INCA033989 for Myeloproliferative Disorder
(LIMBER Trial)
Recruiting in Palo Alto (17 mi)
+13 other locations
Age: 18+
Sex: Any
Travel: May Be Covered
Time Reimbursement: Varies
Trial Phase: Phase 1
Recruiting
Sponsor: Incyte Corporation
Must not be taking: Chemotherapy, Immunotherapy, Endocrine therapy, others
Disqualifiers: Hematological malignancy, Major bleeding, Cardiac disease, others
No Placebo Group
Trial Summary
What is the purpose of this trial?This trial is testing a new drug called INCA033989 in patients with a type of blood cancer. The goal is to find the safest and most effective dose by checking for side effects and how well the drug works.
Will I have to stop taking my current medications?
The trial requires that you stop certain treatments, such as chemotherapy, immunosuppressive therapy, and some growth factors, at least 28 days before starting the study medication. It's best to discuss your specific medications with the trial team to see if they need to be paused.
What data supports the effectiveness of the drug INCA033989 for treating myeloproliferative disorders?
Research on similar drugs, like ruxolitinib, which target the JAK2 gene mutation common in myeloproliferative disorders, shows they can improve symptoms and quality of life by reducing spleen size and controlling blood cell levels. This suggests that INCA033989, if it works similarly, might also be effective in treating these conditions.
12345What safety data exists for JAK2 inhibitors in treating myeloproliferative disorders?
JAK2 inhibitors, used in treating myeloproliferative disorders, have shown to be generally safe with few adverse events. Some side effects include headaches, elevated liver enzymes, and peripheral neuropathy (nerve damage causing tingling or numbness). Monitoring and managing these side effects are important during treatment.
12678How is the drug INCA033989 different from other treatments for myeloproliferative disorders?
INCA033989 is unique because it is a JAK2 inhibitor, which targets the JAK2/STAT pathway involved in myeloproliferative disorders. This pathway is often overactive due to mutations, and INCA033989 aims to reduce this activity, potentially offering a more targeted approach compared to other treatments.
2391011Eligibility Criteria
This trial is for people who have been diagnosed with myeloproliferative neoplasms, specifically Myelofibrosis (MF) or Essential Thrombocythemia (ET), and are expected to live more than 6 months. They must be willing to undergo bone marrow biopsies and have a documented CALR exon-9 mutation.Inclusion Criteria
My tests show a CALR exon-9 mutation.
I have been diagnosed with myelofibrosis or essential thrombocythemia.
I am willing to have bone marrow tests before and during the study.
+1 more
Trial Timeline
Screening
Participants are screened for eligibility to participate in the trial
2-4 weeks
Dose Escalation
INCA033989 is administered in 28-day cycles to identify the maximum tolerated dose (MTD) and/or recommended dose for expansion (RDE) in participants with myelofibrosis (MF) and essential thrombocythemia (ET)
28 days
Dose Expansion
INCA033989 is administered at the RDE(s) identified during Dose Escalation in participants with myelofibrosis (MF) and essential thrombocythemia (ET)
Up to 3 years and 60 days
Follow-up
Participants are monitored for safety and effectiveness after treatment
Up to 3 years and 60 days
Participant Groups
The study tests INCA033989's safety and tolerability in patients with myeloproliferative disorders. It aims to find the highest dose patients can take without serious side effects (MTD) and suggest doses for future studies.
4Treatment groups
Experimental Treatment
Group I: Part 1b: Dose Expansion - with MFExperimental Treatment1 Intervention
INCA033989 will be administered at the RDE(s) identified during Part 1a. Participants with treatment group A (TGA) myelofibrosis MF will enroll in this group.
Group II: Part 1b: Dose Expansion - with ETExperimental Treatment1 Intervention
INCA033989 will be administered at the RDE(s) identified during Part 1a. Participants with treatment group A (TGA) essential thrombocythemia (ET) will enroll in this group.
Group III: Part 1a Dose Escalation Cohort Disease Group A - with MFExperimental Treatment1 Intervention
INCA033989 will be administered at a protocol defined starting regimen in 28-day cycles to identify the maximum tolerated dose (MTD) and/or recommended dose for expansion (RDE\[s\]). Participants with myelofibrosis (MF) will enroll in this group.
