Stem Cell Transplant + Mylotarg for Acute Myeloid Leukemia

No longer recruiting at 16 trial locations

Overseen By Glen Raffel, MD, PhD

Age: 18+

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: Vor Biopharma

Must not be taking: Mylotarg

Disqualifiers: Prior stem cell transplant, CNS leukemia, Gilbert's syndrome, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Approved in 1 Jurisdiction This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 28

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores a new treatment for individuals with acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS) undergoing a stem cell transplant. The treatment involves a special infusion called VOR33, followed by varying doses of the drug Mylotarg (gemtuzumab ozogamicin). The goal is to determine if this combination can reduce the risk of leukemia recurrence. Suitable candidates have specific genetic risk factors for leukemia relapse and plan to undergo a particular type of stem cell transplant. As a Phase 1 trial, this research aims to understand how the treatment works in people, offering participants the opportunity to be among the first to receive this novel therapy.

Will I have to stop taking my current medications?

The trial information does not specify whether you need to stop taking your current medications. It's best to discuss this with the trial coordinators or your doctor.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research has shown that VOR33, when combined with Mylotarg, appears safe for people. Mylotarg is already approved to treat Acute Myeloid Leukemia (AML), though it can cause liver issues and affect blood cells. Studies suggest that using VOR33 with Mylotarg can safely and effectively treat patients after a stem cell transplant. This combination seems to lower the risk of cancer returning, with fewer side effects. As this treatment is in early clinical trials, researchers continue to ensure its safety and determine the correct dose. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Unlike the standard treatments for acute myeloid leukemia, which often involve chemotherapy and targeted therapies, the combination of VOR33 and Mylotarg is unique because it uses genetically modified stem cells. VOR33 is engineered to protect healthy cells from the effects of Mylotarg, a drug that targets leukemia cells, potentially reducing side effects and improving patient outcomes. Researchers are excited about this treatment because it represents a novel approach that not only aims to kill cancer cells more effectively but also spares the patient’s healthy cells, making the overall treatment potentially safer and more effective.

What evidence suggests that this trial's treatments could be effective for acute myeloid leukemia?

Research has shown that combining VOR33 with Mylotarg may help treat acute myeloid leukemia (AML). In this trial, participants will receive VOR33, a specially designed cell therapy that aims to make Mylotarg treatment safer and more effective, followed by different dose levels of Mylotarg. Mylotarg, an approved drug for AML, targets and kills certain cancer cells but can sometimes harm the liver. VOR33 is created by removing a specific protein (CD33) that Mylotarg usually targets, potentially reducing side effects and allowing for more frequent Mylotarg doses. Early results suggest this combination could lower the chance of leukemia returning, offering a hopeful option for patients. ^{1 2 4 6 7}

Are You a Good Fit for This Trial?

This trial is for adults aged 18-70 with CD33+ AML who are candidates for a stem cell transplant from a perfectly matched donor. They should be in remission or have low blast counts, unless approved by the medical monitor. Participants need good heart, lung, kidney, and liver function but can't join if they've had certain other cancers, prior Mylotarg treatment, specific genetic abnormalities related to leukemia, or uncontrolled infections.

Inclusion Criteria

I am eligible for a stem cell transplant from a donor with matching tissue type.

Must have adequate performance status and organ function as defined below: Performance Status: Karnofsky score of ≥70, Cardiac: left ventricular ejection fraction (LVEF) ≥50%, Pulmonary: diffusing capacity of lung for carbon monoxide (DLCO), forced vital capacity (FVC), and forced expiratory volume in one second (FEV1) ≥66%, Renal: estimated glomerular filtration rate (GFR) >60 mL/min, Hepatic: total bilirubin <1.5 × ULN, or if ≥1.5 × ULN direct bilirubin <ULN and ALT/AST <1.5 × ULN (per institutional criteria)

My leukemia is at a high risk of coming back based on specific genetic factors or my response to treatment.

