A Phase I Study of AZD2281 in Combination With Irinotecan in Patients With Locally Advanced or Metastatic Incurable Colorectal Cancer
- To determine the recommended phase II dose of AZD2281 and irinotecan hydrochloride in
patients with locally advanced or metastatic colorectal cancer.
- To determine the safety, tolerability, toxicity profile, dose-limiting toxicities, and
pharmacokinetic profile of this regimen.
- To assess the correlation, if any, between the toxicity profile and pharmacokinetics of
- To assess, preliminarily, the antitumor activity of this regimen in patients with
- To demonstrate the pharmacodynamic activity of this regimen by establishing its effects
in tumor biopsies, cheek swabs, and blood samples.
- To assess the correlation, if any, between patients with tumors demonstrating
microsatellite instability and antitumor activity and pharmacodynamic effects of this
- To investigate the impact of common genetic polymorphisms of genes of relevant pathways
(drug metabolism, DNA repair, and apoptosis) on outcome and toxicity as well as other
OUTLINE: This is a multicenter, dose-escalation study of AZD2281 and irinotecan
- Part I: Patients receive oral AZD2281 twice a day on days -7 to 21 in course 1 and on
days 1-21 in all subsequent courses. Patients also receive irinotecan hydrochloride IV
over 90 minutes on day 1. Courses repeat every 21 days (course 1 is 28 days) until the
maximum tolerated dose is determined in the absence of disease progression or
- Part II: Patients then receive oral AZD2281 once daily on days 1-5 and irinotecan
hydrochloride IV over 90 minutes on day 3 at the maximum tolerated dose determined in
Part I. Courses repeat every 14 days in the absence of disease progression or
Patients undergo cheek swabs, tumor tissue, and blood sample collection periodically for
pharmacokinetic, pharmacodynamic, and correlative studies.
After completion of study treatment, patients are followed at 4 weeks and then every 3
Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment
Recommended phase II dose of AZD2281 and irinotecan hydrochloride
End of study
Eric X. Chen, MD, PhD
Princess Margaret Hospital, Canada
Canada: Health Canada