess additional safety parameters after αβT/B dep-DLI * To assess the efficacy of αβT/B dep-DLI For the dose escalation phase: Maximum Tolerated Dose (MTD) and Maximum Administered Dose (MAD) is defined as the highest dose level where less than 2 of 6 participants experience a dose limiting toxicity (DLT). Each dose level will be followed for DLTs until day 28 post donor lymphocyte infusion (DLI). Starting at dose level 1: * If 0 of 3 participants experiences DLT, increase to next dose level for next 3 participants. * If 1 of 3 participants experience DLT, enroll 3 participants at same dose level. * If no additional DLTs (1 of 6), move on to next dose level. * If 2 of 6 participants experience DLT, enroll 3 participants into lower dose level. * If 0 or 1 participants experience DLT at lower level, this will be the MTD. Once the MTD or MAD is determined, an expansion cohort will be enrolled into that dose level. All participants will be followed for 2 years after DLI.
Interventions
DEVICEAllogeneic donor TCRαβ+/CD19+ cell-depleted peripheral blood mononuclear cells
Single intravenous dose of allogeneic donor TCRαβ+/CD19+ cell-depleted peripheral blood mononuclear cells (i.e., αβT/B dep-DLI), where the dose is based on the natural killer (NK) cell (CD3-CD56+) content in the DLI product. Each participant will receive one of four DLI doses depending upon cohort to which the participant is enrolled.
Sponsors
University of Wisconsin, Madison
Miltenyi Biomedicine GmbH
Study design
Allocation
NON_RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
This is a single-center, phase I 3x3 dose-escalation study with expansion cohort, open label, non-randomized, non-placebo controlled, single-group assignment study.
Eligibility
Sex/Gender
ALL
Age
18 Years to 80 Years
Healthy volunteers
No
Inclusion criteria
* Patients with high-risk myeloid or lymphoid malignancies determined to be eligible to undergo allo-SCT including but not limited to the conditions listed below. These criteria apply at the disease diagnosis or any time prior to the cyto-reductive therapy given before the planned conditioning: * Refractory acute myelogenous (AML) or lymphoid leukemia (ALL) * Relapsed AML or ALL * AML in European LeukemiaNet (ELN) high risk per cytogenetic and mutation * Any patients with minimal residual disease (MRD+) disease by flow cytometry or with active disease (not in complete remission (CR)) prior to allo-SCT * Myelodysplastic syndromes (MDS) with 5% or more blasts at initial diagnosis, or anytime during their treatment prior to allo-SCT. * Myelodysplastic syndrome (MDS) high risk or very high risk per Revised International Prognostic Scoring System (IPSS-R) or Molecular International Prognostic Scoring System (IPSS-M) * Chronic myelogenous leukemia (CML) in chronic phase failed 3 or more treatments, in accelerated or blast phase * High risk primary myelofibrosis (PMF) per Dynamic International Prognostic Scoring System (DIPSS)-plus or Mutation-enhanced International Prognostic Scoring System for Transplant-age Patients (MIPSS70+) * PMF in accelerated or blast phase * Recurrent or refractory malignant lymphoma or Hodgkin's disease with less than a partial response at transplant * High risk chronic lymphocytic leukemia defined as no response or stable disease to the most recent treatment regimen * Other high risk hematologic malignancies for which allo-SCT is deemed clinically necessary per PI and based on institutional standards * The donor for the allo-SCT must be: * Related AND * Matched OR mismatched OR haploidentical at HLA-A, -B, -C, and -DRB1 by molecular methods * ECOG performance score of 0-2 * Ability to understand and willingness to sign written informed consent document * Willing to comply with all study procedures and be available for the duration of the study * Individuals in sexual relationships that could result in pregnancy or impregnation of their partner must use an acceptable method of contraception§ from enrollment until 4 weeks after completing study treatment.
