Results of clinical trials with JAKis in MF
| Agent and primary targets . | Clinical trial and numerosity . | Key inclusion criteria . | SVR ≥35% at 24 wk . | Symptom reduction . | Relevant toxicities with agent on study . | Comments . |
|---|---|---|---|---|---|---|
| RUX JAK1/2 | COMFORT-1 phase 3 RUX (n = 155) vs PBO (n = 154) RUX 15 mg BID (PLT 100 × 109/L-200 × 109/L) or RUX 20 mg BID (PLT >200 × 109/L) | ≥Int-2 MF PLT ≥100 × 109/L Intolerant or refractory to other available therapies | 41.9% (RUX) vs 0.7% (PBO) | ≥50% MFSAF TSS v2.0 at 24 wk: 45.9% (RUX) vs 5.3% (PBO) | G3/4 anemia: 45.2% G3/4 thrombocytopenia: 12.9% G3/4 neutropenia: 7.1% Rate of nonhematological toxicities and discontinuation for AEs: (11%) like PBO | Median OS in pooled analysis: 5.3 y (RUX) vs 3.8 y (PBO/BAT) |
| COMFORT-2 phase 3 RUX (n = 146) vs BAT (n = 73) RUX initial doses as in COMFORT-1 | ≥Int-2 MF PLT ≥100 × 109/L | 32% (RUX) vs 0% (BAT) | EORTC QLQ-C30 mean change from BL: +9.1 (RUX) vs +3.4 (BAT) FACT-Lym score mean change from BL: +11.3 (RUX) vs −0.9 (BAT) | G3/4 anemia: 42% G3/4 thrombocytopenia: 8% Any grade diarrhea: 23% Discontinuation for AEs 8% (RUX) vs 5% (BAT) | ||
| FEDR JAK2 JAK1 TYK2 JAK3 | JAKARTA phase 3 FEDR (n = 193) vs PBO (n = 96) FEDR 400 or 500 mg QD | ≥Int-2 MF PLT ≥50 × 109/L JAKI-naïve | 36% (FEDR 400 mg with 4 wk later confirmation) and 40% (FEDR 500 mg) vs 1% (PBO) | ≥50% modified MFSAF TSS at 24 wk: 36% (FEDR 400 mg) and 34% (FEDR 500 mg) vs 7% (PBO) | G3/4 anemia: 43% (FEDR 400 mg); 60% (FEDR 500 mg) G3/4 thrombocytopenia: 17% (FEDR 400 mg); 27% (FEDR 500 mg) G3/4 neutropenia: 8% (FEDR 400 mg); 18% (FEDR 500 mg) Frequent GI toxicity (mostly G1/2) Encephalopathy in 4 of 97 patients in the FEDR 500 mg group | Suspected cases of Wernicke encephalopathy (WE) led to early study termination; in 2017, however, the FDA decided to lift the clinical hold based on updated clinical data |
| JAKARTA-2 phase 2 FEDR (n = 97) FEDR 400 mg QD | Int-1 with symptoms, Int-2 or high-risk MF PLT ≥50 × 109/L RUX resistant, intolerant | 55% (30% with stringent RUX failure criteria) | ≥50% modified MFSAF TSS at 24 wk: 26% | G3/4 anemia: 38% G3/4 thrombocytopenia: 22% Frequent GI toxicity (mostly G1/2) | ||
| FREEDOM NCT03755518 phase 3b FEDR (estimated n = 110) FEDR 400 mg QD | Int/high-risk MF PLT ≥50 × 109/L RUX exposed | Primary end point | Secondary end point | Out of n = 34 evaluable patients G3/4 anemia: 21% G3/4 thrombocytopenia: 6% Modest GI toxicity (mostly G1/2) | These studies included prospective strategies for preventing or mitigating GI AEs, thiamine level decreases, and potential WE Ongoing | |
