JAB-8263 Monotherapy Demonstrates Early Promise in Myelofibrosis

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The investigative BET inhibitor JAB-8263 was found to be well tolerated and to demonstrate preliminary efficacy in patients with myelofibrosis, according to data from a phase 1/2 study (NCT04686682) presented during the 2024 ASH Annual Meeting.¹

Any treatment-emergent adverse effects (TEAEs) occurred in 93.8% of those who received the agent at any dose level (n = 16), with 37.5% experiencing grade 3 or higher TEAEs and 25.0% experiencing a serious TEAEs. Treatment-related AEs (TRAEs) occurred in 87.5% of patients, with 31.3% experiencing grade 3 or higher TRAEs, and 18.8% experiencing serious TRAEs. TRAEs led to dose interruption and reduction for 43.8% and 25.0% of patients, respectively. One patient experienced a TRAE that led to discontinuation of JAB-8263. No treatment-related events proved to be fatal.

Notably, 1 dose-limiting toxicity occurred in a patient who received the agent at a dose of 0.4 mg; this patient experienced grade 3 increases in alanine and aspartate aminotransferase levels.

In all evaluable patients (n = 13), the mean spleen volume reduction (SVR) was –19.95% (range, –39.4% to 3.6%) at week 24 and –26.16% (range, 56.6% to –11.0%) at best response. Notably, 2 patients achieved an SVR of 35% or higher, and 1 patient experienced an SVR of –34.9%. Moreover, at week 24, 60% of 10 patients had a tumor symptom score reduction of at least 50% (TSS50). Two of 8 patients who had received JAK inhibitors experienced a best response of SVR of –41.2% and 34.9%, respectively. Moreover, 50% of 6 evaluable patients who had received JAK inhibitors achieved TSS50 at week 24.

“JAB-8263 at 0.125 mg [once daily to] 0.3 mg [once daily] was well tolerated…Hematological and gastrointestinal AEs are mild with JAB-8263 continuous dosing [compared with] other BET inhibitors,” Junyuan Qi, MD, of the Institute of Hematology and Blood Disease Hospital, Chinese Academy of Medical Sciences, in Tianjin, China, and coauthors, wrote in the poster of the data. “The preliminary efficacy data in myelofibrosis for JAB-8263 monotherapy is promising. Most patients showed spleen reduction and TSS reduction.”

The early-phase study enrolled patients with confirmed primary myelofibrosis (PMF), post–polycythemia vera myelofibrosis (PV-MF), or post–essential thrombocytopenia myelofibrosis (ET-MF). Patients were at least 18 years of age, had spleen volume of at least 450 cm³, a Dynamic International Prognostic Score (DIPSS) of at least intermediate-1, and an ECOG performance status up to 2.

The median age in the 16 total patients was 62 years (range, 36-69) and 56.3% were female. All patients were Asian. Regarding ECOG performance status, 31.3% had a status of 0, 62.5% had a status of 1, and 6.3% had a status of 2. Regarding disease subtype, 68.8% of patients had PMF, 18.8% had PV-MF, and 12.5% had ET-MF. Half of patients had prior exposure to a JAK inhibitor. Most patients had a JAK2 mutation (93.8%). Regarding DIPSS, 68.8% had intermediate-1 disease and 25.0% had intermediate-2 disease. The median time since initial diagnosis was 13.5 months (range, 0.9-76.6).

In the dose-escalation portion of the study, patients received JAB-8263 at one of the following dose levels: 0.125 mg once daily (n = 1), 0.20 mg once daily (n = 4), 0.30 mg once daily (n = 6), or 0.40 mg once daily (n = 5).

The primary end points of the research were to determine the maximum tolerated dose and recommended phase 2 dose of JAB-8263. Important secondary end points comprised SVR of at least 35% from baseline to week 24, and TSS50 at week 24.

As of the data cutoff date of October 17, 2024, a total of 16 patients with intermediate- or high-risk myelofibrosis were enrolled to the study and received the agent at 1 of 4 dose levels. Eleven patients were still on active treatment at the time of data cutoff. The median exposure to JAB-8263 was 7.9 months.

In the total population of patients, the most common TRAEs included increased blood bilirubin (50.0%), thrombocytopenia (37.5%), increased alanine aminotransferase (37.5%), increased aspartate aminotransferase (31.3%), diarrhea (25.0%), anemia (25.0%), and decreased blood fibrinogen (25.0%).

“The monotherapy expansion is ongoing,” the study authors concluded.

Disclosures: No relevant conflicts of interest were declared.

Reference

Qi J, Jiang B, Yang W, et al. Preliminary results of patients with myelofibrosis (MF) from a phase I trial of Jab-8263, a potent BET inhibitor. Blood. 2024;144(suppl 1):4567. doi:10.1182/blood-2024-209977