REM-422 for Acute Myeloid Leukemia and Higher Risk MDS

Recruiting at 9 trial locations

Overseen By Remix Therapeutics

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: Remix Therapeutics

Must not be taking: CYP3A inhibitors, CYP3A inducers

Disqualifiers: CNS leukemia, Active infection, HIV, 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: Unknown

100 Participants Needed

Trial Summary

Do I need to stop my current medications to join the trial?

The trial requires that you stop systemic non-investigational therapy at least 14 days before starting REM-422. However, you can continue using hydroxyurea to control leukemic blasts before and up to 28 days after starting REM-422. Some medications, like strong CYP3A inhibitors and drugs that reduce stomach acid, must be stopped 7 days before starting the trial.

What data supports the effectiveness of the drug REM-422 for treating acute myeloid leukemia?

Research shows that targeting the MYB protein, which is involved in the growth of leukemia cells, can be effective. Drugs that inhibit MYB, like proteasome inhibitors and protein kinase inhibitors, have shown promise in reducing leukemia cell growth and inducing cell death, suggesting that REM-422, which also targets MYB, may be effective. ^{1 2 3 4 5}

What makes the drug REM-422 unique for treating acute myeloid leukemia?

REM-422 is unique because it specifically targets and degrades the c-MYB mRNA, a key factor in the development and maintenance of acute myeloid leukemia, offering a novel approach compared to traditional chemotherapy which does not specifically target this transcription factor. ^{1 2 4 5 6}

What is the purpose of this trial?

The goal of this study is to determine the safety and antitumor effects of REM-422, a MYB mRNA degrader, in people with Higher Risk MDS and relapsed/refractory AML

Research Team

Christopher Bowden, MD

Principal Investigator

Remix Therapeutics

Eligibility Criteria

This trial is for individuals with higher risk Myelodysplastic Syndrome (MDS) or relapsed/refractory Acute Myeloid Leukemia (AML). Specific eligibility criteria are not provided, but typically include factors like age, disease stage, and overall health.

Inclusion Criteria

I agree to use effective birth control methods.

My organs are functioning well according to recent tests.

People of childbearing potential (POCBP) must have a negative serum beta-human chorionic gonadotropin test result

Exclusion Criteria

Receiving any other investigational treatment for any indication ≤ 3 weeks prior to enrollment

I currently have a serious infection.

I am receiving treatment for an autoimmune disease.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Dose Escalation

Participants receive escalating doses of REM-422 to determine Maximum Tolerated Dose (MTD) and/or Recommended Phase 2 Dose (RP2D)

Until MTD/RP2D is determined

Dose Expansion

Participants receive REM-422 at the identified RP2D to further evaluate safety and anti-tumor activity

Until disease progression, therapy intolerance, or participant withdrawal

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

Treatment Details

Interventions

• REM-422

Trial Overview The study is testing the safety and effectiveness of REM-422, a new treatment designed to target MYB mRNA in patients with high-risk MDS or AML that has come back or hasn't responded to other treatments.

Participant Groups

Group I: REM-422 Experimental Treatment 1 Intervention

Dose Escalation: Participants will receive escalating doses of REM-422 to determine Maximum Tolerated Dose (MTD) and/or Recommended Phase 2 Dose (RP2D)-422, oral capsule administered once daily Dose Expansion: Participants will receive REM-422 at the identified RP2D Treatment will continue until disease progression, therapy intolerance, or participant withdrawal Safety evaluation will continue until 30 days of last administration of REM-422

REM-422 is already approved in United States for the following indications:

Approved in United States as REM-422 for:

• Adenoid Cystic Carcinoma (ACC)
• Acute Myeloid Leukemia (AML)

Who Is Running the Clinical Trial?

Remix Therapeutics

Lead Sponsor

Trials

2

Recruited

170+

Findings from Research

Mebendazole has been identified as a novel therapeutic agent for acute myeloid leukemia (AML) by targeting the c-MYB transcription factor, which is crucial for AML development, particularly in cases with MLL-rearrangements.

