Advertisement

Cancer Chemotherapy and Pharmacology

, Volume 60, Issue 3, pp 391–398 | Cite as

A first-in-man phase I tolerability and pharmacokinetic study of the cyclin-dependent kinase-inhibitor AZD5438 in healthy male volunteers

  • D. Ross Camidge
  • Dominic Smethurst
  • Jim Growcott
  • Nigel C. Barrass
  • John R. Foster
  • Salvatore Febbraro
  • Helen Swaisland
  • Andrew Hughes
Original Article

Abstract

AZD5438 is a novel cyclin-dependent kinase inhibitor with preclinical pharmacodynamic (PD) activity against a range of human tumour xenografts. A first-in-man tolerability and pharmacokinetic (PK) study involving single ascending doses of AZD5438 was conducted in healthy male volunteers. Single oral doses ranging from 5 to 160 mg were studied in 23 subjects. Dose-limiting nausea and vomiting occurred at 160 mg in the absence of prophylactic anti-emetics. The maximum tolerated dose (the dose at which no dose limiting toxicities occurred) was 80 mg, and the maximum well-tolerated dose was deemed to be 60 mg, which was associated with grade1 nausea but no vomiting. T max occurred between 0.5–3.0 hours with a relatively short plasma half-life of 1–3 h. The coefficient of variation of exposures within a dose level ranged from 22–71% (AUC) to 16–63% (C max), and exposure increased with increasing dose across the doses studied. <1% of the parent compound was excreted in the urine, suggesting metabolism as the major clearance mechanism. The maximum well-tolerated dose and a number of doses below this level will be taken forward into a PD study using normal tissue biomarkers in humans to determine proof of AZD5438’s action on the cell cycle. The pharmacokinetic profile of AZD5438 determined within this study will be used to guide the time-points for PD analysis within the planned PD study.

Keywords

Cell cycle AZD5438 CDK Pharmacokinetics Tolerability 

Abbreviations

CPU

Clinical pharmacology unit

UK

United Kingdom

mg

Milligram

kg

Kilogram

mL

Millilitre

DLT

Dose limiting toxicity

SMC

Safety monitoring committee

MWTD

Maximum well-tolerated dose

Notes

Acknowledgments

With thanks to Karen Keating, Sally Ward, John Freeman and Anita Lindsay (Study Team Management, AstraZeneca, Alderley Park).

