Thiotepa-based Conditioning Regimen With De-escalated Post-graft Cyclophosphamide for Allogeneic Stem Cell Transplantation in Hematologic Malignancies

Phase 1 Trial of Thiotepa-based Conditioning Regimen With De-escalated Post-graft Cyclophosphamide for Allogeneic Stem Cell Transplantation in Hematologic Malignancies

This phase 1 trial will investigate the safety and effectiveness of Thiotepa, Busulfan, and Fludarabine (TBF) conditioning regimen with post-transplant cyclophosphamide (PTCy) in HLA-matched related or unrelated donor allogeneic stem cell transplantation (alloSCT).

Study Overview

• Status: Not yet recruiting
• Conditions: Acute Leukemia; Acute Myeloid Leukemia (AML); Acute Lymphocytic Leukemia (ALL); Myelodysplastic Syndrome(MDS); High-risk Myeloproliferative Neoplasm (MPN)
• Intervention / Treatment: Drug: Thiotepa; Drug: Fludarabine; Drug: Busulfan; Procedure: PBSC infusion

Detailed Description

Allogeneic stem cell transplantation (alloSCT) offers potential cures for patients with high-risk hematologic malignancies. Establishing appropriate immune tolerance between the donor and recipient is crucial to prevent graft-versus-host disease (GVHD) and graft rejection. Over the last decade, the introduction of post-graft cyclophosphamide (PTCy)1,2 as a strategy for inducing immune tolerance has significantly transformed the landscape of alloSCT.

This trial will optimize the PTCy regimen through two main strategies: 1) de-escalating the PTCy dose to reduce toxicities, and 2) incorporating thiotepa to enhance the anti-leukemia effect. We hypothesize that this optimization will improve transplant outcomes, specifically with respect to GVHD and relapse-free survival (GRFS), for recipients of HLA-matched donor alloSCT who have high-risk hematologic malignancies. Additionally, in our exploratory aim, we will investigate potential pre-transplant biomarkers that can help stratify toxicity and relapse risks, allowing us to personalize the optimal regimen intensity for individual recipients.

• Study Type: Interventional
• Enrollment (Estimated): 48
• Phase: Phase 1

Contacts and Locations

• Study Contact: Name: Amy Rogers, RN, BSN; Phone Number: 412-623-4036; Email: rodgera@upmc.edu
• Study Contact Backup: Name: Linda Elias, RN, BSN; Phone Number: 412-623-6037; Email: eliaslj@upmc.edu

Study Locations

• United States
  • Pennsylvania
    • Pittsburgh, Pennsylvania, United States, 15213
      • UMPC Hillman Cancer Center
      • Principal Investigator: Sawa Ito, MD
      • Contact: Amy Rogers, RN, BSN; Phone Number: 412-623-4036; Email: rodgera@upmc.edu
      • Contact: Linda Elias, RN, BSN; Phone Number: 412-623-6037; Email: eliaslj@upmc.edu

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Patients must be considered appropriate candidates for either the low- or high-intensity conditioning regimen for allogeneic hematopoietic stem cell transplantation based on the following age-related criteria:

   1. Age 50-70 years old or
   2. Age 18-49 and unfit for a conventional myeloablative conditioning regimen per the treating physician

2. Patients have one of the following diagnoses:

   1. Acute lymphocytic leukemia (ALL) in first or subsequent morphological remission (<5% marrow blasts by morphology).
   2. Acute myeloid leukemia (AML) in first or subsequent morphological remission (<5% marrow blasts by morphology) with or without hematologic recovery.
   3. 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 or chronic myeloid leukemia with blast crisis) in first or subsequent morphological remission (<5% marrow blasts by morphology) with or without hematologic recovery.
   4. Myelodysplastic syndrome (MDS) with a history of excess blasts, with >5% marrow blasts by morphology after receiving at least one cycle of treatment, including but not limited to hypomethylating agent, BCL-2 inhibitor, cytoreductive chemotherapy.
   5. High-risk myeloproliferative neoplasm (MPN) with no evidence of high-grade bone marrow fibrosis or massive splenomegaly at the time of enrollment.
3. Patients with an 8/8 HLA-matched (HLA-A, B, C, DRB1) related or unrelated donor capable of donating peripheral blood stem cells (PBSC)
4. Provision of signed and dated informed consent form
5. Sexually active fertile subjects and their partners must agree to use highly effective methods of contraception prior to study entry, during the course of the study, and until tacrolimus or other immunosuppressive therapy for GVHD is discontinued (whichever is later). An additional contraceptive method, such as a barrier method (e.g., condom), is required. In addition, men must agree not to donate sperm and women must agree not to donate eggs (ova, oocyte) for the purpose of reproduction during these same periods.

