Jordi Andreu

Phase I Pharmacokinetic/Pharmacodynamic Study of MLN8237, an Investigational, Oral, Selective Aurora A Kinase Inhibitor, in Patients with Advanced Solid Tumors

Purpose: Aurora A kinase (AAK) is a key regulator of mitosis and a target for anticancer drug development. This phase I study investigated the safety, pharmacokinetics, and pharmacodynamics of MLN8237 (alisertib), an investigational, oral, selective AAK inhibitor, in 59 adults with advanced solid tumors. Experimental Design: Patients received MLN8237 once daily or twice daily for 7, 14, or 21 consecutive days, followed by 14 days recovery, in 21-, 28-, or 35-day cycles. Dose-limiting toxicities (DLT) and the maximum-tolerated dose (MTD) for the 7- and 21-day schedules were determined. Pharmacokinetic parameters were derived from plasma concentration–time profiles. AAK inhibition in skin and tumor biopsies was evaluated and antitumor activity assessed. Results: Neutropenia and stomatitis were the most common DLTs. The MTD for the 7- and 21-day schedules was 50 mg twice daily and 50 mg once daily, respectively. MLN8237 absorption was fast (median time to maximum concentration, 2 hours). Mean terminal half-life was approximately 19 hours. At steady state, pharmacodynamic effects were shown by accumulation of mitotic and apoptotic cells in skin, and exposure-related increases in numbers of mitotic cells with characteristic spindle and chromosomal abnormalities in tumor specimens, supporting AAK inhibition by MLN8237. Stable disease was observed and was durable with repeat treatment cycles, administered over 6 months, in 6 patients, without notable cumulative toxicity. Conclusions: The recommended phase II dose of MLN8237 is 50 mg twice daily on the 7-day schedule, which is being evaluated further in a variety of malignancies, including in a phase III trial in peripheral T-cell lymphoma. Clin Cancer Res; 18(17); 4764–74. ©2012 AACR.

A Phase I Pharmacokinetic and Pharmacodynamic Study of Dalotuzumab (MK-0646), an Anti-Insulin-like Growth Factor-1 Receptor Monoclonal Antibody, in Patients with Advanced Solid Tumors

Purpose: Insulin-like growth factor-1 receptor (IGF-1R) mediates cellular processes in cancer and has been proposed as a therapeutic target. Dalotuzumab (MK-0646) is a humanized IgG1 monoclonal antibody that binds to IGF-1R preventing receptor activation. This study was designed to evaluate the safety and tolerability of dalotuzumab, determine the pharmacokinetic (PK) and pharmacodynamic (PD) profiles, and identify a recommended phase II dose. Experimental Design: Patients with tumors expressing IGF-1R protein were allocated to dose-escalating cohorts of three or more patients each and received intravenous dalotuzumab weekly, every 2 or 3 weeks. Plasma was collected for PK analysis. Paired baseline and on-treatment skin and tumor biopsy samples were collected for PD analyses. Results: Eighty patients with chemotherapy-refractory solid tumors were enrolled. One dose-limiting toxicity was noted, but a maximum-tolerated dose was not identified. Grade 1 to 3 hyperglycemia, responsive to metformin, occurred in 15 (19%) patients. At dose levels or more than 5 mg/kg, dalotuzumab mean terminal half-life was 95 hours or more, mean Cmin was more than 25 μg/mL, clearance was constant, and serum exposures were approximately dose proportional. Decreases in tumor IGF-1R, downstream receptor signaling, and Ki67 expression were observed. 18F-Fluorodeoxy-glucose positron emission tomography metabolic responses occurred in three patients. One patient with Ewings sarcoma showed a mixed radiologic response. The recommended phase II doses were 10, 20, and 30 mg/kg for the weekly, every other week, and every third week schedules, respectively. Conclusions: Dalotuzumab was generally well-tolerated, exhibited dose-proportional PK, inhibited IGF-1R pathway signaling and cell proliferation in treated tumors, and showed clinical activity. The low clearance rate and long terminal half-life support more extended dosing intervals. Clin Cancer Res; 17(19); 6304–12. ©2011 AACR.

Understanding diluted dispersions of superparamagnetic particles under strong magnetic fields: a review of concepts, theory and simulations

In recent years, there has been a great progress in the development of superparamagnetic particles targeted to a wide range of applications, including fields as diverse as biotechnology or waste removal. However, the physics behind their behaviour under usual conditions (diluted dispersions and high magnetic fields) has many, fundamental, open questions. In this review, we revisit the advances in the basic physical concepts and predictive analytical and simulation tools. We focus on recent developments in the understanding and prediction of phenomena induced by magnetic fields both in uniform fields (for example, chain formation) and in magnetic gradients (cooperative magnetophoresis).

