MBG453 for Preleukemia

Not currently recruiting at 2 trial locations

Overseen By Andrew Brunner, MD

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: Massachusetts General Hospital

Must not be taking: TIM-3 inhibitors, Prednisone

Disqualifiers: Chemotherapy, Radiotherapy, Autoimmune, Transplant, others

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

Prior Safety Data This treatment has passed at least one previous human trial

Compensation: Varies

Number of Visits: 1

Duration: Variable (based on individual response)

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores the effectiveness of MBG453, a humanized monoclonal antibody, in treating myelodysplastic syndromes (MDS), where the bone marrow fails to produce enough healthy blood cells. The study targets individuals with lower-risk MDS who have not responded to or cannot tolerate other treatments, such as red blood cell transfusions or certain drugs. Suitable participants are those with low blood cell counts impacting daily life and limited treatment options. As a Phase 2 trial, the research measures the treatment's effectiveness in an initial, smaller group of people.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications, but there is a requirement to stop any investigational agents and certain treatments at least 14 days before starting the study. It's best to discuss your specific medications with the trial team.

Is there any evidence suggesting that MBG453 is likely to be safe for humans?

Research has shown that MBG453, also known as sabatolimab, was tested for safety in earlier studies involving patients with advanced solid tumors and blood-related cancers. Sabatolimab was generally well-tolerated, with most participants not experiencing serious problems. Some patients did experience side effects, mostly mild to moderate, such as fatigue or nausea. More serious side effects were less common. The data suggests that MBG453 is relatively safe, but monitoring for any possible negative reactions remains important. As this is a phase two trial, earlier studies have already assessed its safety, indicating that MBG453 has a reasonable safety profile. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising for preleukemia?

Most treatments for preleukemia focus on slowing disease progression or managing symptoms, often using drugs like hypomethylating agents. But MBG453 works differently, targeting a protein called TIM-3 on immune cells. This unique mechanism aims to enhance the body's immune response against abnormal blood cells, potentially offering a more precise approach to treating preleukemia. Researchers are excited about MBG453 because it could provide a new strategy to intervene earlier in the disease process, possibly improving outcomes for patients at risk of developing leukemia.

What evidence suggests that MBG453 might be an effective treatment for preleukemia?

Research has shown that MBG453, also known as sabatolimab, could be beneficial in treating myelodysplastic syndromes (MDS), a type of blood cancer. Earlier studies found that MBG453 works in two ways, targeting specific parts of the immune system to combat these cancers. Early trials using MBG453 with another drug, decitabine, showed promising results, indicating it can be both effective and safe. This treatment targets TIM-3, a protein on immune cells, which might enhance the body's ability to fight cancer cells. These findings offer hope for MBG453's potential in managing MDS. Participants in this trial will receive MBG453 on Day 1 of each 28-day study cycle. ^{6 7 8 9 10}

Who Is on the Research Team?

Andrew M Brunner, MD

Principal Investigator

Massachusetts General Hospital

Are You a Good Fit for This Trial?

This trial is for adults with lower risk Myelodysplastic Syndromes (MDS) who need regular red blood cell transfusions, have not responded to previous treatments, or can't tolerate other medications. It's also open to those with specific genetic changes in their MDS and no available standard treatment options.

Inclusion Criteria

Patients with platelets < 50k/uL or ANC < 500 cells/uL who are felt to require treatment per the treating physician

I have MDS with '5q- syndrome' and lenalidomide didn't work for me.

I can't have standard treatments but have had luspatercept before.

Exclusion Criteria

I have another type of cancer that hasn't been treated yet.

Participants with clinically active HBV or HCV

I have not received a live vaccine in the last 28 days.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive MBG453 on Day 1 of each 28-day cycle for as long as they and their doctor believe they are benefiting

Variable (based on individual response)

1 visit per cycle (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment

12 months

What Are the Treatments Tested in This Trial?

Interventions

• MBG453

Trial Overview The study is testing MBG453, a humanized monoclonal antibody designed to treat MDS. Researchers want to see how effective it is at improving the condition of patients who haven't had success with other therapies.

How Is the Trial Designed?

Group I: MG MBG453 Experimental Treatment 1 Intervention

Participants will be given MBG453 On Day 1 of each cycle 28 days (4 weeks) study cycle

Who Is Running the Clinical Trial?