Exclusion Criteria

I have been treated with Mylotarg™ before.

I do not have active brain leukemia or any other active cancer.

I have been diagnosed with Gilbert's syndrome.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Hematopoietic Cell Transplantation

Participants 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).

Up to 28 days

In-patient stay for transplantation and initial recovery

Post-Transplant Treatment

Mylotarg™ is administered after engraftment for up to 4 cycles to target residual CD33+ AML cells.

Up to 4 cycles

Follow-up

Participants are monitored for safety and effectiveness after treatment, including assessments of engraftment, platelet recovery, and survival.

Up to 24 months

Regular follow-up visits at Day 28, 60, 100, 180, and Months 12 and 24

What Are the Treatments Tested in This Trial?

Interventions

• Mylotarg
• VOR33

Trial Overview The study tests VOR33-engineered stem cells lacking CD33 protein followed by Mylotarg post-transplant in patients with AML. It's an early-phase trial to see how safe it is and how well it works when given during a standard HLA-matched allogeneic hematopoietic cell transplant.

How Is the Trial Designed?

Group I: Cohort 3 Experimental Treatment 2 Interventions

VOR33 infusion followed by Mylotarg Dose Level 3

Group II: Cohort 2 Experimental Treatment 2 Interventions

VOR33 infusion followed by Mylotarg Dose Level 2

Group III: Cohort 1 Experimental Treatment 2 Interventions

VOR33 infusion followed by Mylotarg Dose Level 1

VOR33 is already approved in United States for the following indications:

Approved in United States as trem-cel for:

• Acute Myeloid Leukemia (AML)

Who Is Running the Clinical Trial?

Vor Biopharma

Lead Sponsor

Trials

3

Recruited

80+

Published Research Related to This Trial

Mylotarg (gemtuzumab ozogamicin) is an FDA-approved treatment for older patients (60+) with CD33-positive acute myeloid leukemia who cannot undergo standard chemotherapy, showing a 30% overall response rate in a study of 142 patients.

While Mylotarg can cause some side effects like myelosuppression and elevated liver enzymes, it has a lower incidence of severe mucositis and infections compared to traditional chemotherapy, indicating a potentially safer profile for these patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Mylotarg: antibody-targeted chemotherapy comes of age. Sievers, EL., Linenberger, M.[2019]

CART33, a chimeric antigen receptor T cell therapy targeting CD33, showed significant effectiveness in eradicating acute myeloid leukemia (AML) in preclinical models, leading to prolonged survival.

To reduce the risk of long-term toxicity associated with permanent CART cell expression, a transiently expressed mRNA anti-CD33 CAR was developed, demonstrating potent but self-limited activity against AML, making it a safer option for patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

CD33-specific chimeric antigen receptor T cells exhibit potent preclinical activity against human acute myeloid leukemia. Kenderian, SS., Ruella, M., Shestova, O., et al.[2022]

In a pilot study involving 17 patients with refractory acute myeloid leukemia (AML), the combination treatment of Mylotarg, topotecan, and cytarabine (MTA) resulted in a 12% complete remission rate, indicating moderate efficacy.

However, the treatment was associated with significant toxicity, as 29% of patients experienced severe liver complications, highlighting the need for careful monitoring during therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Mylotarg combined with topotecan and cytarabine in patients with refractory acute myelogenous leukemia. Cortes, J., Tsimberidou, AM., Alvarez, R., et al.[2019]

In a study of 142 patients with CD33-positive acute myeloid leukemia (AML) in first relapse, 30% achieved remission after treatment with Mylotarg (gemtuzumab ozogamicin), indicating its efficacy as a targeted chemotherapy agent.

