Dose-proportional Increases In Cmax Research Articles

Pharmacokinetics (PK) and Pharmacodynamics (PD) of Dapagliflozin (DAPA) in Combination with Insulin in Japanese Patients with T1D

This study evaluated the PK/PD of DAPA, a selective SGLT2 inhibitor, in Japanese T1D patients with poor glycemic control (A1C 7-10%; NCT02582840). Patients were randomized 1:1:1 to DAPA 5 mg, 10 mg or placebo (PBO; n=14 each) once daily for 7 days with adjustable insulin. Mean (SD) age was 39 (10) years, mean (SD) T1D duration was 16 (11) years and mean (SD) A1C was 8.0 (0.7)%. DAPA added to insulin resulted in dose-proportional increase in Cmax and AUCτ (Figure). Mean (SD) changes in 24h urinary glucose excretion (UGE) from baseline (BL) to Day 7 were 96.55 (30.08), 101.28 (20.13) and -6.16 (30.34) g/24h for DAPA 5 mg, 10 mg, and PBO, respectively, consistent with previous DAPA experience but with attenuated dose-response. Mean (SE) changes in total daily insulin dose from BL to Day 7 were larger than expected; -36.86 (3.32), -39.13 (2.68) and -4.97 (5.28)% for DAPA 5 mg, 10 mg and PBO, respectively. This reduction may be responsible for the attenuated glycemic response affecting UGE (explored in a separate abstract); mean (SD) changes in 7-point SMBG values from BL to Day 7 were -1.99 (23.58), -5.68 (40.36) and 6.54 (52.69) mg/dL for DAPA 5 mg, 10 mg and PBO, respectively. No DKA was reported. Adverse events and other laboratory findings were in line with the known DAPA safety profile; there was no increase in hypoglycemia. DAPA may be a clinically relevant adjunctive therapy for patients with T1D. Disclosure H. Watada: Advisory Panel; Self; AstraZeneca. Consultant; Self; Astellas Pharma US, Inc., AstraZeneca, Boehringer Ingelheim GmbH, Daiichi Sankyo Company, Limited, Sumitomo Dainippon Pharma Co., Ltd., Eli Lilly and Company, Kissei Pharmaceutical Co., Ltd., Kowa Pharmaceuticals America, Inc., Kyowa Hakko Kirin Co., Ltd., Merck Sharp & Dohme Corp., Mitsubishi Tanabe Pharma Corporation, Novo Nordisk A/S, Novartis AG, Ono Pharmaceutical Co., Ltd., Sanofi, Sanwa Kagaku Kenkyusho Co., Ltd., Takeda Development Center Asia, Pte. Ltd.. Research Support; Self; Abbott, Astellas Pharma US, Inc., AstraZeneca, Bayer AG, Benefit One Health Care Co., Ltd., Boehringer Ingelheim GmbH, Bristol-Myers Squibb Company, Daiichi Sankyo Company, Limited, Sumitomo Dainippon Pharma Co., Ltd., Eli Lilly and Company, Kissei Pharmaceutical Co., Ltd., Kowa Pharmaceuticals America, Inc., Kyowa Hakko Kirin Co., Ltd., Johnson & Johnson Diabetes Institute, LLC., Merck Sharp & Dohme Corp., Mitsubishi Tanabe Pharma Corporation, Mochida Pharmaceutical Co., Ltd., Nitto Boseki Co., Ltd., Novartis AG, Novo Nordisk A/S, Ono Pharmaceutical Co., Ltd., Pfizer Inc., Sanofi, Sanwa Kagaku Kenkyusho Co., Ltd., Taisho Pharmaceutical Co., Ltd., Takeda Development Center Asia, Pte. Ltd., Terumo Medical Corporation. M. Shiramoto: None. S. Ueda: Employee; Self; AstraZeneca. W. Tang: Employee; Self; AstraZeneca. M. Asano: None. F.A. Thoren: Employee; Self; AstraZeneca. H. Kim: Employee; Self; AstraZeneca. Stock/Shareholder; Self; AstraZeneca. T. Yajima: Employee; Self; AstraZeneca. D.W. Boulton: Employee; Self; AstraZeneca. Stock/Shareholder; Self; Bristol-Myers Squibb Company. E. Araki: Speaker's Bureau; Self; Astellas Pharma US, Inc., MSD K.K., Kowa Pharmaceuticals America, Inc., Sanofi, Novo Nordisk Inc.. Research Support; Self; Astellas Pharma US, Inc., MSD K.K., Ono Pharmaceutical Co., Ltd., Shionogi & Co., Ltd., Takeda Pharmaceuticals U.S.A., Inc., Daiichi Sankyo Company, Limited, Nippon Boehringer Ingelheim Co. Ltd., Novartis Pharma K.K., Novo Nordisk Inc., Sanofi, Mitsubishi Tanabe Pharma Corporation, Sumitomo Dainippon Pharma Co., Ltd., Taisho Toyama Pharmaceutical Co..

Pharmacodynamics, Pharmacokinetics, Safety, and Tolerability of Encenicline, a Selective α7 Nicotinic Receptor Partial Agonist, in Single Ascending-dose and Bioavailability Studies

PurposeEncenicline (EVP-6124) is a selective α7 nicotinic acetylcholine receptor partial agonist being developed for cognitive impairment in Alzheimer’s disease and schizophrenia. We report on 2 single-dose studies to assess the relative bioavailability, pharmacokinetic profile, tolerability, and cognitive effects of encenicline in healthy volunteers. MethodsA single ascending-dose study assessed the safety, tolerability, pharmacokinetic, and pharmacodynamic profiles of encenicline in healthy male volunteers. Subjects received a single 1-, 3.5-, 7-, 20-, 60-, or 180-mg oral solution dose of encenicline or placebo. A second single-dose, randomized, open-label, 3-period, crossover study in healthy male and female subjects compared the relative bioavailability of a 1-mg oral capsule versus a 1-mg oral solution dose of encenicline and evaluated the effects of food and sex on encenicline pharmacokinetic profile. FindingsIn the first study, encenicline was well tolerated and dose-proportional increases in Cmax (mean range 0.59−100 ng/mL) and AUC0−∞ (mean range 45.6−8890 ng·h/mL) were observed over a 1- to 180-mg dose range. Procognitive effects on the Digit Symbol Substitution Test were maximal at the 20-mg dose. In the second study, encenicline 1-mg oral capsules and oral solution were bioequivalent and there was no observed food effect on encenicline pharmacokinetic profile with the 90% confidence intervals of the treatment ratios for both comparisons (ie, capsule to solution and fed to fasted) for Cmax and AUC being within 80% to 125%. A 30% to 40% higher encenicline exposure in female subjects than respective values in male subjects was consistent with a 33% higher weight of the male subjects. No clinically relevant safety profile or tolerability effects of encenicline were observed. ImplicationsEncenicline was well tolerated at single doses up to 180 mg, and doses as low as 1 mg had dose- and time-dependent pharmacodynamic effects on the central nervous system. Oral capsule and solution were bioequivalent and were not affected by food. Although a sex effect on pharmacokinetic profile was observed, it was attributable to weight differences. Clinical Trial Registration at EudraCT: 2006-005623-42 and EudracT: 2008-000029-20.

