Table 1. Selected clinical studies of... | American Society of Hematology

Table 1.

Selected clinical studies of fedratinib

Frontline studies
Study	Patient population	Treatment	Outcomes	Notes
TED12037; NCT00631462 (phase 1)	Mayo PSS intermediate- or high-risk, Plt ≥50 × 10⁹/L	Fedratinib 30-800 mg per day (dose-escalation phase, n = 28) Fedratinib 680 mg per day (dose-confirmation phase, n = 40)	DLT in 2/6 patients at 800 mg per day: G3/4 hyperamylasemia ≥50% decrease in palpable spleen size for at least 8 weeks at W24 in 39% of patients	28/40 patients (70%) treated with 680 mg per day required dose reduction Median dose during extension phase was 440 mg per day
ARD11936; NCT01420770 (phase 2)	IWG-MRT int-2 or high-risk, splenomegaly (palpable ≥5 cm below LCM), Plt ≥50 × 10⁹/L	Fedratinib 300, 400, or 500 mg per day (1:1:1 randomization, n = 31)	SVR₃₅W₂₄∗: 30%/50%/64% in 300/400/500 mg per day TSS₅₀W₂₄†: 33%/60%/38% in 300/400/500 mg per day	Mean hemoglobin levels are numerically lowest in the 500 mg group G3/4 TEAEs: 80% in 300 and 400 mg per day, and 100% in the 500 mg per day
JAKARTA; NCT01437787 (phase 3)	IWG-MRT int-2 or high-risk, splenomegaly (palpable ≥ 5 cm below LCM), Plt ≥50 × 10⁹/L	Fedratinib 400 mg per day, 500 mg per day, or placebo (1:1:1 randomization, n = 289)	SVR₃₅W₂₄ (confirmed 4 weeks later): 36%/40%/1% in 400 mg per day/500 mg per day/placebo (P < .001) TSS₅₀W₂₄: 36%/34%/7% in 400 mg per day/500 mg per day/placebo (P < .001)	Discontinued fedratinib due to AEs during the first 24 weeks: 14% (400 mg per day), 25% (500 mg per day), and 8% (PBO) SVR₃₅W₂₄ without 4-week confirmation, 47%
Second-line studies
Study	Patient population	Treatment	Outcomes
JAKARTA2; NCT01523171 (phase 2)	DIPSS int-1 (with constitutional symptoms) or ≥int-2, prior ruxolitinib treatment ≥14 days or discontinued for intolerance, splenomegaly (palpable ≥5 cm below LCM), Plt ≥50 × 10⁹/L	Fedratinib 400 mg per day (n = 97)	SVR₃₅W₂₄: 55%, TSS₅₀W₂₄: 26% Stringent criteria ( $\geq$ 3 months of ruxolitinib for resistance, $\geq$ 28 days for intolerance): SVR₃₅W₂₄, 31%; TSS₅₀W₂₄, 27%	In subgroup analyses, SVR rates not significantly influenced by reason for prior ruxolitinib discontinuation (relapsed/refractory or intolerant)
FREEDOM; NCT03755518 (phase 3b)	DIPSS ≥ int-1, splenomegaly ≥ 450 cm³ or palpable ≥5 cm below LCM, ruxolitinib intolerance/resistance (stringent criteria), Plt ≥ 50 × 10⁹/L	Fedratinib 400 mg per day (n = 38)	SVR₃₅W₂₄: 26%, TSS₅₀W₂₄: 44%	SVR₃₅W₂₄ of 37% when including missing W24 spleen measurements by using LOCF analysis
FREEDOM2; NCT03952039 (phase 3)	DIPSS ≥ int-2, splenomegaly ≥ 450 cm³, ruxolitinib intolerance/resistance (stringent criteria), Plt ≥50 × 10⁹/L	Fedratinib 400 mg per day or BAT (2:1 randomization, n = 201) BAT (n = 67): ruxolitinib (78%), RBC transfusions (28%), hydroxyurea (19%)	SVR₃₅W₂₄: 36% in fedratinib vs 6% in BAT (P < .0001) TSS₅₀W₂₄: 34% in fedratinib vs 17% in BAT (P = .0033)	SVR₃₅W₂₄ benefit numerically higher in ruxolitinib intolerant vs ruxolitinib resistant

