Supplementary Table 12 | Agents that disrupt mitosis: limited activity to date
Compound
Aurora inhibitors
MK-0457
(VX-680)
AZD 1152
PHA 680632
PHA 739358
MLN8054
MLN8237
R763
AT9283
SNS-314
SU 6668
ENMD-2076
BI 811283
Company
Comment
Vertex/Merck
Response in 3 patients with imatinib-resistant T315I CML, suspended
due to cardiac safety;1 SD in 3/16 patients2
No activity reported
No activity reported
SD in 7/42 patients3
SD in 3/43 patients4
SD in 5/23 patients; 1 case of PR and 8/65 patients with SD5
PD in 2/15 patients6
HR in 2/29 patients;7 SD in 3/22 patients;8 1 case of PR and 4/33
patients with SD9
SD in 6/32 patients10
SD in 4/35 patients;11 SD in 3/19 patients12
SD in 4/14 patients13
SD in 33.3% of 57 patients;14 SD in 29% of 52 patients15
Astra Zeneca
Nerviano
Nerviano
Millenium
Millenium
Merck/Serono
Astex
Sunesis
Sugen/Pfizer
EntreMed
Boehringer
Ingelheim
CYC116
Cyclacel
ENMD 981693
Entremed/Miikana
MKC 1693
Entremed/Miikana
Polo-like kinase inhibitors
ON01910
Onconova
BI-2536
Boehringer
GSK-461364
GlaxoSmithKline
HMN-214
Nippon Shinyaku
BI-6727
Boehringer
Kinesin spindle protein inhibitors
Ispinesib
Cytokinetics
(SB-715992)
One study ongoing, one study terminated
Ongoing
Ongoing
SD in 1/23 patients;16 SD in 2/5 patients;17 no response18
PR in 4/95 patients;19 PR in 2/33 patients;20 SD in 7/23 patients21
SD in 2/27 patients22
No activity;23 MR and SD;24 1 TR and 2 SD out of 33 patients25
3 PR, 48% SD and PFS in 6 out of 65 patients26
SD in 4/42 patients;27 SD in 3/27 patients;28 unconfirmed MR in 3/24
patients;29 SD in 2 and MR in 1 out of 27 patients;30 SD in 7/19 patients;31
3 PR and SD in 4/16 patients32
SB-743921
Cytokinetics
1 PR and SD in 1/32 patients;33 PR in 2/51 patients with lymphoma34
MK-0731
MRK
SD in 16/35 patients35
ARRY-520
Array Biopharma
PSD in 3/34 patients;36 PR in 1/13 patients37
Abbreviations: CML, chronic myeloid leukemia; HR, hematologic remission; MR, minor response; PD, progressive
disease; PFS, progression-free survival; PR, partial response; PSD, prolonged stable disease; SD, stable
disease; TR, transient response.
1. Giles, F.J. et al. MK-0457, a novel kinase inhibitor, is active in patients with chronic myeloid leukemia or acute
lymphocytic leukemia with the T315I BCR-ABL mutation. Blood 109, 500-2 (2007).
2. Rubin, E. H. et al. A phase I clinical and pharmacokinetic (PK) trial of the aurora kinase (AK) inhibitor MK-0457
in cancer patients [abstract]. J. Clin. Oncol 24 (18 Suppl.), a3009 (2006).
3. De Jonge, M. et al. Phase I study of the aurora kinases (AKs) inhibitor PHA-739358 administered as a 6 and 3h IV infusion on Days 1, 8, 15 every 4 wks in patients with advanced solid tumors [abstract]. J. Clin. Oncol. 26
(Suppl.), a3507 (2008).
4. Macarulla, T. et al. Phase I pharmacokinetic (PK) and pharmacodynamic (PD) study of the selective aurora A
kinase (AAK) inhibitor MLN8054 in patients (pts) with advanced solid tumors [abstract]. J. Clin. Oncol. 27 (15
Suppl.) a2578 (2009).
5. Dees, E. C. et al. Phase I study of the investigational drug MLN8237, an Aurora A kinase (AAK) inhibitor, in
patients (pts) with solid tumors [abstract]. J. Clin. Oncol. 28 (15 Suppl.), a3010 (2010).
