MMSET Inhibitor for Multiple Myeloma

Recruiting at 30 trial locations

Overseen By Miriam Barnett, Ph.D.

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: K36 Therapeutics, Inc.

Must not be taking: Acid reducers, CYP3A4 inhibitors

Disqualifiers: Plasma cell leukemia, POEMS, others

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

Compensation: Varies

Number of Visits: Unknown

125 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a new pill that blocks an enzyme to help treat adults with a hard-to-treat type of blood cancer. The goal is to see if it is safe and effective.

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

The trial protocol does not specify if you must stop all current medications, but you cannot have had certain cancer treatments recently, like chemotherapy within 2 weeks or a transplant within specific timeframes. You also need to avoid certain medications like acid-reducing agents and strong CYP3A4 inhibitors or inducers within 14 days before starting the trial.

What makes the drug KTX-1001 unique for treating multiple myeloma?

KTX-1001 is unique because it targets the MMSET protein, which is overexpressed in a specific subgroup of multiple myeloma patients with a poor prognosis. This drug works by inhibiting the histone methyltransferase activity of MMSET, potentially altering gene expression and chromatin structure, which is a novel approach compared to existing treatments. ^{1 2 3 4 5}

What data supports the effectiveness of the drug KTX-1001 for treating multiple myeloma?

The research highlights the success of similar treatments like proteasome inhibitors and other novel agents in treating multiple myeloma, suggesting that new drugs like KTX-1001 could potentially be effective. Additionally, the development of new drug classes and combinations has shown promise in overcoming drug resistance in multiple myeloma, which may support the potential effectiveness of KTX-1001. ^{6 7 8 9 10}

Are You a Good Fit for This Trial?

This trial is for adults with relapsed or refractory multiple myeloma who have tried all other treatments without success. They must have certain levels of M protein in their urine or blood, and some may need to show specific genetic changes related to their cancer. People can't join if they've had a recent transplant, major surgery, other active cancers, inadequate organ function, or certain infections.

Inclusion Criteria

I can take care of myself and am up and about more than 50% of my waking hours.

I have had at least 3 treatments including a proteasome inhibitor, an immunomodulatory drug, and an anti-CD38 antibody.

My test results show I have the t(4;14) genetic change or a specific mutation in MMSET.

Exclusion Criteria

I haven't taken strong acid reducers or certain other medications in the last 14 days.

I have not had major surgery in the last 4 weeks.

My kidney, liver, lung, or heart function is not normal.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Dose Escalation

Patients are evaluated for dose-limiting toxicities (DLTs) during Cycle 1 to determine the maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D)

4 weeks

Multiple visits (in-person)

Dose Expansion

Patients receive KTX-1001 at the RP2D alone and in combination with standard of care therapy to further define safety and tolerability and provide preliminary efficacy information

Duration of Study

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

What Are the Treatments Tested in This Trial?

Interventions

• KTX-1001

Trial Overview The study tests KTX-1001, an oral drug designed to inhibit MMSET activity in patients with multiple myeloma that has come back after treatment or hasn't responded to therapy. It's a Phase I trial focused on safety and how well the body tolerates the drug.

How Is the Trial Designed?

Group I: Cohort D (pomalidomide): KTX-1001 + pomalidomide + dex Experimental Treatment 1 Intervention

Cohort D (pomalidomide): KTX-1001 at RP2D1 or RP2D2 + pomalidomide + dex

Group II: Cohort C (carfilzomib): KTX-1001 + carfilzomib + dex Experimental Treatment 1 Intervention

Cohort C1 (carfilzomib): KTX-1001 at RP2D1 + carfilzomib + dex Cohort C2 (carfilzomib): KTX-1001 at RP2D2 + carfilzomib + dex

Group III: Cohort B (Mezigdomide): KTX-1001 + Mezigdomide + dex Experimental Treatment 1 Intervention

Cohort B1 (Mezigdomide): KTX-1001 at RP2D1 + Mezigdomide + dex Cohort B2 (Mezigdomide):: KTX-1001 at RP2D2 + Mezigdomide + dex

Group IV: Cohort A (Single agent): KTX-1001 + dexamethasone Experimental Treatment 1 Intervention

Cohort A1 (single agent): KTX-1001 at RP2D1 + dex Cohort A2 (single agent): KTX-1001 at RP2D2 + dex

Who Is Running the Clinical Trial?

