Phase I dose-escalation study of AZD7762, a checkpoint kinase inhibitor, in combination with gemcitabine in US patients with advanced solid tumors
| Autor: | Richard Knight, Michael A. Carducci, Patricia LoRusso, Mary F. Quinn, Adrian M. Senderowicz, Patricia Oakes, Edward A. Sausville, Judith Carter, David Cosgrove, Felix Agbo, Nilofer S. Azad, Lisa Malburg, Sonya Zabludoff, Peter Barker |
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| Rok vydání: | 2013 |
| Předmět: |
Adult
Male Cancer Research Antimetabolites Antineoplastic Thiophenes Pharmacology Toxicology Deoxycytidine Article chemistry.chemical_compound Pharmacokinetics Neoplasms Antineoplastic Combined Chemotherapy Protocols medicine Dose escalation Humans Urea Pharmacology (medical) CHEK1 Aged Dose-Response Relationship Drug business.industry Chk1 Kinase Kinase Middle Aged Gemcitabine Clinical trial Oncology chemistry Checkpoint Kinase 1 Cancer research Female business Protein Kinases medicine.drug |
| Zdroj: | Cancer chemotherapy and pharmacology. 73(3) |
| ISSN: | 1432-0843 |
| Popis: | 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.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/m(2) on days 1 and 8, every 21 days, in ascending AZD7762 doses (cycle 1; combination therapy).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/m(2) and AZD7762 9 mg cohort).The maximum-tolerated dose of AZD7762 in combination with gemcitabine 1,000 mg/m(2) was 30 mg. Although development of AZD7762 is not going forward owing to unpredictable cardiac toxicity, Chk1 remains an important therapeutic target. |
| Databáze: | OpenAIRE |
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