Lynn Seely

Antitumour activity of MDV3100 in castration-resistant prostate cancer: a phase 1–2 study

BACKGROUND MDV3100 is an androgen-receptor antagonist that blocks androgens from binding to the androgen receptor and prevents nuclear translocation and co-activator recruitment of the ligand-receptor complex. It also induces tumour cell apoptosis, and has no agonist activity. Because growth of castration-resistant prostate cancer is dependent on continued androgen-receptor signalling, we assessed the antitumour activity and safety of MDV3100 in men with this disease. METHODS This phase 1-2 study was undertaken in five US centres in 140 patients. Patients with progressive, metastatic, castration-resistant prostate cancer were enrolled in dose-escalation cohorts of three to six patients and given an oral daily starting dose of MDV3100 30 mg. The final daily doses studied were 30 mg (n=3), 60 mg (27), 150 mg (28), 240 mg (29), 360 mg (28), 480 mg (22), and 600 mg (3). The primary objective was to identify the safety and tolerability profile of MDV3100 and to establish the maximum tolerated dose. The trial is registered with ClinicalTrials.gov, number NCT00510718. FINDINGS We noted antitumour effects at all doses, including decreases in serum prostate-specific antigen of 50% or more in 78 (56%) patients, responses in soft tissue in 13 (22%) of 59 patients, stabilised bone disease in 61 (56%) of 109 patients, and conversion from unfavourable to favourable circulating tumour cell counts in 25 (49%) of the 51 patients. PET imaging of 22 patients to assess androgen-receptor blockade showed decreased (18)F-fluoro-5alpha-dihydrotestosterone binding at doses from 60 mg to 480 mg per day (range 20-100%). The median time to progression was 47 weeks (95% CI 34-not reached) for radiological progression. The maximum tolerated dose for sustained treatment (>28 days) was 240 mg. The most common grade 3-4 adverse event was dose-dependent fatigue (16 [11%] patients), which generally resolved after dose reduction. INTERPRETATION We recorded encouraging antitumour activity with MDV3100 in patients with castration-resistant prostate cancer. The results of this phase 1-2 trial validate in man preclinical studies implicating sustained androgen-receptor signalling as a driver in this disease. FUNDING Medivation, the Prostate Cancer Foundation, National Cancer Institute, the Howard Hughes Medical Institute, Doris Duke Charitable Foundation, and Department of Defense Prostate Cancer Clinical Trials Consortium.

Effect of dimebon on cognition, activities of daily living, behaviour, and global function in patients with mild-to-moderate Alzheimer's disease: a randomised, double-blind, placebo-controlled study

BACKGROUND Although treatments for Alzheimers disease sometimes improve cognition, functional ability, or behaviour compared with baseline levels, such improvements are inconsistent across studies and measures, and effects diminish over time. More effective treatments are needed. We assessed the safety, tolerability, and efficacy of dimebon in the treatment of patients with mild-to-moderate Alzheimers disease. METHODS We enrolled 183 patients with mild-to-moderate Alzheimers disease (mini-mental state examination [MMSE] scores 10-24) at 11 sites in Russia. Patients were randomly assigned by a computer-generated randomisation scheme to receive oral dimebon, 20 mg three times a day (60 mg/day [n=89]), or matched placebo (n=94). Other antidementia drugs were not allowed. The primary outcome measure assessed cognition, the difference in mean change from baseline to week 26, or last completed observation on the cognitive subscale of the Alzheimers disease assessment scale (ADAS-cog). All patients and study personnel were blinded throughout the study. We compared dimebon with placebo with an intention-to-treat analysis, with last observation carried forward (ITT-LOCF) imputation. Analyses were repeated on the fully evaluable population, defined as all patients in the intention-to-treat population who had an ADAS-cog at week 26 and at least 80% compliance. 134 patients (68 in dimebon group, 66 in placebo group) enrolled in the 6-month blinded extension phase of the study. This trial is registered with Clinicaltrials.gov, number NCT00377715. FINDINGS 155 (85%) patients completed the trial (78 [88%] in dimebon group, 77 [82%] in placebo group). Treatment with dimebon resulted in significant benefits in ADAS-cog compared with placebo (ITT-LOCF) at week 26 (mean drug-placebo difference -4.0 [95% CI -5.73 to -2.28]; p<0.0001). Results of the ITT-LOCF and the evaluable population analyses were much the same for all measures. Patients given dimebon were significantly improved over baseline for ADAS-cog (mean difference -1.9 [-2.92 to -0.85]; p=0.0005). Dimebon was well tolerated: dry mouth and depressed mood or depression were the most common adverse events associated with dimebon (12 [14%] patients for each symptom by week 26). The percentage of patients who had adverse events in the two groups did not differ. INTERPRETATION Dimebon was safe, well tolerated, and significantly improved the clinical course of patients with mild-to-moderate Alzheimers disease.

