Fludarabine and Intermediate-dose TBI Followed by PTCy in Patients Undergoing Allo Transplant for Heme Malignancies

Official title

A Phase 2 Study of Fludarabine and Intermediate-dose Total Body Irradiation (800 cGy) Followed by Post-transplant Cyclophosphamide in Patients Aged 18-65 Undergoing Allogeneic Stem Cell Transplant for Hematologic Malignancies

Overview

The Flu-TBI 800 trial is a prospective, single-arm, multicenter, interventional phase 2 study to evaluate whether fludarabine plus intermediate-dose total body irradiation (TBI 800 cGy) with post-transplant cyclophosphamide (PTCy) (experimental regimen) improves the 1-year survival of allogeneic stem cell transplant recipients.

Detailed description

Patients who meet all the inclusion criteria for the study will be enrolled to receive a conditioning regimen consisting of fludarabine, administered at a dose of 30 mg/m2 daily on Days -6 to -2, plus intermediate-dose total body irradiation (TBI), administered at a dose of 800 cGy in 4 total fractions, 2 fractions on Days -2 and and 2 fractions on day -1, followed by an infusion of hematopoietic stem cells on Day 0. GVHD prophylaxis will consist of post-transplant cyclophosphamide (PTCy), administered at a dose of 40 mg/kg on Days +3 and +4, as well as tacrolimus (starting on Day +5) and mycophenolate mofetil (on Days +5 to +35).

Interventions

• Drug Fludarabine
  Patients will receive fludarabine administered at the dose of 30 mg/m2 intravenously daily on Days -6 to -2
• Radiation Intermediate-dose Total Body Irradiation (TBI)
  Patients will receive intermediate-dose total body irradiation (TBI) administered at the dose of 800 cGy in 4 total fractions, 2 fractions per day on Days -2 to -1
• Drug Post-transplant Cyclophosphamide (PTCy)
  Patients will receive post-transplant cyclophosphamide (PTCy) administered at the dose of 40 mg/kg intravenously on Days +3 to +4.
• Drug Tacrolimus
  Patients will receive tacrolimus administered at a dose adjusted to maintain trough levels between 5-15 ng/mL orally starting on Days +5.
• Drug Mycophenolate mofetil (MMF)
  Patients will receive mycophenolate mofetil (MMF) administered at the standard dose of 15 mg/kg orally three times daily starting on Day +5 to Day +35 or per institutional guidelines.

Primary outcome measures

• Overall survival (OS) at 1-year following treatment with fludarabine plus intermediate-dose total body irradiation (TBI 800 cGy) with post-transplant cyclophosphamide (PTCy) [Time frame: Patient status (dead or alive) will be reviewed (e.g., through patient chart review,patient phone call, etc.) up through a period of 1 year]

Secondary outcome measures (7)

• Transplant-related mortality (TRM) at 1-year following treatment with fludarabine plus intermediate-dose total body irradiation (TBI 800 cGy) with post-transplant cyclophosphamide (PTCy) [Time frame: Patient status (dead or alive) will be reviewed (e.g., through patient chart review,patient phone call, etc.) up through a period of 1 year]
• Incidence of grade III-IV acute GVHD following treatment with fludarabine plus intermediate-dose total body irradiation (TBI 800 cGy) with post-transplant cyclophosphamide (PTCy) [Time frame: Patients will be assessed for acute GVHD symptoms weekly from day +7 until day +100. If acute GVHD symptoms remain active after day +100, weekly GVHD documentation will be encouraged until symptom(s) resolution, up through a period of 1 year]
• Incidence of chronic GVHD at 1-year following treatment with fludarabine plus intermediate-dose total body irradiation (TBI 800 cGy) with post-transplant cyclophosphamide (PTCy) [Time frame: Patients will be assessed for chronic GVHD signs and/or symptoms at a minimum of every three months for the first year post-transplant.]
• GVHD-free, relapse-free survival (GRFS) at 1-year following treatment with fludarabine plus intermediate-dose total body irradiation (TBI 800 cGy) with post-transplant cyclophosphamide (PTCy) [Time frame: Patient status (GVHD-free, relapse-free or not) will be reviewed (e.g., throughpatient chart review, patient phone call, etc.) up through a period of 1 year]
• Disease status assessment 2-4 months following treatment with fludarabine plus intermediate-dose total body irradiation (TBI 800 cGy) with post-transplant cyclophosphamide (PTCy) [Time frame: Patient disease status assessments (e.g., PET-CT, bone marrow, peripheral blood,etc.) will be reviewed (e.g., through patient chart review, etc.) up through a period of 2-4 months following treatment]
• Relapse rate at 1-year following treatment with fludarabine plus intermediate-dose total body irradiation (TBI 800 cGy) with post-transplant cyclophosphamide (PTCy) [Time frame: Patient status (relapse or continued response) will be reviewed (e.g., throughpatient chart review, patient phone call, etc.) up through a period of 1 year]
• Incidence of Treatment-Emergent Adverse Events with fludarabine plus intermediate-dose total body irradiation (TBI 800 cGy) with post-transplant cyclophosphamide (PTCy) [Time frame: Following treatment and allogeneic stem cell transplant, all participants will befollowed for safety throughout treatment and the hospital admission as well as longer termsafety follow-up assessments every 3 months for a period of approximately 1 year.]

