KRT-232 or TL-895 for Myelofibrosis

Not currently recruiting at 37 trial locations

Overseen By Jordan Blevins

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: Kartos Therapeutics, Inc.

Must not be taking: JAK inhibitors, MDM2 inhibitors

Disqualifiers: p53 mutation, Major organ 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: Unknown

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests two new treatments, KRT-232 (Navtemadlin) and TL-895, for individuals with myelofibrosis, a rare bone marrow disorder. The goal is to assess the safety and effectiveness of these treatments for those who haven't tried other therapies. Participants will take either KRT-232 for a week each month or TL-895 daily. This trial suits individuals diagnosed with myelofibrosis, rated as high or intermediate risk, who haven't received certain other treatments. As a Phase 2 trial, the research focuses on measuring the treatment's effectiveness in an initial, smaller group.

Will I have to stop taking my current medications?

The trial information does not specify if you need to stop taking your current medications. However, it excludes those who have had certain treatments like JAK inhibitors or MDM2 inhibitors, which might suggest some restrictions.

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

Research has shown that KRT-232, also known as navtemadlin, is generally safe for people with myelofibrosis. In earlier studies, patients who no longer responded to other treatments, such as JAK inhibitors, tolerated navtemadlin well. These studies also indicated that navtemadlin could improve the condition by reducing spleen size in some patients.

TL-895 is a newer treatment belonging to a group of medicines called tyrosine kinase inhibitors, which block certain proteins that help cancer cells grow. Early studies suggested that patients taking TL-895 did not experience severe side effects, and most tolerated the treatment well over several months. This suggests a promising safety profile, but more research is needed to confirm these results.

Both treatments, KRT-232 and TL-895, appear promising with manageable safety profiles based on earlier studies. However, those considering joining a trial should discuss potential risks and benefits with their healthcare provider. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about KRT-232 and TL-895 for treating myelofibrosis because they offer unique approaches compared to current options like JAK inhibitors. KRT-232 stands out by targeting the MDM2 protein, which plays a role in cell growth and survival, potentially leading to more effective control of the disease. TL-895, on the other hand, is a BTK inhibitor that works continuously to disrupt cancer cell signaling, which could provide more consistent disease management. Both treatments provide new avenues for tackling myelofibrosis, offering hope for improved outcomes.

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

Research has shown that KRT-232, also known as navtemadlin, may help treat myelofibrosis. Studies indicate it can significantly shrink the spleen and improve symptoms for patients unresponsive to other treatments. KRT-232 works by blocking a protein called MDM2, which is involved in cell growth. In this trial, some participants will receive KRT-232. Meanwhile, TL-895 is a new drug that blocks certain proteins. Early studies suggest it can help with symptoms and may improve survival in some myelofibrosis patients. Other participants in this trial will receive TL-895. Researchers are carefully studying both treatments to understand their full potential. ^{1 3 4 6 7}

Are You a Good Fit for This Trial?

This trial is for patients with myelofibrosis who haven't had treatment before. They should have a confirmed diagnosis of primary or secondary myelofibrosis, be at high-risk or intermediate risk according to DIPSS, and have good physical functioning (ECOG 0-1). People can't join if they've had certain previous treatments like JAK inhibitors, splenectomy, stem-cell transplant, or if they have specific mutations (p53), heart issues (QTc prolongation), or recent major bleeding.

Inclusion Criteria

I am fully active or can carry out light work.

I have been diagnosed with a form of myelofibrosis.

My condition is classified as high or intermediate risk by DIPSS.

Exclusion Criteria

I have not had radiation to my spleen in the last 6 months.

I have had or plan to have a stem-cell transplant from a donor.

I have had my spleen removed.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Stage 1 Treatment

Stage 1 evaluates safety, tolerability, and efficacy of KRT-232 or TL-895 in treatment naïve patients

24 weeks

Monthly visits (in-person)

Stage 2 Treatment

Stage 2 expands enrollment in Arm 1 and/or Arm 2 if expansion criteria is met

24 weeks

Monthly visits (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment

48 months

What Are the Treatments Tested in This Trial?

Interventions

• KRT-232
• TL-895

Trial Overview The study tests two drugs: KRT-232 and TL-895 in people who haven’t received any prior treatment for myelofibrosis. It's split into two stages; the first checks safety and effectiveness of each drug separately. If successful, stage two will continue with more participants in either one or both groups.

