KRT-232 for Myelofibrosis

(BOREAS Trial)

Recruiting at 229 trial locations

Overseen By John Mei

Age: 18+

Sex: Any

Trial Phase: Phase 2 & 3

Sponsor: Kartos Therapeutics, Inc.

Disqualifiers: Splenectomy, Hemorrhage, Stroke, 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: 49

385 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a new treatment called KRT-232 (Navtemadlin) for individuals with myelofibrosis, a bone marrow disorder that disrupts normal blood cell production. It targets patients who no longer benefit from JAK inhibitor treatments. The trial seeks to determine the optimal dose and schedule for KRT-232 and then compare it to other therapies selected by doctors. Individuals with myelofibrosis who have not responded to JAK inhibitors may be suitable candidates for this trial. As a combined Phase 2 and Phase 3 trial, this research measures the treatment's effectiveness in an initial, smaller group and represents the final step before FDA approval, offering hope for effective new options.

Will I have to stop taking my current medications?

The trial information does not specify if you need to stop taking your current medications. It's best to discuss this with the trial coordinators or your doctor.

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

Research has shown that KRT-232, a pill for patients with myelofibrosis (MF), is generally safe. In studies involving patients who no longer benefit from JAK inhibitors, KRT-232 was well-tolerated. The main side effects were mild to moderate, including tiredness, nausea, and low blood counts, which are common with cancer treatments. These studies did not directly link any serious side effects to KRT-232. This evidence suggests that KRT-232 is generally safe for patients with MF, particularly for those with limited treatment options. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about KRT-232 for myelofibrosis because it offers a new approach by targeting the MDM2-p53 pathway. Most current treatments, like JAK inhibitors, focus on different pathways and don't address this specific mechanism. KRT-232's unique action could potentially overcome resistance seen with current therapies and provide a new option for patients with limited alternatives. Additionally, the oral administration of KRT-232 offers ease of use compared to some traditional intravenous treatments, making it a convenient choice for patients.

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, particularly for patients who no longer benefit from JAK inhibitors. In this trial, participants may receive KRT-232 in different dosing schedules, such as Part A Cohort 1 or Part B Arm 1. One study found that this treatment almost tripled the reduction in spleen size and doubled symptom improvements compared to other therapies. Another study found that after 12 weeks, patients taking navtemadlin experienced a significant reduction in important disease markers. These findings suggest that KRT-232 could be an effective option for people with myelofibrosis, potentially improving symptoms and disease features. Meanwhile, another group in this trial will receive the Best Available Therapy (BAT) as determined by the investigator, providing a comparison to assess the effectiveness of KRT-232. ^{4 6 7 8 9}

Are You a Good Fit for This Trial?

This trial is for patients with myelofibrosis who haven't responded to JAK inhibitor treatment. They should have a performance status score of 2 or less, indicating they can perform daily activities with some effort. The trial excludes those with significant heart issues, recent major organ transplants, brain injuries or strokes within the past 6 months, prior splenectomy, and previous treatments targeting MDM2 or p53.

Inclusion Criteria

My condition is classified as high, intermediate-2, or intermediate-1 risk.

I have been diagnosed with a form of myelofibrosis.

I have been treated with a JAK inhibitor, but it did not work for me.

Exclusion Criteria

I have previously received MDM2 or p53-targeted therapy.

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

Phase 2 Treatment

Phase 2 will determine the KRT-232 recommended dose and dosing schedule

24 weeks

21-day or 28-day cycles

Phase 3 Treatment

Phase 3 will test KRT-232 vs Best Available Therapy (BAT) with an option to cross-over to KRT-232 after 6 months

24 weeks

28-day cycles

Follow-up

Participants are monitored for safety and effectiveness after treatment

48 weeks

What Are the Treatments Tested in This Trial?

Interventions

• Best Available Therapy (BAT)
• KRT-232

Trial Overview The study tests KRT-232 against Best Available Therapy (BAT) in myelofibrosis patients unresponsive to JAK inhibitors. Phase 2 determines the optimal dose of KRT-232; Phase 3 compares its effectiveness to BAT chosen by physicians. Participants are randomly assigned in a 2:1 ratio favoring KRT-232 and may switch from BAT to KRT-232 if needed.

