IS-free Treg HaploHCT
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
1 other identifier
interventional
30
1 country
1
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
Trial Health
Trial Health Score
Automated assessment based on enrollment pace, timeline, and geographic reach
participants targeted
Target at P25-P50 for phase_1
Started Jan 2021
Longer than P75 for phase_1
1 active site
Health score is calculated from publicly available data and should be used for screening purposes only.
Trial Relationships
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Study Timeline
Key milestones and dates
First Submitted
Initial submission to the registry
December 16, 2020
CompletedFirst Posted
Study publicly available on registry
December 22, 2020
CompletedStudy Start
First participant enrolled
January 12, 2021
CompletedPrimary Completion
Last participant's last visit for primary outcome
August 31, 2028
ExpectedStudy Completion
Last participant's last visit for all outcomes
August 31, 2029
October 20, 2025
October 1, 2025
7.6 years
December 16, 2020
October 16, 2025
Conditions
Keywords
Outcome Measures
Primary Outcomes (1)
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.
30 days after hematopoietic cell transplantation (HCT)
Secondary Outcomes (9)
Engraftment rate
30 days after hematopoietic cell transplantation (HCT)
secondary graft failure rate
100 days after hematopoietic cell transplantation (HCT)
graft vs host disease (GVHD) Rate
180 days after hematopoietic cell transplantation (HCT)
Mortality Rate-GVHD Relapse
12 months after hematopoietic cell transplantation (HCT)
Mortality Rate-GVHD Non- Relapse
12 months after hematopoietic cell transplantation (HCT)
- +4 more secondary outcomes
Study Arms (3)
IS-FREE TREG GRAFT_ENGINEERED HaploHCT for relapsed/refractory AML or MDS EB-2 (Closed to Accrual)
EXPERIMENTALPlease 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
EXPERIMENTALThis 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
EXPERIMENTALThis 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
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.
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)
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)
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.
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
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 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.
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.
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)
Eligibility Criteria
You may qualify if:
- 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.
You may not qualify if:
- 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.
- +6 more criteria
Contact the study team to confirm eligibility.
Sponsors & Collaborators
Study Sites (1)
Dana Farber Cancer Institute
Boston, Massachusetts, 02115, United States
MeSH Terms
Conditions
Interventions
Condition Hierarchy (Ancestors)
Intervention Hierarchy (Ancestors)
Study Officials
- PRINCIPAL INVESTIGATOR
John Koreth, MBBS, DPhil
Dana-Farber Cancer Institute
Central Study Contacts
Study Design
- Study Type
- interventional
- Phase
- phase 1
- Allocation
- NON RANDOMIZED
- Masking
- NONE
- Purpose
- TREATMENT
- Intervention Model
- PARALLEL
- Sponsor Type
- OTHER
- Responsible Party
- PRINCIPAL INVESTIGATOR
- PI Title
- Principal Investigator
Study Record Dates
First Submitted
December 16, 2020
First Posted
December 22, 2020
Study Start
January 12, 2021
Primary Completion (Estimated)
August 31, 2028
Study Completion (Estimated)
August 31, 2029
Last Updated
October 20, 2025
Record last verified: 2025-10
Data Sharing
- IPD Sharing
- Will share
- Shared Documents
- STUDY PROTOCOL, SAP, ICF
- Time Frame
- Data can be shared no earlier than 1 year following the date of publication
- Access Criteria
- Contact the Belfer Office for Dana-Farber Innovations (BODFI) at innovation@dfci.harvard.edu
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.