How Is the Trial Designed?

Group I: Arm 2 Experimental Treatment 1 Intervention

TL-895 administered orally as 150 mg twice daily continuously in 28-day cycles

Group II: Arm 1 Experimental Treatment 1 Intervention

KRT-232 administered orally as 240 mg once daily on Days 1-7, off treatment on Days 8-28, in 28-day treatment cycles

Who Is Running the Clinical Trial?

Kartos Therapeutics, Inc.

Lead Sponsor

Trials

17

Recruited

2,100+

Published Research Related to This Trial

Research on myelofibrosis (MF) is advancing rapidly, with numerous novel agents in clinical trials that target various mechanisms, including epigenetic regulation and intracellular signaling, building on the success of ruxolitinib.

New treatment strategies are being developed, such as combining ruxolitinib with agents like luspatercept to manage anemia, and exploring non-JAK inhibitors for second-line therapy, which could significantly improve patient outcomes and address unmet clinical needs.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

SOHO State of the Art Updates and Next Questions: Novel Therapies in Development for Myelofibrosis. Chifotides, HT., Bose, P., Masarova, L., et al.[2022]

In a study of 1607 patients with essential thrombocythemia (ET), several clinical and molecular factors were identified as predictors of inferior myelofibrosis-free survival, including age over 60, male sex, palpable splenomegaly, and specific genetic mutations.

A new 'high molecular risk' category was established for patients with certain genetic profiles, showing significantly higher rates of fibrotic transformation over 10 and 20 years, indicating the need for closer monitoring and counseling for these patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Clinical and molecular predictors of fibrotic progression in essential thrombocythemia: A multicenter study involving 1607 patients. Loscocco, GG., Guglielmelli, P., Gangat, N., et al.[2022]

In a study of 61 patients with myelofibrosis, momelotinib showed promising efficacy with a 72% spleen response rate and a 45% anemia response rate, indicating its potential as a treatment option.

The most common side effects included diarrhea and peripheral neuropathy, but overall, momelotinib was well-tolerated, and it significantly reduced inflammatory cytokines, suggesting a beneficial mechanism of action.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A phase 1/2, open-label study evaluating twice-daily administration of momelotinib in myelofibrosis. Gupta, V., Mesa, RA., Deininger, MW., et al.[2019]

In a phase 2 trial involving 34 patients with myelofibrosis who did not respond to ruxolitinib, 32.4% achieved a significant reduction in spleen volume after 24 weeks of treatment with jaktinib, indicating its potential efficacy for ruxolitinib-refractory patients.

Jaktinib also improved hemoglobin levels in 50% of transfusion-independent patients with low baseline hemoglobin and reduced overall symptoms in 46.4% of patients, although it was associated with notable adverse events like thrombocytopenia and anemia.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety and efficacy of jaktinib (a novel JAK inhibitor) in patients with myelofibrosis who are relapsed or refractory to ruxolitinib: A single-arm, open-label, phase 2, multicenter study. Zhang, Y., Zhang, Q., Liu, Q., et al.[2023]

JAK2 inhibitors, particularly ruxolitinib, have significantly improved the quality of life and overall survival for patients with myelofibrosis (MF), and new therapies like pacritinib and momelotinib are expanding treatment options with unique mechanisms of action.

Novel agents and combinations are currently in advanced clinical trials, aiming to address unmet needs such as anemia and cytopenias, with a focus on improving overall survival and achieving transfusion independence as meaningful endpoints.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

SOHO State of the Art Updates and Next Questions: Novel Therapeutic Strategies in Development for Myelofibrosis. Chifotides, HT., Masarova, L., Verstovsek, S.[2023]

The study introduces a non-invasive immunoassay for measuring procollagen III aminoterminal peptide levels in serum, which can help assess bone marrow involvement in myelofibrosis, based on a sample of 93 individuals (25 healthy controls, 48 with polycythemia vera, and 20 with myelofibrosis).

