Toxicities that were reported included nausea, vomiting, diarrhea, fatigue/asthenia, anemia, and anorexia, these effects were mild or moderate, manageable, and reversible upon treatment discontinuation. AUC and Cmax were found to increase non proportionally with dose and were variable within and among patients. NVP BEZ235 exhibited dose and day dependent PI3K inhibition as measured by elevation of plasma C peptide levels. 2 partial responses and 16 measurable responses were observed. ABT-888 Veliparib 14 of 51 evaluable patients had stable disease for ?? months, tumours from 6 of these 14 patients carried dysregulation of the PI3K pathway. Four of the 14 patients with stable disease for ?? months had breast cancer. 18 of 35 evaluable patients . An improved formulation of the compound will be used in future studies.
XL765 was administered twice daily or daily for 28 day cycles with a standard 33 dose escalation design in patients with solid tumours and lymphoma. The most common related adverse events were observed to be nausea, AZD8330 diarrhoea, anorexia, elevated liver enzymes, skin disorders, and vomiting. Exposure was found to be increased with increasing doses on BID and QD schedules. Robust pharmacodynamic modulation of PI3K and ERK pathway signalling was evident both in tumours and surrogate tissues following dosing of XL765. For example, decreases in phosphorylation of AKTTHR308 or of 4EBP1, as well as ERK, were observed in paired biopsies of various solid tumours from patients receiving 50 mg BID. Eleven patients have been reported to be on study for ??16 weeks and seven patients on treatment for ??24 weeks. The maximum tolerated dose for single agent XL765 is reported as 50 mg BID.
XL765 exhibited potent pharmacodynamic activity in solid tumours and surrogate tissues at generally well tolerated doses. XL765 in combination with the DNA methylating agent temozolomide is well tolerated at doses up to 40 mg QD. There was no apparent pharmacokinetic interaction between XL765 and temozolamide. Maximum tolerated dose determinations for QD and BID schedules are ongoing. Signs of disease stabilisation have been observed. XL765 in combination with erlotinib is also generally well tolerated at daily doses up to 50 mg XL765/100 mg erlotinib with no apparent pharmacokinetic interaction, and results in robust inhibition of PI3K and EGFR signalling in skin and tumour tissue. The maximum tolerated dose for the combination has not yet been determined.
The phase I dose escalation study of GDC 0980 was carried out in patients with solid tumours or non Hodgkin,s lymphoma and used a 33 design. GDC 0980 was given on day 1, followed by 1week washout to investigate single dose pharmacokinetic and pharmacodynamic biomarkers. The most frequently reported adverse events were nausea, fatigue, diarrhoea, and flatulence. GDC 0980 was found to be generally well tolerated up to 16 mg administered orally QD with potential signs of anti tumour activity. Preliminary pharmacokinetic data suggest dose proportional increases in Cmax and AUC. Initial pharmacodynamic biomarker data showed 50% inhibition of phosphorylated AKTSER473 levels assayed in platelet rich plasma after a single dose of 8 mg and higher of GDC 0980. Of potential interest, evidence of anti tumour activity was observed in a mesothelioma patient previously treated with radiation and cisplatin.