IMproveMF update: Phase 1/1B trial of imetelstat (IME)+ruxolitinib (RUX) in patients (pts) with intermediate (INT)-1, INT-2, or high-risk (HR) myelofibrosis (MF).

6515 Background: IME, a first-in-class, direct, and competitive inhibitor of telomerase activity, showed potential survival improvements and disease-modifying activity in the phase 2 IMbark MF trial (NCT02426086). Preclinical evidence demonstrated IME+RUX reduced disease burden better than either agent alone. IMproveMF (NCT05371964) aims to evaluate IME+RUX in pts with INT-1/INT-2/HR MF. Methods: IMproveMF is an open-label, single-arm, phase 1/1b trial (part 1: dose escalation; part 2: dose confirmation and expansion) of IME+RUX in adults with DIPSS INT-1, INT-2, or HR MF. In part 1 (up to 21 pts), RUX was required for ≥12 wk with a stable dose for ≥4 wk immediately before adding IME; pts received IME via intravenous infusion at each dose level cohort (4.7, 6.0, 7.5, and 9.4 mg/kg IME sodium; equivalent to 4.4, 5.6, 7.1, and 8.9 mg/kg active dose, respectively) every 28 d based on Bayesian Optimal Interval design to identify the recommended part 2 dose (RP2D). Pts in part 1 were dose adjusted to the RP2D as needed in part 2, with 2 dose reductions allowed. Part 2 of the trial will enroll pts who are RUX naive. Primary endpoints are adverse events (AE), including dose-limiting toxicity (DLT), in part 1 and AEs and 24-wk response rate (≥50% reduction in MF total symptom score [TSS]) in part 2. Secondary endpoints include pharmacokinetics (PK) and clinical activity. Total planned enrollment is ≈41 pts. Results: As of 11/04/2024, 17 pts were enrolled in part 1 with a median age of 67 y (71% aged ≥65 y); 7 had INT-1, 9 INT-2, and 1 HR MF. Respective to the dose levels in the Methods, 3, 3, 4, and 7 pts received the corresponding IME dose level. No DLTs were reported for IME; 2 pts had dose reductions due to neutropenia. Five pts discontinued IME (none due to AEs). Four pts had RUX dose reductions (due to AEs and other, n=2 each). AEs were experienced by 15 pts; 8 experienced grade 3 events of anemia (n=4), neutropenia (n=3), leukopenia (n=2), abdominal pain, fatigue, epistaxis, and pneumonia (n=1 each; the latter 2 and 1 anemia event were considered serious AEs). There were no grade 4/5 AEs. There was an overall reduction in TSS from baseline (median, −5 points in maximum absolute reduction up to wk 24) with IME regardless of dosing, and a trend of dose-dependent spleen volume decrease. A reduction in variant allele frequency of several driver mutations was also observed. Hematologic, PK, and additional mutational data will be included in the presentation, as available. Conclusions: In part 1 of IMproveMF, no DLTs were observed and the RP2D dose of 9.4 mg/kg IME was determined. AEs were consistent with those observed in other IME clinical trials, and preliminary efficacy was positive, demonstrating the potential of IME+RUX in this pt population with high unmet needs. Part 2 of this trial is ongoing across the US at 6 sites. Clinical trial information: NCT05371964 .