K36 Therapeutics, Inc.

Lead Sponsor

Trials

1

Recruited

130+

Bristol-Myers Squibb

Industry Sponsor

Trials

2,731

Recruited

4,127,000+

Headquarters

New York City, USA

Known For

Oncology & Cardiovascular

Top Products

Eliquis, Opdivo, Revlimid, Orencia

Christopher Boerner

Bristol-Myers Squibb

Chief Executive Officer since 2023

PhD in Business Administration from the Haas School of Business, University of California, Berkeley; BA in Economics and History from Washington University in St. Louis

Deepak L. Bhatt

Bristol-Myers Squibb

Chief Medical Officer since 2024

MD from Yale University; MSc in Clinical Epidemiology from the University of Pennsylvania

Published Research Related to This Trial

Recent advancements in anti-myeloma treatments, including thalidomide, lenalidomide, and bortezomib, have shown significant clinical responses, especially in patients who do not respond to traditional chemotherapy.

The review highlights the ongoing development of various novel therapeutic classes, such as second-generation proteasome inhibitors and HDAC inhibitors, which are currently in clinical trials or advanced preclinical stages, indicating a promising expansion of treatment options for myeloma.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

From the bench to the bedside: emerging new treatments in multiple myeloma. Mitsiades, CS., Hayden, PJ., Anderson, KC., et al.[2023]

Double-refractory multiple myeloma, which does not respond to both proteasome inhibitors and immunomodulatory agents, has a poor prognosis, highlighting the urgent need for new treatment strategies.

Promising new therapies, such as the second-generation proteasome inhibitor carfilzomib and the third-generation IMiD pomalidomide, have recently been approved, along with novel agents like the KSP inhibitor ARRY-520 and HDAC inhibitors, showing potential in improving outcomes for patients with this challenging condition.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Novel approaches to treatment of double-refractory multiple myeloma. Lee, HC., Shah, JJ., Orlowski, RZ.[2022]

MLN9708 (ixazomib citrate) effectively inhibits the formation and activity of osteoclasts, which are responsible for bone resorption, by blocking RANKL-induced NF-κB activation, suggesting it may help protect against bone loss in myeloma patients.

In preclinical models, MLN9708 not only controlled tumor growth similarly to bortezomib but also promoted bone formation, indicating it has both anti-myeloma and bone anabolic effects, making it a promising treatment for myeloma-related bone disease.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Preclinical activity of the oral proteasome inhibitor MLN9708 in Myeloma bone disease. Garcia-Gomez, A., Quwaider, D., Canavese, M., et al.[2021]

Proteasome inhibitors like bortezomib and carfilzomib have greatly improved survival and quality of life for multiple myeloma patients, but many still develop resistance to these treatments.

A newly designed carfilzomib analog showed strong effectiveness against cancer cells that are resistant to the original drug, suggesting that modifications to proteasome inhibitors could help overcome resistance and offer new treatment options.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Development of Novel Epoxyketone-Based Proteasome Inhibitors as a Strategy To Overcome Cancer Resistance to Carfilzomib and Bortezomib. Lee, MJ., Bhattarai, D., Yoo, J., et al.[2020]

The novel tubulin polymerisation inhibitor CYT997 shows promising anti-myeloma activity by disrupting tubulin, inhibiting growth, causing cell cycle arrest, and inducing apoptosis in both human myeloma cell lines and primary multiple myeloma cells at low concentrations.

CYT997 not only demonstrates effectiveness on its own but also works synergistically with bortezomib, enhancing anti-myeloma effects, and has been shown to significantly prolong survival in a murine model of aggressive systemic myelomatosis.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

CYT997 causes apoptosis in human multiple myeloma. Monaghan, K., Khong, T., Smith, G., et al.[2021]

MMSET protein is highly expressed in various tumor types, including gastrointestinal, lung, bladder, and skin cancers, indicating its potential role in cancer progression.

