Recruiting
Phase 2

GVHD-Reduction Strategies

Sponsor:

Fred Hutchinson Cancer Center

Code:

NCT03970096

Conditions

Acute Leukemia

Acute Lymphoblastic Leukemia

Acute Myeloid Leukemia

Myelodysplastic Syndrome

Myeloproliferative Neoplasm

Eligibility Criteria

Sex: All

Age: 1 - 60

Healthy Volunteers: Not accepted

Interventions

Total-Body Irradiation

Thiotepa

Fludarabine

Tacrolimus

Allogeneic CD34+-enriched and CD45RA-depleted PBSCs

Study Details

Brief summary:

This phase II trial investigates two strategies and how well they work for the reduction of graft versus host disease in patients with acute leukemia or MDS in remission. Giving chemotherapy and total-body irradiation before a donor peripheral blood stem cell transplant helps stop the growth of cells in the bone marrow, including normal blood-forming cells (stem cells) and cancer cells. It may also stop the patient's immune system from rejecting the donor's stem cells. When the healthy stem cells from a donor are infused into the patient, they may help the patient's bone marrow make stem cells, red blood cells, white blood cells, and platelets. The donated stem cells may also replace the patient's immune cells and help destroy any remaining cancer cells.

Conditions

Acute Leukemia

Acute Lymphoblastic Leukemia

Acute Myeloid Leukemia

Myelodysplastic Syndrome

Myeloproliferative Neoplasm

Study ID

NCT03970096

Start date

Nov 19, 2019

Status verified date

Mar, 2026

Completion date

Dec 31, 2029

Anticipated

Primary completion date

Dec 31, 2027

Anticipated

Eligibility Criteria

Eligibility Criteria

Sex: All

Age: 1 - 60

Healthy Volunteers: Not accepted

Inclusion Criteria:

  • Patients who are considered appropriate candidates for myeloablative, TBI-containing allogeneic hematopoietic stem cell transplantation and have one of the following diagnoses:

  • Acute lymphocytic leukemia (ALL) in first or subsequent morphological remission (< 5% marrow blasts by morphology).
  • Acute myeloid leukemia (AML) in first or subsequent morphological remission (< 5% marrow blasts by morphology).
  • Other acute leukemia or related neoplasm (including but not limited to 'mixed phenotype' 'biphenotypic', 'acute undifferentiated' or 'ambiguous lineage' acute leukemia, blastic plasmacytoid dendritic cell neoplasm, lymphoblastic lymphoma, Burkitt leukemia/lymphoma, mast cell leukemia, chronic myeloid leukemia \[CML\] with blast crisis or other chronic myeloproliferative neoplasm) in first or subsequent morphological remission (<5% marrow blasts by morphology).
  • Myelodysplastic syndrome (MDS) with a history of excess blasts (≥ approximately 5% in marrow blasts by morphology) and a history of receiving cytoreductive therapy (including but not limited to BCL-2 inhibitors or cytotoxic chemotherapy) within the past 3 months.
  • Patient age 1-60 years old (inclusive) at the time of informed consent

  • Patients aged 1-50 years old (inclusive) are eligible for TBI-based conditioning regimens.
  • Patients aged 1-60 years old (inclusive) are eligible for busulfan-based conditioning regimens (with or without TBI 4 Gy).
  • Patient with an HLA-matched (HLA-A, B, C, DRB1, and DQB1 matched) related or unrelated donor capable of donating PBSC.
  • Recipient informed consent/assent and/or legal guardian permission must be obtained.
  • DONOR: HLA-matched related and unrelated donors (HLA-A, B, C, DRB1 and DQB1 matched based on high-resolution typing).
  • DONOR: >= 18 years old.
  • DONOR: Willing to donate PBSC.
  • DONOR: Matched related donors:

  • Must give informed consent using the related donor informed consent form.
  • Must meet institutional donor eligibility criteria or be ineligible with statement that the donor is a first or second degree relative (exception 21 Code of Federal Regulations \[CFR\] 1271.65(b)(i)).
  • DONOR: Matched unrelated donors:

  • Must consent according to the applicable National Marrow Donor Program (NMDP) donor regulatory requirements.
  • Must meet eligibility criteria as defined by the NMDP or be ineligible with statement of urgent medical need (exception 21 CFR 1271.65(b)(iii)).

