Trial Update from IMproveMF, an Ongoing, Open-Label, Dose-Escalation and -Expansion, Phase 1/1B Trial to Evaluate the Safety, Pharmacokinetics, and Clinical Activity of the Novel Combination of Imetelstat with Ruxolitinib in Patients with Intermediate-1, Intermediate-2, or High-Risk Myelofibrosis (MF)
Authors: Mascarenhas John O. , Otoukesh Salman , Bradley Terrence , Scott Bart L. , Yimer Habte A. , Dougherty Souria , Peng Lixian , Huang Fei , Wan Ying , Feller Faye M. , Rodolf Vivian , Ho Judy , Berry Tymara , Kuykendall Andrew T. 
Published: December 2024

Introduction: MF is a progressive myeloproliferative neoplasm commonly associated with driver mutations in JAK2, CALR, or MPL genes. Janus kinase inhibitors (JAKi; eg, ruxolitinib [RUX]) can reduce MF spleen size and symptom burden but do not have disease-modifying activity. Imetelstat (IME), a first-in-class direct and competitive inhibitor of telomerase enzymatic activity approved in the United States (US) to treat patients (pts) with transfusion-dependent low- to intermediate (INT)-1-risk myelodysplastic syndromes, demonstrated potential survival improvements and disease-modifying activity in the phase 2 IMbark trial (NCT02426086) in pts with MF relapsed or refractory to JAKis. Preclinical evidence demonstrated that the combination of IME+RUX reduced disease burden better than either agent alone. IMproveMF (NCT05371964) aims to evaluate safety, pharmacokinetics (PK), and clinical activity of IME+RUX in pts with INT-1/INT-2/high-risk (HR) MF.

Methods: IMproveMF is an ongoing, open-label, single-arm, multicenter, phase 1/1b trial (part 1: dose escalation; part 2: dose confirmation and expansion) of IME+RUX in adults with Dynamic International Prognostic Scoring System INT-1, INT-2, or HR MF with an Eastern Cooperative Oncology Group performance status of ≤2 and peripheral blood and bone marrow blasts &lt;10%. In part 1 (up to 21 pts), RUX treatment is required for ≥12 weeks with a stable dose for ≥4 weeks immediately before adding IME; IME is administered intravenously at each dose level in cohorts of 3 pts each (4.7, 6.0, 7.5, and 9.4 mg/kg imetelstat sodium, equivalent to 4.4, 5.6, 7.1, or 8.9 mg/kg active dose, respectively) every 28 days based on Bayesian Optimal Interval Design to identify the recommended part 2 dose (RP2D). Once established, enrollment in part 2 of the trial may begin and pts in part 1 may be dose-adjusted to the RP2D as needed, with 2 dose reductions allowed. Part 2 of the trial will enroll pts who are JAKi-naive. Pts will start RUX for ≥12 weeks (24 weeks maximum) and once the dose is stable, the pt will start the IME RP2D dose. Treatment continues until toxicity, disease progression, or withdrawal. Primary endpoints include the following: part 1, adverse events (AE), including dose-limiting toxicity (DLT); part 2, AEs and 24-week response rate (≥50% reduction in total symptom score [TSS] measured by Myelofibrosis Symptom Assessment Form v4.0). Secondary endpoints include PK (assessed with blood samples taken on cycle 1, day 1 and day 1 of each cycle thereafter) and clinical activity. Total planned enrollment is ≈41 pts.

Results: As of 07/10/2024, 13 pts were enrolled in part 1 (9 males/4 females) with a median age of 70 years (77% aged ≥65 years); 5 had INT-1, 7 INT-2, and 1 HR MF. Three pts received each IME dose level (except n=4 at 7.5 mg/kg). There were no DLTs reported for IME. One pt had an IME dose reduction from 7.5 to 6.0 mg/kg at cycle 4 due to grade 3 neutropenia. RUX dose range was 10-20 mg twice daily, with 3 pts who experienced dose reductions from 10 to 5 mg in later cycles. Four pts discontinued IME treatment (2 withdrew, 1 per physician decision, and 1 to enroll in another clinical trial). AEs were experienced by 9 pts. Six pts experienced grade 3 events of neutropenia (n=3), leukopenia (n=2), abdominal pain (n=1), anemia (n=1), fatigue (n=1), and pneumonia (n=1). The grade 3 pneumonia was a serious AE but considered to be related to underlying disease and resolved without dose modification. For IME, maximum plasma concentration (Cmax) was reached at 2 hours (end of infusion) and a more than dose-proportional increase for exposure at the dose range tested was observed, consistent with the IME PK profile from other studies. Cmax was reached at 1-2 hours after receiving RUX, with a trend suggestive of linear PK. Symptom response, hematologic, and biopsy results will be included in the presentation, as available.

Conclusions: In part 1 of the IMproveMF phase 1/1b trial of IME+RUX in pts with INT-1, INT-2, or HR MF, no DLTs were observed, and AEs were consistent with those observed in other clinical trials of IME. IME and RUX PK profiles in the combination study were similar to previous monotherapy studies. This trial is ongoing across the US at 6 sites and will continue to enroll at the 9.4 mg/kg imetelstat sodium dose level to confirm the RP2D before starting part 2. These early results demonstrate promise for the tolerability of the combination of IME+RUX in this pt population with high unmet needs.