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

Edward Sausville, Patricia LoRusso, Michael Carducci, Judith Carter, Mary F. Quinn, Lisa Malburg, Nilofer Azad, David Cosgrove, Richard Knight, Peter Barker, Sonya Zabludoff, Felix Agbo, Patricia Oakes, Adrian Senderowicz

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Abstract

Purpose: ZD7762 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.

Original languageEnglish (US)
Pages (from-to)539-549
Number of pages11
JournalCancer Chemotherapy and Pharmacology
Volume73
Issue number3
DOIs
StatePublished - Mar 2014

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Keywords

  • AZD7762
  • Chk1
  • Pharmacokinetics
  • Phase I
  • Safety
  • Solid tumors

ASJC Scopus subject areas

  • Oncology
  • Toxicology
  • Pharmacology
  • Cancer Research
  • Pharmacology (medical)

Cite this

Sausville, E., LoRusso, P., Carducci, M., Carter, J., Quinn, M. F., Malburg, L., Azad, N., Cosgrove, D., Knight, R., Barker, P., Zabludoff, S., Agbo, F., Oakes, P., & Senderowicz, A. (2014). Phase I dose-escalation study of AZD7762, a checkpoint kinase inhibitor, in combination with gemcitabine in US patients with advanced solid tumors. Cancer Chemotherapy and Pharmacology, 73(3), 539-549. https://doi.org/10.1007/s00280-014-2380-5