Pilot Study of Memory-like Natural Killer (ML NK) Cells After TCRαβ T Cell Depleted Haploidentical Transplant in AML

Study Results

Results pending

The study team has not published outcome measurements, participant flow, or safety data for this trial yet. Check back later for updates.

Basic Information

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Recruitment Status

RECRUITING

Clinical Phase

PHASE1/PHASE2

Total Enrollment

68 participants

Study Classification

INTERVENTIONAL

Study Start Date

2024-05-15

Study Completion Date

2030-05-31

Brief Summary

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This trial represents a single institution phase I/II pilot study with the primary objective of establishing the safety and feasibility of generating and infusing ML NK cells after TCRαβ haplo-HCT.

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Detailed Description

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Conditions

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AML, Childhood Aml Acute Myeloid Leukemia, Pediatric Acute Myeloid Leukemia

Study Design

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Allocation Method

NON_RANDOMIZED

Intervention Model

PARALLEL

The study will enroll both transplant recipients and their haploidentical donors.

Primary Study Purpose

TREATMENT

Blinding Strategy

NONE

Study Groups

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Cohort 1 Recipient: MAC or RIC + Cell graft + ML NK cell infusion

* Patients with high-risk genetic features \&/or poor response to upfront therapy
* Myeloablative Conditioning (MAC): rabbit antithymocyte globulin (rATG), Busulfan, Fludarabine, and Thiotepa. All agents are administered intravenously. rATG is administered from days -9 to -7, followed by Busulfan and Fludarabine from days -6 to -3, \& Thiotepa on day -2 OR
* Reduced Intensity Conditioning (RIC): rabbit antithymocyte globulin (rATG), Fludarabine, Melphalan, and Thiotepa. All agents are administered intravenously. rATG is administered from days -9 to -7. Fludarabine is administered from day -8 to day -5, followed by Thiotepa on day -4 and Melphalan on days -3 and -2
* Patients will undergo infusion of the ex vivo TCRαβ/CD19+ depleted haploidentical HPC graft on day 0. On Day +7, patients will undergo infusion of the memory-like NK (ML NK) cells, followed by IL-2 subcutaneously 4 hours after the infusion. IL-2 will continue every other day through Day +19 for a maximum of 7 doses

Group Type EXPERIMENTAL

No interventions assigned to this group

Cohort 2 Recipient: MAC or RIC + Cell graft + ML NK cell infusion

* Patients with high-risk AML who meet certain criteria listed in the protocol
* Myeloablative Conditioning (MAC): rabbit antithymocyte globulin (rATG), Busulfan, Fludarabine, and Thiotepa. All agents are administered intravenously. rATG is administered from days -9 to -7, followed by Busulfan and Fludarabine from days -6 to -3, \& Thiotepa on day -2 OR
* Reduced Intensity Conditioning (RIC): rabbit antithymocyte globulin (rATG), Fludarabine, Melphalan, and Thiotepa. All agents are administered intravenously. rATG is administered from days -9 to -7. Fludarabine is administered from day -8 to day -5, followed by Thiotepa on day -4 and Melphalan on days -3 and -2
* Patients will undergo infusion of the ex vivo TCRαβ/CD19+ depleted haploidentical HPC graft on day 0. On Day +7, patients will undergo infusion of the memory-like NK (ML NK) cells, followed by IL-2 subcutaneously 4 hours after the infusion. IL-2 will continue every other day through Day +19 for a maximum of 7 doses

Group Type EXPERIMENTAL

No interventions assigned to this group

Donor

Donors who meet the eligibility criteria will be mobilized as per institutional standard practice using G-CSF 10 mcg/kg/day for 5 consecutive days. Leukapheresis will be performed after 5 days of G-CSF administration (on Day -1) with a target volume for collection of 20 liters. If additional collection days are necessary to ensure target CD34+ doses, G-CSF administration may be extended per institutional standard and adjusted per physician discretion. Up to 4 days of pheresis are permitted.

Group Type OTHER

Plerixafor

Intervention Type DRUG

If suboptimal collection of stem cells is predicted, plerixafor may be administered at a dose of 0.24 mg/kg subcutaneous injection once (maximum 40mg/dose). For patients with renal impairment, plerixafor will be administered at a dose of 0.16 mg/kg subcutaneous injection (maximum 27 mg/day).

