CLINICAL TRIALS IN CANCER A number of class I and dual class I/mTOR inhibitors have now entered clinical trial. In this section we provide an update on the current status. 5.1. Pan Class I Selective PI3K Inhibitors Pan class I selective PI3K inhibitors have been shown to be well tolerated and, in general, to induce minimal and reversible effects on serum glucose despite the established role ABT-492 WQ-3034 of p110???in regulating insulin signalling. Other . Encouragingly, tumour responses stable disease and other signs of clinical efficacy have been reported in many clinical studies and in a variety of human cancers. Data on the clinical safety of the peptidic prodrug of LY204002, SF1126, in patients with advanced or metastatic tumours have been reported.
These studies demonstrated good tolerability and activity of the drug administered AZD7762 iv, which led to disease stabilization in patients with refractory tumours, including renal cell carcinoma and chronic lymphocytic leukaemia. Toxicities that were reported include nausea, vomiting, fatigue, urticaria and rash. No glucose or insulin changes have been reported. Evidence of pathway modulation has been claimed. Dose limiting toxicity has been reported at 1100mg/m?? XL147 was assessed in an open label, phase I dose escalation study that was carried out in patients with advanced solid tumours and lymphoma. Using a standard 33 design, patients with solid tumours received once daily XL147 on days 1 21 or as a continuous daily dose in 28 day cycles. The 33 trial design is used for the majority of oncology phase I trials.
According to this design, which is simple and straightforward to use, patients are treated in cohorts of 3, then, depending on the number of doselimiting toxicities seen in the particular patient cohort, decisions are made on which dose to give the next cohort or whether to stop the trial. The maximum tolerated dose was 600 mg in both schedules. The most common drug related toxicity that was seen was skin rash. Inhibition of PI3K and ERK pathway signalling was demonstrated in solid tumours, and prolonged stable disease has been observed in patients with cancers including non Hodgkin,s lymphoma and non small cell lung cancer. Two phase 1 combination studies have been reported with XL147.
The combination with the EGFR inhibitor erlotinib was generally well tolerated at doses up to 400 mg XL147/150 mg erlotinib with no major pharmacokinetic interaction and resulted in clinical activity and robust simultaneous inhibition of PI3K and EGFR signalling. The second combination study with paclitaxel and carboplatin showed that XL147 is well tolerated at doses up to 600 mg in combination with 175 mg/m2 and AUC 6 of paclitaxel and carboplatin respectively with no major pharmacokinetic interaction or emerging toxicities. Robust pharmacodynamic activity and tumour regression in heavily pre treated patients have been observed in this study. Expansion cohorts will include patients with endometrial, ovarian and non small cell lung cancer. Phase I clinical trials are currently being conducted with GDC 0941.