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

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ClinicalTrials.gov Identifier: NCT03342196
Recruitment Status : Recruiting
First Posted : November 14, 2017
Last Update Posted : July 21, 2020
Sponsor:
Information provided by (Responsible Party):
Case Comprehensive Cancer Center

Tracking Information
First Submitted Date  ICMJE November 10, 2017
First Posted Date  ICMJE November 14, 2017
Last Update Posted Date July 21, 2020
Actual Study Start Date  ICMJE March 21, 2018
Estimated Primary Completion Date December 1, 2020   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: November 10, 2017)
Percentage of patients with leukemia free survival [ Time Frame: Up 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.
Original Primary Outcome Measures  ICMJE Same as current
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: November 10, 2017)
  • Average overall survival [ Time Frame: Up to 1 year after transplant ]
    Overall Survival (OS) at 1 year is the percentage of patients alive at 1 year after transplant.
  • Relapse incidence [ Time Frame: Up 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 Mortality [ Time Frame: Up 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 GVHD [ Time Frame: Up 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.
  • Incidence of chronic GVHD [ Time Frame: Up 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 neutrophil engraftment [ Time Frame: Up 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.
  • Rate of platelet engraftment [ Time Frame: Up 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.
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Thiotepa Plus Fludarabine+ Melphalan as the Preparative Regime for Alternative Donor Transplantation
Official Title  ICMJE A Phase II Study of Thiotepa Added to Fludarabine and Melphalan as the Preparative Regime for Alternative Donor Transplantation
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).

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.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE Leukemia
Intervention  ICMJE
  • Drug: Melphalan

    Alkylating agent which is a derivative of mechlorethamine that inhibits DNA and RNA synthesis via formation of carbonium ions; cross-links strands of DNA; acts on both resting and rapidly dividing tumor cells.

    Melphalan may cause a lowering of the white blood cell or platelet counts, leading to an increased risk of infection and frequent bruising or bleeding. It may cause damage to the GI tract causing mouth sores, nausea, vomiting, and diarrhea. Other side effects may include loss of appetite, liver abnormalities, hair loss, swelling, fatigue, sleepiness, skin rash.

    Other Names:
    • Alkeran
    • Evomela
  • Drug: Thiotepa

    Thiotepa is an alkylating agent which produces cross-linking of DNA strands leading to inhibition of DNA, RNA, and protein synthesis; thiotepa is cell-cycle independent.

    Thiotepa may cause a lowering of the white blood cell or platelet counts, leading to an increased risk of infection and frequent bruising or bleeding. It may cause damage to the GI tract causing mouth sores, nausea, vomiting, and diarrhea. Other side effects may include loss of appetite, liver abnormalities, hair loss, swelling, fatigue, sleepiness, skin rash.

    Other Name: Tepadina
  • Drug: Fludarabine

    Fludarabine is an antineoplastic fluorinated nucleoside analog and inhibits DNA synthesis through inhibition of polymoerase alpha after incorporation into DNA.

    Fludarabine may cause a lowering of the white blood cell or platelet counts, leading to an increased risk of infection and frequent bruising or bleeding. Other side effects may include loss of appetite, liver abnormalities, hair loss, swelling, fatigue, sleepiness, skin rash, and lower limb weakness.

    Other Name: Fludara
  • Drug: Keratinocyte Growth Factor (KGF)

    Chemoprotective Agent.Recombinant keratinocyte growth factor (KGF) produced in E. coli. KGF binds to the KGF receptor resulting in proliferation, differentiation and migration of epithelial cells in multiple tissues, including (but not limited to) the tongue, buccal mucosa, esophagus, and salivary gland.

    Palifermin may cause rash, itching, redness, or discoloration of the skin. It may cause edema, an increase in pancreatic enzymes. It may cause arthralgias. It may cause tongue discoloration or tongue edema.

    Other Names:
    • Palifermin
    • Kepivance
    • K
Study Arms  ICMJE Experimental: Thiotepa + Fludarabine + Melphalan + KGF
Melphalan 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. Keratinocyte Growth Factor (KGF) 60mcg/kg IV on day -11, -10, and -9 and 0, +1, and +2.
Interventions:
  • Drug: Melphalan
  • Drug: Thiotepa
  • Drug: Fludarabine
  • Drug: Keratinocyte Growth Factor (KGF)
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: November 10, 2017)
39
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE December 1, 2022
Estimated Primary Completion Date December 1, 2020   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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. 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.

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.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 1 Year to 75 Years   (Child, Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Leland Metheny, MD 216-844-0139 Leland.Metheny@uhhospitals.org
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03342196
Other Study ID Numbers  ICMJE CASE10Z17
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: No
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Case Comprehensive Cancer Center
Study Sponsor  ICMJE Case Comprehensive Cancer Center
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Principal Investigator: Leland Metheny, MD Case Comprehensive Cancer Center
PRS Account Case Comprehensive Cancer Center
Verification Date July 2020

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP