Allogeneic Engineered Hematopoietic Stem Cell Transplant (HCT) Lacking the CD33 Protein, and Post-HCT Treatment With Mylotarg, for Patients With CD33+ AML

Study Overview
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Brief Summary
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This is a Phase 1/2a, multicenter, open-label, first-in-human (FIH) study of VOR33 in participants with AML who are undergoing human leukocyte antigen (HLA)-matched allogeneic hematopoietic cell transplant (HCT).

Detailed Description
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High risk acute myeloid leukemia (AML) frequently relapses despite hematopoietic stem cell transplant (HCT). Post-HCT targeted therapy to reduce relapse is limited by toxicity to the engrafted cells. VOR33, an allogeneic CRISPR/Cas9 genome-edited hematopoietic stem and progenitor cell (HSPC) therapy product, lacking the CD33 protein, is being investigated for participants with CD33+ AML at high risk for relapse after HCT to allow post-HCT targeting of residual CD33+ acute AML cells using Mylotarg™ without toxicity to engrafted VOR33 cells. Participants will undergo a myeloablative HCT with matched related or unrelated donor CD34+-selected hematopoietic stem and progenitor cells (HSPCs) engineered to remove CD33 expression (VOR33 product). Mylotarg™ will be given after engraftment for up to 4 cycles. The primary endpoint assessing safety of VOR33 will be the incidence of successful engraftment at 28 days. Part 1 of this study will evaluate the safety of escalating Mylotarg™ dose levels to determine the maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D). Part 2 will expand the number of participants to evaluate the Mylotarg™ RP2D.

Official Title
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A First-In-Human, Open-Label, Multicenter Study of VOR33 in Patients With Acute Myeloid Leukemia Who Are at High-Risk for Leukemia Relapse Following Hematopoietic Cell Transplantation

Conditions
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Leukemia, Myeloid, Acute

Intervention / Treatment
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* Biological: VOR33
* Drug: Mylotarg


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Must be ≥18 and ≤70 years of age. Patients must have one of the following groups of features that are known to be a risk factor for leukemia relapse: BM in morphological remission (<5% blasts) with adverse-risk disease related genetics at presentation (according to European Leukemia-Net guidelines [ELN, Döhner 2017]), or Intermediate risk genetics in morphologic remission (<5% blasts) with other recognized high risk criteria such as MRD+ following therapy, or BM with evidence of persistent leukemia 5-10% blasts post induction/salvage therapy. Patients with BM Blast count >10% may participate with Sponsor Medical Monitor approval. (Note: these patients may have disease-related genetics of any risk criteria at presentation), or Any patient in second or greater remission. AML sample from the patient must have evidence of CD33 expression (>0%) Candidate for HLA-matched allogeneic HCT using a myeloablative conditioning regimen. Must have a related or unrelated stem cell donor that is a 10/10 match for HLA-A, -B, -C, -DRB1 and -DQB1. Must have adequate performance status and organ function as defined below: Performance Status: Karnofsky score of ≥70. Cardiac: left ventricular ejection fraction (LVEF) ≥50% Pulmonary: diffusing capacity of lung for carbon monoxide (DLCO), forced vital capacity (FVC), and forced expiratory volume in one second (FEV1) ≥66%. Renal: estimated glomerular filtration rate (GFR) >60 mL/min Hepatic: total bilirubin <1.5 × ULN, or if ≥1.5 × ULN direct bilirubin <ULN and ALT/AST <1.5 × ULN (per institutional criteria). Exclusion Criteria: Prior autologous or allogeneic stem cell transplantation. Presence of the following disease-related genetics: t(15; 17)(q22; q21), or t(9; 22)(q34; q11), or other evidence of acute promyelocytic leukemia or chronic myeloid leukemia. Prior treatment with Mylotarg™ (gemtuzumab ozogamicin). Active central nervous system (CNS) leukemia or history of other active malignancy(ies). Patients diagnosed with Gilbert's syndrome. Uncontrolled bacterial, viral, or fungal infections; or known human immunodeficiency virus (HIV), Hepatitis B, or Hepatitis C infection.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 70 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
Allocation: Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Cohort 1<br>VOR33 infusion followed by Mylotarg Dose Level 1 | Biological: VOR33<br>* Allogeneic, human leukocyte antigen (HLA) matched, genome edited hematopoietic stem and progenitor cell (HSPC) therapy product lacking the CD33 myeloid protein<br>Drug: Mylotarg<br>* Infusion of Mylotarg<br>* Other names: gemtuzumab ozogamicin;|
| Experimental: Cohort 2<br>VOR33 infusion followed by Mylotarg Dose Level 2 | Biological: VOR33<br>* Allogeneic, human leukocyte antigen (HLA) matched, genome edited hematopoietic stem and progenitor cell (HSPC) therapy product lacking the CD33 myeloid protein<br>Drug: Mylotarg<br>* Infusion of Mylotarg<br>* Other names: gemtuzumab ozogamicin;|
| Experimental: Cohort 3<br>VOR33 infusion followed by Mylotarg Dose Level 3 | Biological: VOR33<br>* Allogeneic, human leukocyte antigen (HLA) matched, genome edited hematopoietic stem and progenitor cell (HSPC) therapy product lacking the CD33 myeloid protein<br>Drug: Mylotarg<br>* Infusion of Mylotarg<br>* Other names: gemtuzumab ozogamicin;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of neutrophil engraftment | Cumulative incidence of patients who achieve neutrophil engraftment (first day of 3 consecutive days of absolute neutrophil count (ANC) ≥500 cells/mm3) by Day 28. | Day 28 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to neutrophil engraftment | Time to neutrophil engraftment after HCT from Day 0; calculated as the first day of 3 consecutive laboratory values obtained on separate days where the ANC is ≥500 cells/mm3. | Up to approximately 28 days | 
| Time to platelet recovery | Time to platelet recovery defined as first day of a sustained platelet count >20,000/ μL with no platelet transfusion in the preceding seven days. | Up to approximately 60 days | 
| Incidence of acute GVHD Grade (G) G2-G4 and G3-G4 |  | Up to 24 months | 
| Incidence of chronic GVHD (all and moderate-severe) |  | Up to 24 months | 
| Incidence of primary and secondary graft failure | Incidence of primary and secondary graft failure measured by day 28 post HCT. Secondary graft failure is defined as initial neutrophil engraftment by Day 28 followed by subsequent decline. | Up to 24 months | 
| Incidence of toxicities to determine the MTD and RP2D of Mylotarg™ |  | Approximately day 60 until 24 months | 
| Incidence of transplant-related mortality (TRM) post HCT |  | Day 100, 12 months, 24 months | 
| Percentage of CD33-negative myeloid cells | Percent donor myeloid chimerism and CD33-negative myeloid cells in peripheral blood. | Day 28, 60, 100, 180, and Months 12 and 24 | 
| Relapse-free Survival (RFS) | Cumulative incidence of RFS | Months 12 and 24 | 
| Overall Survival (OS) | OS defined as the time from HCT to the date of death from any cause | Months 12 and 24 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Leukemia, Acute Myeloid Leukemia, AML, Hematopoietic stem cell transplant, HCT, CD33, Allogeneic