KRT-232 or TL-895 for Myelofibrosis
Recruiting in Palo Alto (17 mi)
+28 other locations
Age: 18+
Sex: Any
Travel: May Be Covered
Time Reimbursement: Varies
Trial Phase: Phase 2
Recruiting
Sponsor: Kartos Therapeutics, Inc.
Must not be taking: JAK inhibitors, MDM2 inhibitors
Disqualifiers: p53 mutation, Major organ transplant, others
No Placebo Group
Prior Safety Data
Trial Summary
What is the purpose of this trial?This study evaluates either KRT-232 or TL-895 in treatment naïve patients with myelofibrosis (MF)
The study will be conducted in 2 stages. Stage 1 will evaluate safety, tolerability, and efficacy of either KRT-232 (Arm 1) or TL-895 (Arm 2) in treatment naïve patients. Stage 2 will expand enrollment in Arm 1 and/or Arm 2 if expansion criteria is met.
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.
What data supports the effectiveness of the drug KRT-232 or TL-895 for treating myelofibrosis?
Navtemadlin, one of the drugs being studied, is evaluated as a monotherapy in pivotal phase 3 trials for myelofibrosis, indicating its potential effectiveness. Additionally, novel therapies, including those targeting similar mechanisms, are showing promise in improving symptoms and outcomes for myelofibrosis patients.
12345What safety information is available for KRT-232 or TL-895 in humans?
There is no specific safety data available for KRT-232 or TL-895 in the provided research articles.
24567How is the drug KRT-232 or TL-895 different from other treatments for myelofibrosis?
KRT-232 and TL-895 are novel treatments for myelofibrosis that may offer new mechanisms of action compared to existing JAK inhibitors like ruxolitinib. These drugs are being studied for their potential to address unmet needs in patients who are resistant or have suboptimal responses to current therapies.
12489Eligibility Criteria
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.
+6 more
Trial Timeline
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
Participant Groups
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.
2Treatment groups
Experimental Treatment
Group I: Arm 2Experimental Treatment1 Intervention
TL-895 administered orally as 150 mg twice daily continuously in 28-day cycles
Group II: Arm 1Experimental Treatment1 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
Find a Clinic Near You
Research Locations NearbySelect from list below to view details:
Innovative Clinical Research InstituteGlendale, CA
Innovative Clinical Research InstituteWhittier, CA
Gabrail Cancer CenterCanton, OH
MD Anderson Cancer CenterHouston, TX
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Who Is Running the Clinical Trial?
Kartos Therapeutics, Inc.Lead Sponsor
References
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.
A phase 1/2, open-label study evaluating twice-daily administration of momelotinib in myelofibrosis. [2019]Momelotinib, a small-molecule inhibitor of Janus kinase 1 and Janus kinase 2, has demonstrated efficacy in myelofibrosis patients with 300 mg, once-daily dosing. This open-label, non-randomized, phase 1/2 study evaluated the safety and therapeutic benefit of momelotinib with twice-daily dosing. A total of 61 subjects with primary myelofibrosis or post-polycythemia vera/post-essential thrombocythemia myelofibrosis with intermediate- or high-risk disease received momelotinib. A phase 1 dose escalation identified 200 mg twice daily as the optimal dose to be expanded in phase 2. The most frequent adverse events were diarrhea (45.9%), peripheral neuropathy (44.3%), thrombocytopenia (39.3%), and dizziness (36.1%), the latter primarily due to a first-dose effect. The response assessment according to the 2006 International Working Group criteria (≥8 weeks duration at any time point) demonstrated spleen response by palpation of 72% (36/50) and anemia response of 45% (18/40). Spleen response by magnetic resonance imaging obtained at 24 weeks was 45.8% (27/59) for all subjects and 54.0% (27/50) for those with palpable splenomegaly at baseline. The symptoms of myelofibrosis were improved in most subjects. Cytokine analysis showed a rapid decline in interleukin-6 with momelotinib treatment, and a slower reduction in other inflammatory cytokines. In the subgroup of subjects with the JAK2V617F mutation at baseline (n=41), momelotinib significantly reduced the allele burden by 21.1% (median) at 24 weeks. These results provide evidence of tolerability and a potential therapeutic activity of momelotinib for subjects that support further evaluation in ongoing, phase 3 randomized trials. (clinicaltrials. gov identifier:01423058).