Results from CONNECTION: A global, Phase 3 double-blind, placebo-controlled confirmatory trial of dimebon (latrepirdine) in patients with mild-to-moderate Alzheimer's disease

not available S4-01-04 PHASE IIA CLINICAL TRIAL ON ALZHEIMER’S DISEASE WITH NP12, A GSK3 INHIBITOR Teodoro del Ser, Noscira, Tres Cantos, Madrid, Spain. Contact e-mail: tdelser@noscira.com Background: Glycogen Synthase Kinase-3 (GSK-3) plays a major role in the physiopathology of Alzheimer’s disease (AD) and its inhibition is expected to slow down the neurodegenerative process. The thiadiazolidindione NP-12 (Tideglusib, Nypta ), a non-ATP competitive GSK-3 inhibitor, has been examined in a pilot, 20 week, doubleblind, placebo-controlled, randomized, escalating dose, clinical trial in AD patients. Methods: Thirty male and female mild to moderate AD patients (Mini Mental State Examination (MMSE) 16 to 26), under stable and well tolerated anticholinesterasic treatment, were orally administered escalated doses of 400, 600, 800 and 1000 mg of NP-12 or placebo (ratio 2:1) for successive periods of 4, 4, 6 and 6 weeks respectively. The Primary Objective was to evaluate the safety and tolerability of NP12 and strict criteria for dose escalation and drug withdrawal were stated. The effects of NP12 on cognition (MMSE, ADAS-cog, Word fluency), depressive mood (Geriatric Depression Scale) and Global Clinical Assessment were examined as Secondary Objectives by means of ANCOVA or Responder analyses. Results: The incidence of adverse events was similar in both treatment groups; however, they were more commonly drug-related in Active (65%) than in Placebo group (30%). Drug treatment was discontinued in 35% Active cases, mostly due to the restrictive safety rules stated in the Protocol (moderate, asymptomatic and fully reversible increases of transaminases in 30% of cases), and in 10% Placebo cases. The frequency of responders in MMSE was significantly higher in the Active group and positive effects were observed in four (MMSE, ADAS-cog, GDS and GCA) out of five efficacy variables, although the small sample size precluded to reach statistical significance. The magnitude of these effects was consistently higher in moderate cases. Conclusions: This pilot study has provided valuable safety information about treatment of AD patients with NP12. Only efficacy estimates have been obtained due to the small sample size and the dose escalating design. The current results are promising and support further more extended clinical investigations. S4-01-05 NORADRENERGIC MECHANISMS IN THE BEHAVIORAL AND COGNITIVE SYMPTOMS IN ALZHEIMER’S DISEASE Elaine R. Peskind, University of Washington School of Medicine, Seattle, WA, USA. Contact e-mail: peskind@u.washington.edu Abstract not availablenot available S4-01-06 LOCAL DELIVERY OF NGF TO BASAL FOREBRAIN IN AD PATIENTS Maria Eriksdotter Jonhagen, Karolinska Institutet, Stockholm, Sweden. Contact e-mail: maria.eriksdotter.jonhagen@ki.se

Abstract CN02-03: Circulating tumor cells as biomarkers in the development of the androgen receptor antagonist, MDV3100

Background: Selecting targeted therapies and assessing outcome in patients (pts) with castration‐resistant prostate cancer (CRPC) are significant unmet medical needs. A proportion of CRPC remains dependent on androgen receptor (AR) activation. MDV3100, a second‐generation AR antagonist optimized from a screen for nonsteroidal antiandrogens that retain activity in the setting of increased AR expression blocks nuclear translocation of AR and DNA binding and has no known agonist activity when AR is overexpressed. Methods: Pts with progressive CRPC were enrolled in sequential cohorts of 3–6 pts at 30, 60, 150, 240, 360, 480 and 600 mg/day. Once the safety of a dose was established, enrollment was expanded at doses >60 mg/day to include 12 chemotherapy‐naive and 12 post‐chemotherapy pts per cohort. Antitumor effects were assessed using the Prostate Cancer Working Group (PCWG) 2 criteria reporting post‐therapy PSA changes from baseline, and radiologic imaging for soft‐tissue disease by RECIST and osseous disease on radionuclide bone scan as improved, progressed or no change. Circulating tumor cell (CTC) enumeration was performed with the FDA cleared analytically valid CellSearch assay (Veridex, LLC, Huntingdon Valley, PA) and reported as the number of cells per 7.5 ml of blood as previously described. Samples were collected at baseline, 4 weeks, and 12 weeks post‐treatment and at progression of disease. Samples from outside Center were shipped overnight and processed in the CLIA certified MSKCC Clinical Chemistry laboratory. Results: A total of 140 pts were enrolled, of which 65 (46%) were chemotherapy‐naive, and 75 pts (54%) were in post‐chemotherapy setting. Maximal PSA decline from baseline of ≥ 50% was achieved in 40/65 (62%) chemotherapy‐naive and 38/75 (51%) post‐chemotherapy. At 12 weeks, radiographic control (no progression) was observed in 35/47 pts (74%) with evaluable soft tissue lesions per PCWG2 guidelines and 50/81 pts (62%) with bone lesions. At 600 mg/day, 2 of 3 pts had dose limiting toxicity (rash; seizure). Dose reductions due to fatigue were noted at 480 and 360 mg/day. The maximal tolerated dose was 240mg daily based on safety data. CTC counts were obtained from 128/140 (91%) pts enrolled; 16/60 pts chemotherapy‐naive and 35/68 pts post‐chemotherapy had ≥ 5 CTC/7.5 mL blood at baseline. CTC conversion from baseline CTC ≥ 5 (unfavorable) to CTC Conclusions: MDV3100 demonstrated favorable efficacy assessed by prostate‐specific antigen (PSA) decline and CTC enumeration. The efficacy comparable to that at higher doses and the better adverse event profile, led to the selection of 160 mg/day as the recommended dose for future studies. A prospective investigation of pre and post‐therapy CTC counts and clinical outcomes in a phase III randomized, double‐blind, placebo‐controlled efficacy trial of MDV3100 has been recently initiated. Citation Information: Mol Cancer Ther 2009;8(12 Suppl):CN02-03.

