In:
Blood, American Society of Hematology, Vol. 118, No. 21 ( 2011-11-18), p. 118-118
Abstract:
Abstract 118 Background: Myelodysplastic syndromes (MDS) are characterized by excess elaboration of myelosuppressive cytokines contributing to increased apoptotic loss of hematopoietic precursors, the hallmark of lower-risk MDS. p38a MAP kinase (MAPK) is a key downstream convergence point and effector of hematopoietic inhibitory cytokines and death receptors in hematopoietic precursors and stromal elements. The actions of Tie2 complement this regulatory axis by promoting cytokine production and altering cellular quiescence. ARRY-614 is a small-molecule inhibitor of both p38 MAPK and Tie2 that may improve hematopoiesis in lower-risk MDS patients (pts). Methods: This Phase 1 study was designed to determine the maximum tolerated dose (MTD) of ARRY-614 and evaluate safety, pharmacokinetics (PK), preliminary efficacy (International Working Group [IWG] 2006) and pharmacodynamic (PD) effects. Eligible pts had International Prognostic Scoring System (IPSS) risk group Low or Int-1 MDS, and had either received prior therapy or were not eligible or refused treatment. ARRY-614 was administered in 28-day cycles. A standard 3+3 dose escalation design was used and an expansion cohort at the MTD in red blood cell (RBC) transfusion-dependent (TD) pts was evaluated. Results: Forty-five pts with Low (n = 11) or Int-1 (n = 34) risk MDS were enrolled with a median age of 72 years (range 47–84). All but one pt had disease refractory to and/or relapsed from prior therapy with a median of 3 prior regimens (range 0–10); 82% received hypomethylating agents (HMAs), 49% received erythropoietin (EPO)-stimulating agents and 40% received lenalidomide. As of July 2011, 7 pts remain on study. ARRY-614 was administered in a fasting state at doses of 400–1200 mg once daily (QD) and 200–300 mg twice daily (BID), and under fed conditions at 400 mg QD. Dose-limiting toxicities (DLTs) reported at QD doses included single events of Grade (Gr) 3 diarrhea (400 mg QD fasting), Gr 3 macular skin rash (1200 mg QD) and Gr 3 QTc prolongation (400 mg QD fed). Due to the high number of capsules required per dose, the maximum administered QD dose was 1200 mg; the MTD was not reached. The 300 mg BID dose was dose limiting due to 5/7 pts with DLTs of Gr 3 rash (n = 2), Gr 3 asthenia and jitteriness (n = 1), Gr 3 allergic reaction to study medicine (n = 1), and Gr 3 muscle weakness with Gr 3 elevated AST/ALT (n = 1); therefore BID dosing was discontinued. The most common (≥ 10% of pts) treatment-related adverse events (AEs) across all dose cohorts included rash (29%), diarrhea (22%), dry skin (13%) and QTc prolongation (11%). The median duration of treatment was 16 wks (range 1–76). ARRY-614 exposure was dose proportional, but high inter-pt variability was observed. The median Tmax was 3 hours and the t1/2was ∼ 8 hours; both parameters were consistent across all doses evaluated. Plasma EPO was elevated at baseline in pts with erythroid response (471 ± 285 U/L, n = 4) and decreased by 92 ± 4% overall. In non-responding pts, baseline EPO was 984 ± 315 U/L (n = 41) and 68 ± 22% maximal decrease was observed. In 68% (13/19) of pts that were above 500 U/L at baseline, EPO was suppressed below 500 U/L during time on study supporting a drug effect in these pts as well. Eight of 43 evaluable pts experienced hematological improvement (HI) per IWG 2006 criteria. HI responses (duration 8 to 80 wks) occurred in all lineages (4 HI-erythroid, 5 HI-neutrophil and 4 HI-platelet) including 5 bi-lineage responses and some pts had a reduction in platelet transfusions. All IWG 2006 responders failed prior treatment with ≥ 1 HMA. At doses ≥ 900 mg QD, 6 of 18 evaluable pts achieved HI in one or more lineage. Conclusions: ARRY-614 has shown encouraging preliminary multi-lineage hematologic activity as a single agent in a heavily pretreated pt population. At the QD doses studied to date, it has demonstrated an acceptable safety profile. Correlative studies of preliminary drug activity with PD analyses from bone marrow samples are ongoing (final results to be presented). Given the variable but dose-proportional drug exposure, a new oral formulation with improved PK profile will be evaluated in MDS pts starting 4Q2011. Because ARRY-614 has promising preliminary activity, additional investigation in this lower-risk MDS population who have received prior treatment with HMAs is warranted. In addition, the treatment-related reductions in plasma EPO suggest that combination treatment with recombinant EPO may optimize erythroid response. Disclosures: List: Array BioPharma: Consultancy. Winski:Array BioPharma: Employment. Bell:Array BioPharma: Employment. Rush:Array BioPharma: Employment. Maloney:Array BioPharma: Employment. Ptaszynski:Array BioPharma Inc.: Consultancy. Kantarjian:Array BioPharma: Research Funding.
Type of Medium:
Online Resource
ISSN:
0006-4971
,
1528-0020
DOI:
10.1182/blood.V118.21.118.118
Language:
English
Publisher:
American Society of Hematology
Publication Date:
2011
detail.hit.zdb_id:
1468538-3
detail.hit.zdb_id:
80069-7
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