How Is the Trial Designed?

Group I: Part B Arm 1 KRT-232 Experimental Treatment 1 Intervention

KRT-232 240 mg by mouth once daily for Days 1-7, off treatment for Days 8-28 (28-day cycles)

Group II: Part A Cohort 4b Experimental Treatment 1 Intervention

KRT-232 240 mg by mouth once daily for Days 1-5, off treatment for Days 6-28 (28-day cycles)

Group III: Part A Cohort 3 Experimental Treatment 1 Intervention

KRT-232 240 mg by mouth once daily for Days 1-7, off treatment for Days 8-28 (28-day cycles)

Group IV: Part A Cohort 2 Experimental Treatment 1 Intervention

KRT-232 240 mg by mouth once daily for Days 1-7, off treatment for Days 8-21 (21-day cycles)

Group V: Part A Cohort 1 Experimental Treatment 1 Intervention

KRT-232 120 mg by mouth once daily for Days 1-7, off treatment for Days 8-21 (21-day cycles)

Group VI: Part B Arm 2 Best Available Therapy Active Control 1 Intervention

Best available therapy at the discretion of the investigator, on a 28-day cycle.

Who Is Running the Clinical Trial?

Kartos Therapeutics, Inc.

Lead Sponsor

Trials

17

Recruited

2,100+

Published Research Related to This Trial

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]

JAK inhibitors are the primary treatment for myelofibrosis, effectively reducing symptoms and spleen size, but they do not significantly alter disease progression and can worsen blood cell counts in some patients.

Research is ongoing for new therapies targeting different mechanisms, such as epigenetic modification and apoptosis, which may offer alternatives for patients who cannot tolerate JAK inhibitors.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Novel treatments for myelofibrosis: beyond JAK inhibitors. Tremblay, D., Mesa, R.[2022]

JAK inhibitors have significantly improved treatment options for myelofibrosis (MF) by alleviating symptoms, reducing spleen size, and enhancing quality of life, although they may lead to worsening blood cell counts (cytopenias).

Despite their benefits, JAK inhibitors do not stop disease progression or prevent the transformation to leukemia, and their impact on overall survival remains uncertain.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

JAK inhibitors in the treatment of myelofibrosis. Levavi, H., Hoffman, R., Marcellino, BK.[2022]

The discovery of the JAK2 V617F mutation has led to the development of targeted therapies for myelofibrosis (MF), with ruxolitinib being the first approved drug that significantly improves symptoms, reduces spleen size, and enhances survival in patients.

Several new JAK2 inhibitors and other therapeutic agents are in advanced testing stages, aiming to provide additional benefits over ruxolitinib, particularly in managing anemia and other disease features, marking a significant evolution in MF treatment options.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The new landscape of therapy for myelofibrosis. Gowin, K., Emanuel, R., Geyer, H., et al.[2021]

Selective JAK2 inhibitors have shown significant efficacy in reducing symptoms and splenomegaly in myelofibrosis patients, providing benefits that previous treatments could not achieve, although they may cause anemia and gastrointestinal issues.

The development of enhanced prognostic models is improving the ability to assess individual patient outcomes in myelofibrosis, which is crucial for balancing the benefits of new therapies against the risks of more invasive treatments like stem cell transplantation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Assessing new therapies and their overall impact in myelofibrosis. Mesa, RA.[2016]

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]

Recent advances in understanding myelofibrosis (MF) have led to new therapeutic targets and risk stratification methods, enhancing treatment strategies for this complex disease.

JAK2 inhibitors remain a key focus, but new combination therapies and alternative treatments, including immunotherapies and epigenetic modulators, are being actively researched to improve patient outcomes and modify disease progression.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Looking forward: novel therapeutic approaches in chronic and advanced phases of myelofibrosis. Mascarenhas, J.[2023]

Myelofibrosis (MF) is a severe blood disorder characterized by genetic mutations and an inflammatory environment, leading to poor survival rates and requiring personalized treatment approaches.

