TPS6604 Background: In preclinical evaluations, sequential treatment (tx) with RUX, a Janus kinase inhibitor (JAKi), and IME, a telomerase inhibitor, selectively reduced MF hematopoietic stem cells (HSC) and progenitor cells. In the Phase 2 IMbark trial (NCT02426086), IME monotherapy showed clinical activity and disease-modifying potential in pts with INT-2 or HR MF relapsed/refractory to JAKi. These findings, and the nonoverlapping mechanisms of action, supported the evaluation of IME+RUX in frontline MF. IMproveMF (NCT05371964) is an open-label study of IME+RUX in pts with INT-1/INT-2/HR MF. In Phase 1 (dose finding), IME+RUX was generally well tolerated, with no dose-limiting toxicities at any dose, and a safety profile consistent with reports from other IME trials. Notably, a dose-dependent signal of clinical activity was observed. The pharmacokinetics for the combination were similar to those of previous monotherapy studies. Thus, the recommended Phase 1b dose of 8.9 mg/kg IME active dose (equivalent to 9.4 mg/kg IME sodium) was chosen. Methods: Phase 1b (dose confirmation and expansion) will enroll adult pts with INT-1/INT-2/HR MF with an Eastern Cooperative Oncology Group performance status ≤2 and peripheral blood and bone marrow blasts <10%, ≥2 active symptoms with a score of ≥3, or a total score of ≥10 on the MF Symptom Assessment Form v4.0, an absolute neutrophil count of ≥1.5×10 9 /L independent of growth factor support and platelets of ≥75×10 9 /L (updated criterion), no active systemic hepatitis infection, acute or chronic liver disease unrelated to underlying MF, and no prior history of HSC transplantation. The study was planned to evaluate 2 cohorts. In cohort A (JAKi-naive pts), upon enrollment, pts will start RUX for ≥12 weeks (24 weeks max); once the RUX dose is stable for 4 weeks, 8.9 mg/kg IME intravenously (IV) every 4 weeks will be added. Per the updated protocol (November 2025), the study will no longer recruit pts into cohort A. Existing enrollees will continue in the study per schedule. In cohort B, ~15 pts will be enrolled who are currently on first-line RUX per standard of care for ≥12 weeks, with ≥4 weeks at a stable dose, and will begin 8.9 mg/kg IME IV every 4 weeks after enrollment. Tx will continue until toxicity, disease progression, or withdrawal. The primary endpoint includes safety and symptom response rate at week 24 (proportion of pts with ≥50% reduction in total symptom score TSS at week 24 from start of IME+RUX tx). Secondary endpoints include absolute change in TSS at week 24, average absolute change in TSS over 24 weeks, spleen response (≥35% spleen volume reduction) at week 24, and progression-free survival. The primary analysis is planned ~6 months after the last pt’s first dose of IME+RUX; the final analysis will occur after the study ends. Cohort B is actively enrolling. Clinical trial information: NCT05371964 .
Mascarenhas et al. (Thu,) studied this question.