Clinical Trials /

Haploidentical Stem Cell Transplant With Prophylactic Natural Killer DLI for Lymphoma, Multiple Myeloma, and CLL

NCT03524235

Description:

This study seeks to examine the investigational use of the conditioning regimen (bendamustine, fludarabine, and rituximab) prior to haploidentical peripheral blood allogeneic stem cell transplantation with Post-Transplant Cyclophosphamide. The study will also test the investigational use of CD56-enriched Donor Lymphocyte Infusion to see if this treatment is safe, and whether or not it will help patients achieve better outcomes post-transplant, including reduced risk of Graft-Versus-Host Disease (GVHD), and preventing disease relapse.

Related Conditions:
  • Chronic Lymphocytic Leukemia
  • Diffuse Large B-Cell Lymphoma
  • Double-Hit Lymphoma
  • Hodgkin Lymphoma
  • Mantle Cell Lymphoma
  • Mature T-Cell and NK-Cell Non-Hodgkin Lymphoma
  • Multiple Myeloma
  • Non-Hodgkin Lymphoma
  • Plasma Cell Leukemia
  • Triple-Hit Lymphoma
Recruiting Status:

Recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: Haploidentical Stem Cell Transplant With Prophylactic Natural Killer DLI for Lymphoma, Multiple Myeloma, and CLL
  • Official Title: IIT2017-03-Merin-HaploBFR: Bendamustine, Fludarabine, And Rituximab Conditioning For Haploidentical Stem Cell Transplantation With CD56-Enriched Donor Cell Infusion For Relapsed/Refractory Lymphoma, Multiple Myeloma, and CLL

Clinical Trial IDs

  • ORG STUDY ID: IIT2017-03-Merin-HaploBFR
  • NCT ID: NCT03524235

Conditions

  • Multiple Myeloma
  • CLL
  • Chronic Lymphocytic Leukemia
  • Lymphoma
  • Hodgkin Lymphoma

Interventions

DrugSynonymsArms
CD56-Enriched Donor Lymphocyte InfusionSubjects
BendamustineBendeka; TreandaSubjects
FludarabineFludaraSubjects
RituximabRituxanSubjects

Purpose

This study seeks to examine the investigational use of the conditioning regimen (bendamustine, fludarabine, and rituximab) prior to haploidentical peripheral blood allogeneic stem cell transplantation with Post-Transplant Cyclophosphamide. The study will also test the investigational use of CD56-enriched Donor Lymphocyte Infusion to see if this treatment is safe, and whether or not it will help patients achieve better outcomes post-transplant, including reduced risk of Graft-Versus-Host Disease (GVHD), and preventing disease relapse.

Detailed Description

      This is a single center Phase I trial of a new haploidentical stem cell transplant regimen
      intended to assess safety. Two groups of patients are planned: patients with lymphoma and
      patients with multiple myeloma. Each subject will receive a haploidentical stem cell
      transplantation using peripheral blood stem cells. Bendamustine-fludarabine-rituximab-TBI
      conditioning will be used, followed by stem cell infusion, with Post-Transplant
      Cyclophosphamide and tacrolimus for GVHD prophylaxis. Patients will receive a CD56-selected
      DLI on day +8. Evaluations will be taken at baseline and at each of the study visits.
      Screening data will be reviewed to determine subject eligibility. Subjects who meet all
      inclusion criteria and none of the exclusion criteria will be entered into the study. Total
      duration of subject participation will be one year. Total duration of the study is expected
      to be three years.
    

Trial Arms

NameTypeDescriptionInterventions
SubjectsExperimentalPre-Transplantation Conditioning (Bendamustine, Fludarabine, and Rituximab + Total Body Irradiation) + Haploidentical Stem Cell Transplantation with CD56-enriched donor lymphocyte infusion
  • CD56-Enriched Donor Lymphocyte Infusion
  • Bendamustine
  • Fludarabine
  • Rituximab
ControlsNo InterventionPatients undergoing standard-of-care reduced-intensity peripheral blood allogeneic stem cell transplantation (any indication, donor source, conditioning regimen) using PTCy GVHD prophylaxis.

