Propylene Glycol-Free Melphalan HCl (EVOMELA®) in Combination With Fludarabine and Total Body Irradiation Based Reduced Intensity Conditioning for Haploidentical Transplantation
Propylene Glycol-Free Melphalan HCl (EVOMELA®) in Combination With Fludarabine and Total Body Irradiation Based Reduced Intensity Conditioning for Haploidentical Transplantation
This is an open-label, single-arm, phase II study to determine the safety of propylene
 glycol-free melphalan HCl (EVOMELA®), in combination with fludarabine and total-body
 irradiation-based reduced-intensity conditioning for haploidentical transplantation. In
 addition, the study evaluates the one-year progression-free survival of patients undergoing
 this treatment.
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 post HCT, 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 upper limit of normal (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.

 -  Forced expiratory volume (FEV1) or diffusion capacity for carbon monoxide (DLCO)
 corrected for hemoglobin ≥ 50% of predicted.

 -  Karnofsky performance status > 60.

 -  Graft source of peripheral blood (the infused cluster of differentiation 34 (CD34)+
 cell dose will be capped at 5 x 10^6 CD34+ 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 human leukocyte
 antigen (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 acute myeloid leukemia (AML)/myelodysplastic syndrome
 (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.