Phase I assessment of new mechanism-based pharmacodynamic biomarkers for MLN8054, a small-molecule inhibitor of Aurora A kinase

The mitotic kinase Aurora A is an important therapeutic target for cancer therapy. This study evaluated new mechanism-based pharmacodynamic biomarkers in cancer patients in two phase I studies of MLN8054, a small-molecule inhibitor of Aurora A kinase. Patients with advanced solid tumors received MLN8054 orally for 7 consecutive days in escalating dose cohorts, with skin and tumor biopsies obtained before and after dosing. Skin biopsies were evaluated for increased mitotic cells within the basal epithelium. Tumor biopsies were assessed for accumulation of mitotic cells within proliferative tumor regions. Several patients in the highest dose cohorts showed marked increases in the skin mitotic index after dosing. Although some tumors exhibited increases in mitotic cells after dosing, others displayed decreases, a variable outcome consistent with dual mechanisms of mitotic arrest and mitotic slippage induced by antimitotics in tumors. To provide a clearer picture, mitotic cell chromosome alignment and spindle bipolarity, new biomarkers of Aurora A inhibition that act independently of mitotic arrest or slippage, were assessed in the tumor biopsies. Several patients, primarily in the highest dose cohorts, had marked decreases in the percentage of mitotic cells with aligned chromosomes and bipolar spindles after dosing. Evidence existed for an exposure-effect relationship for mitotic cells with defects in chromosome alignment and spindle bipolarity that indicated a biologically active dose range. Outcomes of pharmacodynamic assays from skin and tumor biopsies were concordant in several patients. Together, these new pharmacodynamic assays provide evidence for Aurora A inhibition by MLN8054 in patient skin and tumor tissues.

Aggregation of superparamagnetic colloids in magnetic fields: the quest for the equilibrium state

Previous experimental and simulation studies of superparamagnetic colloids in a strong external field have systematically shown a nonequilibrium aggregation process in which chains of particles steadily grow in the direction of the applied external field with the average length increasing as a power law over time. Here we show, by employing Langevin dynamics simulations, the existence of a different behavior under the effects of an external magnetic field: after a transient period of chain formation, the system attains an equilibrium state. Furthermore, a thermodynamic self-assembly theory supports the simulation results and it also predicts that the average chain length in the equilibrium state depends only on a dimensionless parameter combining the volume fraction of colloids ϕ0 and the magnetic coupling parameter Γ. The conditions under which this new behavior can be observed are discussed here.

Hemangioma of the rectum: CT appearance.

An 18-year-old man who had severe recurrent rectal bleeding and hematuria was found to have a diffuse cavernous hemangioma of the rectosigmoid. A computed tomographic (CT) study was indicated to evaluate tumor extension and therapeutic possibilities. CT scanning revealed a large mass with phleboliths throughout the true pelvis and nodular indentations in the rectosigmoid wall involving the dome and posterior wall of the bladder. A nonhomogeneous and subtle enhancement of the lesion was noticed after injection of contrast medium.

Phase I Pharmacokinetic and Pharmacodynamic Study of Weekly 1-Hour and 24-Hour Infusion BMS-214662, a Farnesyltransferase Inhibitor, in Patients With Advanced Solid Tumors

PURPOSEnBMS-214662 is a potent, nonpeptide, small molecule inhibitor of human farnesyltransferase (FT). We have conducted a phase I pharmacokinetic (PK) and pharmacodynamic study of BMS-214662 administered intravenously weekly with 1- and 24-hour infusions. The objectives were to determine the dose-limiting toxicities and the recommended dose (RD), to describe PKs, and to evaluate the relationships between BMS-214662 exposure, FT inhibition, downstream signaling, and induction of apoptosis in tumor samples.nnnPATIENTS AND METHODSnPatients with advanced solid tumors and adequate organ function were eligible. The dose was escalated according to a modified Fibonacci schedule.nnnRESULTSnhigh (> 80%) but short-lived (< or = 6 hours) in the 1-hour infusion and moderate (> 40%) but long-lived (24 hours) in the 24-hour infusion. BMS-214662 induced apoptosis in tumors but did not inhibit MAPK signaling.nnnCONCLUSIONnBMS-214662 can be safely delivered in both the 1-hour and 24-hour infusions at biologically active doses, with the preclinical, PK, and pharmacodynamic profiles favoring the 24-hour schedule.

