Zilurgisertib With or Without Ruxolitinib Shows Early Tolerability, Activity in Anemic Myelofibrosis

Administration of the selective ALK-2 inhibitor zilurgisertib alone or in combination with ruxolitinib (Jakafi) was safe, well tolerated, and showed preliminary signals of clinical activity in patients with primary or secondary myelofibrosis and disease-related anemia, according to data from the ongoing phase 1/2 INCB 00928-104 study (NCT04455841).

Findings presented at the 2023 ASCO Annual Meeting showed that at the data cutoff date of February 15, 2023, no dose-limiting toxicities (DLTs) were reported in those who received zilurgisertib monotherapy (treatment group A; n = 20) or those who were given the ruxolitinib combination (treatment group B; n = 16). Moreover, at the time of the analysis, the maximum-tolerated dose (MTD) had not yet been reached.

In non–transfusion dependent patients, anemia improvement, defined as experiencing a hemoglobin increase of at least 1.5 g/dL, was observed in 1 of 6 patients in group A at the 200-mg dose and in 3 of 9 patients in group B at the 100-mg and 200-mg dose levels. Two patients with anemia improvement achieved an anemia response that lasted for longer than 12 weeks. Notably, all patients with anemia responses had maintained hemoglobin improvement without transfusion and are still on the study. In transfusion-dependent patients, anemia response was only evaluable in group A at data cutoff, and at that time, none of the 11 evaluable patients had achieved a response.

“Preliminary improvements in anemia were observed in patients who were not transfusion dependent at baseline, indicating potential for therapeutic activity,” said Prithviraj Bose, MD, lead study author and associate professor in the Department of Leukemia of the Division of Cancer Medicine at The University of Texas MD Anderson Cancer Center, in a poster presentation of the data.

For many patients with myelofibrosis, high levels of the iron regulator hepcidin can lead to iron deficiency. Dysregulation of hepcidin results in the development of anemia. “[Anemia] is associated with a poor prognosis, and severe anemia can be burdensome, reducing quality of life,” Bose explained. “ACVR1, also known as ALK2, has emerged as a potential target to manage anemia in patients with myelofibrosis.”

Investigators hypothesized that the use of an ACVR1/ALK2 inhibitor could suppress hepcidin levels and alleviate anemia of chronic inflammation in this population.

The open-label, multicenter trial enrolled patients 18 years of age or older with histologically confirmed primary or post-polycythemia vera/essential thrombocythemia myelofibrosis. Patients in group A were required to have intermediate-2 or high-risk disease, and those in group B had intermediate-1 or intermediate-2/high-risk disease. Risk status was determined using the Dynamic International Prognostic Scoring System (DIPSS).

Eligible patients also needed to be transfusion dependent, which was defined as having received at least 4 units of red blood cell transfusions 8 weeks prior to treatment initiation or presenting with symptomatic anemia, which was defined as having a hemoglobin level of less than 10 g/dL on 3 separate occasions during screening that were 7 days apart.

Those in group A were resistant, refractory, or lost response to JAK inhibitor treatment at a minimum of 12 weeks before treatment initiation; they also could have been intolerant or ineligible for JAK inhibitors. In group B, patients were all on a stable ruxolitinib regimen for 12 weeks or more.

In group A, patients received zilurgisertib at a starting dose of 50 mg once daily. Dosage increased two-fold until patients experienced grade 2 or greater toxicities suspected to be associated with the study drug. Once this occurred, dose increases were limited to less than or equal to 50% until either a MTD was reached or the recommended dose for expansion (RDE) was determined. In group B, the starting dose of zilurgisertib was 100 mg once daily.

The study’s primary end points were safety and tolerability, which included assessment of DLTs, MTD, and RDE. Key secondary end points included efficacy in the form of anemia response, pharmacokinetics (PK), and pharmacodynamics, specifically parameters related to hepcidin concentration and iron metabolism.

At data cutoff, a total of 36 patients were enrolled on the study. Of these patients, 20 were enrolled in group A and 16 were in group B. Dose-escalation was ongoing at the time of analysis. The median ruxolitinib starting dose was 10 mg twice daily (20 mg daily; range, 15-50).

The median age in group A was 73 years (range 53-84) vs 75.5 years (range 54-85) in group B. Most patients in groups A and B were male (65% vs 43.8%) and White (70% vs 68.8%). The time since initial myelofibrosis diagnosis in group A was a median of 2.4 months (range, 0.2-23.1) vs 7.2 months (range, 1.4-24.1) in group B. Most patients in groups A (95%) and B (81.3%) had a DIPSS risk level of intermediate-2; 5% and 18.8% of patients, respectively, had a high risk level.

