NCT05011422招募中1 期
A Pilot Study of Haploidentical Hematopoietic Stem Cell Transplantation With Ex Vivo TCR Alpha/Beta and CD19 Depletion in Pediatric Hematologic Malignancies
适应症
干预措施
试验速览
- 阶段
- 1 期
- 状态
- 招募中
- 入组人数
- 50
- 试验地点
- 2
- 主要终点
- Safety as measured by the number of events occurring within the first 100 days post-transplant
研究概览
简要总结
This single arm pilot phase I study with safety run-in is designed to estimate the safety and efficacy of a familial mismatched or haploidentical hematopoietic stem cell transplantation (haplo-HSCT) using a novel graft modification technique (selective αβ-TCR and CD19 depletion).
研究设计
- 研究类型
- Interventional
- 分配方式
- Non Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- — 至 30 Years（Child, Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Recipient Inclusion Criteria:
- •Must meet at least one of the following disease criteria:
- •B cell ALL in first remission and any of the following:
- •Persistent flow-based MRD at end-of-consolidation:
- •≥ 1% for NCI SR ALL
- •≥ 0.01% for NCI HR ALL
- •TCF3-HLF t(17;19)
- •KMT2A rearranged infant ALL, < 6 months of age and presenting WBC of > 300,000 or poor steroid response (peripheral blasts >= 1000 /uL on day 8 of therapy
- •Other high-risk features not explicitly stated here, after discussion/approval with protocol PI.
- •B cell ALL in second remission and any of the following:
- •Early (<36 months from start of therapy) marrow or combined relapse
- •Late (>36 months from start of therapy) marrow or combined relapse with end-of re-induction flow MRD >= 0.1%
- •Early isolated extramedullary relapse (< 18 months from start of therapy)
- •Any B cell ALL in third or greater remission
- •T cell ALL in first remission
- •End-of consolidation MRD > 0.1%
- •Any T cell ALL in second or greater remission
- •AML in first remission with any of the following high-risk features:
- •MRD ≥ 1% after first induction course
- •MRD ≥ 0.1% after second induction course
- •RPN1-MECOM
- •RUNX1-MECOM
- •NPM1-MLF1
- •DEK-NUP214
- •KAT6A-CREBBP (if >= 90 days at diagnosis)
- •KMT2A-AFF1
- •KMT2A-AFDN
- •KMT2A-ABI1
- •KMT2A-MLLT1
- •11p15 rearrangement (NUP98 - any partner gene)
- •12p13.2 rearrangement (ETV6 - any partner gene)
- •Deletion 12p to include 12p13.2 (loss of ETV6)
- •Monosomy 5/Del(5q) to include 5q31 (loss of EGR1)
- •Monosomy 7
- •10p12.3 rearrangement (MLLT10b - any partner gene)
- •FLT3/ITD with allelic ratio > 0.1%
- •RAM phenotype as evidenced by flow cytometry: bright CD56+, dim to negative CD45 and CD38 and lack of HLA-DR
- •Other high-risk features not explicitly stated here, after discussion/approval with protocol PI.
- •AML in second or greater remission
- •Mixed phenotype or undifferentiated leukemia in any CR
- •Secondary to therapy-associated leukemia in any CR
- •NK cell lineage leukemia in any CR
- •Myelodysplastic syndrome (MDS)
- •Juvenile myelomonocytic leukemia (JMML)
- •May have undergone a prior hematopoietic stem cell transplant provided one of the criteria in Inclusion Criterion #1 are met AND the patient does not have active GVHD (has been off immunosuppression for at least 3 months).
- •Available familial haploidentical donor.
- •Donor and recipient must be identical at a minimum of one allele of each of the following genetic loci: HLA-A, HLA-B, HLA-Cw, HLA-DRB1, and HLA-DQB
- •A minimum of 5/10 match is required and will be considered sufficient evidence that the donor and recipient share one HLA haplotype.
- •No more than 30 years of age
- •Lansky or Karnofsky performance status > 50%
- 另有 10 项未显示
排除标准
- •Available matched related donor. A patient with a matched unrelated donor is eligible if urgent transplantation is required. A prior unrelated donor search is not required for enrollment.
- •Active non-hematologic malignancy. History of other malignancy is acceptable as long as therapy has been complete and there is no evidence of disease.
- •Currently receiving any other investigational agents at the time of transplant.
- •Active CNS or extramedullary disease. History of CNS or extramedullary disease now in remission is acceptable.
- •A history of allergic reactions attributed to compounds of similar chemical or biologic composition to conditioning agents used in the study.
- •Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection (bacterial, viral with clinical instability, or fungal), symptomatic congestive heart failure, or unstable cardiac arrhythmia.
- •Presence of significant anti-donor HLA antibodies per institutional standards. Anti-donor HLA Antibody Testing is defined as a positive crossmatch test of any titer (by complement dependent cytotoxicity or flow cytometric testing) or the mean fluorescence intensity (MFI) of any anti-donor HLA antibody by solid phase immunoassay.
- •Presence of a second major disorder deemed a contraindication for HSCT.
- •Pregnant and/or breastfeeding. Women of childbearing potential must have a negative pregnancy test within 14 days of the start of conditioning.
- •Donor Eligibility Criteria:
- •The preferred donor should be an adult aged at least 18 years or older. However, in circumstances where no suitable adult donor is available, consideration may be given to a minor donor aged 12 years or older. This exception only applies when all identified, otherwise eligible adult donors meet one or more of the following criteria:
- •Have a medical condition that poses unacceptable risk, including autoimmune disease, infection, hematologic disorder, malignancy, or a pathogenic germline mutation.