Massachusetts General Hospital

Lead Sponsor

Trials

3,066

Recruited

13,430,000+

Novartis

Industry Sponsor

Trials

1,646

Recruited

2,778,000+

Vasant Narasimhan

Novartis

Chief Executive Officer since 2018

MD from Harvard Medical School, Bachelor's in Biological Sciences from University of Chicago, Master's in Public Policy from John F. Kennedy School of Government

Shreeram Aradhye

Novartis

Chief Medical Officer since 2022

MD from Yale University, MSc in Clinical Epidemiology from University of Pennsylvania

Published Research Related to This Trial

Sabatolimab, a humanized anti-TIM-3 monoclonal antibody, is being developed for treating myeloproliferative disorders like acute myeloid leukemia, showcasing its potential as a novel immunotherapy.

This therapy works through multiple mechanisms, including blocking TIM-3 and its ligands, modulating leukemic cell self-renewal, and promoting antibody-dependent phagocytosis of TIM-3-expressing leukemic cells, which may enhance the overall antitumor immune response.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

TIM-3: a tumor-associated antigen beyond checkpoint inhibition? Barth, S., Naran, K.[2023]

Sabatolimab, an immunotherapy targeting TIM-3, was found to have a safety profile similar to hypomethylating agents (HMAs) when used in combination for treating high- or very high-risk myelodysplastic syndromes (HR/vHR-MDS) and chronic myelomonocytic leukemia (CMML).

The combination of sabatolimab and HMAs demonstrated durable clinical responses in patients, indicating its potential effectiveness and supporting further research into its use in MDS, CMML, and acute myeloid leukemia.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase Ib study of sabatolimab (MBG453), a novel immunotherapy targeting TIM-3 antibody, in combination with decitabine or azacitidine in high- or very high-risk myelodysplastic syndromes. Brunner, AM., Esteve, J., Porkka, K., et al.[2023]

The small molecule SMI402 effectively binds to the TIM-3 immune checkpoint, preventing its interaction with other molecules that contribute to T cell dysfunction, which is crucial in the tumor microenvironment.

In mouse models of cancer, SMI402 not only inhibited tumor growth but also enhanced the infiltration and function of CD8+ T cells and natural killer (NK) cells, suggesting its potential as a promising candidate for cancer immunotherapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Identification of a novel small-molecule inhibitor targeting TIM-3 for cancer immunotherapy. Wu, M., Wu, A., Zhang, X., et al.[2023]

In a phase I/II study involving 219 patients with advanced solid tumors, the combination of sabatolimab and spartalizumab was well tolerated, with fatigue being the most common treatment-related side effect.

While no responses were observed with sabatolimab alone, the combination treatment showed preliminary antitumor activity, with 5 patients achieving partial responses in various cancers, suggesting potential efficacy in specific populations.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase I/Ib Clinical Trial of Sabatolimab, an Anti-TIM-3 Antibody, Alone and in Combination with Spartalizumab, an Anti-PD-1 Antibody, in Advanced Solid Tumors. Curigliano, G., Gelderblom, H., Mach, N., et al.[2023]

Targeting the Tim-3 inhibitory receptor on T cells may enhance anti-tumor immunity in bladder cancer, especially since many patients do not respond to existing therapies like CTLA-4 and PD-1/PD-L1 blockade.

Tim-3 expression increases with the severity of bladder cancer, suggesting that developing monoclonal antibodies against Tim-3, either alone or with other treatments, could lead to better outcomes for patients with advanced disease.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The Potential of T Cell Immunoglobulin and Mucin-Domain Containing-3 (Tim-3) in Designing Novel Immunotherapy for Bladder Cancer. Mohsenzadegan, M., Bavandpour, P., Nowroozi, MR., et al.[2022]

TIM-3 is a key immune checkpoint protein that plays a significant role in cancer immunosuppression and is a promising target for immunotherapy, particularly in solid tumors and myeloid leukemia stem cells.

Blocking TIM-3 has been shown to directly inhibit leukemia cells while also restoring T cell activation, suggesting it could enhance the effectiveness of cancer treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Targeting TIM-3 for hematological malignancy: latest updates from the 2022 ASH annual meeting. Tan, J., Tan, H., Li, Y.[2023]

In a phase 2 trial involving 127 patients with higher-risk myelodysplastic syndromes, the addition of sabatolimab to hypomethylating agents did not significantly improve complete response rates or progression-free survival compared to placebo.