Preliminary Evidence Of Anti Tumor Activity Of Selinexor (KPT-330) In a Phase I Trial Ofa First-In-Class Oral Selective Inhibitor Of Nuclear Export (SINE) In Patients (pts) With Relapsed / Refractory Non Hodgkin's Lymphoma (NHL) and Chronic Lymphocytic Leukemia (CLL)

BackgroundExportin 1 (CRM1/XPO1) is the exclusive transporter of the majority of Tumor Suppressor Proteins (TSP) out of the nucleus, rendering these TSPs non-functional. Selinexor (KPT-330) is a potent, oral SINE XPO1 antagonist, forcing the nuclear retention and activation of >10 TSPs resulting in NHL and CLL cell death in vitro, while sparing normal lymphocytes and other hematopoietic cells. Oral Selinexor has marked activity in murine models of NHL and CLL including R-CHOP resistant tumors. Dogs with spontaneous B- and T-cell lymphomas exposed to the related SINE Verdinexor demonstrate potent anti tumor effect and good tolerability. MethodsPatients (pts) with advanced NHL or CLL relapsed/refractory to all available drug classes were dosed with oral Selinexor (8-10 doses / 4-week cycle) as part of a Phase 1 trial in hematological malignancies (NCT01607892). Detailed pharmacokinetic (PK) and pharmacodynamic (PDn) analyses and serial tumor biopsies were obtained. Response evaluation was performed every cycle. Results18NHL/CLL pts with median age 66.5yrs; ECOG PS 0/1: 8/10; median number of prior regimens: 4.5 [range 2-11], received KPT-330 across 6 dose levels (3 to 30 mg/m2). Ten pts experienced drug-related grade 3/4 Adverse Events (AEs) including thrombocytopenia without bleeding (n=6), neutropenia (n=5), dehydration (n=1), syncope (n=1), hypotension (n=1), fatigue (n=1). The most common grade 1/2 toxicities were: anorexia (10/18pts; 56%), fatigue (9/18; 50%), diarrhea (6/18; 33%), vomiting (6/18; 33%), neutropenia (5/18; 28%), malaise (3/18; 17%), anemia (3/18; 17%) and weight loss (3/18; 17%). These adverse events were manageable with supportive care. 23mg/m2, one case of Grade 4 thrombocytopenia for >5 days without bleeding was reported as a DLT for the cohort; this patient with refractory follicular NHL was continued on therapy at the same dose and schedule with intermittent platelet support with SD for 83 days on study.Dose escalation continues.There were no clinically significant cumulative toxicities or major organ dysfunction and pts have remained on therapy for ≥6 cycles. Maximum tolerated dose has not been reached; dosing at 35 mg/m2 twice weekly is ongoing.PK analysis at doses of 3-35 mg/m2demonstrated a dose proportional increase in Cmax and AUC with increasing dose. Elimination half-life was independent of dose and ranged from 4.7-7.0 hours. Significant increases (2-20x) in total leukocyte XPO1 mRNA levels (PDn marker) were observed at all doses, with higher doses demonstrating higher levels of XPO1 mRNA induction.Evaluation of lymph node biopsies from 2 pts confirms Selinexor-induced nuclear localization of multiple TSPs as well as apoptosis of tumor cells. Response was evaluable in 15pts; Selinexor treatment induced tumor shrinkage or disease stabilization in 80%(n=12) of pts with relapsed/refractory NHL/CLL who had progressive disease on study entry (Figure 1). 20% (n=3) of pts had clinical progression. One patient with ibrutinib-refractory CLL with Richter's transformation who progressed on chemotherapy achieved a rapid 60% reduction in lymph nodes in Cycle 1 and was referred for transplantation. A patient with DLBCL refractory to R-CHOP and bone marrow transplantation achieved a near CR (93% tumor shrinkage) and remains on study >11 months. [Display omitted] ConclusionsOral Selinexor is generally well tolerated, with favorable PK andPDn parameters. In this cohort of heavily pretreated, refractory/refractoryNHLand CLL with progressive disease on study entry, single agent oral Selinexor induced tumor shrinkage in the majority of pts. Disclosures:Kuruvilla:Seattle Genetics: Consultancy, Honoraria, Research Funding; Hoffman LaRoche: Consultancy, Honoraria, Research Funding; Janssen: Honoraria; Celgene: Consultancy, Honoraria; Lundbeck: Consultancy, Honoraria; Karyopharm: Research Funding. Shah:Seattle Genetics, Inc.: Research Funding; NCCN: Membership on an entity's Board of Directors or advisory committees; SWOG: Membership on an entity's Board of Directors or advisory committees; Celgene: Speakers Bureau; Janssen/Pharmacyclics: Speakers Bureau. Garzon:Karyopharm: Research Funding. Siegel:Celgene, Millennium, Onyx: Honoraria, Speakers Bureau. Baz:Sanofi: Research Funding; Karyopharm: Research Funding; Novartis: Research Funding; Bristol Myers Squibb: Research Funding; Millenium: Research Funding; Celgene: Research Funding. Shacham:Karyopharm Therapeutics Inc.: Employment, Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties. Rashal:Karyopharm Therapeutics: Employment, Equity Ownership. Yau:NPM Pharma Inc: NPM Pharma hired Ozmosis Research as CRO for this trial Other. McCauley:Karyopharm Therapeutics: Employment, Equity Ownership, Patents & Royalties. Saint-Martin:Karyopharm Therapeutics: Employment, Equity Ownership. McCartney:Karyopharm Therapeutics: Employment, Equity Ownership. Landesman:Karyopharm Therapeutics: Employment. Klebanov:Karyopharm Therapeutics: Employment. Pond:Ozmosis Research: Consultancy. Kauffman:Karyopharm Therapeutics Inc.: Employment, Equity Ownership, Membership on an entity's Board of Directors or advisory committees. Mirza:Karyopharm Therapeutics: Consultancy, Equity Ownership, Membership on an entity's Board of Directors or advisory committees.

Abstract LB-66: Results of two phase I multicenter trials of AZD5363, an inhibitor of AKT1, 2 and 3: Biomarker and early clinical evaluation in Western and Japanese patients with advanced solid tumors .

