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Background: Desmoid fibromatosis is a fibroblastic neoplasm driven by aberrations within the WNT pathway, exhibiting mutations in β-catenin or APC. We review the long-term follow-up of patients in a phase I study treated with an oral gamma secretase inhibitor, PF-03084014., Methods: PF-03084014 was administered orally at doses ranging from 20 to 330 mg twice daily. Tumor assessments were performed using computed tomography/magnetic resonance imaging (CT/MRI) within 4 weeks of study entry, and every other cycle through cycle 9. After cycle 9, patients were evaluated as clinically indicated., Results: Seven patients with desmoid fibromatosis were treated between December 2009 and December 2016 at the University of Colorado. Five patients (71.4%, 95% confidence interval [CI] 29.0-96.3%) achieved a partial response (PR), with a mean time to achieving response of 11.9 months (95% CI 2.5-21.4 months). All patients who achieved a PR continue to maintain responses between 47.9 and 73+ months. Four patients stopped treatment yet remain free of progression between 11 and 53+ months. One patient had PFS of 42+ months, with a 17% decrease in the target lesion. A biopsy performed at the end of the study showed decreased tumoral cellularity compared with previous biopsies. Effective treatment doses ranged from 80 to 330 mg administered orally twice daily., Conclusions: PF-03084014 was effective in treating desmoid tumors, with an objective response rate of 71.4% (95% CI 29.0-96.3%) in this small cohort of patients. PF-03084014 exhibits promising activity, even at relatively low doses (80 mg twice daily), with high tolerability leading to prolonged disease control even after therapy discontinuation.

Purpose: The notch pathway is overexpressed in pancreatic adenocarcinoma. RO4929097, an oral inhibitor of the γ-secretase enzyme has been safely given as a single agent in patients with advanced solid tumors. We aimed to evaluate the efficacy of RO4929097 in patients with pancreatic adenocarcinoma (PDA)., Methods: A two-stage, single-arm Phase II trial was conducted in patients with previously treated metastatic PDA. RO4929097 was administered at a dose of 20 mg daily on days 1-3, 8-10 and 15-17 of 21-day cycles. The primary endpoint was survival at 6 months. Secondary endpoints included overall survival (OS), response rate, toxicities, pharmacokinetic and pharmacodynamic analyses., Results: Eighteen patients were recruited, 17 in the first stage and one in the 2nd stage. It was decided to stop further enrollment after RO4929097 was discontinued by the sponsor and was no longer a development candidate. Three (25 %) of 12 evaluable patients achieved stable disease. The 6-month survival rate was 27.8 % (95 % CI 9.7-53.5). The median OS was 4.1 months (95 % CI 2.7-5.8 months) and median progression-free survival was 1.5 months (95 % CI 1.3-1.6 months). Pharmacokinetic properties of RO4929097 in patients (n = 5) with PDA was similar to that previously reported in other patient populations. There was a trend towards a decrease in HeyL (p = 0.08) gene expression in three patients following study drug administration., Conclusions: RO4929097 was well-tolerated in patients with previously treated PDA. Development of RO4929097 has been discontinued, but development of other notch-targeting agents in pancreatic cancer is continuing.

Introduction: Little is known about how the development of a new chronic health condition affects management of existing chronic conditions over time. New conditions might worsen management of existing conditions because of competing demands or improve management of existing conditions because of increased engagement with heath care. We assessed the effect of incident stage 0, 1, 2 or 3 breast, colon or prostate cancer; incident depression; or an exacerbation of chronic pulmonary disease on control of type 2 diabetes (DM2)., Methods: We conducted a longitudinal, historical cohort study within an integrated, not-for-profit HMO. Of a cohort of persons with diagnoses of DM2 between 1998 and 2008, 582, 2,959 and 2,332 developed incident cancer, depression or pulmonary disease exacerbation, respectively. We assessed change in hemoglobin A1c (A1c) as a function of the occurrence of the incident comorbidity in each subcohort for a period of 1 to 5 years after the occurrence of the incident comorbidity. Secondary outcomes were systolic blood pressure (SBP) and low density lipoprotein (LDL) levels. Multivariate linear regression was adjusted for demographics, morbidity level, BMI, numbers of primary and specialty visits, and continuity of primary care. Latent class analyses assessed post-comorbidity outcome trajectories. All time-varying covariates were calculated for a 24-month pre-diagnosis period and 0 to 24- and 24 to 60-month post-diagnosis periods., Results: For each condition, A1c did not change significantly from before to after the incident comorbidity. This was confirmed by latent class growth curve analyses that grouped patients by their A1c trajectories. SBP and LDL were also not significantly changed pre- and post-diagnosis of the incident comorbidities., Discussion: Although incident comorbidities inevitably will affect patients' and clinicians' care priorities, we did not observe changes in these particular outcomes. Additional investigation of interactions between diseases will inform changes in care that benefit complex patient populations.