A Pilot Study of Reduced Intensity HLA-Haploidentical Hematopoietic Cell Transplantation With Post-Transplant Cyclophosphamide in Patients With Advanced Myelofibrosis
试验速览
- 阶段
- 1 期
- 状态
- 进行中（未招募）
- 发起方
- 入组人数
- 22
- 试验地点
- 2
- 主要终点
- Incidence of unacceptable toxicity
研究概览
简要总结
This pilot phase I trial studies the side effects of combination chemotherapy, total body irradiation, and donor blood stem cell transplant in treating patients with secondary myelofibrosis. Drugs used in chemotherapy work in different ways to stop the growth of cancer cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Radiation therapy uses high energy x-rays to kill cancer cells and shrink tumors. Giving combination chemotherapy and total body irradiation before a donor blood stem cell transplant helps to stop the growth of cells in the bone marrow, including normal blood-forming cells (stem cells) and cancer cells. When the healthy stem cells from a donor are infused into the patient they may help the patient's bone marrow make stem cells, red blood cells, white blood cells, and platelets.
详细描述
PRIMARY OBJECTIVE:
I. To evaluate the safety and tolerability of reduced-intensity (fludarabine/melphalan) haploidentical hematopoietic cell transplantation (Haplo-HCT) followed by post-transplant cyclophosphamide (PTCy) in patients with advanced myelofibrosis (MF), as assessed by the evaluation of toxicities, including type, frequency, severity, attribution, time course and duration.
SECONDARY OBJECTIVES:
I. To summarize and evaluate hematologic (neutrophil and platelet) recovery. II. To evaluate and describe cytokine release syndrome (CRS) post haploidentical HCT in the setting of advanced myelofibrosis, as assessed by grade, frequency, severity, duration and reversibility (outcome).
III. To estimate graft failure-free survival (GFS) at 100-days post-transplant. IV. To estimate overall survival (OS), progression-free survival (PFS) and cumulative incidence (CI) of relapse/progression, and non-relapse mortality (NRM) at 100-days, 1-year, and 2-year post transplant.
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 65 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Diagnosis of primary of secondary myelofibrosis with transplant indication by Dynamic International Prognostic Scoring System (DIPSS)-plus (> intermediate-1)
- •Patients >= age 50 must have a comorbidity score (hematopoietic cell transplant-comorbidity index [HCT-CI]) < 4 (Sorror)
- •Patients can be in chronic phase (CP) with bone marrow (BM) blast count =< 15% as long as no evidence of disease acceleration per principal investigator (PI) and treating physician's opinion or after progression to acute myeloid leukemia (AML) and achieved =< 5% BM blasts (morphologic complete remission [CR] prior to transplant)
- •Lack of an human leukocyte antigen (HLA) matched donor or need to proceed fast to transplantation when a patient does not have an immediately available matched unrelated donor (typed by high-resolution in the registry)
- •Performance status >= 70% (Karnofsky); patients > 50 years should have adequate cognitive function; any concerns regarding cognitive function should be addressed by a geriatrician/neurologist
- •Alanine aminotransferase (ALT)/aspartate aminotransferase (AST)/bilirubin =< 5 X upper limit of normal (ULN)
- •Measured creatinine clearance > 60 mls/min
- •Left ventricular ejection fraction (LVEF) >= 50%
- •Corrected carbon monoxide diffusing capability (DLCOc) >= 50%
- •No active infections
- •Prior treatment with JAK2 inhibitor therapy is not excluded; a JAK2 inhibitor will need to be stopped 1-2 days prior to starting conditioning regimen
- •DONOR: Documented informed consent per local, state and federal guidelines
- •DONOR: Genotypically haploidentical as determined by HLA typing
- •Preferably a non-maternal HLA haploidentical relative due to data of high incidence of graft failure with use of maternal HLA haploidentical cells
- •Eligible donors include biological parents, siblings or half-siblings, children, or cousins in rare instances
- •DONOR: Absence of pre-existing donor-specific anti-HLA antibodies (DSA) in the recipient; Patients with pre-existing DSA could undergo desensitization per City of Hope (COH) standard operating procedures [SOP] and should have DSA < MFI of 2000 prior to conditioning at discretion of PI
- •DONOR: Infectious disease screening performed within 30 days prior to stem cell mobilization per federal guidelines and is:
- •Seronegative for HIV 1+2 antibody (Ab) and/or HIV polymerase chain reaction (PCR), human T-cell leukemia virus (HTLV) I/II Ab, hepatitis B virus surface antigen (HBsAg), hepatitis B virus surface antibody (HBcAb), hepatitis C virus (HCV) Ab
- •Negative rapid plasma reagin (RPR) for syphilis
