Description:
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).
Title
- Brief Title: Allogeneic Engineered Hematopoietic Stem Cell Transplant (HCT) Lacking the CD33 Protein, and Post-HCT Treatment With Mylotarg, for Patients With CD33+ AML
- Official Title: 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
Clinical Trial IDs
- ORG STUDY ID:
VBP101
- NCT ID:
NCT04849910
Conditions
Interventions
Drug | Synonyms | Arms |
---|
VOR33 | | Cohort 1 |
Mylotarg | gemtuzumab ozogamicin | Cohort 1 |
Purpose
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
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.
Trial Arms
Name | Type | Description | Interventions |
---|
Cohort 1 | Experimental | VOR33 infusion followed by Mylotarg Dose Level 1 | |
Cohort 2 | Experimental | VOR33 infusion followed by Mylotarg Dose Level 2 | |
Cohort 3 | Experimental | VOR33 infusion followed by Mylotarg Dose Level 3 | |
Eligibility Criteria
Inclusion Criteria:
1. Must be ≥18 and ≤70 years of age.
2. Must have confirmed diagnosis of AML in first or second complete remission (CR1 or
CR2) or have bone marrow blasts ≤10% without circulating blasts.
3. AML sample from the patient must have evidence of CD33 expression (>0%)
4. 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.
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 10/10 match for HLA-A, -B,
-C, -DRB1 and -DQB1.
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).
4. Active central nervous system (CNS) leukemia or history of other active
malignancy(ies).
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.
Maximum Eligible Age: | 70 Years |
Minimum Eligible Age: | 18 Years |
Eligible Gender: | All |
Healthy Volunteers: | No |
Primary Outcome Measures
Measure: | Incidence of neutrophil engraftment |
Time Frame: | Day 28 |
Safety Issue: | |
Description: | 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
Measure: | Time to neutrophil engraftment |
Time Frame: | Up to approximately 28 days |
Safety Issue: | |
Description: | 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. |
Measure: | Time to platelet recovery |
Time Frame: | Up to approximately 60 days |
Safety Issue: | |
Description: | Time to platelet recovery defined as time from Day 0 to achieve platelet count ≥20,000/μL without transfusion in prior 7 days. |
Measure: | Incidence of acute GVHD Grade (G) G2-G4 and G3-G4 |
Time Frame: | Up to 24 months |
Safety Issue: | |
Description: | |
Measure: | Incidence of chronic GVHD (all and moderate-severe) |
Time Frame: | Up to 24 months |
Safety Issue: | |
Description: | |
Measure: | Incidence of primary and secondary graft failure |
Time Frame: | Up to 24 months |
Safety Issue: | |
Description: | 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. |
Measure: | Incidence of toxicities to determine the MTD and RP2D of Mylotarg™ |
Time Frame: | Approximately day 60 until 24 months |
Safety Issue: | |
Description: | |
Measure: | Incidence of transplant-related mortality (TRM) post HCT |
Time Frame: | Day 100, 12 months, 24 months |
Safety Issue: | |
Description: | |
Measure: | Percentage of CD33-negative myeloid cells |
Time Frame: | Day 28, 60, 100, 180, and Months 12 and 24 |
Safety Issue: | |
Description: | Percent donor myeloid chimerism and CD33-negative myeloid cells in peripheral blood. |
Measure: | Relapse-free Survival (RFS) |
Time Frame: | Months 12 and 24 |
Safety Issue: | |
Description: | Cumulative incidence of RFS |
Measure: | Overall Survival (OS) |
Time Frame: | Months 12 and 24 |
Safety Issue: | |
Description: | OS defined as the time from HCT to the date of death from any cause |
Details
Phase: | Phase 1/Phase 2 |
Primary Purpose: | Interventional |
Overall Status: | Not yet recruiting |
Lead Sponsor: | Vor Biopharma |
Trial Keywords
- Leukemia
- Acute Myeloid Leukemia
- AML
- Hematopoietic stem cell transplant
- HCT
- CD33
- Allogeneic
Last Updated
April 19, 2021