6. Renshaw, J. S. et al. A phase I two arm trial of AS703569 (R763), an orally available aurora kinase inhibitor, in
subjects with solid tumors: preliminary results [abstract]. J. Clin. Oncol. 25 (18 Suppl.), a14130 (2007).
7. Foran, J. M. et al. Phase I and pharmacodynamic trial of AT9283, an aurora kinase inhibitor, in patients with
refractory leukemia [abstract]. J. Clin. Oncol. 26 (Suppl.), a2518 (2008).
8. Plummer, E. R. et al. A dose-escalation and pharmacodynamic study of AT9283 in patients with refractory solid
tumours [abstract]. J. Clin. Oncol. 26 (Suppl.), a2519 (2008).
9. Kristeleit, R. et al. A phase I study of AT9283, an aurora kinase inhibitor, in patients with refractory solid tumors
[abstract]. J. Clin. Oncol. 27 (15 Suppl.) a2566 (2009).
10. Robert, F. et al. A phase I trial of sns-314, a novel and selective pan-aurora kinase inhibitor, in advanced solid
tumor patients [abstract]. J. Clin. Oncol. 27 (15 Suppl.) a2536 (2009).
11. Britten, C. D. et al. Phase I trial of SU6668, a small molecule receptor tyrosine kinase inhibitor, given twice daily
in patients with advanced cancers [abstract]. Proc. Am. Soc. Clin. Oncol. 21, a1922 (2002).
12. Brahmer, J. R. et al. A phase I study of SU6668 in patients with refractory solid tumors [abstract]. Proc. Am.
1
Soc. Clin. Oncol. 21, a335 (2002).
13. Bastos, B. R. et al. An open-label, dose escalation, safety, and pharmacokinetic study of ENMD-2076
administered orally to patients with advanced cancer [abstract]. J. Clin. Oncol. 27 (15 Suppl.) a3520 (2009).
14. Mross, K. B. et al. A phase I dose-escalation study of BI 811283, an Aurora B inhibitor, administered every
three weeks in patients with advanced solid tumors [abstract]. J. Clin. Oncol. 28 (15 Suppl.), a3011 (2010).
15. Scheulen, M. E. et al. A phase I dose-escalation study of BI 811283, an Aurora B inhibitor, administered days 1
and 15, every four weeks in patients with advanced solid tumors [abstract]. J. Clin. Oncol. 28 (Suppl.), e13065
(2010).
16. Vainshtein, J. M. et al. Phase I study of ON 01910.Na, a novel polo-like kinase 1 pathway modulator,
administered as a weekly 24-hour continuous infusion in patients with advanced cancer [abstract]. J. Clin.
Oncol. 26 (Suppl.), a2515 (2008).
17. Ohnuma, T. et al. Phase I study of ON 01910.Na by 3-day continuous infusion (CI) in patients (pts) with
advanced cancer [abstract]. J. Clin. Oncol. 24 (18 Suppl.), a13137 (2006).
18. Donehower, R. C. et al. Phase I study of ON-01910.Na, a novel cell cycle inhibitor in adult patients with solid
tumors [abstract]. J. Clin. Oncol. 24 (18 Suppl.), a13026 (2006).
19. Von Pawel, J. et al. Randomized phase II trial of two dosing schedules of BI 2536, a novel Plk-1 inhibitor, in
patients with relapsed advanced or metastatic non-small-cell lung cancer (NSCLC) [abstract]. J. Clin. Oncol. 26
(Suppl.), a8030 (2008).
20. Ellis, P. M. et al. A phase I dose escalation trial of BI 2536, a novel Plk1 inhibitor, with standard dose
pemetrexed in previously treated advanced or metastatic non-small cell lung cancer (NSCLC) [abstract]. J.
Clin. Oncol. 26 (Suppl.), a8115 (2008).
21. Gandhi, L. et al. An open label phase II trial of the Plk1 inhibitor BI 2536, in patients with sensitive relapse small
cell lung cancer (SCLC) [abstract]. J. Clin. Oncol. 27 (15 Suppl.) a8108 (2009).