Conducting an Alzheimer's clinical trial in Russia

not available. F5-02-03 CELL CYCLE AND NEURODEGENERATION IN FLY Mel B. Feany, Harvard Medical School, Boston, MA, USA. Contact e-mail: mel_feany@hms.harvard.edu Background: Drosophila models of human neurodegenerative diseases, including Alzheimer’s disease have been useful in dissecting molecular pathways of neurotoxicity. Methods: We have used a Drosophila model of Alzheimer’s disease and related tauopathies based on expression of human tau to test the role of abnormal cell cycle activation in mediating neurodegeneration. Results: Genetic manipulations that activate cell cycle promote neurodegeneration in our model. Conversely, genetic and pharmacological interventions aimed a blocking cell cycle activation and progression reduced neurodegeneration. Conclusions: Results from our genetic model support a causative role for cell cycle activation in mediating death of postmitotic neurons in response to abnormal tau accumulation. F5-02-04 ALZHEIMER AND TAUOPATHIES Luc Buee, CNRS, Lille, France. Contact e-mail: buee@lille.inserm.fr Abstract not available.not available. F5-02-05 CELL DIVISION IN CNS Karl Herrup, Rutgers University, Piscataway, NJ, USA. Contact e-mail: herrup@biology.rutgers.edu Abstract not available.not available. F5-02-06 THE DYSREGULATION OF THE G1/S TRANSITION POINT IN ALZHEIMER’S DISEASE Zsuzsanna Nagy, University of Birmingham, Birmingham, United Kingdom. Contact e-mail: z.nagy@bham.ac.uk Background: The cell cycle hypothesis for the pathogenesis of Alzheimer’s disease postulates that the development of the disease-specific pathology and associated cell death is the results of neuronal cell cycle re-entry and subsequent regulatory failure at the G1/S transition point. Many identified risk factors of AD, such as elevated plasma homocysteine levels ageing menopause low level prolonged oxidative stress, can potentially represent the mitogenic stimulus necessary to trigger the cell cycle in neurons. However, while cell cycle re-entry of neurons appears to be a prerequisite of Alzheimer’s disease, on its own is not sufficient to cause the disease. The difference between the healthy aging and AD is the extent of cell cycle progression following cell cycle re-entry. Thus the transition from healthy ageing to AD is the point when neurons bypass the G1/S restriction point. There is increasing evidence suggesting that this cell cycle regulatory failure in AD is not restricted to neurons. Methods: Peripheral blood lymphocytes from AD patient (probable AD), control subjects and patients who fulfill the criteria for mild cognitive impairment (MCI) were cultured with PHA and treated with rapamycin. The effect of rapamycin on the G1/S transition was quantified using flow cytometry. Results: We have found that the response to rapamycin was a significantly stronger in control subjects than in AD patients. The rapamycin response discriminates between the two groups with 80% sensitivity and 80% specificity. We have also found that 40% of the MCI patients show a regulatory deficit similar to AD patients. Conclusions: Our study indicates that the detection of the G1/S regulatory failure from peripheral lymphocytes may represent an early biomarker of Alzheimer’s disease. We believe that our novel biomarker would allow the early identification of MCI patients who will develop dementia later. Featured Research Symposia F5-02: Dysregulation of Cell Cycle in the Pathogenesis of Alzheimer’s Disease P171