| FREEDOM 2 NCT03952039 phase 3 FEDR vs BAT (estimated n = 192) FEDR 400 mg QD | ≥Int-2 MF PLT ≥50 × 109/L RUX refractory, resistant or intolerant | Primary end point | Secondary end point | Secondary end point | ||
| PAC JAK2 FLT3 IRAK1 CSF1R ACVR1 | PERSIST-1 phase 3 PAC (n = 220) vs BAT (n = 107, excl. JAKi) PAC 400 mg QD | ≥Int-1 risk MF JAKi-naïve No exclusions for cytopenia | 19% (PAC) vs 5% (BAT) | ≥50% MPNSAF TSS at 24 wk: no significant benefit vs BAT | G3/4 anemia: 17% G3/4 thrombocytopenia: 12% G3/4 diarrhea: 5% Heart failure: 2% | PERSIST-1: 25% of TD patients achieved TI Full clinical hold Feb2016/Jan2017 for fatal hemorrhagic and cardiac toxicity concerns, lifted after updated clinical data |
| PERSIST-2 phase 3 PAC (n = 211) vs BAT (n = 100, including RUX) PAC 400 mg QD or 200 mg BID | ≥Int-1 risk MF PLT <100 × 109/L Previously treated or JAKi-naïve 48% had prior RUX and BAT included RUX in 45% | 18% (PAC) vs 3% (BAT) 22%, if PAC at 200 mg BID | ≥50% MPNSAF TSS at 24 wk: 25% (PAC) vs 14% (BAT) 32%, if PAC at 200 mg BID | Toxicities less frequent in PAC BID dosing compared with QD Cardiac AEs: 7% at PAC 200 mg BID and 13% at PAC 400 mg QD Intracranial hemorrhage: 1% (PAC QD) | ||
| PAC203 phase 2 PAC (n = 165) PAC 100 mg QD or 100 mg BID or 200 mg BID | ≥Int-1 risk MF Any PLT count RUX failure or intolerance | 9.3% (PAC 200 mg BID) vs 1.8% (100 mg BID) vs 0% (100 mg QD) 16.7%, if PAC at 200 mg BID and BL PLT <50 × 109/L | ≥50% MPNSAF TSS at 24 wk: similar among arms (around 7.5%) | G3/4 anemia: 20.4% at 200 mg BID G3/4 thrombocytopenia: 33.3% at 200 mg BID Common GI toxicity, mostly G1/2 at PAC 200 mg BID Uncommon severe cardiac events and bleedings | ||
| PACIFICA NCT03165734 phase 3 PAC 200 mg BID vs physician’s choice (estimated n = 348) | ≥Int-1 risk MF PLT <50 × 109/L No or limited exposure to any JAKi | Primary end point | Primary end point | Secondary end point | Ongoing | |
| MMB JAK1 JAK2 ACVR1 | SIMPLIFY-1 phase 3 MMB (n = 215) vs RUX (n = 217) MMB 200 mg QD | Int-1 with symptoms, Int-2 or high-risk MF PLT ≥50 × 109/L JAKi naïve | MMB not inferior to RUX (26.5% vs 29%) | ≥50% MPNSAF TSS at 24 wk: MMB inferior to RUX (28.4% vs 42.2%) | G3/4 anemia: 6% G3/4 thrombocytopenia: 7% All grade PN: 10% | TI at 24 wk: MMB associated with significantly reduced RBC transfusions needs Correlation between TI at 24 wk and OS (trend in SIMPLIFY-2) |
| SIMPLIFY-2 phase 3 MMB (n = 104) vs BAT (n = 52, 89% RUX) MMB 200 mg QD | Int-1 with symptoms, Int-2 or high-risk MF Any PLT count Suboptimal response, intolerance to RUX | MMB not superior to BAT (around 7% in both arms) | ≥50% MPNSAF TSS at 24 wk: 26.2% (MMB) vs 5.9% (BAT) | G3/4 anemia: 14% G3/4 thrombocytopenia: 7% All grade PN: 11% | ||
