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.
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
Interventions
Drug | Synonyms | Arms |
---|
Melphalan | Alkeran, Evomela | Thiotepa + Fludarabine + Melphalan + KGF |
Thiotepa | Tepadina | Thiotepa + Fludarabine + Melphalan + KGF |
Fludarabine | Fludara | Thiotepa + Fludarabine + Melphalan + KGF |
Keratinocyte Growth Factor (KGF) | Palifermin, Kepivance, K | Thiotepa + Fludarabine + Melphalan + KGF |
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
Name | Type | Description | Interventions |
---|
Thiotepa + Fludarabine + Melphalan + KGF | Experimental | 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. | - Melphalan
- Thiotepa
- Fludarabine
- Keratinocyte Growth Factor (KGF)
|
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. 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 <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.
Maximum Eligible Age: | 65 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
Last Updated
June 23, 2021