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Phase 1b study of the MDM2 inhibitor AMG 232 with or without trametinib in relapsed/refractory acute myeloid leukemia

Harry P. Erba, Pamela S. Becker, Paul J. Shami, Michael R. Grunwald, Donna L. Flesher, Min Zhu, Erik Rasmussen, Haby A. Henary, Abraham A. Anderson and Eunice S. Wang

Article Figures & Data

Figures

  • Figure 1.

    Pharmacokinetics of AMG 232 and trametinib. Mean (±standard deviation) plasma concentration vs time profiles after oral once-daily administration of AMG 232 (A) and trametinib 2 mg (B).

  • Figure 2.

    Pharmacodynamic response of MIC-1 and p53 target gene expression during treatment with AMG 232. Mean (±standard error) ratio of posttreatment vs pretreatment serum MIC-1 in arm 1 (A) and arm 2 (B). (C) Fold change from baseline in expression of BAX, PUMA, P21, MDM2, and TP53 genes in bone marrow. EOT, end of treatment.

  • Figure 3.

    Activity of AMG 232 with or without trametinib. (A) Maximum change from baseline in bone marrow blast percentage and best overall response in 24 evaluable patients in arm 1 (AMG 232 monotherapy) and arm 2 (AMG 232 + trametinib). Unevaluable patients either had no baseline measurement for bone marrow blast count or only 1 measurement in total. (B) Median treatment duration of responders (blue bars; n = 6) and nonresponders (red bars; n = 24). In both panels, dose cohorts are shown next to each bar, and TP53 mutation status, when evaluated in patients with unknown status at screening, is shown as positive (+) or negative (−). PD, progressive disease; TF, treatment failure.

Tables

  • Table 1.

    Demographics and baseline characteristics

    CharacteristicsAll patients (N = 36)
    Age, median (range), y68 (26-86)
    Sex, n (%)
     Male23 (64)
     Female13 (36)
    Race/ethnicity, n (%)
     White30 (83)
     African American4 (11)
     Asian1 (3)
     Hispanic1 (3)
    Evaluable aspirates for TP53 mutation status, n (%)16 (44)
     Negative13 (36)
     Positive3 (8)
    Evaluable aspirates for FLT3 mutation status, n (%)23 (64)
     Negative20 (56)
     FLT3 ITD1 (3)
     FLT3 TKD mutation1 (3)
     FLT3 ITD and TKD mutation1 (3)
    ECOG performance status, n (%)
     010 (28)
     121 (58)
     25 (14)
    Prior stem cell transplant, n (%)4 (11)
    Prior lines of therapy, n (%)35 (97)
     110 (28)
     210 (28)
     ≥315 (42)
    Prior treatment with hypomethylating agents, n (%)
     Azacitidine15 (42)
     Decitabine13 (36)
    Prior treatment with 7+3, n (%)
     Cytarabine plus daunorubicin9 (25)
     Cytarabine plus idarubicin7 (19)
     Cytarabine plus epirubicin1 (3)
     Not specified1 (3)
    • ECOG, Eastern Cooperative Oncology Group; ITD, internal tandem duplication; TKD, tyrosine kinase domain.

  • Table 2.