22. Olmos, D. et al. Phase I first-in-human study of the polo-like kinase-1 selective inhibitor, GSK461364, in
patients with advanced solid tumors [abstract]. J. Clin. Oncol. 27 (15 Suppl.) a3536 (2009).
23. Taylor, C., Dragovich, T., Simpson, A. & Von Hoff, D. A phase I and pharmacokinetic study of HMN-214
administered orally for 21 consecutive days, repeated every 28 days to patients with advanced solid tumors
[abstract]. Proc. Am. Soc. Clin. Oncol. 21, a419 (2002).
24. Patnaik, A. et al. A phase I and pharmacokinetic (PK) study of HMN-214, an oral antimicrotubular agent with
polo-like- and cyclin-dependent kinase inhibitory activities [abstract]. Proc. Am. Soc. Clin. Oncol. 21, a418
(2002).
25. Von Hoff, D. D. et al. A Phase I and pharmacokinetic study of HMN-214, a novel oral polo-like kinase inhibitor,
in patients with advanced solid tumors [abstract]. J. Clin. Oncol. 22 (14 Suppl.), a3034 (2004).
26. Gil, T. et al. Final analysis of a phase I single dose-escalation study of the novel polo-like kinase 1 inhibitor BI
6727 in patients with advanced solid tumors [abstract]. J. Clin. Oncol. 28 (15 Suppl.), a3061 (2010).
27. Chu, Q. S. et al. Phase I trial of novel kinesin spindle protein (KSP) inhibitor SB-715992 IV Q 21 days
[abstract]. J. Clin. Oncol. 22 (14 Suppl.), a2078 (2004).
28. Burris, H. A. et al. Phase I trial of novel kinesin spindle protein (KSP) inhibitor SB-715992 IV days 1, 8, 15 q 28
days [abstract]. J. Clin. Oncol. 22 (14 Suppl.), a2004 (2004).
29. Jones, F. S. et al. Phase I study of ispinesib in combination with carboplatin in patients with advanced solid
tumors [abstract]. J. Clin. Oncol 24 (18 Suppl.), a2027 (2006).
30. Heath, E. I. et al. A phase I dose escalation trial of ispinesib (SB-715992) administered days 1–3 of a 21-day
cycle in patients with advanced solid tumors [abstract]. J. Clin. Oncol 24 (18 Suppl.), a2026 (2006).
31. Beekman, K. W. et al. University of Chicago Consortium phase II study of ispinesib (SB-715992) in patients
(pts) with advanced renal cell carcinoma (RCC) [abstract]. J. Clin. Oncol. 25 (18 Suppl.), a15573 (2007).
32. Gomez, H. L. et al. A phase I/II trial of ispinesib, a kinesin spindle protein (KSP) inhibitor, dosed q14d in
patients with advanced breast cancer previously untreated with chemotherapy for metastatic disease or
recurrence [abstract]. J. Clin. Oncol. 27 (15 Suppl.) a1077 (2009).
33. O'Connor, O. A. et al. A phase I-II trial of the kinesin spindle protein (KSP) inhibitor SB-743921 on days 1 and
15 every 28 days in non-Hodgkin or Hodgkin lymphoma [abstract]. J. Clin. Oncol. 26 (Suppl.), a8539 (2008).
34. Gerecitano, J. F. et al. A phase I/II trial of the kinesin spindle protein (KSP) inhibitor SB-743921 dosed q14d
without and with prophylactic G-CSF in non-Hodgkin lymphoma (NHL) or Hodgkin lymphoma (HL) [abstract]. J.
Clin. Oncol. 27 (15 Suppl.) a8578 (2009).
35. Stein, M. N. et al. Phase I clinical and pharmacokinetic (PK) trial of the kinesin spindle protein (KSP) inhibitor
MK-0731 in patients with solid tumors [abstract]. J. Clin. Oncol. 25 (18 Suppl.), a2548 (2007).
36. Goncalves, P. H. et al. A phase I study of ARRY-520 in solid tumors [abstract]. J. Clin. Oncol. 28 (15 Suppl.),
a2570 (2010).
37. Shah, J. J. et al. Phase I trial of ARRY-520 in relapsed/refractory multiple myeloma (RR MM) [abstract]. J. Clin.
Oncol. 28 (15 Suppl.), a8132 (2010).
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