Thiotepa Plus Fludarabine+ Melphalan as the Preparative Regime for Alternative Donor Transplantation

Phase 2
Completed
Conditions
Leukemia
Interventions
Drug: Melphalan
Drug: Thiotepa
Drug: Fludarabine
Registration Number
NCT03342196
Lead Sponsor
Case Comprehensive Cancer Center
Brief Summary

In the United States, thiotepa has been utilized in reduced intensity conditioning regimens for alternative donor courses (double umbilical cord blood transplant (dUCBT) and haplo-identical transplants).
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Detailed Description

Primary Objective:

To assess the effectiveness of Thiotepa, Fludarabine, and Melphalan in alternative donor transplants as measured by leukemia free survival.

Secondary Objective:

To assess the 1- year OS, Relapse, TRM, aGVHD and cGVHD rates and the rates of neutrophil and platelet engraftment.
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Recruitment & Eligibility

Status
COMPLETED
Sex
All
Target Recruitment
40
Inclusion Criteria

  • Patients with the following hematologic malignancies:

    • Acute myelogenous leukemia (AML): High-risk AML including:

      • Antecedent hematological disease (e.g., myelodysplasia (MDS))
      • Treatment-related leukemia
      • Complete Remission (CR1) with poor-risk cytogenetics or molecular markers (e.g. Flt 3 mutation, 11q23, del 5, del 7, complex cytogenetics)
      • Second complete remission (CR2) or third complete remission (CR3)
      • Induction failure or 1st relapse with ≤ 10% blasts in the marrow

    • Acute lymphoblastic leukemia (ALL)

      • High-risk CR1 including:

        • Poor-risk cytogenetics (e.g., Philadelphia chromosome t(9;22)or 11q23 rearrangements)
        • Presence of minimal disease by flow cytometry after 2 or more cycles of chemotherapy

      • No CR within 4 weeks of initial treatment

      • Induction failure with ≤ 10% blasts in the marrow

      • CR2 or CR3

    • Myelodysplastic syndromes (MDS), Intermediate, High or Very High Risk by the revised international prognostic scoring system (IPSS-R)

    • Mixed Phenotypic Leukemia / Biphenotypic Leukemiain CR

    • Chronic Myelogenous Leukemia (CML) in second chronic phase after accelerated or blast crisis.

    • Myelofibrosis (MF):

      • Intermediate-2 or high risk by Dynamic International Prognostic Scoring System (DIPSS-plus) or
      • Monosomal karyotype or
      • Presence of inv(3)/i(17q) abnormalities or
      • Other unfavorable karyotype OR leukocytes ≥40 × 10(9) /L and
      • Circulating blasts ≤ 9%

    • Relapsed or Refractory Lymphoid Malignancies (including non-Hodgkin Lymphoma, Hodgkin Lymphoma and Chronic Lymphocytic Leukemia) meeting the following criteria:

      • Disease status: Stable Disease, Partial Remission or 2nd and 3rd Complete Remission. OR
      • Have relapsed after autologous transplant or who have failed to collect for an autologous transplant.

  • Eastern Cooperative Oncology Group (ECOG) Performance status ≤ 2

  • Patients without a matched related or unrelated donor

  • Patient with either one or both:

    • Two 5/8 human leukocyte antigen (HLA) high resolution matched umbilical cord blood (UCB) grafts with a cell dose of 2.0x10^7 total number of nucleated cells per kilogram (TNC/kg) each, or
    • A related haplo-identical donor

  • Concurrent Therapy for Extramedullary Leukemia or central nervous system (CNS) Lymphoma: Concurrent therapy or prophylaxis for testicular leukemia, CNS leukemia, and CNS lymphoma including standard intrathecal chemotherapy and/or radiation therapy will be allowed as clinically indicated. Such treatment may continue until the planned course is completed. Subjects must be in CNS remission at the time of protocol enrollment if there is a history of CNS involvement. Maintenance therapy after transplant is allowed.

  • Subjects must have the ability to understand and the willingness to sign a written informed consent document.

