KRT-232 for Myelofibrosis
(BOREAS Trial)
Recruiting in Palo Alto (17 mi)
+185 other locations
Age: 18+
Sex: Any
Travel: May Be Covered
Time Reimbursement: Varies
Trial Phase: Phase 2 & 3
Recruiting
Sponsor: Kartos Therapeutics, Inc.
Disqualifiers: Splenectomy, Hemorrhage, Stroke, Transplant, others
No Placebo Group
Prior Safety Data
Trial Summary
What is the purpose of this trial?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 treatment with a JAK inhibitor. Inhibition of MDM2 is a novel mechanism of action in MF.
This study will be conducted in 2 phases. Phase 2 will determine the KRT-232 recommended dose and dosing schedule; Phase 3 will test KRT-232 vs Best Available Therapy (BAT). Patients in the Phase 3 part of the study will be randomized 2:1 to receive either KRT-232 (Arm 1) or BAT (Arm 2). The BAT administered will be determined by the treating physician, with the option to "cross-over" to KRT-232 treatment after 6 months of BAT or if the disease worsens at any time.
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.
What data supports the effectiveness of the drug KRT-232 for Myelofibrosis?
The research highlights the effectiveness of JAK inhibitors, which are drugs that help reduce spleen size and improve symptoms in myelofibrosis patients. Although KRT-232 is not specifically mentioned, similar drugs in this category have shown benefits in managing myelofibrosis symptoms.
12345What safety data exists for KRT-232 (Navtemadlin) in humans?
Navtemadlin, also known as KRT-232, has been studied for its safety in humans, particularly in the context of myelofibrosis and other conditions. While specific safety data for KRT-232 is not detailed in the provided research, it is mentioned alongside other novel therapies being developed for myelofibrosis, suggesting ongoing evaluation of its safety profile.
16789How is the drug KRT-232 (Navtemadlin) different from other treatments for myelofibrosis?
KRT-232 (Navtemadlin) is unique because it is being studied as a non-JAK inhibitor monotherapy for patients who are resistant to or ineligible for JAK inhibitors, offering a potential new option for those with unmet clinical needs in myelofibrosis treatment.
16101112Eligibility Criteria
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
I have been diagnosed with a form of myelofibrosis.
My condition is classified as high, intermediate-2, or intermediate-1 risk.
I have been treated with a JAK inhibitor, but it did not work for me.
+1 more
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.
+5 more
Trial Timeline
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
Participant Groups
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.
6Treatment groups
Experimental Treatment
Active Control
Group I: Part B Arm 1 KRT-232Experimental Treatment1 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 4bExperimental Treatment1 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 3Experimental Treatment1 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 2Experimental Treatment1 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 1Experimental Treatment1 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 TherapyActive Control1 Intervention
Best available therapy at the discretion of the investigator, on a 28-day cycle.
Find a Clinic Near You
Research Locations NearbySelect from list below to view details:
Health Partners InstituteSaint Paul, MN
Yale UniversityNew Haven, CT
Tom Baker Cancer CenterCalgary, Canada
University of Southern California Norris Comprehensive Cancer CenterLos Angeles, CA
More Trial Locations
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Who Is Running the Clinical Trial?
Kartos Therapeutics, Inc.Lead Sponsor
References
The new landscape of therapy for myelofibrosis. [2021]The landscape of therapy for myelofibrosis (MF) is evolving at a pace not previously seen for this clonal myeloproliferative neoplasm. The discovery of the JAK2 V617F mutation in 2005 has led to the rapid development of therapy specifically developed for afflicted MF patients. Indeed, the successful phase III studies of ruxolitinib demonstrating improved symptomatic burden, splenomegaly and survival led to the first approved myelofibrosis drug in the United States and Europe. Multiple additional JAK2 inhibitors are currently in or nearing phase III testing, including SAR302503 (fedratinib), SB1518 (pacritinib) and CYT387 (momelotinib), seeking to offer incremental benefits to ruxolitinib in regards to cytopenias or other disease features. In parallel, phase III testing of pomalidomide is ongoing, with the goal of solidifying the role of immunomodulatory therapy in MF-associated anemia. Multiple single agents strategies are ongoing with histone deacetylase inhibitors, hedgehog inhibitors and hypomethylation agents. Incremental advances are further sought, either in additive or synergistic fashion, from combination strategies of ruxolitinib with multiple different approaches ranging from allogeneic stem cell transplant to current therapies mitigating anemia and further impacting the bone marrow microenvironment or histology. Transitioning from a pre-2011 era devoid of approved MF therapies to one of multiple agents that target not only disease course but symptomatic burden has indeed changed the platform from which MF providers are able to launch individualized treatment plans. In this article, we discuss the diagnostic and therapeutic milestones achieved through MF research and review the emerging pharmacologic agents on the treatment horizon.
