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

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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.

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References

  1. Bucher N, Britten CD (2008) G2 checkpoint abrogation and checkpoint kinase-1 targeting in the treatment of cancer. Br J Cancer 98:523–528

    Article  PubMed  CAS  Google Scholar 

  2. Ashwell S, Zabludoff S (2008) DNA damage detection and repair pathways—recent advances with inhibitors of checkpoint kinases in cancer therapy. Clin Cancer Res 14:4032–4037

    Article  PubMed  CAS  Google Scholar 

  3. Dai Y, Grant S (2010) New insights into checkpoint kinase 1 in the DNA damage response signaling network. Clin Cancer Res 16:376–383

    Article  PubMed  CAS  Google Scholar 

  4. Mitchell JB, Choudhuri R, Fabre K, Sowers AL, Citrin D, Zabludoff Z, Cook JA (2010) In vitro and in vivo radiation sensitization of human tumor cells by a novel checkpoint kinase inhibitor, AZD7762. Clin Cancer Res 16:2076–2084

    Article  PubMed  CAS  Google Scholar 

  5. Chen Z, Xiao Z, Chen J, Ng SC, Sowin T, Sham H, Rosenberg S, Fesik S, Zhang H (2003) Human Chk1 expression is dispensable for somatic cell death and critical for sustaining G2 DNA damage checkpoint. Mol Cancer Ther 2:543–548

    Article  PubMed  CAS  Google Scholar 

  6. Janetka JW, Ashwell S, Zabludoff S, Lyne P (2007) Inhibitors of checkpoint kinases: from discovery to the clinic. Curr Opin Drug Discov Devel 10:473–486

    PubMed  CAS  Google Scholar 

  7. Morgan MA, Parsels LA, Maybaum J, Lawrence TS (2008) Improving gemcitabine-mediated radiosensitization using molecularly targeted therapy: a review. Clin Cancer Res 14:6744–6750

    Article  PubMed  CAS  Google Scholar 

  8. Zabludoff SD, Deng C, Grondine MR, Sheehy AM, Ashwell S, Caleb BL, Green S, Haye HR, Horn CL, Janetka JW, Liu D, Mouchet E, Ready S, Rosenthal JL, Queva C, Schwartz GK, Taylor KJ, Tse AN, Walker GE, White AM (2008) AZD7762, a novel checkpoint kinase inhibitor, drives checkpoint abrogation and potentiates DNA-targeted therapies. Mol Cancer Ther 7:2955–2966

    Article  PubMed  CAS  Google Scholar 

  9. Ho AL, Bendell JC, Cleary JM, Schwartz GK, Burris HA, Oakes P, Agbo F, Barker PN, Senderowicz AM, Shapiro G (2011) Phase I, open-label, dose-escalation study of AZD7762 in combination with irinotecan (irino) in patients (pts) with advanced solid tumors. J Clin Oncol 29(15S):abst 3033

    Google Scholar 

  10. Sausville EA, LoRusso P, Carducci MA, Barker PN, Agbo F, Oakes P, Senderowicz AM (2011) Phase I dose-escalation study of AZD7762 in combination with gemcitabine (gem) in patients (pts) with advanced solid tumors. J Clin Oncol 29(15S):abst 3058

    Google Scholar 

  11. AstraZeneca (2011) Global policy: bioethics. Available at: http://www.astrazeneca.com/Responsibility/Code-policies-standards/Our-global-policies

  12. Therasse P, Arbuck SG, Eisenhauer EA, Wanders J, Kaplan RS, Rubinstein L, Verweij J, Van Glabbeke M, van Oosterom AT, Christian MC, Gwyther SG (2000) New guidelines to evaluate the response to treatment in solid tumors. European Organization for Research and Treatment of Cancer, National Cancer Institute of the United States, National Cancer Institute of Canada. J Natl Cancer Inst 92:205–216

    Article  PubMed  CAS  Google Scholar 

  13. Takai H, Tominaga K, Motoyama N, Minamishima YA, Nagahama H, Tsukiyama T, Ikeda K, Nakayama K, Nakanishi M, Nakayama K (2000) Aberrant cell cycle checkpoint function and early embryonic death in Chk1(−/−) mice. Genes Dev 14:1439–1447

    PubMed  CAS  Google Scholar 

  14. Erickson JR, He BJ, Grumbach IM, Anderson ME (2011) CaMKII in the cardiovascular system: sensing redox states. Physiol Rev 91:889–915

    Article  PubMed  CAS  Google Scholar 

  15. Doganli C, Kjaer-Sorensen K, Knoeckel C, Beck HC, Nyengaard JR, Honore B, Nissen P, Ribera A, Oxvig C, Lykke-Hartmann K (2012) The alpha2Na+/K+-ATPase is critical for skeletal and heart muscle function in zebrafish. J Cell Sci. doi:10.1242/jcs.115808 [Epub ahead of print]

  16. Aapro MS, Martin C, Hatty S (1998) Gemcitabine—a safety review. Anticancer Drugs 9:191–201

    Article  PubMed  CAS  Google Scholar 

  17. Akaza H, Tsukamoto T, Murai M, Nakajima K, Naito S (2007) Phase II study to investigate the efficacy, safety, and pharmacokinetics of sorafenib in Japanese patients with advanced renal cell carcinoma. Jpn J Clin Oncol 37:755–762

    Article  PubMed  Google Scholar 

  18. Takao S, Tokuda Y, Saeki T, Funai J, Ishii M, Takashima S (2012) Long-term gemcitabine administration in heavily pretreated Japanese patients with metastatic breast cancer: additional safety analysis of a phase II study. Breast Cancer 19:335–342

    Article  PubMed  Google Scholar 

  19. Ueno H, Kosuge T, Matsuyama Y, Yamamoto J, Nakao A, Egawa S, Doi R, Monden M, Hatori T, Tanaka M, Shimada M, Kanemitsu K (2009) A randomised phase III trial comparing gemcitabine with surgery-only in patients with resected pancreatic cancer: Japanese Study Group of Adjuvant Therapy for Pancreatic Cancer. Br J Cancer 101:908–915

    Article  PubMed  CAS  Google Scholar 

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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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Authors and Affiliations

  1. Department of Thoracic Oncology, National Kyushu Cancer Center, Fukuoka, Japan

    Takashi Seto, Fumihiko Hirai, Kaname Nosaki, Takuro Kometani, Motoharu Hamatake & Hiroaki Takeoka

  2. Department of Gastrointestinal and Medical Oncology, National Kyushu Cancer Center, Fukuoka, Japan

    Taito Esaki, Shuji Arita, Akitaka Makiyama & Chinatsu Fujimoto

  3. AstraZeneca, Wilmington, DE, USA

    Felix Agbo

  4. AstraZeneca KK, Osaka, Japan

    Xiaojin Shi

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  1. Takashi Seto
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  2. Taito Esaki
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  3. Fumihiko Hirai
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  4. Shuji Arita
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  5. Kaname Nosaki
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  7. Takuro Kometani
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  9. Motoharu Hamatake
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  11. Felix Agbo
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  12. Xiaojin Shi
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Correspondence to Takashi Seto.

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Seto, T., Esaki, T., Hirai, F. et al. Phase I, dose-escalation study of AZD7762 alone and in combination with gemcitabine in Japanese patients with advanced solid tumours. Cancer Chemother Pharmacol 72, 619–627 (2013). https://doi.org/10.1007/s00280-013-2234-6

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  • DOI: https://doi.org/10.1007/s00280-013-2234-6

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