Ongoing phase 3 trials in JAKi-exposed patients with MF
| Agent mechanism of action . | Clinical trial characteristics . | Key inclusion criteria . | Definition of failure to first-line therapy . | Primary end point . |
|---|---|---|---|---|
| Imetelstat (IME) Telomerase inhibitor | IMpactMF/MYF3001 NCT04576156 IME vs BAT (excluded JAKis) (estimated n = 320) IME 9.4 mg/kg q21 | DIPSS Int-2/high-risk symptomatic MF PLT ≥75 × 109/L Spleen length ≥5 cm below LCM or volume ≥450 cm3 | ≥6 mo of JAKi with no spleen/symptoms reduction ≥3 mo of JAKi at MTD with no spleen/symptoms reduction ≥3 mo of JAKi at MTD and relapsing splenomegaly | OS |
| Navitoclax (NAVI) BCL-XL/BCL-2 inhibitor | TRANSFORM-2 NCT04468984 NAVI+RUX vs BAT, (included JAKis) (estimated n = 330) NAVI 100 or 200 mg QD, based on PLT count RUX at prior stable dose or 10 mg BID | DIPSS+ Int-2/high-risk symptomatic MF PLT ≥100 × 109/L Spleen length ≥5 cm below LCM or volume ≥450 cm3 | ≥6 mo of RUX, stopped for lack/loss or spleen response or for relapsed symptom control ≥6 mo of RUX, continued despite relapsed/refractory status <6 mo of RUX, with progression/appearance of splenomegaly ≥1 mo of RUX at ≥15 mg BID to keep efficacy with RBC units need | SVR35 at 24 wk |
| Navtemadlin (NAVT) MDM2 inhibitor | BOREAS NCT03662126 NAVT vs BAT (excluded JAKi) (estimated n = 385) NAVT 240 mg QD d 1-7 of 28-d cycle | DIPSS Int/high-risk MF PLT ≥50 × 109/L TP53 wild-type | Relapsed to prior JAKi: progressive from BL or after a response-increased splenomegaly Refractory to prior JAKi: lack of spleen response after ≥3 mo | SVR35 at 24 wk |
| Parsaclisib (PARS) PI3Kδ inhibitor | LIMBER-304 NCT04551053 PARS + RUX vs PBO + RUX (estimated n = 212) PARS 5 mg QD, RUX on the ongoing 2-mo stable dose | DIPSS Int/high-risk symptomatic MF PLT ≥50 × 109/L Spleen length ≥5 cm below LCM | ≥3 mo of RUX, at stable dose for ≥2 mo Suboptimal response to RUX: spleen of ≥5 cm below LCM and active symptoms at the screening visit | SVR35 at 24 wk |
| Luspatercept (LUS) Activin receptor ligand trap | INDEPENDENCE NCT04717414 LUS vs PBO in ongoing JAKi (estimated n = 309) LUS 1.33 mg/kg q21 | RBC-TD DIPSS Int/high-risk MF PLT as approved for the concomitant JAKi, neither <25 × 109/L nor ≥1000 × 109/L | JAKi for ≥8 mo with stable dose for ≥4 mo, and requirement of 4-12 RBC units/12 wk up to randomization | RBC-TI ≥12 wk up to wk 24 |
| Agent mechanism of action . | Clinical trial characteristics . | Key inclusion criteria . | Definition of failure to first-line therapy . | Primary end point . |
|---|---|---|---|---|
| Imetelstat (IME) Telomerase inhibitor | IMpactMF/MYF3001 NCT04576156 IME vs BAT (excluded JAKis) (estimated n = 320) IME 9.4 mg/kg q21 | DIPSS Int-2/high-risk symptomatic MF PLT ≥75 × 109/L Spleen length ≥5 cm below LCM or volume ≥450 cm3 | ≥6 mo of JAKi with no spleen/symptoms reduction ≥3 mo of JAKi at MTD with no spleen/symptoms reduction ≥3 mo of JAKi at MTD and relapsing splenomegaly | OS |
| Navitoclax (NAVI) BCL-XL/BCL-2 inhibitor | TRANSFORM-2 NCT04468984 NAVI+RUX vs BAT, (included JAKis) (estimated n = 330) NAVI 100 or 200 mg QD, based on PLT count RUX at prior stable dose or 10 mg BID | DIPSS+ Int-2/high-risk symptomatic MF PLT ≥100 × 109/L Spleen length ≥5 cm below LCM or volume ≥450 cm3 | ≥6 mo of RUX, stopped for lack/loss or spleen response or for relapsed symptom control ≥6 mo of RUX, continued despite relapsed/refractory status <6 mo of RUX, with progression/appearance of splenomegaly ≥1 mo of RUX at ≥15 mg BID to keep efficacy with RBC units need | SVR35 at 24 wk |
| Navtemadlin (NAVT) MDM2 inhibitor | BOREAS NCT03662126 NAVT vs BAT (excluded JAKi) (estimated n = 385) NAVT 240 mg QD d 1-7 of 28-d cycle | DIPSS Int/high-risk MF PLT ≥50 × 109/L TP53 wild-type | Relapsed to prior JAKi: progressive from BL or after a response-increased splenomegaly Refractory to prior JAKi: lack of spleen response after ≥3 mo | SVR35 at 24 wk |
| Parsaclisib (PARS) PI3Kδ inhibitor | LIMBER-304 NCT04551053 PARS + RUX vs PBO + RUX (estimated n = 212) PARS 5 mg QD, RUX on the ongoing 2-mo stable dose | DIPSS Int/high-risk symptomatic MF PLT ≥50 × 109/L Spleen length ≥5 cm below LCM | ≥3 mo of RUX, at stable dose for ≥2 mo Suboptimal response to RUX: spleen of ≥5 cm below LCM and active symptoms at the screening visit | SVR35 at 24 wk |
| Luspatercept (LUS) Activin receptor ligand trap | INDEPENDENCE NCT04717414 LUS vs PBO in ongoing JAKi (estimated n = 309) LUS 1.33 mg/kg q21 | RBC-TD DIPSS Int/high-risk MF PLT as approved for the concomitant JAKi, neither <25 × 109/L nor ≥1000 × 109/L | JAKi for ≥8 mo with stable dose for ≥4 mo, and requirement of 4-12 RBC units/12 wk up to randomization | RBC-TI ≥12 wk up to wk 24 |
BAT, best available therapy; BID, twice daily; BL, baseline; DIPSS: Dynamic International Prognostic Scoring System; JAKi, JAK inhibitor; LCM, left costal margin; MF, myelofibrosis; MTD, maximum tolerated doses; OS, overall survival; PBO, placebo; PLT, platelets; QD, once daily; RBC, red blood cells; RUX, ruxolitinib; SVR35, spleen volume reduction of 35%; TD, transfusion-dependence; TI, transfusion-independence.