| MOMENTUM phase 3 MMB (n = 130) vs Danazol (DAN, n = 65) MMB 200 mg QD, DAN 600 mg QD | Int/high-risk symptomatic MF Hb <10 g/dL PLT ≥25 × 109/L Previous exposure to any JAKi | 23% (MMB) vs 3% (DAN) | MFSAF TSS at 24 wk: 32% (MMB) vs 6% (DAN) | G3/4 anemia: 61% G3/4 thrombocytopenia: 28% | TI at 24 wk: 31% (MMB) vs 20% (DAN) | |
| Jaktinib (JAKT) JAK2 JAK1 ACVR1 TYK2 | NCT03886415 phase 2 JAKT 100 mg BID vs 200 mg QD (n = 118) | ≥Int-1 risk symptomatic MF PLT ≥75 × 109/L | 54.8% (JAKT 100 mg BID), 31.3% (JAKT 200 mg QD) | ≥50% MFSAF TSS at 24 wk: 69.6% (JAKT 100 mg BID), 57.5% (JAKT 200 mg QD) | G3/4 anemia: ∼25% G3/4 thrombocytopenia: ∼15% | Increased Hb levels in 36% of patients with baseline Hb ≤10 g/dL |
| NCT04217993 phase 2b JAKT 100 mg BID (estimated n = 43 in the extended research part) | ≥Int-1 risk symptomatic MF PLT >30 × 109/L Intolerant to RUX | Primary end point | Secondary end point | Secondary end point | Ongoing | |
| NCT04851535 phase 2 JAKT 100 mg BID (estimated n = 30) | ≥Int-1 risk symptomatic MF PLT ≥75 × 109/L Relapsed, refractory to RUX | Primary end point | Secondary end point | Ongoing | ||
| NCT04617028 phase 3 JAKT + PBO vs HU + PBO (estimated n = 105) | ≥Int-2 MF JAKi naïve | Primary end point | Ongoing | |||
| TQ05105 (TQ) JAK2 | NCT05020652 phase 2 TQ + HU blank tablets vs TQ blank tablets + HU | ≥Int-1 risk MF PLT ≥100 × 109/L JAKi-naïve | Primary end point | Secondary end point | Secondary end point | Ongoing |
| Itacitinib (ITA) JAK1 | NCT01633372 phase 2 ITA (n = 87) ITA 100 mg BID vs 200 mg BID vs 600 mg QD | ≥Int-1 risk symptomatic MF PLT ≥50 × 109/L Prior JAKi not excluded | 17% (across doses) | ≥50% MFSAF TSS at 24 wk: 20% (100 mg BID) vs 29% (200 mg BID) vs 35% (600 mg QD) | G3/4 anemia: 25%-38% G3/4 thrombocytopenia: 15%-44% Fatigue: 28.7% | |
| LIMBER-213 NCT04629508 phase 2 Immediate release ITA (RP2D) | ≥Int-1 risk MF PLT ≥50 × 109/L Previous RUX and/or FEDR | Primary end point | Secondary end point | Secondary end point | Ongoing | |
| NCT03144687 phase 2 Cohort A: ITA 200 mg QD + ongoing RUX at <10 mg BID (estimated n = 21) Cohort B: ITA 600 mg QD (estimated n = 21) | PLT ≥50 × 109/L Cohort A: patients already on RUX <10 mg BID Cohort B: RUX failure or intolerance | Primary end point | Secondary end point | Secondary end point | Ongoing |
| Agent and primary targets . | Clinical trial and numerosity . | Key inclusion criteria . | SVR ≥35% at 24 wk . | Symptom reduction . | Relevant toxicities with agent on study . | Comments . |
|---|---|---|---|---|---|---|