While Mylotarg was associated with some adverse effects, such as myelosuppression and elevated liver enzymes, it had a favorable safety profile overall, with low incidences of severe nausea, vomiting, and no significant cardiotoxicity or hair loss.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy and safety of gemtuzumab ozogamicin in patients with CD33-positive acute myeloid leukemia in first relapse. Sievers, EL., Larson, RA., Stadtmauer, EA., et al.[2022]

The MFAC regimen, which includes Mylotarg, was evaluated in 22 patients with relapsed acute myeloid leukemia (AML) and showed a 12-month survival rate of 55%, indicating its potential effectiveness as post-remission therapy.

The treatment was well tolerated, with similar rates of severe toxicities (like sepsis and neutropenic fever) compared to the standard idarubicin and ara-C regimen, suggesting that MFAC is a safe option for patients in complete remission.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Mylotarg, fludarabine, cytarabine (ara-C), and cyclosporine (MFAC) regimen as post-remission therapy in acute myelogenous leukemia. Tsimberidou, AM., Estey, E., Cortes, JE., et al.[2019]

In a study of 28 patients undergoing allogeneic bone marrow transplantation (BMT) for acute myeloid leukemia (AML), the risk of leukemic relapse was significantly lower (32%) compared to 54 patients receiving high-dose cytarabine-based chemotherapy (60%), indicating BMT may reduce relapse rates.

However, BMT was associated with a higher treatment-related mortality (32% vs. 6%), and there was no significant difference in 5-year disease-free survival between the two groups (45% for BMT vs. 38% for chemotherapy), suggesting that while BMT may lower relapse risk, it also carries higher risks and does not improve long-term survival.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Bone marrow transplantation versus high-dose cytarabine-based consolidation chemotherapy for acute myelogenous leukemia in first remission. Schiller, GJ., Nimer, SD., Territo, MC., et al.[2017]

Regulatory T (Treg) cells play a significant role in antitumor immunity, and targeting CD25+ Treg cells, especially in combination with TGF-β blockade, shows promise for improving patient survival in Acute Myeloid Leukemia (AML).

The review highlights that while Treg cells are elevated in various cancers, the effectiveness of Treg-based immunotherapy varies, suggesting that strategies focusing on CD25 inhibition may be more beneficial for AML compared to other cancers.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Molecular Markers of Regulatory T Cells in Cancer Immunotherapy with Special Focus on Acute Myeloid Leukemia (AML) - A Systematic Review. Kaboli, PJ., Zhang, L., Xiang, S., et al.[2020]

The study developed tremtelectogene empogeditemcel (trem-cel), a genetically modified hematopoietic stem cell product that lacks the CD33 protein, which is targeted by certain AML therapies, thus reducing the risk of toxicity to healthy cells.

Preclinical studies demonstrated that trem-cel can be manufactured with over 70% efficiency without affecting cell viability or function, and it showed resistance to the CD33-targeted drug gemtuzumab ozogamicin, supporting its potential safety and efficacy for treating acute myeloid leukemia in upcoming clinical trials.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Development of a gene edited next-generation hematopoietic cell transplant to enable acute myeloid leukemia treatment by solving off-tumor toxicity. Lydeard, JR., Lin, MI., Ge, HG., et al.[2023]

Modified Vγ9Vδ2 T cells expressing anti-CD123 CAR showed significantly improved ability to kill acute myeloid leukemia (AML) cells in laboratory tests, indicating their potential effectiveness as a treatment.

In a mouse model of AML, these modified T cells demonstrated enhanced tumor control, suggesting they could be a promising alternative therapy for patients with this type of leukemia.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A CD123-specific chimeric antigen receptor augments anti-acute myeloid leukemia activity of Vγ9Vδ2 T cells. Zhang, X., Ang, WX., Du, Z., et al.[2022]

In a study of 23 younger patients with acute myeloid leukemia (AML) treated with standard chemotherapy, the overall response rate was 44%, indicating that a significant portion achieved complete or incomplete remission.

