Clinical Trials /

Provision of TCRγδ T Cells and Memory T Cells Plus Selected Use of Blinatumomab in Naïve T-cell Depleted Haploidentical Donor Hematopoietic Cell Transplantation for Hematologic Malignancies Relapsed or Refractory Despite Prior Transplantation

NCT02790515

Description:

This study seeks to examine treatment therapy that will reduced regimen-related toxicity and relapse while promoting rapid immune reconstitution with limited serious graft-versus-host-disease (GVHD) and also improve disease-free survival and quality of life. The investigators propose to evaluate the safety and efficacy of selective naive T-cell depleted (by TCRɑβ and CD45RA depletion, respectively) haploidentical hematopoietic cell transplant (HCT) following reduced intensity conditioning regimen that avoids radiation in patients with hematologic malignancies that have relapsed or are refractory following prior allogeneic transplantation. PRIMARY OBJECTIVE: - To estimate engraftment by day +30 post-transplant in patients who receive TCRɑβ-depleted and CD45RA-depleted haploidentical donor progenitor cell transplantation following reduced intensity conditioning regimen without radiation. SECONDARY OBJECTIVES: - Assess the safety and feasibility of the addition of Blinatumomab in the early post-engraftment period in patients with CD19+ malignancy. - Estimate the incidence of malignant relapse, event-free survival, and overall survival at one-year post-transplantation. - Estimate incidence and severity of acute and chronic (GVHD). - Estimate the rate of transplant related mortality (TRM) in the first 100 days after transplantation.

Related Conditions:
  • Acute Lymphoblastic Leukemia
  • Acute Myeloid Leukemia
  • Juvenile Myelomonocytic Leukemia
  • Myelodysplastic Syndromes
  • Myeloid Sarcoma
  • Non-Hodgkin Lymphoma
Recruiting Status:

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Provision of TCRγδ T Cells and Memory T Cells Plus Selected Use of Blinatumomab in Naïve T-cell Depleted Haploidentical Donor Hematopoietic Cell Transplantation for Hematologic Malignancies Relapsed or Refractory Despite Prior Transplantation
  • Official Title: Provision of TCRγδ T Cells and Memory T Cells Plus Selected Use of Blinatumomab in Naïve T-cell Depleted Haploidentical Donor Hematopoietic Cell Transplantation for Hematologic Malignancies Relapsed or Refractory Despite Prior Transplantation

Clinical Trial IDs

  • ORG STUDY ID: REF2HCT
  • SECONDARY ID: NCI-2016-00812
  • NCT ID: NCT02790515

Conditions

  • Acute Lymphoblastic Leukemia (ALL)
  • Acute Myeloid Leukemia (AML)
  • Myeloid Sarcoma
  • Chronic Myeloid Leukemia (CML)
  • Juvenile Myelomonocytic Leukemia (JMML)
  • Myelodysplastic Syndrome (MDS)
  • Non-Hodgkin Lymphoma (NHL)

Interventions

DrugSynonymsArms
Anti-thymocyte globulin (rabbit)Thymoglobulin®, rabbit ATGTreatment
BlinatumomabBlincytoTreatment
CyclophosphamideCytoxanTreatment
FludarabineFludaraTreatment
G-CSFFilgrastim, Neupogen®Treatment
MelphalanL-phenylalanine mustard, Phenylalanine mustard, L-PAM, L-sarcolysin, AlkeranTreatment
MesnaMesnexTreatment
RituximabRituxanTreatment
TacrolimusFK506, Prograf®, Protopic®Treatment
ThiotepaThioplex® by Immunex, TESPA, TSPATreatment
HPC,A InfusionTransplantTreatment

Purpose

This study seeks to examine treatment therapy that will reduced regimen-related toxicity and relapse while promoting rapid immune reconstitution with limited serious graft-versus-host-disease (GVHD) and also improve disease-free survival and quality of life. The investigators propose to evaluate the safety and efficacy of selective naive T-cell depleted (by TCRɑβ and CD45RA depletion, respectively) haploidentical hematopoietic cell transplant (HCT) following reduced intensity conditioning regimen that avoids radiation in patients with hematologic malignancies that have relapsed or are refractory following prior allogeneic transplantation. PRIMARY OBJECTIVE: - To estimate engraftment by day +42 post-transplant in patients who receive TCRɑβ-depleted and CD45RA-depleted haploidentical donor 30ogenitor cell transplantation following reduced intensity conditioning regimen without radiation. SECONDARY OBJECTIVES: - Assess the safety and feasibility of the addition of Blinatumomab in the early post-engraftment period in patients with CD19+ malignancy. - Estimate the incidence of malignant relapse, event-free survival, and overall survival at one-year post-transplantation. - Estimate incidence and severity of acute and chronic (GVHD). - Estimate the rate of transplant related mortality (TRM) in the first 100 days after transplantation.

Detailed Description

      Blood progenitor cells will be obtained from a partially matched adult family member
      (donor). After processing and filtration using the CliniMACS device, cells will be infused
      into participants meeting eligibility criteria.

