Stem Cell Transplant ComplicationsPhase 1NCT04678401
IS-free Treg HaploHCT
A Phase 1 study testing Radiation, Fludarabine and Thiotepa in people with Stem Cell Transplant Complications and Graft Vs Host Disease, run by Dana-Farber Cancer Institute at 1 site in United States.
Trial 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… Read more about this study
- Who is it for?
- Ages 18 to 75 years
- Conditions the study is for
- Stem Cell Transplant Complications, Graft Vs Host Disease, Myeloid Leukemia, Acute
- What is being tested?
- Radiation, Fludarabine and Thiotepa
- Type of treatment
- Injection or infusion, Surgery or procedure
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 30 participants
- Where
- 1 siteUnited States
- Study dates
- 12 Jan 2021to 31 Aug 2029
- Phase
- Phase 1
- Are there results?
- Not yet: the study is under way
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 to 75 years
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- 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).
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- 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.
Who cannot join
- 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.
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- 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.
Trial locations and contacts
1 site in 1 country. Contact the study team or a site near you to ask about taking part.
United States1 site, 1 recruiting
- Recruiting
Dana Farber Cancer Institute
Boston, Massachusetts, 02115
John Koreth, MBBS, DPhil, 617-632-5168, john_koreth@dfci.harvard.edu
John Koreth, MD
About this study
Official title: A Pilot/Phase 1 Study of Immunosuppression-free Regulatory T-cell Graft-engineered Haploidentical Hematopoietic Cell Transplantation in Relapsed/Refractory and Ultra-High-risk AML/MDS
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
Read the detailed description
This study is assessing whether the IS-free Treg-cell graft-engineered haplo HSCT approach will reduce risk of relapse while preventing usual toxicities related to stem cell transplants (e.g., graft-versus-host-disease (GVHD)).
GVHD is a complication of transplantation where the T cells (a type of white blood cell that helps protect the body from relapse by killing cancer cells) in the donor graft attack and damage some of the host tissues. Patients who receive an allogeneic (using another person as the donor) hematopoietic stem cell transplant (HSCT) may develop graft-versus-host disease (GVHD) toxicity and are also at risk of disease relapse.
The research study procedures include the following: screening for eligibility, study treatment, and follow up visits.
Participants will receive the study intervention Treg-enriched donor cells and will then be followed for 1 year after transplantation.
It is expected that about 30 people will take part in this research study.
Dana-Farber Cancer Institute research funds along with charitable donations are supporting this research study. Regeneron Pharmaceuticals, Inc. (a pharmaceutical company) supported this research study by providing funding and support for correlative laboratory tests.
- Conditions
- Stem Cell Transplant Complications, Graft Vs Host Disease, Myeloid Leukemia, Acute, Myeloid Leukemia in Relapse (Disorder), Myelodysplastic Syndromes
- Being tested
- Radiation, Fludarabine, Thiotepa, Cyclophosphamide, Mesna
- Keywords
- Stem Cell Transplant Complications, Graft Vs Host Disease, Myeloid Leukemia, Acute, Myeloid Leukemia in Relapse (Disorder), Myelodysplastic Syndromes
- Medical subject headings
- Graft vs Host Disease, Leukemia, Myeloid, Acute, Myelodysplastic Syndromes
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
RadiationRadiation
Also called Radiotherapy, TMLI, TBI
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.
FludarabineDrug
Also called Fludara
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)
ThiotepaDrug
Also called Tepadina
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)
CyclophosphamideDrug
Also called cytophosphane
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.
MesnaDrug
Also called Mesnex
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 cellBiological
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 CellBiological
Unmodified donor PBMCs will be infused at a calculated 'Teff' dose of 1x10^6 CD3+ T cells/kg, adjusted per the caveats below:
- 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.
- 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.
- 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 CellProcedure or surgery
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.
