Leukemia, Myeloid, Acute, Myelodysplastic Syndromes
Conditions
Keywords
Leukemia, Acute Myeloid Leukemia, AML, Hematopoietic stem cell transplant, HCT, CD33, Allogeneic, Myelodysplastic Syndromes, Myelodysplastic Syndromes with excess blasts, MDS, MDS-EB, Cell therapy
Brief summary
This is a Phase 1/2a, multicenter, open-label, first-in-human (FIH) study of VOR33 in participants with AML or MDS who are undergoing human leukocyte antigen (HLA)-matched allogeneic hematopoietic cell transplant (HCT).
Detailed description
High risk acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS) 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 or MDS 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.
Interventions
Sponsors
Vor Biopharma
Study design
Allocation
RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 70 Years
Healthy volunteers
No
Inclusion criteria
1. Must be ≥18 and ≤70 years of age. 2. Patients with AML 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. 3. Patients with MDS must have all of the following: * Previous or current IPSS-R score of High or Very High risk; AND * Previous or current MDS-IB1 or MDS-IB2 per the 2022 WHO criteria (Khoury 2022) 4. AML sample from the patient must have evidence of CD33 expression (\>0%) 5. Candidate for HLA-matched allogeneic HCT using a myeloablative conditioning regimen. 6. Must have a related or unrelated stem cell donor that is a 8/8 match for HLA-A, -B, -C, and -DRB1. 7. Must have adequate performance status and organ function as defined below: 1. Performance Status: Karnofsky score of ≥70. 2. Cardiac: left ventricular ejection fraction (LVEF) ≥50% 3. Pulmonary: diffusing capacity of lung for carbon monoxide (DLCO), forced vital capacity (FVC), and forced expiratory volume in one second (FEV1) ≥66%. 4. Renal: estimated glomerular filtration rate (GFR) \>60 mL/min 5. 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
1. Prior autologous or allogeneic stem cell transplantation. 2. 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. 3. Prior treatment with Mylotarg™ (gemtuzumab ozogamicin) in the past 3.5 months. 4. Active central nervous system (CNS) leukemia. 5. Patients diagnosed with Gilbert's syndrome. 6. Uncontrolled bacterial, viral, or fungal infections; or known human immunodeficiency virus (HIV), Hepatitis B, or Hepatitis C infection.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Incidence of neutrophil engraftment | Day 28 | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Time to platelet recovery | Up to approximately 60 days | 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. |
| 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 | Up to 24 months | 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. |
| Time to neutrophil engraftment | Up to approximately 28 days | 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. |
| Incidence of transplant-related mortality (TRM) post HCT | Day 100, 12 months, 24 months | — |
| Percentage of CD33-negative myeloid cells | Day 28, 60, 100, 180, and Months 12 and 24 | Percent donor myeloid chimerism and CD33-negative myeloid cells in peripheral blood. |
| Relapse-free Survival (RFS) | Months 12 and 24 | Cumulative incidence of RFS |
| Overall Survival (OS) | Months 12 and 24 | OS defined as the time from HCT to the date of death from any cause |
| Incidence of toxicities to determine the MTD and RP2D of Mylotarg™ | Approximately day 60 until 24 months | — |
Countries
Canada, United States
Outcome results
None listed