Group IV: Part 1a Dose Escalation Cohort Disease Group A - with ETExperimental Treatment1 Intervention
INCA033989 will be administered at a protocol defined starting regimen in 28-day cycles to identify the maximum tolerated dose (MTD) and/or recommended dose for expansion (RDE\[s\]). Participants with essential thrombocythemia (ET) will enroll in this group.
Find a Clinic Near You
Research Locations NearbySelect from list below to view details:
Stanford Cancer InstitutePalo Alto, CA
Icahn School of Medicine At Mount SinaiNew York, NY
University of Miami Health SystemMiami, FL
Cleveland ClinicCleveland, OH
More Trial Locations
Loading ...
Who Is Running the Clinical Trial?
Incyte CorporationLead Sponsor
References
Kinase drug discovery approaches in chronic myeloproliferative disorders. [2021]Myeloproliferative disorders (MPDs) are clonal malignancies that arise from hematopoietic progenitors and characterized by overproduction of mature, functional blood cells. These disorders can be broadly characterized into Philadelphia chromosome-positive (Ph(+)) or negative (Ph(-)) genetic groupings. Chronic myeloid leukemia (CML) is a Ph(+) MPD that is defined on the basis of its molecular lesion, the BCR-ABL fusion gene. Inhibitors directed at the constitutive kinase activity of BCR-ABL have been shown to be disease modifying in CML and have dramatically altered the standard of care for this leukemia. The three main Ph(-) MPDs are polycythemia vera (PV), essential thrombocythemia (ET) and primary myelofibrosis (PMF). The key features of these Ph(-) MPDs are an increased red blood cell mass in PV, a high platelet count in ET and bone marrow fibrosis in PMF, respectively. These disorders also share many clinical features such as long clinical course, increased risk for thrombosis, hemorrhage and elevated risk of leukemic transformation. Interest in these disorders has been ignited by the recent discovery of activating mutations in the tyrosine kinase gene, JAK2, in the predominance of Ph(-) MPD patients and has highlighted JAK2 as a therapeutic intervention point for drug discovery efforts with selective kinase inhibitors. This review will focus on the comparison of Ph(+) and Ph(-) MPDs, drug discovery and development efforts targeting these disorders, and will assess the new opportunities for targeted therapies for these diseases.
JAK2 inhibitor therapy in myeloproliferative disorders: rationale, preclinical studies and ongoing clinical trials. [2013]The recent identification of somatic mutations such as JAK2V617F that deregulate Janus kinase (JAK)-signal transducer and activator of transcription signaling has spurred development of orally bioavailable small-molecule inhibitors that selectively target JAK2 kinase as an approach to pathogenesis-directed therapy of myeloproliferative disorders (MPD). In pre-clinical studies, these compounds inhibit JAK2V617F-mediated cell growth at nanomolar concentrations, and in vivo therapeutic efficacy has been demonstrated in mouse models of JAK2V617F-induced disease. In addition, ex vivo growth of progenitor cells from MPD patients harboring JAK2V617F or MPLW515L/K mutations is also potently inhibited. JAK2 inhibitors currently in clinical trials can be grouped into those designed to primarily target JAK2 kinase (JAK2-selective) and those originally developed for non-MPD indications, but that nevertheless have significant JAK2-inhibitory activity (non-JAK2 selective). This article discusses the rationale for using JAK2 inhibitors for the treatment of MPD, as well as relevant aspects of clinical trial development for these patients. For instance, which group of MPD patients is appropriate for initial Phase I studies? Should JAK2V617F-negative MPD patients be included in the initial studies? What are the likely consequences of 'off-target' JAK3 and wild-type JAK2 inhibition? How should treatment responses be monitored?