Granulocyte Colony-Stimulating Factor

Intervention Type BIOLOGICAL

G-CSF will be administered at a dose of 10 mcg/kg/day for 5 days, or 6 days if two days of collection are needed.

Interventions

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Rabbit Anti thymocyte globulin

rATG is administered intravenously over 6-18 hours for a total of 2 to 3 doses. The daily dose is based on body weight and lymphocyte count.

Intervention Type DRUG

Busulfan

Busulfan is administered intravenously either Q6H or Q24H, with a recommended target Busulfan AUC of 70-90 mg\*h/L.

Intervention Type DRUG

Fludarabine

Fludarabine is administered intravenously at a dose of 40 mg/m\^2/dose once daily for 4 days.

Intervention Type DRUG

Thiotepa

Thiotepa is administered intravenously at a dose of 5 mg/kg/dose Q12H for 2 doses.

Intervention Type DRUG

Melphalan

Melphalan is administered intravenously at a dose of 70 mg/m\^2/dose once daily for 2 days.

Intervention Type DRUG

TCR alpha beta / CD19+ depleted haploidentical hematopoietic progenitor cell graft

The HPC product obtained from a haploidentical donor will undergo ex vivo TCR alpha beta and CD19+ depletion, and will be infused fresh on Day 0. There is no maximum limit for CD34+ dose. A maximum dose of 1 x 10\^5/kg recipient weight of TCRαβ cells should not be exceeded in the final HPC product.

Intervention Type BIOLOGICAL

memory-like natural killer cells

The ML NK cells (dose: max capped at 20 x 10\^6/kg recipient weight, minimum dose allowed is 0.5 x 10\^6/kg recipient weight) will be infused on Day +7.

Intervention Type BIOLOGICAL

IL-2

IL-2 is administered subcutaneously at a dose of 1 million units/m\^2 on Days +7, +9, +11, +13, +15, +17, and +19 (7 doses total).

Intervention Type BIOLOGICAL

Plerixafor

If suboptimal collection of stem cells is predicted, plerixafor may be administered at a dose of 0.24 mg/kg subcutaneous injection once (maximum 40mg/dose). For patients with renal impairment, plerixafor will be administered at a dose of 0.16 mg/kg subcutaneous injection (maximum 27 mg/day).

Intervention Type DRUG

Granulocyte Colony-Stimulating Factor

G-CSF will be administered at a dose of 10 mcg/kg/day for 5 days, or 6 days if two days of collection are needed.

Intervention Type BIOLOGICAL

CliniMACS

After stem cells are collected by leukapheresis, in order to create the HPC product, the stem cells will be washed to remove platelets and the cell concentration will be adjusted per laboratory and CliniMACS technology recommendations. The cells are then labeled using the CliniMACS TCRαβ 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.

Intervention Type DEVICE

Other Intervention Names

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rATG Evolema Alkeran TCRab/CD19+ depleted haploidentical HPC graft ML NK cells G-CSF

Eligibility Criteria

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Inclusion Criteria

1. High risk acute myeloid leukemia (AML) in either:

1. Complete remission (CR) defined by \< 5% marrow blasts by morphology in the context of hematological recovery (ANC ≥ 0.5× 10\^9/L, platelet count ≥ 50 × 10\^9/L).
2. Morphological leukemia free state (MLFS) defined by the absence of hematological recovery and \< 5% marrow blasts by morphology
2. Patients must further meet one of the below for inclusion into the study:

1. De novo AML in CR1 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%, without bZIP CEBPA or NPM1
* RAM phenotype as evidenced by flow cytometry
* Other high-risk features not explicitly stated here, after discussion/approval with protocol PI.
2. De novo AML in ≥ CR2
3. Therapy-related AML in CR1
4. AML evolving from myelodysplastic syndrome (MDS)
3. One prior hematopoietic cell transplant is allowed, provided remission criteria as defined above are met.

