PK Results Research Articles

Prophylaxis Dose Adjustment in Hemophilia a Using a New Version of Population Pharmacokinetics Estimation Model Based on Bayesian Procedure

INTRODUCTIONProphylaxis with factor VIII (FVIII) is considered the gold standard for managing hemophilia A (HA) patients without inhibitors to prevent bleedings and to preserve normal musculoskeletal function. Classically, the prophylaxis with a standard half-life FVIII is 20 to 40 IU/kg administered every other day. In practice this “one-size-fits-all” way of dosing does not work in many patients due to the interindividual variability on the concentration-time profile of FVIII, body weight, age, blood group and level of Von Willebrand factor.Pharmacokinetic (PK)-guided regimens have been proposed as an effective way to optimize prophylaxis efficacy. Different online PK tools have been developed to estimate patients' PK with only 2 blood samples. The integration of PK and clinical data can help physicians to adjust dosing.Since 2014 we have been using an online tool to perform PK estimation in patients using the FVIII product Advate® (myPKFiT®, www.mypkfit.com; Baxter Healthcare Corporation; Haemophilia 2014, 20 (Suppl.2):15). In June 2018 a new version has been launch, the version 3.0. This v3.0 includes a dose calculation update based on the ability to modify an individual dose or trough level of an individual prophylaxis regimen providing an accurate adjustment of prophylaxis dosing in comparison with version 2.0 (v2.0).This report describes the impact of the PK estimation in the infusion frequency and factor consumption, comparing both versions, in a cohort of people with HA.METHODSThis is an observational case series from a single hemophilia treatment Spanish center. The inclusion criteria were: patients receiving prophylaxis with octocog alfa who accepted to participate in the PK study. Two blood samples have been collected for the estimation of FVIII PK (3-4 hours and 24-28 hours after administration of their usual dose of FVIII) in real world practice. We measured FVIII using one-stage assay. The FVIII trough levels were adjusted between 1% and 3% according to patients characteristics. Demographic data, PK parameters, infusion frequency, dosage and consumption after PK adjustment of prophylaxis using the v2.0 and v3.0 tool were analyzed.RESULTSEleven patients were evaluated (7 severe, 3 moderate, 1 mild HA) aged 2-43 years (median 14 years). There were no differences in PK parameters between v2.0 and v3.0 as the applied algorithm for both versions is the same. PK results are shown in the Panel A of the table below. The elected trough level was between 1-3% depending of the physical activity and joint health of every individual patient. Prophylaxis regimen was modified in 6/11 patients after PK analysis with both versions of the App: 2 pediatric patients increased their FVIII dose and 3 adults increased their treatment frequency. We have only observed differences in 3 patients comparing the two versions: Patient 1 started a new infusion regimen (every 48h to 48-48-72h) with a mild increase in consumption, and patient 2 and 5 maintained the regimen every 48h with slight reductions in consumption. Results are shown in the Panel B of the table below.CONCLUSIONSBoth versions of myPKFit™ are a helpful tool to adjust FVIII dosing regimens. This latest version allows to individualize even more the treatment regimen and to achieve a more efficient consumption. Prospective evaluation of the use of PK‐tailored prophylaxis in routine care and its impact on patient outcomes is needed. DisclosuresNo relevant conflicts of interest to declare.

Phase Ib pharmacokinetics of non-hormonal SM88 in patients with non-metastatic recurrent prostate cancer.

