A phase 3 study with the goal of demonstrating overall survival benefit with imetelstat versus best available therapy in patients with refractory myelofibrosis has dosed the first patient with the experimental agent.
A phase 3 study (ImpactMF; NCT04576156) with the goal of demonstrating overall survival (OS) benefit with imetelstat (GRN163L) versus best available therapy (BAT) in patients with refractory myelofibrosis (MF) has dosed the first patient with the experimental agent, announced the Geron Corporation, in a press release.1
Imetelstat is a first-in-class telomerase inhibitor. The nucleic acid backbone provides resistance to the effect of cellular nucleases. This helps to improve the stability in plasma and tissues while also improving the binding affinity to its target. The lipid group inside the agent increases potency and improves pharmacokinetic and pharmacodynamic properties by enhancing cell permeability.2
So far, 6 clinical trials have evaluated the safety and tolerability of imetelstat. Dosing was performed in a variety of scheduling and ranged from 0.5 mg/kg to 11.7 mg/kg. According to Geron, there were dose-dependent increases in exposure with a plasma half-life ranging from 4-5 hours. Additionally, resident in bone marrow was observed between 41-45 hours after a 7.5 mg/kg dose.1
The safety of imetelstat was consistent across the completed phase 1 and 2 clinical trials. Reported adverse events (AE) included cytopenias, transient prolonged active partial thromboplastin, gastrointestinal symptoms, hepatic biochemistry abnormalities, and infusion reactions. Dose-limiting toxicities included thrombocytopenia and neutropenia.
The current, randomized, 2-armed, phase 3 clinical trial has an estimated enrollment of 320 participants and an estimated competition date of May 2024. In arm 1, patients will receive imetelstat every 21 days at 9.4 mg/kg until disease progression, unacceptable toxicity, treatment discontinuation, or study end. In arm 2, patients will receive BAT until any one of the same endpoints as arm 1.
The primary outcome of the study is overall survival (OS). Secondary outcomes include symptom response rate, progression-free survival, spleen response rate, complete remission, reduction in the degree of bone marrow fibrosis, and the number of participants with adverse events.
In order to participate, patients must have a primary MF diagnosis and be refractory to JAK-inhibitor treatment. They must also have active MF symptoms and measurable splenomegaly. Patients with prior treatment with imetelstat or any chemotherapy of MF directed therapy are not eligible to participate.
"As the only study in refractory MF with overall survival as the primary endpoint, dosing of the first patient in IMpactMF is an important step in developing imetelstat as a potential treatment for these patients," said Aleksandra Rizo, MD, PhD, Geron’s chief medical officer in a press release. "With a median overall survival of only approximately 14 to 16 months for patients who fail or no longer respond to JAK inhibitor treatment, there is a significant unmet medical need for therapies that will improve survival."
The final OS analysis is planned to be conducted after more than half of trial participants have died. An interim analysis is will be conducted after approximately 70% of the total number of predicted deaths have occurred. Under current assumptions, an interim analysis is expected in 2024 and a final analysis in 2025.