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.
Study Type
INTERVENTIONAL
Allocation
NA
Purpose
TREATMENT
Masking
NONE
Enrollment
43
140 mg/m\^2/day IV on Day -6 for patients who are \< 60 years of age. 70 mg/m\^2/day IV on Day -6 For patients who are ≥60 years or have a HCT-CI score of \>3
40 mg/ m\^2/day intravenous on Days: -5 -4, -3, -2
200 cGy on Day: -1
This is a procedure that uses healthy blood-forming cells from a half-matched donor, typically a family member, to replace a patient's unhealthy ones.
Froedtert Hospital & the Medical College of Wisconsin
Milwaukee, Wisconsin, United States
Progression-free Survival (PFS) of Participants With Hematological Malignancies Undergoing Treatment.
Progression-free survival (PFS) is defined as the interval from the date of transplantation to the earlier of the following events: (1) the first documented objective disease progression; (2) death from any cause. Subjects without documented PD/death will be censored at the earliest of the of the following times: (1) the starting time of a new treatment other than the study treatment; (2) the last efficacy assessment date.
Time frame: 1 year
Serious Adverse Events (SAE).
An SAE is defined as any untoward medical occurrence at any dose, including death, life threatening, hospitalization, disability/incapacity, medically important event. The measure of this outcome is the number of participants with SAEs.
Time frame: 2 Years
Nonrelapse Mortality Rate.
This is the number of participants expiring without recurrent or progressive disease after transplantation.
Time frame: 1 Year
Overall Survival
The number of participants still alive at one year and 2 years.
Time frame: 1 Year and 2 Year
Number of Subjects With Relapse of Disease.
The number of participants who relapse following reduced-intensity conditioning haploidentical transplantation at Day 100 and 1 Year.
Time frame: Day 100 and 1 Year
Neutrophil Recovery
The average of the number of days that it takes for neutrophil recovery from reduced-intensity conditioning haploidentical transplantation. Neutrophil recovery means absolute neutrophil count of 0.5x10\^3 cells/uL.
Time frame: Day 30
Platelet Recovery
The average of the number of days that it takes for platelet recovery from reduced-intensity conditioning haploidentical transplantation. Platelet recovery means absolute neutrophil count of 50x10\^3 cells/uL.
Time frame: Day 30
Acute Graft-versus-host Disease (GVHD) at Day 100 and 180.
The number of participants with graft-versus-host disease using the Center for International Bone Marrow Transplant Research criteria.
Time frame: Days 100 and 180
Rates of Chronic GVHD at One-year Post Transplantation.
The number of participants with chronic GVHD at one-year post transplantation using the Center for International Bone Marrow Transplant Research criteria.
Time frame: 1 Year
Primary Graft Failure
Number of subjects whose grafts failed to implant.
Time frame: Day 30
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