Exclusion Criteria:

  • Patients with central nervous system (CNS) involvement refractory to intrathecal chemotherapy and/or standard cranial-spinal radiation. A patient may have a history of CNS disease. However, any CNS disease must be cleared by the end of the pre-conditioning evaluation time frame. If CNS disease is identified on cerebrospinal fluid (CSF) evaluation within 30 days of the start of the preparative regimen a repeat CSF evaluation must be performed and show no evidence of disease in order for the patient to be eligible for the protocol.
  • Patients on other experimental protocols for prevention of GVHD.
  • Patient weight:

  • Patients with HLA-matched related donors will be excluded if they weigh >= 110 kg.
  • Patients with HLA-matched unrelated donors will be excluded if they weigh >= 110 kg and must be discussed with the Fred Hutch protocol principal investigator (PI) if they weigh >= 90 kg.
  • Patients who are positive for human immunodeficiency virus (HIV)-1, HIV-2, human T-cell lymphotropic virus (HTLV)1 or HTLV2.
  • Patients with uncontrolled infections for whom myeloablative HCT is considered contraindicated by the consulting infectious disease physician; i.e. patients with active infections require infectious disease consultation and documentation by the infectious disease team that myeloablative HCT is not considered to be contraindicated. Upper respiratory tract infection is not considered to represent an uncontrolled infection in this context.
  • Patients with organ dysfunction, including:

  • Renal insufficiency (creatinine > 1.5 mg/dl) at the time of evaluation for the protocol. Patients with a known history of creatinine > 1.5 mg/dl or a current serum creatinine above the normal range for age must have a current creatinine clearance of > 60 ml/min/1.73 m\^2 (measured by 24-hr urine specimen or nuclear glomerular filtration rate \[GFR\]).
  • Left ventricular ejection fraction < 45%.
  • Carbon monoxide diffusing capability (DLCO) corrected < 60%. Patients who are unable to perform pulmonary function tests (for example, due to young age and/or developmental status) will be excluded if the oxygen (O2) saturation is < 92% on room air.
  • Liver function abnormality. Patients who have liver function test (LFT)s (specifically, total bilirubin, aspartate aminotransferase \[AST\] or alanine aminotransferase \[ALT\]) >= twice the upper limit of normal should be evaluated by a gastrointestinal (GI) physician unless there is a clear precipitating factor (such as an azole, MTX, trimethoprim-sulfamethoxazole, or another drug). If the GI physician considers that HCT on the protocol is contraindicated, that patient will be excluded from the protocol. Patients with Gilbert's syndrome require GI physician consultation but may be included on the protocol. Patients with no other known liver function abnormality or with reversible drug-related transaminitis do not necessarily require GI consultation and may be included on the protocol.
  • Patients who have received previous myeloablative allogeneic or autologous transplantation.
  • Patients with a life expectancy < 12 months from co-existing disease other than the leukemia or MDS.
  • Patients who are pregnant or breast-feeding.
  • Patients of childbearing age who are presumed to be fertile and are unwilling to use an effective birth control method or refrain from sexual intercourse during and for 12 months post-HCT.
  • Patients with any other significant medical conditions that would make them unsuitable for transplantation, as determined by the PI.
  • Patients with a known hypersensitivity to tacrolimus or MTX
  • Patients who have received checkpoint inhibitors within three months of transplantation unless an exception is made by the PI
  • DONOR: Donors who are HIV-1, HIV-2, HTLV-1, HTLV-2 seropositive or with active hepatitis B or hepatitis C virus infection. Test must be performed using Food and Drug Administration (FDA) licensed, cleared, and approved test kits (serological and/or nucleic acid amplification test \[NAT\] and/or other approved testing) in a Clinical Laboratory Improvement Act (CLIA)-certified laboratory.
  • Unrelated donors donating outside of the USA.

Study Design

Enrollment

120 participants

Anticipated

Allocation

Randomized

Intervention Model

Parallel Assignment

Primary purpose

Treatment

Interventions and Outcome Measures

Arms

experimental: Arm A1 (TBI, TnD)

Patients undergo TBI BID on days -10 to -7, and receive thiotepa IV over 3 hours on days -6 and -5, fludarabine IV over 30 to 60 minutes on days -6 to -2, tacrolimus (or cyclosporine or sirolimus if toxicities occur) IV continuously starting on day -1, CD34+ enriched CD45RA-depleted donor T-lymphocytes IV on day 0, and methotrexate IV on days 1, 3, 6, and 11. If there is no evidence of grade II-IV acute GVHD on or prior to day 50, tacrolimus (or cyclosporine or sirolimus) is tapered per month for capsules (or per week for liquid). Patients also undergo bone marrow aspiration/biopsy, ECHO or MUGA scan, and collection of blood samples throughout the trial.

experimental: Arm A2 (busulfan, TnD)

Patients receive fludarabine IV over 30 to 60 minutes on days -6 to -2, busulfan IV over 180 minutes on days -5 to -2, and undergo TBI BID on day -1. Patients also receive tacrolimus (or cyclosporine or sirolimus if toxicities occur) IV continuously starting on day -1, CD34+ enriched CD45RA-depleted donor T-lymphocytes IV on day 0, and methotrexate IV on days 1, 3, 6, and 11. If there is no evidence of grade II-IV acute GVHD on or prior to day 50, tacrolimus (or cyclosporine or sirolimus) is tapered per month for capsules (or per week for liquid). Patients also undergo bone marrow aspiration/biopsy, ECHO or MUGA scan, and collection of blood samples throughout the trial.

experimental: Arm C1 (TBI, PTCy, tacrolimus)