| RUX JAK1/2 | COMFORT-1 phase 3 RUX (n = 155) vs PBO (n = 154) RUX 15 mg BID (PLT 100 × 109/L-200 × 109/L) or RUX 20 mg BID (PLT >200 × 109/L) | ≥Int-2 MF PLT ≥100 × 109/L Intolerant or refractory to other available therapies | 41.9% (RUX) vs 0.7% (PBO) | ≥50% MFSAF TSS v2.0 at 24 wk: 45.9% (RUX) vs 5.3% (PBO) | G3/4 anemia: 45.2% G3/4 thrombocytopenia: 12.9% G3/4 neutropenia: 7.1% Rate of nonhematological toxicities and discontinuation for AEs: (11%) like PBO | Median OS in pooled analysis: 5.3 y (RUX) vs 3.8 y (PBO/BAT) |
| COMFORT-2 phase 3 RUX (n = 146) vs BAT (n = 73) RUX initial doses as in COMFORT-1 | ≥Int-2 MF PLT ≥100 × 109/L | 32% (RUX) vs 0% (BAT) | EORTC QLQ-C30 mean change from BL: +9.1 (RUX) vs +3.4 (BAT) FACT-Lym score mean change from BL: +11.3 (RUX) vs −0.9 (BAT) | G3/4 anemia: 42% G3/4 thrombocytopenia: 8% Any grade diarrhea: 23% Discontinuation for AEs 8% (RUX) vs 5% (BAT) | ||
| FEDR JAK2 JAK1 TYK2 JAK3 | JAKARTA phase 3 FEDR (n = 193) vs PBO (n = 96) FEDR 400 or 500 mg QD | ≥Int-2 MF PLT ≥50 × 109/L JAKI-naïve | 36% (FEDR 400 mg with 4 wk later confirmation) and 40% (FEDR 500 mg) vs 1% (PBO) | ≥50% modified MFSAF TSS at 24 wk: 36% (FEDR 400 mg) and 34% (FEDR 500 mg) vs 7% (PBO) | G3/4 anemia: 43% (FEDR 400 mg); 60% (FEDR 500 mg) G3/4 thrombocytopenia: 17% (FEDR 400 mg); 27% (FEDR 500 mg) G3/4 neutropenia: 8% (FEDR 400 mg); 18% (FEDR 500 mg) Frequent GI toxicity (mostly G1/2) Encephalopathy in 4 of 97 patients in the FEDR 500 mg group | Suspected cases of Wernicke encephalopathy (WE) led to early study termination; in 2017, however, the FDA decided to lift the clinical hold based on updated clinical data |
| JAKARTA-2 phase 2 FEDR (n = 97) FEDR 400 mg QD | Int-1 with symptoms, Int-2 or high-risk MF PLT ≥50 × 109/L RUX resistant, intolerant | 55% (30% with stringent RUX failure criteria) | ≥50% modified MFSAF TSS at 24 wk: 26% | G3/4 anemia: 38% G3/4 thrombocytopenia: 22% Frequent GI toxicity (mostly G1/2) | ||
| FREEDOM NCT03755518 phase 3b FEDR (estimated n = 110) FEDR 400 mg QD | Int/high-risk MF PLT ≥50 × 109/L RUX exposed | Primary end point | Secondary end point | Out of n = 34 evaluable patients G3/4 anemia: 21% G3/4 thrombocytopenia: 6% Modest GI toxicity (mostly G1/2) | These studies included prospective strategies for preventing or mitigating GI AEs, thiamine level decreases, and potential WE Ongoing | |
| FREEDOM 2 NCT03952039 phase 3 FEDR vs BAT (estimated n = 192) FEDR 400 mg QD | ≥Int-2 MF PLT ≥50 × 109/L RUX refractory, resistant or intolerant | Primary end point | Secondary end point | Secondary end point | ||
