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

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

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

Conditions
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Hematological Malignancy, Multiple Myeloma

Intervention / Treatment
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* Drug: Evomela
* Drug: Fludarabine
* Radiation: Total Body Irradiation


Participation Criteria
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Eligibility Criteria
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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 10^8/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.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Interventional 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)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: MEL/FLU and Total-Body Irradiation (TBI)<br>For patients who are < 60 years. Melphalan: 140 mg/m2/day IV on Day: -6 Fludarabine: 40 mg/ m2/day IV Days: -5 -4, -3, -2 (Adults: creatinine clearance (CrCl) may be estimated by the Cockcroft Formula: CrCl = [(140-age) x weight (kg) x 0.85 (for women only)]/ [72 x creat (mg/dl)].) TBI: 200 cGy Day: -1. 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): Melphalan: 70 mg/m2/day IV on Day -6. Fludarabine: 40 mg/m2/day IV Days -5, -4, -3, -2. TBI: 200 cGy; Days -1. | Drug: Evomela<br>* 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<br>* Other names: Melphalan;Drug: Fludarabine<br>* 40 mg/ m^2/day intravenous on Days: -5 -4, -3, -2<br>* Other names: Fludara;Radiation: Total Body Irradiation<br>* 200 cGy on Day: -1<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-free survival (PFS) of participants with hematological malignancies undergoing treatment. | 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. | 1 year | 
| The safety of this trial will be evaluated with the nonrelapse mortality rate. | This is the number of participants expiring unrelated to relapse of disease. | 1 Year | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall survival | The number of participants still alive at one year and 2 years. | 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. | 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. | 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. | 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. | 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. | 1 Year | 
| Primary graft failure | Number of subjects whose grafts failed to implant. | Day 30 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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hematological malignancy, EVOMELA, Melphalan HCl, Total Body Irradiation, Reduced Intensity Conditioning, Haploidentical Transplantation, Fludarabine, Hematologic Diseases