Assessing new therapies and their overall impact in myelofibrosis. [2016]Clinical management of myelofibrosis (MF)--whether primary or arising from an antecedent myeloproliferative neoplasm (post-essential thrombocythemia/polycythemia vera MF)--is currently in a period of transition that began with the discovery of the JAK2-V617F mutation 5 years ago. Selective JAK2 inhibitors have been developed, and clinical trials thus far have demonstrated that several of these agents meaningfully reduce MF-associated splenomegaly and constitutional symptoms. JAK2 inhibitors have durable benefits, act across the spectrum of MF subtypes, and provide a level of symptomatic benefit not seen with previous generations of nontargeted therapies. However, the JAK2 inhibitors can cause anemia and/or gastrointestinal disturbance, and their impact on JAK2 allele burden and the natural history is not yet fully defined. Several additional therapies that do not directly target JAK2 (eg, immunomodulatory drugs, histone deacetylase inhibitors, and inhibitors of the mammalian target of rapamycin [mTOR]) may ameliorate MF-associated anemia and morbidity-inducing symptoms. Balancing the potential benefits of these new agents against the risks and benefits of allogeneic stem cell transplantation (which can be curative, but carries a high risk of treatment-associated morbidity and mortality) requires an accurate estimation of the prognosis for an individual patient. Enhanced prognostic modeling systems are helping us to better characterize prognosis in MF patients not only at diagnosis, but also along the dynamic and variable course of the illness. Future advancements in the efficacy of MF-targeted therapy will likely arise from new pathogenetic insights and from combining JAK2 inhibitors with other agents.
JAK inhibitors in the treatment of myelofibrosis. [2022]Myelofibrosis (MF) is a myeloproliferative neoplasm driven by constitutive activation of the JAK/STAT pathway, resulting in clonal hematopoiesis, fibrotic replacement of the bone marrow, extramedullary hematopoiesis, splenomegaly, and debilitating constitutional symptoms. The advent of JAK inhibitors has changed the landscape of treatment options for patients with MF, providing relatively tolerable drug options that control symptoms, reduce splenomegaly, and improve quality of life, but often at the expense of worsening cytopenias. JAK inhibitors do not appear to halt the progression of disease or prevent leukemic transformation, and their effect on survival is debated. Here, we review both the US Food and Drug Administration-approved JAK inhibitors and those in late-phase clinical trials, with a focus on clinical activity and unique adverse effects. We also provide a schema for choosing among these options for patients with MF.
Emerging drugs for the treatment of Myelofibrosis. [2021]Myelofibrosis (MF) is a Philadelphia chromosome-negative myeloproliferative neoplasm (MPN). It can be sub-categorized into primary myelofibrosis, post polycythemia vera myelofibrosis and post essential thrombocythemia myelofibrosis. MF is a life-threatening hematologic malignancy characterized by dysregulation of the Janus associated kinase (JAK)/signal transducer and activator of transcription (STAT) signaling network and a heightened inflammatory state. Areas covered: We cover the pathogenesis, clinical features, new prognostic models, current treatment of MF and discuss agents in development. We also cover market review and health care costs associated with some of these therapies. Expert opinion: There are many ongoing clinical trials evaluating novel therapeutic approaches, including selective JAK inhibitors, histone deacetylase/DNA methyltransferase inhibitors, PI3K-inhibitors, Hedgehog/mammalian target of rapamycin (MTOR) inhibitors, anti-fibrotic agents, immunomodulators, monoclonal antibodies and immune checkpoint inhibitors. Ruxolitinib, a potent oral JAK1/JAK2 inhibitor remains the only Food and Drug Administration (FDA)-approved medicinal therapy for the treatment of MF. Unmet needs include alleviation of limiting thrombocytopenia and anemia, halting disease progression to acute leukemia, and extending survival. The development of biomarker driven clinical trials of mechanism based novel therapeutics will usher in a new era of advances in the treatment of this chronic and progressive myeloid malignancy.
