KRT-232 + TL-895 for Myelofibrosis

Not currently recruiting at 39 trial locations

Overseen By Irene Dea

Age: 18+

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: Kartos Therapeutics, Inc.

Must not be taking: MDM2 inhibitors, p53 therapies

Disqualifiers: Splenectomy, Thrombosis, QTc prolongation, others

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

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 treatments, KRT-232 (Navtemadlin) and TL-895, to determine their effectiveness for people with myelofibrosis, a type of bone marrow cancer. It targets those whose myelofibrosis has returned or has not responded to previous treatments, specifically JAK inhibitors. The trial includes different groups, with some participants receiving both drugs and others only KRT-232. Individuals diagnosed with myelofibrosis who did not respond well to JAK inhibitors or cannot tolerate them might be suitable candidates for this trial. As a Phase 1/Phase 2 trial, the study aims to understand how the treatments work in people and measure their effectiveness in an initial, smaller group, offering participants a chance to contribute to important research.

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

The trial does not specify if you need to stop taking your current medications. However, you cannot have had certain treatments like MDM2 inhibitors or p53-directed therapies before joining.

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, was safe and tolerable in earlier studies. Common side effects included mild nausea, diarrhea, and vomiting. Some patients experienced more serious issues like low blood platelet levels, but these were less common.

Studies have also found TL-895 to be well-tolerated. As a selective inhibitor, it targets specific proteins related to the disease. In one study, most participants managed the treatment well over several months.

While both KRT-232 and TL-895 have demonstrated promising safety in past research, this current trial will provide more detailed safety information about using them together to treat myelofibrosis. ^{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 these drugs offer novel approaches compared to current options like JAK inhibitors. KRT-232 targets the MDM2-p53 interaction, potentially restoring the tumor-suppressing activity of p53, which is a mechanism not utilized by existing treatments. TL-895, a BTK inhibitor, is unique in its dual administration method, either once or twice daily, which could provide greater flexibility and effectiveness for patients with different needs. Together, these treatments could offer a more targeted and potentially more effective approach for patients who are resistant or intolerant to existing therapies.

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, a type of bone marrow cancer. Earlier studies found that it significantly reduced spleen size and improved symptoms in patients who no longer benefited from JAK inhibitors, a common treatment for this condition. KRT-232 works by blocking MDM2, a protein that helps cancer cells survive.

In this trial, participants will receive different combinations of KRT-232 and TL-895. TL-895 is a selective tyrosine kinase inhibitor, meaning it blocks certain enzymes that help cancer cells grow. Although not everyone experienced a reduction in spleen size, some patients did find relief from symptoms. These findings suggest that the combination of KRT-232 and TL-895 could effectively manage myelofibrosis. ^{2 3 6 7 8}

Are You a Good Fit for This Trial?

This trial is for adults with a confirmed diagnosis of primary or secondary myelofibrosis who have either not responded to JAK inhibitor treatment or cannot tolerate it. Participants should be relatively active (ECOG ≤ 2) and haven't had certain treatments like BCR-ABL inhibitors, splenectomy, or specific cancer therapies recently.

Inclusion Criteria

I cannot tolerate JAK inhibitor treatment.

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

I have relapsed or didn't respond after JAK inhibitor treatment.

Exclusion Criteria

I have previously been treated with MDM2 inhibitors or p53 therapies.

I have had my spleen removed.

I have not had radiation to my spleen in the last 3 months.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Dose Escalation

Cohorts 1 and 2 undergo a 3+3 dose escalation design to determine the MTD/MAD and RP2D of TL-895 in combination with KRT-232

8 weeks

Regular safety reviews by SRC

Dose Expansion

Cohort 3 undergoes a 2-stage design with expansion based on responder criteria

24 weeks

Regular assessments and safety reviews

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

What Are the Treatments Tested in This Trial?

Interventions

• KRT-232
• TL-895

Trial Overview The study is testing KRT-232 in combination with TL-895 for those whose myelofibrosis has relapsed after treatment, as well as KRT-232 alone for patients intolerant to JAK inhibitors. It aims to evaluate the effectiveness and safety of these combinations.

How Is the Trial Designed?

Group I: Cohort 3 (JAKi Intolerant MF) Experimental Treatment 1 Intervention

KRT-232 at 240mg will be administered orally, once daily (QD), on days 1-7 in a 28-day cycle.

