AKT inhibition in the central nervous system induces signaling defects resulting in psychiatric symptomatology

Cell & Bioscience

Table 1 Psychiatric adverse events in patients with advanced cancer treated on a phase I study of the brain-penetrant p70S6K/AKT1/AKT3 inhibitor M2698

Dose of M2698 (mg/day)	Patients in cohort (n)	Patients with AEs (n)	Psychiatric AEs in cohort (count)	Number of treatment-emergent adverse events (any grade)
Dose of M2698 (mg/day)	Patients in cohort (n)	Patients with AEs (n)	Psychiatric AEs in cohort (count)	Abnormal dreams/nightmares/insomnia/sleep disorders	Anxiety/emotional distress	Depression/pathy/ euphoric mood/ mania	Delusion/ paranoia	Hallucination/auditory hallucination	Reading disorder	Confusional state	Affect lability
Mono-therapy
15	3	0	0	0	0	0	0	0	0	0	0
30	3	0	0	0	0	0	0	0	0	0	0
60	6	2	2	0	1	0	0	0	0	0	1
75	4	1	2	2	0	0	0	0	0	0	0
110	4	0	0	0	0	0	0	0	0	0	0
160	6	2	3	2	0	1	0	0	0	0	0
200	3	1	1	0	1	0	0	0	0	0	0
240	17	5	5	2	1	2	0	0	0	0	0
320	12	4	9	4	2	1	2	0	0	0	0
380	4	1	1	0	1	0	0	0	0	0	0
M2698 (+ tamoxifen)
80	4	4	9	1	4	0	1	1	1	1	0
160	9	2	3	1	1	1	0	0	0	0	0
200	6	2	3	2	1	0	0	0	0	0	0
240	7	1	2	1	0	1	0	0	0	0	0
M2698 (+ trastuzumab) 0 0
80	4	1	1	0	0	1	0	0	0	0	0
160	9	3	12	3	3	4	1	1	0	0	0
TOTAL	101	29	53	18	15	11	4	2	1	1	1

Overall, 29% (29/101) of the patients reported 53 psychiatric treatment-emergent AEs without evident M2698 dose dependency. Some patients developed multiple psychiatric AEs. Notably, 5 patients, who had 3 to 5 psychiatric AEs each, accounted for 40% (21/53) of psychiatric AEs (Additional file 1: Table S2). The most affected cohort was the trastuzumab cohort, where 3 patients reported 12 AEs at the highest dose level (160 mg). In the M2698 monotherapy cohort at a dose level of 320 mg and in the trastuzumab combination cohort at a dose level of 80 mg M2698, one patient each had 5 and 4 AEs, respectively. A medical history of psychiatric symptoms was documented in 56/101 (55%) patients corresponding to the observed AEs in the trial, i.e., mainly anxiety, depression, and insomnia

ISSN: 2045-3701