Abstract Background: AZD5363 is an oral, potent, and selective inhibitor of AKT1, 2 and 3, with activity in a wide range of tumor cell lines and xenografts dependent upon PI3K/AKT signaling. Methods: Two phase I studies (NCT01226316 [West], NCT01353781 [Japan]) were initiated to define the toxicity, pharmacokinetic (PK), and pharmacodynamic (PD) profile of AZD5363. Two schedules, continuous bid dosing (7/7) and an intermittent schedule bid dosing 4 days on 3 days off (4/7), were investigated. PD biomarkers of AKT signaling were assessed (using pre- and on-treatment samples) in plasma (pPRAS40, pGSK3β, pAKT, glucose, insulin), plucked hair (pPRAS40) and tumor tissue (pPRAS40, pGSK3β, pAKT). Results: At data cut-off (January 2013), 92 patients had been treated in the dose-escalation phases of both studies. In the Western study, the maximum tolerated dose (MTD) for each schedule was 320 mg bid (7/7) and 480 mg bid intermittent dosing (4/7). In the Japanese study, 320 mg bid (7/7) was not tolerated; the MTD for intermittent dosing (4/7) was 480 mg bid. The most commonly reported adverse events, of note, were hyperglycemia, rash, and diarrhea. The PK profile suggests a dose proportional increase in Cmax and AUC. Exposures achieved at doses of 320 mg bid (7/7) and 480 mg bid (4/7) and above are consistent with activity seen in xenograft models. At the doses described, target engagement was seen as evidenced by PD changes in normal tissue (>50% reduction in pPRAS40 in 7/10 patients on AZD5363 480 mg bid (4/7) in plucked hair samples and 30-50% reduction in pPRAS40 and >30% reduction in pGSK3β in platelet rich plasma). Importantly, 7/9 paired biopsies showed an increase in pAKT consistent with the non allosteric inhibition of AKT. Investigation of another intermittent schedule of AZD5363 bid, 2 days on/5 days off treatment, is ongoing. Exploratory mutation analyses of plasma samples are ongoing. Two partial responses were observed, one endometrioid cancer of the ovary and one cervical cancer, in patients on AZD5363 at 480 mg bid (4/7) and 400 mg bid (7/7), respectively. Mutation of either AKT1 or PIK3CA was identified in tumor tissue from both patients. A further patient, with endometrioid cancer of ovary (PIK3CA mutation), had stable disease (SD) for 156 days. Conclusions: AZD5363 administered at 480 mg bid (4/7) was generally well tolerated and showed a PK and PD profile consistent with activity in preclinical models. Partial responses were noted in patients with mutations driving the PI3K pathway. Footnote: AZD5363 was discovered by AstraZeneca subsequent to collaboration with Astex Therapeutics (and its collaboration with the Institute of Cancer Research and Cancer Research Technology Ltd). Citation Format: Udai Banerji, Malcolm Ranson, Jan HM Schellens, Taito Esaki, Emma Dean, Andrea Zivi, Ruud van der Noll, Paul K. Stockman, Marcelo Marotti, Michelle D. Garrett, Barry R. Davies, Paul Elvin, Andrew Hastie, Peter Lawrence, SY Amy Cheung, Christine Stephens, Kenji Tamura. Results of two phase I multicenter trials of AZD5363, an inhibitor of AKT1, 2 and 3: Biomarker and early clinical evaluation in Western and Japanese patients with advanced solid tumors . [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr LB-66. doi:10.1158/1538-7445.AM2013-LB-66

Pharmacokinetics, Pharmacodynamics, and Tolerability of ACT-077825, a New Direct Renin Inhibitor After Multiple-ascending Doses in Healthy Subjects

This study was conducted to characterize the multiple-dose tolerability, pharmacokinetics, and pharmacodynamics of ACT-077825, a new direct renin inhibitor, in healthy male subjects. In this single-center, double-blind, placebo-controlled, active-controlled (20 mg of enalapril), randomized multiple-ascending dose study, ACT-077825 was administered once a day. for 7 days in the 50-1000 mg dose range to sodium- and potassium-restricted subjects. ACT-077825 pharmacokinetics on days 1 and 7 were characterized by dose-proportional increases in Cmax and AUCτ. At steady state, accumulation was modest (1.5- to 1.7-fold). Enalapril caused an increase in plasma active renin concentration and plasma renin activity (PRA). ACT-077825 dose dependently increased active renin on days 1 and 7 and inhibited PRA dose dependently only on day 1. On day 7, the maximal PRA inhibition was attained after 250 mg of ACT-077825. In contrast to enalapril, ACT-077825 did not induce any consistent lowering effect on blood pressure when compared with placebo. Of the reported adverse events, diarrhea, headache, and postural dizziness were more frequent. The incidence of diarrhea was greater in the 1000-mg group and a dose of 500 mg of ACT-077825 was identified as the maximum tolerated dose. Overall, pharmacokinetic, pharmacodynamic, and tolerability profiles warrant the further investigation of ACT-077825 in patients with hypertension.

Pharmacokinetic Properties of Mirabegron, a β3-Adrenoceptor Agonist: Results From Two Phase I, Randomized, Multiple-Dose Studies in Healthy Young and Elderly Men and Women

BackgroundMirabegron (YM178) is a β3-adrenoceptor agonist for the treatment of overactive bladder (OAB). As part of the clinical development program for mirabegron, 2 human volunteer studies were performed to derive detailed data on the multiple-dose pharmacokinetic (PK) properties of mirabegron. ObjectiveTwo randomized Phase I studies were conducted to evaluate the PK properties of mirabegron, including metabolic profile and effects of age and sex, following multiple oral doses in healthy subjects. MethodsIn study 1, mirabegron oral controlled absorption system (OCAS) tablets were administered once daily to healthy young subjects (18–55 years) at doses of 50, 100, 200, and 300 mg and in elderly subjects (65–80 years) at 50 and 200 mg in a double-blind placebo-controlled, parallel-group design. In study 2, mirabegron OCAS was administered once daily to healthy young (18–45 years) and older (≥55 years) subjects at doses of 25, 50, and 100 mg in an open-label crossover design. Blood samples were collected up to 72 hours (study 1) and 168 hours (study 2) after the last dose. Urine samples were collected up to 24 hours after the last dose. Plasma and urine concentrations of mirabegron and its metabolites (study 2 only) were analyzed by LC-MS/MS. PK parameters were determined using noncompartmental methods. Tolerability assessments included physical examinations, supine blood pressure and pulse rate, orthostatic stress testing (study 1), resting 12-lead ECGs, clinical laboratory tests (biochemistry, hematology, and urinalysis), and adverse-events (AE) monitoring using investigators' questionnaires and subjects' spontaneous reports. ResultsThirty-two young male (mean age, 30.3 years; mean weight, 77.1 kg), 32 young female (27.6 years; 64.6 kg), 16 elderly male (69.8 years; 79.3 kg), and 16 elderly female (68.1 years; 67.4 kg) subjects were enrolled in study 1. Eighteen young male (mean age, 28.6 years; mean weight, 68.9 kg), 18 young female (28.7 years; 58.8 kg), 21 older male (63.4 years; 72.6 kg), and 18 older female (65.1 years; 62.3 kg) subjects were enrolled in study 2. Most of the subjects were white (91% in study 1 and 88% in study 2). Mirabegron plasma concentrations peaked at ∼3 to 5 hours and declined multiexponentially with a t▪ of ∼32 hours in study 1 and 60 hours in study 2. Steady state was achieved within 7 days of once daily administration, with an accumulation ratio of ∼2. Mirabegron and its metabolites demonstrated a greater–than–dose-proportional increase in Cmax and AUC0–τ after multiple-dose administration. Two major circulating metabolites were observed, representing 17% and 10% of total drug-related AUC0–τ. Excretion of unchanged mirabegron in urine over the 24-hour dosing interval (Ae0–τ%) increased from approximately 7% at 25 mg to 18% at 300 mg once daily in young subjects. Renal clearance (CLR) of mirabegron was independent of dose and averaged ∼13 L/h. Mirabegron Cmax and AUC0–τ were similar in older and young subjects. Women exhibited ∼40% higher mirabegron Cmax and AUC0–τ than men; weight-corrected values were ∼20% higher in women. Mirabegron was generally well tolerated up to 300 mg once daily. No clear trends for increased incidence of AEs occurred with higher doses of mirabegron. The AE with the highest incidence was headache. ConclusionOral mirabegron exhibited a greater–than–dose-proportional increase in exposure. Sex but not age significantly affected mirabegron exposure. ClinicalTrials.gov identifier: NCT01478503 (Study 1) and NCT01285596 (Study 2).

