A phase i study of MK-5108, an oral aurora a kinase inhibitor, administered both as monotherapy and in combination with docetaxel, in patients with advanced or refractory solid tumors

Manik Amin, Susan E. Minton, Patricia M. Lorusso, Smitha S. Krishnamurthi, Cheryl A. Pickett, Jared Lunceford, Darcy Hille, David Mauro, Mark N. Stein, Andrea Wang-Gillam, Lauren Trull, Albert Lockhart

Research output: Contribution to journalArticle

12 Citations (Scopus)

Abstract

Background MK-5108 is a potent/highly selective Aurora A kinase inhibitor. Methods A randomized Phase I study of MK-5108, administered p.o. BID Q12h on days 1-2 in 14-21 day cycles either alone (MT; Panel1/n = 18; 200 to 1800 mg) or in combination (CT; Panel2/n = 17; 100 to 225 mg) with IV docetaxel 60 mg/m2, determined the maximum tolerated dose (MTD), pharmacokinetics (PK), pharmacodynamics (Panel1, only) and tumor response in patients with advanced solid tumors. This study was terminated early due to toxicities in Panel2 at MK-5108 doses below the anticipated PK exposure target. Results 35 patients enrolled (33 evaluable for tumor response). No dose-limiting toxicities (DLTs) were observed in Panel1; three patients had 3 DLTs in Panel2 (G3 and G4 febrile neutropenia at 200 and 450 mg/day, respectively; G3 infection at 450 mg/day). In Panel1, AUC0-12hr and Cmax increased less than dose proportionally following the first MT dose but increased roughly dose proportionally across 200 to 3600 mg/day after 4th dose. The t1/2 ranged from 6.6 to 13.5 h across both panels. No clear effects on immunohistochemistry markers were observed; however, significant dose-related increases in gene expression were seen pre-/post-treatment. Best responses were 9/17 stable disease (SD) (Panel1) as well as 1/16 PR and 7/16 SD (Panel2) (450 mg/day). Conclusions MK-5108 MT was well tolerated at doses up to 3600 mg/day with plasma levels exceeding the minimum daily exposure target (83 μM∗hr). The MTD for MK-5108 + docetaxel (CT) was established at 300 mg/day, below the exposure target. Use of pharmacodynamic gene expression assays to determine target engagement was validated.

Original languageEnglish (US)
Pages (from-to)84-95
Number of pages12
JournalInvestigational New Drugs
Volume34
Issue number1
DOIs
StatePublished - Feb 1 2016
Externally publishedYes

Fingerprint

docetaxel
Aurora Kinases
Maximum Tolerated Dose
Neoplasms
Pharmacokinetics
Aurora Kinase A
Gene Expression
Febrile Neutropenia
Immunohistochemistry
4-(3-chloro-2-fluorophenoxy)-1-((6-(1,3-thiazol-2-ylamino)pyridin to 2-yl)methyl) cyclohexanecarboxylic acid

Keywords

  • Aurora A kinase inhibitor
  • Combination therapy
  • Docetaxel
  • Pharmacodynamics
  • Pharmacokinetics
  • Tumor response

ASJC Scopus subject areas

  • Oncology
  • Pharmacology
  • Pharmacology (medical)

Cite this

A phase i study of MK-5108, an oral aurora a kinase inhibitor, administered both as monotherapy and in combination with docetaxel, in patients with advanced or refractory solid tumors. / Amin, Manik; Minton, Susan E.; Lorusso, Patricia M.; Krishnamurthi, Smitha S.; Pickett, Cheryl A.; Lunceford, Jared; Hille, Darcy; Mauro, David; Stein, Mark N.; Wang-Gillam, Andrea; Trull, Lauren; Lockhart, Albert.

In: Investigational New Drugs, Vol. 34, No. 1, 01.02.2016, p. 84-95.