The role of JAK2 inhibitors in MPNs 7 years after approval. [2021]Myeloproliferative neoplasms (MPNs) include essential thrombocythemia, polycythemia vera (PV), and primary myelofibrosis (MF). Phenotype-driver mutations of JAK2, CALR, and MPL genes are present in MPNs and can be variably combined with additional mutations. Driver mutations entail a constitutive activation of the JAK2/STAT pathway, the key signaling cascade in MPNs. Among JAK2 inhibitors (JAKis), ruxolitinib (RUX) has been approved for the treatment of intermediate and high-risk MF and for PV inadequately controlled by or intolerant of hydroxyurea. Other JAKis, such as fedratinib and pacritinib, proved to be useful in MF. The primary end points in MF trials were spleen volume response (SVR) and symptom response, whereas in PV trials they were hematocrit control with or without spleen response. In advanced MF, RUX achieved a long lasting SVR of >35% in ∼60% of patients, establishing a new benchmark for MF treatment. RUX efficacy in early MF is also remarkable and toxicity is mild. In PV, RUX achieved hematocrit control in ∼60% of cases and SVR in 40%. Symptom relief was evident in both conditions. In the long-term, however, many MF patients lose their SVR. Indeed, the definition of RUX failure and the design of new trials in this setting are unmet needs. Decrease of hemoglobin/platelet levels and increased infection rates are the most common side effects of RUX, and nonmelanoma skin tumors need to be monitored while on treatment. In conclusion, the introduction of JAKis raises the bar of treatment goals in MF and PV.
Complications and conversions in myeloproliferative disorders: an analysis of 356 cases. [2004]To investigate the complications and conversions in myeloproliferative disorders (MPD).
Therapeutic advances in myeloproliferative neoplasms: the role of new-small molecule inhibitors. [2023]The discovery that a somatic point mutation (JAK2V617F) in the Janus kinase 2 (JAK2) is highly prevalent in patients with myeloproliferative neoplasms (MPNs) has been a crucial breakthrough in our understanding of the underlying molecular mechanisms of these diseases. Therefore, preclinical and clinical research in recent years has focused intensely on the development of new therapies targeted to JAK2. These efforts culminated in recent approval of ruxolitinib as the first official therapy for patients with intermediate- or high-risk myelofibrosis (MF). Therapy with JAK2 inhibitors substantially improves quality of life and reduces organomegaly in MF with or without JAKV617F mutation. Recent results suggest that patients with advanced MF may live longer when receiving therapy with ruxolitinib. However, JAK2 inhibitors do not eliminate the disease and new medications are needed to expand on the benefits seen with JAK2 inhibitors. Although many agents are still in the early stages of development, the wealth of publications and presentations has continued to support our growing understanding of the pathophysiology of MF as well as the potential short- and long-term outcomes of these new and diverse approaches to treatment. Focus of ongoing efforts is particularly on the improvements in anemia and fibrosis, as well as on rational combination trials of JAK2 inhibitors and other potentially active agents. Therapeutic potential and limitations of JAK2 inhibitors and other novel medications in clinical studies are reviewed.
Safety and efficacy of CYT387, a JAK1 and JAK2 inhibitor, in myelofibrosis. [2021]JAK-STAT is a rational drug target in myelofibrosis (MF) given its association with JAK2/MPL mutations and aberrant inflammatory cytokine expression. We conducted a Phase 1/2 trial of CYT387, a potent JAK1/2 inhibitor, in patients with high- or intermediate-risk primary or post-polycythemia vera/essential thrombocythemia MF. Pre-planned safety and efficacy analysis has been completed for the initial 60 patients. In the dose-escalation phase (n=21), the maximum-tolerated dose was 300 mg/day based on reversible grade 3 headache and asymptomatic hyperlipasemia. Twenty-one and 18 additional patients were accrued at two biologically effective doses, 300 mg/day and 150 mg/day, respectively. Anemia and spleen responses, per International Working Group criteria, were 59% and 48%, respectively. Among 33 patients who were red cell-transfused in the month prior to study entry, 70% achieved a minimum 12-week period without transfusions (range 4.7->18.3 months). Most patients experienced constitutional symptoms improvement. Grade 3/4 adverse reactions included thrombocytopenia (32%), hyperlipasemia (5%), elevated liver transaminases (3%) and headache (3%). New-onset treatment-related peripheral neuropathy was observed in 22% of patients (sensory symptoms, grade 1). CYT387 is well tolerated and produces significant anemia, spleen and symptom responses in MF patients. Plasma cytokine and gene expression studies suggested a broad anticytokine drug effect.
