IS-free Treg HaploHCT

NCT ID: NCT04678401

Last Updated: 2025-10-20

Basic Information

• Recruitment Status: RECRUITING
• Clinical Phase: PHASE1
• Total Enrollment: 30 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2021-01-12
• Study Completion Date: 2029-08-31

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

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

Study Design

• Allocation Method: NON_RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

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).

Group Type: EXPERIMENTAL

Radiation

Intervention Type: 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

Intervention Type: DRUG

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

Intervention Type: DRUG

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

Intervention Type: DRUG

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

Intervention Type: DRUG

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

Intervention Type: BIOLOGICAL

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

Intervention Type: BIOLOGICAL

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

Intervention Type: PROCEDURE

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.

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).

Group Type: EXPERIMENTAL

Radiation

Intervention Type: 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

Intervention Type: DRUG

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

Intervention Type: DRUG

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

Intervention Type: DRUG

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

Intervention Type: DRUG

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

Intervention Type: BIOLOGICAL

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

Intervention Type: BIOLOGICAL

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

Intervention Type: PROCEDURE

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.

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).

Group Type: EXPERIMENTAL

Radiation

Intervention Type: 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

Intervention Type: DRUG

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

Intervention Type: DRUG

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)

Treg-enriched donor cell

Intervention Type: BIOLOGICAL

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

Intervention Type: BIOLOGICAL

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

Intervention Type: PROCEDURE

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

Intervention Type: DRUG

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)

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.

Intervention Type: RADIATION

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)

Intervention Type: 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)

Intervention Type: 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.

Intervention Type: 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

Intervention Type: DRUG

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.

Intervention Type: 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.

Intervention Type: BIOLOGICAL

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.

Intervention Type: PROCEDURE

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)

Intervention Type: DRUG

Other Intervention Names

Radiotherapy, TMLI, TBI; Fludara; Tepadina; cytophosphane; Mesnex; Alkeran

Eligibility Criteria

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.

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 75 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Dana-Farber Cancer Institute

OTHER

Sponsor Role: lead

Responsible Party

John Koreth, MD

Principal Investigator

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

John Koreth, MBBS, DPhil

Role: PRINCIPAL_INVESTIGATOR

Dana-Farber Cancer Institute

Locations

Dana Farber Cancer Institute

Boston, Massachusetts, United States

Site Status: RECRUITING

Countries

United States

Central Contacts

John Koreth, MBBS, DPhil

Role: CONTACT

john_koreth@dfci.harvard.edu

(617) 632-2949

Facility Contacts

John Koreth, MBBS, DPhil

Role: primary

john_koreth@dfci.harvard.edu

617-632-5168

Other Identifiers

20-336

Identifier Type: -

Identifier Source: org_study_id