Eligibility criteria

Inclusion criteria

• Patients ages 18-65 years.
• Patients with a diagnosis of one of the following hematologic malignancies:
• Acute myeloid leukemia or chronic myeloid leukemia with no circulating blasts and less than 5% blasts in the bone marrow;
• Myelodysplastic syndrome with less than 5% blasts in the bone marrow by IHC or flow cytometry whichever is highest;
• Myeloproliferative neoplasms with less than 5% blast in the marrow and peripheral blood;
• Acute lymphoblastic leukemia in CR (CIBMTR criteria); or Lymphoma in CR (CIBMTR criteria).
• Patients who are eligible for allogeneic stem cell transplant per Transplant Program SOPs.
• Patients with a Karnofsky performance status (KPS) of ≥60%.
• Patients with adequate organ function defined by:

• Cardiac: LVEF ≥50%
• Pulmonary: DLCO ≥50% of predicted
• Hepatic: Bilirubin ≤1.5x ULN, ALT/AST ≤2.5x ULN
• Renal: Creatinine clearance ≥50 mL/min
• All participants of reproductive potential must use effective contraception following allogeneic hematopoietic stem cell transplantation (allo-HSCT), in accordance with guidelines from the American Society for Transplantation and Cellular Therapy (ASTCT), the FDA, and other expert bodies.
• For Male Participants:

○ Male participants must use effective contraception for at least 12 months after transplant, and longer if receiving immunosuppressive or cytotoxic medications. Chemotherapy and radiation can cause DNA damage to sperm, and even if fertility returns, mutations may persist for months. In cases where drugs such as mycophenolate mofetil (MMF) or lenalidomide are used, FDA guidance requires contraception for at least 90 days after discontinuation. Sperm cryopreservation should be offered prior to conditioning. Participants must avoid fathering a child during this time frame.15-17

• For Female Participants:

• Female participants of childbearing potential are required to use highly effective contraception for a minimum of 12 to 24 months post-transplant, or longer if still receiving immunosuppressive or teratogenic therapy. For drugs such as MMF, sirolimus, or ruxolitinib, contraception must continue for 3 months after the last dose.
• A woman is considered to be of childbearing potential if she is postmenarchal, has not reached a postmenopausal state (≥ 12 continuous months of amenorrhea with no identified cause other than menopause), and has not undergone surgical sterilization (removal of ovaries and/or uterus). The definition of childbearing potential may be adapted for alignment with local guidelines or requirements.15-17
• Patients with a suitable donor for allogeneic stem cell transplant defined by:

• Matched sibling donors willing to donate mobilized peripheral blood (PBSC) or bone marrow (BM), meeting all institutional criteria for donation;
• Unrelated donors at >7/8 (i.e., mismatched at only one of the HLA-A, HLA-B, HLA-C, and HLA-DRB1 loci) willing to donate mobilized PBSC or BM, and medically eligible to donate cells according to National Marrow Donor Program criteria; or Related Haploidentical donors willing to donate PBSC or BM and meeting criteria for donation.
• Patients who are able to comply with follow-up visits and treatment plans.
• Patients who are able to give informed consent.