Patients with myelofibrosis showed significantly higher levels of this propeptide (average 38.1 ng/ml) compared to controls (7.6 ng/ml) and those with polycythemia vera (9.9 ng/ml), indicating its potential as a sensitive biomarker for disease progression and response to treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Development of polycythemia to myelofibrosis. Monitoring by the assay of the procollagen III amino-propeptide]. Arrago, JP., Poirier, O., Najean, Y.[2016]

Myelofibrosis (MF) is a complex blood disorder with various forms, and recent advancements in understanding its genetic drivers have led to the development of targeted therapies like JAK2 inhibitors, although their use can be limited by side effects such as anemia.

New treatments, including pacritinib for thrombocytopenic patients and momelotinib for symptomatic patients, show promise in managing MF symptoms and anemia, with ongoing research into novel therapies that may improve outcomes for patients resistant to current treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Novel therapeutics for myelofibrosis. Lee, SE.[2023]

In a phase 2 study involving 39 patients with polycythemia vera (PV) and essential thrombocythemia (ET), momelotinib showed limited efficacy, with only 5.1% of patients meeting the primary efficacy endpoint after treatment.

The treatment was associated with a high incidence of adverse events, affecting 79.5% of patients, with common side effects including headache, dizziness, and fatigue, indicating a need for careful monitoring of safety in future studies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A phase 2 study of momelotinib, a potent JAK1 and JAK2 inhibitor, in patients with polycythemia vera or essential thrombocythemia. Verstovsek, S., Courby, S., Griesshammer, M., et al.[2021]

In a phase 1/2 trial involving 100 patients with high/intermediate-risk myelofibrosis, treatment with the JAK1/2 inhibitor momelotinib led to clinical improvement in 57% of patients, particularly in those without ASXL1 mutations and with low circulating blasts.

Despite some patients experiencing significant side effects, such as thrombocytopenia and peripheral neuropathy, the overall survival after discontinuation of momelotinib was similar to that of a comparable group of patients not receiving the treatment, suggesting that while momelotinib may provide some benefits, it does not significantly alter long-term outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Momelotinib therapy for myelofibrosis: a 7-year follow-up. Tefferi, A., Barraco, D., Lasho, TL., et al.[2020]

Citations

1. ashpublications.org ashpublications.org/blood/article/144/Supplement%201/1000/530415/Results-from-the-Randomized-Multicenter-Global

Results from the Randomized, Multicenter, Global Phase 3 ... In this phase 3 study, navtemadlin monotherapy was safe and effective, demonstrating clinically relevant efficacy with disease-modifying ...

2. ascopost.com ascopost.com/issues/february-25-2025/boreas-trial-navtemadlin-demonstrates-clinical-benefit-in-jak-inhibitor-refractory-myelofibrosis/

BOREAS Trial Navtemadlin Demonstrates Clinical Benefit ... Findings from the phase III BOREAS study showed navtemadlin nearly tripled spleen volume reductions and doubled symptom score improvements ...

3. targetedonc.com targetedonc.com/view/navtemadlin-monotherapy-shows-improvements-in-hallmarks-of-r-r-myelofibrosis

Navtemadlin Monotherapy Shows Improvements in ... Navtemadlin, a novel MDM2 inhibitor, demonstrated potential in treating relapsed or refractory myelofibrosis in the phase 3 BOREAS trial.

4. onclive.com onclive.com/view/navtemadlin-will-be-evaluated-as-add-on-therapy-to-ruxolitinib-in-myelofibrosis

Navtemadlin Will Be Evaluated as Add-On Therapy to ... KRT-232-109 study identified navtemadlin's recommended phase 2 dose and demonstrated its efficacy as an add-on to ruxolitinib.

5. clinicaltrials.gov clinicaltrials.gov/study/NCT03662126

Study Details | NCT03662126 | KRT-232 Versus Best ... This study evaluates KRT-232, a novel oral small molecule inhibitor of MDM2, for the treatment of patients with myelofibrosis (MF) who no longer benefit from ...

6. targetedonc.com targetedonc.com/view/navtemadlin-monotherapy-shows-safety-efficacy-in-r-r-myelofibrosis

Navtemadlin Monotherapy Shows Safety, Efficacy in R/R ... Navtemadlin monotherapy demonstrated safety and efficacy in patients with myelofibrosis (MF) who were relapsed or refractory to JAK inhibitors.

7. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/36416118/

a global, phase III study of the MDM2 inhibitor navtemadlin ... Navtemadlin demonstrated promising clinical and disease-modifying activity and acceptable safety in a phase II study in patients with relapsed/ ...