e14061 Background: SM88 is a combination of tyrosine isomers ( TI) and repurposed drugs (modulators of CYP3A4, mTOR, and oxidative stress). This regimen has previously reported non-toxic activity in cancers including prostate (PC) ( J Clin Oncol 2013 31: e22095). We present summary data from a completed Ib trial of non-metastatic recurrent PC (nmPC), an ideal candidate for a well-tolerated, non-androgen based treatment. Methods: This was an open-label safety and PK trial of SM88 in patients with nmPC. Cohort 1 received 230 and cohort 2 - 460 mg/day of TI, along with the lowest available doses of the other 3 agents. Multiple samples were drawn at pre-dose and up to 48 h post dosing from 4 patients after a single TI dose; after a single dose of all 4 components; and after 2 weeks of steady state daily combined dosing (SS). Only cohort 2 results are presented. Results: See table below. Each of the 3 approved drugs had expected PK results that will be provided. There was no evidence that the combination altered the expected PKs at SS. There were no serious drug related adverse events. Favorable biomarker activity was documented at both TI dose levels. Conclusions: Single dose and SS TI results from this completed phase Ib trial are consistent with preclinical predictions (ESMO 2016. Ann Oncol (2016) 27 (suppl_6): 1605P). TI PK results changed transiently with the additional components but returned to desirable levels at SS including a higher Cmax, AUC, and more rapid Tmax, indicating rapid absorption. The PK results (not shown) are consistent with the published data for the approved agents, despite the use of lower than typical label doses. Based on these results, the higher TI dose was chosen for the ongoing phase II expansion cohort in nmPC patients. SM-88 appears to have predictable PK as an effective metabolomic regimen for the treatment of advanced prostate cancer devoid of significant toxicities. [Table: see text]

A randomized, controlled, open label phase II study of erlotinib (E) with or without the MET antibody emibetuzumab (Emi) as first-line treatment for EGFRmt non-small cell lung cancer (NSCLC) patients who have disease control after an 8-week lead-in treatment with erlotinib.

9019 Background: MET expression is a mechanism of resistance to EGFR inhibition in EGFRmt NSCLC and correlated with poor prognosis. Emi (LY2875358) is a humanized IgG4 monoclonal bivalent MET antibody that blocks ligand dependent and independent HGF/MET signaling. This Phase 2 study compared the clinical activity of Emi + E versus single agent E in 1st line EGFRmt metastatic NSCLC. Methods: Stage IV, EGFRmt NSCLC pts with disease control following an 8-week lead-in E (150 mg PO QD) treatment were randomized 1:1 to receive Emi (750 mg IV Q2W) + E or E alone. Pts were stratified by ECOG PS, ethnicity, MET expression status, and response at the end of the lead-in. The primary endpoint was PFS from randomization. Additional endpoints included safety, OS, PK, and exploratory analysis of MET-expressing populations. Results: Out of181 pts enrolled, 141 pts were randomized (Emi+E: 71; E: 70). In the ITT population, median PFS for EMI+E was 9.3 months (m) compared with 9.5 m for E (HR = 0.89: 90% CI 0.64-1.23; p = 0.534). Exploratory analysis of MET-high expressing pts (MET 3+ expression in ≥90% of tumor cells; n = 24 pts) showed a 15.3 m improvement in PFS (EMI+E: 20.7 m; E: 5.4 m [HR: 0.39; 90% CI: 0.17-0.91]). No difference in PFS was observed in the complementary population (HR: 1.1 [90% CI: 0.7-1.7]). Similar frequencies of related AEs were reported for both treatment arms. Drug-related TEAEs that were more frequent ( > 10%) for Emi+E were peripheral edema and fatigue (all grade 1 or 2). Emi serum concentrations were consistent with previously obtained PK results, and no apparent exposure-response was observed. Median OS in the ITT population was not achieved (NA) for either arm. In MET-high expressing pts, median OS was 20.6 m for E (90% CI: 8.87, NA) whereas it was not achieved for Emi+E (90% CI: NA, NA). Conclusions: No statistically significant difference in PFS was noted in the ITT population.Exploratory analysis confirmed that high MET expression is a negative prognostic marker for pts treated with E and indicated that these pts may receive clinically meaningful benefit from Emi+E. Clinical trial information: NCT01897480.