| PAC JAK2 FLT3 IRAK1 CSF1R ACVR1 | PERSIST-1 phase 3 PAC (n = 220) vs BAT (n = 107, excl. JAKi) PAC 400 mg QD | ≥Int-1 risk MF JAKi-naïve No exclusions for cytopenia | 19% (PAC) vs 5% (BAT) | ≥50% MPNSAF TSS at 24 wk: no significant benefit vs BAT | G3/4 anemia: 17% G3/4 thrombocytopenia: 12% G3/4 diarrhea: 5% Heart failure: 2% | PERSIST-1: 25% of TD patients achieved TI Full clinical hold Feb2016/Jan2017 for fatal hemorrhagic and cardiac toxicity concerns, lifted after updated clinical data |
| PERSIST-2 phase 3 PAC (n = 211) vs BAT (n = 100, including RUX) PAC 400 mg QD or 200 mg BID | ≥Int-1 risk MF PLT <100 × 109/L Previously treated or JAKi-naïve 48% had prior RUX and BAT included RUX in 45% | 18% (PAC) vs 3% (BAT) 22%, if PAC at 200 mg BID | ≥50% MPNSAF TSS at 24 wk: 25% (PAC) vs 14% (BAT) 32%, if PAC at 200 mg BID | Toxicities less frequent in PAC BID dosing compared with QD Cardiac AEs: 7% at PAC 200 mg BID and 13% at PAC 400 mg QD Intracranial hemorrhage: 1% (PAC QD) | ||
| PAC203 phase 2 PAC (n = 165) PAC 100 mg QD or 100 mg BID or 200 mg BID | ≥Int-1 risk MF Any PLT count RUX failure or intolerance | 9.3% (PAC 200 mg BID) vs 1.8% (100 mg BID) vs 0% (100 mg QD) 16.7%, if PAC at 200 mg BID and BL PLT <50 × 109/L | ≥50% MPNSAF TSS at 24 wk: similar among arms (around 7.5%) | G3/4 anemia: 20.4% at 200 mg BID G3/4 thrombocytopenia: 33.3% at 200 mg BID Common GI toxicity, mostly G1/2 at PAC 200 mg BID Uncommon severe cardiac events and bleedings | ||
| PACIFICA NCT03165734 phase 3 PAC 200 mg BID vs physician’s choice (estimated n = 348) | ≥Int-1 risk MF PLT <50 × 109/L No or limited exposure to any JAKi | Primary end point | Primary end point | Secondary end point | Ongoing | |
| MMB JAK1 JAK2 ACVR1 | SIMPLIFY-1 phase 3 MMB (n = 215) vs RUX (n = 217) MMB 200 mg QD | Int-1 with symptoms, Int-2 or high-risk MF PLT ≥50 × 109/L JAKi naïve | MMB not inferior to RUX (26.5% vs 29%) | ≥50% MPNSAF TSS at 24 wk: MMB inferior to RUX (28.4% vs 42.2%) | G3/4 anemia: 6% G3/4 thrombocytopenia: 7% All grade PN: 10% | TI at 24 wk: MMB associated with significantly reduced RBC transfusions needs Correlation between TI at 24 wk and OS (trend in SIMPLIFY-2) |
| SIMPLIFY-2 phase 3 MMB (n = 104) vs BAT (n = 52, 89% RUX) MMB 200 mg QD | Int-1 with symptoms, Int-2 or high-risk MF Any PLT count Suboptimal response, intolerance to RUX | MMB not superior to BAT (around 7% in both arms) | ≥50% MPNSAF TSS at 24 wk: 26.2% (MMB) vs 5.9% (BAT) | G3/4 anemia: 14% G3/4 thrombocytopenia: 7% All grade PN: 11% | ||
| MOMENTUM phase 3 MMB (n = 130) vs Danazol (DAN, n = 65) MMB 200 mg QD, DAN 600 mg QD | Int/high-risk symptomatic MF Hb <10 g/dL PLT ≥25 × 109/L Previous exposure to any JAKi | 23% (MMB) vs 3% (DAN) | MFSAF TSS at 24 wk: 32% (MMB) vs 6% (DAN) | G3/4 anemia: 61% G3/4 thrombocytopenia: 28% | TI at 24 wk: 31% (MMB) vs 20% (DAN) | |
