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Purpose

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.

Conditions

Eligibility

Eligible Ages
Over 18 Years
Eligible Sex
All
Accepts Healthy Volunteers
No

Inclusion Criteria

  • Cohort 1: 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. Patient Inclusion Criteria - Cohort 2: 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. Patient Inclusion Criteria - Both Cohorts: 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. Patient

Exclusion Criteria

  • Both Cohorts 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.

Study Design

Phase
Phase 1/Phase 2
Study Type
Interventional
Allocation
Non-Randomized
Intervention Model
Parallel Assignment
Intervention Model Description
The study will enroll both transplant recipients and their haploidentical donors.
Primary Purpose
Treatment
Masking
None (Open Label)

Arm Groups

ArmDescriptionAssigned Intervention
Experimental
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
Experimental
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
Other
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.
  • Drug: 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).
  • Biological: 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.
    Other names:
    • G-CSF

Recruiting Locations

Washington University in St. Louis and nearby locations

Washington University School of Medicine
St Louis 4407066, Missouri 4398678 63110
Contact:
Thomas M Pfeiffer, M.D.
314-273-2070
pthomas@wustl.edu

More Details

NCT ID
NCT06158828
Status
Recruiting
Sponsor
Washington University School of Medicine

Study Contact

Thomas M Pfeiffer, M.D.
314-273-2070
pthomas@wustl.edu

Notice

Study information shown on this site is derived from ClinicalTrials.gov (a public registry operated by the National Institutes of Health). The listing of studies provided is not certain to be all studies for which you might be eligible. Furthermore, study eligibility requirements can be difficult to understand and may change over time, so it is wise to speak with your medical care provider and individual research study teams when making decisions related to participation.