Improvemf: Phase 1b trial of imetelstat plus ruxolitinib in patients with intermediate-2 or high-risk myelofibrosis

Abstract Introduction: Myelofibrosis (MF) is a type of myeloproliferative neoplasm characterized by ineffective hematopoiesis, aberrant expression of inflammatory cytokines, and bone marrow fibrosis. JAK inhibitors (JAKi) block the JAK/STAT-signaling pathway that is dysregulated in patients with MF, resulting in relief of splenomegaly and debilitating MF-related constitutional symptoms. However, JAKi have limited disease-altering activity due to failure to eliminate the malignant clonal stem cells that drive disease progression. Imetelstat is a first-in-class, direct, and competitive inhibitor of telomerase enzymatic activity approved in the United States and Europe for the treatment of certain adult patients with lower-risk myelodysplastic syndromes with red blood cell transfusion–dependent anemia. Given the nonoverlapping mechanisms of action of JAKi and imetelstat, preclinical data showing that sequential therapy with ruxolitinib and imetelstat selectively targeted and reduced MF hematopoietic stem cells and progenitor cells, and the clinical activity and disease-modifying potential of single-agent imetelstat in the relapsed/refractory MF setting demonstrated in MYF2001 (NCT02426086), a combination trial of imetelstat plus ruxolitinib in patients with and without prior JAKi treatment was warranted. IMproveMF (NCT05371964) is an open-label study evaluating imetelstat plus ruxolitinib in patients with intermediate (INT)-1, INT-2, or high-risk (HR) MF. In the dose-finding (Phase 1) portion of IMproveMF, imetelstat plus ruxolitinib was generally well tolerated, with no dose-limiting toxicities observed at any dose level, and a safety profile consistent with that observed in other clinical trials of imetelstat. Importantly, a dose-dependent signal of clinical activity was observed with imetelstat plus ruxolitinib, encouraging dose expansion evaluation of efficacy. The pharmacokinetic profile for the combination treatment was similar to those reported for previous monotherapy studies. Thus, the recommended Phase 2 dose of 8.9 mg/kg imetelstat active dose (equivalent to 9.4 mg/kg imetelstat sodium) was determined. Methods: The dose-confirmation and expansion (Phase 1b) portion of IMproveMF will include approximately 30 patients. Eligible adult patients must have INT-1, INT-2, or HR MF with an Eastern Cooperative Oncology Group performance status ≤2 and peripheral blood and bone marrow blasts <10%. Patients must also be both symptomatic (≥2 active symptoms with a score of ≥3, or a total score of ≥10 on the Myelofibrosis Symptom Assessment Form 4.0) and have splenomegaly, and be without active systemic hepatitis infection, acute or chronic liver disease unrelated to underlying MF, or prior history of hematopoietic stem cell transplant. The study will evaluate 2 distinct cohorts. In Cohort A, upon enrollment patients who are JAKi naive will start ruxolitinib for ≥12 weeks (24 weeks maximum); once the ruxolitinib dose is stable for 4 weeks, 8.9 mg/kg imetelstat intravenously (IV) every 4 weeks will be added. In Cohort B, patients who are currently receiving any first-line JAKi treatment per standard of care for ≥12 weeks (48 weeks maximum), including 4 weeks at a stable dose, will begin 8.9 mg/kg imetelstat IV every 4 weeks after enrollment. Treatment will continue until toxicity, disease progression, or withdrawal. The primary endpoint of this study includes safety and symptom response rate at week 24 (defined as proportion of patients with ≥50% reduction in total symptom score [TSS] at week 24 from start of combination treatment). Secondary endpoints include absolute change in TSS at week 24, average absolute change in TSS over 24 weeks, spleen response (defined as ≥35% spleen volume reduction) at week 24, and progression-free survival. The primary analysis for this part of the study is planned at approximately 6 months after the last participant's first dose of imetelstat plus ruxolitinib/JAKi treatment; the final analysis will be performed after the end of the study. The Phase 1b portion of IMproveMF is actively enrolling, with 3 patients enrolled as of July 21, 2025. The first patient first treatment visit occurred on January 10, 2025.