    Eligibility Criteria

            General Inclusion Criteria (For Treatment Groups)
    
              -  Patient age 18 - 75 years
    
              -  ECOG 0 - 2
    
              -  HIV-positive patients are allowed if these criteria are met:
    
                   1. No history of opportunistic infections
    
                   2. CD4+ cell count greater or equal to 250 cells/mm3
    
                   3. No history of non-malignancy AIDS-defining conditions other than historical low
                      CD4+ cell counts
    
                   4. Patient is on antiretroviral therapy with undetectable viral load. There must be
                      minimal interactions of the antiviral therapy with the experimental treatment
                      (antiretroviral such as ritonavir is potent CYP3A4 inhibitor and p-gp inducer may
                      interact with tacrolimus resulted in increased serum concentration of
                      tacrolimus).
    
              -  Patients must have a related donor or who is at minimum HLA haploidentical. The donor
                 and recipient must be identical at least one allele of each of the following genetic
                 loci: HLA-A, HLA-B, HLA-Cw, HLA-DRB1, and HLA-DQB1. A minimum match of 5/10 is
                 therefore required, and will be considered sufficient evidence that the donor and
                 recipient share one HLA haplotype. An unrelated donor search is not required.
                 (Patients with a readily-available, suitable, fully-matched sibling donor less than
                 age 55 are not eligible for this trial, these patients should proceed to transplant
                 using the matched related donor as standard-of-care).
    
            Criteria for Donor Eligibility
    
              -  Age greater than 12 years
    
              -  Donors must meet the selection criteria as defined by the Foundation for the
                 Accreditation of Hematopoietic Cell Therapy (FACT).
    
              -  In the event that two or more eligible donors are identified, the following order of
                 priority will be used to determine the preferred donor:
    
                   -  Medically and psychologically fit and willing to donate
    
                   -  For CMV seronegative recipients, a CMV seronegative donor
    
                   -  Red blood-cell compatibility
    
                        -  RBC cross-match compatible
    
                        -  Minor ABO incompatibility
    
                        -  Major ABO incompatibility
    
              -  If more than one preferred donor is identified and there is no medical, HLA- or KIR
                 ligand reason to prefer one of them, then the following guidelines are recommended:
    
            If the patient is male, choose a male donor:
    
              -  Choose the youngest preferred donor
    
              -  If the patient and family express a strong preference for a particular donor, use that
                 one.
    
            Inclusion Criteria (Lymphoma)
    
              -  Diagnosis of resistant or relapsed CLL, Non-Hodgkin Lymphoma, Hodgkin Lymphoma, T-cell
                 lymphoma, NK or NK/T Lymphoma.
    
              -  Meets one of the following criteria:
    
                   -  relapsed after auto-transplant, or
    
                   -  failed to mobilize autologous stem cells, or
    
                   -  for whom allogeneic stem cell transplant is deemed appropriate given disease risk
                      factors that make cure with autologous transplant seem unlikely, such as history
                      of chemotherapy refractoriness, high risk disease
                      features/mutations/translocations (e.g., Double Hit / Double Expressor DLBCL),
                      short remission after prior chemotherapy, or histologic transformation (see
                      below).
    
              -  For Patients with Aggressive Mantle Cell and Diffuse Large B Cell Lymphoma who have
                 not had a prior autologous transplant:
    
                   -  Must have received at least 2 lines of prior therapy, and
    
                   -  Have been exposed to anthracycline, and
    
                   -  High and High-Intermediate aaIPI score (2 or 3 factors), and
    
                   -  Have relapsed within one year of primary therapy
    
              -  For diagnosis of other aggressive lymphoma (e.g. NK/T Lymphoma, T Cell
    
            Lymphoma, etc.):
    
              -  Must have received at least 2 lines of prior therapy, and
    
              -  Relapsed within 12 months of most recent therapy
    
                   -  For low-grade lymphomas / CLL:
    
                   -  Standard risk patients (absence of del(17p), absence of del(11q), no TP53
                      mutation and absence of complex karyotype) must have progressed on BCR inhibitor,
                      or undergone histologic transformation, to be eligible.
    
