Propylene Glycol-Free Melphalan HCl (EVOMELA®) in Combination With Fludarabine and Total Body Irradiation Based Reduced Intensity Conditioning for Haploidentical Transplantation
试验速览
- 阶段
- 2 期
- 状态
- 已完成
- 入组人数
- 43
- 试验地点
- 1
- 主要终点
- Progression-free Survival (PFS) of Participants With Hematological Malignancies Undergoing Treatment.
研究概览
简要总结
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.
详细描述
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®.
研究设计
- 研究类型
- Interventional
- 分配方式
- Na
- 干预模型
- Single Group
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •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 >
- •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-DRB
- •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.
排除标准
- •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.
研究组 & 干预措施
MEL/FLU and Total-Body Irradiation (TBI)
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.
干预措施: Evomela (Drug)
MEL/FLU and Total-Body Irradiation (TBI)
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.
干预措施: Fludarabine (Drug)
MEL/FLU and Total-Body Irradiation (TBI)
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.
干预措施: Total Body Irradiation (Radiation)
MEL/FLU and Total-Body Irradiation (TBI)
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.
干预措施: Haploidentical Hematopoietic Cell Transplantation (Other)
结局指标
主要结局
Progression-free Survival (PFS) of Participants With Hematological Malignancies Undergoing Treatment.
时间窗: 1 year
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.
Serious Adverse Events (SAE).
时间窗: 2 Years
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.
次要结局
- Nonrelapse Mortality Rate.(1 Year)
- Overall Survival(1 Year and 2 Year)
- Number of Subjects With Relapse of Disease.(Day 100 and 1 Year)
- Neutrophil Recovery(Day 30)
- Platelet Recovery(Day 30)
- Acute Graft-versus-host Disease (GVHD) at Day 100 and 180.(Days 100 and 180)
- Rates of Chronic GVHD at One-year Post Transplantation.(1 Year)
- Primary Graft Failure(Day 30)
研究者
Mehdi Hamadani
Professor, Department of Medicine, Division of Hematology/Oncology
Medical College of Wisconsin