    Patient incidence of AEs

    Patients with AEs, n (%)Arm 1 (AMG 232)Arm 2 (AMG 232 +T)All patients (N = 36)
    60 mg (n = 4)90 mg (n = 4)180 mg (n = 5)240 mg (n = 3)360 mg (n = 10)60 mg (n = 10)
    Any AE4 (100)3 (75)5 (100)3 (100)10 (100)10 (100)35 (97)
    Any serious AE3 (75)2 (50)4 (80)2 (67)4 (40)3 (30)17 (47)
    Treatment-related AEs3 (75)2 (50)5 (100)3 (100)9 (90)9 (90)31 (86)
     Grade 31 (25)2 (50)2 (40)2 (67)4 (40)5 (50)16 (44)
     Grade 41 (25)1 (25)3 (60)1 (33)1 (10)3 (30)10 (28)
    Common treatment-related AEs*
     Nausea3 (75)1 (25)3 (60)1 (33)5 (50)8 (80)21 (58)
      Worst grade 30 (0)0 (0)0 (0)0 (0)0 (0)1 (10)1 (3)
     Diarrhea1 (25)1 (25)4 (80)2 (67)7 (70)5 (50)20 (56)
      Worst grade 30 (0)0 (0)0 (0)0 (0)1 (10)1 (10)2 (6)
     Vomiting0 (0)1 (25)2 (40)1 (33)2 (20)6 (60)12 (33)
      Worst grade 30 (0)0 (0)0 (0)0 (0)2 (20)0 (0)2 (6)
     Decreased appetite0 (0)0 (0)2 (40)0 (0)3 (30)4 (40)9 (25)
     Anemia0 (0)2 (50)1 (20)1 (33)1 (10)3 (30)8 (22)
      Worst grade 30 (0)2 (50)1 (20)1 (33)0 (0)3 (30)7 (19)
     Leukopenia0 (0)1 (25)2 (40)0 (0)1 (10)2 (20)6 (17)
      Worst grade 40 (0)1 (25)2 (40)0 (0)1 (10)2 (20)6 (17)
     Thrombocytopenia1 (25)1 (25)1 (20)1 (33)1 (10)1 (10)6 (17)
      Worst grade 31 (25)0 (0)0 (0)0 (0)0 (0)0 (0)1 (3)
      Worst grade 40 (0)1 (25)1 (20)1 (33)1 (10)1 (10)5 (14)
     Fatigue0 (0)0 (0)2 (40)0 (0)1 (10)2 (20)5 (14)
      Worst grade 30 (0)0 (0)0 (0)0 (0)0 (0)1 (10)1 (3)
     Abdominal pain1 (25)0 (0)0 (0)1 (33)0 (0)2 (20)4 (11)
    • T, trametinib.

    • * Treatment-related AEs occurring in ≥10% of all patients are shown.

  • Table 3.

    AMG 232 pharmacokinetic parameters

    Cycle 1, day 1Cycle 1, day 7
    tmax, hCmax, ng/mLAUC24h, ng⋅h/mLtmax, hCmax, ng/mLAUC24h, ng⋅h/mLCL/F, L/hAUC24h AR
    AMG 232 60 mg
     n44444444
     MeanNC6693310NC665544012.41.79
     SDNC226884NC21020805.040.984
    AMG 232 60 mg + trametinib 2 mg
     n10109
     MeanNC5202850
     SDNC2111120
    AMG 232 90 mg
     n44333333
     MeanNC17907140NC135012 5007.271.77
     SDNC7021100NC10916701.050.291
    AMG 232 180 mg
     n55455554
     MeanNC9626540NC141017 10017.72.38
     SDNC4633790NC79111 90014.80.834
    AMG 232 240 mg
     n33022220
     MeanNC1280NCNC211020 10013.4NC
     SDNC194NCNC*NC*NC*NC*NC
    AMG 232 360 mg
     n1010888886
     MeanNC509027 900NC352034 70022.51.11
     SDNC232016 500NC247031 70020.40.728
    • AR, accumulation ratio (AUC24h cycle 1, day 1/AUC24h cycle 1, day 7); Cmin, minimum observed serum concentration; NC, not calculated; SD, standard deviation.

    • * Standard deviation is not reported when n ≤ 2.

  • Table 4.

    Trametinib pharmacokinetic parameters

    Cycle 1, day 1Cycle 2, day 1
    tmax, hCmax, ng/mLAUC6h, ng⋅h/mLtmax, hCmax, ng/mLAUC6h, ng⋅h/mL
    n101010663
    MeanNC8.9327.7NC28.0120
    SDNC3.3410.1NC9.8117.1