A Pilot Study to Evaluate the Safety and Feasibility of Induction of Mixed Chimerism in Severe Aplastic Anemia Patients With COH-MC-17: A Non-Myeloablative/ Reduced-Intensity, Conditioning Regimen and CD4+ T-Cell-Depleted Haploidentical Hematopoietic Transplant
概览
- 阶段
- 1 期
- 干预措施
- Anti-Thymocyte Globulin
- 疾病 / 适应症
- Recurrent Severe Aplastic Anemia
- 发起方
- City of Hope Medical Center
- 入组人数
- 6
- 试验地点
- 1
- 主要终点
- Incidence of adverse events
- 状态
- 招募中
- 最后更新
- 3个月前
概览
简要总结
This phase I trial evaluates the safety and feasibility of using a reduced-intensity regimen of cyclophosphamide, pentostatin, and anti-thymocyte globulin prior to a CD4+ T-cell depleted haploidentical hematopoietic cell transplant (haploHCT) for the treatment of patients with severe aplastic anemia that does not respond to treatment (refractory) or that has come back (recurrent). Cyclophosphamide is in a class of medications called alkylating agents. It works by damaging the cell's deoxyribonucleic acid. It may also lower the body's immune response. Pentostatin blocks a protein needed for cell growth. Anti-thymocyte globulin is an immunosuppressive drug can destroy immune cells known as T-cells. HaploHCT transfers blood-forming stem cells from a healthy partially-matched donor to a patient. Administering a regimen of cyclophosphamide, pentostatin, and anti-thymocyte globulin before haploHCT may help make room for the new, healthy cells and may reduce the risk of graft versus host disease.
详细描述
PRIMARY OBJECTIVES: I. To determine if the infusion of CD4+ T-cell-depleted hematopoietic cells from a haploidentical donor, following a non-myeloablative/ reduced-intensity preparative regimen is safe in patients with severe aplastic anemia (SAA). II. To determine the feasibility of producing an infusion ready CD4+ T-cell-depleted hematopoietic product, as assessed by: IIa. Ability to meet the minimum required CD34+ cell dose, and; IIb. Ability to meet the CD4+ T-cell depletion product release requirements. SECONDARY OBJECTIVES: I. To evaluate toxicities including type, frequency, severity, attribution, time course, and duration. (Safety/tolerability) II. To summarize and evaluate hematologic (neutrophil and platelet) recovery, including marrow failure. (Safety/tolerability) III. To estimate the incidence of infection and infectious disease related complications at 100 days. (Safety/tolerability) IV. To estimate the incidence of SAA related complications. (Safety/tolerability) V. To estimate the cumulative incidence of non-relapse mortality at 100-days, 1-year and 2-years post hematopoietic stem-cell transplantation (HCT). (Safety/tolerability) VI. To estimate the cumulative incidence of acute graft versus host disease (GvHD) (grades: II-IV, III-IV) at 100-days and chronic GvHD (grades: any, moderate-severe) at 6-months, 1-year and 2-years post HCT. (Safety/tolerability) VII. To estimate the overall survival probability at 100-days, 1-year and 2-years post HCT. (Survival/relapse) VIII. To estimate the disease-free survival probability at 100-days, 1-year and 2-years post HCT. (Survival/relapse) IX. To estimate the event-free survival probability at 100-days, 1-year and 2-years post HCT. (Survival/relapse) X. To estimate the cumulative incidence of disease relapse at 100-days, 1-year and 2-years post HCT. (Survival/relapse) XI. To describe response as categorized by graft failure, persistent post-immunosuppressant (IS) mixed chimerism, persistent IS-dependent mixed chimerism, complete chimerism. (Chimerism) XII. To summarize/characterize patient chimerism (percent of donor total nucleated and donor lineage specific cells) over time. (Kinetics) EXPLORATORY OBJECTIVES: I. To describe the ratio of donor to recipient de novo thymic T cells over the course of 2 years within the peripheral blood compartment. II. To describe the ratio of donor to recipient regulatory T cells and regulatory B cells over the course of 2 years within the peripheral blood and bone marrow compartments. III. To describe the tolerance status of donor and host-type T cells over the course of 2 years within the peripheral blood compartment. IV. To describe the T-cell repertoire of donor- and host-type T cells over the course of 2 years within the peripheral blood compartment. V. To describe the bone marrow niche and peripheral blood cytokine profile over time. VI. To describe bone marrow progenitor chimerism over time. OUTLINE: Patients receive cyclophosphamide orally (PO) and intravenously (IV), pentostatin IV, anti-thymocyte globulin IV and undergo CD4+ T-cell depleted haploHCT on study. Patients also undergo bone marrow aspirate, bone marrow biopsy, and collection of blood samples at screening and follow-up.
研究者
入排标准
入选标准
- •RECIPIENT: Documented informed consent of the participant.
