Haploidentical Hematopoietic Stem Cell Transplantation With Ex Vivo TCR Alpha/Beta and CD19 Depletion in Pediatric Hematologic Malignancies

Study Overview
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Brief Summary
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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).

Official Title
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A Pilot Study of Haploidentical Hematopoietic Stem Cell Transplantation With Ex Vivo TCR Alpha/Beta and CD19 Depletion in Pediatric Hematologic Malignancies

Conditions
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Pediatric Hematologic Malignancies

Intervention / Treatment
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* Device: Ex Vivo T-cell receptor alpha-beta and CD19+ Depletion using CliniMACs Plus


Participation Criteria
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Eligibility Criteria
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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) FUS-ERG 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-DQB1. 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% Adequate organ function as defined below: Cardiac: LVEF ≥ 40% at rest or SF ≥ 26% Hepatic: Total bilirubin < 3 x IULN for age AST(SGOT)/ALT(SGPT) < 5 x IULN Renal: GFR ≥ 60 mL/min/1.73m2 as estimated by updated Schwartz formula for ages 1-17 years (see Appendix B), 24-hour creatinine clearance, or renal scintigraphy. If GFR is abnormal for age based on updated Schwartz formula, accurate measurement should be obtained by either 24-hour creatinine clearance or renal scintigraphy. Renal function may also be estimated by serum creatinine based on age/gender. A minimum serum creatinine of 2x upper limit of normal is required for inclusion on this protocol. Pulmonary: O2 saturation ≥ 92% on room air without positive pressure support FEV1, FVC, and DLCO ≥ 50% of predicted (for children unable to perform a pulmonary function test, a high-resolution CT chest may be obtained) The effects of these treatments on the developing human fetus are unknown. For this reason, patients of childbearing potential must agree to use adequate contraception (hormonal or barrier method of birth control, abstinence) prior to study entry and for 24 months following transplant. Should a woman become pregnant or suspect she is pregnant while participating in this study, she must inform her treating physician immediately. Ability to understand and willingness to sign an IRB approved written informed consent document (or that of legally authorized representative, if applicable). Recipient Exclusion Criteria: 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. 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: At least 6 months of age 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).

Ages Eligible for Study
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Maximum Age: 30 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
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: ex vivo αβ-TCR/CD19 depleted haplo-hematopoietic stem cell infusion (HSCT)<br>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. | Device: Ex Vivo T-cell receptor alpha-beta and CD19+ Depletion using CliniMACs Plus<br>* Once pheresed, the product will be washed to remove platelets and the cell concentration will be adjusted per laboratory and ClinicMACS technology recommendations. It is then labeled using the CliniMACS αβ-TCR Biotin Kit and CD19+ immunomagnetic microbeads. After labeling, the cells are washed to remove unbound microbeads. The partially processed product is loaded on the CliniMACS device where labeled cells are depleted and the negative fraction is eluted off the device. The negative fraction is centrifuged and volume reconstituted to obtain the final product<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety as measured by the number of events occurring within the first 100 days post-transplant | -Events are death, disease recurrence or progression, and graft failure | Through 100 days post-transplant | 
| Engraftment as measured by time to neutrophil count recovery | 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. | From day of transplant (day 0) to 42 days (+/- 14 days) post transplant | 
| Engraftment as measured by time to platelet count recovery | 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. | From day of transplant (day 0) to 75 days (+/- 14 days) post transplant) | 
| Donor cell chimerism as measured by short tandem repeat analysis | Can use peripheral blood samples or bone marrow samples The percent of donor-derived cells are sequentially followed. | Through day +100 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Event free survival (EFS) | -Death, disease recurrence or progression, and graft failure are considered events | At 2 years post transplant | 
| Change in Lansky/Karnofsky performance score | Lansky is used for participants <15.99 years of age Karnofsky is used for participants >16.00 years of age | Day +14, Day +30, Day +60, Day +100, Day +180, Day +365, +18 months, and +24 months | 
| Incidence and severity of acute GVHD | -Incidence and severity of acute GVHD as graded according to the NIH consensus criteria. Severe aGVHD (Grades III-IV) is considered an event. | Weekly through day +100 | 
| Incidence and severity of chronic GVHD | Incidence and severity of acute GVHD as graded according to the NIH consensus criteria. Severe cGHVD is considered an event. | Day 101 through 24 months | 
| Number of neurologic toxicities | -As evidence by clinical assessment and/or imaging at physician discretion | Through 24 months | 
| Number of pulmonary toxicities | -As determined by clinical context and serial assessment of TLC, FVC, FEV1, DLCO, or high-resolution CT Chest | Through 24 months | 
| Number of cardiac toxicities | -As determined by clinical assessment and EKG and/or echocardiogram | Through 24 months | 
| Number of renal toxicities | -As determined by clinical assessment and BUN, creatinine, urinalysis, estimated GFR, or renal scintigraphy | Through 24 months | 
| Number of hepatic toxicities | -As determined by clinical assessment and liver function tests | Through 24 months | 
| Number of participants with infections |  | Through 24 months | 
| Number of metabolic toxicities | -Metabolic toxicities will be collected using a complete metabolic panel | Through 24 months | 
| Number of thyroid toxicities | -Thyroid toxicities will be collected using a thyroid function test | 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 | Immune reconstitution is defined as regain of function of donor-derived immunogenic cells. Immune reconstitution is to be measured by recovery of individual cellular compartments Via flow cytometry | Over 24 months | 
| Immune reconstitution as measured by regain of function of T cell populations | Immune reconstitution is defined as regain of function of donor-derived immunogenic cells. Immune reconstitution is to be measured by recovery of individual cellular compartments Via flow cytometry | Through 24 months | 
| Immune reconstitution as measured by regain of function of B cell populations | Immune reconstitution is defined as regain of function of donor-derived immunogenic cells. Immune reconstitution is to be measured by recovery of individual cellular compartments Via flow cytometry | Through 24 months | 
| Immune reconstitution as measured by regain of function of immunoglobulin G (IgG) | Immune reconstitution is defined as regain of function of donor-derived immunogenic cells. Immune reconstitution is to be measured by recovery of individual cellular compartments Via serum analysis | Over 24 months | 
| Immune reconstitution as measured by regain of function of immunoglobulin A (IgA) | Immune reconstitution is defined as regain of function of donor-derived immunogenic cells. Immune reconstitution is to be measured by recovery of individual cellular compartments Via serum analysis | Over 24 months | 
| Immune reconstitution as measured by regain of function of immunoglobulin M (IgM) | Immune reconstitution is defined as regain of function of donor-derived immunogenic cells. Immune reconstitution is to be measured by recovery of individual cellular compartments Via serum analysis | Over 24 months |