Safety and Efficacy of Fedratinib in Patients With Primary or Secondary Myelofibrosis: A Randomized Clinical Trial

Animesh Pardanani, Claire Harrison, Jorge E. Cortes, Francisco Cervantes, Ruben A. Mesa, Donald Milligan, T. Masszi, Elena Mishchenko, Eric Jourdan, Alessandro M. Vannucchi, Mark W. Drummond, Mindaugas Jurgutis, Kazimierz Kuliczkowski, Emanuil Gheorghita, Francesco Passamonti, Frank Neumann, Abhay Patki, Guozhi Gao, Ayalew Tefferi

Research output: Contribution to journalArticle

84 Citations (Scopus)

Abstract

DESIGN, SETTING, AND PARTICIPANTS: Double-blind, randomized, placebo-controlled phase 3 study in 94 sites in 24 countries in which 289 adult patients (≥18 years of age) with intermediate-2 or high-risk primary MF, post-polycythemia vera MF, or post-essential thrombocythemia MF were randomly assigned between December 2011 and September 2012 to once-daily oral fedratinib, at a dose of 400 mg or 500 mg, or placebo, for at least 6 consecutive 4-week cycles.

MAIN OUTCOMES AND MEASURES: The primary end point was spleen response (≥35% reduction in spleen volume from baseline as determined by magnetic resonance imaging or computed tomography) at week 24 and confirmed 4 weeks later. The main secondary end point was symptom response (≥50% reduction in total symptom score, assessed using the modified Myelofibrosis Symptom Assessment Form).

IMPORTANCE: Myelofibrosis (MF) is a BCR-ABL-negative myeloproliferative neoplasm characterized by anemia, splenomegaly, debilitating constitutional symptoms, and shortened survival. Fedratinib, a JAK2-selective inhibitor, previously demonstrated clinically beneficial activity in patients with MF in early-phase trials.

OBJECTIVE: To evaluate the efficacy and safety of fedratinib therapy in patients with primary or secondary (post-polycythemia vera or post-essential thrombocythemia) MF.

RESULTS: The primary end point was achieved by 35 of 96 (36% [95% CI, 27%-46%]) and 39 of 97 (40% [95% CI, 30%-50%]) patients in the fedratinib 400-mg and 500-mg groups, vs 1 of 96 (1% [95% CI, 0%-3%]) in the placebo group (P 

CONCLUSIONS AND RELEVANCE: Fedratinib therapy significantly reduced splenomegaly and symptom burden in patients with MF. These benefits were accompanied by toxic effects in some patients, the most important being encephalopathy of unknown mechanism. Clinical development of fedratinib was subsequently discontinued.

TRIAL REGISTRATION: clinicaltrials.gov identifier: NCT01437787.

Original languageEnglish
Pages (from-to)643-651
Number of pages9
JournalJAMA oncology
Volume1
Issue number5
DOIs
Publication statusPublished - Aug 1 2015

Fingerprint

Primary Myelofibrosis
Randomized Controlled Trials
Safety
Essential Thrombocythemia
Polycythemia Vera
Splenomegaly
Placebos
Spleen
Symptom Assessment
TG101348
Poisons
Brain Diseases
Anemia
Tomography
Magnetic Resonance Imaging
Survival
Therapeutics

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Pardanani, A., Harrison, C., Cortes, J. E., Cervantes, F., Mesa, R. A., Milligan, D., ... Tefferi, A. (2015). Safety and Efficacy of Fedratinib in Patients With Primary or Secondary Myelofibrosis: A Randomized Clinical Trial. JAMA oncology, 1(5), 643-651. https://doi.org/10.1001/jamaoncol.2015.1590

Safety and Efficacy of Fedratinib in Patients With Primary or Secondary Myelofibrosis : A Randomized Clinical Trial. / Pardanani, Animesh; Harrison, Claire; Cortes, Jorge E.; Cervantes, Francisco; Mesa, Ruben A.; Milligan, Donald; Masszi, T.; Mishchenko, Elena; Jourdan, Eric; Vannucchi, Alessandro M.; Drummond, Mark W.; Jurgutis, Mindaugas; Kuliczkowski, Kazimierz; Gheorghita, Emanuil; Passamonti, Francesco; Neumann, Frank; Patki, Abhay; Gao, Guozhi; Tefferi, Ayalew.

In: JAMA oncology, Vol. 1, No. 5, 01.08.2015, p. 643-651.