- •DONOR: Women of childbearing potential (WOCBP): Urine pregnancy testing performed within 7 days prior to stem cell mobilization
- •DONOR: Is approved and completed evaluation prior to recipient initiation of the preparative regimen per institutional guidelines
排除标准
- •Evidence of severe portal hypertension with evidence of decompensation either with bleeding varices, large volume ascites, or hepatic encephalopathy
- •In a bone marrow biopsy 4 weeks prior to start of conditioning on study:
- •> 15% bone marrow blasts at transplant if no history of AML and per PI and treating physician's opinion of disease acceleration
- •> 5% if had previous progression to AML
- •Human immunodeficiency virus (HIV) positive; active hepatitis B or C
- •Patients with active infections; the PI is the final arbiter of the eligibility
- •Patients with evidence of severe pulmonary hypertension by echocardiogram and confirmed by a subsequent right side cardiac catheterization pre-enrollment
- •Liver cirrhosis
- •Prior central nervous system (CNS) involvement by tumor cells
- •History of another primary malignancy that has not been in remission for at least 3 years (the following are exempt from the 3-year limit: non-melanoma skin cancer, fully excised melanoma in situ [stage 0], curatively treated localized prostate cancer, and cervical or breast carcinoma in situ on biopsy or a squamous intraepithelial lesion on papanicolaou [PAP] smear)
- •Positive beta human chorionic gonadotropin (HCG) test in a woman with child bearing potential defined as not post-menopausal for 12 months or no previous surgical sterilization
- •Noncompliance - inability or unwillingness to comply with medical recommendations regarding therapy or follow-up, including smoking tobacco
- •DONOR: Has undergone solid organ, stem cell, bone marrow or blood transplantation
- •DONOR: Receiving any investigational agents, or concurrent biological, chemotherapy, immunosuppression or radiation therapy
- •DONOR: Active infection
- •DONOR: Thrombocytopenia < 150,000 cells /mm^3 at baseline evaluation
- •DONOR: Sero-positive for HIV-1 & 2 antibody, HTLV-I & II antibody, hepatitis B virus (HBV) and HCV
- •DONOR: Medical or physical reason which makes the donor unlikely to tolerate or cooperate with growth factor therapy and leukapheresis
- •DONOR: Factors which place the donor at increased risk for complications from leukapheresis or G-CSF therapy
- •DONOR: WOCBP: Pregnant or =< 6 months breastfeeding
研究组 & 干预措施
Treatment (combination chemotherapy, TBI, HCT)
Patients receive melphalan IV over 30 minutes on day -5, fludarabine IV over 30-60 minutes on days -5 to -2. Patients undergo TBI on day -1 and HCT on day 0. Patients receive cyclophosphamide IV over 1-2 hours on days 3 and 4. Starting on day 5, patients receive tacrolimus IV then PO for 6 months followed by a taper, mycophenolate mofetil PO TID until day 35, and G-CSF IV daily until absolute neutrophil count > 1,500/mm^3 for 3 consecutive days. Treatment continues in the absence of disease progression or unexpected toxicity.
干预措施: Fludarabine (Drug)
Treatment (combination chemotherapy, TBI, HCT)
Patients receive melphalan IV over 30 minutes on day -5, fludarabine IV over 30-60 minutes on days -5 to -2. Patients undergo TBI on day -1 and HCT on day 0. Patients receive cyclophosphamide IV over 1-2 hours on days 3 and 4. Starting on day 5, patients receive tacrolimus IV then PO for 6 months followed by a taper, mycophenolate mofetil PO TID until day 35, and G-CSF IV daily until absolute neutrophil count > 1,500/mm^3 for 3 consecutive days. Treatment continues in the absence of disease progression or unexpected toxicity.
干预措施: Cyclophosphamide (Drug)
Treatment (combination chemotherapy, TBI, HCT)
Patients receive melphalan IV over 30 minutes on day -5, fludarabine IV over 30-60 minutes on days -5 to -2. Patients undergo TBI on day -1 and HCT on day 0. Patients receive cyclophosphamide IV over 1-2 hours on days 3 and 4. Starting on day 5, patients receive tacrolimus IV then PO for 6 months followed by a taper, mycophenolate mofetil PO TID until day 35, and G-CSF IV daily until absolute neutrophil count > 1,500/mm^3 for 3 consecutive days. Treatment continues in the absence of disease progression or unexpected toxicity.
干预措施: Melphalan (Drug)
Treatment (combination chemotherapy, TBI, HCT)
Patients receive melphalan IV over 30 minutes on day -5, fludarabine IV over 30-60 minutes on days -5 to -2. Patients undergo TBI on day -1 and HCT on day 0. Patients receive cyclophosphamide IV over 1-2 hours on days 3 and 4. Starting on day 5, patients receive tacrolimus IV then PO for 6 months followed by a taper, mycophenolate mofetil PO TID until day 35, and G-CSF IV daily until absolute neutrophil count > 1,500/mm^3 for 3 consecutive days. Treatment continues in the absence of disease progression or unexpected toxicity.
