Allogeneic Stem Cell Transplant Recipient
Conditions
Brief summary
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
DRUGFludarabine
Patients will receive fludarabine administered at the dose of 30 mg/m2 intravenously daily on Days -6 to -2
RADIATIONIntermediate-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
Patients will receive post-transplant cyclophosphamide (PTCy) administered at the dose of 40 mg/kg intravenously on Days +3 to +4.
DRUGTacrolimus
Patients will receive tacrolimus administered at a dose adjusted to maintain trough levels between 5-15 ng/mL orally starting on Days +5.
DRUGMycophenolate 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.
Sponsors
Hackensack Meridian Health
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 65 Years
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Overall survival (OS) at 1-year following treatment with fludarabine plus intermediate-dose total body irradiation (TBI 800 cGy) with post-transplant cyclophosphamide (PTCy) | 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 | OS is defined as the time from the first dose of study treatment to the time of death due to any cause. Patients who are still alive will be censored at the date last known alive of the data cut-off date (if applicable), whichever is earlier. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| 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) | 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 | TRM is defined as death due to causes unrelated to the underlying disease. Patients relapsing are censored as surviving at the time of relapse. |
| 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) | 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 | Acute GVHD will be assessed using the Przepiorka criteria,13 Modified Glucksberg/Keystone criteria, and Center for International Blood and Marrow Transplant Research (CIBMTR) severity index (A-D) according to HMH's standard operating procedure (SOP), "Management of Acute Graft versus Host Disease, BMT 500 15." |
| 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) | Patients will be assessed for chronic GVHD signs and/or symptoms at a minimum of every three months for the first year post-transplant. | Chronic GVHD will be assessed based on the 2014 National Institutes of Health (NIH) Consensus Conference Criteria according to HMH's SOP, "Chronic Graft Versus Host Disease, BMT 500 11." |
| 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) | 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 | GVHD-free, relapse-free survival (GRFS) is a composite endpoint that includes grades 3-4 acute GVHD, chronic GVHD requiring systemic therapy, relapse, or death in the first post-transplant 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) | 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 | Disease status assessment is based on the CIBMTR criterion (see section 8 for more information). |
| Relapse rate at 1-year following treatment with fludarabine plus intermediate-dose total body irradiation (TBI 800 cGy) with post-transplant cyclophosphamide (PTCy) | 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 | Relapse is based on the CIBMTR criterion (see section 8 for more information). |
| Incidence of Treatment-Emergent Adverse Events with fludarabine plus intermediate-dose total body irradiation (TBI 800 cGy) with post-transplant cyclophosphamide (PTCy) | 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. | Adverse events (AEs) will be assessed and graded according to the Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 or severity grade when CTCAE grading does not exist. Grade 1 to 5 will be used to characterize the severity of the AE. If CTCAE grading does not exist for an AE, the severity of mild, moderate, severe, life-threatening and death due to the AE, corresponding respectively to Grades 1 - 5, will be used. This grading system applies except for hematological toxicity where grade 4 cytopenias are anticipated in transplant recipients. |
Countries
United States
Contacts
CONTACTOncology Clinical Research Referral Office
PRINCIPAL_INVESTIGATORMichele Donato, MD
Hackensack Meridian Health
Outcome results
None listed