Clinical Trials /

IMRT-TMI With Fludarabine as Myeloablative Conditioning for Allogeneic HSCT

NCT03696537

Description:

The purpose of this study is to find the maximum tolerated dose (MTD) of Total Marrow Irradiation (TMI), a type of radiation treatment administered with fludarabine, a type of chemotherapy to prepare patients for allogeneic hematopoietic stem cell transplantation (Allo-HSCT). The study will also examine the efficacy of fludarabine and total marrow radiation treatment. Patients in this study will receive fludarabine and TMI during their conditioning regimen for 7 days prior to Allo-HSCT

Related Conditions:
  • Acute Lymphoblastic Leukemia
  • Acute Myeloid Leukemia
  • Chronic Myeloid Leukemia
  • Myelodysplastic Syndromes
Recruiting Status:

Recruiting

Phase:

Phase 1/Phase 2

Trial Eligibility

Document

Title

  • Brief Title: IMRT-TMI With Fludarabine as Myeloablative Conditioning for Allogeneic HSCT
  • Official Title: A Dose Escalation Study of Intensity Modulated Total Marrow Irradiation (IMRT-TMI) With Fludarabine as a Myeloablative Conditioning Regimen for Allogeneic Hematopoietic Stem Cell Transplantation for Patients With Relapsed and Refractory Hematologic Malignancies

Clinical Trial IDs

  • ORG STUDY ID: IUSCC-0652
  • NCT ID: NCT03696537

Conditions

  • Acute Myeloid Leukemia
  • Chronic Myeloid Leukemia
  • Acute Lymphatic Leukemia
  • Myelodysplastic Syndromes

Interventions

DrugSynonymsArms
FludarabineFludarabine + Total Marrow Irradiation

Purpose

The purpose of this study is to find the maximum tolerated dose (MTD) of Total Marrow Irradiation (TMI), a type of radiation treatment administered with fludarabine, a type of chemotherapy to prepare patients for allogeneic hematopoietic stem cell transplantation (Allo-HSCT). The study will also examine the efficacy of fludarabine and total marrow radiation treatment. Patients in this study will receive fludarabine and TMI during their conditioning regimen for 7 days prior to Allo-HSCT

Detailed Description

      This is a phase I/II clinical trial to determine the maximum tolerated dose (MTD) of
      intensity modulated radiation therapy based total marrow irradiation (TMI) in combination
      with fludarabine in the context of a myeloablative conditioning regimen for allogeneic
      hematopoietic stem cell transplantation (Allo-HSCT), as well as to determine the efficacy of
      the regimen in patients with high-risk and relapsed or refractory leukemia and
      myelodysplasia. TMI, which allows for conformal dosing of target bone marrow tissue while
      giving lower doses to organs at risk, is considered by many to be a superior alternative to
      conventional total body irradiation (TBI)

      Primary Objectives:

      Phase I component:

      Determine the MTD of TMI given concurrently with fludarabine (fixed at 150 mg/m2) as a
      conditioning regimen for Allo-HSCT for patients with high risk (relapsed/refractory) acute
      lymphocytic leukemia (ALL), acute myeloid leukemia (AML), myelodysplastic syndrome (MDS), and
      chronic myelogenous leukemia (CML).

      Phase II component:

      Single-arm exploratory study to expand the cohort at the MTD level to estimate 1- year
      overall survival (OS), with the objective of increasing the OS from the historical rate of
      30% (null hypothesis ) to 50% (alternate hypothesis) with 80% power and a one-sided type I
      error of 0.05.

      Secondary Objectives

        1. Describe the extramedullary toxicity and the incidence of complications, including
           mucositis, acute and chronic graft versus host disease (GvHD), sinusoidal obstruction
           syndrome (SOS), and pneumonitis.

        2. Describe the time to engraftment of neutrophils and platelets

        3. Describe the disease response rate at day 30 after transplantation

        4. Describe the overall survival and disease-free survival

        5. Describe the cumulative incidence of relapse and non-relapse mortality

        6. Determine the correlation between plasma/serum markers and radiation induced acute and
           long term toxicities.
    

Trial Arms

NameTypeDescriptionInterventions
Fludarabine + Total Marrow IrradiationExperimental
  • Fludarabine

Eligibility Criteria

        Inclusion Criteria:

          1. Patients must be diagnosed with one of the following conditions:

             Acute Myeloid Leukemia (AML) who are not in complete remission, and who have either
             primary refractory or relapsed disease, and who do not have more than one of the
             following adverse factors:

               1. Duration of first CR < 6 months (if previously in CR)

               2. Poor risk karyotype including any of the following: complex karyotype with ≥3
                  clonal abnormalities, 5q-/-5, 7q-/-7, 11q23 abnormalities, inv(3q), 20q or 21q
                  abnormalities, t(6;9), t(9;22), 17p abnormalities [or TP53 mutations] or
                  monosomal karyotype. Molecular typing (except for TP53 mutation) will not be used
                  for eligibility criteria determination.