Pharmacokinetic/Pharmacodynamic Modeling of the PDE4 Inhibitor TAK‐648 in Type 2 Diabetes: Early Translational Approaches for Human Dose Prediction

TAK‐648 is a PDE4 inhibitor with demonstrated preclinical antidiabetic properties. Our objective was to develop a translational pharmacokinetic/pharmacodynamic (PK/PD) model for human type 2 diabetes (T2D) dose prediction using HbA1c results from a db/db mouse study. Estimated parameters in combination with tPDE4i values calculated for the clinical roflumilast dose of 500 μg were used to translate preclinical effects of TAK‐648 to required exposure in humans. A first‐in‐human study with single TAK‐648 doses of 0.05–0.85 mg in healthy volunteers yielded mean maximum TAK‐648 concentrations (Cmax) and area under the curve (AUC) values from 0.62–11.9 μg/L and 4.58–93.8 μg*h/L, respectively. Based on the performed pharmacokinetic/pharmacodynamic analysis and clinical PK results, clinical efficacy would be expected at a daily dose of 0.1 mg, which is well within the investigated clinical dose range. This result significantly enhanced the confidence in TAK‐648 for type 2 diabetes treatment and underlines the necessity of translational approaches in early preclinical phases.

Prediction of pharmacokinetics and drug-drug interaction potential using physiologically based pharmacokinetic (PBPK) modeling approach: A case study of caffeine and ciprofloxacin.

Over the last decade, physiologically based pharmacokinetics (PBPK) application has been extended significantly not only to predicting preclinical/human PK but also to evaluating the drug-drug interaction (DDI) liability at the drug discovery or development stage. Herein, we describe a case study to illustrate the use of PBPK approach in predicting human PK as well as DDI using in silico, in vivo and in vitro derived parameters. This case was composed of five steps such as: simulation, verification, understanding of parameter sensitivity, optimization of the parameter and final evaluation. Caffeine and ciprofloxacin were used as tool compounds to demonstrate the “fit for purpose” application of PBPK modeling and simulation for this study. Compared to caffeine, the PBPK modeling for ciprofloxacin was challenging due to several factors including solubility, permeability, clearance and tissue distribution etc. Therefore, intensive parameter sensitivity analysis (PSA) was conducted to optimize the PBPK model for ciprofloxacin. Overall, the increase in Cmax of caffeine by ciprofloxacin was not significant. However, the increase in AUC was observed and was proportional to the administered dose of ciprofloxacin. The predicted DDI and PK results were comparable to observed clinical data published in the literatures. This approach would be helpful in identifying potential key factors that could lead to significant impact on PBPK modeling and simulation for challenging compounds.

Abstract CT050: A Phase I/II Study of MCLA-128, a full length IgG1 Bispecific Antibody Targeting HER2 and HER3, in Patients with Solid Tumors

