A Phase I Study of AZD0424 Alone and in Combination in Advanced Solid Tumours (AZD0424)
|Study Design:||Endpoint Classification: Safety Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
|Official Title:||A Cancer Research UK Phase I Study to Determine the Maximum Tolerated Dose of the Oral Src/Abl Inhibitor AZD0424, and to Identify Tolerable and Effective AZD0424 Combination Regimens for the Treatment of Advanced Solid Tumours|
- Establishing the Maximum Tolerated Dose (MTD) of AZD0424 alone and in combination [ Designated as safety issue: Yes ]
- Determining the causality and duration of adverse events observed during the study according to NCI CTCAE Version 4.02 [ Designated as safety issue: Yes ]
- Determining the correlation between PK studies and toxicity and/or efficacy. [ Designated as safety issue: No ]
- Measurement of urinary and serum N terminal Telopeptide (NTx) and serum C-terminal peptide (CTx) levels before the first AZD0424 administration and then following first AZD0424 administration, to evaluate bone turnover [ Designated as safety issue: No ]
- Measurement of the following biomarkers in tumour tissue before and after the first AZD0424 administration: p-Src, MKI67 (Ki-67), p-PAX, p-CRKL, p-FAK. [ Designated as safety issue: No ]
- Evaluate responses (stable disease (SD), partial response (PR) or complete response (CR)) in any of the patients as determined by Response Evaluation Criteria in Solid Tumours (RECIST) version 1.1. [ Designated as safety issue: No ]
|Study Start Date:||October 2012|
|Study Completion Date:||May 2016|
|Primary Completion Date:||May 2016 (Final data collection date for primary outcome measure)|
AZD0424 will be administered as a flat dose orally once a day. One treatment cycle consists of 28 days of continuous drug administration with AZD0424, with the flexibility to introduce treatment breaks if required due to cumulative toxicity.
Combination agents and treatment regimen with AZD0424 will be confirmed and approved at a later date.
AZD0424 is a potent orally available, potent (IC50 approximately 4 nM) inhibitor of Src and ABL1 kinases with additional activity against Src family kinase (SFK) members including Yes and Lck. AZD0424 was selective for SFKs and ABL1 kinase over C-terminal Src kinase (a negative regulator of Src) and a range of other kinase targets. The anti-cancer activity of AZD0424 is thought to be mediated primarily by anti-migratory and anti-invasive signalling and, as such, it is expected that in the late stage cancer setting strong signals of efficacy with this compound used as a single agent are unlikely, requiring it to be administered in combination with other anti-cancer agents.
In summary the study will be performed in four main stages:
- AZD0424 monotherapy, dose escalation: Phase Ia single agent (AZD0424) dose escalation study to determine the MTD.
- AZD0424 monotherapy, dose expansion: Phase Ib single agent dose expansion at MTD (up to six additional patients may be recruited in order to provide paired tumour biopsies for PD analysis).
- Combination arm dose escalation: Provided that it is deemed appropriate (after review of available clinical data from the monotherapy part of the trial, and available preclinical and published data on the combination), a Phase Ia dose escalation arm of AZD0424 in combination with the selected agent will proceed to determine the MTD for the combination and a recommended Phase II dose.
- Combination arm dose expansion: Phase Ib combination arm using the recommended Phase II dose for both AZD0424 and the combination agent.
Please refer to this study by its ClinicalTrials.gov identifier: NCT01668550
|Belfast City Hospital|
|Belfast, United Kingdom|
|Edinburgh Cancer Centre - Western General Hospital|
|Edinburgh, United Kingdom|
|Oxford University Hospitals NHS Trust|
|Oxford, United Kingdom|
|Study Chair:||Professor Adrian Harris||Oxford University Hospitals NHS Trust|