6. Female subjects of childbearing potential must not be pregnant or breastfeeding at screening. Female subjects are considered to be of childbearing potential unless one of the following criteria is met:

   1. Permanent sterilization (hysterectomy, bilateral salpingectomy, or bilateral oophorectomy) or documented postmenopausal status (defined as 12 months of amenorrhea in a woman > 45 years-of-age in the absence of other biological or physiological causes). Note: Documentation may include review of medical records, medical examination, or medical history interview by study site staff.

Exclusion Criteria:

Subjects will be excluded from the study if they meet any of the following criteria.

For high-intensity regimen:

1. Poor performance status with Karnofsky Score <70%
2. Center for International Blood and Marrow Transplant Research (CIBMTR) hematopoietic cell transplant co-morbidity index (HCT-CI) score >5
3. Patients with active central nervous system (CNS) involvement refractory to intrathecal chemotherapy and/or standard craniospinal radiation.
4. Patients who are positive for HIV-1, HIV-2, HTLV1 or HTLV2.
5. Patients with uncontrolled infections for whom alloSCT is considered contraindicated by the consulting infectious disease physician.

6. Patients with organ dysfunction, including:

   1. Renal insufficiency creatinine clearance <45 ml/min/1.72m2 measured by 24-hr urine specimen
   2. Left ventricular ejection fraction <45%
   3. Diffusing capacity of the lung for carbon monoxide (DLCO) corrected <50% or FEV1 <50%
   4. Liver function abnormality: total bilirubin, aspartate aminotransferase (AST), and alanine aminotransferase (ALT) >5 times the upper limit of normal should be evaluated by a gastroenterologist. If a gastroenterologist considers that alloSCT is contraindicated, the patient will be excluded from the protocol.
7. Patients who have received previous allogeneic transplantation.
8. Patients with a life expectancy <12 months due to co-existing diseases other than hematologic malignancies.
9. Patients with any other significant medical conditions that would make them unsuitable for transplantation, as determined by the PI.
10. Patients with a known hypersensitivity to cyclophosphamide, thiotepa, fludarabine, busulfan, tacrolimus, or mycophenolate mofetil (MMF).
11. Patients who have received checkpoint inhibitors within three months of transplantation, unless an exception is made by the PI.

For low-intensity regimen

1. Poor performance status with Karnofsky Score <60%
2. Patients with active CNS involvement refractory to intrathecal chemotherapy and/or standard craniospinal radiation.
3. Patients who are positive for HIV-1, HIV-2, HTLV1 or HTLV2.
4. Patients with uncontrolled infections for whom alloSCT is considered contraindicated by the consulting infectious disease physician.