Despite the lack of significant efficacy, sabatolimab was generally well-tolerated, with manageable safety profiles, although there was one treatment-related death due to pneumonitis.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Sabatolimab plus hypomethylating agents in previously untreated patients with higher-risk myelodysplastic syndromes (STIMULUS-MDS1): a randomised, double-blind, placebo-controlled, phase 2 trial. Zeidan, AM., Ando, K., Rauzy, O., et al.[2023]

Sabatolimab is a novel immunotherapy targeting TIM-3, designed to reactivate the immune system and directly attack TIM-3+ leukemic cells, which could improve outcomes for patients with higher-risk myelodysplastic syndromes (MDS) and chronic myelomonocytic leukemia (CMML).

The phase III STIMULUS-MDS2 trial is investigating the combination of sabatolimab and azacitidine to assess its effectiveness in enhancing survival rates for patients who are unfit for hematopoietic stem cell transplantation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

STIMULUS-MDS2 design and rationale: a phase III trial with the anti-TIM-3 sabatolimab (MBG453) + azacitidine in higher risk MDS and CMML-2. Zeidan, AM., Giagounidis, A., Sekeres, MA., et al.[2023]

Citations

1. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/37994196/

Phase Ib study of sabatolimab (MBG453), a novel ... The safety and efficacy of sabatolimab, a novel immunotherapy targeting T-cell immunoglobulin domain and mucin domain-3 (TIM-3), was assessed in combination ...

2. clinicaltrials.gov clinicaltrials.gov/study/NCT04823624

Study Details | NCT04823624 | MBG453 in Lower Risk MDS This research study is assessing the efficacy of MBG-453, a humanized monoclonal antibody, in treating myelodysplastic syndromes (MDS). The name of the ...

3. ascpt.onlinelibrary.wiley.com ascpt.onlinelibrary.wiley.com/doi/10.1002/psp4.12962

Sabatolimab (MBG453) model‐informed drug development for ... It has shown immuno-myeloid activity with a potential dual mechanism against acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS).

4. sciencedirect.com sciencedirect.com/science/article/abs/pii/S2152265020307278

AML-187: The STIMULUS Clinical Trial Program ... In a phase 1b study (NCT03066648 ), the anti–TIM-3 monoclonal antibody, MBG453, plus decitabine showed promising preliminary efficacy with a good safety profile ...

5. dana-farber.org dana-farber.org/clinical-trials/20-637

TIM3 Inhibition with MBG453 for Patients with Lower Risk ... This research study is assessing the efficacy of MBG-453, a humanized monoclonal antibody, in treating myelodysplastic syndromes (MDS).

6. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC10681456/

Sabatolimab (MBG453) model‐informed drug development for ... The objectives of this analysis were to report PK, receptor occupancy, and exposure‐response data from patients with advanced solid tumors and hematologic ...

7. aacrjournals.org aacrjournals.org/clincancerres/article/27/13/3620/671520/Phase-I-Ib-Clinical-Trial-of-Sabatolimab-an-Anti

Phase I/Ib Clinical Trial of Sabatolimab, an Anti–TIM-3 ... This phase I/II study evaluated the safety and efficacy of sabatolimab, with or without spartalizumab, in patients with advanced solid tumors.

8. clinicaltrials.gov clinicaltrials.gov/study/NCT03946670

NCT03946670 | A Study of MBG453 in Combination With ... To determine if MBG453 combined with standard HMA therapy improves progression free survival (PFS) in subjects with intermediate, high or very high risk MDS.

9. ascpt.onlinelibrary.wiley.com ascpt.onlinelibrary.wiley.com/doi/abs/10.1002/psp4.12962

Sabatolimab (MBG453) model‐informed drug development for ... Sabatolimab (MBG453) model-informed drug development for dose selection in patients with myelodysplastic syndrome/acute myeloid leukemia and ...

10. sciencedirect.com sciencedirect.com/science/article/abs/pii/S2352302623003332

Sabatolimab plus hypomethylating agents in previously ... Here, we present the primary safety and efficacy results of the STIMULUS-MDS1 study, in which sabatolimab plus a hypomethylating agent was compared with placebo ...