Exclusion criteria
• Poor organ function as follows (According to the pre-transplant workups results): * Creatinine ≥ 2.0 mg/dL * SGOT and SGPT ≥ 5 x ULN. Liver biopsy per clinician discretion. * Bilirubin ≥ 3 x ULN (unless Gilbert's syndrome) * DLCO \< 50% corrected for hemoglobin * Left ventricular ejection fraction or shortening fraction \< 40% NOTE: Exceptions to the above organ function
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Incidence of Adverse Events (AEs) from DLI to day 28 post-DLI | up to day 28 post-DLI (approximately day 63 on study) | To assess safety of prophylactic TCRαβ+/CD19+ depleted donor lymphocyte infusion (αβT/B dep-DLI) after allogeneic stem cell transplant (allo-SCT) in high-risk patients with hematologic malignancies, incidence of AEs will be reported. |
| Maximum Tolerated Dose or Maximum Administered Dose | up to day 28 post-DLI (approximately day 63 on study) | MTD/MAD defined as the highest dose level at which less than 2 of 6 participants experience a DLT. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Incidence of grade II-IV acute Graft-versus-Host Disease (aGVHD) after αβT/B dep-DLI | up to day 28 post-DLI (approximately day 63 on study) | To assess additional safety parameters after allo-SCT in high-risk patients with hematologic malignancies, Incidence of grade II-IV aGVHD after αβT/B dep-DLI will be reported. |
| Cumulative incidence of severe grade III-IV aGVHD after αβT/B dep-DLI | up to day 28 post-DLI (approximately day 63 on study) | To assess additional safety parameters after allo-SCT in high-risk patients with hematologic malignancies, cumulative incidence of severe grade III-IV aGVHD after αβT/B dep-DLI will be reported. |
| Chronic Graft-versus-Host Disease (GVHD) incidence after αβT/B dep-DLI | up to day 28 post-DLI (approximately day 63 on study) | To assess additional safety parameters after allo-SCT in high-risk patients with hematologic malignancies, chronic GVHD incidence after αβT/B dep-DLI will be reported. |
| Efficacy assessed by 1 year Progression Free Survival (PFS) | up to 1 year | To assess the efficacy of prophylactic αβT/B dep-DLI after allo-SCT in high-risk patients with hematologic malignancies, 1 year PFS will be reported. |
| Efficacy Assessed by Non-Relapse Mortality | up to 2 years | To assess the efficacy of prophylactic αβT/B dep-DLI after allo-SCT in high-risk patients with hematologic malignancies, non-relapse mortality will be reported. |
| Efficacy Assessed by Overall Survival | up to 2 years | To assess the efficacy of prophylactic αβT/B dep-DLI after allo-SCT in high-risk patients with hematologic malignancies, overall survival will be reported. |
| Efficacy Assessed by Incidence of Cytomegalovirus (CMV) Reactivation | up to 2 years | To assess the efficacy of prophylactic αβT/B dep-DLI after allo-SCT in high-risk patients with hematologic malignancies, incidence of CMV Reactivation will be reported. |
| Efficacy Assessed by Incidence of Fungal Infection | up to 2 years | To assess the efficacy of prophylactic αβT/B dep-DLI after allo-SCT in high-risk patients with hematologic malignancies, incidence of fungal infections will be reported. |
| Efficacy Assessed by Incidence of Full Chimerism (CD3 compartment) | up to 2 years | To assess the efficacy of prophylactic αβT/B dep-DLI after allo-SCT in high-risk patients with hematologic malignancies, incidence of full chimerism will be reported. |
| Efficacy Assessed by Immunoglobulin Levels | up to 2 years | To assess the efficacy of prophylactic αβT/B dep-DLI after allo-SCT in high-risk patients with hematologic malignancies, quantitative immunoglobulin levels will be reported. |
| Efficacy Assessed by Lymphocyte Panel Analysis | up to 2 years | To assess the efficacy of prophylactic αβT/B dep-DLI after allo-SCT in high-risk patients with hematologic malignancies, lymphocyte subset panel analysis will be conducted and reported. |
| Feasibility assessed by percentage of enrolled participants who are able to receive depleted DLI | up to approximately 35 days | To assess the feasibility of prophylactic αβT/B dep-DLI after allo-SCT in high-risk patients with hematologic malignancies, the percentage of enrolled participants who are able to receive depleted DLI will be reported. |
Countries
United States
Contacts
CONTACTCancer Connect
STUDY_DIRECTORJacques Galipeau, MD, FRCP(C)
UW School of Medicine and Public Health
PRINCIPAL_INVESTIGATORHongtao Liu, MD, PhD
UW Carbone Cancer Center
Outcome results
None listed