Clinical pharmacokinetics (PK) of BMS-936558, a fully human anti-PD-1 monoclonal antibody.

TPS2622 Background: BMS-936558 is a fully human IgG4 monoclonal antibody targeted against human Programed Death-1 (PD1) receptor on activated T and B lymphocytes. Blocking of PD-1 prevents these activated cells from becoming anergic, thereby maintaining anti-tumor immunologic activity. Methods: The PK of BMS-936558 was characterized with data from a single ascending dose (SAD) and a multiple ascending dose (MAD) study in subjects with advanced solid malignancies. Subjects received a single IV infusion of 0.3 to 10 mg/kg BMS-936558 in the SAD study (MDX-1106-01 Study) and 0.1 to 10 mg/kg BMS-936558 every two weeks in the MAD study (MDX-1106-03/CA209003 Study). The PK of BMS-936558 was characterized by non-compartmental analysis of intensively sampled PK data from a SAD study, as well as by population PK analysis of available intensive and sparse PK data from the SAD and MAD studies, respectively. Results: The PK of BMS-936558 is linear in the studied dose range with dose-proportional increase in Cmax and AUC with low to moderate (20-44%) inter-subject variability. Geometric mean clearance ranged from 0.13 - 0.19 mL/h/kg, whereas mean volume of distribution ranged from 83 -113 mL/kg. The range of mean terminal elimination half-life of BMS-936558 is 17 to 25 days which is consistent with half-life of endogenous IgG4. BMS-936558 PK was adequately described by a linear two-compartment model, and there was no evidence of a contribution of target mediated drug disposition to drug elimination within tested dose range. Body weight and gender are potentially clinically significant covariate for both clearance and volume of distribution (> 20% effect); and baseline CRP, LDH, and albumin are potentially clinically significant covariates for CL. The body weight normalized dosing employed produces trough concentrations that are approximately constant over a wide range of body weights. Conclusions: The pharmacokinetics of BMS-936558 is dose-proportional and body weight normalized dosing is appropriate to ensure consistent exposure over a wide range of body weights.

Single- and multiple-dose safety, tolerability and pharmacokinetics of a Novel 5HT6 receptor full antagonist (SAM-760) for the treatment of the symptoms of Alzheimer's disease in healthy young adults and elderly subjects

Preclinical and preliminary clinical studies suggest that blocking 5 hydroxytrypamine receptors[5-HT6R] improves cognition and promotes synaptic plasticity by releasing acetylcholine and glutamate. Alzheimer's disease (AD) is partly characterized by deficits in these neurotransmitters. Antagonism of 5-HT6R, specifically brain localized, may result in less peripheral side effects than existing AD treatments. Ascending single oral doses 0.25-70 mg SAM-760 were administered to young subjects and multiple doses 1.5-30 mg and 10-20 mg to young and elderly subjects, respectively, using a randomized, double-blind, sponsor un-blinded, placebo-controlled, sequential dose study design. Additional cohorts in the SAD study included: elderly (10 mg SAM-760), food effect (10 mg SAM-760) and ketoconazole interaction (5 mg SAM-760; 400 mg ketoconazole). Study assessments consisted of safety, tolerability SAM-760 pharmacokinetics (plasma and urine). SAM-760 was safe and well tolerated as a single oral dose up to 70 mg in young subjects, at 10 mg in elderly and as multiple oral doses (QD 14 days) up to 30 mg and 20 mg in young and elderly subjects, respectively. There were no dose-limiting adverse events (AE). The most frequently reported treatment emergent AEs was headache. There were no subjects withdrawn for safety reasons, serious adverse events or deaths. SAM-760 exhibited dose proportional increases in Cmax and AUC0-INF for single doses up to 60 mg (young). Mean accumulation was 3.2-fold for AUC0-TAU and 2.7-fold for Cmax after 14-days of daily dosing, with approximate steady state exposure being reached following 7-days. SAM-760 elimination was similar in young and elderly subjects (t1/2 of approximately 32 hr) . Co-administration of ketoconazole with a single dose of SAM-760 increased AUC0-INF and Cmax, by 38% and 32%, respectively. There was no detectable PK food effect. SAM-760 was safe and well tolerated as a single and multiple oral dose over the dose ranges tested in healthy young and elderly subjects. SAM-760 exhibits linear PK for single doses up to 60 mg, with an accumulation of approximately 3-fold following multiple dose administration. SAM-760 elimination was comparable between healthy young and elderly subjects.

Abstract 1304: Clinical pharmacokinetics of GDC-0973, an oral MEK inhibitor, in cancer patients: data from a Phase 1 study

Abstract Background: GDC 0973 is a potent, selective, orally administered MEK1/2 inhibitor. It has shown antitumor activity in preclinical models. A first-in-human, phase 1 dose escalation study in cancer patients was conducted using a 3+3 design with two dosing schedules, followed by an expansion at the MTD for each dosing schedule. The pharmacokinetic objective was to evaluate GDC-0973 PK in patients on both dosing schedules. Methods: GDC-0973 was administered orally, once daily on a 21 day on/7 day off (21/7) or on a 14 day on/14 day off (14/14) dosing schedule. Plasma samples for PK analysis were collected on Day 1 and Day 21 (for 21/7) or Day 14 (14/14) of Cycle 1, and during the dosing holiday to determine half-life of GDC-0973. Urine samples were collected on Day 1 and on Day 21 (21/7) or Day 14 (14/14) over a 24-hour period for exploratory analysis. Plasma samples were analyzed using a validated LC/MS/MS method. GDC-0973 pharmacokinetic data was analyzed using a non-compartmental approach with the program WinNonlin. Results: GDC-0973 pharmacokinetics was evaluated at doses administered in the 21/7 schedule (0.05, 0.1 and 0.2 mg/kg in a liquid solution and 10, 20, 40, 60, and 80 mg as capsules) and the 14/14 schedule (60, 80, 100 and 125 mg as capsules). Pharmacokinetic data was available in 41 patients on the 21/7 and 11 patients on the 14/14 schedule. GDC-0973 Cmax was observed at 1-4 hours post-dose, and was similar across the entire dose range. Cmax and AUC increased dose proportionally in the dose range up to 100 mg. The mean apparent oral clearance ranged from 4.30 to 11.7 L/h in the 0.05 mg/kg-100 mg dose range. The mean elimination half-life ranged from 31.6 to 53.5 hours in all dose levels in both schedules. Following daily oral dosing, the mean accumulation ratio was 2.0 to 4.0, which is consistent with its half-life and dosing interval, indicating that the PK was constant over time. Given the mean half-life of ∼40 hours, steady-state exposures are expected to be achieved in 8-10 days. Preliminary data suggest that approximately 1-8% of intact drug is excreted in urine; hence, renal excretion is a minor pathway for elimination. Exploratory analysis showed no clear association between exposure and demographic factors (age, weight, sex) or concomitant medications. PK was consistent between patients in the 21/7 and 14/14 dose escalation stages, as well as the expansion stages when compared at the same doses. Doses of 40 mg or higher in patients achieved steady-state concentrations consistent with antitumor activity observed in xenograft models. Conclusion: GDC-0973 preliminary PK analysis shows a moderate rate of absorption; with generally dose-proportional increases in Cmax and AUC. Updated data will be presented. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1304. doi:10.1158/1538-7445.AM2011-1304

