Recruiting
Phase 1

IS-free Treg

Sponsor:

Dana-Farber Cancer Institute

Code:

NCT04678401

Conditions

Stem Cell Transplant Complications

Graft Vs Host Disease

Myeloid Leukemia, Acute

Myeloid Leukemia in Relapse (Disorder)

Myelodysplastic Syndromes

Eligibility Criteria

Sex: All

Age: 18 - 70+

Healthy Volunteers: Not accepted

Interventions

Radiation

Fludarabine

Thiotepa

Cyclophosphamide

Mesna

Study Details

Brief 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

Study ID

NCT04678401

Start date

Jan 12, 2021

Status verified date

Oct, 2025

Completion date

Aug 31, 2029

Anticipated

Primary completion date

Aug 31, 2028

Anticipated

Eligibility Criteria

Eligibility Criteria

Sex: All

Age: 18 - 70+

Healthy Volunteers: Not accepted

Inclusion Criteria:

  • Cohort A: Histologically confirmed disease in the prior 4 weeks, despite at least 1 prior line of therapy (e.g., 3+7 chemotherapy, HMA therapy): Rel/ref AML (de novo or secondary) with ≥5% blasts in BM (or extramedullary sites); MDS EB-2 (BM ≥10% blasts, PB 5-19% blasts).
  • Cohort B: Ultra high-risk AML or MDS that meets definition of 'Myeloid Neoplasms with mutated TP53' per 2022 International Consensus Classification (Appendix L) regardless of response
  • Cohort C: Ultra high-risk AML or MDS that meets definition of 'Myeloid Neoplasms with multi-hit or complex karyotype (CK+) mutated TP53' per 2022 International Consensus Classification (Appendix L) with response: AML (de novo or secondary) with <5% blasts in BM; MDS with <10% blasts in BM or PB.
  • Available haploidentical HLA-matched (-A, -B, -C, -DRB1) related donor aged 18-65 years.
  • Age ≥18 to 65 years for Cohort A and B. Age ≥18 to 75 years for Cohort C. Because no dosing or adverse event data are currently available on the use of IS-free haploHCT in participants <18 years of age, children are excluded from this study but will be eligible for future pediatric trials.
  • ECOG performance status ≤2 (Karnofsky ≥60, see Appendix A).
  • Adequate organ and marrow function as defined below:

  • Pulmonary Function: FEV1, FVC and DLCO ≥ 60% of predicted (corrected for hemoglobin)
  • Cardiac Ejection Fraction ≥ 45%, and no evidence of pulmonary hypertension
  • Hepatic: Total bilirubin within normal institutional limits (exception permitted in Gilbert's Syndrome after discussion with study PI, on a case-by-case basis); and AST (SGOT)/ALT (SGPT) <2x institutional upper limit of normal
  • Renal: Serum Creatinine within normal institutional limits or creatinine clearance >50 mL/min/1.73 m2 (see Appendix B) for participants with creatinine levels above institutional normal.
  • The effects of IS-free haploHCT on the developing human fetus are unknown. For this reason and because radiation and chemotherapeutic agents are known to be teratogenic, women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation. Should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately. Men treated or enrolled on this protocol must also agree to use adequate contraception prior to the study, for the duration of study participation, and a minimum of 4 months after completion of study.
  • Ability to understand and the willingness to sign a written informed consent document.

Exclusion Criteria:

