Phase 3 Study of Uproleselan for R/R AML to Continue to Final OS Events Trigger

A pivotal phase 3 study (NCT03616470) of uproleselan (GMI-1271) in relapsed/refractory (R/R) acute myeloid leukemia (AML) has been reviewed by the Data Monitoring Committee (DMC) and was recommended to continue to the originally planned final overall survival (OS) events trigger, according to GlycoMimetics, Inc.¹

The interim utility analysis was added to the study and conducted in fall 2022. The analysis used a high statistical threshold to preserve the integrity of the originally planned final analysis, and the plan for the independent DMC to review the efficacy/safety data at approximately 80% of planned survival events was cleared by the FDA.

A review of the blinded pooled survival data demonstrated that patients lived longer than expected based on the historical benchmarks used to design the study. Additionally, the DMC expressed no concerns about safety. The final survival event trigger is now expected to be announced in the first half of 2024.

“We thank the independent DMC for its recommendation and are strongly encouraged as the blinded pooled survival data continues to show patients living longer than historical benchmarks. Going forward, survival duration for new events in the study will be greater than 14 months since the last patient was randomized, giving us confidence in the potential for uproleselan to improve outcomes for people living with R/R AML,” said Harout Semerjian, MBA, chief executive officer of GlycoMimetics, in the press release.

Uproleselan is a novel E-selectin antagonist which disrupts cell survival pathways and enhances chemotherapy response. Preclinical studies have shown the agent to improve survival and decrease chemotherapy toxicity in vivo.

The phase 3 trial is investigating the addition of uproleselan to a cytarabine-based chemotherapy regimen as treatment for patients with relapsed/refractory AML. The study previously completed enrollment in November 2021 with a total of 388 patients randomized in the trial across 70 sites in 9 countries.^1,2

The the activity of uproleselan at 5 mg/kg to 20 mg/kg with mitoxantrone, etoposide, and cytarabine (MEC) was evaluated in patients with relapsed/refractory AML and investigators assessed the primary end points of the study included frequency, severity, and relatedness of treatment-emergent adverse events (TEAEs).

According to findings from the phase 1/2 study of uproleselan given with a conventional salvage chemotherapeutic regimen, there was a complete response (CR) rate of 35% and median OS of 8.8 months in a cohort of patients with relapsed/refractory AML. Adding uproleselan to the regimen led to low rates of oral mucositis and proved to be safe and well-tolerated in this patient population.²

In the study, 19 patients were enrolled into the initial dose-escalation portion of the trial, and put into 3 separate dose-level groups of 5 mg/kg (n = 6), 10 mg/kg (n = 7), and 20 mg/kg (n = 6). No dose-limiting toxicities were observed in any of the 19 patients and investigators determined the recommended phase 2 dose (RP2D) of the agent to be 10 mg/kg twice daily. An additional 47 patients with relapsed/refractory AML were then administered uproleselan at the RP2D plus MEC. Here, the remission rate was 41% with CR observed in 35% of patients. The CR vs CR with incomplete count recovery (CRi) rate of 52% in patients with relapsed disease who had received 1 prior induction regimen.

Among the patients who relapsed, the CR/CRi rate was 28% in patients with an initial CR duration of less than 12 months compared with 83% for those who had an initial CR duration of greater than 12 months. A total of 51% of patients were previously administered high doses of cytarabine (at least1 g/m2) as an induction and/or as post remission therapy. The CR/CRi rate for these patients was 47%.

In the final cohort of 25 patients aged 60 years and older with newly diagnosed AML, uproleselan was administered at the RP2D in addition to cytarabine and idarubicin. Findings showed that the CR/CRi was 72% (CR, 52%). The median OS was 12.6 months, and the median time to count recovery for neutrophils and platelets in responding patients was 32.0 days (90% CI, 28.0-32.0).

In the cohort of patients with relapsed/refractory AML, incidence of TEAEs was similar across all dose levels of uproleselan. No patients discontinued treatment due to an AE, but all patients in this cohort had evidence of grade 4 myelosuppression during the study.

Most of the TEAEs observed were normal with few TEAEs attributed to uproleselan. The only grade 3 or 4 TEAE seen in at least 10% of patients was sepsis (12% of patients), while other AEs included nausea, vomiting, diarrhea, and colitis. Among these AEs, each was mild, with grade 3 events only occurring in less than 5% of patients. Hepatic and renal TEAEs were mostly grade 1 or 2.

Overall, adding uproleselan to chemotherapy proved to be well-tolerated, and demonstrated high remission rates, low induction mortality, and low rates of mucositis in patients with relapsed/refractory AML. These findings have led to a strong rationale for phase 3 randomized confirmatory studies of the combination.

“We are proud to be advancing a novel treatment with significant potential to address the urgent unmet medical need in this acute leukemia, and we look forward to continuing the study to the originally planned final overall survival analysis, now expected within the first half of 2024,” added Semerjian, in the press release.

REFERENCES:

1. GlycoMimetics announces continuation of phase 3 study of e-selectin antagonist uproleselan in relapsed/refractory AML to originally planned final analysis following interim analysis by independent data monitoring committee. News release. GlycoMimetics, Inc. February 15, 2023. Accessed February 15, 2023. https://bit.ly/3xr8rug

2. DeAngelo DJ, Jonas BA, Liesveld JL, et al. Phase 1/2 study of uproleselan added to chemotherapy in patients with relapsed or refractory acute myeloid leukemia. Blood. 2022;139(8):1135-1146. doi:10.1182/blood.2021010721