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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

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

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)
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
  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