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

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.

Read more here: Sausville E, LoRusso P, Carducci M, Carter J, Quinn M, 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 patients with advanced solid tumors. Cancer Chemother Pharmacol. 73(3):539-49

By |2018-06-27T17:03:44+00:00March 20th, 2014|Toxicology, Publications|Comments Off on Phase I dose-escalation study of AZD7762, a checkpoint kinase inhibitor, in combination with gemcitabine in patients with advanced solid tumors.

About the Author:

Dr Richard Knight PhD, ERT, is a Director and Co-founder of ApconiX, a preclinical toxicology and ion channel company that brings together a team of world-renowned nonclinical safety experts. Richard graduated from the University of Bradford in 1989 with a degree in Biomedical Sciences (Pharmacology) before gaining a PhD at the University of Leeds researching the role of adenosine receptors in renal function and toxicity. His research then included post-doctoral studies at University of California, Los Angeles (UCLA) into the effects of ischaemia/reperfusion injury on cardiac metabolism. Richard joined Zeneca Pharmaceuticals, Safety of Medicines Group in 1996 as a Study Director, and then Project Toxicologist across multiple therapy areas, from early discovery through to market. As Lead Toxicologist for Oncology, Richard was a member of both the Drug Safety and Metabolism, and Oncology Leadership teams with responsibility for safety across the AZ oncology portfolio. In this senior role he provided leadership and mentoring support to other project toxicologists. Richard has worked on many drug platforms over this time including small molecules, biologics, proteins and oligonucleotides and has been involved in bringing over 30 new candidate drugs into clinical trials and 5 to marketing approval.