Thus, the refinement of a selection of biomarkers for AKT inhibitors is needed to improve their monotherapy activity. mutation was identified as a probable oncogenic driver in patients, indicating that the inhibition of AKT1 presents a novel and specific drug target in this disease [5,6]. the 78 patients enrolled, one patient had a partial response, 30 had stable disease, and 38 had progressive disease. The clinical benefit rate was 27.9% among 43 patients treated at the R2D. mutation status was not associated with tumor response. Genetic analyses revealed additional mutations that could promote tumor cell growth despite the inhibition of AKT1/2. BAY 1125976 was well tolerated and inhibited AKT1/2 signaling but did not lead to radiologic PTC-209 HBr or clinical tumor responses. Thus, the refinement of a selection of biomarkers for AKT inhibitors is needed to improve their monotherapy activity. mutation was identified as a probable oncogenic driver in patients, indicating that the inhibition of AKT1 presents a novel and specific drug target in this disease [5,6]. However, as the prevalence of the mutation was considered low (6.3%), a patient selection strategy was necessary. Several (pan-)AKT inhibitors have been developed recently . These compounds are either ATP-competitive (e.g., AZD5363 ) or allosteric (e.g., MK-2206 ) inhibitors and were investigated in various indications. BAY 1125976 is an oral, small-molecule allosteric inhibitor of AKT1/2 with high selectivity. It inhibits the proliferation of cells with PI3K/AKT/mTOR pathway alterations at submicromolar IC50 values and showed its highest activity in luminal breast cancer cell lines. BAY 1125976 exhibited in vivo antitumor activity in preclinical breast cancer models after oral application . Furthermore, a potent inhibition of the downstream signaling cascade was exhibited PTC-209 HBr by reduced levels of p-AKT, p-PRAS40, p-S6RP, or p-70S6K, leading to antitumor efficacy in mutation (Physique 1). Overall, 61 patients (77.2%) were female. The mean age of all the patients was 56.7 years (range 31C82 years). Except for one patient in the 80 mg QD dose escalation and one patient in PTC-209 HBr the 80 mg BID dose escalation, all patients had a baseline Eastern Cooperative Oncology Group (ECOG) performance status of 0 (59.5%) or 1 (38.0%). Only one patient (40 mg BID cohort) did not receive any prior systemic anticancer therapy. Sixty patients (75.9%) had prior radiotherapy. The baseline characteristics for patients with mutations were comparable to the whole study population. Open in a separate window Physique 1 Study outline and patient disposition during dose escalation steps and for the breast cancer expansion cohort at 60 mg BID BAY 1125976. Table 1 Baseline patient demographics in Rabbit polyclonal to ACTA2 the BAY 1125976 phase 1 study. BID: twice daily, ECOG: Eastern Cooperative Oncology Group, LSF: liquid support formulation, QD: continuous once daily, WT: wild-type. mutation are also part of the 60 mg BID expansion cohort. 2.2. Dose Escalation and Maximum Tolerated Dose During the initial QD dose escalation, no dose-limiting toxicity was observed until the 120 mg QD cohort. Here, two patients experienced Grade 3 or Grade 4 liver enzyme elevation of aspartate animotransferase (AST), alanine animotransferase (ALT), -glutamyltransferase (-GT), and one patient experienced Grade 3 elevation of alkaline phosphatase (AP). Based on PK and modeling data, a re-escalation using a BID schedule was initiated at 40 mg BID with the intent of maintaining target engagement whilst reducing Cmax under the hypothesis that higher Cmax may be linked to observed events. Two patients at the 80 mg BID dose level experienced Grade 3 liver enzyme elevation (AST, ALT), with one of these patients also showing Grade 3 hyperglycemia. Dose was then de-escalated to 60 mg BID and two patients experienced Grade 3 liver enzyme elevation (AST, ALT, -GT), too. The MTD estimate based on posterior dose-limiting toxicity (DLT) rates of the Bayesian dose response analysis was 81.1 mg for the QD schedule (with a coefficient of variation of 25.5%) and 65.1 mg for the BID schedule (with a coefficient of variation of 38.1%), respectively. Therefore, the MTD and recommended dose for the expansion phase was selected as 60 mg BID. 2.3. Safety During the study, 77 (97.5%) patients reported at least one treatment-emergent adverse event (TEAE), drug-related TEAEs were reported by 69 (87.3%) patients, and nine (11.4%) patients had TEAEs related to procedures required by the protocol. Eighteen (22.8%) patients PTC-209 HBr had TEAEs that were Common Terminology Criteria for Adverse Events (CTCAE) Grade 1 or Grade 2, and 52 (65.8%) patients had TEAEs that were CTCAE Grade 3 or Grade 4, with overall only one patient in the 120.