Research output: Contribution to journalArticle

Amin, Manik ; Minton, Susan E. ; Lorusso, Patricia M. ; Krishnamurthi, Smitha S. ; Pickett, Cheryl A. ; Lunceford, Jared ; Hille, Darcy ; Mauro, David ; Stein, Mark N. ; Wang-Gillam, Andrea ; Trull, Lauren ; Lockhart, Albert. / A phase i study of MK-5108, an oral aurora a kinase inhibitor, administered both as monotherapy and in combination with docetaxel, in patients with advanced or refractory solid tumors. In: Investigational New Drugs. 2016 ; Vol. 34, No. 1. pp. 84-95.
@article{9356cdcfef714ca7801c024651d8e014,
title = "A phase i study of MK-5108, an oral aurora a kinase inhibitor, administered both as monotherapy and in combination with docetaxel, in patients with advanced or refractory solid tumors",
abstract = "Background MK-5108 is a potent/highly selective Aurora A kinase inhibitor. Methods A randomized Phase I study of MK-5108, administered p.o. BID Q12h on days 1-2 in 14-21 day cycles either alone (MT; Panel1/n = 18; 200 to 1800 mg) or in combination (CT; Panel2/n = 17; 100 to 225 mg) with IV docetaxel 60 mg/m2, determined the maximum tolerated dose (MTD), pharmacokinetics (PK), pharmacodynamics (Panel1, only) and tumor response in patients with advanced solid tumors. This study was terminated early due to toxicities in Panel2 at MK-5108 doses below the anticipated PK exposure target. Results 35 patients enrolled (33 evaluable for tumor response). No dose-limiting toxicities (DLTs) were observed in Panel1; three patients had 3 DLTs in Panel2 (G3 and G4 febrile neutropenia at 200 and 450 mg/day, respectively; G3 infection at 450 mg/day). In Panel1, AUC0-12hr and Cmax increased less than dose proportionally following the first MT dose but increased roughly dose proportionally across 200 to 3600 mg/day after 4th dose. The t1/2 ranged from 6.6 to 13.5 h across both panels. No clear effects on immunohistochemistry markers were observed; however, significant dose-related increases in gene expression were seen pre-/post-treatment. Best responses were 9/17 stable disease (SD) (Panel1) as well as 1/16 PR and 7/16 SD (Panel2) (450 mg/day). Conclusions MK-5108 MT was well tolerated at doses up to 3600 mg/day with plasma levels exceeding the minimum daily exposure target (83 μM∗hr). The MTD for MK-5108 + docetaxel (CT) was established at 300 mg/day, below the exposure target. Use of pharmacodynamic gene expression assays to determine target engagement was validated.",
keywords = "Aurora A kinase inhibitor, Combination therapy, Docetaxel, Pharmacodynamics, Pharmacokinetics, Tumor response",
author = "Manik Amin and Minton, {Susan E.} and Lorusso, {Patricia M.} and Krishnamurthi, {Smitha S.} and Pickett, {Cheryl A.} and Jared Lunceford and Darcy Hille and David Mauro and Stein, {Mark N.} and Andrea Wang-Gillam and Lauren Trull and Albert Lockhart",
year = "2016",
month = "2",
day = "1",
doi = "10.1007/s10637-015-0306-7",
language = "English (US)",
volume = "34",
pages = "84--95",
journal = "Investigational New Drugs",
issn = "0167-6997",
publisher = "Kluwer Academic Publishers",
number = "1",

}

TY - JOUR

T1 - A phase i study of MK-5108, an oral aurora a kinase inhibitor, administered both as monotherapy and in combination with docetaxel, in patients with advanced or refractory solid tumors

AU - Amin, Manik

AU - Minton, Susan E.

AU - Lorusso, Patricia M.

AU - Krishnamurthi, Smitha S.

AU - Pickett, Cheryl A.

AU - Lunceford, Jared

AU - Hille, Darcy

AU - Mauro, David

AU - Stein, Mark N.

