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

Study Overview
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Brief Summary
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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
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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.

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

Conditions
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Leukemia

Intervention / Treatment
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* Drug: Melphalan
* Drug: Thiotepa
* Drug: Fludarabine


Participation Criteria
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Eligibility Criteria
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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. 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.

Ages Eligible for Study
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Minimum Age: 1 Year
Maximum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Thiotepa + Fludarabine + Melphalan<br>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. | Drug: Melphalan<br>* 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.<br>* Other names: Evomela;Drug: Thiotepa<br>* 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.<br>* Other names: Tepadina;Drug: Fludarabine<br>* 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.<br>* Other names: Fludara;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of patients with leukemia free survival | Leukemia Free Survival (LFS) at 1 year is the percentage of patients alive and without evidence of hematologic malignancy at 1 year after transplant. | Up to 1 year after transplant | 

Secondary Outcome Measures

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

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Thiotepa, Fludarabine, Melphalan