Group II: Cohort 2 (R/R MF), Dose Level 2 Experimental Treatment 2 Interventions

TL-895 at 150 mg twice a day (BID) continuously starting on Cycle 1 Day 1 in a 28-day cycle. KRT-232 at 240mg will be administered orally, once daily (QD), on days 1-7 in a 28-day cycle starting on Cycle 2 Day 1.

Group III: Cohort 2 (R/R MF), Dose Level 1 Experimental Treatment 2 Interventions

TL-895 at 100 mg twice a day (BID) continuously starting on Cycle 1 Day 1 in a 28-day cycle. KRT-232 at 240mg will be administered orally, once daily (QD), on days 1-7 in a 28-day cycle starting on Cycle 2 Day 1.

Group IV: Cohort 1 (R/R MF), Dose Level 2 Experimental Treatment 2 Interventions

TL-895 at 300 mg once a day (QD) continuously starting on Cycle 1 Day 1 in a 28-day cycle. KRT-232 at 240mg will be administered orally, once daily (QD), on days 1-7 in a 28-day cycle starting on Cycle 2 Day 1.

Group V: Cohort 1 (R/R MF), Dose Level 1 Experimental Treatment 2 Interventions

TL-895 at 200 mg once a day (QD) continuously starting on Cycle 1 Day 1 in a 28-day cycle. KRT-232 240mg will be administered orally, once daily (QD), on days 1-7 in a 28-day cycle starting on Cycle 2 Day 1.

Who Is Running the Clinical Trial?

Kartos Therapeutics, Inc.

Lead Sponsor

Trials

17

Recruited

2,100+

Telios Pharma, Inc.

Industry Sponsor

Trials

11

Recruited

1,700+

Published Research Related to This Trial

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]

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 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]

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]

Ruxolitinib, an oral JAK1/JAK2 inhibitor, has been the standard treatment for intermediate or high-risk myelofibrosis (MF) since its FDA approval in 2011, demonstrating significant efficacy in improving patient outcomes based on data from the phase 3 COMFORT trials.

The review highlights the importance of dose optimization and management of common side effects, such as anemia and thrombocytopenia, to maximize the safety and clinical benefits of ruxolitinib, supported by findings from subsequent trials like JUMP, ROBUST, EXPAND, and REALISE.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Ten years of treatment with ruxolitinib for myelofibrosis: a review of safety. Verstovsek, S., Mesa, RA., Livingston, RA., et al.[2023]

INCB018424, a JAK2 inhibitor, has shown significant clinical activity in treating myelofibrosis (MF), leading to rapid reductions in spleen size and improvements in symptoms for patients taking 10-25 mg twice daily.

The treatment was generally well tolerated, with reversible thrombocytopenia occurring in 30% of patients at the higher dose, while it was not observed at the lower dose, indicating a manageable safety profile.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

JAK2 inhibitors: A reality? A hope? Apostolidou, E., Kantarjian, HM., Verstovsek, S.[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]

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]

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 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]

Primary myelofibrosis (PMF) is linked to specific genetic mutations, with type 1-like CALR mutations associated with a better prognosis, while others like ASXL1 and SRSF2 indicate worse outcomes, highlighting the importance of genetic profiling in treatment decisions.

Allogeneic stem cell transplantation is currently the only treatment that can significantly extend survival in PMF, while existing drug therapies, including JAK2 inhibitors, primarily address symptoms rather than the underlying disease, indicating a need for more effective targeted therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Myelofibrosis: Genetic Characteristics and the Emerging Therapeutic Landscape. Tefferi, A., Gangat, N., Pardanani, A., et al.[2023]

Citations

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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 ...

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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 ...

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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.

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BOREAS Trial Navtemadlin Demonstrates Clinical Benefit ... In the phase III BOREAS trial, navtemadlin significantly improved spleen volume reduction and symptom control in patients with JAK inhibitor– ...

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

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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.

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BOREAS: A global phase 3 study of KRT-232, a first-in- ... KRT-232 demonstrated a tolerable safety profile that included prophylaxis for nausea/vomiting (Al-Ali. EHA 2020). Methods: BOREAS is a ...

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KRT-232-109: Navtemadlin plus ruxolitinib in MF with a ... Safety · The most common gastrointestinal toxicities were Grade 1–2 nausea, diarrhea, and vomiting. · Grade 3/4 TEAEs included thrombocytopenia ( ...