AU - Wang-Gillam, Andrea

AU - Trull, Lauren

AU - Lockhart, Albert

PY - 2016/2/1

Y1 - 2016/2/1

N2 - Background MK-5108 is a potent/highly selective Aurora A kinase inhibitor. Methods A randomized Phase I study of MK-5108, administered p.o. BID Q12h on days 1-2 in 14-21 day cycles either alone (MT; Panel1/n = 18; 200 to 1800 mg) or in combination (CT; Panel2/n = 17; 100 to 225 mg) with IV docetaxel 60 mg/m2, determined the maximum tolerated dose (MTD), pharmacokinetics (PK), pharmacodynamics (Panel1, only) and tumor response in patients with advanced solid tumors. This study was terminated early due to toxicities in Panel2 at MK-5108 doses below the anticipated PK exposure target. Results 35 patients enrolled (33 evaluable for tumor response). No dose-limiting toxicities (DLTs) were observed in Panel1; three patients had 3 DLTs in Panel2 (G3 and G4 febrile neutropenia at 200 and 450 mg/day, respectively; G3 infection at 450 mg/day). In Panel1, AUC0-12hr and Cmax increased less than dose proportionally following the first MT dose but increased roughly dose proportionally across 200 to 3600 mg/day after 4th dose. The t1/2 ranged from 6.6 to 13.5 h across both panels. No clear effects on immunohistochemistry markers were observed; however, significant dose-related increases in gene expression were seen pre-/post-treatment. Best responses were 9/17 stable disease (SD) (Panel1) as well as 1/16 PR and 7/16 SD (Panel2) (450 mg/day). Conclusions MK-5108 MT was well tolerated at doses up to 3600 mg/day with plasma levels exceeding the minimum daily exposure target (83 μM∗hr). The MTD for MK-5108 + docetaxel (CT) was established at 300 mg/day, below the exposure target. Use of pharmacodynamic gene expression assays to determine target engagement was validated.

AB - Background MK-5108 is a potent/highly selective Aurora A kinase inhibitor. Methods A randomized Phase I study of MK-5108, administered p.o. BID Q12h on days 1-2 in 14-21 day cycles either alone (MT; Panel1/n = 18; 200 to 1800 mg) or in combination (CT; Panel2/n = 17; 100 to 225 mg) with IV docetaxel 60 mg/m2, determined the maximum tolerated dose (MTD), pharmacokinetics (PK), pharmacodynamics (Panel1, only) and tumor response in patients with advanced solid tumors. This study was terminated early due to toxicities in Panel2 at MK-5108 doses below the anticipated PK exposure target. Results 35 patients enrolled (33 evaluable for tumor response). No dose-limiting toxicities (DLTs) were observed in Panel1; three patients had 3 DLTs in Panel2 (G3 and G4 febrile neutropenia at 200 and 450 mg/day, respectively; G3 infection at 450 mg/day). In Panel1, AUC0-12hr and Cmax increased less than dose proportionally following the first MT dose but increased roughly dose proportionally across 200 to 3600 mg/day after 4th dose. The t1/2 ranged from 6.6 to 13.5 h across both panels. No clear effects on immunohistochemistry markers were observed; however, significant dose-related increases in gene expression were seen pre-/post-treatment. Best responses were 9/17 stable disease (SD) (Panel1) as well as 1/16 PR and 7/16 SD (Panel2) (450 mg/day). Conclusions MK-5108 MT was well tolerated at doses up to 3600 mg/day with plasma levels exceeding the minimum daily exposure target (83 μM∗hr). The MTD for MK-5108 + docetaxel (CT) was established at 300 mg/day, below the exposure target. Use of pharmacodynamic gene expression assays to determine target engagement was validated.

KW - Aurora A kinase inhibitor

KW - Combination therapy

KW - Docetaxel

KW - Pharmacodynamics

KW - Pharmacokinetics

KW - Tumor response

UR - http://www.scopus.com/inward/record.url?scp=84958903980&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84958903980&partnerID=8YFLogxK

U2 - 10.1007/s10637-015-0306-7

DO - 10.1007/s10637-015-0306-7

M3 - Article

C2 - 26620496

AN - SCOPUS:84958903980

VL - 34

SP - 84

EP - 95

JO - Investigational New Drugs

JF - Investigational New Drugs

SN - 0167-6997

IS - 1

ER -