干预措施: Glycosylated Recombinant Human G-CSF AVI-014 (Biological)
Treatment (combination chemotherapy, TBI, HCT)
Patients receive melphalan IV over 30 minutes on day -5, fludarabine IV over 30-60 minutes on days -5 to -2. Patients undergo TBI on day -1 and HCT on day 0. Patients receive cyclophosphamide IV over 1-2 hours on days 3 and 4. Starting on day 5, patients receive tacrolimus IV then PO for 6 months followed by a taper, mycophenolate mofetil PO TID until day 35, and G-CSF IV daily until absolute neutrophil count > 1,500/mm^3 for 3 consecutive days. Treatment continues in the absence of disease progression or unexpected toxicity.
干预措施: Laboratory Biomarker Analysis (Other)
Treatment (combination chemotherapy, TBI, HCT)
Patients receive melphalan IV over 30 minutes on day -5, fludarabine IV over 30-60 minutes on days -5 to -2. Patients undergo TBI on day -1 and HCT on day 0. Patients receive cyclophosphamide IV over 1-2 hours on days 3 and 4. Starting on day 5, patients receive tacrolimus IV then PO for 6 months followed by a taper, mycophenolate mofetil PO TID until day 35, and G-CSF IV daily until absolute neutrophil count > 1,500/mm^3 for 3 consecutive days. Treatment continues in the absence of disease progression or unexpected toxicity.
干预措施: Mycophenolate Mofetil (Drug)
Treatment (combination chemotherapy, TBI, HCT)
Patients receive melphalan IV over 30 minutes on day -5, fludarabine IV over 30-60 minutes on days -5 to -2. Patients undergo TBI on day -1 and HCT on day 0. Patients receive cyclophosphamide IV over 1-2 hours on days 3 and 4. Starting on day 5, patients receive tacrolimus IV then PO for 6 months followed by a taper, mycophenolate mofetil PO TID until day 35, and G-CSF IV daily until absolute neutrophil count > 1,500/mm^3 for 3 consecutive days. Treatment continues in the absence of disease progression or unexpected toxicity.
干预措施: Allogeneic Hematopoietic Stem Cell Transplantation (Procedure)
Treatment (combination chemotherapy, TBI, HCT)
Patients receive melphalan IV over 30 minutes on day -5, fludarabine IV over 30-60 minutes on days -5 to -2. Patients undergo TBI on day -1 and HCT on day 0. Patients receive cyclophosphamide IV over 1-2 hours on days 3 and 4. Starting on day 5, patients receive tacrolimus IV then PO for 6 months followed by a taper, mycophenolate mofetil PO TID until day 35, and G-CSF IV daily until absolute neutrophil count > 1,500/mm^3 for 3 consecutive days. Treatment continues in the absence of disease progression or unexpected toxicity.
干预措施: Total-Body Irradiation (Radiation)
Treatment (combination chemotherapy, TBI, HCT)
Patients receive melphalan IV over 30 minutes on day -5, fludarabine IV over 30-60 minutes on days -5 to -2. Patients undergo TBI on day -1 and HCT on day 0. Patients receive cyclophosphamide IV over 1-2 hours on days 3 and 4. Starting on day 5, patients receive tacrolimus IV then PO for 6 months followed by a taper, mycophenolate mofetil PO TID until day 35, and G-CSF IV daily until absolute neutrophil count > 1,500/mm^3 for 3 consecutive days. Treatment continues in the absence of disease progression or unexpected toxicity.
干预措施: Tacrolimus (Drug)
结局指标
主要结局
Incidence of unacceptable toxicity
时间窗: Up to 2 years
Assessed by Bearman Toxicity Scale and NCI CTCAE version 4.03. Observed toxicities will be summarized in terms of type (organ affected or laboratory determination), severity, time of onset, duration, probable association with the study regimen and reversibility or outcome.
Incidence of adverse events
时间窗: Up to 100 days post-hematopoietic cell transplantation (HCT)
Assessed by Bearman Toxicity Scale and National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events version (CTCAE) 4.03. Observed toxicities will be summarized in terms of type (organ affected or laboratory determination), severity, time of onset, duration, probable association with the study regimen and reversibility or outcome.
次要结局
- Neutrophil recovery(Up to 2 years)
- Incidence of cytokine release syndrome (CRS)(After haploidentical HCT, assessed up to 2 years)
- Overall survival(Time from start of protocol treatment/infusion of stem cell product to death (from any cause), or last contact, whichever occurs first, assessed up to 36 months)
- Non-relapse mortality (NRM)(Up to 2 years)
- Graft failure-free survival(Time from start of protocol treatment/infusion of stem cell product to graft-failure, death (from any cause), or last contact, whichever occurs first, assessed up to 2 years)
- Cumulative incidence of acute graft versus host disease (GvHD)(Up to day 100 post-HCT)
- Progression-free survival(Time from start of protocol treatment/infusion of stem cell product to, relapse, progression, death (from any cause), or last contact, whichever occurs first, assessed up to 2 years)
- Platelet recovery(Up to 2 years)
- Cumulative incidence of relapse/progression(Up to 2 years)
- Cumulative incidence of chronic graft versus host disease GvHD(Up to 2 years post-HCT)