A phase Ib combination study of RO4929097, a gamma-secretase inhibitor, and temsirolimus in patients with advanced solid tumors.

BACKGROUND: To determine the recommended phase II dose (RP2D) and assess the safety, pharmacokinetics (PKs) and pharmacodynamics of RO4929097in combination with temsirolimus. METHODS: Escalating doses of RO4929097 and temsirolimus were administered at three dose levels. Patients received once daily oral RO4929097 on a 3 days on/4 days off schedule every week, and weekly intravenous temsirolimus. Blood samples were collected for PK analysis. Archival tissue specimens were collected for Notch pathway biomarker analysis and genotyping of frequent oncogenic mutations. RESULTS: Seventeen patients with refractory advanced solid tumors were enrolled in three dose levels (DLs): DL1 (RO4929097 10 mg; Temsirolimus 25 mg), DL2 (RO4929097 20 mg; Temsirolimus 25 mg), and DL3 (RO4929097 20 mg; Temsirolimus 37.5 mg). The most common toxicities related to the study drug combination included: fatigue (82 %; grade 3 6 %), mucositis, (71 %; grade 3 6 %), neutropenia (59 %; grade 3 12 %), anemia (59 %; grade 3 0 %), and hypertriglyceridemia (59 %; grade 3 0 %). Two dose-limiting toxicities, grade 3 rash and grade 3 mucositis, were observed in the same patient in the first dose level prompting dose expansion. Eleven patients (73 %) had stable disease as their best response. Co-administration of RO4929097 was associated with increased clearance and reduced exposure to temsirolimus, suggestive of drug-drug interaction via CYP3A4 induction. No correlation between the expression of Notch pathway biomarkers or genotype and time to progression was noted. CONCLUSIONS: RO4929097 can be safely combined with temsirolimus in patients with advanced solid tumors. The RP2D was established at 20 mg of RO4929097 combined with 37.5 mg of temsirolimus.

Technology as a force for improved diagnosis and treatment of breast disease.

Increasing numbers of women are seeking evaluation of screen-detected breast abnormalities, and more women with breast cancer are living with the consequences of treatment. Improved technologies have helped to individualize diagnostic evaluation and treatment, improve efficacy and minimize morbidity. This article highlights some of these technologies. Superior imaging techniques have improved breast cancer screening and show promise for intraoperative surgical guidance and postoperative specimen evaluation. Digital mammography improves the sensitivity of mammography for women younger than 50 years with dense breasts, and tomosynthesis may improve specificity. Magnetic resonance imaging provides sensitive delineation of the extent of the disease and superior screening for women with a greater than 25% lifetime risk of breast cancer Minimally invasive techniques have been developed for the assessment of intraductal lesions, biopsy of imaging abnormalities, staging of the axilla and breast radiotherapy. Ductoscopy facilitates intraductal biopsy and localization of lesions for excision, sentinel lymph node biopsy is becoming standard for axillary staging, and intraoperative radiotherapy has the potential to reduce treatment time and morbidity. Three-dimensional imaging allows correlation of final histology with preoperative imaging for superior margin assessment. Related techniques show promise for translation to the intraoperative setting for surgical guidance. New classifications of breast cancers based on gene expression, rather than morphology, describe subtypes with different prognoses and treatment implications, and new targeted therapies are emerging. Genetic fingerprints that predict treatment response and outcomes are being developed to assign targeted treatments to individual patients likely to benefit. Surgeons play a vital role in the successful integration of new technologies into practice.