Regarding prior therapy for their disease, 65% and 100% of patients in groups A and B, respectively, had previously received ruxolitinib; 15% and 12.5% of patients, respectively, had received another prior JAK inhibitor, and 45% and 50% of patients, respectively, had another prior agent. The rates of transfusion-dependent patients in groups A and B were 55% in and 25%, respectively.

Additionally, median hemoglobin level at baseline in group A was 7.7 g/dL (range, 6.5-9.7) vs 8.0 g/dL (range, 5.1-9.0) in group B; median hepcidin concentration at baseline in these groups was 171 ng/mL (range, 18-535) and 126 ng/mL (range, 7-421), respectively.

To assess PK, blood sampling was performed on days 1 and 15 of cycle 1. Sampling was conducted before treatment administration, and again at 2, 4, and 6 to 8 hours following treatment. Investigators also measured hepcidin concentration from plasma at the same time points using a validated fluorometric immunoassay.

Analysis of zilurgisertib’s PK profile at steady state showed that the agent reached its time of peak plasma concentration 2 to 4 hours after administration across dose groups. The agent also was predicted to have a mean half-life ranging from 24 to 27 hours across the dose groups. When given at the 400-mg dose level, exposure at trough surpassed the target thresholds for inhibition of hepcidin and its downstream signaling molecule pSMAD1.

Hepcidin levels were observed to have decreased from baseline in both groups. This effect was observed across all dose levels, although dose levels of 400 mg and 200 mg were associated with greater control of hepcidin over time. Maximal hepcidin reduction occurred 6 to 8 hours after the first dose of zilurgisertib was administered in day 1 of cycle 1.

Further safety analysis showed that 11 patients across both groups experienced treatment-emergent adverse effects (TEAEs) that were grade 3 or higher. The most common grade 3 or higher toxicities included thrombocytopenia (group A, 15%; group B, 6.3%), followed by COVID-19 (10%; 0%), epistaxis (0%; 6.3%), and asthenia (0%; 6.3%).

Common any-grade TEAEs occurring in 3 or more patients on groups A and B, respectively, included hyperuricemia (25%; 6.3%) nausea (25%; 12.5%), dyspnea (20%; 18.8%), peripheral edema (20%; 6.3%), COVID-19 (15%; 6.3%), cough (15%; 6.3%), dysphagia (15%; 6.3%), epistaxis (15%; 6.3%), fatigue (15%; 0%), insomnia (15%; 0%), myalgia (15%; 0%), pruritis (15%; 6.3%), thrombocytopenia (15%; 18.8%), vomiting (15%; 6.3%), asthenia (10%; 18.8%), hyperkalemia (10%; 25%), and urinary tract infection (5%; 18.8%).

Of all patients enrolled in the study, 1 patient in group B who received the agent at the 200-mg dose level discontinued treatment due to grade 2 hyperferritinemia.

The trial is currently enrolling patients who are transfusion dependent to the combination cohort; results from this cohort will be reported separately. An additional cohort is being planned to evaluate zilurgisertib plus ruxolitinib as first-line treatment for patients with myelofibrosis and anemia who are JAK inhibitor naïve.

Disclosures: Dr Bose reported serving as a consultant or in an advisory role for AbbVie, Bristol-Myers Squibb/Celgene, GlaxoSmithKline/Sierra Oncology, and Karyopharm Therapeutics. He received honoraria from AbbVie, Blueprint Medicines, Bristol-Myers Squibb/Celgene, Cogent Biosciences, CTI BioPharma Corp, GlaxoSmithKline/Sierra Oncology, Incyte; Karyopharm Therapeutics, Novartis, and PharmaEssentia. Institutional research funding was provided by Astellas Pharma, Blueprint Medicines, Bristol-Myers Squibb/Celgene, Cogent Biosciences, Constellation Pharmaceuticals, CTI BioPharma Corp, Disc Medicine, Incyte, Ionis Pharmaceuticals, Kartos Therapeutics, NS Pharma, Pfizer, Promedior, and Telios.

Reference

Bose P, Mohan S, Oh S, et al. Phase 1/2 study of the activin receptor-like kinase (ALK)-2 inhibitor zilurgisertib (INCB000928, LIMBER-104) as monotherapy or with ruxolitinib (RUX) in patients (pts) with anemia due to myelofibrosis (MF). J Clin Oncol. 2023;41(suppl 16):7017. doi:10.1200/JCO.2023.41.16_suppl.7017