Propylene Glycol-Free Melphalan HCl (EVOMELA®) in Combination With Fludarabine and Total Body Irradiation Based Reduced Intensity Conditioning for Haploidentical Transplantation

OVERVIEW:

Elderly and infirm patients with hematological malignancies often cannot undergo allogeneic
hematopoietic cell transplantation (HCT) because of high-toxicity rates and nonrelapse
mortality (NRM) associated with higher-intensity conditioning allografts.

Reduced-intensity conditioning (RIC) transplantation has emerged as an attractive alternative
for these populations.

FLUDARABINE/MELPHALAN. In RIC, fludarabine is often used as the lymphocyte-depleting
component to facilitate donor-cell engraftment. This drug can be given once daily because of
its plasma half-life. M.D. Anderson pioneered the use of fludarabine melphalan (Flu/Mel)
conditioning, which has since gained wide usage. (1) Melphalan is convenient, has broad
antitumor activity in hematologic malignancies and has immunosuppressive effects. The Flu/Mel
conditioning regimen can provide long-term disease control, especially in the subset of
patients with chemo sensitive disease. (1) TOTAL-BODY IRRADIATION. In a recent study,
total-body irradiation (200 cGy) was used with flu/mel for advanced lymphoma treated with
HCT. With a median follow-up time close to two years, the survival of these mostly advanced,
relapsed/refractory patients was very encouraging with overall survival of 54% and
progression-free survival of 54% for the entire group. (2) Treatment-related mortality was
low at day 100 (9.1%) and two years (19%) after transplantation, with stable engraftment
achieved in the great majority of patients.

PROPYLENE GLYCOL-FREE MELPHALAN HCL (EVOMELA®). In theory, intensifying the dose of melphalan
in flu/mel conditioning could provide better disease control postHCT, allowing more time for
curative graft-versus-leukemia effects to emerge. The use of the commercial formulation of
melphalan (Alkeran®) proved somewhat problematic, however, because it must be reconstituted
with propylene glycol, a substance that has been associated with toxic side effects. The
substitution of Captisol® in propylene glycol-free melphalan HCl (EVOMELA®) for Injection
(Spectrum Pharmaceuticals, Inc.) for the excipients found in Alkeran®, directly overcomes the
formulation limitations noted with Alkeran®.

STUDY RATIONALE. The preliminary data suggest that the substitution of Captisol® in EVOMELA®
for the excipients found in Alkeran® directly overcomes the formulation limitations and
provides a potentially safer melphalan formulation for administration at higher doses used in
HCT conditioning regimens.

Based on these observations, we now propose a phase II study of a RIC regimen consisting of
EVOMELA® in combination with fludarabine and total-body irradiation for patients undergoing
haplo-HCT. The study will investigate the safety and tolerability of this conditioning
approach. While the FDA indication for EVOMELA® is for myeloablative conditioning prior to
autologous HCT in patients with multiple myeloma, we anticipate our study will provide
critical preliminary data to explore this formulation in allogeneic HCT conditioning.

Inclusion Criteria:

- Patients with a diagnosis of hematological malignancy undergoing a related donor
haploidentical HCT.*

- Patients aged ≥18 are eligible.

- Bilirubin ≤ 2 x the ULN. For patients with Gilbert's syndrome or suspected mild
veno-occlusive disease, bilirubin ≤ 3 x ULN is permitted.

- Adequate renal function as defined by a serum creatinine clearance of > 30 mL/min
calculated by Cockcroft-Gault equation.

- Left ventricular ejection fraction ≥40%. No uncontrolled arrhythmias or New York Heart
Association class III-IV heart failure.

- FEV1 or DLCO (diffusion capacity; corrected for hemoglobin) ≥ 50% of predicted.

- Karnofsky performance status > 60.

- Graft source of peripheral blood (the infused CD34+ cell dose will be capped at 5 x
106 CD 34+ cells/kg recipients actual body weight) or bone marrow (the ideal infused
total nucleated cell dose (TNC) will be targeted at 4 x 108/kg recipient actual body
weight).

- A negative pregnancy test will be required for all women of child bearing potential.
Females of child bearing potential should agree to practice 2 effective methods of
contraception, at the same time, from the time of signing the informed consent form
through 90 days after the last dose of study drug and must also adhere to the
guidelines of any treatment-specific pregnancy prevention program, if applicable, or
agree to practice true abstinence when this is in line with the preferred and usual
lifestyle of the subject. (Periodic abstinence [e.g., calendar, ovulation,
symptothermal, postovulation methods] and withdrawal are not acceptable methods of
contraception.). Breast-feeding is not permitted.

- Male patients, even if surgically sterilized (i.e., status post-vasectomy), must agree
to one of the following: practice effective barrier contraception during the entire
study treatment period and through 90 days after the last dose of study drug, or must
also adhere to the guidelines of any treatment-specific pregnancy prevention program,
if applicable, or agree to practice true abstinence when this is in line with the
preferred and usual lifestyle of the subject. (Periodic abstinence (e.g., calendar,
ovulation, symptothermal, post-ovulation methods] and withdrawal are not acceptable
methods of contraception.)

- No evidence of uncontrolled bacterial, viral or fungal infections at the time of
enrollment.

- Transplant recipient able to give informed consent. * Patients must be HLA typed at
high resolution using DNA based typing at the following HLA loci: HLA-A, -B, -C and
DRB1 and have available: A related haploidentical bone marrow donor with two, three or
four HLA-mismatches. A unidirectional mismatch in either the graft-versus-host or
host-versus-graft direction is considered a mismatch. The donor and recipient must be
HLA identical for at least one antigen (using high-resolution DNA-based typing) at the
following genetic loci: HLA-A, HLA-B, HLA-C, and HLA-DRB1. Fulfillment of this
criterion shall be considered sufficient evidence that the donor and recipient share
one HLA haplotype, and typing of additional family members is not required.

Exclusion Criteria:

- Patient must not have a healthy, eligible and readily available HLA-identical sibling
donor or a volunteer adult unrelated donor (matched at allele-level at HLA-A, -B, -C
and -DRB1).

- No serious medical or psychiatric illness that could, in the investigator's opinion,
potentially interfere with the completion of treatment according to this protocol.\

- Presence of active disease in AML/MDS: patients with active disease defined as >5%
blasts in bone marrow and/or circulating leukemic blasts in peripheral blood, patients
with known active central nervous disease involvement with leukemia/lymphoma or
lymphoma patients with progressive disease on clinical and/or radiographic assessment
are not eligible for this study.