References

  1. 1.
    Benson C, Kaye S, Workman P, Garrett M, Walton M, deBono J (2005) Clinical anticancer drug development: targeting the cyclin-dependent kinases. Br J Cancer 92:7–12PubMedCrossRefGoogle Scholar
  2. 2.
    Dupont J, Bienvenu B, Aghajanian C, Pezzulli S, Sabbatini P, Vongphrachanh P, Chang C, Perkell C, Ng K, Passe S, Breimer L, Zhi J, DeMario M, Spriggs D, Soignet SL (2004) Phase I and pharmacokinetic study of the novel oral cell-cycle inhibitor Ro 31–7453 in patients with advanced solid tumors. J Clin Oncol 22(16):3366–3374PubMedCrossRefGoogle Scholar
  3. 3.
    Fischer PM, Gianella-Borradori A (2003) CDK inhibitors in clinical development for the treatment of cancer. Expert Opin Investig Drugs 12(6):955–970PubMedCrossRefGoogle Scholar
  4. 4.
    Fischer PM, Gianella-Borradori A (2005) Recent progress in the discovery and development of cyclin-dependent kinase inhibitiors. Expert Opin Investig Drugs 14:457–477PubMedCrossRefGoogle Scholar
  5. 5.
    Gorgoulis VG, Zacharatos P, Kotsinas A, Mariatos G, Liloglou T, Vogiatzi T, Foukas P, Rassidakis G, Garinis G, Ioannides T, Zoumpourlis V, Bramis J, Michail PO, Asimacopoulos PJ, Field JK, Kittas C (2000) Altered expression of the cell cycle regulatory molecules pRb, p53 and MDM2 exert a synergetic effect on tumor growth and chromosomal instability in non-small cell lung carcinomas (NSCLCs). Mol Med 6(3):208–237PubMedGoogle Scholar
  6. 6.
    Gugger M, Kappeler A, Vonlanthen S, Altermatt HJ, Ris HB, Lardinois D, Borner MM, Heighway J, Betticher DC (2001) Alterations of cell cycle regulators are less frequent in advanced non-small cell lung cancer than in resectable tumours. Lung Cancer 33(2–3):229–239PubMedCrossRefGoogle Scholar
  7. 7.
    Le Frere-Belda MA, Gil Diez de Medina S, Daher A, Martin N, Albaud B, Heudes D, Abbou CC, Thiery JP, Zafrani ES, Radvanyi F, Chopin D (2004) Profiles of the 2 INK4a gene products, p16 and p14ARF, in human reference urothelium and bladder carcinomas, according to pRb and p53 protein status. Hum Pathol 35(7):817–824PubMedCrossRefGoogle Scholar
  8. 8.
    Lundberg AS, Weinberg RA (1998) Functional inactivation of the retinoblastoma protein requires sequential modification by at least two distinct cyclin-cdk complexes. Mol. Cell. Biol 18:753–761PubMedGoogle Scholar
  9. 9.
    Macalusmo M, Montanari M, Cinti C, Giordano A (2005) Modulation of cell-cycle components by genetic and epigenetic events. Semin Oncol 32(5):452–457CrossRefGoogle Scholar
  10. 10.
    Omura-Minamisawa M, Mitchell B. Diccianni MB, Chang RC, Batova A, Bridgeman LJ, Schiff J, Cohn SL, London WB, Yu AL (2001) p16/p14(ARF) cell cycle regulatory pathways in primary neuroblastoma: p16 expression is associated with advanced stage disease. Clin Cancer Res 7(11):3481–3490PubMedGoogle Scholar
  11. 11.
    Schwartz GK, Shah MA (2005) Targetting the cell cycle: a new approach to cancer therapy. J Clin Oncol 23:9408–9421PubMedCrossRefGoogle Scholar
  12. 12.
    Senderowicz PM (1999) Flavopiridol: the first cyclin-dependent kinase inhibitor in human clinical trials. Invest New Drugs 17(3):313–320PubMedCrossRefGoogle Scholar
  13. 13.
    Soni S, Kaur J, Kumar A, Chakravarti N, Mathur M, Bahadur S, Shukla NK, Deo SV, Ralhan R (2005) Alterations of rb pathway components are frequent events in patients with oral epithelial dysplasia and predict clinical outcome in patients with squamous cell carcinoma. Oncology 68(4–6):314–325PubMedCrossRefGoogle Scholar
  14. 14.
    Wheeler C, Stephens T, Byth K et al (2003) Novel approaches in oncology at AstraZeneca. Eur J Cancer Suppl 1(8):3–8CrossRefGoogle Scholar

Copyright information

© Springer-Verlag 2006

Authors and Affiliations

  • D. Ross Camidge
    • 1
    • 6
  • Dominic Smethurst
    • 2
  • Jim Growcott
    • 2
  • Nigel C. Barrass
    • 3
  • John R. Foster
    • 3
  • Salvatore Febbraro
    • 4
  • Helen Swaisland
    • 5
  • Andrew Hughes
    • 2
  1. 1.Edinburgh Cancer CentreWestern General HospitalEdinburghUK
  2. 2.AstraZeneca Discovery MedicineCheshireUK
  3. 3.AstraZeneca Safety AssessmentCheshireUK
  4. 4.AstraZeneca Clinical DevelopmentCheshireUK
  5. 5.AstraZeneca Clinical Pharmacology Unit, E Floor, South BlockQueen’s Medical CentreNottinghamUK
  6. 6.Division of Medical OncologyUniversity of Colorado Health Sciences CenterDenverUSA

Personalised recommendations