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3006 Long-Term Safety of Fedratinib in Patients with Intermediate- or High-Risk Myelofibrosis (MF)

Program: Oral and Poster Abstracts
Session: 624. Hodgkin Lymphoma and T/NK Cell Lymphoma—Clinical Studies: Poster III
Hematology Disease Topics & Pathways:
Diseases, MPN, Myeloid Malignancies, Clinically relevant
Monday, December 7, 2020, 7:00 AM-3:30 PM

Animesh Pardanani, MBBS, PhD1, Richard M. Stone, MD2, Moshe Talpaz, MD3*, Jorge E. Cortes, MD4, Catriona Jamieson, MD, PhD5, Shelonitda Rose, MD6*, Jun Zhang, PhD6* and Ayalew Tefferi, MD1

1Mayo Clinic of Rochester, Rochester, MN
2Dana-Farber Cancer Institute, Boston, MA
3University of Michigan Comprehensive Cancer Center, Ann Arbor, MI
4Georgia Cancer Center, Augusta, GA
5Moores Cancer Center, University of California, San Diego, La Jolla, CA
6Bristol Myers Squibb, Princeton, NJ

INTRODUCTION: Fedratinib is an oral, selective inhibitor of Janus kinase 2 (JAK2) approved in the United States for treatment of adult patients (pts) with intermediate-2 or high-risk MF. A clinical hold placed on fedratinib development in November 2013 related to suspected Wernicke’s encephalopathy (WE), which was later lifted, limited long-term follow-up from fedratinib studies. The longest follow-up for pts treated with fedratinib is available from a phase I/II extension study (TED12015; NCT00724334) that followed a 6-cycle dose-finding study in 59 pts with intermediate- or high-risk MF (TED12037; NCT00631462) (Pardanani, JCO, 2011).

OBJECTIVE: Report long-term safety of fedratinib in pts with MF who received > 24 treatment cycles in the TED12037 and TED12015 studies.

METHODS: These open-label, dose-finding and extension studies included pts with intermediate- or high-risk primary, post-polycythemia vera, or post-essential thrombocythemia MF. During the TED12037 dose-finding study, pts received continuous fedratinib at doses ranging from 30–800 mg/day for up to 6 28-day treatment cycles. The maximum tolerated dose was 680 mg/day. Pts with stable disease, clinical improvement, or complete or partial remission (IWG-MRT response criteria) after 6 cycles could enter the TED12015 extension study at the last fedratinib dose they received in the dose-finding study. During the extension study, site visits occurred every 3 cycles until cycle 13 and then every 6 cycles. Here, we report long-term safety of fedratinib in pts who received > 24 total treatment cycles in TED12037 and TED12015, as assessed by treatment-emergent adverse event (TEAE) reporting, summarized in 6-cycle intervals up to cycle 36 and collectively after 36 cycles. Late-emerging TEAEs of special interest were cardiac, infectious, and neurologic events. TEAEs were coded according to the Medical Dictionary for Regulatory Activities (MedDRA; version 11.0) and graded using the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE).

RESULTS: In all, 59 pts enrolled in the TED12037 dose-finding study; 43 of those pts (73%) entered the TED12015 extension study, and 28 pts (47%) received > 24 cycles of fedratinib across both studies and comprise the Long-term (LT) Cohort. 11 of 59 pts (19%) discontinued before cycle 24 due to a TEAE.

In the LT Cohort, median age at study entry was 62.5 years (range 43–82). Pts received fedratinib for a median of 46 cycles (range 25–72) for a total of 100.6 pt-years of exposure. The median average fedratinib dose per pt was 462 mg/day (range 283–800), and overall treatment compliance rate was 98% (80%–100%). Reasons for fedratinib discontinuation in > 1 pt in the LT Cohort were investigator decision (n = 10), TEAEs (n = 5), study termination (n = 5), and disease progression (n = 4).

TEAE frequencies were highest during treatment cycles 1–6 and generally decreased or remained stable in later cycles (Table). The most common TEAEs after > 24 cycles of fedratinib were hematologic and gastrointestinal (GI) events, reported at rates lower or similar to those in early treatment cycles. Grade 3–4 TEAEs reported in > 1 pt after cycle 24 were thrombocytopenia, anemia, neutropenia, and pneumonia.

Few pts experienced late-emerging cardiac events or severe/opportunistic infections. The only cardiac event of interest was 1 case of congestive cardiac failure (grade 1) during cycle 7. The only infectious event observed in > 1 pt after cycle 24 was pneumonia; of 5 events reported in 4 pts, all were grade 3 or grade 4, and 2 were considered possibly related to treatment. Three grade 3–4 serious neurologic events were reported at any time: post-herpetic neuralgia (in 2 pts, at cycle 10 and cycle 36) and cerebrovascular accident (in 1 pt during cycle 1). No suspected cases of WE were reported.

CONCLUSIONS: Fedratinib remained well tolerated in pts who stayed on treatment for >24 cycles. TEAE frequencies generally decreased or remained stable after cycles 1–6. Among TEAEs of interest, pneumonia was the only event reported in > 1 pt (n = 4) after cycle 24. Although limited to a small pt population, these findings provide valuable information to guide clinical practice for pts who require long-term therapy. The ongoing phase III FREEDOM (NCT03755518) and FREEDOM2 (NCT03952039) studies include assessment of long-term outcomes with fedratinib in pts with MF previously treated with ruxolitinib.

Disclosures: Stone: Actinium: Consultancy; Trovagene: Consultancy; Daiichi-Sankyo: Consultancy; Macrogenics: Consultancy; Hoffman LaRoche: Consultancy; Gemoab: Consultancy; Janssen: Consultancy; Novartis: Consultancy, Research Funding; Otsuka: Consultancy; Takeda: Consultancy; Astellas: Consultancy, Membership on an entity's Board of Directors or advisory committees; Arog: Research Funding; Argenx: Consultancy, Other: Data and safety monitoring board; Agios: Consultancy, Research Funding; AstraZeneca: Consultancy; Jazz: Consultancy; Celgene: Consultancy, Other: Data and safety monitoring board; Biolinerx: Consultancy; AbbVie: Consultancy, Research Funding; Syros: Consultancy; Elevate: Consultancy; Pfizer: Consultancy; Stemline: Consultancy; Syndax: Consultancy; Syntrix: Consultancy. Talpaz: IMAGO: Consultancy; Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees; Constellation: Membership on an entity's Board of Directors or advisory committees. Cortes: Bristol-Myers Squibb: Research Funding; Merus: Research Funding; BiolineRx: Consultancy, Research Funding; Daiichi Sankyo: Consultancy, Research Funding; Telios: Research Funding; Astellas: Research Funding; Amphivena Therapeutics: Research Funding; Arog: Research Funding; Sun Pharma: Research Funding; BioPath Holdings: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Jazz Pharmaceuticals: Consultancy, Research Funding; Immunogen: Research Funding; Takeda: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Novartis: Consultancy, Research Funding. Jamieson: Forty Seven Inc: Patents & Royalties; Bristol-Myers Squibb: Other. Rose: Bristol-Myers Squibb Company: Current Employment, Current equity holder in publicly-traded company. Zhang: Bristol-Myers Squibb Company: Current Employment, Current equity holder in publicly-traded company.

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