PRO#1278: Fludarabine and Busulfan vs. Fludarabine, Busulfan and Total Body Irradiation

Study Overview
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Brief Summary
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This is a single institution study of fludarabine and busulfan versus fludarabine, busulfan and low dose total body irradiation in patients undergoing allogeneic stem cell transplantation. A study population of 80 subjects will be enrolled from The John Theurer Cancer Center at Hackensack University Medical Center. Subjects who are eligible to receive allogeneic hematopoietic stem cell transplantation according to the eligibility criteria will be consented and enrolled. Subjects will be randomly assigned to receive one of 2 conditioning regimen: fludarabine and busulfan, or fludarabine busulfan and low dose total body irradiation (TBI). Subjects will be followed until 1 year post transplantation to assess the relapse rate in each arm and transplant-related toxicity. The combination of fludarabine and busulfan is the current standard of care for patients with myeloid malignancies (AML, CML and other myeloproliferative disorders, or MDS) undergoing allogeneic transplantation at HUMC. In this study we will be comparing in a randomized fashion the standard regimen to a regimen of fludarabine, busulfan and TBI.

Detailed Description
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This is a single institution study of fludarabine and busulfan versus fludarabine, busulfan and low dose total body irradiation in patients undergoing allogeneic stem cell transplantation. A study population of 80 subjects will be enrolled from The John Theurer Cancer Center at Hackensack University Medical Center. Subjects who are eligible to receive allogeneic hematopoietic stem cell transplantation according to the eligibility criteria will be consented and enrolled. Subjects will be randomly assigned to receive one of 2 conditioning regimen: fludarabine and busulfan, or fludarabine busulfan and low dose total body irradiation (TBI). Subjects will be followed until 1 year post transplantation to assess the relapse rate in each arm and transplant-related toxicity. The combination of fludarabine and busulfan is the current standard of care for patients with myeloid malignancies (myelogenous leukemia, chronic myelogenous leukemia, other myeloproliferative disorder, or myelodysplastic syndrome) undergoing allogeneic transplantation at HUMC. In this study we will be comparing in a randomized fashion the standard regimen to a regimen of fludarabine, busulfan and TBI. Primary Objective The primary objective is to compare the relapse rate at 1 year of patients with myeloid malignancies receiving each regimen. Secondary Objectives The secondary objective is to compare the toxicity of each regimen

Official Title
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PRO#1278: A Phase III Study of Fludarabine and Busulfan Versus Fludarabine, Busulfan and Low Dose Total Body Irradiation in Patients Receiving an Allogeneic Hematopoietic Stem Cell Transplant

Conditions
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Myeloid Malignancies, Acute Myelogenous Leukemia, Chronic Myelogenous Leukemia, Myeloproliferative Disorders, Myelodysplastic Syndrome

Intervention / Treatment
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* Drug: Fludarabine and Busulfan plus/minus Total Body Irradiation (low dose)
* Drug: Fludarabine and Busulfan + Low Dose Total Body Irradiation (LD TBI)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Diagnosis of acute myelogenous leukemia, chronic myelogenous leukemia, other myeloproliferative disorder, or myelodysplastic syndrome Any stage of disease will be considered for transplantation Have a suitable related or unrelated donor (Section 3.3) Age ≥18 but <70 yrs KPS of ≥70% Recovery from all hematologic and non-hematology toxicities from previous therapies. Exclusion Criteria: Diagnosis other than acute myelogenous leukemia, myeloproliferative disorder, or myelodysplastic syndrome Chemotherapy or radiotherapy within 14 days of initiating treatment in this study with the exception of lenalidomide, decitabine, azacitidine, imatinib mesylate, dasatinib, nilotinib hydrochloride and hydroxyurea Prior dose-intense therapy requiring HSC support within 56 days of initiating treatment in this study Uncontrolled bacterial, viral, fungal or parasitic infections Uncontrolled CNS metastases Known amyloid deposition in heart Organ dysfunction LVEF <40% or cardiac failure not responsive to therapy FVC, FEV1, or DLCO <50% of predicted and/or receiving supplementary continuous oxygen Evidence of hepatic synthetic dysfunction, or total bilirubin >2x or AST >3x ULN Measured creatinine clearance <20 ml/min Karnofsky score <70% Life expectancy limited by another co-morbid illness Diagnosed or treated for another malignancy within 3 years of enrollment, with the exception of complete resection of basal cell carcinoma or squamous cell carcinoma of the skin, an in situ malignancy, or low-risk prostate cancer after curative therapy Female subject is pregnant or breast-feeding (women) or unwilling to use acceptable birth control methods (men or women) for twelve months after treatment. Confirmation that the subject is not pregnant must be established by a negative serum β-human chorionic gonadotropin (β-hCG) pregnancy test result obtained during screening. Pregnancy testing is not required for post-menopausal or surgically sterilized women. Documented hypersensitivity to fludarabine or melphalan or to bortezomib, boron or mannitol or any components of the formulation Patients unable or unwilling to provide consent Myocardial infarction within 6 months prior to enrollment or has New York Heart Association (NYHA) Class III or IV heart failure (see section 8.4), uncontrolled angina, severe uncontrolled ventricular arrhythmias, or electrocardiographic evidence of acute ischemia or active conduction system abnormalities. Prior to study entry, any ECG abnormality at screening has to be documented by the investigator as not medically relevant Patient has received other investigational drugs with 14 days before enrollment Serious medical or psychiatric illness likely to interfere with participation in this clinical study Donor Inclusion and Exclusion Criteria Donor Inclusion Criteria: HLA 6/6 (HLA-A, B, DrB1) related donor or 7/8 (HLA-A, B, C, DrB1) unrelated donor Related donors will be evaluated in accordance with HUMC standard practice guidelines for the evaluation and management of allogeneic donors Unrelated donors will be identified, evaluated, and managed in accordance with National Marrow Donor Program standards Age ≥18 and <70 yrs KPS of ≥70% Willing to donate bone marrow using standard techniques or peripheral blood HSC by leukapheresis Have adequate veins for apheresis or agree to placement of a central venous catheter (femoral, subclavian) if donating peripheral blood HSC Donor Exclusion Criteria Identical twin Female donors who are pregnant or breastfeeding Infection with HIV or viral hepatitis (B or C) Known allergy to filgrastim Current serious systemic illness Uncontrolled bacterial, viral, or fungal infection Receiving experimental therapy or investigational agents History of cancer other than treated basal cell cancer of the skin or carcinoma in situ of the cervix. Cancer treated with curative intent >5 yrs before donation will be reviewed on a case-by-case basis by the principal investigator

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 70 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
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Group 1<br>FLUDARABINE AND BUSULFAN | Drug: Fludarabine and Busulfan plus/minus Total Body Irradiation (low dose)<br>* Fludarabine 40mg/m2 and Busulfan 130mg/m2 on days -6, -5, -4 and -3 of transplant. rATG on days -3, -2 and -1<br>* Other names: Busulfex;|
| Experimental: Group 2<br>FLUDARABINE, BUSULFAN AND LOW DOSE TOTAL BODY IRRADIATION | Drug: Fludarabine and Busulfan + Low Dose Total Body Irradiation (LD TBI)<br>* Fludarabine 40mg/m2 and Busulfan 130mg/m2 on days -6, -5, -4 and -3 of transplant. rATG on days -3, -2 and -1 TBI 200cGY (as randomized) on day -1<br>* Other names: Busulfex;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| To Compare the Relapse Rate at 1 Year of Patients With Myeloid Malignancies Receiving Each Treatment |  | 1 year | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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AML, Allogeneic Stem Cell Transplant, CML, MDS