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Cancer Chemotherapy and Pharmacology

, Volume 72, Issue 3, pp 619–627 | Cite as

Phase I, dose-escalation study of AZD7762 alone and in combination with gemcitabine in Japanese patients with advanced solid tumours

  • Takashi SetoEmail author
  • Taito Esaki
  • Fumihiko Hirai
  • Shuji Arita
  • Kaname Nosaki
  • Akitaka Makiyama
  • Takuro Kometani
  • Chinatsu Fujimoto
  • Motoharu Hamatake
  • Hiroaki Takeoka
  • Felix Agbo
  • Xiaojin Shi
Original Article

Abstract

Purpose

AZD7762, a potent Chk1/Chk2 inhibitor, has shown chemosensitizing activity with gemcitabine in xenograft models.

Methods

This open-label, Phase I, dose-escalation study evaluated the safety, pharmacokinetics (PK) and preliminary efficacy (RECIST) of AZD7762 alone and in combination with gemcitabine in Japanese patients with advanced solid tumours (NCT00937664). Patients received intravenous AZD7762 alone on days 1 and 8 of a 14-day cycle (cycle 0), followed by AZD7762 plus gemcitabine 1,000 mg/m2 on days 1 and 8 of 22-day cycles, in ascending AZD7762 dose cohorts.

Results

Twenty patients received AZD7762 at doses of 6 mg (n = 3), 9 mg (n = 3), 21 mg (n = 6) and 30 mg (n = 8). Dose-limiting toxicities occurred in 2/6 evaluable patients in the 30-mg cohort: one, CTCAE grade 3 elevated troponin T (cycle 0: AZD7762 monotherapy); one, neutropenia, thrombocytopenia, and elevated aspartate aminotransferase and alanine aminotransferase (cycle 1: combination therapy). The 30 mg dose was therefore regarded as non-tolerable. The most common adverse events (AEs) in cycle 0 (AZD7762 monotherapy) were bradycardia (50 %), hypertension (25 %) and fatigue (15 %). Overall, the most common AEs were bradycardia (55 %), neutropenia (45 %) and hypertension, fatigue and rash (30 % each). Grade ≥3 AEs were reported in 11 patients, the most common being neutropenia (45 %) and leukopenia (25 %). AZD7762 exposure increased approximately linearly. Gemcitabine did not appear to affect AZD7762 PK. There were no objective responses; five patients (all lung cancer) had stable disease.

Conclusions

The maximum tolerated dose of AZD7762 in combination with gemcitabine, 1,000 mg/m2 was determined as 21 mg in Japanese patients.

Keywords

AZD7762 Chk1 Solid tumours Japanese Phase I Safety 

Notes

Acknowledgments

We would like to thank Zoё van Helmond PhD from Mudskipper Bioscience who provided medical writing assistance funded by AstraZeneca.

Conflict of interest

T.S., T.E., F.H., S.A., K.N., A.M., T.K., C.F., M.H. and H.T. have no conflicts of interest to declare; X.S. and F.A. are employees of AstraZeneca and F.A. also owns stock.

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Copyright information

© Springer-Verlag Berlin Heidelberg 2013

Authors and Affiliations

  • Takashi Seto
    • 1
    Email author
  • Taito Esaki
    • 2
  • Fumihiko Hirai
    • 1
  • Shuji Arita
    • 2
  • Kaname Nosaki
    • 1
  • Akitaka Makiyama
    • 2
  • Takuro Kometani
    • 1
  • Chinatsu Fujimoto
    • 2
  • Motoharu Hamatake
    • 1
  • Hiroaki Takeoka
    • 1
  • Felix Agbo
    • 3
  • Xiaojin Shi
    • 4
  1. 1.Department of Thoracic OncologyNational Kyushu Cancer CenterFukuokaJapan
  2. 2.Department of Gastrointestinal and Medical OncologyNational Kyushu Cancer CenterFukuokaJapan
  3. 3.AstraZenecaWilmingtonUSA
  4. 4.AstraZeneca KKOsakaJapan

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