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Table 4 AKIs in clinical development

From: Targeting AURKA in Cancer: molecular mechanisms and opportunities for Cancer therapy

Drug name Targets
(IC50/Ki value)
Phase
of trial
Clinical Trial ID Patients Administration Efficiency Ref
AMG900 IC50 value:
AURKA (5 nM)
AURKB (4 nM)
AURKC (1 nM)
I NCT01380756 Acute myeloid leukemia (n = 35) Doses from 15 to 100 mg or doses from 30 to 50 mg, orally, once daily. CRi = 9% (80% confidence interval: 3, 18%). [102]
I NCT00858377 TPROC (n = 29)
TNBC (n = 14) CRPC (n = 12)
40 mg, orally, once daily. PR = 10.3%for TPROC patients; No responses for TNBC and CRPC. [103]
AS703569
(R763)
(MSC1992371A)
IC50 value:
AURKA (4.0 nM)
AURKB (4.8 nM)
AURKC (6.8 nM)
I NCT00391521 Solid tumors (n = 92) 60–74 mg/m2/21-day cycle, orally. No patients had PR or PR. [104]
I NCT01080664 Hematologic malignancies (n = 75) 37 or 28 mg/m2/day, orally. 3 patients obtained CR. [105]
I NCT01097512 Solid tumors
(n = 66)
37 mg/m2/day, orally. Combined with standard 1000 mg/m2 dose of gemcitabine. 2 patients obtained PR.
5 patients had SD.
[106]
AT9283 IC50 value:
AURKA (3 nM)
AURKB (3 nM)
JAK3 (1.1 nM)
JAK2 (1.2 nM)
Abl (T315I)
(4 nM)
I NCT00443976 Advanced malignancies (n = 35) 40 mg/m2/day on days 1, 8 of a 21-day cycle, i.v. 1 patient had PR.
4 patients had SD.
[107]
I NCT00522990 R/R leukemia or myelofibrosis (n = 48) 108 mg/m2/d for 72-h infusion and 40 mg/m2/d for 96-h infusion. 2 patients showed benefit. [108]
I CR0708–11 Solid tumors (n = 33) 18.5 mg/m2/d, i.v. 1 patient had PR. [109]
I /II NCT01431664 Leukemia (n = 7) 9,14.5 or 23 mg/m2/day, i.v. No patients showed responses. [110]
II NCT01145989 R/R multiple myeloma (n = 8) 40 mg/m2/day or 30 mg/m2/day, i.v. No objective responses. [111]
BI-847325 IC50 value:
AURKA (25 nM)
AURKC (15 nM)
MEK1 (25 nM)
MEK2 (4 nM)
I NCT01324830 Advanced solid tumors (n = 69) Cumulative dose was 1680 or 2250 mg per 3-week cycle. Orally, once daily. 1 patient had PR.
21 patients had SD.
[112]
CYC116 Ki value:
AURKA (8 nM)
AURKB (9.2 nM)
I NCT00560716
(Terminated)
Advanced solid tumors (n = 40) NA NA NA
ENMD-2076 IC50 value:
AURKA(14 nM)
FLT3 (3 nM)
I NCT00658671 Solid tumors (n = 67) 60 to 200 mg/m2, Orally, once daily. 2 patients had PR. [113]
I NCT00904787 R/R AML/CML (n = 27) 225 mg, 375 mg, 325 mg or 275 mg. Orally, once daily. 1 patient had CRi. 3 patients had MLFS. [114]
II NCT01104675 Ovarian cancer (n = 64) 250 mg or 275 mg/d. Orally, once daily. PFS rate at 6 months was 22%. [115]
II NCT01639248 TNBC (n = 41) 250 mg. Orally, once daily. 6-month CBR was 16.7%, 2 PR. 4-month CBR was 27.8%. [116]
II NCT01914510 Ovarian clear cell carcinoma (n = 40) 275 mg (250 mg for patients ≤1.65 m2). 3 patients had PR, 26 patients had SD. [117]
II NCT01719744 Advanced soft-tissue sarcomas (n = 25) 275 mg. Orally, once daily. 2 patients had PR, 2 patients had SD.