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.
The current status and the future of JAK2 inhibitors for the treatment of myeloproliferative diseases. [2021]Janus kinases (JAKs) are critical components of cytokine signaling pathways which regulate immunity, inflammation, hematopoiesis, growth, and development. The recent discovery of JAK2-activating mutations as a causal event in the majority of patients with Philadelphia chromosome negative (Ph-) myeloproliferative disorders (MPDs) prompted many pharmaceutical companies to develop JAK2-selective inhibitors for the treatment of MPDs. JAK2 inhibitors effectively reduce JAK2-driven phosphorylation of signal transducer and activator of transcription 5, and cell proliferation and cell survival in JAK2-activated cells in vitro and in vivo. Most inhibitors are currently being evaluated in patients with one form of MPD, myelofibrosis. Patients treated with these inhibitors experienced a rapid reduction of splenomegaly, significant improvement of constitutional symptoms, and increased daily activity with few adverse events. A partial reduction of JAK2V617F disease burden during the treatment with JAK2 inhibitors was also observed. The inhibitors appear to have a therapeutic benefit in the treatment of these disorders. The results of ongoing clinical trials will allow further evaluation of clinical benefits and safety of these compounds. In this review, the authors summarize the status of JAK2 inhibitors in development and discuss their benefits and challenges.
Efficacy of TG101348, a selective JAK2 inhibitor, in treatment of a murine model of JAK2V617F-induced polycythemia vera. [2022]We report that TG101348, a selective small-molecule inhibitor of JAK2 with an in vitro IC50 of approximately 3 nM, shows therapeutic efficacy in a murine model of myeloproliferative disease induced by the JAK2V617F mutation. In treated animals, there was a statistically significant reduction in hematocrit and leukocyte count, a dose-dependent reduction/elimination of extramedullary hematopoiesis, and, at least in some instances, evidence for attenuation of myelofibrosis. There were no apparent toxicities and no effect on T cell number. In vivo responses were correlated with surrogate endpoints, including reduction/elimination of JAK2V617F disease burden assessed by quantitative genomic PCR, suppression of endogenous erythroid colony formation, and in vivo inhibition of JAK-STAT signal transduction as assessed by flow cytometric measurement of phosphorylated Stat5.
[Clinical and gene involved of one case of 8p11 myeloproliferative syndrome with ins(13;8)(q12;p11p23)]. [2020]To improve the understanding of patients with 8p11 myeloproliferative syndrome (EMS) harboring ins(13;8)(q12;p11p23)/ZNF198 -FGFR1.
JAK2 inhibitors: A reality? A hope? [2023]Myelofibrosis (MF; primary or post-polycythemia vera/essential thrombocythemia) carries the worst prognosis among BCR-ABL-negative myeloproliferative neoplasms (MPNs). Stem cell transplantation is the only curative approach but is hampered by significant nonrelapse mortality. Thus, effective, targeted therapies are needed. A mutated Janus kinase 2 (JAK2) gene (JAK2(V617F)), found in a significant portion of patients with MPN, results in increased JAK2 tyrosine kinase activity, leading to clonal proliferation; several small molecules inhibit the growth of hematopoietic colonies harboring JAK2(V617). Several JAK2 inhibitors have reached the clinical trial stage and are reviewed here. The most developed among them is INCB018424, which has demonstrated noteworthy clinical activity, with a rapid and profound reduction in splenomegaly and associated improvement in constitutional symptoms in MF patients receiving 10-25 mg orally twice daily, continuously. Thrombocytopenia (reversible) was the most common adverse event, seen in 30% of patients treated with 25 mg twice daily but not with 10 mg twice daily. Interestingly, INCB018424 was equally active in patients with and without JAK2 mutation. Other JAK2 inhibitors are less developed but show a similar type of clinical benefit. Conclusively, JAK2 inhibitors, particularly INCB018424, are clinically active in MF and are well tolerated. Whether they have an effect on the natural course of MF in treated patients remains to be elucidated.