Research output: Contribution to journalArticle

Pardanani, A, Harrison, C, Cortes, JE, Cervantes, F, Mesa, RA, Milligan, D, Masszi, T, Mishchenko, E, Jourdan, E, Vannucchi, AM, Drummond, MW, Jurgutis, M, Kuliczkowski, K, Gheorghita, E, Passamonti, F, Neumann, F, Patki, A, Gao, G & Tefferi, A 2015, 'Safety and Efficacy of Fedratinib in Patients With Primary or Secondary Myelofibrosis: A Randomized Clinical Trial', JAMA oncology, vol. 1, no. 5, pp. 643-651. https://doi.org/10.1001/jamaoncol.2015.1590
Pardanani, Animesh ; Harrison, Claire ; Cortes, Jorge E. ; Cervantes, Francisco ; Mesa, Ruben A. ; Milligan, Donald ; Masszi, T. ; Mishchenko, Elena ; Jourdan, Eric ; Vannucchi, Alessandro M. ; Drummond, Mark W. ; Jurgutis, Mindaugas ; Kuliczkowski, Kazimierz ; Gheorghita, Emanuil ; Passamonti, Francesco ; Neumann, Frank ; Patki, Abhay ; Gao, Guozhi ; Tefferi, Ayalew. / Safety and Efficacy of Fedratinib in Patients With Primary or Secondary Myelofibrosis : A Randomized Clinical Trial. In: JAMA oncology. 2015 ; Vol. 1, No. 5. pp. 643-651.
@article{2b9df14e05004d329707ef8427af9419,
title = "Safety and Efficacy of Fedratinib in Patients With Primary or Secondary Myelofibrosis: A Randomized Clinical Trial",
abstract = "DESIGN, SETTING, AND PARTICIPANTS: Double-blind, randomized, placebo-controlled phase 3 study in 94 sites in 24 countries in which 289 adult patients (≥18 years of age) with intermediate-2 or high-risk primary MF, post-polycythemia vera MF, or post-essential thrombocythemia MF were randomly assigned between December 2011 and September 2012 to once-daily oral fedratinib, at a dose of 400 mg or 500 mg, or placebo, for at least 6 consecutive 4-week cycles.MAIN OUTCOMES AND MEASURES: The primary end point was spleen response (≥35{\%} reduction in spleen volume from baseline as determined by magnetic resonance imaging or computed tomography) at week 24 and confirmed 4 weeks later. The main secondary end point was symptom response (≥50{\%} reduction in total symptom score, assessed using the modified Myelofibrosis Symptom Assessment Form).IMPORTANCE: Myelofibrosis (MF) is a BCR-ABL-negative myeloproliferative neoplasm characterized by anemia, splenomegaly, debilitating constitutional symptoms, and shortened survival. Fedratinib, a JAK2-selective inhibitor, previously demonstrated clinically beneficial activity in patients with MF in early-phase trials.OBJECTIVE: To evaluate the efficacy and safety of fedratinib therapy in patients with primary or secondary (post-polycythemia vera or post-essential thrombocythemia) MF.RESULTS: The primary end point was achieved by 35 of 96 (36{\%} [95{\%} CI, 27{\%}-46{\%}]) and 39 of 97 (40{\%} [95{\%} CI, 30{\%}-50{\%}]) patients in the fedratinib 400-mg and 500-mg groups, vs 1 of 96 (1{\%} [95{\%} CI, 0{\%}-3{\%}]) in the placebo group (P CONCLUSIONS AND RELEVANCE: Fedratinib therapy significantly reduced splenomegaly and symptom burden in patients with MF. These benefits were accompanied by toxic effects in some patients, the most important being encephalopathy of unknown mechanism. Clinical development of fedratinib was subsequently discontinued.TRIAL REGISTRATION: clinicaltrials.gov identifier: NCT01437787.",
author = "Animesh Pardanani and Claire Harrison and Cortes, {Jorge E.} and Francisco Cervantes and Mesa, {Ruben A.} and Donald Milligan and T. Masszi and Elena Mishchenko and Eric Jourdan and Vannucchi, {Alessandro M.} and Drummond, {Mark W.} and Mindaugas Jurgutis and Kazimierz Kuliczkowski and Emanuil Gheorghita and Francesco Passamonti and Frank Neumann and Abhay Patki and Guozhi Gao and Ayalew Tefferi",
year = "2015",
month = "8",
day = "1",
doi = "10.1001/jamaoncol.2015.1590",
language = "English",
volume = "1",
pages = "643--651",
journal = "JAMA oncology",
issn = "2374-2437",
publisher = "American Medical Association",
number = "5",

}

TY - JOUR

T1 - Safety and Efficacy of Fedratinib in Patients With Primary or Secondary Myelofibrosis

T2 - A Randomized Clinical Trial

AU - Pardanani, Animesh

AU - Harrison, Claire

AU - Cortes, Jorge E.

AU - Cervantes, Francisco

AU - Mesa, Ruben A.

AU - Milligan, Donald

AU - Masszi, T.

AU - Mishchenko, Elena

AU - Jourdan, Eric

AU - Vannucchi, Alessandro M.

AU - Drummond, Mark W.