Abstract 1288: A Phase I evaluation of safety, pharmacokinetics (PK) and pharmacodynamics (PD) of LDE225, a smoothened (Smo) antagonist, in patients with advanced solid tumors

Abstract Dysregulation of the Hedgehog (Hh) signaling pathway is implicated in the pathogenesis of multiple human cancers. LDE225 is a potent selective and orally bioavailable inhibitor of Smo-dependent Hh signaling. This first-in-human study aims to determine the MTD and recommended phase II dose (RP2D) of LDE225, with secondary objectives assessing safety, PK, PD and efficacy. Patients (N=71) with advanced solid tumors were treated with oral LDE225 100 to 3000 mg once daily (QD) or 400 and 750 mg twice daily (BID) on a continuous 28-day dosing schedule, with a single dose 7-day PK run-in prior to the first treatment cycle. A minimum of 3 patients were enrolled at each dose level, with dose escalations guided by a Bayesian logistic regression model. Clinical assessments for safety and antitumor activity were performed and blood was sampled for PK assessments. Skin and tumor biopsies were collected for PD analysis. Once daily dosing of LDE225, up to 800 mg/day, is well tolerated with no reports of DLTs. At QD doses ≥1500 mg and BID doses ≥400 mg, dose-limiting CTCAE G3/4 increases in plasma creatine phosphokinase (CK) associated with muscle pain have been observed. Common (>5%) treatment-related G1/2 AEs reported include nausea, vomiting, dysgeusia, decreased appetite, diarrhea, myalgia, asthenia, headache, muscle cramps, fatigue, and increased plasma CK. Preliminary PK data demonstrates less than dose-proportional increases in Cmax and AUC. Increases in Cmax and AUC0-24h of 3- and 6-fold, respectively, were observed on day 15 compared with day 1, with an effective half-life >4 days (range: 1-14 days). Predicted target LDE225 exposures were achieved between days 15 and 28 at doses ≥400mg/day. Dose- and plasma exposure-dependent inhibition of Hh, indicated by reduction in Gli-1 mRNA expression, were observed, with up to 95% mean reduction in skin compared with baseline values suggesting that PD effect in the skin is a good surrogate for the effect in tumor. Using a logistic regression analysis, a relationship between LDE225 plasma exposure and G3/4 CPK elevation was identified. As predicted, evidence of antitumor activity has been demonstrated in patients with medulloblastoma (1 PR and 1 partial metabolic response) and advanced basal cell carcinoma (1 CR, 2 PRs and 1 SD). Disease stabilization (>4 months) in 4 patients with other cancers (lung adenocarcinoma, spindle cell, sarcoma, breast cancer) were also observed. Updated safety, PK/PD and preliminary efficacy will be presented. LDE225 is well tolerated following once daily administration at doses up to 800 mg. Exposure-dependent target inhibition in surrogate tissues has been demonstrated and tumor responses have been observed, particularly in tumors with evidence of Hh pathway activation, at tolerable systemic exposures. Further clinical development of LDE225 is supported by the encouraging emerging data. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1288. doi:10.1158/1538-7445.AM2011-1288

Abstract 4716: A first-in-human phase 1 study to evaluate the MEK1/2 inhibitor GDC-0973 administered daily in patients with advanced solid tumors

Abstract Background: The RAS/RAF/MEK/ERK signaling pathway, which is deregulated in a variety of tumor types, plays a major role in mediating cell growth and differentiation. GDC-0973 is a potent, selective, orally bioavailable MEK1/2 inhibitor which has shown antitumor activity in preclinical models. Methods: A phase I dose-escalation study using a 3+3 design was initiated in patients (pts) with solid tumors to evaluate the safety and pharmacokinetic (PK) characteristics of GDC-0973. FDG-PET was evaluated as a pharmacodynamic (PD) marker. Pts were treated QD with oral GDC-0973 on a 21-day on/7-day off (21/7) or a 14-day on/14-day off (14/14) dosing schedule. Serial plasma samples for GDC-0973 pharmacokinetic (PK) analysis were collected following first dose (Day 1) and last dose (Day 21 or Day 14, respectively) in Cycle 1. At expansion stages, pts with RAS or RAF mutant tumors were treated at the maximum tolerated dose (MTD) of the 21/7 or 14/14 schedule, and underwent serial FDG-PET scans (baseline, C1D10-14 (steady state) and C1D26-28 (trough). Results: In the 21/7 dose escalation, 36 pts enrolled in eight successive cohorts (0.05 mg/kg-80 mg). Dose-limiting toxicities (DLTs) reported were Grade 4 hepatic encephalopathy (40 mg), Grade 3 diarrhea (80 mg) and Grade 3 rash (60 mg and 80 mg). On a 21/7 dosing schedule, the MTD was 60 mg, and the most frequent adverse events (AE) attributed to GDC-0973 by the investigator were diarrhea, rash, nausea, fatigue, dry skin, and edema. In the 14/14 dose escalation, 16 pts enrolled in four successive cohorts (60-125 mg). The DLTs reported were Grade 3 rash (125 mg) and Grade 3 blurred vision associated with presence of reversible subretinal fluid (125 mg). On a 14/14 dosing schedule, the MTD was 100 mg, and the most frequent AEs attributed to GDC-0973 by the investigator were diarrhea, rash, pruritus, nausea, vomiting, blurred and impaired vision, fatigue, and abdominal pain. Preliminary GDC-0973 PK data showed dose-proportional increases in Cmax and AUC, and a mean elimination half-life of approximately 40 hours. With daily oral dosing, there was approximately 2.5-fold accumulation, consistent with the GDC-0973 half-life and dosing interval. Of 17 patients in the 21/7 cohort with PET scans read to date, 9 (53%) had a partial metabolic response (> 20% decrease in mean SUVmax from baseline) in at least one timepoint. Of 6 patients in the 14/14 cohort with PET scans read to date, 5 (83%) had a partial metabolic response in at least one timepoint. Confirmed partial responses were observed in 3 melanoma patients, of which two had BRAFV600E mutation. Six pts with prolonged stable disease (≥ 5 mo) were observed to date. Conclusion: GDC-0973 is generally well tolerated and has signs of antitumor activity. Preliminary analysis indicates GDC-0973 has linear PK with a half-life that allows once daily dosing. Updated data will be presented. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4716. doi:10.1158/1538-7445.AM2011-4716