- •RECIPIENT: Age: \>= 40 years but =\< 75 years of age at time of enrollment.
- •RECIPIENT: Failed at least one trial of immunosuppressive therapy (IST) by being refractory (persistence of severe cytopenia and fulfillment of SAA disease criteria at least 3 months after initial IST) or having relapsed (initial improvement of cytopenia after first-line IST but then a later return to fulfillment of SAA disease criteria when IST is decreased or ceased). IST could have included anti-thymocyte globulin (ATG) based regimens, calcineuPririn inhibitors and/or other higher dose therapy directed at the treatment of primary SAA.
- •RECIPIENT: Karnofsky performance score \>= 60%.
- •RECIPIENT: Confirmed diagnosis of severe aplastic anemia as:
- •Bone marrow cellularity \< 25% or marrow cellularity \< 50% but with \< 30% residual hematopoietic cells;
- •Two out of three of the following (in peripheral blood):
- •Neutrophils \< 0.5 x 10\^9/L;
- •Platelets \< 20 x 10\^9/L;
- •Reticulocyte count \< 20 x 10\^9/L (\< 60 x 10\^9/L using an automated analysis).
排除标准
- •RECIPIENT: Inherited and acquired (non-aplastic anemia) bone marrow failure syndromes such as Fanconi anemia must be ruled out according to center standards.
- •RECIPIENT: Clonal cytogenetic abnormalities consistent with pre-myelodysplastic syndrome (pre-MDS) or MDS on marrow examination (e.g. Monosomy 7).
- •RECIPIENT: Any somatic mutations (including TERT, TERC, DKC1, NOP10) other than PIG-A (PNH) or BCOR mutation.
- •RECIPIENT: Diagnosis of myelodysplastic syndrome (MDS).
- •RECIPIENT: Presence of anti-donor HLA antibodies (positive anti-donor HLA antibody is defined as a positive cross-match test of any titer by complement-dependent cytotoxicity or flow cytometric testing or the presence of anti-donor HLA antibody to the high expression loci HLA-A, B, C, DRB1, or DPB1 with mean fluorescence intensity \[MFI\] \> 1000 by solid phase immunoassay).
- •RECIPIENT: Prior allogeneic stem cell transplant.
- •RECIPIENT: Prior solid organ transplant.
- •RECIPIENT: Known life-threatening reaction (i.e., anaphylaxis) to Thymoglobulin (registered trademark) that would prohibit use for the patient as this study requires use of the Thymoglobulin (registered trademark) preparation of ATG.
- •RECIPIENT: Uncontrolled bacterial, viral, or fungal infection at the time of enrollment. Uncontrolled is defined as currently taking medication and with progression or no clinical improvement on adequate medical treatment.
- •RECIPIENT: Seropositive for the human immunodeficiency virus (HIV).
研究组 & 干预措施
Treatment (conditioning, haploHCT)
Patients receive cyclophosphamide PO and IV, pentostatin IV, anti-thymocyte globulin IV and undergo CD4+ T-cell depleted haploHCT on study. Patients also undergo bone marrow aspirate, bone marrow biopsy, and collection of blood samples at screening and follow-up.
干预措施: Anti-Thymocyte Globulin
Treatment (conditioning, haploHCT)
Patients receive cyclophosphamide PO and IV, pentostatin IV, anti-thymocyte globulin IV and undergo CD4+ T-cell depleted haploHCT on study. Patients also undergo bone marrow aspirate, bone marrow biopsy, and collection of blood samples at screening and follow-up.
干预措施: Biospecimen Collection
Treatment (conditioning, haploHCT)
Patients receive cyclophosphamide PO and IV, pentostatin IV, anti-thymocyte globulin IV and undergo CD4+ T-cell depleted haploHCT on study. Patients also undergo bone marrow aspirate, bone marrow biopsy, and collection of blood samples at screening and follow-up.
干预措施: Bone Marrow Aspirate
Treatment (conditioning, haploHCT)
Patients receive cyclophosphamide PO and IV, pentostatin IV, anti-thymocyte globulin IV and undergo CD4+ T-cell depleted haploHCT on study. Patients also undergo bone marrow aspirate, bone marrow biopsy, and collection of blood samples at screening and follow-up.
干预措施: Bone Marrow Biopsy
Treatment (conditioning, haploHCT)
Patients receive cyclophosphamide PO and IV, pentostatin IV, anti-thymocyte globulin IV and undergo CD4+ T-cell depleted haploHCT on study. Patients also undergo bone marrow aspirate, bone marrow biopsy, and collection of blood samples at screening and follow-up.
干预措施: Cyclophosphamide
Treatment (conditioning, haploHCT)
Patients receive cyclophosphamide PO and IV, pentostatin IV, anti-thymocyte globulin IV and undergo CD4+ T-cell depleted haploHCT on study. Patients also undergo bone marrow aspirate, bone marrow biopsy, and collection of blood samples at screening and follow-up.
