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

Phase 1

Recruiting

• Conditions: Aml; Acute Myeloid Leukemia, Pediatric; Acute Myeloid Leukemia; AML, Childhood
• Interventions: Drug: Rabbit Anti thymocyte globulin; Drug: Plerixafor; Biological: Granulocyte Colony-Stimulating Factor; Drug: Busulfan; Drug: Fludarabine; Drug: Thiotepa; Drug: Melphalan; Biological: TCR alpha beta / CD19+ depleted haploidentical hematopoietic progenitor cell graft; Biological: memory-like natural killer cells; Biological: IL-2; Device: CliniMACS

• Registration Number: NCT06158828
• Lead Sponsor: Washington University School of Medicine

Brief Summary

This phase I/II pilot study aims to enhance the effectiveness of stem cell transplant for children and young adults with high-risk acute myeloid leukemia (AML). Patients will undergo a stem cell transplant from a half-matched family donor. One week later, patients will receive an additional infusion of immune cells and a drug called interleukin-2.
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Detailed Description

Not available

Basic Information
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Recruitment & Eligibility
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Study & Design
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Trial Locations

Study Timeline

• Study First Submitted: 2023-11-27
• Study First Submitted QC: 2023-11-27
• Study First Posted: 2023-12-06
• Status Verified: 2024-05
• Study Start: 2024-05-15
• Last Update Submitted: 2024-05-16
• Last Update Posted: 2024-05-17
• Primary Completion: 2028-09-15
• Study Completion: 2030-05-31

Recruitment & Eligibility

• Status: RECRUITING
• Sex: All
• Target Recruitment: 48

Inclusion Criteria

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

   1. Complete remission (CR) per ELN criteria as 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), per ELN criteria defined by the lack of hematological recovery, < 5% marrow blasts by morphology with at least 200 nucleated cells present in the bone marrow aspirate.

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. Prior hematopoietic cell transplant is allowed, provided remission criteria as defined above are met.

4. No more than 30 years of age.

5. Lansky (<16 years) or Karnofsky (≥16 years) performance status of >60%.

6. 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.

7. Adequate cardiac function, defined by left ventricular ejection fraction (LVEF) at rest ≥50% or shortening fraction (SF) ≥27% (via echocardiogram or MUGA).

8. 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.

9. 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.

10. 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.

11. 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.

12. 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.

Patient

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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.
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

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 30 days prior to apheresis.
6. Donor must be able to understand and willing to sign an IRB-approved written informed consent document.

