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

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

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