A phase 1/2 study of uproleselan combined with chemotherapy led to a complete response of 35% and median overall survival of 8.8 months in a cohort of patients with relapsed/refractory acute myeloid leukemia.
The addition of uproleselan (GMI-1271) to chemotherapy was well-tolerated, led to high rates of remission, low induction mortality, and low rates of mucositis in patients with relapsed/refractory acute myeloid leukemia (AML).1
Findings from a phase 1/2 study (NCT02306291) showed that treatment with uproleselan in addition to a conventional salvage chemotherapeutic regimen led to a complete response of 35% and median overall survival of 8.8 months in a cohort of patients with relapsed/refractory AML.
With the addition of uproleselan, low rates of oral mucositis were also observed, proving the combination to be safe and well-tolerated in this patient population. These findings provide a strong rationale for phase 3 randomized confirmatory studies evaluating the combination.
"Relapsed/refractory AML is a devastating diagnosis. Since approximately 75% of adult patients with AML will die of their disease, relapses in this condition are common and a huge area of unmet need. Uproleselan is a novel E-selectin antagonist that may benefit patients with AML through both enhancing sensitivity to cytotoxic chemotherapy and potentially decreasing mucosal chemotherapy toxicity," Dale Lee Bixby, MD, PhD, University of Michigan Health System, told Targeted OncologyTM. "Recent updates of the phase I/II trial noted that patients receiving uproleselan had high risk disease with 75% having had a prior remission of less than 1 year and 50% of patients having unfavorable cytogenetics. Approximately 40% of these high-risk patients obtained a composite complete remission using cytotoxic chemotherapy and uproleselan, and the addition of uproleselan added little to the toxicity profile of the backbone chemotherapy."
Uproleselan is a novel E-selectin antagonist that disrupts cell survival pathways and enhances chemotherapy response. In preclinical studies, the agent has improved survival and decreased chemotherapy toxicity in vivo.
In a multicenter, open-label, phase 1/2 study, investigators sought to evaluate the safety, tolerability, and antileukemic activity of uproleselan at 5-20 mg/kg with mitoxantrone, etoposide, and cytarabine (MEC) in patients with relapsed/refractory AML. The trial enrolled patients at 10 sites across the United States, Ireland, and Australia.
The first part of the trial was the dose-escalation phase which enrolled patients with relapsed/refractory AML to determine the safety, tolerability, pharmacokinetics, and recommended phase 2 dose (RP2D) of uproleselan in addition to a conventional salvage chemotherapeutic regimen.
Then, the expansion phase sought to assess the efficacy of uproleselan at the RP2D when given with salvage chemotherapy in the same relapsed/refractory AML population. This portion also evaluated uproleselan in combination with a standard (7 + 3) frontline AML induction regimen in older patients newly diagnosed with AML.
Patients were eligible for enrollment if aged 18 years and older with relapsed/refractory AML who were eligible to receive an intensive induction regimen including MEC. Enrollment was open to patients who had prior stem cell transplantation, and all were required to have an ECOG performance status of 0-2, and adequate baseline renal and hepatic function.
In a separate cohort of newly diagnosed patients, those enrolled were required to be 60 years of age or older and candidates for intensive chemotherapy. Patients could not have had prior treatment for AML, except for hydroxyurea, and those with secondary AML could have received prior therapy for their antecedent hematologic disorder. Other eligibility criteria for this cohort followed that of the relapsed/refractory cohort of patients.
Uproleselan was administered to all cohorts as a 20-minute IV infusion given 24 hours prior, twice daily throughout, and twice daily for 48 hours after chemotherapy. Patients with relapsed/refractory disease were also given the salvage chemotherapy regimen of IV mitoxantrone at 10 mg/m2 per day over 15-20 minutes, 100 mg/m2 of IV etoposide per day over 60 minutes, and 1000 mg/m2 of IV cytarabine per day over 60 minutes for 5 days for 1 induction cycle.
Frequency, severity, and relatedness of treatment-emergent adverse events (TEAEs) in patients given uproleselan in combination with chemotherapy served as the primary end points of the study.