  • Participants who have had cytotoxic chemotherapy or radiotherapy within 2 weeks (4 weeks for nitrosoureas or mitomycin C) prior to entering the study. Use of hydroxyurea, HMA, e.g., azacytidine, decitabine) and/or FDA-approved novel targeted agents (e.g., venetoclax, FLT-3 inhibitors, IDH 1/2 inhibitors) are permitted up to a day prior to start of HCT conditioning.
  • Participants who have not recovered from adverse events due to prior anti-cancer therapy (i.e., have residual non-hematologic toxicities > Grade 1) with exception of alopecia, unless cleared by study PI.
  • Participants who received Mylotarg or other therapies associated with increased risk of hepatic veno-occlusive disease (VOD) or have known prior or active VOD. All novel therapies will be reviewed with PI.
  • Participants who are receiving any other investigational agents within 21 days (or 5 half-lives) prior to study entry, whichever is longer, unless cleared by the study PI.
  • Participants with extramedullary disease at immune privileged sites (e.g., CNS, testes, eye) are excluded, as these sites are less susceptible to the curative graft vs. leukemia effect of HCT.
  • Myocardial infarction within 2 years prior to enrollment.
  • Venous thromboembolic event (VTE) of DVT/ PE within 1 year prior to enrollment, unless approved by study PI. Patients with line-associated DVT within the past year may be enrolled if they have completed anticoagulation therapy.
  • Stroke or transient ischemic attack (TIA) within 1 year prior to enrollment.
  • History of bleeding peptic ulcer disease, erosive gastritis, intestinal perforation or clinically significant gastrointestinal (GI) hemorrhage or hemoptysis within the prior 6 months.
  • Patients with a history of thrombotic microangiopathy (TMA) or hemolytic uremic syndrome/thrombotic thrombocytopenic purpura (HUS/TTP).
  • History of life-threatening reactions to iron infusions or murine antibody-containing products.
  • Known donor-specific antibodies (DSA) in the recipient of clinical significance (e.g., requiring DSA depletion with plasmapheresis, rituximab) are excluded.
  • Inability to withhold agents that may interact with hepatic cytochrome P450 enzymes involved in cyclophosphamide and/or thiotepa metabolism (see Section 5.5) during day -10 through day -5. It is acceptable use alternative non-interacting medications during this period, and then restart prior medications
  • Participants with uncontrolled bacterial, viral or fungal infections (i.e., currently taking medications with progression of clinical symptoms or signs).
  • Recipients of prior allogeneic or autologous hematopoietic cell transplantation, or solid organ transplantation.
  • Prior radiation exposure or other medical condition (e.g., Fanconi syndrome) that precludes use of myeloablative radiation (TMLI).
  • HIV-positive participants on combination antiretroviral therapy are ineligible because of the potential for pharmacokinetic interactions with the multiple agents used routinely in myeloablative allogeneic stem cell transplantation. In addition, these individuals are at increased risk of lethal infections when treated with marrow-suppressive therapy. Appropriate studies will be undertaken in participants receiving combination antiretroviral therapy when indicated.
  • Participants seropositive for hepatitis B or C infection are ineligible as they are at high risk of lethal treatment-related hepatotoxicity after myeloablative HCT.
  • Participants with psychiatric illness/social situations that would limit compliance with study requirements.
  • Pregnant women are excluded from this study because radiation and conditioning chemotherapy has the potential for teratogenic or abortifacient effects. A negative pregnancy test is required for females of childbearing potential. Because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with IS-free haploHCT breastfeeding should be discontinued if the mother is treated with IS-free haploHCT.
  • Participants with a history of another non-hematologic malignancy are ineligible except for the following circumstances: Individuals with a history of other malignancies are eligible if they have been disease-free for at least 5 years and are deemed by the investigator to be at low risk for recurrence of that malignancy. Individuals with the following cancers are eligible if diagnosed and treated within the past 5 years: cervical cancer in situ, and basal cell or squamous cell carcinoma of the skin.

Study Design

Enrollment

30 participants

Anticipated

Allocation

Non randomized

Intervention Model

Parallel Assignment

Primary purpose

Treatment

Interventions and Outcome Measures

Arms

experimental: IS-FREE TREG GRAFT ENGINEERED HaploHCT for relapsed/refractory AML or MDS EB-2 (Closed to Accrual)

Please note that this arm is closed due to meeting accrual goal as of June 2024.

This arm (Cohort A) included patients with rel/ref AML/MDS, with active disease despite at least 1 prior line of therapy.

