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. 2021 Jan 15;20:15. doi: 10.1186/s12943-020-01305-3

Table 4.

AKIs in clinical development

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

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)