SOHO State of the Art Updates and Next Questions: Novel Therapeutic Strategies in Development for Myelofibrosis. [2023]Development of myelofibrosis (MF) therapeutics has reached fruition as the transformative impact of JAK2 inhibitors in the MPN landscape is complemented/expanded by a profusion of novel monotherapies and rational combinations in the frontline and second line settings. Agents in advanced clinical development span various mechanisms of action (eg, epigenetic or apoptotic regulation), may address urgent unmet clinical needs (cytopenias), increase the depth/duration of spleen and symptom responses elicited by ruxolitinib, improve other aspects of the disease besides splenomegaly/constitutional symptoms (eg, resistance to ruxolitinib, bone marrow fibrosis or disease course), provide personalized strategies, and extend overall survival (OS). Ruxolitinib had a dramatic impact on the quality of life and OS of MF patients. Recently, pacritinib received regulatory approval for severely thrombocytopenic MF patients. Momelotinib is advantageously poised among JAK inhibitors given its differentiated mode of action (suppression of hepcidin expression). Momelotinib demonstrated significant improvements in anemia measures, spleen responses, and MF-associated symptoms in MF patients with anemia; and will likely receive regulatory approval in 2023. An array of other novel agents combined with ruxolitinib, such as pelabresib, navitoclax, parsaclisib, or as monotherapies (navtemadlin) are evaluated in pivotal phase 3 trials. Imetelstat (telomerase inhibitor) is currently evaluated in the second line setting; OS was set as the primary endpoint, marking an unprecedented goal in MF trials, wherein SVR35 and TSS50 at 24 weeks have been typical endpoints heretofore. Transfusion independence may be considered another clinically meaningful endpoint in MF trials given its correlation with OS. Overall, therapeutics are at the cusp of an exponential expansion and advancements that will likely lead to the golden era in treatment of MF.
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.
Clinical and molecular predictors of fibrotic progression in essential thrombocythemia: A multicenter study involving 1607 patients. [2022]The current retrospective study involving a total of 1607 patients was designed to identify clinical and molecular variables that were predictive of inferior myelofibrosis-free survival (MFS) in WHO-defined essential thrombocythemia (ET), utilizing three independent patient cohorts: University of Florence, Italy (n = 718); Mayo Clinic, USA (n = 479) and Policlinico Gemelli, Catholic University, Rome, Italy (n = 410). The Florence patient cohort was first examined to identify independent risk factors for MFS, which included age > 60 years (HR 2.5, 95% CI 1.3-4.9), male sex (2.1, 1.2-3.9), palpable splenomegaly (2.1, 1.2-3.9), CALR 1/1-like or MPL mutation (3.4, 1.9-6.1) and JAK2V617F variant allele frequency > 35% (4.2, 1.6-10.8). Subsequently, an operational molecular risk category was developed and validated in the other two cohorts from Mayo Clinic and Rome: "high molecular risk" category included patients with JAK2V617F VAF >35%, CALR type 1/1-like or MPL mutations; all other driver mutation profiles were assigned to "low molecular risk" category. The former, compared to the latter molecular risk category, displayed significantly higher risk of fibrotic transformation: Florence cohort with respective fibrotic transformation risk rates of 8% vs. 1.2% at 10 years and 33% vs. 8% at 20 years (p
Momelotinib therapy for myelofibrosis: a 7-year follow-up. [2020]One-hundred Mayo Clinic patients with high/intermediate-risk myelofibrosis (MF) received momelotinib (MMB; JAK1/2 inhibitor) between 2009 and 2010, as part of a phase 1/2 trial (NCT00935987); 73% harbored JAK2 mutations, 16% CALR, 7% MPL, 44% ASXL1, and 18% SRSF2. As of July 2017, MMB was discontinued in 91% of the patients, after a median treatment duration of 1.4 years. Grade 3/4 toxicity included thrombocytopenia (34%) and liver/pancreatic test abnormalities (