MelphalanDrug
Also called Alkeran
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)
| Study group | Role | What they receive |
|---|---|---|
| IS-FREE TREG GRAFT_ENGINEERED HaploHCT for relapsed/refractory AML or MDS EB-2 (Closed to Accrual) | Experimental | 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). Receives: Radiation: Radiation; Drug: Fludarabine; Drug: Thiotepa; Drug: Cyclophosphamide; Drug: Mesna; Biological: Treg-enriched donor cell; Biological: Unmodified donor T Cell; Procedure: CD34+ Haplo Peripheral Blood Stem Cell |
| IS-FREE TREG GRAFT_ENGINEERED HaploHCT for Ultra high-risk AML or MDS with mutated TP53 | Experimental | 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). Receives: Radiation: Radiation; Drug: Fludarabine; Drug: Thiotepa; Drug: Cyclophosphamide; Drug: Mesna; Biological: Treg-enriched donor cell; Biological: Unmodified donor T Cell; Procedure: CD34+ Haplo Peripheral Blood Stem Cell |
| IS-FREE TREG GRAFT_ENGINEERED HaploHCT for Ultra high-risk AML or MDS with multi-hit or CK+ mut-TP53 | Experimental | 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). Receives: Radiation: Radiation; Drug: Fludarabine; Drug: Thiotepa; Biological: Treg-enriched donor cell; Biological: Unmodified donor T Cell; Procedure: CD34+ Haplo Peripheral Blood Stem Cell; Drug: Melphalan |
What is being measured
The primary outcome is the main question the study is designed to answer.
Dose-limiting toxicities (DLT)
Safety will be assessed by dose-limiting toxicities (DLT) summarized by patient, type and grade as defined by the CTCAE v5.0.
Measured: 30 days after hematopoietic cell transplantation (HCT)
Secondary outcomes (9)
Engraftment rate
Will be summarized descriptively and estimated in the competing risks framework treating death without GVHD or without engraftment as a competing event depending on the actual enrolled and evaluable number of patients.
Measured: 30 days after hematopoietic cell transplantation (HCT)
secondary graft failure rate
Will be summarized descriptively and estimated in the competing risks framework treating death without GVHD or without engraftment as a competing event depending on the actual enrolled and evaluable number of patients.
Measured: 100 days after hematopoietic cell transplantation (HCT)
graft vs host disease (GVHD) Rate
Incidence of grade II-IV and III-IV acute graft vs host disease (GVHD) by day 180 after HCT
Measured: 180 days after hematopoietic cell transplantation (HCT)
Mortality Rate-GVHD Relapse
Will also be summarized descriptively, estimated in the competing risks framework treating each event as a competing event. Corresponding 95% CIs will be provided.
Measured: 12 months after hematopoietic cell transplantation (HCT)
Mortality Rate-GVHD Non- Relapse
Will also be summarized descriptively, estimated in the competing risks framework treating each event as a competing event. Corresponding 95% CIs will be provided.
Measured: 12 months after hematopoietic cell transplantation (HCT)
Survival Rate-Relapse-Free
Estimated using Kaplan-Meier method with exact pointwise confidence intervals
Measured: 12 months after hematopoietic cell transplantation (HCT)
Progression Free-Survival (PFS)
Estimated using Kaplan-Meier method with exact pointwise confidence intervals
Measured: 12 months after hematopoietic cell transplantation (HCT)
Survival Rate-Relapse-Free-GVHD
Estimated using Kaplan-Meier method with exact pointwise confidence intervals
Measured: 12 months after hematopoietic cell transplantation (HCT)
Overall survival rate
Estimated using Kaplan-Meier method with exact pointwise confidence intervals
Measured: 12 months after hematopoietic cell transplantation (HCT)
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted22 Dec 2020
- Study start12 Jan 2021
- Primary completion31 Aug 2028 (estimated)
- Study completion31 Aug 2029 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for Stem Cell Transplant ComplicationsStudies of the same condition, open and under way.
