A phase 1/2, open-label study evaluating twice-daily administration of momelotinib in myelofibrosis

Gupta, Vikas; Mesa, Ruben A.; Deininger, Michael W.; Rivera, Candido E.; Sirhan, Shireen; Brachmann, Carrie Baker; Collins, Helen; Kawashima, Jun; Yan, Xin; Verstovšek, Srđan

doi:10.3324/haematol.2016.148924

Cited by 87 publications

(62 citation statements)

References 15 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…67,68 Intriguingly, multivariate analysis suggested best responses occurred in CALR 1 /ASXL1 2 patients. 69 Peripheral neuropathy was reported and may be important in deciding where momelotinib sits in the therapeutic algorithm.…”

Section: Other Jak Inhibitorsmentioning

confidence: 99%

Emerging treatments for classical myeloproliferative neoplasms

Vannucchi

Harrison

2017

Blood

View full text Add to dashboard Cite

There has been a major revolution in the management of patients with myeloproliferative neoplasms (MPN), and in particular those with myelofibrosis and extensive splenomegaly and symptomatic burden, after the introduction of the JAK1 and JAK2 inhibitor ruxolitinib. The drug also has been approved as second-line therapy for polycythemia vera (PV). However, the therapeutic armamentarium for MPN is still largely inadequate for coping with patients’ major unmet needs, which include normalization of life span (myelofibrosis and some patients with PV), reduction of cardiovascular complications (mainly PV and essential thrombocythemia), prevention of hematological progression, and improved quality of life (all MPN). In fact, none of the available drugs has shown clear evidence of disease-modifying activity, even if some patients treated with interferon and ruxolitinib showed reduction of mutated allele burden, and ruxolitinib might extend survival of patients with higher-risk myelofibrosis. Raised awareness of the molecular abnormalities and cellular pathways involved in the pathogenesis of MPN is facilitating the development of clinical trials with novel target drugs, either alone or in combination with ruxolitinib. Although for most of these molecules a convincing preclinical rationale was provided, the results of early phase 1 and 2 clinical trials have been quite disappointing to date, and toxicities sometimes have been limiting. In this review, we critically illustrate the current landscape of novel therapies that are under evaluation for patients with MPN on the basis of current guidelines, patient risk stratification criteria, and previous experience, looking ahead to the chance of a cure for these disorders.

show abstract

Section: Other Jak Inhibitorsmentioning

confidence: 99%

Emerging treatments for classical myeloproliferative neoplasms

Vannucchi

Harrison

2017

Blood

View full text Add to dashboard Cite

show abstract

“…The most frequent toxicities were diarrhea (45.9%), PN (44.3%), dizziness (36.1%) and hypotension (24.6%), particularly with the first dose, and thrombocytopenia (39.3%). (103) SVR of ≥35% at 24 weeks was documented in 45.8%, and the overall anemia response rate was 45%. (103) BM fibrosis improved in 11 of 39 evaluable subjects, and worsened in three.…”

Section: New Jak Inhibitors In Phase III Trials: Pacritinib and Momentioning

confidence: 94%

“…(103) 250 mg twice daily was not found to be tolerable, and the 200 mg twice daily dose was chosen for expansion. The most frequent toxicities were diarrhea (45.9%), PN (44.3%), dizziness (36.1%) and hypotension (24.6%), particularly with the first dose, and thrombocytopenia (39.3%).…”

