Clinical and Biologic Effects of the Angiopoietin 1/2 Neutralizing Peptibody Trebananib (AMG 386) in Acute Myeloid Leukemia Patients

Abstract

Background Marrow angiogenesis plays an important role in the pathogenesis of acute myeloid leukemia (AML). Among the most prominent pro-angiogenic factors produced by AML cells are the angiopoietins (Ang-1/2), ligands of the Tie2 endothelial cell receptor. Elevated expression of Ang-2 is an independent prognostic factor for overall survival in AML. Trebananib (AMG 386) is a first-in-class neutralizing peptibody that provides potent and selective inhibition of angiopoietins by sequestering Ang1 and Ang2 and preventing their interaction with the Tie2 receptor. Purpose Here we evaluated the safety, tolerability, pharmacokinetic profile, and biologic effects of trebananib in de novo and relapsed/refractory AML patients considered to be poor candidates for standard induction chemotherapy. Methods Thirteen AML patients were enrolled in single agent arm A of this open-label, non-randomized phase Ib trial. ([ClinicalTrials.gov][1] ID: [NCT01555268][2], NCI-2011-02979). Drug was administered at two dose levels (15 and 30 mg/kg) via weekly intravenous infusion over 1 hour. Circulating angiogenic factor levels (Ang-2, VEGF-A/C/D, HGF, IL-8, FGF-1/2, G-CSF, PlGF) in the plasma were measured by multiplex flow cytometry prior to first dose, on cycle 1 day 29 (following 4 weekly doses of trebananib), and at the end of study. Results Median age was 76 years (range 53-82). Nine patients were male (69%). Two patients had de novo, 7 had refractory, and 4 had relapsed AML. One patient had undergone prior allogeneic stem cell transplantation. Aside from one possibly drug-related incident of grade 3 mucositis on the 15 mg/kg cohort, no other dose-limiting toxicities were reported. The most common toxicities were abdominal bloating, diarrhea, edema, and weight gain. Preliminary pharmacokinetic analysis of trebananib was dose-proportional. At the 15 and 30 mg/kg dose levels, median Cmaxand AUC on Day 1 were 193 and 473 ug/mL and 11,670 and 35,217 ug-hr/mL, respectively. No neutralizing antibodies to trebananib were detected. Among seven AML patients with consecutive plasma samples, therapy was associated with marked elevations of Ang-2 levels (from 15 to 336-fold higher than baseline) after 1-4 weeks of therapy (Table 1). Induction of Ang-2 did not differ significantly between the 15 mg/kg and 30 mg/kg cohorts. Ang-2 levels measured in bone marrow or plasma samples at the same time point were comparable. In contrast, levels of other angiogenic growth factors (VEGF-A/C/D, IL-8, G-CSF, HGF, FGF-1/2, PlGF) were not consistently altered by trebananib therapy. One AML patient (on the 15 mg/kg cohort) had a partial response with >50% decrease in marrow blasts. Two patients (15 mg/kg, 30 mg/kg) had stable disease over >1 cycle. Conclusions We report here the preliminary results of phase 1b study evaluating the safety, tolerability, pharmacokinetic profile, and biologic effects of trebananib in adult AML patients. Weekly infusions of trebananib administered at 15 and 30 mg/kg were well tolerated. Drug pharmacokinetics were similar to those previously reported in solid tumor patients. Trebananib resulted in substantial elevations in measurable circulating and marrow Ang-2 levels in AML patients, presumably due to a negative compensatory feedback loop resulting from potent in vivo Ang-1/2 inhibition. Arm B of this study (trebananib plus low dose cytarabine) is currently accruing. Further in depth studies examining the biological effects of trebananib on marrow angiogenesis and clinical response in AML patients are ongoing. Disclosures: Becker: Millenium: Research Funding. [1]: http://ClinicalTrials.gov [2]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT01555268&atom=%2Fbloodjournal%2F122%2F21%2F2701.atom