- •Have comorbidities that preclude safe administration of granulocyte colony-stimulating factor (G-CSF), placement of a pheresis catheter and/or a pathogenic germline mutation.
- •Served as a donor in prior haploidentical HCT.
- •Significant psychosocial or logistical barriers.
- •Meets the selection criteria as defined by the Foundation for the Accreditation of Hematopoietic Cell Therapy (FACT).
- •Able to understand and willing to sign an IRB-approved written informed consent document (or that of legally authorized representative, if applicable).
研究组 & 干预措施
Recipients: ex vivo αβ-TCR/CD19 depleted haplo-hematopoietic stem cell infusion (HSCT)
Experimental
- Patients will undergo standard of care conditioning regiment prior to HSCT
- On Day 0, patients will undergo infusion of the ex vivo αβ-TCR/CD19 depleted haplo-HSCT from a stimulated peripheral stem cell source per institutional standard of care. Patients whose graft has a residual CD20+ count > 1.0 x 10^5 may receive a single infusion of rituximab on Day +1 at a dose of 375 mg/m^2 at provider's discretion.
干预措施: Ex Vivo T-cell receptor alpha-beta and CD19+ Depletion using CliniMACs Plus (Device)
Donors:
No Intervention
Donors who meet the eligibility criteria will be mobilized as per institutional standard practice using G-CSF 10 mcg/kg/day with leukapheresis to take place on Day 5. The target volume for collection is 20 L. Up to 4 days of pheresis are permitted to ensure target collection.
结局指标
主要结局
Safety as measured by the number of events occurring within the first 100 days post-transplant
时间窗: Through 100 days post-transplant
-Events are death, disease recurrence or progression, and graft failure
Engraftment as measured by time to neutrophil count recovery
时间窗: From day of transplant (day 0) to 42 days (+/- 14 days) post transplant
Time to neutrophil recovery is defined as the first of 3 measurements on different days when the patient has an absolute neutrophil count of \>500/μL after conditioning.
Engraftment as measured by time to platelet count recovery
时间窗: From day of transplant (day 0) to 75 days (+/- 14 days) post transplant)
Time to platelet recovery is defined as the first day of a minimum of 3 measurements on different days that the patient has achieved a platelet count \> 50,000/μL AND did not receive a platelet transfusion in the previous 7 days. The exception is the case in which a patient receives platelet transfusions specifically to achieve a higher platelet threshold to allow for an invasive procedure or protection if determined to be at elevated bleeding risk.
Donor cell chimerism as measured by short tandem repeat analysis
时间窗: Through day +100
* Can use peripheral blood samples or bone marrow samples * The percent of donor-derived cells are sequentially followed.
次要结局
- Immune reconstitution as measured by regain of function of T cell populations(Through 24 months)
- Number of pulmonary toxicities(Through 24 months)
- Number of cardiac toxicities(Through 24 months)
- Number of renal toxicities(Through 24 months)
- Number of hepatic toxicities(Through 24 months)
- Number of metabolic toxicities(Through 24 months)
- Number of thyroid toxicities(Through 24 months)
- Immune reconstitution as measured by recovery of absolute neutrophil count(Over 24 months)
- Immune reconstitution as measured by recovery of absolute monocyte count(Over 24 months)
- Immune reconstitution as measured by regain of function of NK cell populations(Over 24 months)
- Immune reconstitution as measured by regain of function of B cell populations(Through 24 months)
- Immune reconstitution as measured by regain of function of immunoglobulin G (IgG)(Over 24 months)
- Immune reconstitution as measured by regain of function of immunoglobulin A (IgA)(Over 24 months)
- Immune reconstitution as measured by regain of function of immunoglobulin M (IgM)(Over 24 months)
- Event free survival (EFS)(At 24 months post transplant)
- Overall survival (OS)(At 24 months post transplant)
- Incidence of grade IV acute GVHD(Weekly through day +100)
- Incidence of severe chronic GVHD(Day 101 through 24 months)
- Change in Lansky/Karnofsky performance score(Day +100, Day +180, Day +365, and +24 months)
- Number of pulmonary toxicities(Through 24 months)
- Number of neurologic/neurocognitive toxicities(Through 24 months)
- Number of cardiac toxicities(Through 24 months)
- Number of renal toxicities(Through 24 months)
- Immune reconstitution as measured by recovery of absolute monocyte count(Over 24 months)
- Number of hepatic toxicities(Through 24 months)
- Number of metabolic toxicities(Through 24 months)
- Number of thyroid toxicities(Through 24 months)
- Incidence and severity of acute GVHD(From day +14 through Day +100)
- Incidence and severity of chronic GVHD(From day +101 through 24 months)
- Number of participants with infections requiring hospitalizations(Through 24 months)
- Immune reconstitution as measured by recovery of absolute neutrophil count(Over 24 months)
- Immune reconstitution as measured by regain of function of NK cell populations(Over 24 months)
- Immune reconstitution as measured by regain of function of T cell populations(Through 24 months)
- Immune reconstitution as measured by regain of function of B cell populations(Through 24 months)
- Immune reconstitution as measured by regain of function of immunoglobulin G (IgG)(Over 24 months)
- Immune reconstitution as measured by regain of function of immunoglobulin A (IgA)(Over 24 months)
- Immune reconstitution as measured by regain of function of immunoglobulin M (IgM)(Over 24 months)
研究者
研究点 (2)
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