Treatment plan and follow up schedule:

Day -15 to -6: Myeloablative conditioning regimen Radiation: Total Myeloid and Lymphoid Irradiation (TMLI) on Days -15 to -11 OR Total Body Irradiation (TBI) on Days -13 to -11 Chemotherapy: Fludarabine on Days -10 to -6, Thiotepa on Days -10 to -9, and Cyclophosphamide and Mesna on Days -8 and -7

Day -4: Treg-enriched donor cell infusion and GVHD assessment

Day -1: Unmodified donor T Cell infusion and GVHD assessment

Day 0: CD34+ Haplo Peripheral Blood Stem Cell Transplant and GVHD assessment

Days 30, 60, 100, 180, 365 post-HSCT, participants will undergo testing and assessment of minimal residual disease (MRD) and (GVHD).

experimental: IS-FREE TREG GRAFT ENGINEERED HaploHCT for Ultra high-risk AML or MDS with mutated TP53

This arm (Cohort B) includes patients with ultra-high-risk AML/MDS that meets the definition of "Myeloid Neoplasms with mutated TP53" per the 2022 International Consensus Classification, regardless of remission status at the time of transplant.

Treatment plan and follow up schedule:

Day -15 to -6: Myeloablative conditioning regimen Radiation: Total Myeloid and Lymphoid Irradiation (TMLI) on Days -15 to -11 OR Total Body Irradiation (TBI) on Days -13 to -11 Chemotherapy: Fludarabine on Days -10 to -6, Thiotepa on Days -10 to -9, and Cyclophosphamide and Mesna on Days -8 and -7

Day -4: Treg-enriched donor cell infusion and GVHD assessment

Day -1: Unmodified donor T Cell infusion and GVHD assessment

Day 0: CD34+ Haplo Peripheral Blood Stem Cell Transplant and GVHD assessment

Days 30, 60, 100, 180, 365 post-HSCT, participants will undergo testing and assessment of minimal residual disease (MRD) and (GVHD).

experimental: IS-FREE TREG GRAFT ENGINEERED HaploHCT for Ultra high-risk AML or MDS with multi-hit or CK+ mut-TP53

This arm (Cohort C) includes patients with ultra-high-risk AML/MDS that meets definition of 'Myeloid Neoplasms with multi-hit or complex karyotype (CK+) mutated TP53' per 2022 International Consensus Classification, with response (AML with <5% BM blasts/MDS with <10% BM blasts).

Treatment plan and follow up schedule:

Day -11 to -5: Reduced intensity conditioning regimen Chemotherapy: Thiotepa on Day -11, Fludarabine on Days -10 to -7, and Melphalan on Day -6 Radiation: Total Body Irradiation (TBI) on Day -5

Day -4: Treg-enriched donor cell infusion and GVHD assessment

Day -1: Unmodified donor T Cell infusion and GVHD assessment

Day 0: CD34+ Haplo Peripheral Blood Stem Cell Transplant and GVHD assessment

Days 30, 60, 100, 180, 365 post-HSCT, participants will undergo testing and assessment of minimal residual disease (MRD) and (GVHD).

Interventions

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.

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)

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)

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.

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

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.

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.

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.

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)

Primary outcome measure

  • Dose-limiting toxicities (DLT) [ Time Frame: 30 days after hematopoietic cell transplantation (HCT) ]

Central Contacts and Locations

Central contacts

John Koreth, MBBS, DPhil

(617) 632-2949john_koreth@dfci.harvard.edu

Locations

Dana Farber Cancer Institute

Recruiting

Boston, Massachusetts, United States, 02115

Contacts

John Koreth, MBBS, DPhil

617-632-5168john_koreth@dfci.harvard.edu

Principal Investigator:

John Koreth, MD

More Information

Sponsor

Dana-Farber Cancer Institute

Last update posted

Oct 20, 2025

Last verified

Oct, 2025

Keywords

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

Trial information was received from ClinicalTrials.gov and was last updated on 2026-09-10. This information was provided to ClinicalTrials.gov by Dana-Farber Cancer Institute on 2025-10-20.