Phase 1/2 study of uproleselan added to chemotherapy in patients with relapsed or refractory acute myeloid leukemia.

Uproleselan (GMI-1271) is a novel E-selectin antagonist that disrupts cell survival pathways, enhances chemotherapy response, improves survival in mouse xenograft and syngeneic models, and decreases chemotherapy toxicity in vivo. A phase 1/2 study (NCT02306291) evaluated the safety, tolerability, and anti-leukemic activity of uproleselan (5-20 mg/kg) with MEC (mitoxantrone, etoposide, cytarabine) among patients with relapsed/refractory (R/R) acute myeloid leukemia (AML). Among the first 19 patients, no dose-limiting toxicities were observed. The recommended phase 2 dose (RP2D) was 10 mg/kg twice daily. An additional 47 patients with R/R AML were treated with uproleselan at the RP2D plus MEC. At the RP2D, the remission rate (complete response [CR]/complete response with incomplete count recovery [CRi]) was 41% (CR 35%) and the median overall survival (OS) was 8.8 months. In a separate cohort, 25 newly diagnosed patients aged ≥60 years received uproleselan at the RP2D plus cytarabine and idarubicin (7+3). In these front-line patients, the CR/CRi rate was 72% (CR 52%) and the median OS was 12.6 months. The addition of uproleselan was associated with low rates of oral mucositis. E‑selectin ligand expression on leukemic blasts was higher in patients with relapsed vs primary refractory AML, and with high-risk cytogenetics and secondary AML in newly diagnosed older patients. In the R/R cohort, E‑selectin expression above 10% was associated with a higher response rate and improved survival. The addition of uproleselan to chemotherapy was well tolerated with high remission rates, low-induction mortality, and low rates of mucositis, providing strong rationale for phase 3 randomized confirmatory studies.