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Exclusion Criteria

  • Patients with inadequate Organ Function as defined by:

    • Creatinine clearance <50ml/min
    • Bilirubin > twice institutional upper limit of normal
    • aspartate aminotransferase (AST) serum glutamic-oxaloacetic transaminase (SGOT) ≥ three times institutional upper limit of normal
    • Alanine aminotransferase (ALT) serum glutamic pyruvic transaminase (SGPT) ≥ three times institutional upper limit of normal
    • Pulmonary function: diffusing capacity of the lung for carbon monoxide corrected for hemoglobin (DLCOc) < 60% normal
    • Cardiac: left ventricular ejection fraction < 50%
    • Karnofsky Performance Statue (KPS) < 80

  • Patients with uncontrolled inter-current illness including, but not limited to ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements.

  • Pregnant or breastfeeding women are excluded from this study because chemotherapy involved with Reduced Intensity Conditioning (RIC) have the significant potential for teratogenic or abortifacient effects.

  • Any condition that would, in the investigator's judgment, interfere with full participation in the study, including administration of study drug and attending required study visits; pose a significant risk to the subject; or interfere with interpretation of study data.

  • Known allergies, hypersensitivity, or intolerance to any of the study medications, excipients, or similar compounds

  • Presence of donor-specific antibodies against chosen graft source.

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Study & Design

Study Type
INTERVENTIONAL
Study Design
SINGLE_GROUP
Arm && Interventions
GroupInterventionDescription
Thiotepa + Fludarabine + MelphalanMelphalanMelphalan 100 mg/m2 on day -8 Thiotepa 10 mg/kg on day -7 Fludarabine 160 mg/m2 in divided doses given on days -6, -5, -4 and -3.
Thiotepa + Fludarabine + MelphalanThiotepaMelphalan 100 mg/m2 on day -8 Thiotepa 10 mg/kg on day -7 Fludarabine 160 mg/m2 in divided doses given on days -6, -5, -4 and -3.
Thiotepa + Fludarabine + MelphalanFludarabineMelphalan 100 mg/m2 on day -8 Thiotepa 10 mg/kg on day -7 Fludarabine 160 mg/m2 in divided doses given on days -6, -5, -4 and -3.
Primary Outcome Measures
NameTimeMethod
Percentage of patients with leukemia free survivalUp to 1 year after transplant

Leukemia Free Survival (LFS) at 1 year is the percentage of patients alive and without evidence of hematologic malignancy at 1 year after transplant.

Secondary Outcome Measures
NameTimeMethod
Relapse incidenceUp to 1 year after transplant

Relapse incidence at 1 year is the percentage of patients who experience relapse of their hematologic malignancy up to 1 year after transplant.

Treatment Related MortalityUp to 1 year after transplant

Treatment Related Mortality (TRM) at 1 year is the percentage of patients who expire from treatment related toxicity attributed to transplant up to 1 year after transplant.

Incidence of acute GVHDUp to 1 year after transplant

Acute graft versus host disease (aGVHD) 1 year cumulative incidence is the percentage of patients who experience any aGVHD up to 1 year after transplant.

Rate of neutrophil engraftmentUp to 1 year after transplant

Neutrophil engraftment will be calculated as the days from transplant where the absolute neutrophil count (ANC) reaches \>500cells/ul x 3 days.

Average overall survivalUp to 1 year after transplant

Overall Survival (OS) at 1 year is the percentage of patients alive at 1 year after transplant.

Incidence of chronic GVHDUp to 1 year after transplant

Chronic graft versus host disease (cGVHD) 1-year cumulative incidence is the percentage of patients who experience any cGVHD up to 1 year after transplant.

Rate of platelet engraftmentUp to 1 year after transplant

Platelet engraftment will be calculated as the days from transplant where the platelet count reaches 20,000 platelets /ul without the need of transfusion of platelets for 7 days.

Trial Locations

Locations (1)

University Hospitals Seidman Cancer Center, Case Comprehensive Cancer Center

🇺🇸

Cleveland, Ohio, United States

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