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

Sponsor
Vor Biopharma (Industry)
Overall Status
Recruiting
CT.gov ID
NCT04849910
Collaborator
(none)
18
9
3
48
2
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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

Study Type:
Interventional
Anticipated Enrollment :
18 participants
Allocation:
Randomized
Intervention Model:
Sequential Assignment
Masking:
None (Open Label)
Primary Purpose:
Treatment
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
Actual Study Start Date :
Aug 31, 2021
Anticipated Primary Completion Date :
May 1, 2023
Anticipated Study Completion Date :
Sep 1, 2025

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:
  • gemtuzumab ozogamicin
  • 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:
  • gemtuzumab ozogamicin
  • 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:
  • gemtuzumab ozogamicin
  • Outcome Measures

    Primary Outcome Measures

    1. 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

    1. 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.

    2. 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.

    3. Incidence of acute GVHD Grade (G) G2-G4 and G3-G4 [Up to 24 months]

    4. Incidence of chronic GVHD (all and moderate-severe) [Up to 24 months]

    5. 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.

    6. Incidence of toxicities to determine the MTD and RP2D of Mylotarg™ [Approximately day 60 until 24 months]

    7. Incidence of transplant-related mortality (TRM) post HCT [Day 100, 12 months, 24 months]

    8. 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.

    9. Relapse-free Survival (RFS) [Months 12 and 24]

      Cumulative incidence of RFS

    10. 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

    Ages Eligible for Study:
    18 Years to 70 Years
    Sexes Eligible for Study:
    All
    Accepts Healthy Volunteers:
    No
    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:

    8. Performance Status: Karnofsky score of ≥70.

    9. Cardiac: left ventricular ejection fraction (LVEF) ≥50%

    10. Pulmonary: diffusing capacity of lung for carbon monoxide (DLCO), forced vital capacity (FVC), and forced expiratory volume in one second (FEV1) ≥66%.

    11. Renal: estimated glomerular filtration rate (GFR) >60 mL/min

    12. 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.

    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.
    Responsible Party:
    Vor Biopharma
    ClinicalTrials.gov Identifier:
    NCT04849910
    Other Study ID Numbers:
    • VBP101
    First Posted:
    Apr 19, 2021
    Last Update Posted:
    Aug 25, 2022
    Last Verified:
    Aug 1, 2022
    Studies a U.S. FDA-regulated Drug Product:
    Yes
    Studies a U.S. FDA-regulated Device Product:
    No
    Keywords provided by Vor Biopharma
    Additional relevant MeSH terms:

    Study Results

    No Results Posted as of Aug 25, 2022