Allogeneic Engineered Hematopoietic Stem Cell Transplant (HCT) Lacking the CD33 Protein, and Post-HCT Treatment With Mylotarg, for Patients With CD33+ AML
Study Details
Study Description
Brief Summary
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).
Condition or Disease | Intervention/Treatment | Phase |
---|---|---|
|
Phase 1/Phase 2 |
Detailed Description
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.
Study Design
Arms and Interventions
Arm | Intervention/Treatment |
---|---|
Experimental: Cohort 1 VOR33 infusion followed by Mylotarg Dose Level 1 |
Biological: VOR33
Allogeneic, human leukocyte antigen (HLA) matched, genome edited hematopoietic stem and progenitor cell (HSPC) therapy product lacking the CD33 myeloid protein
Drug: Mylotarg
Infusion of Mylotarg
Other Names:
|
Experimental: Cohort 2 VOR33 infusion followed by Mylotarg Dose Level 2 |
Biological: VOR33
Allogeneic, human leukocyte antigen (HLA) matched, genome edited hematopoietic stem and progenitor cell (HSPC) therapy product lacking the CD33 myeloid protein
Drug: Mylotarg
Infusion of Mylotarg
Other Names:
|
Experimental: Cohort 3 VOR33 infusion followed by Mylotarg Dose Level 3 |
Biological: VOR33
Allogeneic, human leukocyte antigen (HLA) matched, genome edited hematopoietic stem and progenitor cell (HSPC) therapy product lacking the CD33 myeloid protein
Drug: Mylotarg
Infusion of Mylotarg
Other Names:
|
Outcome Measures
Primary Outcome Measures
- 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 Outcome Measures
- 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.
- Time to platelet recovery [Up to approximately 60 days]
Time to platelet recovery defined as time from Day 0 to achieve platelet count ≥20,000/μL without transfusion in prior 7 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.
- 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 [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
Eligibility Criteria
Criteria
Inclusion Criteria:
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Must be ≥18 and ≤70 years of age.
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Must have confirmed diagnosis of AML in first or second complete remission (CR1 or CR2) or have bone marrow blasts ≤10% without circulating blasts.
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AML sample from the patient must have evidence of CD33 expression (>0%)
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AML must have intermediate or high-risk disease-related genetics and the presence of minimal residual disease (MRD). Subjects in CR2 or with persistent morphologic blasts; may have favorable disease-related genetics.
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Candidate for HLA-matched allogeneic HCT using a myeloablative conditioning regimen.
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Must have a related or unrelated stem cell donor that is a 10/10 match for HLA-A, -B, -C, -DRB1 and -DQB1.
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Must have adequate performance status and organ function as defined below:
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Performance Status: Karnofsky score of ≥70.
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Cardiac: left ventricular ejection fraction (LVEF) ≥50%
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Pulmonary: diffusing capacity of lung for carbon monoxide (DLCO), forced vital capacity (FVC), and forced expiratory volume in one second (FEV1) ≥66%.
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Renal: estimated glomerular filtration rate (GFR) >60 mL/min
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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:
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Prior autologous or allogeneic stem cell transplantation.
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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.
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Prior treatment with Mylotarg™ (gemtuzumab ozogamicin).
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Active central nervous system (CNS) leukemia or history of other active malignancy(ies).
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Patients diagnosed with Gilbert's syndrome.
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Uncontrolled bacterial, viral, or fungal infections; or known human immunodeficiency virus (HIV), Hepatitis B, or Hepatitis C infection.
Contacts and Locations
Locations
Site | City | State | Country | Postal Code | |
---|---|---|---|---|---|
1 | University of California San Diego Moores Cancer Center | La Jolla | California | United States | 92037 |
2 | Miami Cancer Institute | Miami | Florida | United States | 33176 |
3 | National Institutes of Health, Clinical Center | Bethesda | Maryland | United States | 20892 |
4 | Washington University School of Medicine Siteman Cancer Center | Saint Louis | Missouri | United States | 63110 |
5 | John Theurer Cancer Center at Hackensack University Medical Center | Hackensack | New Jersey | United States | 07601 |
6 | Memorial Sloan Kettering Cancer Center | New York | New York | United States | 10065 |
7 | University Hospitals Seidman Cancer Center | Cleveland | Ohio | United States | 44106 |
8 | Fred Hutchinson Cancer Research Center | Seattle | Washington | United States | 98109 |
9 | Hôpital Maisonneuve-Rosemont | Montréal | Quebec | Canada | H1T2M4 |
Sponsors and Collaborators
- Vor Biopharma
Investigators
None specified.Study Documents (Full-Text)
None provided.More Information
Publications
None provided.- VBP101