JAK Be Nimble: Reviewing the Development of JAK Inhibitors and JAK Inhibitor Combinations for Special Populations of Patients with Myelofibrosis. [2022]Myelofibrosis (MF) is a myeloproliferative neoplasm hallmarked by uncontrolled blood counts, constitutional symptoms, extramedullary hematopoiesis, and an increased risk of developing acute myeloid leukemia. Janus kinase (JAK) inhibitors are the most common treatment for MF due to their ability to reduce spleen size and improve disease-related symptoms; however, JAK inhibitors are not suitable for every patient and their impact on MF is limited in several respects. Novel JAK inhibitors and JAK inhibitor combinations are emerging that aim to enhance the treatment landscape, providing deeper responses to a broader population of patients with the continued hope of providing disease modification and improving long-term outcomes. In this review, we highlight several specific areas of unmet need within MF. Subsequently, we review agents that target those areas of unmet need, focusing specifically on the JAK inhibitors, momelotinib, pacritinib, itacitinib, and NS-018 as well as JAK inhibitor combination approaches using CPI-0610, navitoclax, parsaclisib, and luspatercept.
Novel therapeutics for myelofibrosis. [2023]Myelofibrosis (MF) includes primary MF, post-essential thrombocythemia MF, and post-polycythemia vera MF. MF is a progressive myeloid neoplasm characterized by ineffective clonal hematopoiesis, extramedullary hematopoiesis, a reactive bone marrow environment resulting in reticulin deposition and fibrosis, and a propensity for leukemia transformation. The identification of driver mutations in JAK2, CALR, and MPL has contributed to a better understanding of disease pathogenesis and has led to the development of MF-specific therapies, such as JAK2 inhibitors. Despite the fact that ruxolitinib and fedratinib have been clinically developed and approved, their use is limited due to adverse effects such as anemia and thrombocytopenia. Recently, pacritinib has been approved for a group of thrombocytopenic patients with significant unmet clinical needs. In symptomatic and anemic patients with prior JAK inhibitor exposure, momelotinib was superior to danazol in preventing exacerbation of anemia and in controlling MF-associated signs and symptoms, such as spleen size. Although the development of JAK inhibitors is remarkable, modifying the natural course of the disease remains a priority. Therefore, many novel treatments are currently under clinical development. Agents targeting bromodomain and extra-terminal protein, anti-apoptotic protein Bcl-xL, and phosphatidylinositol-3-kinase delta have been studied in combination with JAK inhibitors. These combinations have been employed in both the frontline and "add-on" approaches. In addition, several agents are being studied as monotherapies for ruxolitinib-resistant or -ineligible patients. We reviewed several new MF treatments in the advanced stages of clinical development and treatment options for cytopenic patients.
Novel treatments for myelofibrosis: beyond JAK inhibitors. [2022]Myelofibrosis is a chronic hematologic malignancy characterized by constitutional symptoms, bone marrow fibrosis, extramedullary hematopoiesis resulting in splenomegaly and a propensity toward leukemic progression. Given the central role of the JAK-STAT pathway in the pathobiology of myelofibrosis, JAK inhibitors are the mainstay of current pharmacologic management. Although these therapies have produced meaningful improvements in splenomegaly and symptom burden, JAK inhibitors do not significantly impact disease progression. In addition, many patients are ineligible because of disease-related cytopenias, which are exacerbated by JAK inhibitors. Therefore, there is a continued effort to identify targets outside the JAK-STAT pathway. In this review, we discuss novel therapies in development for myelofibrosis. We focus on the preclinical rationale, efficacy and safety data for non-JAK inhibitor therapies that have published or presented clinical data. Specifically, we discuss agents that target epigenetic modification (pelabresib, bomedemstat), apoptosis (navitoclax, navtemdalin), signaling pathways (parsaclisib), bone marrow fibrosis (AVID200, PRM-151), in addition to other targets including telomerase (imetelstat), selective inhibitor of nuclear transport (selinexor), CD123 (tagraxofusp) and erythroid maturation (luspatercept). We end by providing commentary on the ongoing and future therapeutic development in myelofibrosis.