Among those enrolled, patients had a median age of 59 years (range, 26-84). Thirty-three percent of patients had primary refractory disease at the time of study entry and 67% were in relapse after a previous response. Among patients with relapsed AML, the length of initial remission duration was 12 months or less in 75% of patients and greater than 12 months in 25%. Then, 67% of patients had been given 1 previous induction regimen, and 33% had received 2 or more. A total of 12 patients had undergone prior hematopoietic stem cell transplantation.
For patients with newly diagnosed AML, the median age was 67 years (range, 60-79), and 13 (52%) of the 25 patients had secondary AML at the time of study entry. Among the 25 patients, 7 (28%) were treated with hypomethylating agents (HMAs) prior to progression to AML. A classification of unfavorable cytogenetic risk per SWOG criteria was observed in 8 (32%) patients, and intermediate risk was seen in 16 (64%). Forty-eight percent were in the adverse-risk category, and 28% were intermediate risk, according to ELN risk criteria.
In the initial dose-escalation portion of the trial, 19 patients were enrolled and put into 3 separate dose-level groups of 5 (n = 6), 10 (n = 7), and 20 mg/kg (n = 6).Among the 19 patients, no dose-limiting toxicities were observed. Investigators determined the RP2D of the agent to be 10 mg/kg twice daily.
Then, an additional 47 patients with relapsed/refractory AML were administered uproleselan at the RP2D plus MEC. With this dose, the remission rate was 41% with complete responses (CR) observed in 35% of patients. The median overall survival (OS) in this group was 8.8 months (95% CI, 5.7-11.4).There was a CR/CRi rate of 52% in patients with relapsed disease who had received 1 prior induction regimen, and 36% for patients treated with ≥2 prior regimens.
For the patients who relapsed, the CR/CRi rate was observed in 28% of patients with an initial CR duration of less than 12 months vs an 83% response rate for patients with an initial CR duration of greater than 12 months. Moreover, 51% of patients had been previously given high doses of cytarabine (≥1 g/m2) as a prior induction and/or as post remission therapy. For these patients, the CR/CRi rate was 47%.
In the final cohort of 25 patients aged 60 years and older with newly diagnosed AML, patients were given uproleselan at the RP2D plus cytarabine and idarubicin. Findings revealed the CR/CR with incomplete count recovery to be 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).
Regarding safety in the cohort of patients with relapsed/refractory AML, the incidence of TEAEs was similar across all dose levels of uproleselan dose levels. None of the 66 patients discontinued treatment due to an AE. However, all patients in this cohort had evidence of grade 4 myelosuppression during the study.
Most of the TEAEs observed were typical of the background chemotherapy, with few TEAEs attributed to uproleselan. Besides hematologic toxicities, the only grade 3 or 4 TEAEs seen in ≥ 10% of patients were sepsis (12% of patients). Other AEs included nausea, vomiting, diarrhea, and colitis; however, each were mild with grade 3 events occurring in <5% of patients. Moreover, hepatic, and renal TEAEs were mostly grade 1-2, and grade 3-4 AEs were observed in 5% and 5% of patients, respectively.
One patient (2%) died within 30 days of the start of therapy and the 60-day mortality rate was 9% (n = 6). Further, grade 3 mucositis was reported in 2% of patients and other nonhematologic TEAEs were deemed mild and/or unrelated to the study drug.
With the addition of uproleselan, patients with relapsed/refractory AML had lower rates of oral mucositis. There were higher rates of E-selectin ligand expression on leukemic blasts in patients with relapsed AML compared with primary refractory AML and newly diagnosed, older patients with high-risk cytogenetics and secondary AML.
For patients in the relapsed/refractory cohort of the trial, E-selectin expression >10% was associated with a higher response rate and improved survival.
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.
“Given the encouraging response rate and tolerability in this high-risk AML population, randomized investigation are ongoing to confirm the potential beneficial effects of uprolesean on relapsed/refractory AML patient’s survival. There has been a decades long dream that mobilizing leukemia cells from the potentially protective bone marrow niche will enhance chemotherapy sensitivity, and these studies will again test this long-sought paradigm. There is also a strong clinical interest to investigate this same potential benefit in fit adult patients receiving an anthracycline-based induction therapy for newly diagnosed AML. It would be a tremendous asset to develop a non-cytotoxic synergistic therapy for AML patients that carries only modest side-effects while also potentially protecting patients from a common toxicity of that same treatment," added Bixby.