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

  • STATUS
    Recruiting
  • End date
    Jul 1, 2023
  • participants needed
    43
  • sponsor
    Medical College of Wisconsin
Updated on 24 January 2021
vasectomy
renal function
cancer
total body irradiation
fludarabine
hematologic malignancy
hla-a
carbon monoxide
ejection fraction
melphalan
karnofsky performance status
fungal infection
myeloablative conditioning
bone marrow procedure
gilbert's syndrome

Summary

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.

Description

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.

Details
Condition Hematologic Malignancy, Multiple Myeloma, Blood disorder, Lymphoma, leukemia, Lymphoproliferative Disorder, Lymphoma, Non-Hodgkin's Lymphoma, Leukemia (Pediatric), Hematological Malignancy Undergoing a Related Donor Haploidentical HCT, Blood Cancer, Hematologic Cancer, Hematological Disorders, Hematologic Neoplasms, Lymphoproliferative disorders, leukemias, lymphomas, multiple myeloma (mm), hematological malignancy, hematologic malignancies, hematological tumor, haematological malignancy, hematological malignancies
Treatment Fludarabine, Total body irradiation, Evomela
Clinical Study IdentifierNCT03159702
SponsorMedical College of Wisconsin
Last Modified on24 January 2021

Eligibility

Yes No Not Sure

Inclusion Criteria

Is your age greater than or equal to 18 yrs?
Gender: Male or Female
Do you have any of these conditions: Hematological Disorders or Non-Hodgkin's Lymphoma or Lymphoproliferative Disorder or Blood Cancer or Lymphoma or Leukemia (Pediatric) or Hematological...?
Do you have any of these conditions: hematologic malignancies or Hematologic Neoplasms or lymphomas or Lymphoproliferative disorders or Hematological Disorders or hematological malignancy...?
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
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