Beyond Ruxolitinib: Fedratinib and Other Emergent Treatment Options for Myelofibrosis. [2020]Myelofibrosis (MF) is a myeloproliferative neoplasm characterized by clonal proliferation of differentiated myeloid cells leading to bone marrow fibrosis, cytopenias and extramedullary hematopoiesis. In late 2019, the FDA approved the highly selective JAK2 inhibitor, fedratinib, for intermediate-2 or high-risk primary or secondary MF, making it the second drug approved for MF after ruxolitinib, a JAK1/2 inhibitor, which was approved for MF in 2011. The approval of fedratinib was based on phase II trials and the phase III JAKARTA trial, in which the drug significantly reduced splenomegaly and symptom burden compared to placebo, including some patients previously treated with ruxolitinib. The main side effects of fedratinib include anemia, gastrointestinal symptoms, and elevations in liver transaminases. Fedratinib also has ablack box warning for encephalopathy, although this occurred only in about 1% of the treated patients, most of which were ultimately felt not to represent Wernicke's encephalopathy. Nonetheless, monitoring of thiamine levels and supplementation are recommended especially in high-risk patients. This concern has led to a prolonged clinical hold and delayed the drug approval by several years during which the drug exchanged manufacturers, highlighting the need for meticulous investigation and adjudication of serious, but rare, adverse events in drug development that could end up preventing drugs with favorable risk/benefit ratio from being approved. In this review, we discuss the pharmacokinetic data and efficacy, as well as the toxicity results of clinical trials of fedratinib. We also review ongoing trials of JAK inhibitors in MF and explore future treatment options for MF patients who are refractory to ruxolitinib.
New strategies in myelofibrosis: the evolving paradigm of disease pathogenesis, prognostication and treatment. [2017]Myelofibrosis (MF) is the most severe among the classical Philadelphia-negative myeloproliferative neoplasms that also include essential thrombocytemia and polycythemia vera. Myelofibrosis is characterized by numerous genetic lesions, often variously associated with each other, and by an aggressive clinical phenotype leading to severely reduced survival. Also, the inflammatory microenvironment plays a key role in disease initiation and progression. Because of the complexity of its pathogenesis and the variability of clinical features, MF is a disease that requires a personalized approach and remains orphan of curative treatments besides allogeneic transplantation. JAK2 inhibitors have marked a remarkable progress, because they alleviate systemic symptoms and reduce splenomegaly but have a limited effect on survival, on mutation load, and on marrow fibrosis. Here, we review the main contributing factors to MF pathogenesis and prognosis, focusing on how these factors relate to therapeutic choices. We discuss results from ongoing studies of JAK2 inhibitors and report on new therapeutic strategies that proved effective in early preclinical and clinical trials, including combination treatments, antifibrotic agents, and telomerase inhibitors.
Clinical and laboratory features of myelofibrosis and limitations of current therapies. [2022]Myelofibrosis (MF) is a life-threatening clonal stem cell malignancy characterized by progressive bone marrow fibrosis and ineffective hematopoiesis. The term "MF" encompasses primary myelofibrosis (PMF) as well as 2 other phenotypically similar malignancies: post-polycythemia vera (PV) MF (PPV-MF) and post-essential thrombocythemia (ET) MF (PET-MF). The World Health Organization classification system for myeloid malignancies recognizes PMF, PV, ET, and chronic myeloid leukemia (CML) as the "classic" myeloproliferative neoplasms (MPNs). Patients with low- or intermediate-1-risk disease have a median survival of 6-15 years, in contrast to those with intermediate-2- or high-risk disease, which is associated with a considerably worse prognosis. Following transformation into (secondary) acute myeloid leukemia (AML), the prognosis of MF is even worse, with a median survival of 3 months or less. Due to the heterogeneous nature of MF, the diagnosis and treatment of this malignancy can be challenging. At present, the only treatment that can be applied with curative intent is allogeneic stem cell transplantation (SCT), whereas no other specific therapies exist that are approved by the US Food and Drug Administration (FDA) for MF. Since most patients with MF appear not to be eligible for allogeneic SCT, patients are often treated by conventional "older" drugs such as androgens and hydroxyurea (HU; hydroxycarbamide), with the principal objective being palliation. Following the establishment of a causal role of a specific mutation in the Janus kinase type 2 (JAK2) gene, namely JAK2V617F, in the molecular pathogenesis of MPNs in 2005, many efforts have been directed towards the development of novel JAK2 (including JAK1/JAK2) inhibitors. Other investigative approaches include immunomodulatory agents, histone deacetylase inhibitors, hedgehog inhibitors, and others. Recently, the positive results of the first in class of the JAK1/JAK2 inhibitors, ruxolitinib (formerly INCB18242), from 2 large phase III studies were presented and are discussed herein.
