First-in-Human, Phase I Dose-Escalation Study of CGM097, a HDM2 Inhibitor in Adult Patients With p53 Wild-type Advanced Solid Malignancies

Background: CGM097 inhibits p53-HDM2 interaction, thus activates p53 downstream effector pathways inducing cell cycle arrest and/or apoptosis. This phase I study aimed at assessing the safety, MTD, PK/PD, and preliminary antitumor activity of CGM097 in advanced solid tumors patients (NCT01760525). Methods: Fifty-one patients received oral treatment with CGM097 10-400mg 3qw (n=31) and on an alternative regimen of 3qw 2 weeks on/1 week off (300-700mg; n=20). Choice of dose regimen was guided by PD biomarkers, PK/PD relationship, and modeling of drug-induced changes in platelet kinetics. Results: No dose-limiting toxicities were reported in any regimens. Grade 3/4 AEs suspected to be drug-related were reported in 21 patients. Main reason for discontinuation was disease progression (n=41). CGM097 plasma concentrations increased in a dose proportional manner. Disease control rate was 39%, including one partial response (300mg, 3qw) and 19 patients in stable disease (10-700mg 3qw). Forty patients had a cumulative treatment duration of >16 weeks, with 8 patients on treatment for >32 weeks. The MTD was not determined. Conclusions: Despite delayed-onset thrombocytopenia frequently observed, the tolerability of CGM097 appears manageable. Although CGM097 is not being further developed, this study led to important modeling-derived learnings to optimize dose scheduling of next generation HDM2 inhibitors