While JAK2 inhibitors have improved symptoms and reduced spleen size in MF patients, they do not significantly impact survival or disease progression, highlighting the need for new therapeutic strategies such as combination treatments and antifibrotic agents.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

New strategies in myelofibrosis: the evolving paradigm of disease pathogenesis, prognostication and treatment. Palandri, F., Auteri, G., Baccarani, M.[2017]

Ruxolitinib is currently the only FDA-approved treatment for myelofibrosis (MF), a serious blood cancer characterized by JAK/STAT signaling dysregulation, highlighting its importance in managing this condition.

Ongoing clinical trials are exploring various novel therapies, including selective JAK inhibitors and immunomodulators, aiming to address unmet needs such as improving blood cell counts and preventing disease progression.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Emerging drugs for the treatment of Myelofibrosis. Shreenivas, A., Mascarenhas, J.[2021]

Fedratinib, a selective JAK2 inhibitor, was approved by the FDA for treating intermediate-2 or high-risk myelofibrosis (MF) based on phase II and phase III trials, showing significant reductions in spleen size and symptom burden compared to placebo.

While fedratinib is effective, it has notable side effects including anemia and gastrointestinal issues, and carries a black box warning for encephalopathy, which occurred in about 1% of patients, necessitating careful monitoring of thiamine levels.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Beyond Ruxolitinib: Fedratinib and Other Emergent Treatment Options for Myelofibrosis. Bewersdorf, JP., Jaszczur, SM., Afifi, S., et al.[2020]

Myelofibrosis (MF) is a serious blood cancer with varying prognoses; patients with low-risk disease can survive 6-15 years, while those with high-risk disease or transformed acute myeloid leukemia (AML) have a much poorer prognosis, often less than 3 months.

The only curative treatment for MF is allogeneic stem cell transplantation, but since most patients are ineligible, they typically receive older drugs for symptom relief. However, new JAK1/JAK2 inhibitors like ruxolitinib show promise based on positive results from large phase III studies, indicating a potential shift in treatment options.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Clinical and laboratory features of myelofibrosis and limitations of current therapies. Gregory, SA., Mesa, RA., Hoffman, R., et al.[2022]

Myelofibrosis (MF) is primarily treated with JAK inhibitors, which help reduce spleen size and alleviate symptoms, but these treatments have limitations and are not suitable for all patients.

Emerging novel JAK inhibitors and combination therapies aim to address unmet needs in MF treatment, potentially offering deeper responses and improved long-term outcomes for a wider range of patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

JAK Be Nimble: Reviewing the Development of JAK Inhibitors and JAK Inhibitor Combinations for Special Populations of Patients with Myelofibrosis. Kuykendall, AT., Komrokji, RS.[2022]

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. 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.

3. 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 ...

4. 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 ...

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

Navtemadlin Monotherapy Shows Improvements in ... At 12 weeks, CD34+ cells showed a median reduction of 68% from baseline in 50 patients in the treatment arm and 52% in 25 patients in the BAT ...

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. clinicaltrials.gov clinicaltrials.gov/study/NCT06479135

Study of Navtemadlin add-on to Ruxolitinib in JAK Inhibitor- ... This clinical trial is evaluating whether addition of navtemadlin to ruxolitinib treatment will provide more clinical benefit than ruxolitinib alone for ...

8. orpha.net orpha.net/en/research-trials/clinical-trial/698348

POIESIS/KRT-232-115: A Phase 3, Randomized, Double- ... POIESIS/KRT-232-115: A Phase 3, Randomized, Double-blind, Add-on Study Evaluating the Safety and Efficacy of Navtemadlin Plus Ruxolitinib Vs Placebo Plus ...

9. ascopubs.org ascopubs.org/doi/10.1200/JCO.2022.40.16_suppl.TPS7063

An open-label, multicenter, phase 1b/2 study of ... Methods: The open-label, multicenter Phase 1b/2 KRT-232-104 study (NCT04113616) is evaluating TP53WT patients with R/R AML secondary to MPN ( ...