In bladder cancer, high MMSET expression correlates with tumor aggressiveness, while in colon cancer, it is associated with early dysplastic stages but predicts worse survival in patients with high levels, suggesting its complex role as a prognostic marker.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The histone methyltransferase and putative oncoprotein MMSET is overexpressed in a large variety of human tumors. Hudlebusch, HR., Santoni-Rugiu, E., Simon, R., et al.[2019]

MMSET is overexpressed in multiple myeloma patients with the t(4;14) translocation and acts as a key regulator of chromatin structure and gene transcription in these cancer cells.

High levels of MMSET lead to specific changes in histone methylation patterns that promote cell growth and survival, while loss of MMSET expression can trigger cell death and alter adhesion properties, highlighting its role as an important epigenetic regulator in multiple myeloma.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The MMSET histone methyl transferase switches global histone methylation and alters gene expression in t(4;14) multiple myeloma cells. Martinez-Garcia, E., Popovic, R., Min, DJ., et al.[2021]

LEM-06 is a newly discovered small molecule inhibitor of the NSD2 enzyme, showing an IC50 of 0.8 mM in inhibiting H3K36 methylation in vitro, which is significant for targeting multiple myeloma.

This research highlights the potential of LEM-06 and its derivatives as therapeutic options against multiple myeloma, particularly for the aggressive t(4;14) subtype, where effective treatments are urgently needed.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Inhibition of Nuclear Receptor Binding SET Domain 2/Multiple Myeloma SET Domain by LEM-06 Implication for Epigenetic Cancer Therapies. di Luccio, E.[2020]

MMSET, a protein overexpressed in multiple myeloma due to a specific genetic fusion, has methyltransferase activity that modifies histones, which plays a crucial role in regulating gene expression.

Knockdown of MMSET in myeloma cells reduces their viability, indicating that MMSET is important for the growth of these cancer cells and may contribute to the disease's progression.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The MMSET protein is a histone methyltransferase with characteristics of a transcriptional corepressor. Marango, J., Shimoyama, M., Nishio, H., et al.[2021]

The t(4; 14) chromosomal translocation is a significant factor in multiple myeloma, leading to poor prognosis due to the overexpression of the oncogenes FGFR3 and MMSET, with MMSET being universally expressed in affected patients.

Recent research highlights the oncogenic role of MMSET in multiple myeloma, particularly its influence on histone methylation, suggesting that targeting MMSET could be a promising therapeutic strategy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

MMSET: role and therapeutic opportunities in multiple myeloma. Xie, Z., Chng, WJ.[2021]

Citations

1. Netherlands pubmed.ncbi.nlm.nih.gov

From the bench to the bedside: emerging new treatments in multiple myeloma. [2023]

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

Novel approaches to treatment of double-refractory multiple myeloma. [2022]

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

Preclinical activity of the oral proteasome inhibitor MLN9708 in Myeloma bone disease. [2021]

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

Development of Novel Epoxyketone-Based Proteasome Inhibitors as a Strategy To Overcome Cancer Resistance to Carfilzomib and Bortezomib. [2020]

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

CYT997 causes apoptosis in human multiple myeloma. [2021]

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

The histone methyltransferase and putative oncoprotein MMSET is overexpressed in a large variety of human tumors. [2019]

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

The MMSET histone methyl transferase switches global histone methylation and alters gene expression in t(4;14) multiple myeloma cells. [2021]

8. Korea (South) pubmed.ncbi.nlm.nih.gov

Inhibition of Nuclear Receptor Binding SET Domain 2/Multiple Myeloma SET Domain by LEM-06 Implication for Epigenetic Cancer Therapies. [2020]

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

The MMSET protein is a histone methyltransferase with characteristics of a transcriptional corepressor. [2021]

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

MMSET: role and therapeutic opportunities in multiple myeloma. [2021]