Phase I study of everolimus (E) plus low-dose weekly cisplatin (C) for patients with advanced solid tumors.

e13013 Background: Preclinical studies demonstrate synergistic antitumor activity with the combination of E + C. Methods: Part A used a standard 3 + 3 dose escalation scheme. There were 4 planned dose levels (DLs) of E: 2.5, 5, 7.5, and 10 mg/day. Regimen was E per oral for days 1-21 and C 20 mg/m2 intravenously (fixed dose) on days 1, 8, and 15 of a 28-day cycle. For pharmacokinetics (PK), blood samples were collected on Day 1 and Day 8 of Cycle 1 in Part A. After the phase II-recommended dose was established (Part A), 6 additional subjects with easily accessible tumors for office biopsy were enrolled for pharmacodynamic correlates (Part B). Response was assessed by RECIST q 2 cycles for all subjects. Results: 30 patients enrolled (29 treated): 18 M, 12F; median age 62 (31-79); median number of prior cytotoxic chemotherapy regimens 1 (0-3; 80% with prior RT). DLTs were: DL1, 1 (sudden death of unclear cause in patient with melanoma metastatic to liver); DL2, 1 (bowel obstruction); DL3, 0; DL4, 0. Most common adverse events (≥ grade 3) among 29 patients evaluable for toxicity: lymphopenia (33%), hypophosphatemia (13%), hemoglobin (10%), and hyperglycemia (11%). PK analysis of E demonstrated dose proportional increases in Cmax (mean 91.9 ng/ml at DL4) and AUC0-INF(mean 680.4 hr*ng/ml at DL4). Two objective responses were seen (CR, metastatic pulmonary carcinoid; PR, metastatic sinus carcinoma). Prolonged SD ≥ 6 cycles occurred in 2 pulmonary carcinoid subjects, and in oropharyngeal SCC, basal cell carcinoma, and esthesioneuroblastoma (n=1 each). In Part B, pretreatment and on-treatment biopsies (Day 20) obtained in the oropharynx SCC subject showed no significant changes in expression of p-AKT, p21, or p53 as assessed by immunohistochemistry. Conclusions: The phase II recommended dose is E 10 mg/day (days 1 - 21) + C 20 mg/m2 (days 1, 8, and 15) on a 28-day cycle. PK data demonstrate dose-proportional increases in exposure, as previously described for E monotherapy. Antitumor activity was observed in several tumor types, including metastatic sinus carcinoma that had been previously treated with C. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Novartis

A first-in-human, phase l study to evaluate the dual PI3K/mTOR inhibitor GDC-0980 administered QD in patients with advanced solid tumors or non-Hodgkin's lymphoma.

3079 Background: The PI3K-AKT-mTOR signaling pathway is deregulated in a wide variety of cancers. GDC-0980 is a potent, highly selective, oral, dual inhibitor of class I PI3K and mTOR kinase. GDC-0980 demonstrates broad preclinical activity in breast, ovarian, lung, and prostate cancer models. Methods: This phase I dose escalation study (PIM4604g) for patients (pts) with solid tumors or non-Hodgkin's lymphoma used a 3+3 design. GDC-0980 was given on day 1, followed by 1wk washout to study single-dose pharmacokinetic (PK) and pharmacodynamic (PD) markers. GDC-0980 was then dosed QD on a 3wk on/1wk off schedule. Steady-state PK and PD were evaluated after 1wk of continuous dosing. Objectives were to determine maximum tolerated dose and dose-limiting toxicity (DLT), evaluate PD endpoints (pAKT in platelet-rich plasma [PRP] and optional fluorodeoxyglucose [FDG] uptake via positron emission tomography imaging [PET]), and describe anti-tumor activity. Results: Twelve pts have been enrolled in 4 successive dose-escalation cohorts with dose levels of 2-, 4-, 8-, and 16 mg GDC-0980 daily. The most frequently reported adverse events were nausea (25%), fatigue (50%), diarrhea (42%), and flatulence (25%). No drug-related grade 3 or higher events or DLT have been reported to date. Preliminary PK data suggest dose-proportional increases in Cmax and AUC. Preliminary PD data shows >50% inhibition of pAKT levels assayed in PRP (relative to baseline) following a single dose of 8 mg and higher GDC-0980. Potential signs of antitumor activity have been observed in a mesothelioma pt (previously treated with radiation and cisplatin/pemetrexed) who had a decrease in target lesions of ∼32% by RECIST after one cycle of 8 mg GDC-0980 QD and a soft tissue sarcoma pt who had a decrease in tumor mean SUVmax of ∼31% assessed by FDG-PET after 2 weeks of 16 mg GDC- 0980 QD. Conclusions: GDC-0980 is generally well tolerated up to 16 mg administered orally QD with potential signs of antitumor activity. Preliminary PK data suggest dose-proportional increases in exposure over the dose levels evaluated. Dose-escalation continues and updated data will be presented. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Genentech, Institute of Cancer Research Arno Therapeutics, AstraZeneca, Exelixis, Genentech, GlaxoSmithKline, Merck, Novartis, Pfizer Roche Arno Therapeutics, AstraZeneca, Exelixis, Genentech, GlaxoSmithKline, Merck, Novartis, Pfizer Genentech

Pharmacokinetics of a New, Ultra-Low Molecular Weight Heparin, Semuloparin (AVE5026), in Healthy Subjects. Results From the First Phase I Studies.