- More trials run by Dana-Farber Cancer InstituteThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 1
- Primary purpose
- Treatment
- Allocation
- Non-randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Enrolment
- 30 participants (estimated)
Sponsor and investigators
- Lead sponsor
- Dana-Farber Cancer Institute
- Sponsor type
- University, hospital or other
- Responsible party
- Principal investigator, John Koreth, MD, Dana-Farber Cancer Institute
- Investigators
- John Koreth, MBBS, DPhil, Principal investigator, Dana-Farber Cancer Institute
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT04678401
- Sponsor's protocol ID
- 20-336
- Status last verified
- Oct 2025
- First submitted
- 16 Dec 2020
- Last updated
- 20 Oct 2025
- Results posted
- No
- Data monitoring committee
- Yes
- FDA-regulated drug
- Yes
- FDA-regulated device
- No
- Individual data sharing
- Yes: The Dana-Farber / Harvard Cancer Center encourages and supports the responsible and ethical sharing of data from clinical trials. De-identified participant data from the final research dataset used in the published manuscript may only be shared under the terms of a Data Use Agreement. Requests may be directed to: \[contact information for Sponsor Investigator or designee\]. The protocol and statistical analysis plan will be made available on Clinicaltrials.gov only as required by federal regulation or as a condition of awards and agreements supporting the research.
Study at a glance
From the registry record, last updated by the sponsor on 20 Oct 2025. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- A Pilot/Phase 1 Study of Immunosuppression-free Regulatory T-cell Graft-engineered Haploidentical Hematopoietic Cell Transplantation in Relapsed/Refractory and Ultra-High-risk AML/MDS
- ClinicalTrials.gov ID
- NCT04678401
- Acronym / sponsor ID
- 20-336
- Conditions
- Stem Cell Transplant Complications, Graft Vs Host Disease, Myeloid Leukemia, Acute, Myeloid Leukemia in Relapse (Disorder), Myelodysplastic Syndromes
- Keywords
- Stem Cell Transplant Complications, Graft Vs Host Disease, Myeloid Leukemia, Acute, Myeloid Leukemia in Relapse (Disorder), Myelodysplastic Syndromes
- Phase
- Phase 1
- Study type
- Interventional
- Recruitment status
- Recruiting
- Enrolment
- 30 participants (estimated)
- Lead sponsor
- Dana-Farber Cancer InstituteUniversity, hospital or other
- Study start
- 12 Jan 2021 (actual)
- Primary completion
- 31 Aug 2028 (estimated)
- Study completion
- 31 Aug 2029 (estimated)
- First posted
- 22 Dec 2020 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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
Detailed description
This study is assessing whether the IS-free Treg-cell graft-engineered haplo HSCT approach will reduce risk of relapse while preventing usual toxicities related to stem cell transplants (e.g., graft-versus-host-disease (GVHD)).
GVHD is a complication of transplantation where the T cells (a type of white blood cell that helps protect the body from relapse by killing cancer cells) in the donor graft attack and damage some of the host tissues. Patients who receive an allogeneic (using another person as the donor) hematopoietic stem cell transplant (HSCT) may develop graft-versus-host disease (GVHD) toxicity and are also at risk of disease relapse.
The research study procedures include the following: screening for eligibility, study treatment, and follow up visits.
Participants will receive the study intervention Treg-enriched donor cells and will then be followed for 1 year after transplantation.
It is expected that about 30 people will take part in this research study.
Dana-Farber Cancer Institute research funds along with charitable donations are supporting this research study. Regeneron Pharmaceuticals, Inc. (a pharmaceutical company) supported this research study by providing funding and support for correlative laboratory tests.
