Clinical Trials /

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

NCT03342196

Description:

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). The hypothesis is that thiotepa at a dose of 10mg/kg, in combination with melphalan (100mg/m2) and fludarabine (160mg/m2) as a reduced intensity conditioning regimen for alternative donor transplant is safe and effective in patients with hematologic malignancies. Given that this regimen has been investigated extensively, and the current study proposes to confirm those previous observations with a small modification (melphalan dose reduction due to previous mucositis rates with higher doses), this will be a phase II study designed to measure disease-free-survival.

Related Conditions:
  • Acute Lymphoblastic Leukemia
  • Acute Myeloid Leukemia
  • Chronic Lymphocytic Leukemia
  • Chronic Myeloid Leukemia
  • Hematopoietic and Lymphoid Malignancy
  • Hodgkin Lymphoma
  • Myelofibrosis
  • Non-Hodgkin Lymphoma
  • Primary Myelofibrosis
Recruiting Status:

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Thiotepa Plus Fludarabine+ Melphalan as the Preparative Regime for Alternative Donor Transplantation
  • Official Title: A Phase II Study of Thiotepa Added to Fludarabine and Melphalan as the Preparative Regime for Alternative Donor Transplantation

Clinical Trial IDs

  • ORG STUDY ID: CASE10Z17
  • NCT ID: NCT03342196

Conditions

  • Leukemia

Interventions

DrugSynonymsArms
MelphalanAlkeran, EvomelaThiotepa + Fludarabine + Melphalan
ThiotepaTepadinaThiotepa + Fludarabine + Melphalan
FludarabineFludaraThiotepa + Fludarabine + Melphalan

Purpose

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). The hypothesis is that thiotepa at a dose of 10mg/kg, in combination with melphalan (100mg/m2) and fludarabine (160mg/m2) as a reduced intensity conditioning regimen for alternative donor transplant is safe and effective in patients with hematologic malignancies. Given that this regimen has been investigated extensively, and the current study proposes to confirm those previous observations with a small modification (melphalan dose reduction due to previous mucositis rates with higher doses), this will be a phase II study designed to measure disease-free-survival.

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.

      Study Design This is a Phase II study of Thiotepa, Fludarabine, and Melphalan in alternative
      donor transplants.

      Subjects will be assessed for safety and tolerability (including adverse events, serious
      adverse events, and clinical/laboratory assessments) using a continuous monitoring approach.
      Subjects will be followed for up to 1 year or until progression of disease, relapse, or
      death.
    

Trial Arms

NameTypeDescriptionInterventions
Thiotepa + Fludarabine + MelphalanExperimentalMelphalan 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.
  • Melphalan
  • Thiotepa
  • Fludarabine

Eligibility Criteria

        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)

               -  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.

                    -  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.

        Exclusion Criteria:

          -  Patients with inadequate Organ Function as defined by:

               -  Creatinine clearance < 30ml/min

               -  Bilirubin > twice institutional upper limit of normal

               -  aspartate aminotransferase (AST) serum glutamic-oxaloacetic transaminase (SGOT) ≥
                  twice institutional upper limit of normal

               -  Alanine aminotransferase (ALT) serum glutamic pyruvic transaminase (SGPT) ≥ twice
                  institutional upper limit of normal

               -  Pulmonary function: diffusing capacity of the lung for carbon monoxide corrected
                  for hemoglobin (DLCOc) < 40% normal

               -  Cardiac: left ventricular ejection fraction < 35%

          -  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.
      
Maximum Eligible Age:75 Years
Minimum Eligible Age:1 Year
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Percentage of patients with leukemia free survival
Time Frame:Up to 1 year after transplant
Safety Issue:
Description: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

Measure:Average overall survival
Time Frame:Up to 1 year after transplant
Safety Issue:
Description:Overall Survival (OS) at 1 year is the percentage of patients alive at 1 year after transplant.
Measure:Relapse incidence
Time Frame:Up to 1 year after transplant
Safety Issue:
Description:Relapse incidence at 1 year is the percentage of patients who experience relapse of their hematologic malignancy up to 1 year after transplant.
Measure:Treatment Related Mortality
Time Frame:Up to 1 year after transplant
Safety Issue:
Description: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.
Measure:Incidence of acute GVHD
Time Frame:Up to 1 year after transplant
Safety Issue:
Description: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.
Measure:Incidence of chronic GVHD
Time Frame:Up to 1 year after transplant
Safety Issue:
Description: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.
Measure:Rate of neutrophil engraftment
Time Frame:Up to 1 year after transplant
Safety Issue:
Description:Neutrophil engraftment will be calculated as the days from transplant where the absolute neutrophil count (ANC) reaches >500cells/ul x 3 days.
Measure:Rate of platelet engraftment
Time Frame:Up to 1 year after transplant
Safety Issue:
Description: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.

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Case Comprehensive Cancer Center

Trial Keywords

  • Thiotepa
  • Fludarabine
  • Melphalan

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