The purpose of this study was to determine a recommended phase II dose and schedule of LY2940680 (taladegib) for safe administration to patients with locally advanced/metastatic cancer. This was a phase I, multicenter, open-label study of oral LY2940680. The maximum tolerable dose (MTD) was determined using a 3+3 design, the dose was confirmed, and then treatment-naïve and previously hedgehog (Hh)-inhibitor-treated patients with basal cell carcinoma (BCC) were enrolled. Eighty-four patients were treated (dose escalation, = 25; dose confirmation, = 19; and BCC dose expansion, = 40). Common treatment-emergent adverse events were dysgeusia [41 (48.8%)], fatigue [40 (47.6%)], nausea [38 (45.2%)], and muscle spasms [34 (40.5%)]. Four patients experienced events (3 were grade 3; 1 was grade 2) that were considered dose-limiting toxicities (DLT). The MTD was determined to be 400 mg because of DLTs and dose reductions. Pharmacokinetic analyses showed no clear relationship between exposure and toxicity. Analysis of Gli1 mRNA from skin biopsies from unaffected areas suggested that all doses were biologically active [inhibition median of 92.3% (80.9% to 95.7%)]. All clinical responses (per RECIST 1.1) were in patients with BCC ( = 47); the overall and estimated response rate was 46.8% (95% confidence interval, 32.1%-61.9%). Responses were observed in patients previously treated with Hh therapy (11/31) and in Hh treatment-naïve (11/16) patients. LY2940680 treatment resulted in an acceptable safety profile in patients with advanced/metastatic cancer. Clinical responses were observed in patients with locally advanced/metastatic BCC who were previously treated with Hh therapy and in Hh treatment-naïve patients. .
A model of cerebral pulsatile blood flow through multiple arterial bifurcations is developed, based on the physics of wave propagation in compliant vessels. The model identifies the conditions for the optimum antegrade flow of blood into the arterioles as a function of the areas and stiffnesses of the arteries. The model predicts and quantifies the reduction in vessel diameter which occurs in progressing from the large central arteries into the arterioles. It also predicts and quantifies the change in vessel compliance which occurs in progressing from the large central arteries, through the small arteries, into the arterioles. Physics predicts that the clinically observed compliance changes are consistent with the efficient delivery of blood to the cerebral capillary bed. The model predicts that increasing arterial stiffening with age, reduces pulsatile cerebral blood flow substantially, potentially resulting in ischemia, hypoperfusion and hypoxia, with attendant neurological and cognition consequences. The model predicts that while central pulse pressure increases with aging, small vessel pulse pressure reduces, contrary to the concept of a pressure wave tsunami in the small vessels. The model also predicts that increased luminal diameters with increasing age, mitigate, somewhat the negative consequences of arterial stiffening, a form of adaptive arterial remodelling.
2594 Background: Aberrant Hedgehog (Hh) signaling is implicated in carcinogenesis and is associated with poor prognosis in multiple tumours types. Hh inhibitors increase sensitivity to paclitaxel in taxane-resistant cell lines. Taladegib is an orally bioavailable, potent inhibitor of Smoothened, a key Hh pathway component, with activity in basal cell carcinoma. The single agent recommended dose is 400mg od. We present the dose escalation phase of a phase I study of weekly paclitaxel with oral taladegib. Methods: Primary objective: determine the dose limiting toxicity (DLT) and maximum tolerated dose (MTD) of taladegib on a continuous oral daily dosing regimen in combination with paclitaxel (80mg/m2, iv, day 1, 8 and 15 q 28) in patients with advanced solid cancers. Secondary objectives: assess the safety and tolerability, determine the recommended phase II dose (RP2D), and evaluate the pharmacokinetics of taladegib and paclitaxel. Exploratory objective: assess preliminary efficacy. A standard 3 + 3 dose escalation design was used. All patients received up to 6 cycles of paclitaxel. In addition, successive cohorts received continuous oral taladegib continued until progression or unacceptable toxicity as follows: dose level 1: 100mg od; 2: 200mg od; 3: 400mg od. Results: No DLTs were seen at dose level 1 or in the first 3 patients at dose level 2. 3 DLTs of grade 2 neuropathy were seen at dose level 3 (400mg taladegib); therefore, dose level 2 was expanded to 6 patients. No DLT was seen in the fourth patient and 2 additional patients have started treatment. After the DLT period 2 patients developed G2 and 4 developed G1 neuropathy. Other non DLT, drug-related G3 toxicities: uncomplicated neutropenia x2, muscle cramp x1 and fatigue x1. To date, 3 patients have had partial responses. Conclusions: The combination of daily oral taladegib and weekly paclitaxel is feasible. DLT of G2 neuropathy was seen at 400mg. Promising activity has been seen in solid tumours. A dose expansion cohort is due to commence in high grade ovarian carcinoma. ISRCTN No:ISRCTN15903698 Eudract Ref:2014-004695-37 Funded by Cancer Research UK C8361/A18775 and Ignyta. Sponsored by NHS Greater Glasgow and Clyde. Clinical trial information: ISRCTN15903698.
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