While higher levels of T regulatory cells (Tregs) in diagnostic bone marrow aspirates were associated with a better molecular/cytogenetic risk group, they did not correlate with overall response to treatment, suggesting that Tregs may not be a reliable predictor of treatment efficacy in AML.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Impact of Bone Marrow Aspirate Tregs on the Response Rate of Younger Newly Diagnosed Acute Myeloid Leukemia Patients. Delia, M., Carluccio, P., Mestice, A., et al.[2018]

Allogeneic stem cell transplantation (SCT) is a key treatment for adult patients with acute myeloid leukemia, especially for those with unfavorable karyotypes or intermediate prognoses, ideally performed in the first complete remission.

The introduction of reduced-intensity conditioning regimens has made SCT accessible for older patients, improving tolerance despite ongoing risks such as graft-versus-host disease and relapse.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Current indications of allogeneic stem cell transplant in adults with acute myeloid leukemia]. Thomas, X.[2014]

Autologous stem cell transplantation (ASCT) has evolved to effectively consolidate treatment in adult patients with acute myelogenous leukemia (AML), particularly benefiting those in complete remission with no detectable minimal residual disease.

Recent studies suggest that ASCT can be safely applied to well-selected patients, offering reduced toxicity, lower non-relapse mortality, and improved quality of life, especially when combined with maintenance therapies like hypomethylating agents.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

History and Development of Autologous Stem Cell Transplantation for Acute Myeloid Leukemia. Gorin, NC.[2023]

Citations

1. ashpublications.org ashpublications.org/blood/article/144/Supplement%201/2873/531068/A-CD33-Deleted-Allograft-Trem-cel-Enables-Post

A CD33-Deleted Allograft (Trem-cel) Enables Post ... GO (MylotargTM) is an anti-CD33 antibody-drug conjugate approved for use in AML, but its use has been limited by hepatotoxicity and on-target, ...

2. sciencedirect.com sciencedirect.com/science/article/abs/pii/S2666636725001265

A CD33-Deleted Allograft (Trem-cel) Enables Post ... These data support safe and effective administration of GO after trem-cel HCT, enabling repeated maintenance dosing intended to reduce risk of relapse.

3. clinicaltrials.gov clinicaltrials.gov/study/NCT04849910

Study Details | NCT04849910 | Allogeneic Engineered ... 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 ( ...

4. hematologyadvisor.com hematologyadvisor.com/reports/trem-cel-may-help-reduce-toxicity-of-gemtuzumab-ozogamicin-in-aml/

Trem-Cel May Help Reduce Toxicity of Gemtuzumab ... Trem-cel may make gemtuzumab ozogamicin maintenance safer for patients with high-risk AML, data suggest.

5. sciencedirect.com sciencedirect.com/science/article/pii/S2666636723020468

Trem-Cel, a CRISPR/Cas9 Gene-Edited Allograft Lacking ... Trem-cel (formerly VOR33) is manufactured from CD34+ cells isolated from matched-donor apheresis and modified by CRISPR/Cas9 gene-editing to remove CD33.

6. library.ehaweb.org library.ehaweb.org/eha/2025/eha2025-congress/4159221/guenther.koehne.a.cd33-deleted.allograft.28trem-cel29.enables.gemtuzumab.html?f=menu%3D6%2Abrowseby%3D8%2Asortby%3D2%2Amedia%3D3%2Ace_id%3D2882%2Aot_id%3D31560%2Amarker%3D5843%2Afeatured%3D19588

A CD33-DELETED ALLOGRAFT (TREM-CEL) ENABLES ... A CD33-DELETED ALLOGRAFT (TREM-CEL) ENABLES GEMTUZUMAB OZOGAMICIN MAINTENANCE POST-HEMATOPOIETIC CELL TRANSPLANT WITH THERAPEUTIC EXPOSURES ...

7. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/38027064/

Development of a gene edited next-generation ... Importantly, CD33-knockout myeloid cells were resistant to the CD33-targeted agent gemtuzumab ozogamicin in vitro and in vivo. These studies ...