Abstract 1073Poster Board I-95 Background:AVE5026 is a new generation hemisynthetic ultra-low molecular weight heparin (average molecular weight 2500 Da) with high anti-Factor Xa (anti-Xa) and residual anti-Factor IIa (anti-IIa) activities (ratio anti-Xa/IIa > 30). As a consequence, AVE5026 has the potential to improve the risk benefit ratio compare to low molecular weight heparins. AVE5026 is currently in phase III clinical trials of venous thromboembolism prevention. Aims/Objectives:Pharmacokinetic (PK) data from the first 3 Phase I studies were examined to evaluate the dose proportionality of anti-Xa concentration, absolute bioavailability, and accumulation of AVE5026 after single and repeated subcutaneous (SC) dosing in healthy young and elderly subjects. Methods:The first study was a double-blind, randomized, single-dose escalation study in healthy male subjects (aged 18–42 years) given single SC doses of AVE5026 in 7 ascending steps from 0.05 to 1.4 mg/kg or a matched placebo. The second study was a randomized, double-blind, placebo-controlled, repeat dose-escalation study of AVE5026 at doses of 5 mg (only in elderly), 20, 60, and 100 mg given SC once daily for 14 days in healthy young male (aged 18–40 years) and elderly male and female (aged 65–80 years) subjects, and AVE5026 40 mg SC once daily for 28 days in young healthy males. The third study was a randomized open-label study carried out in 15 healthy male and female subjects (aged 18–45 years) to determine bioavailability after a 60 mg single SC dose compared to a 3-hour intravenous (IV) infusion. In all studies, plasma and urine samples were analyzed for anti-Xa activity concentration using a chromogenic enzyme assay to determine the maximum plasma concentration (Cmax), area under the plasma concentration-time curve (AUC), and terminal plasma half-life (t1/2-z). In the repeat dosing study, accumulation ratios were calculated for each age and dose group. In the third study, AUC mean ratios between the SC and IV routes were calculated to assess bioavailability. Anti-IIa plasma activity was also analyzed after the 2 highest doses in the first study and in the 2 other studies using a chromogenic enzyme assay. Results:The single-dose escalation study included 56 subjects. Anti-Xa concentration increased in proportion to the dose from 0.1 to 1.4 mg/kg: the mean Cmax ranged 0.406–10.9 μgEq/mL and AUC0-∞ ranged 11.0–173 μgEq·h/mL. Mean t1/2-z was approximately 11 hours (range 9.8–11.4) for doses 0.3 mg/kg and up. Similarly, anti-IIa levels increased proportional to dose at the 1.2 and 1.4 mg/kg (84 and 98 mg) doses with a mean Cmax of 0.013–0.017 U/mL. The mean amount of drug excreted in the 24-h urine collection as active anti-Xa fragments (fe0-24 ) ranged 20.7–31.5% of the dose. In the repeated dose escalation study, data from 72 subjects were available for the anti-Xa PK analysis. Steady state was reached before the fourth injection in young and before the fifth in elderly subjects. In young subjects, Cmax increased 1.21-fold from Day 1 to Day 14 and AUC0-24 increased 1.37-fold over all doses. A dose-proportional increase in Cmax and AUC0-24 was observed on Day 1 and Day 14. On Day 14, t1/2-z ranged 16.4–20.5 hours across the doses. On Day 14, fe0-24 ranged 25.0–49.1% of the dose from 20 to 100 mg. Plasma anti-IIa levels were assessed at 100 mg: Cmax was 0.015 U/mL on Day 1 and 0.014 U/mL on Day 14. In elderly subjects, anti-Xa Cmax increased 1.37-fold from Day 1 to Day 14, and AUC0-24 increased 1.47-fold over the dose range. A dose-proportional increase in Cmax and AUC0-24 was observed on Day 1 and Day 14. On Day 14, t1/2-z ranged 14.6–21.9 hours across the doses. On Day 14, fe0-24 ranged 20.5–40.8% of the dose from 5 to 100 mg. Most elderly subjects had mild renal impairment. After a single SC 60 mg dose of AVE5026, absolute bioavailability was 97.7% (90% confidence interval 89.7–107%). Fe0-24 was 30.6% of the dose. The total clearance of AVE5026 was 0.600 ± 0.173 L/h with a distribution volume of 7.88 ± 1.45 L. Overall, AVE5026 was well-tolerated and safe. Conclusions:AVE5026 presents a linear PK profile indicated by dose proportionality after single and repeat dosing, and is completely absorbed after SC injection. The accumulation ratio is in line with the terminal half-life. After repeat dosing in elderly subjects, a slight increase in accumulation of AVE5026 was seen, and steady state was reached a day later. The limited impact of age observed may reflect the mild renal impairment. Disclosures:Dubruc:sanofi-aventis: Employment. Karimi-Anderesi:sanofi-aventis: Employment. Lunven:sanofi-aventis: Employment. Zhang:sanofi-aventis: Employment. Grossmann:sanofi-aventis: Consultancy. Potgieter:Farmovs-Parexel Research Center: Employment.

A first-in-human phase I study to evaluate the pan-PI3K inhibitor GDC-0941 administered QD or BID in patients with advanced solid tumors

3501 Background: The PI3K-PTEN-AKT signaling pathway is deregulated in a wide variety of cancers. GDC-0941 is a potent and selective oral inhibitor of the class I PI3K with 3 nM IC50 for the p110-alpha subunit in vitro and 28 nM IC50 in a cell-based pAKT assay and demonstrates broad activity in breast, ovarian, lung, and prostate cancer models. Methods: A Phase I dose escalation study using a 3+3 design was initiated in patients (pts) with solid tumors. GDC-0941 was given on d1, followed by 1 wk washout to study single-dose PK and PD markers. GDC-0941 was then administered qd on a 3 wk on, 1 wk off, schedule. Steady-state PK and PD were evaluated after 1 wk of continuous dosing. A separate concurrent dose-escalation arm with bid dosing was initiated after the third qd cohort. Results: Nineteen pts have been enrolled in 5 successive dose-escalation cohorts in the qd arm with dose levels up to 80 mg daily. Seven pts were enrolled in 2 cohorts in the bid arm at total daily doses of 60 and 80 mg. The most frequently reported drug-related AEs were Grade 1/2 nausea, fatigue, diarrhea, peripheral edema, and dysgeusia; no drug related grade >3 events have been reported. PK data suggest dose-proportional increases in Cmax and AUC. Potential signs of anti-tumor activity have been observed with a soft tissue sarcoma pt on-study for >176 days with stable disease (30 mg qd), an ovarian cancer pt with an on-study 2.8-fold decrease in CA-125 response to normal levels (30 mg bid) and a pt with endometrial cancer with a decrease in tumor FDG-PET uptake (80 mg qd). Conclusions: GDC-0941 is generally well-tolerated with potential signs of anti-tumor activity. Preliminary PK data suggest dose-proportional increases in exposure over the dose levels evaluated. Dose-escalation on both the qd and bid schedules continues with updated data to be presented. [Table: see text]

A Phase I Study of CNTO 328, An Anti-Interleukin-6 Monoclonal Antibody in Patients with B-Cell Non-Hodgkin's Lymphoma, Multiple Myeloma, or Castleman's Disease.