| Jaktinib (JAKT) JAK2 JAK1 ACVR1 TYK2 | NCT03886415 phase 2 JAKT 100 mg BID vs 200 mg QD (n = 118) | ≥Int-1 risk symptomatic MF PLT ≥75 × 109/L | 54.8% (JAKT 100 mg BID), 31.3% (JAKT 200 mg QD) | ≥50% MFSAF TSS at 24 wk: 69.6% (JAKT 100 mg BID), 57.5% (JAKT 200 mg QD) | G3/4 anemia: ∼25% G3/4 thrombocytopenia: ∼15% | Increased Hb levels in 36% of patients with baseline Hb ≤10 g/dL |
| NCT04217993 phase 2b JAKT 100 mg BID (estimated n = 43 in the extended research part) | ≥Int-1 risk symptomatic MF PLT >30 × 109/L Intolerant to RUX | Primary end point | Secondary end point | Secondary end point | Ongoing | |
| NCT04851535 phase 2 JAKT 100 mg BID (estimated n = 30) | ≥Int-1 risk symptomatic MF PLT ≥75 × 109/L Relapsed, refractory to RUX | Primary end point | Secondary end point | Ongoing | ||
| NCT04617028 phase 3 JAKT + PBO vs HU + PBO (estimated n = 105) | ≥Int-2 MF JAKi naïve | Primary end point | Ongoing | |||
| TQ05105 (TQ) JAK2 | NCT05020652 phase 2 TQ + HU blank tablets vs TQ blank tablets + HU | ≥Int-1 risk MF PLT ≥100 × 109/L JAKi-naïve | Primary end point | Secondary end point | Secondary end point | Ongoing |
| Itacitinib (ITA) JAK1 | NCT01633372 phase 2 ITA (n = 87) ITA 100 mg BID vs 200 mg BID vs 600 mg QD | ≥Int-1 risk symptomatic MF PLT ≥50 × 109/L Prior JAKi not excluded | 17% (across doses) | ≥50% MFSAF TSS at 24 wk: 20% (100 mg BID) vs 29% (200 mg BID) vs 35% (600 mg QD) | G3/4 anemia: 25%-38% G3/4 thrombocytopenia: 15%-44% Fatigue: 28.7% | |
| LIMBER-213 NCT04629508 phase 2 Immediate release ITA (RP2D) | ≥Int-1 risk MF PLT ≥50 × 109/L Previous RUX and/or FEDR | Primary end point | Secondary end point | Secondary end point | Ongoing | |
| NCT03144687 phase 2 Cohort A: ITA 200 mg QD + ongoing RUX at <10 mg BID (estimated n = 21) Cohort B: ITA 600 mg QD (estimated n = 21) | PLT ≥50 × 109/L Cohort A: patients already on RUX <10 mg BID Cohort B: RUX failure or intolerance | Primary end point | Secondary end point | Secondary end point | Ongoing |
AE, adverse event; BAT, best available therapy; BID, twice daily; EORTC QLQ, European Organization for the research and treatment of cancer quality of life questionnaire; FACT-Lym, Functional Assessment of cancer therapy-lymphoma; FDA, Food and Drug Administration; G, grade; GI, gastrointestinal; Hb, hemoglobin; HU, hydroxyurea; JAKi, JAK inhibitor; MF, myelofibrosis; MFSAF, Myelofibrosis Symptom Assessment Form; MPNSAF, Myeloproliferative Neoplasm Symptom Assessment Form; OS, overall survival; PBO, placebo; PLT, platelets; PN, peripheral neuropathy; QD, once daily; RBC, red blood cells; RP2D, recommended phase 2 dose; SVR35, spleen volume reduction of 35%; TD, transfusion-dependent; TI, transfusion-independent; TSS, total symptom score.