Study design
- Primary purpose
- Treatment
- Allocation
- Non-randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Number of arms
- 3
| Arm | Type | Receives |
|---|---|---|
| IS-FREE TREG GRAFT_ENGINEERED HaploHCT for relapsed/refractory AML or MDS EB-2 (Closed to Accrual) | Experimental | Radiation: Radiation, Drug: Fludarabine, Drug: Thiotepa, Drug: Cyclophosphamide, Drug: Mesna, Biological: Treg-enriched donor cell, Biological: Unmodified donor T Cell, Procedure: CD34+ Haplo Peripheral Blood Stem CellPlease 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). |
| IS-FREE TREG GRAFT_ENGINEERED HaploHCT for Ultra high-risk AML or MDS with mutated TP53 | Experimental | Radiation: Radiation, Drug: Fludarabine, Drug: Thiotepa, Drug: Cyclophosphamide, Drug: Mesna, Biological: Treg-enriched donor cell, Biological: Unmodified donor T Cell, Procedure: CD34+ Haplo Peripheral Blood Stem CellThis 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). |
| IS-FREE TREG GRAFT_ENGINEERED HaploHCT for Ultra high-risk AML or MDS with multi-hit or CK+ mut-TP53 | Experimental | Radiation: Radiation, Drug: Fludarabine, Drug: Thiotepa, Biological: Treg-enriched donor cell, Biological: Unmodified donor T Cell, Procedure: CD34+ Haplo Peripheral Blood Stem Cell, Drug: MelphalanThis 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). |
Who may qualify
- Ages
- 18 to 75 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (13 listed)
- 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.
Key exclusion criteria (21 listed)
- 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.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| RadiationAlso: Radiotherapy, TMLI, TBIFor 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. | Radiation | IS-FREE TREG GRAFT_ENGINEERED HaploHCT for Ultra high-risk AML or MDS with multi-hit or CK+ mut-TP53, IS-FREE TREG GRAFT_ENGINEERED HaploHCT for Ultra high-risk AML or MDS with mutated TP53, IS-FREE TREG GRAFT_ENGINEERED HaploHCT for relapsed/refractory AML or MDS EB-2 (Closed to Accrual) |
| FludarabineAlso: FludaraFor 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 | IS-FREE TREG GRAFT_ENGINEERED HaploHCT for Ultra high-risk AML or MDS with multi-hit or CK+ mut-TP53, IS-FREE TREG GRAFT_ENGINEERED HaploHCT for Ultra high-risk AML or MDS with mutated TP53, IS-FREE TREG GRAFT_ENGINEERED HaploHCT for relapsed/refractory AML or MDS EB-2 (Closed to Accrual) |
| ThiotepaAlso: TepadinaFor 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 | IS-FREE TREG GRAFT_ENGINEERED HaploHCT for Ultra high-risk AML or MDS with multi-hit or CK+ mut-TP53, IS-FREE TREG GRAFT_ENGINEERED HaploHCT for Ultra high-risk AML or MDS with mutated TP53, IS-FREE TREG GRAFT_ENGINEERED HaploHCT for relapsed/refractory AML or MDS EB-2 (Closed to Accrual) |
| CyclophosphamideAlso: cytophosphaneFor 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 | IS-FREE TREG GRAFT_ENGINEERED HaploHCT for Ultra high-risk AML or MDS with mutated TP53, IS-FREE TREG GRAFT_ENGINEERED HaploHCT for relapsed/refractory AML or MDS EB-2 (Closed to Accrual) |
| MesnaAlso: MesnexFor 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 | Drug | IS-FREE TREG GRAFT_ENGINEERED HaploHCT for Ultra high-risk AML or MDS with mutated TP53, IS-FREE TREG GRAFT_ENGINEERED HaploHCT for relapsed/refractory AML or MDS EB-2 (Closed to Accrual) |
| Treg-enriched donor cellTarget '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 | IS-FREE TREG GRAFT_ENGINEERED HaploHCT for Ultra high-risk AML or MDS with multi-hit or CK+ mut-TP53, IS-FREE TREG GRAFT_ENGINEERED HaploHCT for Ultra high-risk AML or MDS with mutated TP53, IS-FREE TREG GRAFT_ENGINEERED HaploHCT for relapsed/refractory AML or MDS EB-2 (Closed to Accrual) |
| Unmodified donor T CellUnmodified 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. | Biological | IS-FREE TREG GRAFT_ENGINEERED HaploHCT for Ultra high-risk AML or MDS with multi-hit or CK+ mut-TP53, IS-FREE TREG GRAFT_ENGINEERED HaploHCT for Ultra high-risk AML or MDS with mutated TP53, IS-FREE TREG GRAFT_ENGINEERED HaploHCT for relapsed/refractory AML or MDS EB-2 (Closed to Accrual) |