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Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Recipient, Myeloablative Conditioning (MAC)	Rabbit Anti thymocyte globulin	Patients will undergo Myeloablative Conditioning (MAC) consisting of 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, and Thiotepa on day -2. On Day 0, patients will undergo infusion of the ex vivo TCRαβ/CD19+ depleted haploidentical HPC graft. On Day +7, patients will undergo infusion of the memory-like NK (ML NK) cells, followed by IL-2 subcutaneously 4 hours after the ML NK infusion. IL-2 will continue every other day through Day +19 for a maximum of 7 doses.
Recipient, Myeloablative Conditioning (MAC)	TCR alpha beta / CD19+ depleted haploidentical hematopoietic progenitor cell graft	Patients will undergo Myeloablative Conditioning (MAC) consisting of 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, and Thiotepa on day -2. On Day 0, patients will undergo infusion of the ex vivo TCRαβ/CD19+ depleted haploidentical HPC graft. On Day +7, patients will undergo infusion of the memory-like NK (ML NK) cells, followed by IL-2 subcutaneously 4 hours after the ML NK infusion. IL-2 will continue every other day through Day +19 for a maximum of 7 doses.
Recipient, Myeloablative Conditioning (MAC)	memory-like natural killer cells	Patients will undergo Myeloablative Conditioning (MAC) consisting of 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, and Thiotepa on day -2. On Day 0, patients will undergo infusion of the ex vivo TCRαβ/CD19+ depleted haploidentical HPC graft. On Day +7, patients will undergo infusion of the memory-like NK (ML NK) cells, followed by IL-2 subcutaneously 4 hours after the ML NK infusion. IL-2 will continue every other day through Day +19 for a maximum of 7 doses.
Recipient, Myeloablative Conditioning (MAC)	IL-2	Patients will undergo Myeloablative Conditioning (MAC) consisting of 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, and Thiotepa on day -2. On Day 0, patients will undergo infusion of the ex vivo TCRαβ/CD19+ depleted haploidentical HPC graft. On Day +7, patients will undergo infusion of the memory-like NK (ML NK) cells, followed by IL-2 subcutaneously 4 hours after the ML NK infusion. IL-2 will continue every other day through Day +19 for a maximum of 7 doses.
Recipient, Myeloablative Conditioning (MAC)	CliniMACS	Patients will undergo Myeloablative Conditioning (MAC) consisting of 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, and Thiotepa on day -2. On Day 0, patients will undergo infusion of the ex vivo TCRαβ/CD19+ depleted haploidentical HPC graft. On Day +7, patients will undergo infusion of the memory-like NK (ML NK) cells, followed by IL-2 subcutaneously 4 hours after the ML NK infusion. IL-2 will continue every other day through Day +19 for a maximum of 7 doses.
Recipient, Reduced Intensity Conditioning (RIC)	Rabbit Anti thymocyte globulin	Patients will undergo Reduced Intensity Conditioning (RIC) consisting of 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. On Day 0, patients will undergo infusion of the ex vivo TCRαβ/CD19+ depleted haploidentical HPC graft. On Day +7, patients will undergo infusion of the memory-like NK (ML NK) cells, followed by IL-2 subcutaneously starting 4 hours after the ML NK infusion. IL-2 will continue every other day through Day +19 for a maximum of 7 doses.
Recipient, Reduced Intensity Conditioning (RIC)	TCR alpha beta / CD19+ depleted haploidentical hematopoietic progenitor cell graft	Patients will undergo Reduced Intensity Conditioning (RIC) consisting of 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. On Day 0, patients will undergo infusion of the ex vivo TCRαβ/CD19+ depleted haploidentical HPC graft. On Day +7, patients will undergo infusion of the memory-like NK (ML NK) cells, followed by IL-2 subcutaneously starting 4 hours after the ML NK infusion. IL-2 will continue every other day through Day +19 for a maximum of 7 doses.
Recipient, Reduced Intensity Conditioning (RIC)	memory-like natural killer cells	Patients will undergo Reduced Intensity Conditioning (RIC) consisting of 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. On Day 0, patients will undergo infusion of the ex vivo TCRαβ/CD19+ depleted haploidentical HPC graft. On Day +7, patients will undergo infusion of the memory-like NK (ML NK) cells, followed by IL-2 subcutaneously starting 4 hours after the ML NK infusion. IL-2 will continue every other day through Day +19 for a maximum of 7 doses.
Recipient, Reduced Intensity Conditioning (RIC)	IL-2	Patients will undergo Reduced Intensity Conditioning (RIC) consisting of 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. On Day 0, patients will undergo infusion of the ex vivo TCRαβ/CD19+ depleted haploidentical HPC graft. On Day +7, patients will undergo infusion of the memory-like NK (ML NK) cells, followed by IL-2 subcutaneously starting 4 hours after the ML NK infusion. IL-2 will continue every other day through Day +19 for a maximum of 7 doses.
Donor	Granulocyte Colony-Stimulating Factor	Donors will undergo 2 leukapheresis collections. First, patients will be mobilized using G-CSF for 5 days followed by leukapheresis on the day prior to planned stem cell transplant. The second collection will occur on Day +6 after stem cell transplant and will be non-mobilized.
Recipient, Reduced Intensity Conditioning (RIC)	CliniMACS	Patients will undergo Reduced Intensity Conditioning (RIC) consisting of 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. On Day 0, patients will undergo infusion of the ex vivo TCRαβ/CD19+ depleted haploidentical HPC graft. On Day +7, patients will undergo infusion of the memory-like NK (ML NK) cells, followed by IL-2 subcutaneously starting 4 hours after the ML NK infusion. IL-2 will continue every other day through Day +19 for a maximum of 7 doses.
Recipient, Myeloablative Conditioning (MAC)	Busulfan	Patients will undergo Myeloablative Conditioning (MAC) consisting of 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, and Thiotepa on day -2. On Day 0, patients will undergo infusion of the ex vivo TCRαβ/CD19+ depleted haploidentical HPC graft. On Day +7, patients will undergo infusion of the memory-like NK (ML NK) cells, followed by IL-2 subcutaneously 4 hours after the ML NK infusion. IL-2 will continue every other day through Day +19 for a maximum of 7 doses.
Recipient, Myeloablative Conditioning (MAC)	Fludarabine	Patients will undergo Myeloablative Conditioning (MAC) consisting of 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, and Thiotepa on day -2. On Day 0, patients will undergo infusion of the ex vivo TCRαβ/CD19+ depleted haploidentical HPC graft. On Day +7, patients will undergo infusion of the memory-like NK (ML NK) cells, followed by IL-2 subcutaneously 4 hours after the ML NK infusion. IL-2 will continue every other day through Day +19 for a maximum of 7 doses.
Recipient, Myeloablative Conditioning (MAC)	Thiotepa	Patients will undergo Myeloablative Conditioning (MAC) consisting of 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, and Thiotepa on day -2. On Day 0, patients will undergo infusion of the ex vivo TCRαβ/CD19+ depleted haploidentical HPC graft. On Day +7, patients will undergo infusion of the memory-like NK (ML NK) cells, followed by IL-2 subcutaneously 4 hours after the ML NK infusion. IL-2 will continue every other day through Day +19 for a maximum of 7 doses.
Recipient, Reduced Intensity Conditioning (RIC)	Melphalan	Patients will undergo Reduced Intensity Conditioning (RIC) consisting of 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. On Day 0, patients will undergo infusion of the ex vivo TCRαβ/CD19+ depleted haploidentical HPC graft. On Day +7, patients will undergo infusion of the memory-like NK (ML NK) cells, followed by IL-2 subcutaneously starting 4 hours after the ML NK infusion. IL-2 will continue every other day through Day +19 for a maximum of 7 doses.
Recipient, Reduced Intensity Conditioning (RIC)	Fludarabine	Patients will undergo Reduced Intensity Conditioning (RIC) consisting of 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. On Day 0, patients will undergo infusion of the ex vivo TCRαβ/CD19+ depleted haploidentical HPC graft. On Day +7, patients will undergo infusion of the memory-like NK (ML NK) cells, followed by IL-2 subcutaneously starting 4 hours after the ML NK infusion. IL-2 will continue every other day through Day +19 for a maximum of 7 doses.
Recipient, Reduced Intensity Conditioning (RIC)	Thiotepa	Patients will undergo Reduced Intensity Conditioning (RIC) consisting of 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. On Day 0, patients will undergo infusion of the ex vivo TCRαβ/CD19+ depleted haploidentical HPC graft. On Day +7, patients will undergo infusion of the memory-like NK (ML NK) cells, followed by IL-2 subcutaneously starting 4 hours after the ML NK infusion. IL-2 will continue every other day through Day +19 for a maximum of 7 doses.
Donor	Plerixafor	Donors will undergo 2 leukapheresis collections. First, patients will be mobilized using G-CSF for 5 days followed by leukapheresis on the day prior to planned stem cell transplant. The second collection will occur on Day +6 after stem cell transplant and will be non-mobilized.

