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Phase I dose-escalation study of AZD7762, a checkpoint kinase inhibitor, in combination with gemcitabine in US patients with advanced solid tumors

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Abstract

Purpose

AZD7762 is a Chk1 kinase inhibitor which increases sensitivity to DNA-damaging agents, including gemcitabine. We evaluated the safety of AZD7762 monotherapy and with gemcitabine in advanced solid tumor patients.

Experimental design

In this Phase I study, patients received intravenous AZD7762 on days 1 and 8 of a 14-day run-in cycle (cycle 0; AZD7762 monotherapy), followed by AZD7762 plus gemcitabine 750–1,000 mg/m2 on days 1 and 8, every 21 days, in ascending AZD7762 doses (cycle 1; combination therapy).

Results

Forty-two patients received AZD7762 6 mg (n = 9), 9 mg (n = 3), 14 mg (n = 6), 21 mg (n = 3), 30 mg (n = 7), 32 mg (n = 6), and 40 mg (n = 8), in combination with gemcitabine. Common adverse events (AEs) were fatigue [41 % (17/42) patients], neutropenia/leukopenia [36 % (15/42) patients], anemia/Hb decrease [29 % (12/42) patients] and nausea, pyrexia and alanine aminotransferase/aspartate aminotransferase increase [26 % (11/42) patients each]. Grade ≥3 AEs occurred in 19 and 52 % of patients in cycles 0 and 1, respectively. Cardiac dose-limiting toxicities occurred in two patients (both AZD7762 monotherapy): grade 3 troponin I increase (32 mg) and grade 3 myocardial ischemia with chest pain, electrocardiogram changes, decreased left ventricular ejection fraction, and increased troponin I (40 mg). AZD7762 exposure increased linearly. Gemcitabine did not affect AZD7762 pharmacokinetics. Two non-small-cell lung cancer patients achieved partial tumor responses (AZD7762 6 mg/gemcitabine 750 mg/m2 and AZD7762 9 mg cohort).

Conclusions

The maximum-tolerated dose of AZD7762 in combination with gemcitabine 1,000 mg/m2 was 30 mg. Although development of AZD7762 is not going forward owing to unpredictable cardiac toxicity, Chk1 remains an important therapeutic target.

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Acknowledgments

We would like to thank Judith Ochs, Louise Grochow (both of Astrazeneca, US) and Victor Sandor (Incyte Corporation, US) for their assistance in protocol design and initiation of the study. We are also grateful to The General Clinical Research Center, University of Maryland, US. We thank Zoë van Helmond, PhD from Mudskipper Business Ltd, for medical writing support funded by AstraZeneca.

Conflict of interest

P. LoRusso, M. Carducci and E. Sausville have received research funding and attended advisory boards for AstraZeneca. P. Oakes, A. Senderowicz, P. Barker, S. Zabludoff, R. Knight and F. Agbo are all employees of and own stock in AstraZeneca. All other authors have no conflicts of interest to declare.

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Authors and Affiliations

  1. Marlene and Stewart Greenebaum Cancer Center, University of Maryland, 22 S. Greene Street, Baltimore, MD, 21201, USA

    Edward Sausville, Judith Carter & Mary F. Quinn

  2. Karmanos Cancer Center, Wayne State University School of Medicine, Detroit, MI, USA

    Patricia LoRusso & Lisa Malburg

  3. Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins Medical Institutions, Baltimore, MD, USA

    Michael Carducci, Nilofer Azad & David Cosgrove

  4. AstraZeneca, Wilmington, DE, USA

    Richard Knight, Peter Barker, Sonya Zabludoff, Felix Agbo, Patricia Oakes & Adrian Senderowicz

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  1. Edward Sausville
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  4. Judith Carter
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Correspondence to Edward Sausville.

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Sausville, E., LoRusso, P., Carducci, M. et al. Phase I dose-escalation study of AZD7762, a checkpoint kinase inhibitor, in combination with gemcitabine in US patients with advanced solid tumors. Cancer Chemother Pharmacol 73, 539–549 (2014). https://doi.org/10.1007/s00280-014-2380-5

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