SOHO State of the Art Updates and Next Questions: Novel Therapies in Development for Myelofibrosis. [2022]Myeloproliferative neoplasms research has entered a dynamic and exciting era as we witness exponential growth of novel agents in advanced/early phase clinical trials for myelofibrosis (MF). Building on the success and pivotal role of ruxolitinib, many novel agents, spanning a wide range of mechanisms/targets (epigenetic regulation, apoptotic/intracellular signaling pathways, telomerase, bone marrow fibrosis) are in clinical development; several are studied in registrational trials and hold great potential to expand the therapeutic arsenal/shift the treatment paradigm if regulatory approval is granted. Insight into MF pathogenesis and its molecular underpinnings, preclinical studies demonstrating synergism of ruxolitinib with investigational agents, urgent unmet clinical needs (cytopenias, loss of response to JAK inhibitors); and progressive disease fueled the rapid rise of innovative therapeutics. New strategies include pairing ruxolitinib with erythroid maturation agents to manage anemia (luspatercept), designing rational combinations with ruxolitinib to boost responses in both the frontline and suboptimal response settings (pelabresib, navitoclax, parsaclisib), treatment with non-JAK inhibitor monotherapy in the second-line setting (navtemadlin, imetelstat), novel JAK inhibitors tailored to subgroups with challenging unmet needs (momelotinib and pacritinib for anemia and thrombocytopenia, respectively); and agents potentially enhancing longevity (imetelstat). Beyond typical endpoints evaluated in MF clinical trials (spleen volume reduction ≥ 35%, total symptom score reduction ≥ 50%) thus far, emerging endpoints include overall survival, progression-free survival, transfusion independence, anemia benefits, bone marrow fibrosis and driver mutation allele burden reduction. Novel biomarkers and additional clinical features are being sought to assess new agents and tailor emerging therapies to appropriate patients. New strategies are needed to optimize the design of clinical trials comparing novel combinations to standard agent monotherapy.
Looking forward: novel therapeutic approaches in chronic and advanced phases of myelofibrosis. [2023]Myelofibrosis (MF) is complex at the pathobiologic level and heterogeneous at the clinical level. The advances in molecular characterization of MF provide important insight into the mechanisms driving this chronic myeloid malignancy, refine risk stratification, offer novel therapeutic targets, and serve to measure therapeutic response. Although JAK2 inhibition has been the focus of laboratory and clinical efforts over the last decade, current experimental therapeutic approaches have broadened to include inhibitors of key alternative signaling pathways, epigenetic modulators, anti-fibrotics, and immunotherapies. Based on compelling preclinical rationale, a number of JAK2 inhibitor based combination therapies are now actively being evaluated in the clinic with the goal of disease course modification. The role and timing of hematopoietic stem cell transplant (HSCT) for MF has been challenged with the availability of commercial ruxolitinib and the plethora of experimental treatment options that exist. Integration of preconditioning JAK2 inhibition, reduced intensity conditioning regimens, and alternative donor sources are all being explored in an attempt to optimize this potentially curative modality. This review will summarize modern MF risk stratification, current clinical research approaches to chronic and advance phase MF focusing on novel agents alone and in combination, and update the reader on new directions in HSCT.