AU - Jurgutis, Mindaugas

AU - Kuliczkowski, Kazimierz

AU - Gheorghita, Emanuil

AU - Passamonti, Francesco

AU - Neumann, Frank

AU - Patki, Abhay

AU - Gao, Guozhi

AU - Tefferi, Ayalew

PY - 2015/8/1

Y1 - 2015/8/1

N2 - DESIGN, SETTING, AND PARTICIPANTS: Double-blind, randomized, placebo-controlled phase 3 study in 94 sites in 24 countries in which 289 adult patients (≥18 years of age) with intermediate-2 or high-risk primary MF, post-polycythemia vera MF, or post-essential thrombocythemia MF were randomly assigned between December 2011 and September 2012 to once-daily oral fedratinib, at a dose of 400 mg or 500 mg, or placebo, for at least 6 consecutive 4-week cycles.MAIN OUTCOMES AND MEASURES: The primary end point was spleen response (≥35% reduction in spleen volume from baseline as determined by magnetic resonance imaging or computed tomography) at week 24 and confirmed 4 weeks later. The main secondary end point was symptom response (≥50% reduction in total symptom score, assessed using the modified Myelofibrosis Symptom Assessment Form).IMPORTANCE: Myelofibrosis (MF) is a BCR-ABL-negative myeloproliferative neoplasm characterized by anemia, splenomegaly, debilitating constitutional symptoms, and shortened survival. Fedratinib, a JAK2-selective inhibitor, previously demonstrated clinically beneficial activity in patients with MF in early-phase trials.OBJECTIVE: To evaluate the efficacy and safety of fedratinib therapy in patients with primary or secondary (post-polycythemia vera or post-essential thrombocythemia) MF.RESULTS: The primary end point was achieved by 35 of 96 (36% [95% CI, 27%-46%]) and 39 of 97 (40% [95% CI, 30%-50%]) patients in the fedratinib 400-mg and 500-mg groups, vs 1 of 96 (1% [95% CI, 0%-3%]) in the placebo group (P CONCLUSIONS AND RELEVANCE: Fedratinib therapy significantly reduced splenomegaly and symptom burden in patients with MF. These benefits were accompanied by toxic effects in some patients, the most important being encephalopathy of unknown mechanism. Clinical development of fedratinib was subsequently discontinued.TRIAL REGISTRATION: clinicaltrials.gov identifier: NCT01437787.

AB - DESIGN, SETTING, AND PARTICIPANTS: Double-blind, randomized, placebo-controlled phase 3 study in 94 sites in 24 countries in which 289 adult patients (≥18 years of age) with intermediate-2 or high-risk primary MF, post-polycythemia vera MF, or post-essential thrombocythemia MF were randomly assigned between December 2011 and September 2012 to once-daily oral fedratinib, at a dose of 400 mg or 500 mg, or placebo, for at least 6 consecutive 4-week cycles.MAIN OUTCOMES AND MEASURES: The primary end point was spleen response (≥35% reduction in spleen volume from baseline as determined by magnetic resonance imaging or computed tomography) at week 24 and confirmed 4 weeks later. The main secondary end point was symptom response (≥50% reduction in total symptom score, assessed using the modified Myelofibrosis Symptom Assessment Form).IMPORTANCE: Myelofibrosis (MF) is a BCR-ABL-negative myeloproliferative neoplasm characterized by anemia, splenomegaly, debilitating constitutional symptoms, and shortened survival. Fedratinib, a JAK2-selective inhibitor, previously demonstrated clinically beneficial activity in patients with MF in early-phase trials.OBJECTIVE: To evaluate the efficacy and safety of fedratinib therapy in patients with primary or secondary (post-polycythemia vera or post-essential thrombocythemia) MF.RESULTS: The primary end point was achieved by 35 of 96 (36% [95% CI, 27%-46%]) and 39 of 97 (40% [95% CI, 30%-50%]) patients in the fedratinib 400-mg and 500-mg groups, vs 1 of 96 (1% [95% CI, 0%-3%]) in the placebo group (P CONCLUSIONS AND RELEVANCE: Fedratinib therapy significantly reduced splenomegaly and symptom burden in patients with MF. These benefits were accompanied by toxic effects in some patients, the most important being encephalopathy of unknown mechanism. Clinical development of fedratinib was subsequently discontinued.TRIAL REGISTRATION: clinicaltrials.gov identifier: NCT01437787.

UR - http://www.scopus.com/inward/record.url?scp=84964694744&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84964694744&partnerID=8YFLogxK

U2 - 10.1001/jamaoncol.2015.1590

DO - 10.1001/jamaoncol.2015.1590

M3 - Article

C2 - 26181658

AN - SCOPUS:84964694744

VL - 1

SP - 643

EP - 651

JO - JAMA oncology

JF - JAMA oncology

SN - 2374-2437

IS - 5

ER -