Frontline studies
Study	Patient population	Treatment	Outcomes	Notes
TED12037; NCT00631462 (phase 1)	Mayo PSS intermediate- or high-risk, Plt ≥50 × 10⁹/L	Fedratinib 30-800 mg per day (dose-escalation phase, n = 28) Fedratinib 680 mg per day (dose-confirmation phase, n = 40)	DLT in 2/6 patients at 800 mg per day: G3/4 hyperamylasemia ≥50% decrease in palpable spleen size for at least 8 weeks at W24 in 39% of patients	28/40 patients (70%) treated with 680 mg per day required dose reduction Median dose during extension phase was 440 mg per day
ARD11936; NCT01420770 (phase 2)	IWG-MRT int-2 or high-risk, splenomegaly (palpable ≥5 cm below LCM), Plt ≥50 × 10⁹/L	Fedratinib 300, 400, or 500 mg per day (1:1:1 randomization, n = 31)	SVR₃₅W₂₄∗: 30%/50%/64% in 300/400/500 mg per day TSS₅₀W₂₄†: 33%/60%/38% in 300/400/500 mg per day	Mean hemoglobin levels are numerically lowest in the 500 mg group G3/4 TEAEs: 80% in 300 and 400 mg per day, and 100% in the 500 mg per day
JAKARTA; NCT01437787 (phase 3)	IWG-MRT int-2 or high-risk, splenomegaly (palpable ≥ 5 cm below LCM), Plt ≥50 × 10⁹/L	Fedratinib 400 mg per day, 500 mg per day, or placebo (1:1:1 randomization, n = 289)	SVR₃₅W₂₄ (confirmed 4 weeks later): 36%/40%/1% in 400 mg per day/500 mg per day/placebo (P < .001) TSS₅₀W₂₄: 36%/34%/7% in 400 mg per day/500 mg per day/placebo (P < .001)	Discontinued fedratinib due to AEs during the first 24 weeks: 14% (400 mg per day), 25% (500 mg per day), and 8% (PBO) SVR₃₅W₂₄ without 4-week confirmation, 47%
Second-line studies
Study	Patient population	Treatment	Outcomes
JAKARTA2; NCT01523171 (phase 2)	DIPSS int-1 (with constitutional symptoms) or ≥int-2, prior ruxolitinib treatment ≥14 days or discontinued for intolerance, splenomegaly (palpable ≥5 cm below LCM), Plt ≥50 × 10⁹/L	Fedratinib 400 mg per day (n = 97)	SVR₃₅W₂₄: 55%, TSS₅₀W₂₄: 26% Stringent criteria ( $\geq$ 3 months of ruxolitinib for resistance, $\geq$ 28 days for intolerance): SVR₃₅W₂₄, 31%; TSS₅₀W₂₄, 27%	In subgroup analyses, SVR rates not significantly influenced by reason for prior ruxolitinib discontinuation (relapsed/refractory or intolerant)
FREEDOM; NCT03755518 (phase 3b)	DIPSS ≥ int-1, splenomegaly ≥ 450 cm³ or palpable ≥5 cm below LCM, ruxolitinib intolerance/resistance (stringent criteria), Plt ≥ 50 × 10⁹/L	Fedratinib 400 mg per day (n = 38)	SVR₃₅W₂₄: 26%, TSS₅₀W₂₄: 44%	SVR₃₅W₂₄ of 37% when including missing W24 spleen measurements by using LOCF analysis
FREEDOM2; NCT03952039 (phase 3)	DIPSS ≥ int-2, splenomegaly ≥ 450 cm³, ruxolitinib intolerance/resistance (stringent criteria), Plt ≥50 × 10⁹/L	Fedratinib 400 mg per day or BAT (2:1 randomization, n = 201) BAT (n = 67): ruxolitinib (78%), RBC transfusions (28%), hydroxyurea (19%)	SVR₃₅W₂₄: 36% in fedratinib vs 6% in BAT (P < .0001) TSS₅₀W₂₄: 34% in fedratinib vs 17% in BAT (P = .0033)	SVR₃₅W₂₄ benefit numerically higher in ruxolitinib intolerant vs ruxolitinib resistant

DLT, Dose limiting toxicity; G3/4, grade 3/4; int-1, intermediate-1; int-2, intermediate-2; IWG-MRT, IWG–Myeloproliferative Neoplasms Research and Treatment; LCM, left costal margin; PBO, placebo; Plt, platelet; PSS, prognostic scoring system.

∗

Spleen volume reduction ≥35% at week 24.

†

Total symptom score reduction ≥35% at week 24.

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