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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

Primary Purpose

Acute Lymphoblastic Leukemia (ALL), Acute Myeloid Leukemia (AML), Myeloid Sarcoma

Status

Recruiting

Phase

Phase 2

Locations

United States

Study Type

Interventional

Intervention

Anti-thymocyte globulin (rabbit)

Blinatumomab

Cyclophosphamide

Fludarabine

G-CSF

Melphalan

Mesna

Rituximab

Tacrolimus

Thiotepa

HPC,A Infusion

CliniMACS

Sirolimus

About this trial

This is an interventional treatment trial for Acute Lymphoblastic Leukemia (ALL)

Eligibility Criteria

undefined - 21 Years (Child, Adult)All SexesDoes not accept healthy volunteers

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.

Sites / Locations

St. Jude Children's Research HospitalRecruiting

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Treatment

Arm Description

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.

Outcomes

Primary Outcome Measures

The number of patients engrafted by day +30 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.

Secondary Outcome Measures

The number of patients experiencing Blinatumomab permanent discontinuation due to toxicity

If the drug is held for more than 2 weeks due to toxicity, it will be permanently discontinued.

The estimate of cumulative incidence of relapse

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.

The cumulative incidence of acute and chronic Graft-Versus-Host Disease (GVHD)

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.

The cumulative incidence of transplant related mortality

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.

Full Information

NCT ID

NCT02790515

First Posted

May 31, 2016

Last Updated

February 22, 2023

Sponsor

St. Jude Children's Research Hospital

1. Study Identification

Unique Protocol Identification Number

NCT02790515

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

Study Type

Interventional

2. Study Status

Record Verification Date

February 2023

Overall Recruitment Status

Recruiting

Study Start Date

July 14, 2016 (Actual)

Primary Completion Date

July 1, 2024 (Anticipated)

Study Completion Date

July 1, 2025 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

St. Jude Children's Research Hospital

4. Oversight

Studies a U.S. FDA-regulated Drug Product

Yes

Studies a U.S. FDA-regulated Device Product

Yes

Device Product Not Approved or Cleared by U.S. FDA

Yes

Data Monitoring Committee

5. Study Description

Brief Summary

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.

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

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)

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 2

Interventional Study Model

Single Group Assignment

Masking

None (Open Label)

Allocation

N/A

Enrollment

52 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title

Treatment

Arm Type

Experimental

Arm Description

Intervention Type

Drug

Intervention Name(s)

Anti-thymocyte globulin (rabbit)

Other Intervention Name(s)

Thymoglobulin®, rabbit ATG

Intervention Description

Given intravenous (IV) prior to transplant on Days -14, -13, -12.

Intervention Type

Drug

Intervention Name(s)

Blinatumomab

Other Intervention Name(s)

Blincyto

Intervention Description

Given by continuous IV infusion at least 2 weeks post-engraftment. Blinatumomab will be given only to patients with CD19+ malignancies.

Intervention Type

Drug

Intervention Name(s)

Cyclophosphamide

Other Intervention Name(s)

Cytoxan

Intervention Description

Given by IV infusion prior to transplant on Day -9.

Intervention Type

Drug

Intervention Name(s)

Fludarabine

Other Intervention Name(s)

Fludara

Intervention Description

Given IV prior to transplant on Days -8, -7, -6, -5, and -4.

Intervention Type

Drug

Intervention Name(s)

G-CSF

Other Intervention Name(s)

Filgrastim, Neupogen®

Intervention Description

Given IV or subcutaneous (SQ) following transplant on Days 6 and 7.

Intervention Type

Drug

Intervention Name(s)

Melphalan

Other Intervention Name(s)

L-phenylalanine mustard, Phenylalanine mustard, L-PAM, L-sarcolysin, Alkeran

Intervention Description

Given IV prior to transplant on Days -2 and -1.

Intervention Type

Drug

Intervention Name(s)

Mesna

Other Intervention Name(s)

Mesnex

Intervention Description

Given IV prior to cyclophosphamide administration and at approximately 3, 6, and 9 hours after cyclophosphamide infusion.

Intervention Type

Drug

Intervention Name(s)

Rituximab

Other Intervention Name(s)

Rituxan™

Intervention Description

Given IV prior to transplant on Day -1.

Intervention Type

Drug

Intervention Name(s)

Tacrolimus

Other Intervention Name(s)

FK506, Prograf®, Protopic®

Intervention Description

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.

Intervention Type

Drug

Intervention Name(s)

Thiotepa

Other Intervention Name(s)

Thioplex® by Immunex, TESPA, TSPA

Intervention Description

Given IV prior to transplant on Day -3.

Intervention Type

Biological

Intervention Name(s)

HPC,A Infusion

Other Intervention Name(s)

Transplant

Intervention Description

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.

Intervention Type

Device

Intervention Name(s)

CliniMACS

Other Intervention Name(s)

Cell Selection System

Intervention Description

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.

Intervention Type

Drug

Intervention Name(s)

Sirolimus

Other Intervention Name(s)

Rapamycin, Rapamune®

Intervention Description

Given orally (PO) starting Day 0. The dose will be tapered off over two weeks starting on Day +42 in the absence of GVHD.

Primary Outcome Measure Information:

Title

The number of patients engrafted by day +30 post-transplant

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.

Time Frame

30 days post-transplant

Secondary Outcome Measure Information:

Title

The number of patients experiencing Blinatumomab permanent discontinuation due to toxicity

Description

If the drug is held for more than 2 weeks due to toxicity, it will be permanently discontinued.

Time Frame

3 months post-transplant

Title

The estimate of cumulative incidence of relapse

Description

Time Frame

One year post-transplant

Title

The cumulative incidence of acute and chronic Graft-Versus-Host Disease (GVHD)

Description

Time Frame

One year post transplant

Title

The cumulative incidence of transplant related mortality

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.

Time Frame

100 days post transplant

10. Eligibility

Sex

All

Maximum Age & Unit of Time

21 Years

Accepts Healthy Volunteers

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.

Central Contact Person:

First Name & Middle Initial & Last Name or Official Title & Degree

Brandon Triplett, MD

Phone

866-278-5835

referralinfo@stjude.org

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Brandon Triplett, MD

Organizational Affiliation

St. Jude Children's Research Hospital

Official's Role

Principal Investigator

Facility Information:

Facility Name

St. Jude Children's Research Hospital

City

Memphis

State/Province

Tennessee

ZIP/Postal Code

38105

Country

United States

Individual Site Status

Recruiting

Facility Contact:

First Name & Middle Initial & Last Name & Degree

Brandon Triplett, MD

Phone

866-278-5833

referralinfo@stjude.org

First Name & Middle Initial & Last Name & Degree

Brandon Triplett, MD

12. IPD Sharing Statement

Links:

URL

http://www.stjude.org

Description

St. Jude Children's Research Hospital

URL

http://www.stjude.org/protocols

Description

Clinical Trials Open at St. Jude

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