Table 4 AKIs in clinical development

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