CD33-armed immune cell treatment for adults with MRD-positive AML or MDS

Phase Ib Study of Anti-CD3 x Anti-CD33 Bispecific Antibody (CD33Bi) Armed Fresh Peripheral Blood Mononuclear Cells (CD33 FPBMC) in Patients With Measurable Residual Disease (MRD)+ Acute Myeloid Leukemia or Myelodysplastic Syndrome

This treatment will try giving adults with MRD-positive AML or MDS infusions of their own T cells coated with a CD33-directed bispecific antibody together with standard hypomethylating therapy (and possibly venetoclax) to see if it is safe and lowers residual disease.

Quick facts

• Phase: Phase 1
• Study type: Interventional
• Enrollment: 23 (estimated)
• Ages: 18 Years and up
• Sex: All
• Sponsor: University of Virginia (Academic / other)
• Drugs / interventions: chemotherapy, prednisone
• Locations: 1 site (Charlottesville, Virginia)
• Trial ID: NCT07270978 on ClinicalTrials.gov

What this trial studies

Eligible participants undergo leukapheresis to collect peripheral blood mononuclear cells, whose T cells are coated (or "armed") with an anti-CD3 x anti-CD33 bispecific antibody and then reinfused. Patients receive four weekly infusions of the CD33-armed PBMCs followed by 4–6 weeks of a hypomethylating agent with or without venetoclax, and this cycle may be repeated up to four times with a second leukapheresis after about two cycles. Blood samples for immune monitoring and disease assessments are collected before, during, and after treatment to track safety, immune response, and changes in minimal residual disease. The primary goal is to characterize safety and get an early estimate of anti-leukemia activity in MRD-positive AML and MDS patients.

Who should consider this trial

Good fit: Adults (≥18) with MRD-positive acute myeloid leukemia or relapsed/refractory MDS or MDS/MPN who have received prior induction chemotherapy or the specified prior cycles of hypomethylating therapy ± venetoclax are the intended candidates.

Not a fit: Patients who cannot undergo leukapheresis, who require immediate alternative therapy for rapidly progressive disease, or whose leukemia is unlikely to express CD33 may be less likely to benefit.

Why it matters

Potential benefit: If successful, this approach could help clear minimal residual disease and reduce relapse risk, potentially extending remission durations.

How similar studies have performed: Other CD33-targeting and T-cell redirecting therapies have shown early promise, but using autologous PBMCs armed with a CD33 bispecific antibody is a relatively novel approach that is not yet proven.

Eligibility criteria

Inclusion Criteria:

1\. Adults: ≥18 years of age 2. Diagnosis of either:

1. Newly diagnosed or relapsed/refractory AML who have received either intensive induction chemotherapy or at least 2 cycles of a non-intensive options such as hypomethylating agent and venetoclax or other targeted agent
2. Relapsed/ refractory (R/R) MDS who have received at least 2 prior cycles of hypomethylating agent and venetoclax or single agent hypomethylating agent for at least 4 cycles
3. Relapsed/refractory (R/R) MDS/MPN overlap syndromes like CMML who have received at least 2 prior cycles of azacitidine and venetoclax or single agent hypomethylating agent for at least 4 cycles 3. For patients with targetable mutations (IDH1, IDH2, KMT2A, or FLT3): Receipt of and/or decision not to receive associated inhibitor.

   4\. Patients with R/R MDS or R/R MDS/MPN overlap syndromes must have at least one of the following:
   1. Bone marrow blasts ≥ 5%
   2. Appearance of previously absent leukemic blasts in peripheral blood
   3. Absolute neutrophil count \<1 x 109/L and 50% below best unsupported on-study value
   4. Platelet count \<100 x 109/L and 50% below best unsupported on-study value
   5. Hemoglobin \<11g/dL, and ≥2 g/dL reduction from best unsupported on-study value
   6. Increase of the volume of transfused red blood cells by more than 30% in an 8-week period
   7. Increase of the number of transfused platelet units by more than 30% in an 8-week period In the case of criteria 4-8 above, no reasonable alternative explanation such as drug toxicity should be identified.