A phase 2 study of momelotinib, a potent JAK1 and JAK2 inhibitor, in patients with polycythemia vera or essential thrombocythemia. [2021]Momelotinib is a potent inhibitor of JAK1 and JAK2 that demonstrated efficacy in patients with primary and secondary myelofibrosis. This phase 2, open-label, randomized study evaluated the efficacy and safety of oral once-daily momelotinib (100mg and 200mg) for the treatment of polycythemia vera (PV) and essential thrombocythemia (ET). The primary endpoint for PV was overall response rate (ORR), defined as the proportion of patients with hematocrit <45%, white blood cell count <10×109/L, platelet count ≤400×109/L, and resolution of palpable splenomegaly, each lasting ≥4 weeks. The definition of ORR for ET excluded the hematocrit component. A total of 39 patients (28 PV, 11 ET) were enrolled, with 28 patients receiving ≥12 weeks of treatment. The study was terminated due to limited efficacy. Two patients (ORR 5.1%) met the primary efficacy endpoint (both PV 200mg). Predose plasma levels of momelotinib were stable over time. A total of 31 (79.5%) patients experienced momelotinib-related adverse events (AEs), the most frequent being headache (23.1%), dizziness (18.0%), somnolence (15.4%), nausea (15.4%), and fatigue (15.4%). Three patients experienced serious AEs (7.7%), with 1 considered related to momelotinib (dyspnea). Peripheral neuropathy occurred in 7 (17.9%) patients (4 PV, 3 ET).
[Development of polycythemia to myelofibrosis. Monitoring by the assay of the procollagen III amino-propeptide]. [2016]The conventional methods used in the follow-up of myelofibrosis being both invasive and expensive, we propose an easy and sensitive immunoassay of the procollagen III aminoterminal peptide (propeptide) which is separated and released in serum during synthesis of collagen III by bone marrow fibroblasts. This propeptide was assayed in the sera of 25 healthy adults (controls), 48 patients with polycythaemia vera and 20 patients with myelofibrosis (secondary to polycythaemia in 14). Significant differences in mean values were found between controls (7.6 +/- 2.1 ng/ml), patients with polycythaemia (9.9 +/- 4.3 ng/ml) and patients with myelofibrosis (38.1 ng/ml). There was some overlapping between values in controls and in patients with polycythaemia, partly due to the fact that 12 of these 48 patients without reticulin bone marrow fibrosis had normal serum propeptide levels. Propeptide values in patients with myelofibrosis were much scattered (range: 13-103 ng/ml). Moreover, values above 25 ng/ml were associated with myelofibrosis of recent onset (less than or equal to 2 years) and values below 25 ng/ml with myelofibrosis of more than 4 years' duration. The procollagen III aminoterminal peptide immunoassay therefore is a non-invasive and sensitive method for accurate assessment of bone marrow progressive involvement in myeloproliferative diseases associated with myelofibrosis. It could also be used to evaluate the effectiveness of antifibrosing agents.
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. [2023]Ruxolitinib has demonstrated efficacy in patients with myelofibrosis (MF). However, substantial number of patients may not respond after 3-6 months of treatment or develop resistance over time. In this phase 2 trial, patients with a current diagnosis of intermediate or high-risk MF who either had an inadequate splenic response or spleen regrowth after ruxolitinib treatment were enrolled. All patients received jaktinib 100 mg Bid. The primary endpoint was the proportion of patients with ≥35% reduction in spleen volume (SVR 35) at week 24. The secondary endpoints included change of MF-related symptoms, anemic response, and safety profile. From July 6, 2021, to January 24, 2022, 34 ruxolitinib-refractory or relapsed patients were enrolled, 52.9% (18 of 34) were DIPSS intermediate 2 or high risk. SVR 35 at week 24 was 32.4% (11 of 34, 95% CI 19.1%-49.2%) in all patients and 33.3% (6 of 18, 95% CI 16.3%-56.3%) in the intermediate 2 or high-risk group. A total of 50% (8 of 16) transfusion-independent patients with hemoglobin (HGB)