Exclusion criteria

• Hematopoietic cell transplantation comorbidity index above 3.
• Patients with a Karnofsky performance status (KPS) of <60%.
• Patients with active infections or other contraindications for allogeneic stem cell transplant.
• Patients who are unable or unwilling to give informed consent.
• Patients who have received a prior allogeneic transplant.
• Patients who are unable to comply with follow-up visits and treatment plans.

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

N/A

Model

Single group

Masking

Open label

Primary purpose

Treatment

Study locations

United States · 3 centers

• Lombardi Comprehensive Cancer Center at Georgetown University Medical Center — Washington D.C.
• John Theurer Cancer Center at Hackensack University Medical Center — Hackensack
• John Theurer Cancer Center at Jersey Shore University Medical Center — Neptune City

Publications

• Martens MJ, Lian Q, Geller NL, Leifer ES, Logan BR. Sequential monitoring of time-to-event safety endpoints in clinical trials. Clin Trials. 2025 Jun;22(3):267-278. doi: 10.1177/17407745241304119. Epub 2024 Dec 29. PMID 40396502
• Wu J, Chen L, Wei J, Weiss H, Chauhan A. Two-stage phase II survival trial design. Pharm Stat. 2020 May;19(3):214-229. doi: 10.1002/pst.1983. Epub 2019 Nov 21. PMID 31749311
• Mycophenolate REMS (Risk Evaluation and Mitigation Strategy). https://www.accessdata.fda.gov
• Vaxman I, Muchtar E, Jacob E, Kapoor P, Kumar S, Dispenzieri A, Buadi F, Dingli D, Gonsalves W, Kourelis T, Warsame R, Lacy M, Hogan W, Gertz MA. The Efficacy and Safety of Chemotherapy-Based Stem Cell Mobilization in Multiple Myeloma Patients Who Are Poor Responders to Induction: The Mayo Clinic Experience. Transplant Cell Ther. 2021 Sep;27(9):770.e1-770.e7. doi: 10.1016/j.jtct.2021.06.016. Epub PMID 34153504
• Xhaard A, Rocha V, Bueno B, de Latour RP, Lenglet J, Petropoulou A, Rodriguez-Otero P, Ribaud P, Porcher R, Socie G, Robin M. Steroid-refractory acute GVHD: lack of long-term improved survival using new generation anticytokine treatment. Biol Blood Marrow Transplant. 2012 Mar;18(3):406-13. doi: 10.1016/j.bbmt.2011.06.012. Epub 2011 Jul 4. PMID 21736868
• Sengsayadeth S, Wang T, Lee SJ, Haagenson MD, Spellman S, Fernandez Vina MA, Muller CR, Verneris MR, Savani BN, Jagasia M. Cytotoxic T-lymphocyte antigen-4 single nucleotide polymorphisms are not associated with outcomes after unrelated donor transplantation: a center for international blood and marrow transplant research analysis. Biol Blood Marrow Transplant. 2014 Jun;20(6):900-3. doi: 10.1016/j PMID 24631737
• Przepiorka D, Weisdorf D, Martin P, Klingemann HG, Beatty P, Hows J, Thomas ED. 1994 Consensus Conference on Acute GVHD Grading. Bone Marrow Transplant. 1995 Jun;15(6):825-8. PMID 7581076
• Lee JW, Cho BS, Lee SE, Eom KS, Kim YJ, Kim HJ, Lee S, Min CK, Cho SG, Min WS, Park CW. The Outcome of Unrelated Hematopoietic Stem Cell Transplants with Total Body Irradiation (800 cGy) and Cyclophosphamide (120 mg/kg) in Adult Patients with Acquired Severe Aplastic Anemia. Biol Blood Marrow Transplant. 2011 Jan;17(1):101-8. doi: 10.1016/j.bbmt.2010.06.014. Epub 2010 Jun 25. PMID 20601037

Identifiers

NCT: NCT07214688 · Pro2025-0254 · FLU-TBI-800-PTCY

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