The first patient has been dosed in a phase III clinical trial investigating the addition of uproleselan (GMI-1271) to standard 7+3 chemotherapy in older patients with previously untreated acute myeloid leukemia.
Geoffrey Uy, MD
The first patient has been dosed in a phase III clinical trial investigating the addition of uproleselan (GMI-1271) to standard 7+3 chemotherapy in older patients with previously untreated acute myeloid leukemia (AML).
The trial (NCT03701308) is being conducted under a Cooperative Research and Development Agreement (CRADA) between GlycoMimetics, the company developing the agent, and the National Cancer Institute (NCI). The Alliance for Clinical Trials in Oncology is also collaborating on the trial, which is the second of 3 studies planned to evaluate uproleselan across the AML spectrum.
“The initiation of the NCI-sponsored trial is an important milestone for our uproleselan program, a drug candidate with the potential to address significant unmet treatment needs across the spectrum of AML,” said Helen Thackray, MD, GlycoMimetics’ senior vice president of clinical development and chief medical officer. “Along with our global pivotal phase III clinical trial testing the investigational drug in patients with relapsed/refractory acute myeloid leukemia (NCT03616470), this trial will facilitate our growing understanding of how uproleselan may fit into the continuum of care for individuals living with AML.”
As a specific E-selectin antagonist, uproleselan blocks E-selectin from binding with cancer cells in the bone marrow, which disrupts the mechanisms of leukemic cell resistance.
An estimated 932 patients aged 60 and older will be enrolled on the trial. One group of patients will receive induction therapy with daunorubicin intravenously (IV) on days 1-3 and cytarabine via continuous IV infusion (CIVI) over 168 hours on days 1-7. Patients who have residual disease upon bone marrow examination will receive a second induction including daunorubicin via IV on days 1-3 and cytarabine CIVI over 12 hours on days 1-5.
For consolidation therapy, the control arm will receive cytarabine IV over 3 hours on days 1-5. Treatment repeats every 28 days for up to 3 courses in the absence of disease progression or unacceptable toxicity.
The investigative arm will receive induction therapy with IV uproleselan on day 1 and then every 12 hours on days 2-10. Patients will also receive daunorubicin IV on days 2-4 and cytarabine CIVI over 168 hours on days 2-8. Patients with residual disease shown on bone marrow examination will receive a second induction including uproleselan IV on day 1 and then every 12 hours on days 2-10, daunorubicin IV on days 2-3, and cytarabine CIVI over 120 hours on days 2-6.
Patients in the uproleselan arm who achieve a complete response or a complete response with incomplete hematologic recovery will receive consolidation therapy with uproleselan IV on day 1 and every 12 hours on days 2-8, and cytarabine IV over 3 hours on days 2-6. Treatment will repeat every 28 days for up to 3 courses in the absence of disease progression or unacceptable toxicity.
The primary endpoint of the study will be overall survival (OS), with an interim analysis based on event-free survival (EFS) planned for after the first 250 patients have been enrolled. Geoffrey Uy, MD, an associate professor of medicine, bone marrow transplantation, and leukemia from Washington University School of Medicine in St. Louis will be leading the trial.
In data from a phase I/II trial of uproleslan reported during the 2018 ASH Annual Meeting, adding uproleselan to chemotherapy was well tolerated and demonstrated high remission rates, high rates of minimal residual disease negativity, and high transplant rates in older patients with relapsed/refractory and newly diagnosed AML.
The trial enrolled a total of 91 patients over the age of 60: 19 relapsed/refractory patients in phase I, 47 relapsed/refractory patients in phase II, and 25 treatment-naïve patients in phase II. The phase I portion of the study evaluated escalating doses of uproleselan (5-20 mg/kg) combined with mitoxantrone, etoposide, and cytarabine (MEC) in the 19 relapsed/refractory patients, determining a recommended phase II dose of 10 mg/kg.
In the phase II portion, patients were treated with uproleselan and 7+3 chemotherapy (cytarabine and idarubicin), with uproleselan given 24 hours prior, every 12 hours during, and 48 hours post-chemotherapy. Patients who responded could receive consolidation therapy of 1 cycle of MEC or 1-3 cycles of intermediate-dose cytarabine (IDAC) with uproleselan.
At the 10 mg/kg dose, the median OS among 36 evaluable patients was 8.8 months (95% CI, 5.7-11.4), the remission duration was 9.1 months (95% CI, 3.2-15.2), and the 1-year OS was 35%. Eleven of 16 evaluable patients (69%) were MRD-negative, with a 1-year OS of 73% in this subgroup.
Among 24 evaluable treatment-naïve patients, the median EFS was 9.2 months (95% CI, 3.0-12.6), the median OS was 12.6 months (95% CI, 9.9-not reached), and the remission duration was 10.4 months (95% CI, 7.1-17.8). The 1-year OS rate in the 24 patients was 52%. Five of 9 evaluable patients were MRD negative, with a 1-year OS rate of 60% in these patients.
A third trial investigating uproleselan is expected to initiate later this year, to be hosted by the European HOVON consortium.
DeAngelo DJ, Jonas BA, Liesveld JL, et al. Uproleselan (GMI-1271), an e-selectin antagonist, improves the efficacy and safety of chemotherapy in relapsed/refractory (R/R) and newly diagnosed older patients with acute myeloid leukemia: final, correlative, and subgroup analyses. Blood. 2018;132(suppl 1; abstr 331). doi: 10.1182/blood-2018-99-114286.