In laboratory studies, mebendazole effectively inhibited the growth of AML cells without affecting normal blood cells, and it demonstrated the ability to impair AML progression in mouse models, suggesting it could be a safe treatment option for patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Targeting acute myeloid leukemia by drug-induced c-MYB degradation. Walf-Vorderwülbecke, V., Pearce, K., Brooks, T., et al.[2019]

MYB is identified as a promising drug target for acute myeloid leukemia (AML) and adenoid cystic carcinoma (ACC), with recent studies showing that it can be effectively inhibited by low molecular weight compounds.

The proteasome inhibitor oprozomib was found to significantly inhibit MYB activity and reduce the proliferation of AML and ACC cells, suggesting a novel therapeutic approach by targeting MYB through proteasome inhibition.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Proteasome inhibitors suppress MYB oncogenic activity in a p300-dependent manner. Yusenko, MV., Biyanee, A., Andersson, MK., et al.[2022]

The study identifies several protein kinase inhibitors, including bosutinib, as potential MYB-inhibitory agents, which could be repurposed to target malignancies like acute myeloid leukemia (AML).

These inhibitors disrupt MYB's ability to activate genes by interfering with its interaction with the coactivator p300, leading to increased cell death in AML cells, indicating a promising mechanism for treating MYB-dependent cancers.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Src-Family Protein Kinase Inhibitors Suppress MYB Activity in a p300-Dependent Manner. Biyanee, A., Yusenko, MV., Klempnauer, KH.[2022]

The transcription factor MYB is crucial for the self-renewal of acute myeloid leukemia (AML) cells, indicating its importance in the progression of the disease.

C/EBPβ has been identified as a key collaborator with MYB and p300 in sustaining leukemic cells, suggesting it could be a promising therapeutic target for AML treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

C/EBPβ cooperates with MYB to maintain the oncogenic program of AML cells. Klempnauer, KH.[2023]

The Myb protein is linked to various cancers, particularly acute myeloid leukemia (AML), but its exact role in these diseases is still not fully understood despite extensive research over the past 30 years.

Recent studies have identified Myb's transcriptional targets, suggesting that targeting Myb and its co-regulators could lead to new therapeutic strategies for treating hematopoietic malignancies, potentially improving patient outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Role and potential for therapeutic targeting of MYB in leukemia. Pattabiraman, DR., Gonda, TJ.[2013]

RUVBL2 is crucial for the function of the c-MYB transcription factor in acute myeloid leukemia (AML), as it represses genes associated with myeloid differentiation, allowing leukemia cells to self-renew.

Inhibiting RUVBL2 led to increased c-MYB activity, resulting in apoptosis of AML cells and significantly slowing disease progression in mouse models, while sparing normal blood cell development, suggesting a targeted therapeutic strategy for AML.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The AAA+ATPase RUVBL2 is essential for the oncogenic function of c-MYB in acute myeloid leukemia. Armenteros-Monterroso, E., Zhao, L., Gasparoli, L., et al.[2022]

References

1. England pubmed.ncbi.nlm.nih.gov

Targeting acute myeloid leukemia by drug-induced c-MYB degradation. [2019]

2. Ireland pubmed.ncbi.nlm.nih.gov

Proteasome inhibitors suppress MYB oncogenic activity in a p300-dependent manner. [2022]

3. Switzerland pubmed.ncbi.nlm.nih.gov

Src-Family Protein Kinase Inhibitors Suppress MYB Activity in a p300-Dependent Manner. [2022]

4. United States pubmed.ncbi.nlm.nih.gov

C/EBPβ cooperates with MYB to maintain the oncogenic program of AML cells. [2023]

5. England pubmed.ncbi.nlm.nih.gov

Role and potential for therapeutic targeting of MYB in leukemia. [2013]

6. England pubmed.ncbi.nlm.nih.gov

The AAA+ATPase RUVBL2 is essential for the oncogenic function of c-MYB in acute myeloid leukemia. [2022]