Updated results of the placebo‐controlled, phase III JAKARTA trial of fedratinib in patients with intermediate‐2 or high‐risk myelofibrosis

Abstract

Fedratinib, an oral Janus kinase-2 (JAK2) inhibitor, reduces splenomegaly and improves symptom burden in patients with myelofibrosis. Regulatory approval of fedratinib 400-mg daily was based on results of an updated analysis of the pivotal phase III, placebo-controlled JAKARTA trial in patients with JAK-inhibitor-na€ ıve myelofibrosis. At week 24, spleen volume response rate was 47% and symptom response rate was 40% with fedratinib 400 mg, versus 1% and 9% respectively, with placebo. Common adverse events were diarrhoea, nausea, anaemia, and vomiting. No Wernicke encephalopathy occurred in patients receiving fedratinib 400 mg/day. These updated data support use of first-line fedratinib in patients with myelofibrosis.

The clinical dilemma of JAK inhibitor failure in myelofibrosis: Predictive characteristics and outcomes

“…In the cohort randomized to fedratinib 400 mg daily, most of the discontinuations by the end of week 24 were for AEs (13 of 21 patients). In the reanalyzed JAKARTA safety data, patients randomized to fedratinib had AE‐related treatment interruption and dose reduction rates 21% and 14%, respectively, mostly for gastrointestinal AEs (eg, diarrhea; responsible for 5% and 4% of patients interrupting or dose‐reducing treatment) or anemia (the most common cause of dose reductions; 6% of patients) 19 . Thirteen patients, or 14%, had permanent discontinuations of fedratinib: 3 of these patients had cardiac failure, and 2 each discontinued for thrombocytopenia, myocardial ischemia, diarrhea, or increased blood creatinine.…”

“…Fedratinib was evaluated in a pivotal phase 3 clinical trial, JAKARTA (ClinicalTrials.gov identifier NCT01437787) and demonstrated spleen volume reductions along with symptomatic and quality-of-life benefits relative to placebo in patients with intermediate-2-risk or high-risk, primary or secondary MF (Table 2). 3,4,9,19,20 Of note, the JAKARTA trial had been terminated in 2013 in response to a clinical hold on development because of a suspected emergence of Wernicke encephalopathy; however, the hold was lifted in 2017 after consideration of additional safety data (supporting that these cases were in patients receiving 500 mg daily), thus resuming the regulatory submission process. 4,19 Reanalyzed efficacy results from JAKARTA, which formed the basis for the US Food and Drug Administration approval of fedratinib 400 mg daily, showed a 24-week spleen response rate of 47% (vs 1% with placebo) or 37% when confirmed with 4-week scans, along with a symptom response rate of 40%.…”

“…3,4,9,19,20 Of note, the JAKARTA trial had been terminated in 2013 in response to a clinical hold on development because of a suspected emergence of Wernicke encephalopathy; however, the hold was lifted in 2017 after consideration of additional safety data (supporting that these cases were in patients receiving 500 mg daily), thus resuming the regulatory submission process. 4,19 Reanalyzed efficacy results from JAKARTA, which formed the basis for the US Food and Drug Administration approval of fedratinib 400 mg daily, showed a 24-week spleen response rate of 47% (vs 1% with placebo) or 37% when confirmed with 4-week scans, along with a symptom response rate of 40%. 19 A subsequent phase 2 clinical trial specifically in ruxolitinibresistant or ruxolitinib-intolerant patients, JAKARTA-2 (ClinicalTrials.gov identifier NCT01523171), met its primary end point of spleen response in the primary analysis 3 and in an updated analysis using stringent criteria for ruxolitinib failure (Table 2), 9 with quality-of-life benefits also demonstrated.…”

“…4,19 Reanalyzed efficacy results from JAKARTA, which formed the basis for the US Food and Drug Administration approval of fedratinib 400 mg daily, showed a 24-week spleen response rate of 47% (vs 1% with placebo) or 37% when confirmed with 4-week scans, along with a symptom response rate of 40%. 19 A subsequent phase 2 clinical trial specifically in ruxolitinibresistant or ruxolitinib-intolerant patients, JAKARTA-2 (ClinicalTrials.gov identifier NCT01523171), met its primary end point of spleen response in the primary analysis 3 and in an updated analysis using stringent criteria for ruxolitinib failure (Table 2), 9 with quality-of-life benefits also demonstrated. 21 Survival data have been presented for patients receiving fedratinib 400 mg daily in JAKARTA and JAKARTA-2.…”

“…In the reanalyzed JAKARTA safety data, patients randomized to fedratinib had AE-related treatment interruption and dose reduction rates 21% and 14%, respectively, mostly for gastrointestinal AEs (eg, diarrhea; responsible for 5% and 4% of patients interrupting or dose-reducing treatment) or anemia (the most common cause of dose reductions; 6% of patients). 19 Thirteen patients, or 14%, had permanent discontinuations of fedratinib: 3 of these patients had cardiac failure, and 2 each discontinued for thrombocytopenia, myocardial ischemia, diarrhea, or increased blood creatinine. In JAKARTA-2, most study discontinuations were related to the aforementioned fedratinib clinical hold (65%), followed by AEs (19%), and PD (6%).…”