1. High risk acute myeloid leukemia (AML) defined by either of the following:

1. Treatment refractory disease: AML that is not in complete remission despite prior standard or salvage therapies.
2. Multiply relapsed disease: AML that has relapsed after 2 or more hematopoietic cell transplantations.
2. BM disease burden: Less than 25% bone marrow blasts by morphology must be present (M2 marrow), irrespective of peripheral hematological recovery.

1. Less than or equal to 40 years of age.
2. Lansky (\<16 years) or Karnofsky (≥16 years) performance status of \>60%.
3. Adequate organ function as defined below:

1. Total bilirubin ≤ 3 x IULN for age
2. AST(SGOT)/ALT(SGPT) ≤ 5 x IULN for age
3. GFR ≥ 60 mL/min/1.73m2 as estimated by (1) updated Schwartz formula for ages 1-17 years or Cockcroft-Gault formula for ages ≥ 18 years, (2) 24-hour creatinine clearance, or (3) renal scintigraphy. If GFR is abnormal for age based on updated Schwartz or Cockcroft-Gault formula, accurate measurement should be obtained by either 24-hour creatinine clearance or renal scintigraphy.
4. Renal function may also be estimated by serum creatinine based on age/gender. A serum creatinine \< 2 x IULN for age/gender is required for inclusion on this protocol.
4. Adequate cardiac function, defined by left ventricular ejection fraction (LVEF) at rest ≥50% or shortening fraction (SF) ≥27% (via echocardiogram or MUGA).
5. Adequate pulmonary function, defined by:

1. FEV1, FVC, and DLCO ≥50% of predicted.
2. O2 saturation ≥ 92% on room air by pulse oximetry and no supplemental O2 at rest for children \< 8 years of age or those unable to perform pulmonary function testing (PFT). For children unable to perform PFT, a high-resolution CT chest should be obtained.
6. The effects of these treatments on the developing human fetus are unknown. For this reason, women of childbearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control, abstinence) prior to study entry, for the duration of study participation, 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.
7. Ability to understand and willingness to sign an IRB approved written informed consent document, or patient has a guardian who has the ability to understand and willingness to sign an IRB approved written informed consent document.
8. Available familial haploidentical donor. The HCT donor must be available and willing to undergo 2 leukapheresis procedures: (I) one mobilized collection for the HPC graft and (II) one non-mobilized leukapheresis collection for the manufacturing of ML NK cells.
9. 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.

Exclusion Criteria

1. Active GvHD. If patient had prior GvHD, patient must be off immunosuppression for at least 3 months prior to starting study treatment.
2. Active non-hematologic malignancy. History of other malignancy is acceptable as long as therapy has been completed and there is no current evidence of disease.
3. Currently receiving any other investigational agents at the time of transplant.
4. Active CNS or extramedullary disease. History of CNS or extramedullary disease currently in remission is acceptable.
5. A history of allergic reactions attributed to compounds of similar chemical or biologic composition to agents used in the study.
6. Inability to discontinue medications that are likely to interfere with ML NK cell activity, i.e., glucocorticoids and other immunosuppressants.
7. 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 \> 3000.
8. Presence of a second major disorder deemed a contraindication for HCT.
9. Patients with Fanconi Anemia or Down Syndrome.
10. 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.
11. 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 - Both Cohorts

1. Donor must be at least 18 years of age.
2. Donor must be HLA haploidentical (≥ 5/10 and ≤ 9/10 allele match at the -A, -B, -C, DRB1 and DQ loci) by high resolution typing and related to the patient.
3. Donor must meet the selection criteria as defined by the Foundation for the Accreditation of Hematopoietic Cell Therapy (FACT).
4. Donor must be available and willing to undergo one mobilized and one non-mobilized leukapheresis procedure.
5. Donor may not be pregnant and/or breastfeeding. Women of childbearing potential must have a negative pregnancy test within 7 days prior to initiation of recipient's conditioning regimen, within 7 days of donor stem cell mobilization regimen and prior to second non-mobilized leukapheresis..
6. Donor must be able to understand and willing to sign an IRB-approved written informed consent document.

Minimum Eligible Age

18 Years

Eligible Sex

ALL

Accepts Healthy Volunteers

No