CRUKD/21/005 CURATE A CRUK first in human Phase I/II trial of TT702, a selective adenosine A2BR agonist, given orally as a monotherapy & in combination in advanced cancer including prostate cancer (mCRPC)

Adenosine is a purine nucleoside which confers potent immunosuppressive as well as direct tumour-promoting effects in the tumour microenvironment (TME). Approaches to block adenosine signalling in the TME by either blockade of adenosine generating enzymes (e.g. CD39, CD73 and CD38) or antagonism of adenosine receptors A2AR and A2BR are attractive therapeutic interventions.

A2BR is a G protein-coupled receptor which, unlike other adenosine receptor subtypes, is only activated by high concentrations of adenosine found under pathophysiological conditions. It is also hypoxia-induced leading to high expression in the TME.

It is expressed on both tumour and immune cells, promoting cancer cell proliferation and mediating immunosuppressive effects via regulatory T cells (Tregs), myeloid-derived suppressor cells (MDSCs) and dendritic cells (DCs). Selective small molecule antagonists of A2BR have proved challenging due to low aqueous solubility.

The parent compound, TT478 (GS6201/CVT-6883), is highly selective for A2BR but shows poor aqueous solubility. Nevertheless, TT478 advanced to the clinic and was shown to be safe in Phase II trials for asthma.

To improve exposure, TT478 was modified to generate the pro-drug TT702 or CURATE, which shows a 4-fold greater exposure than TT478 in vivo and is rapidly and completely converted to TT478 in plasma. CURATE is the only selective A2BR antagonist with pharmacological properties that allow for oral once daily dosing.

Current clinical data from other adenosine receptor antagonists support the importance of A2BR as a therapeutic target in metastatic prostate and possibly colorectal cancer. CURATE is being developed initially for the treatment of metastatic castration-resistant prostate cancer (mCRPC). A2BR is upregulated by androgen receptor activation and its expression correlates with poor survival in mCRPC.

CURATE alone improves anti-tumour immune response and, in combination with enzalutamide, synergistically inhibits the growth of human prostate cancer cells.

CURATE therefore has the potential to be a novel therapy for mCRPC by enhancing anti-cancer immunity and inhibiting prostate cancer proliferation. A phase 1 first in human trial of CURATE in mCRPC patients is proposed.

Starting oral dose will be determined by the GLP toxicology study and dose escalation will proceed using a 3+3 design with accelerated titration if needed.

Alongside the monotherapy, combination arms will also be considered in the dose escalation, e.g. with pembrolizumab or enzalutamide, and additional indications may be explored in the expansion phase.