Introduction

7HP349 is a first in class allosteric agonist of the integrins α4β1 and αLβ2 which promotes both T-cell extravascular trafficking and T cell antigen priming.  In B16 and CT26 syngeneic models 7HP349 monotherapy has anti-tumor efficacy and in combination with anti-CTLA-4/anti-PD-1 enhanced tumoricidal effects. 7HP349 has a very safe preclinical acute and chronic toxicity profile.  We undertook a placebo-controlled Phase I single ascending (SAD) and multiple ascending dose (MAD) study to determine (i) the safety and tolerability of oral 7HP349 (ii) the optimal pharmacokinetic dose (OPD) of 7HP349. 

Methods

Four cohorts (1- 4) of healthy male volunteers (n=8; 6 active; 2 placebo) received single oral 7HP349/placebo doses of 50, 100, 200 or 300 mg after a standard breakfast. Two further cohorts [5 and 6 (n=8); 6 active; 2 placebo] received 100 or 300 mg 7HP349/placebo daily for five days. Subjects were monitored for clinical and laboratory adverse events (AEs) for up to 7 days post single dose and up to 10 days post multiple dosing. AEs were graded using CTCAE criteria v 5.0. Samples for 7HP349 pharmacokinetics in plasma and urine were collected pre-treatment and up to 96h post single dose (SAD) and through 24h first dose and 96h after the last multiple dose administration.  7HP349 plasma and urine concentrations were measured by LC-MS/MS, plasma concentration vs. time data were initially analyzed using non-compartmental models.

Results

Forty-eight healthy male volunteers median age 32 (range 21-44 y) were enrolled in the study; thirty-six received 7HP349 and twelve placebo.  In subjects receiving 7HP349 there were no SAEs or clinically significant AEs observed. Treatment emergent, reversible, non-clinically significant minor safety lab abnormalities included:

SAD cohort 100 mg Gr 1. amylase/lipase n= 1/6                                                                                                        

SAD cohort 200 mg Gr 1 isolated ALT n=1/6 and Gr 1 amylase/lipase n=1/6                                                       

SAD cohort 300 mg 1/6 isolated Gr 1 ALT n=1/6                                                                                                     

MAD cohort 100 mg isolated Gr 1 ALT n=1/6                                                                                                           

MAD cohort 300 mg Gr 1 AST/ALT & Gr 1 amylase/lipase n=1/6 and Gr 1 AST/ALT n=1/6

The 7HP349 terminal elimination half-life ranged from 20.6-34.6h with greater than dose proportional increases in C_max and AUC, but no evidence of accumulation over five days of dosing. Urine 7HP349 concentrations were all undetectable as they were below the lower level of quantitation (LLOQ=1 ng/mL) of the assay. 

Conclusion

Oral 7HP349 at single and multiple doses (daily x 5) up to 300 mg were found to be safe and very well tolerated. The 7HP349 terminal T_1/2 supported once daily dosing and the 7HP349 OPD was 100-300 mg/day x 5. A Phase Ib/IIa study combining 7HP349, over the OPD dose range, with anti CTLA-4 followed by anti-PD-1 monotherapy in patients who have advanced solid tumors with secondary resistance to anti PD-1 treatment is planned to start in late Q4 2023/Q1 2024 and is supported by CPRIT award DP230062.