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 drug, KTX-1001 (an MMSET inhibitor), to determine its safety for treating multiple myeloma, a type of blood cancer, in patients unresponsive to other treatments. Researchers are exploring different combinations of KTX-1001 with other medicines to identify the most effective mix. Individuals who have tried at least three different treatments for multiple myeloma without success and possess a specific genetic marker (t(4;14)) might be suitable candidates for this trial. As a Phase 1 trial, participants will be among the first to receive this new treatment, aiding researchers in understanding its effects in people.

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.

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

Research has shown that KTX-1001 is a new treatment being tested for safety in treating multiple myeloma, a type of blood cancer. Past studies provide limited direct information about its safety in humans. As this is an early-stage study, the primary goal is to assess how well participants tolerate the treatment and to identify any side effects.

KTX-1001 works by blocking a protein called NSD2, which is often found in high amounts in some cancers. By targeting NSD2, KTX-1001 aims to stop cancer cells from growing.

For those considering joining this study, it is important to know that early studies primarily focus on safety. Researchers are still learning about possible side effects. Joining a clinical trial at this stage involves some uncertainty but also offers a chance to help discover new treatments for multiple myeloma. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about KTX-1001 for multiple myeloma because it targets the MMSET protein, which is often overactive in this type of cancer, offering a novel mechanism of action compared to current treatments like proteasome inhibitors and immunomodulatory drugs. Unlike standard therapies, which primarily target the cancer cells directly, KTX-1001 aims to interfere with the underlying genetic drivers of the disease, potentially leading to more effective and lasting responses. Additionally, KTX-1001 is being tested in various combinations, including with carfilzomib, mezigdomide, and pomalidomide, potentially enhancing its efficacy and offering new options for patients with different treatment needs.

What evidence suggests that this trial's treatments could be effective for multiple myeloma?

Research shows that KTX-1001 is a promising treatment for multiple myeloma, a type of blood cancer. In early lab studies, KTX-1001 successfully lowered levels of a specific protein change linked to cancer cell growth, causing these cancer cells to die. The drug blocks a protein called MMSET, which helps cancer cells survive. In this trial, participants may receive KTX-1001 with other treatments like carfilzomib, mezigdomide, or pomalidomide, and these combinations have shown potential in stopping tumor growth. Early research also suggests that KTX-1001 is well tolerated, meaning it does not cause severe side effects. These findings provide hope that KTX-1001 could be an effective option for those with relapsed or hard-to-treat multiple myeloma. ^{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.

I had a stem cell transplant less than 6 months ago or have ongoing GVHD.

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/KYPROLIS®): KTX-1001 + carfilzomib + dex Experimental Treatment 1 Intervention

Cohort C1 (carfilzomib/KYPROLIS®): KTX-1001 at RP2D1 + carfilzomib + dex Cohort C2 (carfilzomib/KYPROLIS®): 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

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]

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]

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]

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]

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]

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 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]

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. ashpublications.org ashpublications.org/blood/article/144/Supplement%201/3370/532698/First-Results-from-the-Dose-Escalation-Part-of-the

First Results from the Dose Escalation Part of the Phase 1 ... KTX-1001 is a first-in-class, selective and potent small molecule inhibitor of MMSET, and is the first investigational drug that targets the t(4 ...

2. clinicaltrials.gov clinicaltrials.gov/study/NCT05651932

NCT05651932 | A Study of an MMSET Inhibitor in Patients ... A Phase I study to evaluate the safety of a novel, orally available, selective, and potent small molecule inhibitor of the histone lysine methyl transferase ...

3. prnewswire.com prnewswire.com/news-releases/k36-therapeutics-provides-clinical-update-on-ktx-1001-in-multiple-myeloma-302556647.html

K36 Therapeutics Provides Clinical Update on KTX-1001 ... In preclinical models, KTX-1001 reduced H3K36me2 levels in t(4;14) multiple myeloma, suppressed tumor growth and triggered cancer cell death in ...

4. ashpublications.org ashpublications.org/blood/article/142/Supplement%201/3391/503584/Trial-in-Progress-A-Phase-1-Study-of-KTX-1001-an

Trial in Progress: A Phase 1 Study of KTX-1001, an Oral, First ... KTX-1001 had favorable drug-like properties, demonstrated in vivo activity, and was well tolerated in non-clinical studies. Based on these data ...

5. sciencedirect.com sciencedirect.com/science/article/abs/pii/S0006497124046251

Ktx-1029, a Potent, Selective MMSET/NSD2 Inhibitor Is ... Here we report the biological characterization and efficacy of KTX-1029 in preclinical MM models. Results:KTX-1029 inhibited MMSET activity with ...

6. pubchem.ncbi.nlm.nih.gov pubchem.ncbi.nlm.nih.gov/compound/KTX-1001-D-tartrate

KTX-1001 D-tartrate | C29H32F4N8O8 - PubChem - NIH KTX-1001 D-tartrate | C29H32F4N8O8 | CID 168429488 - structure, chemical names, physical and chemical properties, classification, patents, literature, ...

7. go.drugbank.com go.drugbank.com/drugs/DB18171

KTX-1001: Uses, Interactions, Mechanism of Action (S)-1-((R)-3-amino-1-(4-((6-amino-9H-purin-9-yl)methyl)-6-(2,5-difluoro-4-methoxyphenyl)pyridin-3-yl)piperidin-3-yl)-2,2-difluoroethan-1-ol.

8. gsrs.ncats.nih.gov gsrs.ncats.nih.gov/ginas/app/beta/substances/8T4LU8M9TG

KTX-1001 D-TARTRATE Chemical Moieties ; Molecular Formula: C4H6O ; Molecular Weight: 150.09 ; Charge: 0 ; Count: MOL RATIO. 1 MOL RATIO (average).

9. medkoo.com medkoo.com/products/54688

KTX-1001 | CAS# 2604513-16-6 | NSD2 Inhibitor KTX-1001 is a potent NSD2 inhibitor that targets and inhibits NSD2, which is overexpressed in many cancers.

10. go.drugbank.com go.drugbank.com/salts/DBSALT003427

KTX-1001 D-tartrate Synonyms: (S)-1-((R)-3-amino-1-(4-((6-amino-9H-purin-9-yl)methyl)-6-(2,5-difluoro-4-methoxyphenyl)pyridin-3-yl)piperidin-3-yl)-2,2-difluoroethan-1-ol D ...