| CD34+ Haplo Peripheral Blood Stem CellThe 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. | Procedure or surgery | IS-FREE TREG GRAFT_ENGINEERED HaploHCT for Ultra high-risk AML or MDS with multi-hit or CK+ mut-TP53, IS-FREE TREG GRAFT_ENGINEERED HaploHCT for Ultra high-risk AML or MDS with mutated TP53, IS-FREE TREG GRAFT_ENGINEERED HaploHCT for relapsed/refractory AML or MDS EB-2 (Closed to Accrual) |
| MelphalanAlso: AlkeranFor 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) | Drug | IS-FREE TREG GRAFT_ENGINEERED HaploHCT for Ultra high-risk AML or MDS with multi-hit or CK+ mut-TP53 |
Primary outcome
Dose-limiting toxicities (DLT)
Time frame: 30 days after hematopoietic cell transplantation (HCT)
Safety will be assessed by dose-limiting toxicities (DLT) summarized by patient, type and grade as defined by the CTCAE v5.0.
9 secondary outcomes
Engraftment rate
Time frame: 30 days after hematopoietic cell transplantation (HCT)
secondary graft failure rate
Time frame: 100 days after hematopoietic cell transplantation (HCT)
graft vs host disease (GVHD) Rate
Time frame: 180 days after hematopoietic cell transplantation (HCT)
Mortality Rate-GVHD Relapse
Time frame: 12 months after hematopoietic cell transplantation (HCT)
Mortality Rate-GVHD Non- Relapse
Time frame: 12 months after hematopoietic cell transplantation (HCT)
Survival Rate-Relapse-Free
Time frame: 12 months after hematopoietic cell transplantation (HCT)
Progression Free-Survival (PFS)
Time frame: 12 months after hematopoietic cell transplantation (HCT)
Survival Rate-Relapse-Free-GVHD
Time frame: 12 months after hematopoietic cell transplantation (HCT)
Overall survival rate
Time frame: 12 months after hematopoietic cell transplantation (HCT)
Results and safety
This study is still under way. Results are not available in the source record yet.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 20 Oct 2025.
- Individual participant dataSharing planned: Yes. The Dana-Farber / Harvard Cancer Center encourages and supports the responsible and ethical sharing of data from clinical trials. De-identified participant data from the final research dataset used in the published manuscript may only be shared under the terms of a Data Use Agreement. Requests may be directed to: [contact information for Sponsor Investigator or designee]. The protocol and statistical analysis plan will be made available on Clinicaltrials.gov only as required by federal regulation or as a condition of awards and agreements supporting the research.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part.
John Koreth, MBBS, DPhil principal investigator
Dana-Farber Cancer Institute
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 1 study testing Radiation, Fludarabine and Thiotepa in people with Stem Cell Transplant Complications and Graft Vs Host Disease, run by Dana-Farber Cancer Institute at 1 site in United States.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 13 inclusion and 21 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: looking for participants now, as of the sponsor's last update on 20 Oct 2025. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in United States. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
This study is still under way. Results are not available in the source record yet.
How can a doctor refer a patient or contact the research team?
Contact John Koreth, MBBS, DPhil ((617) 632-2949, john_koreth@dfci.harvard.edu), or a site near the patient. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Dose-limiting toxicities (DLT) (time frame: 30 days after hematopoietic cell transplantation (HCT)). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 20 Oct 2025; AzTrials last refreshed its copy on 26 Oct 2026.