Section: New Jak Inhibitors In Phase III Trials: Pacritinib and Momentioning

confidence: 99%

Myelofibrosis: an update on drug therapy in 2016

Bose

Verstovšek

2016

Expert Opinion on Pharmacotherapy

Self Cite

View full text Add to dashboard Cite

INTRODUCTION Primary myelofibrosis (PMF) is the least common but the most aggressive of the classic Philadelphia chromosome-negative myeloproliferative neoplasms. Survival is much shorter in PMF than in polycythemia vera (PV) or essential thrombocythemia (ET). Post-PV/ET myelofibrosis (MF) is clinically indistinguishable from PMF and approached similarly. AREAS COVERED Current pharmacologic therapy of MF revolves around the Janus kinase 1/2 (JAK1/2) inhibitor ruxolitinib, which dramatically improves constitutional symptoms and splenomegaly in the majority of patients, and improves overall survival (OS). However, allogeneic stem cell transplantation remains the only potential cure. Other JAK inhibitors continue to be developed for MF, and momelotinib and pacritinib are in phase III clinical trials. Anemia is common in MF, and initially worsened by ruxolitinib. Momelotinib and pacritinib may prove advantageous in this regard. Current strategies for managing anemia of MF include danazol, immunomodulatory drugs and erythroid stimulating agents, either alone or in combination with ruxolitinib. EXPERT OPINION A number of other agents, representing diverse drug classes, are in various stages of development for MF. These include newer JAK inhibitors, other signaling inhibitors, epigenetic modifiers, anti-fibrotic agents, telomerase inhibitors, and activin receptor ligand traps (for anemia). Hopefully, these novel therapies will further extend the clinical benefits of ruxolitinib.

show abstract

“…77 The dose chosen for expansion in the phase II portion was 200 mg twice daily. Diarrhea (45.9%), PN (44.3%), thrombocytopenia (39.3%) and dizziness (36.1%) were the most common AEs.…”

Section: Developmental Therapeutics In Mfmentioning

confidence: 99%

“…MF symptoms improved in most subjects, and the median reduction in the JAK2 V617F allele burden was 21.1% at 24 weeks. 77 …”

Section: Developmental Therapeutics In Mfmentioning

confidence: 99%

Developmental Therapeutics in Myeloproliferative Neoplasms

Bose

Verstovšek

2017

Clinical Lymphoma Myeloma and Leukemia

Self Cite

View full text Add to dashboard Cite

The unprecedented success of the Janus kinase (JAK) 1/2 inhibitor ruxolitinib in myelofibrosis provided much-needed impetus for clinical drug development for the Philadelphia chromosome negative myeloproliferative neoplasms (MPN). The survival benefit conferred by this agent, along with its marked efficacy with regard to spleen volume and symptom reduction, have made ruxolitinib the cornerstone of drug therapy in myelofibrosis. However, there remain significant unmet needs in the treatment of patients with MF, and many novel classes of agents continue to be investigated in efforts to build upon the progress made with ruxolitinib. These include inhibitors of histone deacetylases (HDACs) and DNA methyltransferases, phosphatidylinositol-3-kinase isoforms, heat shock protein 90, cyclin-dependent kinases 4/6, and Hedgehog signaling, among others. In parallel, other JAK inhibitors with potential for less myelosuppression or even improvement of anemia, greater selectivity for JAK1 or JAK2, and the ability to overcome JAK inhibitor “persistence” are in various stages of development. First-in-class agents such as the activin receptor IIA ligand trap sotatercept (for anemia of myelofibrosis), the telomerase inhibitor imetelstat, and the anti-fibrotic agent PRM-151 (recombinant human pentraxin-2) are also in clinical trials. In polycythemia vera, a novel interferon administered every 2 weeks is being developed for frontline therapy in high-risk individuals, and inhibitors of human double minute 2 (HDM2) have shown promise in preclinical studies, as have HDAC inhibitors, e.g., givinostat (both in the laboratory and in the clinic). Ruxolitinib is approved for second-line therapy of polycythemia vera, and is being developed for essential thrombocythemia.

show abstract

A phase 1/2, open-label study evaluating twice-daily administration of momelotinib in myelofibrosis

Cited by 87 publications

References 15 publications

Emerging treatments for classical myeloproliferative neoplasms

Emerging treatments for classical myeloproliferative neoplasms

Myelofibrosis: an update on drug therapy in 2016

Developmental Therapeutics in Myeloproliferative Neoplasms

Contact Info

Product

Resources

About