                   -  Patients with high risk disease (del(17p) or TP53 mutations and/or complex
                      phenotype) who relapse after frontline therapy, demonstrate refractory disease to
                      second line therapy (not BCR inhibitors), but show an objective response to BCR
                      inhibitors are eligible to be taken off BCR inhibitors in order to proceed to
                      alloHSCT on trial. Patients with high risk disease who relapse after frontline
                      therapy, demonstrate refractory disease to second line therapy including BCR
                      inhibitors (not BCL-2 inhibitors), but show an objective response to BCL-2
                      inhibitors (venetoclax) are eligible to be taken off BCL-2 inhibitors in order to
                      proceed to alloHSCT on trial.
    
                   -  For aggressive lymphomas, partial or complete remission (PR or CR) is required
                      prior to alloHSCT.
    
                   -  Regarding CD20 expression: Patients with B cell malignancies that were CD20+ at
                      any level at the time of relapse diagnosis (including partial / dim staining on
                      IHC or partial / low level expression by flow cytometry) will receive rituximab
                      as part of allogeneic transplant conditioning, if indicated. Patients with
                      primary-refractory disease who were CD20+ at any level at the time of diagnosis
                      will likewise receive rituximab, if indicated. Patients with histologies that
                      were CD20- will not receive rituximab (T cell lymphoma, NK/T lymphoma, etc.).
                      Fresh tissue / repeat biopsy is not required; the most recent biopsy will be
                      reviewed to assess CD20 status.
    
            Inclusion Criteria (Multiple Myeloma)
    
            - Patient age 18 - 75 years with:
    
              -  Early relapse (less than 24 months) after primary therapy that included an autologous
                 HSCT, or
    
              -  High risk multiple myeloma defined as t(4;14), del(17p), -13, t(14;16), amp (1q21),
                 chromosome 8q24.1/c-MYC abnormality, or LDH > ULN at diagnosis, provided patients
                 respond favorably to salvage therapy before enrollment for alloHSCT on trial and
                 patient is age < 55, or
    
              -  Patients failing to mobilize peripheral blood stem cells for autologous
                 transplantation, or
    
              -  Extramedullary disease at diagnosis or relapse, or
    
              -  Plasma-cell leukemia with chemosensitive disease
    
            Inclusion Criteria - Control Patients (specimen collection, only)
    
              -  Age 18-75 years
    
              -  Undergoing standard-of-care reduced-intensity peripheral blood allogeneic stem cell
                 transplantation (any indication, donor source, conditioning regimen) using PTCy GVHD
                 prophylaxis.
    
              -  Willing to provide longitudinal blood samples per Control Specimen Collection Calendar
                 for correlative studies (for comparison to specimens from patients treated on the
                 trial).
    
              -  Agrees to let study personnel collect excess bone marrow aspirate whenever a bone
                 marrow biopsy is performed for clinical purposes, and use for research.
    
            Exclusion Criteria
    
              -  Patient has a readily-available, suitable, fully-matched sibling donor (MRD) less than
                 age 55. 'Suitable' means no high-titre donor-specific antibodies present, and negative
                 IDM testing with no contraindications.
    
              -  Patient has a clinically-significant donor-specific antibody for the selected donor
                 (DSA clearance is not allowed).
    
              -  Poor cardiac function: left ventricular ejection fraction <45% as determined by MUGA
                 or ECHO.
    
