Propylene Glycol-Free Melphalan HCl (EVOMELA®) in Combination With Fludarabine and Total Body Irradiation Based Reduced Intensity Conditioning for Haploidentical Transplantation
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|ClinicalTrials.gov Identifier: NCT03159702|
Recruitment Status : Recruiting
First Posted : May 19, 2017
Last Update Posted : June 14, 2022
|Condition or disease||Intervention/treatment||Phase|
|Hematological Malignancy Leukemia Multiple Myeloma Lymphoma||Drug: Evomela Drug: Fludarabine Radiation: Total Body Irradiation||Phase 2|
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 (Clinical Trial)|
|Estimated Enrollment :||43 participants|
|Intervention Model:||Single Group Assignment|
|Intervention Model Description:||Study subjects will receive different doses of Melphalan during the trial. This is done for safety per FDA recommendations. Subjects younger than 60 years or have will receive doses at 140 mg/m^2/day while subject 60 years or old or have a Hematopoietic Cell Transplant-Co-morbidity Index (HCT-CI) score of >3 will receive 70 mg/m^2/day. The populations will be combined for analysis and reporting.|
|Masking:||None (Open Label)|
|Official Title:||Propylene Glycol-Free Melphalan HCl (EVOMELA®) in Combination With Fludarabine and Total Body Irradiation Based Reduced Intensity Conditioning for Haploidentical Transplantation|
|Actual Study Start Date :||December 8, 2017|
|Estimated Primary Completion Date :||July 1, 2023|
|Estimated Study Completion Date :||July 1, 2024|
Experimental: MEL/FLU and Total-Body Irradiation (TBI)
For patients who are < 60 years.
For patients who are ≥60 years and/or Hematopoietic Cell Transplant-Co-morbidity Index (HCT-CI) score of >3 (at the discretion of treating physician will have an option to receive):
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
Other Name: Melphalan
40 mg/ m^2/day intravenous on Days: -5 -4, -3, -2
Other Name: Fludara
Radiation: Total Body Irradiation
200 cGy on Day: -1
- Progression-free survival (PFS) of participants with hematological malignancies undergoing treatment. [ Time Frame: 1 year ]Progression-free survival (PFS) is defined as the length of time during and after the treatment that a participant lives with the disease but it does not get worse.
- The safety of this trial will be evaluated with the nonrelapse mortality rate. [ Time Frame: 1 Year ]This is the number of participants expiring unrelated to relapse of disease.
- Overall survival [ Time Frame: 1 Year and 2 Year ]The number of participants still alive at one year and 2 years.
- Number of subjects with relapse of disease. [ Time Frame: Day 100 and 1 Year ]The number of participants who relapse following reduced-intensity conditioning haploidentical transplantation at Day 100 and 1 Year.
- Neutrophil recovery [ Time Frame: Day 30 ]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.
- Platelet recovery [ Time Frame: Day 30 ]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.
- Acute graft-versus-host disease (GVHD) at day 100 and 180. [ Time Frame: Days 100 and 180 ]The number of participants with graft-versus-host disease using the Center for International Bone Marrow Transplant Research criteria.
- Rates of chronic GVHD at one-year post transplantation. [ Time Frame: 1 Year ]The number of participants with chronic GVHD at one-year post transplantation using the Center for International Bone Marrow Transplant Research criteria.
- Primary graft failure [ Time Frame: Day 30 ]Number of subjects whose grafts failed to implant.
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03159702
|Contact: Medical College of Wisconsin Cancer Center Clinical Trials Officeemail@example.com|
|United States, Wisconsin|
|Froedtert Hospital & the Medical College of Wisconsin||Recruiting|
|Milwaukee, Wisconsin, United States, 53226|
|Contact: Mehdi Hamadani, MD 414-805-4600 firstname.lastname@example.org|
|Principal Investigator: Mehdi H Hamadani, MD|
|Principal Investigator:||Mehdi Hamadani||Medical College of Wisconsin|