Interleukin (IL)-6 is a multifunctional cytokine that serves as a growth factor for B-cell non-Hodgkin's lymphoma (NHL), multiple myeloma (MM) and Castleman's Disease (CD). CNTO 328 is a chimeric monoclonal antibody that binds with both high specificity and high affinity while neutralizing the biological activity of human IL-6. Interim results are presented here from an ongoing open-label, dose-finding, phase I trial to assess the safety, pharmacokinetics, pharmacodynamics and clinical activity of CNTO 328 in patients with B-cell NHL (including Waldenstrom's macroglobulinemia [WM]), MM, and CD. Evaluation of six dose cohorts with the following infusion schedules: 3 mg/kg q 2 weeks, 6 mg/kg q 2 weeks, 12 mg/kg q 3 weeks, 6 mg/kg q 1 week, 12 mg/kg q 2 weeks, 12 mg/kg q 3 weeks has been completed. A seventh cohort evaluating CNTO 328 9-mg/kg administered with a tri-weekly infusion schedule in CD patients is also ongoing. Fifty-two patients (NHL n=17, MM n=13, CD n=22) have been enrolled. The median age is 56 years (range 21–82). Patients received an average of 15 doses (up to 87 doses) of CNTO 328 with a median exposure of 131 days (up to 1051 days). Preliminary pharmacokinetic data from cohorts 1 through 5 show that serum concentrations declined in a bi-exponential manner with a terminal half-life of ~15 days. Dose-proportional increases in Cmax and AUC (0–14 days) were observed. No apparent differences in pharmacokinetics were observed when comparing patients with NHL, MM or CD. The median baseline C-reactive protein (CRP) level, a surrogate for IL-6 activity (n=47) was 9.21 mg/L (range 1–260 mg/L). Of patients with post-baseline CRP values, 83% of patients demonstrated complete suppression of CRP (a surrogate for IL-6 activity) on at least one follow up assessment (median baseline level of 13.6 mg/L (range 1–260 mg/L). CNTO 328 was well tolerated with no doselimiting toxicity observed in any of the study cohorts. Forty-nine (94%) of 52 patients had one or more adverse events. Of these 49 patients, 23 (47%) had adverse events with a maximum toxicity grade of grade 2 or less . The following adverse events were observed in more than 15% of patients: upper respiratory or urinary tract infection, thrombocytopenia, neutropenia, leukopenia, anemia, elevated ALT, hypertriglyceridemia, nausea, diarrhea, fatigue, headache. Adverse events of Grade 3 or higher, observed in more than 5% of patients overall, were limited to neutropenia (21%, none febrile), thrombocytopenia (8%), anemia (6%), cellulitis (8%), and pleural effusion (6%); most were not attributable to CNTO 328. Clinical activity has been seen in all diseases types, particularly CD and WM. Among patients with NHL, 1 patient with MALT lymphoma, 1 with follicular lymphoma and 1 with mantle cell lymphoma demonstrated stable disease for more than 6 months. Among patients with WM, 2 demonstrated partial response (1 not yet confirmed) and the remaining 3 showed stable disease. Among patients with MM, 3 had at least partial response (the low baseline serum M-protein levels of 2 patients became undetectable during treatment) and 2 patients had long-lasting stable disease (1 patient for 224 days, 1 patient for more than 533 days). A high response rate was observed in patients with CD; whose results are presented in a separate abstract. In summary, these interim results show that CNTO 328 appears to have a favorable safety profile and demonstrate clinical activity as a single agent in the treatment of MM, NHL, WM and CD.

A Phase 1 dose-escalation study of the safety and pharmacokinetics (PK) of the oral Hsp90 inhibitor SNX-5422

14613 Background: SNX-5422 is an oral pro-drug of SNX-2112, a potent and highly selective small-molecule inhibitor of the molecular chaperone heat shock protein 90 (Hsp90). SNX-2112 potently inhibits solid and hematological tumor cell proliferation with IC50 values of 1–10 nM, and is more potent than 17-AAG and 17-DMAG in a majority of the cell lines tested. Due to its involvement in the maturation and maintenance of numerous proteins critical for tumor cell viability and growth, Hsp90 is an exciting therapeutic target for a broad range of solid tumor and hematological malignancies. Methods: Eligibility included patients (pt) with refractory solid tumors or lymphomas, Karnofsky performance status ≥60, adequate organ function, and no known CNS involvement, primary or metastatic. SNX-5422 was given orally every other day daily for 21 days followed by 7 days of rest. Dose escalation is proceeding at 100% with standard 3 pt cohorts until a grade (gr) 2 adverse event (AE) occurs, then escalation decreases to 33%. The objectives are to determine the dose limiting toxicities (DLTs) and maximum tolerated dose (MTD), safety, and PK of SNX-5422. Results: 11 patients have been dosed to date; 3 in cohort 1 (4 mg/m2); 3 in cohort 2 (5.32 mg/m2); 4 in cohort 3 (10.64 mg/m2); and 1 in cohort 4 (21.28 mg/m2) for a total of 20 cycles. Tumor types included: 3 melanoma; 2 breast cancer; 1 anal; 1 prostate; 1 adrenal; 1 adenocystic; 1 NSCLC; and 1 squamous cell carcinoma of unknown primary. SNX-5422 has been well tolerated with no DLTs observed. All drug related toxicities have been gr 1 (nausea 3 pt and fatigue 2 pt). The predicted effective human dosing range based on animal models is approximately13–53 mg/m2. PK results of the first two cohorts demonstrate dose proportional increases in Cmax and AUC and a half-life of ∼ 8–10 hours. Proof of mechanism will be supported by PBMC evaluation of multiple biomarkers including p-Erk and p-S6. Conclusions: SNX-5422 has been well tolerated through the first three dose levels and is enrolling at 21.28 mg/m2, which is within the effective human dose range predicted by pre-clinical studies. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Serenex, Inc. Serenex, Inc. Serenex, Inc. Serenex, Inc.

Clinical Pharmacokinetics of Halofantrine

Halofantrine is a phenanthrenemethanol antimalarial that is effective against asexual forms of multidrug-resistant Plasmodium falciparum malaria. It has no action on gametocytes or hypnozoites in the liver. The drug is administered as a racemic mixture but the (+)- and (-)-enantiomers show no difference in activity in vitro. Three formulations for oral administration are available for human use, i.e. tablets, capsules and suspension. Toxicity studies in animals suggest that halofantrine has very low toxicity both in short term and long term animal studies, and there has been no evidence of mutagenicity in these studies. Phase I, II and III clinical trials of halofantrine conducted in several tropical countries found the drug to be well tolerated and effective against multidrug-resistant P. falciparum malaria when 500mg was administered every 6 hours for 3 doses. The majority of clinical adverse effects reported, including nausea, vomiting, abdominal pain, diarrhoea, orthostatic hypotension, prolongation of QTc interval, pruritus and rash, have been mild and transient. There is wide interindividual variation in halofantrine absorption. The maximal plasma concentration (Cmax) is achieved approximately 6 hours after oral administration. Bioavailability is not dose-proportional for doses over 500mg, but there is a dose-proportional increase in Cmax and area under the plasma concentration-time curve (AUC) for doses between 250 and 500mg. In patients with malaria the bioavailability of halofantrine is decreased. The mean half-life of absorption is 4 hours and Cmax is significantly lower than that obtained in healthy individuals. Furthermore, halofantrine absorption is enhanced when the drug is taken with fatty food. Therefore, halofantrine should be taken with food to ensure optimal absorption in patients with malaria. The terminal elimination half-life is 5 days in patients with malaria. Halofantrine is biotransformed in the liver to its major metabolite N-debutyl-halofantrine. Plasma concentrations of this metabolite are observed soon after administration of halofantrine, but in much lower concentrations. The elimination half-life is similar to that of halofantrine. There have been increasing reports of halofantrine treatment failure, particularly in the eastern part of Thailand. The majority of treatment failures have been associated with incomplete drug absorption. The dose-dependent cardiotoxic effects (e.g. cardiac arrhythmia) are a major concern, particularly when the bioavailability of the drug cannot be predicted. Ongoing and future studies should aim at developing more appropriate drug formulation(s) and/or optimising dosage regimens. This will allow therapeutic concentrations to be achieved with minimum adverse effects, particularly cardiotoxicity.