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

February 26, 2024 updated by: St. Jude Children's Research Hospital

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.

Study Overview

Status

Recruiting

Conditions

Intervention / Treatment

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.

Study Type

Interventional

Enrollment (Estimated)

52

Phase

  • Phase 2

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

Study Locations

  • United States
    • Tennessee
      • Memphis, Tennessee, United States, 38105
        • Recruiting
        • St. Jude Children's Research Hospital
        • Contact:
        • Principal Investigator:
          • Brandon Triplett, MD

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

No older than 21 years (Child, Adult)

Accepts Healthy Volunteers

No

Description

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.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: N/A
  • Interventional Model: Single Group Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: Treatment

Participants receive a conditioning regimen of antithymocyte globulin (rabbit), cyclophosphamide, mesna, fludarabine, thiotepa, tacrolimus (first 5 participants enrolled), sirolimus (used beginning with 6th enrolled participant), 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.
Device: CliniMACS
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, such as CD3+ human T cells.
Other Names:
  • Cell Selection System
Drug: Anti-thymocyte globulin (rabbit)
Given intravenous (IV) prior to transplant on Days -14, -13, -12.
Other Names:
  • Thymoglobulin®
  • rabbit ATG
Drug: Blinatumomab
Given by continuous IV infusion at least 2 weeks post-engraftment. Blinatumomab will be given only to patients with CD19+ malignancies.
Other Names:
  • Blincyto
Drug: Cyclophosphamide
Given by IV infusion prior to transplant on Day -9.
Other Names:
  • Cytoxan
Drug: Fludarabine
Given IV prior to transplant on Days -8, -7, -6, -5, and -4.
Other Names:
  • Fludara
Drug: G-CSF
Given IV or subcutaneous (SQ) following transplant on Days 6 and 7.
Other Names:
  • Filgrastim
  • Neupogen®
Drug: Melphalan
Given IV prior to transplant on Days -2 and -1.
Other Names:
  • Phenylalanine mustard
  • Alkeran
  • L-PAM
  • L-phenylalanine mustard
  • L-sarcolysin
Drug: Mesna
Given IV prior to cyclophosphamide administration and at approximately 3, 6, and 9 hours after cyclophosphamide infusion.
Other Names:
  • Mesnex
Drug: Rituximab
Given IV prior to transplant on Day -1.
Other Names:
  • Rituxan™
Drug: Tacrolimus
Given oral (PO) or IV beginning prior to transplant on Day -2. The dose will begin to taper at approximately day +60 after transplant in the absence of GVHD. Tacrolimus was used for the first 5 participants enrolled on study. Subsequent participants receive sirolimus.
Other Names:
  • FK506
  • Protopic®
  • Prograf®
Drug: Thiotepa
Given IV prior to transplant on Day -3.
Other Names:
  • TESPA
  • TSPA
  • Thioplex® by Immunex
Biological: HPC,A Infusion
Hematopoietic Progenitor Cell, Apheresis (HPC,A) infusion of TCRɑβ+ depleted cells on day of transplant (Day 0) and HPC,A infusion of CD45RA+ depleted cells on Day +1 following transplant.
Other Names:
  • Transplant
Drug: Sirolimus
Given orally (PO) starting Day 0. The dose will be tapered off over two weeks starting on Day +42 in the absence of GVHD.
Other Names:
  • Rapamycin
  • Rapamune®

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
The number of patients engrafted by day +30 post-transplant
Time Frame: 30 days post-transplant
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.
30 days post-transplant

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
The number of patients experiencing Blinatumomab permanent discontinuation due to toxicity
Time Frame: 3 months post-transplant
If the drug is held for more than 2 weeks due to toxicity, it will be permanently discontinued.
3 months post-transplant
The estimate of cumulative incidence of relapse
Time Frame: One year post-transplant

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.
One year post-transplant
The cumulative incidence of acute and chronic Graft-Versus-Host Disease (GVHD)
Time Frame: One year post transplant

The cumulative incidence of acute and chronic GVHD will be estimated using Kalbfleisch-Prentice method. Death is the competing risk event. GVHD will be reported separately for participants receiving tacrolimus and those receiving sirolimus.

The severity of acute GVHD and chronic GVHD will be described.
One year post transplant
The cumulative incidence of transplant related mortality
Time Frame: 100 days post transplant
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.
100 days post transplant

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

St. Jude Children's Research Hospital

Investigators

  • Principal Investigator: Brandon Triplett, MD, St. Jude Children's Research Hospital

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

Helpful Links

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

July 14, 2016

Primary Completion (Estimated)

July 1, 2024

Study Completion (Estimated)

July 1, 2025

Study Registration Dates

First Submitted

May 31, 2016

First Submitted That Met QC Criteria

May 31, 2016

First Posted (Estimated)

June 6, 2016

Study Record Updates

Last Update Posted (Actual)

February 28, 2024

Last Update Submitted That Met QC Criteria

February 26, 2024

Last Verified

February 1, 2024

More Information

Terms related to this study

Additional Relevant MeSH Terms

Other Study ID Numbers

  • REF2HCT
  • NCI-2016-00812 (Registry Identifier: NCI Clinical Trial Registration Program)

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

Yes

Studies a U.S. FDA-regulated device product

Yes

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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