A Novel JAK2 Inhibitor OB756 in Treatment of Janus Kinase Inhibitor-Naive Patients with Myelofibrosis: A Phase 1/2, Open-Label, Multicenter Study

Introduction ：OB756 is a novel small molecule Janus kinase2（JAK2）inhibitor which inhibits cell proliferation, induces cell apoptosis by affecting JAK-STAT signaling pathway in preclinical studies. Here we investigated the safety and efficacy of OB756 in phase 1/2 study in treatment of MF patients. Methods ：We conducted a multicenter, phase 1/2 trial (CTR20201950) at 17 sites in China. This study included dose-escalation cohort (phase 1) and dose-expansion cohort (phase 2). Aged ≥18 with MF, international prognostic scoring system (IPSS) intermediate- 1/2 or higher risk of MF were enrolled. Eligible pts received escalating doses of oral OB756 at 4 dose cohorts ranging from 8 to 32 mg of each 28-day cycle, and a modified “3 + 3” design was used in phase 1. In phase 2 study, patients (pts) were treated with OB756 with RP2D of 16mg or 20mg twice daily for 28-day cycles until progressive disease or intolerance. The primary endpoints were the maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D) in phase 1, and the proportion of pts with ≥35% spleen volume reduction (SVR35) from baseline at week 24 in phase 2. The main secondary endpoint included symptom response (≥50% reduction in total symptom score, TSS50) from baseline at week 24, platelet and anemia improvement, and safety in phase 2. Results ：Between November 3, 2020 and May 16, 2024, 296 pts were assessed for eligibility, 75 pts of MF were enrolled and treated with OB756 including, 9 pts in phase 1 and 66 pts in phase 2. In phase 1, the number of pts enrolled per dose level was one at 8 mg BID, three at 16 mg BID, four at 24 mg BID, and one at 32 mg BID. No pts experienced dose-limiting toxicities (DLTs) of OB756 form 8 to 32mg BID. Given the safety profile and shrinking spleen, 16 mg BID and 20mg BID was identified as RP2D according to p-STAT3 inhibited percentage in Imax model. In phase 2, median age was 58 (range, 55-69) years. 47/66 (71.2%) pts had a diagnosis of PMF, 14/66 (21.2%) post-PV MF, and 5/66 (7.6%) post-ET MF, with IPSS assessment of intermediate-1 risk in 19/66 (28.8%) pts, intermediate-2 risk in 27/66 (40.9%) pts, and high risk in 21/66 (31.8%) pts. Baseline median spleen volume was 1780.2 (rang, 1132.5~2728.7) ml. Pts identified JAK2 V617F, CALR and MPL mutation were 87.1% (57/66), 12.1% (7/66), 1.6% (1/66), respectively. A total of 36/66 (54.5%) pts achieved SVR35 at EOC6, especially with 7/25 (28%) pts quickly shrinked spleen more than 5cm from baseline at week 1. In addition, pts had SVR35 during study period and EOC12 were 39/66 (59.1%), 12/24 (50.0%), respectively. In secondary endpoints, 31/55 (51.4%), 34/53 (64.2%), and 7/8 (87.5%) pts achieved TSS50 at EOC3, EOC6, and EOC20, respectively. OB756 had quick spleen reduction and durable SVR. OB756 treatment increased hemoglobin level to ≥20 g/L in 15.0% (3/20) of pts with hemoglobin ≤100 g/L at baseline. The most common treatment-emergent adverse events (TEAEs) were 1~2 grade. Only three commonly non-hematological TEAEs (incidence ≥10%) were reported with serum creatinine increased (12/66, 18.2%), aspartate aminotransferase increased (13/66, 29.7%), gamma-glutamyl transferase increased (7/66,10.6%). The most common grade≥3 hematological TEAE (≥10%) were thrombocytopenia (15/66, 22.7%) and anemia (23/66, 34.8%). Occurrence of other grade≥3 non-hematologic TEAEs was very low. No death was reported with related to disease progression of MF or OB756. TEAEs were generally manageable. Conclusion ：OB756 is well tolerated and showed meaningful clinical activity in patients with MF, especially for quick and durable spleen reduction. OB756 also showed few non-hematological TEAEs, and may be a new treatment option for MF patients.