              -  Symptomatic pulmonary disease. Poor pulmonary function: FEV1, FVC, and DLCO <50%
                 predicted (corrected for hemoglobin) for patients who have not received thoracic or
                 mantle irradiation. For patients who have received thoracic or mantle irradiation,
                 FEV1 and FVC <70% predicted or DLCO < 50 of predicted.
    
              -  Poor liver function: bilirubin >2 mg/dl (not due to hemolysis, Gilbert's or primary
                 malignancy). ALT or AST > 5 x laboratory upper normal limits.
    
              -  Poor renal function: Creatinine >2.0mg/dl or creatinine clearance (calculated
                 creatinine clearance is permitted) < 60 mL/min based on Traditional Cockcroft-Gault
                 formula
    
              -  Women of childbearing potential who currently are pregnant (Β-HCG+) or who are not
                 practicing adequate contraception.
    
              -  Uncontrolled viral, bacterial, or fungal infections. Patients with symptoms consistent
                 with RSV, influenza A, B, or parainfluenza at the time of enrollment will be assayed
                 for the above viruses and if positive are not eligible for the trial until they are no
                 longer symptomatic (patients may have continued assay positivity for a period of time
                 post resolution of symptoms secondary to the nature of the assay).
    
              -  Uncontrolled CNS involvement by malignancy (patients with prior history of CNS disease
                 controlled with intrathecal chemotherapy or prior systemic therapy are allowed).
    
              -  Patients who have any debilitating medical or psychiatric illness which would preclude
                 their giving informed consent or their receiving optimal treatment and follow-up.
    
            Exclusion Criteria - Control Patients (specimen collection, only)
    
              -  Undergoing myeloablative alloHSCT.
    
              -  Non-PTCy GVHD prophylaxis.
    
              -  Non-PBSC transplant (bone marrow stem cell source).
    
              -  Not willing to give longitudinal blood specimens for research use or not willing to
                 allow access to medical records for non-clinical purposes.
          
    Maximum Eligible Age:75 Years
    Minimum Eligible Age:18 Years
    Eligible Gender:All
    Healthy Volunteers:No

    Primary Outcome Measures

    Measure:Rate of Survival at 30 days post -transplantation
    Time Frame:30 Days
    Safety Issue:
    Description:Proportion of patients undergoing BFR-TBI conditioning + haploidentical alloHSCT alive at 30 days post-transplantation.

    Secondary Outcome Measures

    Measure:Rate of neutrophil engraftment at 30 days
    Time Frame:30 days
    Safety Issue:
    Description:Proportion of patients undergoing BFR-TBI conditioning + haploidentical alloHSCT with neutrophil engraftment at 30 days post-transplantation. -Neutrophil engraftment is defined as ANC recovery to >500/uL.
    Measure:Rate of platelet recovery at 100 days post-transplantation
    Time Frame:100 days
    Safety Issue:
    Description:Proportion of patients with platelets > 20/uL with no platelet transfusions within the prior 7 days at day 100 post-transplantation.
    Measure:Rate of severe chronic GVHD at 365 days post-transplantation
    Time Frame:365 days
    Safety Issue:
    Description:Proportion of patients with severe chronic GVHD at day 365 post-transplantation. -Severe chronic GVHD is defined by NIH Consensus Criteria for GVHD severity

    Details

    Phase:Phase 1
    Primary Purpose:Interventional
    Overall Status:Recruiting
    Lead Sponsor:Noah Merin

    Trial Keywords

    • Relapsed/Refractory Lymphoma
    • Multiple Myeloma
    • CLL
    • Bendamustine
    • Haploidentical Stem Cell Transplantation
    • GVHD
    • Allogeneic Stem Cell Transplantation
    • Natural Killer Cell
    • CliniMACS
    • Post-transplantation cyclophosphamide
    • Donor Lymphocyte Infusion
    • Minimal Residual Disease
    • Hodgkin Lymphoma

    Last Updated

    December 9, 2019