5. Patients with organ dysfunction, including:

   1. Renal insufficiency creatinine clearance <40 ml/min/1.72m2 measured by 24-hr urine specimen
   2. Left ventricular ejection fraction <40%
   3. DLCO corrected< 50% or FEV1<50%
   4. Liver function abnormality: total bilirubin, AST, ALT>5 times the upper limit of normal should be evaluated by a gastroenterologist. If a gastroenterologist considers that alloSCT is contraindicated, the patient will be excluded from the protocol.
6. Patients who have received previous allogeneic transplantation.
7. Patients with a life expectancy <12 months from co-existing disease other than hematologic malignancies
8. Patients with any other significant medical conditions that would make them unsuitable for transplantation, as determined by the PI.
9. Patients with a known hypersensitivity to cyclophosphamide, thiotepa, fludarabine, busulfan, tacrolimus, or mycophenolate mofetil (MMF).
10. Patients who have received checkpoint inhibitors within three months of transplantation, unless an exception is made by the PI.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Cohort 1: T1FluBu2 (low-intensity); Thiotepa: 5 mg/kg - administered on Day -5 prior to PBSC infusion Fludarabine: 30 mg/m2/day - administered on Day -4, Day -3, Day -2 and Day -1 prior to PBSC infusion Busulfan: 3.2 mg/kg/day IV - administered on Day -4 and Day -3 prior to PBSC infusion PBSC infusion: given on Day 0	Drug: Thiotepa; Thiotepa is an alkylating agent used in combination with other chemotherapy agents to treat cancer.; Other Names: Tepadina; Drug: Fludarabine; Fludarabine is a chemotherapy drug used in the treatment of chronic lymphocytic leukemia. It acts at DNA polymerase alpha, ribonucleotide reductase and DNA primase, results in the inhibition of DNA synthesis, and destroys the cancer cells.; Drug: Busulfan; Busulfan is a chemotherapy drug used in preparation for a stem cell transplant.; Procedure: PBSC infusion; Peripheral Blood Stem Cell (PBSC) infusion is a medical procedure used to replace diseased or damaged stem cells in patients, particularly after cancer treatments.
Experimental: Cohort 2: T2FluBu2 (high-intensity); Thiotepa: 5 mg/kg - administered on Day -5 prior to PBSC infusion Fludarabine: 40 mg/m2/day - administered on Day -4, Day -3, Day -2 and Day -1 prior to PBSC infusion Busulfan: 3.2 mg/kg/day IV - administered on Day -4 and Day -3 prior to PBSC infusion PBSC infusion: given on Day 0	Drug: Thiotepa; Thiotepa is an alkylating agent used in combination with other chemotherapy agents to treat cancer.; Other Names: Tepadina; Drug: Fludarabine; Fludarabine is a chemotherapy drug used in the treatment of chronic lymphocytic leukemia. It acts at DNA polymerase alpha, ribonucleotide reductase and DNA primase, results in the inhibition of DNA synthesis, and destroys the cancer cells.; Drug: Busulfan; Busulfan is a chemotherapy drug used in preparation for a stem cell transplant.; Procedure: PBSC infusion; Peripheral Blood Stem Cell (PBSC) infusion is a medical procedure used to replace diseased or damaged stem cells in patients, particularly after cancer treatments.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
GVHD-free, relapse-free survival (GRFS)	Graft Versus Host Disease (GVHD)-free, relapse-free survival (GRFS) is defined by survival without a qualifying event including Death, Relapse of primary disease, Grade III-IV acute graft-versus-host disease (GVHD), graded via MAGIC criteria, Chronic moderate or severe GVHD requiring systemic immunosuppression, graded via NIH consensus criteria.	At 1 year