      Prior to transplant, participants will receive a conditioning treatment of rabbit ATG,
      cyclophosphamide, fludarabine, thiotepa, melphalan, and rituximab. Mesna will be given to
      help prevent side effects of cyclophosphamide. Tacrolimus will be given to help reduce the
      risk of GVHD. G-CSF will be given after transplant to help the donor progenitor cells make
      white blood cells faster so that the immune system is better able to fight infection.

      Blood progenitor cells will be given in two infusions on Day 0 and Day +1. Progenitor cells
      then move through the blood stream to the bone marrow space where they should begin to grow.
      Participant blood will be monitored for 100 days to assure that the progenitor cells begin
      to grow. If the growth is low, additional progenitor cells may be given.

      Blood tests will be monitored for up to one year to observe how well the donor cells grow
      and their effect on the infection-fighting system.
    

Trial Arms

NameTypeDescriptionInterventions
TreatmentExperimentalParticipants receive a conditioning regimen of antithymocyte globulin (rabbit), cyclophosphamide, mesna, fludarabine, thiotepa, tacrolimus, melphalan, rituximab. This is followed by HPC,A infusion (transplant), then by G-CSF and blinatumomab. Cells for infusion are prepared using the CliniMACS System.
  • Anti-thymocyte globulin (rabbit)
  • Blinatumomab
  • Cyclophosphamide
  • Fludarabine
  • G-CSF
  • Melphalan
  • Mesna
  • Rituximab
  • Tacrolimus
  • Thiotepa

Eligibility Criteria

        Inclusion Criteria for Transplant Recipient:

          -  Age less than or equal to 21 years.

          -  Any of the following hematologic malignancies that has relapsed or remains refractory
             after prior allogeneic HCT (this includes any stage of disease - such as refractory
             due to induction failure, refractory in relapse, or in any CR - as long as the
             hematologic malignancy remained persistent or returned after a previous allogeneic
             HCT):

               -  ALL, AML, Myeloid Sarcoma, CML, Juvenile myelomonocytic leukemia (JMML),
                  myelodysplastic syndrome (MDS), non-Hodgkin lymphoma (NHL)

          -  Has a suitable single haplotype matched (≥ 3 of 6) family member donor.

          -  Does not have any other active malignancy other than the one for which this
             transplant is indicated.

          -  If prior CNS leukemia, it must be treated and in CNS CR

          -  Does not have current uncontrolled bacterial, fungal, or viral infection.

          -  There is no minimum time from the previous transplant, but patients must meet the
             following criteria:

               -  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) ≥ 40% 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.

               -  Not pregnant. If female with child bearing potential, must be confirmed by
                  negative serum or urine pregnancy test within 14 days prior to enrollment.

               -  Not breast feeding

        Inclusion Criteria for Haploidentical Donor:

          -  At least single haplotype matched (≥ 3 of 6) family member

          -  At least 18 years of age.

          -  HIV negative.

          -  Not pregnant as confirmed by negative serum or urine pregnancy test within 14 days
             prior to enrollment (if female).

          -  Not breast feeding.

          -  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.
      
Maximum Eligible Age:21 Years
Minimum Eligible Age:N/A
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:The number of patients engrafted by day +30 post-transplant
Time Frame:30 days post-transplant
Safety Issue:
Description:ANC engraftment is defined as the first of 3 consecutive tests performed on different days of an ANC ≥ 500/mm^3 with evidence of donor cell engraftment.

Secondary Outcome Measures

Measure:The number of patients experiencing Blinatumomab permanent discontinuation due to toxicity
Time Frame:3 months post-transplant
Safety Issue:
Description:If the drug is held for more than 2 weeks due to toxicity, it will be permanently discontinued.
Measure:The estimate of cumulative incidence of relapse
Time Frame:One year post-transplant
Safety Issue:
Description:The estimate of cumulative incidence of relapse will be estimated using Kalbfleisch-Prentice method. Death is the competing risk event. The Kaplan-Meier estimates of overall survival (OS) and event-free survival (EFS) along with their standard errors will be calculated. OS is defined as time from transplantation to death or last follow-up, whichever comes first. EFS is defined as time from transplantation to events including relapse, graft failure, death due to any cause and last follow-up whichever comes first. The participants surviving at the time of analysis without events will be censored.
Measure:The cumulative incidence of acute and chronic Graft-Versus-Host Disease (GVHD)
Time Frame:One year post transplant
Safety Issue:
Description:The cumulative incidence of acute and chronic GVHD will be estimated using Kalbfleisch-Prentice method. Death is the competing risk event. The severity of acute GVHD and chronic GVHD will be described.
Measure:The cumulative incidence of transplant related mortality
Time Frame:100 days post transplant
Safety Issue:
Description:The cumulative incidence of transplant related mortality will be estimated using Kalbfleisch-Prentice method. Deaths before day 100 because of other reasons are the competing risk events.

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:St. Jude Children's Research Hospital

Last Updated

March 29, 2017