Patients undergo TBI BID on days -4 to -2 or -3 to -1, and receive PBSC IV on day 0. Patients also receive cyclophosphamide IV over 1 to 2 hours on days 3 and 4, and tacrolimus (or cyclosporine or sirolimus if toxicities occur) IV continuously starting on day 5. If there is no evidence of grade II-IV acute GVHD on or prior to day 50, tacrolimus (or cyclosporine or sirolimus) is tapered per month for capsules (or per week for liquid). Patients also undergo bone marrow aspiration/biopsy, ECHO or MUGA scan, and collection of blood samples throughout the trial.

experimental: Arm C2 (busulfan, PTCy, tacrolimus)

Patients receive fludarabine IV over 30 to 60 minutes on days -5 to -2, busulfan IV over 180 minutes on days -5 to -2, PBSC IV on day 0, cyclophosphamide IV over 1 to 2 hours on days 3 and 4, and tacrolimus (or cyclosporine or sirolimus if toxicities occur) IV continuously starting on day 5. If there is no evidence of grade II-IV acute GVHD on or prior to day 50, tacrolimus (or cyclosporine or sirolimus) is tapered per month for capsules (or per week for liquid). Patients also undergo bone marrow aspiration/biopsy, ECHO or MUGA scan, and collection of blood samples throughout the trial.

experimental: Arm D1 (TBI, tacrolimus, methotrexate) [DISCONTINUED NOVEMBER 2021]

Patients undergo TBI BID on days -6 to -4, and receive cyclophosphamide IV over 1 hour on days -3 to -2, tacrolimus (or cyclosporine or sirolimus if toxicities occur) IV continuously starting on day -1, PBSC IV on day 0, and methotrexate IV on days 1, 3, 6, and 11. If there is no evidence of grade II-IV acute GVHD on or prior to day 50, tacrolimus (or cyclosporine or sirolimus) is tapered per month for capsules (or per week for liquid). Patients also undergo bone marrow aspiration/biopsy, ECHO or MUGA scan, and collection of blood samples throughout the trial.

experimental: Arm D2 (busulfan, tacrolimus, methotrexate) [DISCONTINUED NOVEMBER 2021]

Patients receive busulfan IV over 180 minutes on days -8 to -5, cyclophosphamide IV over 1 hour on days -3 to -2, tacrolimus (or cyclosporine or sirolimus if toxicities occur) IV continuously starting on day -1, PBSC IV on day 0, and methotrexate IV on days 1, 3, 6, and 11. If there is no evidence of grade II-IV acute GVHD on or prior to day 50, tacrolimus (or cyclosporine or sirolimus) is tapered per month for capsules (or per week for liquid). Patients also undergo bone marrow aspiration/biopsy, ECHO or MUGA scan, and collection of blood samples throughout the trial.

Interventions

Total-Body Irradiation

Undergo TBI

Thiotepa

Given IV

Fludarabine

Given IV

Tacrolimus

Given IV

Allogeneic CD34+-enriched and CD45RA-depleted PBSCs

Given IV

Methotrexate

Given IV

Cyclophosphamide

Given IV

Peripheral Blood Stem Cell

Given IV

Cyclosporine

Given IV

Sirolimus

Given IV

Busulfan

Given IV

Bone Marrow Aspiration and Biopsy

Undergo bone marrow aspiration/biopsy

Echocardiography

Undergo ECHO

Multigated Acquisition Scan

Undergo MUGA

Biospecimen Collection

Undergo blood sample collection

Primary outcome measure

  • Graft versus host disease (GVHD)-free relapse-free survival (RFS) [ Time Frame: At 2 years ]

Central Contacts and Locations

Central contacts

Marie Bleakley

206-667-6572mbleakle@fredhutch.org

Locations

Moffitt Cancer Center

Recruiting

Tampa, Florida, United States, 33612

Contacts

Taiga Nishihori

813-745-4673taiga.nishihori@moffitt.org

Principal Investigator:

Taiga Nishihori

University of Pittsburgh Cancer Institute (UPCI)

Recruiting

Pittsburgh, Pennsylvania, United States, 15232

Contacts

Alison Sehgal

412-623-2861sehgalar@upmc.edu

Principal Investigator:

Alison Sehgal

Fred Hutch/University of Washington Cancer Consortium

Recruiting

Seattle, Washington, United States, 98109

Contacts

Marie Bleakley

206-667-6572mbleakle@fredhutch.org

Principal Investigator:

Marie Bleakley

More Information

Sponsor

Fred Hutchinson Cancer Center

Last update posted

Mar 12, 2026

Last verified

Mar, 2026

Keywords

  • Lymphoid Leukemia
  • Myeloid and Monocytic Leukemia
  • Other Hematopoietic

Trial information was received from ClinicalTrials.gov and was last updated on 2026-09-08. This information was provided to ClinicalTrials.gov by Fred Hutchinson Cancer Center on 2026-03-12.