干预措施: Haploidentical Hematopoietic Cell Transplantation
Treatment (conditioning, haploHCT)
Patients receive cyclophosphamide PO and IV, pentostatin IV, anti-thymocyte globulin IV and undergo CD4+ T-cell depleted haploHCT on study. Patients also undergo bone marrow aspirate, bone marrow biopsy, and collection of blood samples at screening and follow-up.
干预措施: Pentostatin
Treatment (conditioning, haploHCT)
Patients receive cyclophosphamide PO and IV, pentostatin IV, anti-thymocyte globulin IV and undergo CD4+ T-cell depleted haploHCT on study. Patients also undergo bone marrow aspirate, bone marrow biopsy, and collection of blood samples at screening and follow-up.
干预措施: Questionnaire Administration
结局指标
主要结局
Incidence of adverse events
时间窗: From day -22 to day +100 or occurrence of unacceptable toxicity, whichever occurs first
Toxicity will be graded according to the National Cancer Institute's-Common Terminology Criteria for Adverse Events version 5.0. Graft versus host disease (GVHD) specific toxicities will be defined per 1994 Keystone Consensus Criteria. 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. This will include infectious disease related complications and autoimmune disease related complications. Cumulative incidence curves will be used for time to event variables with competing risks events such as acute GVHD or chronic GVHD. Point estimates and 90% confidence intervals will be used.
Ability to meet CD4+ T-cell depleted product release requirements (feasibility)
时间窗: Up to 3 years
The feasibility of producing an infusion ready CD4+ T-cell-depleted hematopoietic product will be assessed by the ability to meet product release requirements. Product release requirements include the following: (1) CD34+ cells: Post-processing CD34+ cell target of 7.5-13.0 x 106 cells/kg of recipient body weight; (2) CD4+ T-cell depletion: \>= 97% of CD4+ T-cells in the the hematopoietic cell product for manufacturing; (3) Sterility (e.g. endotoxin and gram staining). Descriptive statistics will be used to characterize feasibility.
Ability to meet minimum required cell dose (feasibility)
时间窗: Up to 3 years
The feasibility of producing an infusion ready CD4+ T-cell-depleted hematopoietic product will be assessed by the ability to meet minimum required cell doses. This outcome will be evaluated using the following: (1) CD34+ collected (per day of apheresis); (2) CD34+ recovery: % CD34+ cells recovered from the CD34+ cell number in the product being manufactured (pre-CD4+ T cell depletion); (3) Cell dose: pooled and back up product; (4) Cell dose adequate given recipient's body weight plus the required pre-processed back-up set aside (yes/no); (5) Number (median, range) of apheresis; (6) % CD4+ T-cell depletion; (7) reason for not meeting product release requirements. Descriptive statistics will be used to characterize feasibility.
次要结局
- Marrow failure(Up to 28 days post transplant for primary graft failure or after initial engraftment for secondary graft failure, assessed up to 3 years)
- Incidence of adverse events of grade 3 or higher(Up to 3 years)
- Incidence of infection(Up to 3 years)
- Time to neutrophil recovery(From the date of CD4+ T-cell-depleted product infusion to the first of three consecutive days of absolute neutrophil count (ANC) >= 500/mm^3 and ANC >= 1000/mm^3, assessed up to 3 years)
- Time to platelet recovery(Time to the first day of the first of three consecutive laboratory values when the platelet count is >= 20,000/mm^3 and 100,000/mm^3 without a platelet transfusion in the previous seven, assessed up to 3 years)
- Cumulative incidence of chronic GvHD (any and moderate-severe)(From day +100 to +2 years post-transplant)
- Cumulative incidence of non-relapse mortality (NRM)(From enrollment until non-disease related death or last follow up and from date of CD4+ T-cell-depleted product infusion, assessed up to 3 years)
- Cumulative incidence of acute GvHD (II-IV and III-IV)(From day 0 through day +100 post-transplant)
- Overall survival(Time from enrollment to death, assessed up to 3 years)
- Cumulative incidence of relapse(Time from enrollment/infusion of depleted hematopoietic product to first observation of disease relapse, assessed up to 3 years)
- Disease-free survival (DFS)(Time from enrollment/ infusion of CD4+ T-cell-depleted hematopoietic product to relapse, therapy for hemoglobinopathy, death from any cause, assessed up to 3 years)
- Kinetics(At 7, 15, 30, 60, 100, 180 days and 1, 1.5, and 2 years post-transplant)
- Event-free survival (EFS)(Time from enrollment/infusion of CD4+ T-cell product to any of the following events (whichever occurs first): therapy for hemoglobinopathy, primary/secondary graft failure, acute GvHD, chronic GvHD, death from any cause, assessed up to 3 years)
- Chimerism(Up to 2 years)