IS-free Treg HaploHCT

Summary

This research study is evaluating the safety and efficacy of the IS-free Treg-cell graft-engineered haplo transplant method in people with relapsed/refractory and Ultra-high risk acute myeloid leukemia (AML) and/or myelodysplastic syndromes (MDS) receiving a haploidentical donor allogeneic hematopoietic stem cell transplant (HSCT).

The names of the study interventions involved in this study are:

* Radiation-Total Myeloid and Lymphoid Irradiation (TMLI)
* Chemotherapy (Fludarabine, Thiotepa, Cyclophosphamide plus Mesna)
* Infusion of haplo Treg-enriched donor cells (experimental therapy)
* Infusion of unmodified haplo donor T cells (includes cancer-fighting T effector cells)
* Infusion of haplo donor CD34+ Peripheral Blood Stem Cells

Conditions

• Stem Cell Transplant Complications
• Graft Vs Host Disease
• Myeloid Leukemia, Acute
• Myeloid Leukemia in Relapse (Disorder)
• Myelodysplastic Syndromes

Interventions

RADIATION

Radiation

For MAC regimen: Total Myeloid and Lymphoid Irradiation (TMLI) delivered through Radiation Oncology institutional standards and comprised of 13.5 Gy TMI (9 fractions, 1.5 Gy per fraction, 2 fractions per day) and 11.7 Gy TLI (9 fractions, 1.3 Gy per fraction, 2 fractions per day). OR Total Body Irradiation (TBI) comprised of 12 Gy (6 fractions, 2 Gy per fraction, 2 fractions per day) For RIC regimen: TBI comprised of 2 Gy in 1 fraction.

DRUG

Fludarabine

For MAC regimen: 30 mg/m\^2/d in 100 ml normal saline (NS) will be administered as a bolus infusion administered by IV infusion over approximately 30 minutes for 5 days (on day -10, -9, -8, -7, -6) For RIC regimen: 40 mg/m\^2/d in 100 ml NS will be administered as a bolus by IV infusion over approximately 30 minutes for 4 days (on day -10, -9, -8, -7)

DRUG

Thiotepa

For MAC regimen: 3.75 mg/kg diluted in NS to a final concentration of 1mg/mL will be administered by IV infusion over approximately 4 hours daily for 2 days (on day -10, -9) For RIC regimen: 5 mg/kg diluted in NS to a final concentration of 1mg/mL will be administered by IV infusion over approximately 4 hours twice daily for 1 day (on day -11)

DRUG

Cyclophosphamide

For MAC regimen only: 15 mg/kg diluted in NS per institutional standard and will be administered by IV over 1 hour or as directed per institutional standard practice, daily on D-8, -7.

DRUG

Mesna

For MAC regimen only: 3.75mg/kg (25% of cyclophosphamide dose) diluted in 50 mL NS and administered IV over 30 min, will be infused starting 30 min prior to cyclophosphamide and for 3 doses thereafter, at 3, 6 and 9h after cyclophosphamide

BIOLOGICAL

Treg-enriched donor cell

Target 'Treg-enriched' cell dose is 1-2 x 10\^6 cells/kg. Cells will be given intravenously on Day -4. The day -1 calculated unmodified PBMC T ('Teff') cell dose will be adjusted to maintain a targeted cell ratio of 2 'Treg-enriched' cells:1 'Teff' cell.

BIOLOGICAL

Unmodified donor T Cell

Unmodified donor PBMCs will be infused at a calculated 'Teff' dose of 1x10\^6 CD3+ T cells/kg, adjusted per the caveats below: A) If the 'Treg-enriched' product infused was at target dose of 2x106 cells/kg but had ≥30% CD4+CD25+CD127hi cells, the unmodified 'Teff' (calculated) cell dose infused on day -1 will be halved to 0.5x10\^6 CD3+ T cells/kg. B) If the 'Treg-enriched' product was in the range of 1-2x106 cells/kg, the unmodified 'Teff' (calculated) cell dose on day -1 will be adjusted to between 0.5-1x10\^6 CD3+ T cells/kg, dosed to maintain a 2 'Treg-enriched':1 'Teff' (calculated) ratio of infused cells. C) If the 'Treg-enriched' product infused met both caveats A and B above, the unmodified 'Teff' (calculated) cell dose infused on day -1 will be halved to 0.5x10\^6 CD3+ T cells/kg.

PROCEDURE

CD34+ Haplo Peripheral Blood Stem Cell

The megadose donor CD34+ PBSC infusion target is \>10x10\^6 CD34+ cells/kg (ABW or IBW, whichever is greater). If the CD34+ graft has \<6x10\^6 CD34+ cells/kg (ABW or IBW, whichever is greater) (below megadose minimum) it WILL be infused in order to rescue recipient hematopoiesis, and the patient will remain on study.

DRUG

Melphalan

For RIC regimen only: 100 mg/m2 will be administered as a bolus by IV infusion over approximately 30 minutes for 1 day (on day -6)

Sponsors & Collaborators

• Dana-Farber Cancer Institute

  lead OTHER

Principal Investigators

• John Koreth, MBBS, DPhil · Dana-Farber Cancer Institute

Study Design

Allocation

NON_RANDOMIZED

Purpose

TREATMENT

Masking

NONE

Model

PARALLEL

Eligibility

Min Age

18 Years

Max Age

75 Years

Sex

ALL

Healthy Volunteers

No

Timeline & Regulatory

Start

2021-01-12

Primary Completion

2028-08-31

Completion

2029-08-31

FDA Drug

Yes

Countries

• United States

Study Locations