Initial results have been reported from a phase I study using a 33 escalation design with a single dose of GDC 0941 and a 1 week washout, followed by GDC 0941 QD administered on a 3 week on, 1 week off schedule. A doseproportional increase in drug exposure was observed from 15 to 450mg.  phosphorylation in platelet rich plasma at doses above 80mg and a decrease ABT-737 in RPS6 immunostaining in tumours. In addition, objective decreases in metabolic activity as measured by positron emission tomography of fluorodeoxyglucose have been observed in patients, tumours at doses above 80mg. GDC 0941 was generally well tolerated and exhibited signs of antitumour activity in a variety of cancers including breast, ovarian cancer, gastro intestinal stromal tumour and melanoma patients. Toxicities include fatigue, nausea, diarrhea and rash. Transient hyperglyceamia has been described. GDC 0941 is being evaluated in non small cell lung cancer in combination with paclitaxel and carboplatin with or without bevacizumab.
So far, these combinations appear to be well tolerated and no sign of pharmacokinetic interaction have been observed. Dose escalation is ongoing and clinical activity has AZD8055 been recorded. A phase II study in breast cancer is recruiting In an initial phase 1 dose escalation study evaluating an intermittent dosing schedule, PX 866 was well tolerated with diarrhoea and nausea observed as main toxicities. PX 866 was rapidly converted to an active metabolite which demonstrated improved potency relative to parent compound in kinase and cellular assays. PX 866 was further evaluated using a continuous dosing schedule and has been well tolerated at 8??mg per day and associated with better disease control in heavily pre treated patients than intermittent dosing.
Clinical responses have been observed in pancreatic islet cell, colorectal, and prostate cancer. Predictive biomarkers are being explored. Patients were treated at 6 doses of BMK30 ranging from 12.5 mg to 150 mg. The maximum tolerated dose was 100 mg. Treatment related adverse events included rash, hyperglycaemia, diarrhoea, nausea, anorexia, pruritus, fatigue, mood alteration, malaise, vomiting, and mucositis. Preliminary pharmacokinetic analysis showed rapid absorption and low clearance from plasma leading to steady state drug exposure estimated to be potentially efficacious based on preclinical data. Downregulation of pS6 in skin was seen in all patients at 100/150 mg. At 100 mg, 8 of 10 evaluable patients showed metabolic partial response by FDG PET.
Clinical responses were observed in triple negative breast cancer, colorectal cancer, angiosarcoma and lung cancer. 5.2. Dual Pan Class I PI3K/mTOR Inhibitors The safety profile and tolerability of the dual pan PI3K/mTOR inhibitors generally appears to be similar to that of the paninhibitors. Several organizations are developing candidates with both profiles and it is currently unclear what the ideal PI3K family isoform selectivity profile or profiles in the clinic will be. Signs of clinical activity are also encouraging for the development of these agents. The first reports from clinical trials conducted in patients with solid tumours showed promising drug safety and tolerability for NVP BEZ235 with signs of clinical activity in patients with tumours bearing PI3K pathway alterations.