Phase I Pharmacokinetic/Pharmacodynamic Study of EKB-569, an Irreversible Inhibitor of the Epidermal Growth Factor Receptor Tyrosine Kinase, in Combination with Irinotecan, 5-Fluorouracil, and Leucovorin (FOLFIRI) in First-Line Treatment of Patients with Metastatic Colorectal Cancer

Purpose: To determine the recommended dose (RD) of EKB-569, an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor, in combination with FOLFIRI chemotherapy in patients with metastatic colorectal cancer (mCRC). Methods: Patients with previously untreated mCRC received FOLFIRI and EKB-569 at doses of 10, 25, 50, and 75 mg/day (EKB started on day 3). Three sequential skin biopsies were obtained in selected patients to assess the pharmacodynamic effects on EGFR signaling of FOLFIRI alone and with EKB-569. Complete pharmacokinetic sampling and tumor biopsies, when feasible, were conducted. Results: Forty-seven patients were enrolled. Dose-limiting toxicities (grade 3 diarrhea or asthenia) were observed in 1/7 patients at 50 mg EKB-569 and in 2/3 at 75 mg. Two additional dose levels (35 mg EKB-569/day and 50 mg EKB-569/day plus modified FOLFIRI) were evaluated. The RD was 25 mg EKB-569/full dose FOLFIRI. Grades 3 to 4 toxicities in >10% of patients were diarrhea (30%), neutropenia (21%), and asthenia (17%). Twenty-one patients had an objective response [48%; 95% confidence interval (95% CI), 32-65%]. The median time to tumor progression was 7.7 months. At the RD, EKB-569 resulted in complete inhibition of phosphorylated EGFR (pEGFR) and downstream receptor signaling in skin and tumor samples. FOLFIRI alone did not affect pEGFR, but inhibited epidermal proliferation and activated mitogen-activated protein kinase (MAPK) and induced p27 expression in the skin. Conclusion: The RD of EKB-569 is 25 mg/day when combined with FOLFIRI and results in complete EGFR inhibition. Chemotherapy alone interferes with pharmacodynamic markers, an observation to be taken into account in future studies of targeted agents with chemotherapy.

CT findings in metastatic ovarian tumors from gastrointestinal tract neoplasms (Krukenberg tumors)

The computed tomographic (CT) findings are reviewed in 7 patients with metastatic ovarian tumors from gastrointestinal tract neoplasms (Krukenberg tumors). All patients presented mixed ovarian masses. In 6 cases the masses were mainly cystic, with internal septa and focal or uniform enlargement of the cyst wall. In the seventh patient the ovarian mass appeared on the CT as mainly solid. The size of the neoplasm varied between 5 and 46 cm. Ascites was only seen in 1 case and in another the existence of a primary tumor in the sigmoid colon was demonstrated. In our cases the CT signs of ovarian metastasis were indistinguishable from primary tumors of the ovary.

Rationalization of market demand on finite domains

The hypothesis that individuals behave as utility maximizers is the basis of the microeconomic theory of demand. This hypothesis, however, is not observable and therefore its content and strength have to be evaluated through its implications for the properties of demand functions. The implications for the properties of individual demand functions have been well known for some time, but it is only recently that substantial work on the features of aggregate behavior has been undertaken. In 1972 Sonnenschein (6) conjectured that Walras Law, homogeneity of degree zero in prices, and boundedness from below characterize market excess demand functions, i.e., functions defined on a set of normalized price vectors. A succession of papers by Sonnenschein [7], Mantel [4], Debreu [ 11, and MC Fadden et al. [3] established such a result in a variety of precise formulations. After these conributions it could be said that the structure of excess demand functions was well understood. An analogous problem concerning the decomposition of market demand functions, i.e., functions defined on a set of price-income vectors, was also posed by Sonnenschein [8]. By means of a simple example he showed that when the income distribution is constant it is not possible, in general, to decompose functions that satisfy the balance and zero homogeneity conditions if we require postivity of individual demands. He also conjectured that abstracting from restrictions which follow from the positivity of individual demand, any function satisfying the two previously mentioned conditions can be decomposed into a finite number of individual demand functions derived from utility maximization and sharing market income in some fixed proportion. A proof of the conjecture for the case of two commodities was also provided.