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

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ClinicalTrials.gov Identifier: NCT04849910
Recruitment Status : Not yet recruiting
First Posted : April 19, 2021
Last Update Posted : April 19, 2021
Sponsor:
Information provided by (Responsible Party):
Vor Biopharma

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
Leukemia, Myeloid, Acute Biological: VOR33 Drug: Mylotarg 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.

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Study Type : Interventional  (Clinical Trial)
Estimated 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
Estimated Study Start Date : April 2021
Estimated Primary Completion Date : May 2023
Estimated Study Completion Date : September 2025


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 Name: 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 Name: 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 Name: gemtuzumab ozogamicin




Primary Outcome Measures :
  1. Incidence of neutrophil engraftment [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: Up to 24 months ]
  4. Incidence of chronic GVHD (all and moderate-severe) [ Time Frame: Up to 24 months ]
  5. Incidence of primary and secondary graft failure [ Time Frame: 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™ [ Time Frame: Approximately day 60 until 24 months ]
  7. Incidence of transplant-related mortality (TRM) post HCT [ Time Frame: Day 100, 12 months, 24 months ]
  8. Percentage of CD33-negative myeloid cells [ Time Frame: 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) [ Time Frame: Months 12 and 24 ]
    Cumulative incidence of RFS

  10. Overall Survival (OS) [ Time Frame: Months 12 and 24 ]
    OS defined as the time from HCT to the date of death from any cause



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Ages Eligible for Study:   18 Years to 70 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04849910


Locations
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United States, California
University of California San Diego Moores Cancer Center
La Jolla, California, United States, 92093
Contact: Joseph Maroge    858-246-0682    jmaroge@health.ucsd.edu   
Principal Investigator: Divya Koura, MD         
United States, Florida
Miami Cancer Institute
Miami, Florida, United States, 33176
Contact: Guenther Koehne, MD, PhD    786-527-8427    guentherk@baptisthealth.net   
Principal Investigator: Guenther Koehne, MD, PhD         
United States, New Jersey
John Theurer Cancer Center at Hackensack University Medical Center
Hackensack, New Jersey, United States, 07601
Contact: Hyung Suh, MD       Hyung.Suh@hmhn.org   
Principal Investigator: Hyung Suh, MD         
United States, New York
Memorial Sloan Kettering Cancer Center
New York, New York, United States, 10065
Contact: Christina Cho, MD    646-608-3785      
Principal Investigator: Christina Cho, MD         
United States, Ohio
University Hospitals Seidman Cancer Center
Cleveland, Ohio, United States, 44106
Contact: Cancer Information Service Line    800-641-2422      
Principal Investigator: Brenda Cooper, MD         
United States, Washington
Fred Hutchinson Cancer Research Center
Seattle, Washington, United States, 98109
Contact: Roland Walter, MD, PhD, MS       rwalter@fredhutch.org   
Principal Investigator: Roland Walter, MD, PhD, MS         
Canada, Quebec
Hôpital Maisonneuve-Rosemont
Montréal, Quebec, Canada, H1T2M4
Contact: Nadia Bambace, MD    514-252-3404    nadia.bambace@umontreal.ca   
Principal Investigator: Nadia Bamace, MD         
Sponsors and Collaborators
Vor Biopharma
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Responsible Party: Vor Biopharma
ClinicalTrials.gov Identifier: NCT04849910    
Other Study ID Numbers: VBP101
First Posted: April 19, 2021    Key Record Dates
Last Update Posted: April 19, 2021
Last Verified: April 2021

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Vor Biopharma:
Leukemia
Acute Myeloid Leukemia
AML
Hematopoietic stem cell transplant
HCT
CD33
Allogeneic
Additional relevant MeSH terms:
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Leukemia
Leukemia, Myeloid
Leukemia, Myeloid, Acute
Neoplasms by Histologic Type
Neoplasms
Gemtuzumab
Antineoplastic Agents, Immunological
Antineoplastic Agents