   5\. Patients with AML must have persistent or recurrent MRD positivity defined by presence of blasts ≥5% AND/OR disease detected by multiparametric flow cytometry (MFC) at a level of ≥0.1%, AND/OR persistent genomic mutations other than those found most with CHIP AND/OR persistent cytogenetic abnormalities related to underlying myeloid neoplasm

   6\. Residual blasts must be positive for CD33 expression at any level. Note: Patients whose most recent disease-positive evaluation by flow cytometry showed CD33 expression but whose current assessment for MRD is only positive for genomics or cytogenetics may be included.

   7\. Left Ventricular Ejection Fraction (LVEF) ≥ 45% at rest (MUGA or echocardiogram)

   8\. Performance status ≤ 2 (ECOG Scale)

   9\. Females of childbearing potential and males must agree to use an effective method for contraception for the duration of the treatment with study drug plus 90 days (duration of sperm turnover). Males must also abstain from sperm donations during study treatment and for at least 90 days after the last dose of study drug.

   10\. Ability to provide informed consent and provision of written informed consent In order to be eligible to participate in the dose expansion portion of this study, an individual must meet all criteria that apply to the R/R MDS or R/R AML population (Newly diagnosed patients and patients with MDS/MPN overlap syndromes are not eligible for the expansion phase of the study).

In order to be eligible to participate in the dose expansion portion of this study, an individual must meet all criteria that apply to the R/R MDS or R/R AML population (Newly diagnosed patients and patients with MDS/MPN overlap syndromes are not eligible for the expansion phase of the study).

Exclusion Criteria:

1. Pregnancy or lactation
2. Prior treatment with anti-CD33 therapy
3. Patients who are being actively considered for stem cell transplant, unless participation in the study prior to the planned stem cell transplant is considered to be in the best interest of the patient in the opinion of the treating investigator in consultation with the transplant team. This does not exclude patients that may be eligible for stem cell transplant at some future (undetermined) date.
4. Past hematopoietic stem cell transplant (HSCT) with graft vs host disease requiring systemic immunosuppression other than low dose prednisone (10 mg) (or the equivalent dose of another immunosuppressant) within the 4 weeks before registration
5. Clinically significant organ dysfunction, defined as any of the following:

   * AST or ALT \>3x the upper limit of normal (ULN)
   * Total bilirubin \>1.5x the ULN, unless due to ongoing hemolysis or Gilbert's syndrome, in which case \> 3.0 mg/dL
   * Absolute lymphocyte count (ALC) \< 300 lymphocytes/microliter
   * Creatinine clearance \<30 mL/min
   * Active serious infection not controlled by oral or intravenous antibiotics (e.g. persistent fever or lack of clinical improvement despite antimicrobial treatment).
6. Known human immunodeficiency virus (HIV) with detectable viral load.
7. Known hepatitis B surface antigen seropositive or known or suspected active hepatitis C infection

   a. Note: Patients who have isolated positive hepatitis B core antibody (ie, in the setting of negative hepatitis B surface antigen and negative hepatitis B surface antibody) must have an undetectable hepatitis B viral load. Patients who have positive hepatitis C antibody may be included if they have an undetectable hepatitis C viral load.
8. Patients with a prior or concurrent malignancy whose natural history or treatment is anticipated to interfere with the safety or efficacy assessment of the investigational regimen (according to the treating investigator).
9. Treatment with any antileukemic agents or chemotherapy (other than hypomethylating agents or venetoclax) agents in the last 7 days or 5 half-lives (whichever is sooner) before study entry. Note: treatment with hydroxyurea may continue through the first cycle of study treatment.
10. Known allergy to hypomethylating agents
11. Blasts ≥ 25%

Where this trial is running

Charlottesville, Virginia

• University of Virginia — Charlottesville, Virginia, United States (Recruiting)

Study contacts

• Principal investigator: Daniel Reed, MD — Assistant Professor
• Study coordinator: Ashley Donihee

Conditions Acute Myeloid Leukemia; Myelodysplastic Syndromes; Myelodysplastic/Myeloproliferative Neoplasm