Primary Outcome Measures

Name	Time	Method
Safety of patients being administered donor-derived ML NK cells following TCR alpha beta depleted haploidentical cell transplant	From transplant through Day +100	Safety will be determined by events occurring following transplant. Non-relapse mortality, engraftment failure, and development of severe GvHD will be considered events.
Feasibility of manufacturing and administering donor-derived ML NK cells following TCR alpha beta depleted haploidentical cell transplant	Through time of ML NK cell infusion (around Day +7)	Feasibility is defined by product manufacture failure, i.e., the inability to infuse ML NK cells due to product contamination or insufficient cell dose (\<0.5x10\^6 / kg recipient weight).

Secondary Outcome Measures

Name	Time	Method
Development of chronic graft versus host disease (cGvHD)	From transplant through Day +365	Incidence and severity of chronic GvHD as graded according to the NIH consensus criteria. Severe cGvHD is considered an event.
Development of acute graft versus host disease (aGvHD)	From transplant through Day +100	Incidence of grade II, III, or IV acute GvHD as graded according to the NIH consensus criteria. Severe aGvHD (Grades III-IV) is considered an event.
Analysis of immune reconstitution	From transplant through Month 24	Immune reconstitution is defined as regain of function of donor-derived immunogenic cells and is measured by recovery of individual cellular compartments.
Relapse Free Survival (RFS)	From transplant through Month 12	Defined as the time between the date of transplant and date of last follow up, relapse, or death due to any cause.
Overall Survival (OS)	From transplant through Month 12	Defined as death from any cause following transplant.
Development of infections	From transplant through Day +180	Significant infections include, but are not limited to, bacterial or fungal sepsis, viral reactivation with or without clinical disease, other viral infections, and community acquired infections.

Trial Locations

Locations (1)

Washington University School of Medicine; 🇺🇸 Saint Louis, Missouri, United States