A Phase I/II Study of GMI-1271, a Novel E-Selectin Antagonist, in Combination with Induction Chemotherapy in Relapsed/Refractory and Elderly Previously Untreated Acute Myeloid Leukemia; Results to Date

Background

The treatment of patients with relapsed acute myeloid leukemia (AML) remains a significant challenge with poor outcomes due to a low response rate. Although cytotoxic chemotherapy remains the standard approach for treatment, novel agents are needed to improve clinical outcomes. Binding of leukemic blasts to E-selectin (E-sel), an adhesion molecule expressed constitutively in the bone marrow endothelium, activates leukemic cell survival pathways, thereby contributing to chemotherapy resistance. GMI-1271 is a novel antagonist of E-sel, putatively disrupting leukemia cell survival pathways and enhancing chemotherapy response. We performed a phase 1/2 trial of GMI-1271 plus MEC (mitoxantrone, etoposide and cytarabine) for the treatment of relapsed/refractory (R/R) and a pilot study adding GMI-1271 to 7+3 for previously untreated elderly patients with AML.

Methods

A phase 1/2 open label trial of patients with R/R AML, with escalation of a single cycle of GMI-1271 across 3 dose levels combined with MEC, was conducted to assess safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD) and antileukemic activity. In addition, a pilot study was performed at the recommended phase 2 dose (RP2D) plus infusional cytarabine and idarubicin (7+3) in patients ≥60 years with untreated AML. Eligible patients (R/R AML) had an ECOG score of 0-2, received ≤2 prior induction regimens, WBC <20K (raised to <40K after 2 dose levels), no active CNS disease, and adequate renal and hepatic function. Eligibility for elderly patients in the untreated AML group was similar. GMI-1271 was administered with chemotherapy (24 hours prior, throughout, and 48 hours post induction). Dose limiting toxicity (DLT) was defined as myelosuppression beyond day 42 in the absence of disease or Grade 3 non-hematologic toxicity attributable to GMI-1271 and not resolving to Grade 2 by day 42. PK data were analyzed by population PK methods. PD for on-target activity was assessed by change from baseline in plasma sE-selectin levels (sE-sel) compared by 2-way analysis of variance.

Results

The phase 1 (Ph1) dose escalation in the R/R AML arm was completed with 19 subjects treated with GMI-1271 BID at 5 mg/kg (N=6), 10 mg/kg (N=7), and 20 mg/kg (N=6). The median age was 51 (range 26-77); 13 were male; 6 were refractory to prior intensive induction; 10 relapsed in ≤12 mos and 3 in >12 mos; number of prior induction regimens: 1 (N=15) and 2 (N=4); risk based on the SWOG cytogenetic classification was intermediate (9) or unfavorable (10). There were no DLTs observed in the R/R dose escalation and no early deaths (30 d). Transient mucositis developed in only 5 subjects (4 at 5 mg/kg), of whom 2 required IV nutrition (5 mg/kg). Median time to count recovery was 37d (ANC >1K) and 35 d (platelets >100K) in responders. AEs were typical for MEC.

Ph1 CR/CRi rate was 47% (42% CR%) with no observable dose response; 26% proceeded to subsequent stem cell transplant. Six of 9 remain in CR at data cut-off. Median OS and PFS have not been reached. One subject >70yrs with refractory disease who achieved CR (negative by flow) was retreated with GMI-1271/MEC again off protocol and remains in CR (9mo).

PK analysis showed linear kinetics; an average 50 y.o. had clearance 1.28 L/h with elimination t_1/2>3h; Cl decreased 2%/yr of increased age, and was 28% lower than in healthy adults. No accumulation was seen. Time over IC50 for E-sel binding was >50% of the dosing interval for most patients at 10 mg/kg, and well in excess of effective preclinical exposure. PD analysis showed sE-sel on Day 8 decreased below baseline (p˂0.0013) with no dose response, suggesting on-target activity at all dose levels. Normal HSCs were not mobilized into the periphery after sentinel GMI-1271 dose. RP2D was determined to be 10 mg/kg BID based on drug exposure, time over IC50 for E-sel binding, lack of DLT, and similar on-target PD and clinical outcomes.

To date, 10 patients enrolled on the Ph2 R/R AML arm; an additional 37 will be enrolled. In the previously untreated elderly AML arm, 3 patients enrolled in the safety run-in and no DLTs were observed, therefore an additional 22 patients will be enrolled. Updated response data will be presented at ASH.

Conclusion

We report on early clinical assessment of novel E-selectin antagonist GMI-1271 in R/R AML patients, with a high response rate (CR/CRi 47%) in this challenging group. No significant toxicities and no DLT were observed for GMI-1271. Ph2 dose expansion is ongoing.