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Median time to neutrophil engraftment	Median time to neutrophil engraftment will be defined as the median number of days from transplant at which the cumulative engraftment rate reaches 50%.	Up to 30 days
Median time to platelet engraftment	Median number of days from transplant at which the cumulative engraftment rate of platelet recovery to 20,000/mm3 and 50,000/mm3 reaches 50% respectively.	Up to 30 days
Frequency of severe mucositis	Percentage of patients experiencing severe mucositis, defined as grade 3-4 by WHO criteria.	Up to 30 days post-transplant
Frequency of total parental nutrition	Percentage of patients who require TPN at any time from the start of conditioning through day +30 post-transplant.	Up to 30 days post-transplant
Frequency of severe pulmonary complications requiring ICU-level support	Percentage of patients with first occurrence of any respiratory failure, severe infectious lower respiratory tract infection, or noninfectious acute lung injury, requiring ICU-level support between Day 0 and Day +30 after stem cell infusion. ICU-level support is defined by either 1) ICU admission due to respiratory failure, 2) need for new non-invasive ventilation (BiPAP or CPAP), or 3) requirement of high-flow nasal cannula >30L/min at FiO2>40%.	Up to 30 days
Cumulative incidence of infectious disease complications	Cumulative incidence of all Grade II and higher infections will be reported according to Blood and Marrow Transplant Clinical Trials Network (BMT-CTN) Infection Grading Criteria. The BMT CTN grading system provides a standardized approach for capturing and monitoring infectious complications in clinical trials.	Up to 1-year post-transplant
Cumulative incidence of thrombotic microangiopathy	. Microangiopathic hemolytic anemia, defined by: a. Evidence of schistocytes on peripheral blood smear, and b. Elevated lactate dehydrogenase (LDH) above the upper limit of normal, and c. Decreased haptoglobin or other laboratory evidence of hemolysis (e.g., indirect hyperbilirubinemia), and d. Negative Coombs (direct antiglobulin) test.; Thrombocytopenia: a. New or progressive thrombocytopenia not explained by disease relapse, infection, drug effect, or disseminated intravascular coagulation (DIC).; Renal and/or neurologic dysfunction temporally associated with hemolysis, not fully explained by other causes: a. Rising serum creatinine or new/worsening hypertension, and/or b. New-onset or worsening neurologic signs/symptoms (e.g., confusion, seizures, focal deficits).; No alternative explanation: a. ADAMTS13 activity not suggestive of TTP (if available) and clinical evaluation not consistent with DIC, severe sepsis, or malignant hypertension as the primary cause.	Up to 180 days post-transplant
Grade III-IV acute GVHD-free survival	Time from date of stem cell infusion to the first occurrence of grade III or IV acute Graft Versus Host Disease (GVHD), with follow-up through 100 days post-transplant or death.	Up to 100 days post-transplant
Moderate to severe chronic GVHD-free survival	Time from date of stem cell infusion to the first occurrence of moderate-to-severe chronic Graft Versus Host Disease (GVHD) with follow up through 1-year post-transplant or death.	At 1 year1 year post-transplant
Primary graft failure	Failure to achieve an absolute neutrophil count (ANC) > 0.5 x 109/L by day +42 after stem cell infusion.	Up to Day 42

Collaborators and Investigators

• Sponsor: Sawa Ito, MD
• Investigators: Principal Investigator: Sawa M Ito, MD, UPMC Hillman Cancer Center

Study record dates

Study Major Dates

• Study Start (Estimated): June 1, 2026
• Primary Completion (Estimated): June 1, 2029
• Study Completion (Estimated): November 1, 2030

Study Registration Dates

• First Submitted: April 27, 2026
• First Submitted That Met QC Criteria: April 27, 2026
• First Posted (Actual): May 4, 2026

Study Record Updates

• Last Update Posted (Actual): May 4, 2026
• Last Update Submitted That Met QC Criteria: April 27, 2026
• Last Verified: April 1, 2026

More Information

Terms related to this study

• Keywords: HLA; allogeneic hematopoietic stem cell transplantation; graft-versus-host disease (GVHD)
• Additional Relevant MeSH Terms: Neoplasms; Immune System Diseases; Neoplasms by Histologic Type; Hematologic Diseases; Lymphatic Diseases; Lymphoproliferative Disorders; Immunoproliferative Disorders; Leukemia, Myeloid; Bone Marrow Diseases; Leukemia, Lymphoid; Leukemia; Hemic and Lymphatic Diseases; Leukemia, Myeloid, Acute; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Myelodysplastic Syndromes; Graft vs Host Disease; Sulfur Compounds; Organic Chemicals; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Hydrocarbons, Acyclic; Hydrocarbons; Alkanes; Alcohols; Butylene Glycols; Glycols; Mesylates; Alkanesulfonates; Alkanesulfonic Acids; Sulfonic Acids; Sulfur Acids; Phosphoramides; Organophosphorus Compounds; Triethylenephosphoramide; Aziridines; Azirines; Busulfan; Thiotepa; fludarabine
• Other Study ID Numbers: HCC 26-008

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No