CBR was 17% and ORR was 9%.
[118]
II NCT02234986 Advanced fibrolamellar carcinoma (n = 35) 150–250 mg. Orally, once daily 1 patient had PR, 20 patients had SD. [119]
MK-0457
(VX-680, Tozasertib)
Ki value:
AURKA (0.6 nM)
AURKB (18 nM)
AURKC (4.6 nM)
I NCT02532868 Advanced solid tumors (n = 27) 64 mg/m2/h 24-h infusion every 21 days. 12 patients had SD. [120]
I/II NCT00111683 BCR-ABL T315I leukemia (n = 77) 40 mg/m2/h 5-day infusion or 144 mg/m2/h 24-h infusion. 1 patient had CR. 8 patients had hematologic responses. [121]
II NCT00405054 T315I mutant CML and Ph+ ALL (n = 52) 40 mg/ m2/h, 32 mg/ m2/h or 24 mg/ m2/h 5-day infusion. 8% of patients had major cytogenetic response. 6% achieved unconfirmed complete or partial response. [122]
MK-5108
(VX-689)
IC50 value:
AURKA
(0.064 nM)
I NCT00543387 Advanced or refractory solid tumors (n = 35) 200 or 450 mg/day. Orally, twice daily. 1 patient had PR. 16 patients had SD. [123]
MLN8054 IC50 value:
AURKA (4 nM)
I NCT00249301 Advanced solid tumors (n = 61) 60 mg/day plus methylphenidate or modafinil, four times daily, orally. 3 patients had SD. [124]
I NCT00652158 Advanced solid tumors (n = 43) 10-80 mg/day, four times daily, orally. 3 patients had SD. [125]
PF-03814735 IC50 value:
AURKA (5 nM)
AURKB (0.8 nM)
I NCT00424632 Advanced solid tumors (n = 57) Days 1–5 (5-100 mg); or days 1–10 (40-60 mg). Orally, once daily. 19 patients had SD. [126]
PHA-739358
(Danusertib)
IC50 value:
AURKA (13 nM)
AURKB (79 nM)
AURKC (61 nM)
I NA Advanced or metastatic solid tumors (n = 50) 45 mg/m2 6-h infusion, 250 mg/m2 3-h infusion. MTD: 330 mg/m2, 6-h infusion. 23.7% patients had SD. [127]
I NA Advanced solid tumors (n = 56) Without G-CSF: 500 mg/m2; with G-CSF: 750 mg/m2, 24-h infusion. 1 patient had an objective response. 1 patient had 27% tumor regression and 30% CA125 decline. [128]
I 2007–004070-18 Accelerated or blastic phase CML, Ph+ ALL (n = 37) 180 mg/m2 3-h infusion for 7 days in a 14-day cycle. Responses were observed in four (20%) of the 20 evaluable patients. [129]
II NCT00766324 Prostate cancer (n = 88) 330 mg/m2 6-h infusion or 500 mg/m2 24-h infusion. 11 out of 81 (13.6%) patients had SD. [130]
II NA Solid tumors (n = 223) 500 mg/m2 24-h infusion every 14 days. 2 patients had PR. [131]
SNS-314 IC50 value:
AURKA (9 nM)
AURKB (31 nM)
AURKC (3 nM)
  NCT00519662 Advanced solid tumors (n = 32) NA NA NA
  1. Complete response (CR); Partial response (PR); Stable disease (SD); Complete response with incomplete count recovery (CRi); Morphologic leukemia-free state (MLFS); Progression free survival (PFS); Granulocyte colony-stimulating factor (G-CSF); Taxane- and platinum-resistant ovarian cancer (TPROC); Triple-negative breast cancer (TNBC); Castration-resistant and taxane- or cisplatin/etoposide–resistant prostate cancer (CRPC); Acute myelogenous leukaemia (AML); Chronic myelogenous leukaemia (CML); Relapsed or Refractory (R/R); Philadelphia Chromosome Positive (Ph+); Clinical benefit rate (CBR); Objective response rate (ORR); Not available (NA)