First Patient Dosed in IMproveMF Trial of Frontline Imetelstat Myelofibrosis

Following promising preclinical data, the phase 1 IMproveMF trial in myelofibrosis doses its first patient with imetelstat and ruxolitinib.

The first patient has been dosed in the phase 1 IMproveMF trial (NCT05371964) examining the first-in-class telomerase inhibitor imetelstat in combination with ruxolitinib (Jakafi) administered in the front-line setting to patients with frontline myelofibrosis, according to Geron Corporation.1

Preclinical data has previously shown the combination of imetelstat and ruxolitinib to have synergistic and additive effects in this patient population. Now, this phase 1 study aims to explore potential for disease modification with imetelstat in the earlier and frontline myelofibrosis setting.

“We designed the phase 1 IMproveMF study based on preclinical data that showed the sequential treatment of ruxolitinib followed by imetelstat had a selective inhibitory effect on malignant myelofibrosis stem cells, while sparing normal hematopoietic stem cells. This disease-modifying potential of imetelstat to affect the malignant clones driving disease progression differentiates it from any other drug currently approved or in development for myelofibrosis treatment,” said Faye Feller, MD, executive vice president, chief medical officer of Geron Corporation, in the press release. “Given these preclinical data, we want to explore the potential for disease modification with imetelstat in the earlier, frontline disease setting. In parallel, our separate IMpactMF phase 3 trial is ongoing in myelofibrosis patients who are relapsed/refractory to JAK inhibitors.”

The single-arm, open-label, 2-part, phase 1 IMproveMF study aims to evaluate the safety, pharmacokinetics, pharmacodynamics and clinical activity of imetelstat when combined with ruxolitinib in the frontline for patients with Intermediate-2 or high-risk myelofibrosis.

Patients will be administered ruxolitinib followed by imetelstat in both portions of the trial. This dosing schedule demonstrated synergistic and additive effects of ruxolitinib and imetelstat in preclinical experiments.

During part 1 of the trial, up to 20 patients with frontline myelofibrosis patients will be enrolled. Enrollment is open to those who, at the time of enrollment, have received an optimized dose of ruxolitinib in which imetelstat treatment will be added to at increasing dose levels based on safety and tolerability. Further, patients must have dynamic international prognostic scoring system intermediate-1, intermediate-2 or high-risk myelofibrosis, hematology laboratory test values, and biochemical laboratory test values within protocol-defined limits, an ECOG performance status of 0,1, or 2, and participants should follow protocol-defined contraceptives procedures.

If a safe dose is identified within part 1, JAK inhibitor naïve patients will be enrolled in part 2 and will receive treatment with ruxolitinib following screening and enrollment at a starting dose based on standard-of-care or local prescribing information. Single-agent ruxolitinib will be administered to patients for at least 12 weeks, including 4 consecutive weeks at a stable dose prior to the addition of imetelstat.

The primary goal of part 1 is to identify a safe dose for treating patients with frontline myelofibrosis, a combination of imetelstat and ruxolitinib. Part 2 is designed to confirm the safety profile of imetelstat in combination with ruxolitinib and to evaluate for preliminary clinical activity of the combination. Secondary end points for both parts include pharmacokinetics, progression-free survival, duration of response, reduction of bone marrow fibrosis, and the percentage of participants with complete remission, partial remission, clinical improvement.

Patients are currently being enrolled and the trial is being conducted at 3 sites in the United States. Preliminary results from this study are expected to be released by the end of 2023.

A separate phase 3 trial is currently evaluating single-agent imetelstat to confirm the clinically meaningful benefits observed in a phase 2 study of relapsed/refractory myelofibrosis patients.

“Upon diagnosis, intermediate-2 and high-risk myelofibrosis patients typically receive ruxolitinib as the primary therapy, which reduces enlarged spleens and alleviates symptoms but does not change the course of the disease. As a non-JAK inhibitor treatment option with a potentially novel mechanism of action, imetelstat could provide an additive benefit of disease modification when combined with ruxolitinib,” said John Mascarenhas, MD, professor of medicine at the Icahn School of Medicine at Mount Sinai and a principal investigator on the IMproveMF study, in the press release. “The dosing of the first patient is an important step in identifying a potential safe and efficacious dose and schedule of imetelstat and ruxolitinib in frontline myelofibrosis.”

References:
Geron announces first patient dosed in IMproveMF phase 1 combination study in frontline myelofibrosis. News release. Geron Corporation. August 22, 2022. Accessed August 25, 2022. https://bit.ly/3RblGaA
A study to evaluate the safety, pharmacokinetics, pharmacodynamics and clinical activity of imetelstat in combination with ruxolitinib in participants with myelofibrosis. ClinicalTrials.gov. Updated July 14, 2022. Accessed August 25, 2022. https://clinicaltrials.gov/ct2/show/NCT05371964