               3. Circulating peripheral blood blasts at time of enrollment

               4. Karnofsky performance status <90%

             Acute Lymphocytic Leukemia (ALL) who are not in complete remission, and who have
             either primary refractory or relapsed disease, and who do not have more than one of
             the following adverse factors:

               1. First refractory relapse. Patients in second or subsequent relapse are excluded.

               2. Donor is CMV seropositive

               3. Bone marrow blasts >25% (within 30 days of admission)

               4. Age >40 years

             Myelodysplasia with a Revised International Prognostic Score (IPSS-R) of greater than
             4.5 (i.e., high- or very-high risk).

             Chronic Myelogenous Leukemia (CML) in either

               1. Accelerated phase, defined by any of the following:

                    -  Blasts 10-19% in peripheral blood white cells or bone marrow

                    -  Peripheral blood basophils at least 20%

                    -  Persistent thrombocytopenia (<100 x 109/l) unrelated to therapy, or
                       persistent thrombocytosis (>1000 x 109/l) unresponsive to therapy

                    -  Increasing spleen size and increasing white blood cell (WBC) count
                       unresponsive to therapy

                    -  Cytogenetic evidence of clonal evolution (i.e., the appearance of an
                       additional genetic abnormality that was not present in the initial specimen
                       at the time of diagnosis of chronic phase)

               2. Chronic phase provided a complete hematologic remission was not achieved by 3
                  months or a complete cytogenetic remission by 18 months and the patient had
                  received at least 2 tyrosine kinase inhibitors.

          2. Patient age 18-65 years

          3. Availability of a consenting human leukocyte antigens(HLA) -matched donor

          4. Karnofsky Performance Status 70% or higher

          5. Required baseline laboratory values:

               1. Estimated creatinine clearance ≥ 60 ml/min

               2. Aspartate aminotransferase and alanine aminotransferease ≤ 2.5 x upper limit of
                  normal value

               3. Bilirubin ≤ 1.5 x upper limit of normal value

          6. Required baseline cardiac function of left ventricular ejection fraction (LVEF) > 45 %
             corrected

          7. Required baseline pulmonary function of lung diffusing capacity (DLCO) > 45 %
             predicted (corrected for hemoglobin)

          8. Patient must be capable of understanding the investigational nature of this study,
             potential risks and benefits of the study, and be able to provide a valid informed
             consent.

        Exclusion Criteria:

          1. Patients with ALL who are in second or subsequent relapse

          2. Active infection: Patients with active infections requiring oral or intravenous
             antimicrobial drugs are not eligible for enrollment until resolution of infection.

          3. HIV seropositive patients.

          4. Pregnant or nursing females are excluded from this study.

          5. Prior radiation therapy

          6. Patients who have had a prior autologous or allogeneic bone marrow or stem cell
             transplantation
      
Maximum Eligible Age:65 Years
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Dose limiting toxicity (DLT) of Total Marrow Irradiation (TMI) in combination with 150 mg/m2 fludarabine
Time Frame:Day -7 of conditioning regimen through 30 days post transplant (37 days)
Safety Issue:
Description:

Secondary Outcome Measures

Measure:Frequency of non hematologic toxicities
Time Frame:100 days
Safety Issue:
Description:
Measure:Incidence of infection
Time Frame:100 days
Safety Issue:
Description:
Measure:Type of infections
Time Frame:100 days
Safety Issue:
Description:
Measure:Incidence of graft versus host disease (GvHD)
Time Frame:100 days
Safety Issue:
Description:
Measure:Incidence of chronic graft versus host disease (GvHD)
Time Frame:3 years
Safety Issue:
Description:
Measure:Incidence of sinusoidal obstruction syndrome (SOS)
Time Frame:100 days
Safety Issue:
Description:
Measure:Incidence of pneumonitis
Time Frame:100 days
Safety Issue:
Description:
Measure:Incidence of mucositis
Time Frame:100 days
Safety Issue:
Description:
Measure:Time to engraftment of neutrophils
Time Frame:from date of transplant to the first of three consecutive days after transplantation during which the absolute neutrophil count (ANC) is greater than or equal to 0.5 x 10^9/liter
Safety Issue:
Description:
Measure:Time to engraftment of platelets
Time Frame:from date of transplant until he first of seven consecutive days after transplantation during which the platelet count is greater than or equal to 20 x10^9/liters without transfusion.
Safety Issue:
Description:
Measure:Disease response rate
Time Frame:Day 30 after transplant (30 days)
Safety Issue:
Description:
Measure:Incidence of relapse mortality
Time Frame:30 days
Safety Issue:
Description:
Measure:Incidence of relapse mortality
Time Frame:100 days
Safety Issue:
Description:
Measure:Incidence of relapse mortality
Time Frame:1 year
Safety Issue:
Description:
Measure:Incidence of non-relapse mortality
Time Frame:30 days
Safety Issue:
Description:
Measure:Incidence of non-relapse mortality
Time Frame:100 days
Safety Issue:
Description:
Measure:Incidence of non-relapse mortality
Time Frame:1 year
Safety Issue:
Description:
Measure:Disease-Free Survival
Time Frame:3 years
Safety Issue:
Description:

Details

Phase:Phase 1/Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Naoyuki G. Saito, M.D., Ph.D.

Trial Keywords

  • Radiation
  • Total Marrow Irradiation
  • Fludarabine
  • Human Leukocyte Antigen donor

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