Abstract CT168: Clinical pharmacology of AZD4635 (A2ARi): Integration of PK data from cancer patients (CP) and healthy volunteer (HV) clinical trials to provide dosing recommendations
Authors: Moorthy Ganesh , Pouliot Gayle Pageau , Graham Lorraine , Wilks Chris , Sarvotham Tinnu , Mitchell Patrick , Jung Lindsey , Li Yan , Shao Wenlin , Mugundu Ganesh 
Published: September 2020

AZD4635 is an orally administered, selective adenosine 2A receptor (A2AR) antagonist, being evaluated in patients with advanced solid tumors. In the phase 1 trial, safety and pharmacokinetics (PK) of AZD4635 nanosuspension (NS) was assessed as monotherapy or in combination with durvalumab. In the HV study, a single dose of AZD4635 was evaluated to assess relative bioavailability, effect of high fat meal and effect of proton pump inhibitor (PPI) on new capsule formulation (CF). Here we present PK results from both trials to provide dosing and formulation recommendation for ongoing clinical trials.

Methods: Phase 1 Study in CP: An open-label, multicenter study in advanced solid malignancies (121 patients PK evaluable), AZD4635 was administered as a NS at various dose levels (125 mg BID, 75mg QD, 100 mg QD) as monotherapy or in combination (75 or 100 mg QD) with durvalumab (NCT02740985). The PK parameters of AZD4635 and its metabolites have been characterized in patients after single and multiple doses.

Phase 1 Study in HV: An open-label, single-dose (50 mg), 2-part crossover clinical pharmacology study was conducted in 20 HV (non-smoking, male) (NCT03710434). Part A was a 2-period randomized crossover study of AZD4635 as NS or CF. Part B was a fixed-sequence crossover study to evaluate effect of high fat meal and co-administration of PPI (lansoprazole) on AZD4635 CF. PK and safety assessments were obtained for up to 120 h post-dose in each treatment period, and the treatments were separated with at least a 9-day washout period.

Results: AZD4635 NS rapidly appeared in plasma after single or multiple oral administration with tmax of 1 h and Cmax were 594.13, 580.21, and 770.66 ng/mL and AUC were 4780.3, 4364.8, and 5972.89 ng•hr/mL at 75, 100 and 125 mg, respectively with a mean t1/2 of 13.1 - 18.1 h following a single-dose administration. There was minimal accumulation at steady state with high inter-individual variability (43 - 114%). Metabolites PK will be presented.

In HV, administration of CF resulted in absorption rates similar to NS with tmax of 1.5 h and had 27% and 10% higher Cmax and AUC, respectively compared to NS. Administering AZD4635 CF after a high fat meal resulted in 56% and 12% decrease in Cmax and AUC, respectively compared to the fasted state. In the presence of PPI (lansoprazole), peak and overall exposures (Cmax, AUC and tmax) were similar to those for CF administered alone.

Conclusion: Based on totality of exposure and safety data from ongoing Phase I study in CP at various doses of AZD4635 NS, and data from HV study for both NS and CF, a dose of 75 mg CF is proposed RP2D for further clinical studies. As food can mitigate gastrointestinal toxicities, and there was a lack of significant effect on AUC, the current fasting restrictions have been relaxed to allow patients to receive AZD4635 with or without food. No impact of PPI allows for better compliance as the target patient population may also be receiving gastric modifiers.

Citation Format: Ganesh Moorthy, Gayle Pageau Pouliot, Lorraine Graham, Chris Wilks, Tinnu Sarvotham, Patrick Mitchell, Lindsey Jung, Yan Li, Wenlin Shao, Ganesh Mugundu. Clinical pharmacology of AZD4635 (A2ARi): Integration of PK data from cancer patients (CP) and healthy volunteer (HV) clinical trials to provide dosing recommendations [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr CT168.