Safety and efficacy of INCB018424, a JAK1 and JAK2 inhibitor, in myelofibrosis.
Abstract | BACKGROUND: METHODS: RESULTS: A total of 153 patients received INCB018424 for a median duration of more than 14.7 months. The initial dose-escalation phase established 25 mg twice daily or 100 mg once daily as maximum tolerated doses, on the basis of reversible thrombocytopenia. A dose-dependent suppression of phosphorylated signal transducer and activator of transcription 3 (STAT3), a marker of JAK signaling, was demonstrated in patients with wild-type JAK2 and in patients with the JAK2 V617F mutation. We studied additional doses and established that a 15-mg twice-daily starting dose, followed by individualized dose titration, was the most effective and safest dosing regimen. At this dose, 17 of 33 patients (52%) had a rapid objective response (≥50% reduction of splenomegaly) lasting for 12 months or more, and this therapy was associated with grade 3 or grade 4 adverse events (mainly myelosuppression) in less than 10% of patients. Patients with debilitating symptoms, including weight loss, fatigue, night sweats, and pruritus, had rapid improvement. Clinical benefits were associated with a marked diminution of levels of circulating inflammatory cytokines that are commonly elevated in myelofibrosis. CONCLUSIONS:
INCB018424 was associated with marked and durable clinical benefits in patients with myelofibrosis for whom no approved therapies existed. (Funded by Incyte; ClinicalTrials.gov number, NCT00509899.)
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Authors | Srdan Verstovsek, Hagop Kantarjian, Ruben A Mesa, Animesh D Pardanani, Jorge Cortes-Franco, Deborah A Thomas, Zeev Estrov, Jordan S Fridman, Edward C Bradley, Susan Erickson-Viitanen, Kris Vaddi, Richard Levy, Ayalew Tefferi |
Journal | The New England journal of medicine
(N Engl J Med)
Vol. 363
Issue 12
Pg. 1117-27
(Sep 16 2010)
ISSN: 1533-4406 [Electronic] United States |
PMID | 20843246
(Publication Type: Clinical Trial, Phase I, Clinical Trial, Phase II, Journal Article, Research Support, Non-U.S. Gov't)
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Chemical References |
- Biomarkers
- Cytokines
- Nitriles
- Pyrazoles
- Pyrimidines
- STAT3 Transcription Factor
- STAT3 protein, human
- ruxolitinib
- Janus Kinase 1
- Janus Kinase 2
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Topics |
- Adult
- Aged
- Aged, 80 and over
- Anemia
(drug therapy, etiology)
- Biomarkers
(blood)
- Cytokines
(blood)
- Dose-Response Relationship, Drug
- Female
- Hepatomegaly
(drug therapy, etiology)
- Humans
- Janus Kinase 1
(antagonists & inhibitors)
- Janus Kinase 2
(antagonists & inhibitors, genetics)
- Male
- Middle Aged
- Mutation
- Nitriles
- Primary Myelofibrosis
(blood, complications, drug therapy, genetics)
- Pyrazoles
(administration & dosage, adverse effects)
- Pyrimidines
- STAT3 Transcription Factor
(drug effects, metabolism)
- Spleen
(drug effects, pathology)
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