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
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.
- Combination arm(s) dose escalation: Provided that it is deemed appropriate (post review
of available clinical data from the monotherapy dose escalation and available
preclinical and published data on the combinations), up to three Phase Ia dose
escalation arms of AZD0424 in combination with selected agent(s) will proceed to
determine the MTD for the combination and a recommended Phase II dose.
- Combination arm(s) dose expansion: Up to three Phase Ib combination arm(s) as
appropriate using the recommended Phase II dose for both AZD0424 and the combination
Endpoint Classification: Safety Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment
Establishing the Maximum Tolerated Dose (MTD) of AZD0424 alone and in combination
Professor Adrian Harris
Oxford University Hospitals NHS Trust
United Kingdom: Medicines and Healthcare Products Regulatory Agency