The PI3K–AKT–mTOR pathway is frequently activated in cancer. PI3K inhibitors, including the pan-PI3K inhibitor buparlisib (BKM120) and the PI3Kα-selective inhibitor alpelisib (BYL719), currently in clinical development by Novartis Oncology, may therefore be effective as anticancer agents. Early clinical studies with PI3K inhibitors have demonstrated preliminary antitumor activity and acceptable safety profiles. However, a number of unanswered questions regarding PI3K inhibition in cancer remain, including: what is the best approach for different tumor types, and which biomarkers will accurately identify the patient populations most likely to benefit from specific PI3K inhibitors? This review summarizes the strategies being employed by Novartis Oncology to help maximize the benefits of clinical studies with buparlisib and alpelisib, including stratification according to PI3K pathway activation status, selective enrollment/target enrichment (where patients with PI3K pathway-activated tumors are specifically recruited), nonselective enrollment with mandatory tissue collection, and enrollment of patients who have progressed on previous targeted agents, such as mTOR inhibitors or endocrine therapy. An overview of Novartis-sponsored and Novartis-supported trials that are utilizing these approaches in a range of cancer types, including breast cancer, head and neck squamous cell carcinoma, non-small cell lung carcinoma, lymphoma, and glioblastoma multiforme, is also described.

Methods A multicentre, parallel‐group, double‐blind, double‐placebo study was carried out to compare the efficacy, tolerability, and safety of racecadotril and loperamide in children aged 2 to 10 years who were suffering from acute diarrhoea. Patients received racecadotril (1.5 mg/kg) or loperamide (0.03 mg/kg) three times daily plus matching placebo until recovery. Fifty‐two children received racecadotril and 50 loperamide. Results Patients on racecadotril passed a mean (± S.E.M.) of 2.7 ± 0.4 stools before recovery compared with 2.1 ± 0.4 stools for loperamide. The duration of diarrhoea was similar with both treatments. The incidence of adverse events was lower with racecadotril than with loperamide (11.5% vs. 22%), and significantly more patients on loperamide suffered from constipation (58% vs. 36.5%; P = 0.03). Moreover, significantly more children receiving loperamide required concomitant medication during the study (38%v 19.2%; P = 0.047). Measurement of abdominal circumference at the final consultation, 6 days after entry to the study, revealed no significant differences between treatments. Conclusions Racecadotril and loperamide were equally effective in treating acute diarrhoea in these children, and racecadotril had a superior tolerability and safety profile.

The PI3K/Akt/mTOR pathway is one of the most frequently dysregulated signaling pathways in cancer and an important target for drug development. PI3K signaling plays a fundamental role in tumorigenesis, governing cell proliferation, survival, motility, and angiogenesis. Activation of the pathway is frequently observed in a variety of tumor types and can occur through several mechanisms. These mechanisms include (but are not limited to) upregulated signaling via the aberrant activation of receptors upstream of PI3K, amplification or gain-of-function mutations in the PIK3CA gene encoding the p110α catalytic subunit of PI3K, and inactivation of PTEN through mutation, deletion, or epigenetic silencing. PI3K pathway activation may occur as part of primary tumorigenesis, or as an adaptive response (via molecular alterations or increased phosphorylation of pathway components) that may lead to resistance to anticancer therapies. A range of PI3K inhibitors are being investigated for the treatment of different types of cancer; broad clinical development plans require a flexible yet well-structured approach to clinical trial design.

Methods A multicentre, randomized, double‐blind, double‐placebo, parallel‐group study was carried out to compare the efficacy, tolerability, and safety of racecadotril (100 mg three times daily) and loperamide (2 mg after each diarrhoeic stool) in 157 adults with acute diarrhoea. Patients were treated for 7 days or until recovery, if this took place earlier. Results Both groups of patients passed similar numbers (mean ± S.E.M.) of stools before recovery (3.5 ± 0.5 for racecadotril vs. 2.9 ± 0.4 for loperamide), and the duration of diarrhoea (mean ± S.E.M.) was similar in both groups (14.9 ± 2.0 h for racecadotril and 13.7 ± 2.2 h for loperamide). Both treatments reduced the incidence of associated symptoms and signs during the study, and both were similarly well tolerated. However, more patients on loperamide reported rebound constipation during treatment (18.7% vs. 9.8% with racecadotril). Conclusions The enkephalinase inhibitor, racecadotril, and the intestinal transit inhibitor, loperamide, were similarly and rapidly effective in resolving the symptoms and associated signs of diarrhoea.

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