Abstract BACKGROUND: MCLA-128 is a novel humanized full length IgG1 bispecific antibody with enhanced antibody-dependent cell-mediated cytotoxicity (ADCC) activity that targets the transmembrane tyrosine kinase receptors, HER2 and HER3 present on a variety of epithelial tumor cells. In preclinical studies, MCLA-128 demonstrated potent anti-tumor activity. The primary objectives of this First-in-Human (FIH) study are to establish the MTD and Phase 2 recommended dose (RP2D) of MCLA-128 and to assess its safety, tolerability, PK, PD, and anti-tumor activity in selected patient (pt) groups. METHOD: The trial consists of 2 parts. In Part 1 (dose-escalation) patients (pts) with advanced epithelial tumors with no standard management options were enrolled with an initial accelerated 1 pt per cohort design shifting to a 3 + 3 design. The DLT evaluation period was 21 days ( = 1 cycle). MCLA-128 was administered every 3 weeks (q3w) as an intravenous infusion over 60-120 minutes. Toxicities were assessed throughout dose escalation (40 mg up to 900 mg flat dose). Part 2 consists of several expansion cohorts of pts at the RP2D (expansion phase). Here we present interim results for Part 1 of the study. RESULTS: Twenty-eight pts received MCLA-128 in 9 dose-escalation cohorts (40-160 mg in cohorts of 1 evaluable pt, 240-900 mg in cohorts of 3 to 6 evaluable pts). The most frequent drug related adverse events (AEs) observed in Part 1 were mild to moderate (G1-G2) with prompt recovery in general. AEs included infusion-related reactions (IRR), diarrhea, nausea, vomiting, fatigue, maculopapular rash, oral mucositis and G2 neutropenia in 1 pt. IRR occurred in 50% of pts with a trend for increased incidence with dose; modest and transient dose dependent cytokine release was also observed. Increasing the infusion duration to 120 min and premedication with corticosteroids was successfully implemented to mitigate IRRs and cytokine levels were no longer correlative with MCLA-128 dose levels. One drug related serious AE (SAE) has been reported: IRR G3, due to prolonged hospitalization (SUSAR). No DLTs were observed. In serum samples from 12 pts, 1 pt was positive for MCLA-128 anti-drug antibodies 36 days after starting treatment at a dose of 160 mg. A MTD was not reached in the study; PK analysis was used to support a RP2D of 750 mg q3w. Exposure to MCLA-128 increased in proportion to dose. The RP2D was calculated to maintain trough concentrations at the end of each treatment cycle significantly above the Kd of MCLA-128 as determined on HER2 amplified cell lines in vitro and above the Km in a population PK model. Preliminary signs of anti-tumor activity assessed by RECIST are encouraging. Three pts remain on study to date including 1 non-small-cell lung cancer pt who is experiencing an ongoing partial response for more than 10 months, 1 gastroesophageal junction pt and 1 colorectal cancer pt with stable disease for 5 months. In addition, 1 metastatic breast cancer pt received 5 months of MCLA-128 treatment until disease progression. CONCLUSION: MCLA-128 was well-tolerated with a favorable safety profile in pts with advanced tumors treated at doses up to 900 mg q3w. PK results and preliminary signs of anti-tumor activity support the further clinical evaluation of MCLA-128 at the RP2D of 750 mg q3w. The expansion phase of the study is ongoing at this dose level. Citation Format: Emiliano Calvo, Maria Alsina, Jan H.M. Schellens, Alwin DR Huitema, Josep Tabernero, Aurelia de Vries-Schultink, Valentina Boni, Bernard Doger, Cecile Geuijen, Robert Doornbos, Kees Bol, Martine Westendorp, Mark Throsby, Lex Bakker, Setareh Shamsili. A Phase I/II Study of MCLA-128, a full length IgG1 Bispecific Antibody Targeting HER2 and HER3, in Patients with Solid Tumors. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr CT050.

Abstract 3958: Tubulin hyper-acetylation in blood lymphocytes: pharmacodynamic (PD) biomarker for the selective histone deacetylase (HDAC) 6 inhibitors ricolinostat and ACY-241 in multiple myeloma (MM) patients

Abstract INTRODUCTION: HDACs are a family of enzymes that remove acetyl groups from proteins and are involved in key cellular processes. Nonselective HDAC inhibitors have shown promise in treating MM in combination with standard therapies such as proteasome inhibitors (PIs) and immunomodulatory agents, but are limited by adverse effects. The selectivity profile of clinical HDAC inhibitors is critically important as the same drug may exert its effects via alternative mechanisms depending on the partner therapeutic. An example is HDAC6 inhibitors in combination with bortezomib, a proteasome inhibitor (PI). Delivery of protein-bearing vesicles to the aggresome involves HDAC6 through its role in vesicle trafficking, thus supporting a secondary survival pathway. In the case of lenalidomide or pomalidomide, inhibiting class I HDACs can suppress MYC protein levels, which potentially enhances activity in a clinical setting. Ricolinostat (ACY-1215) and ACY-241 that are currently in clinical trials have a selectivity profile tuned toward HDAC6 over HDACs 1, 2, and 3, which is hypothesized to enhance anti-cancer activity with multiple standard of care regimes while minimizing toxicity. METHODS: Peripheral blood from patients that received escalating oral doses of ricolinostat or ACY-241 that range from 40 mg to 360 mg was collected for matched PK and PD assessment. Lymphocytes were examined for tubulin and histone hyper-acetylation by flow cytometry. RESULTS & CONCLUSION: Plasma concentration for both ricolinostat and ACY-241 reach a maximal level (Cmax) 1-2 hr after administration. An exposure plateau was reached at dose levels ≥160 mg of ricolinostat, with Cmax observed to be ∼2 μM. ACY-241 exposures reached higher levels, Cmax of ∼3 μM and ∼7 μM at 180 and 360 mg, respectively, and no evidence of an exposure plateau. Correlating to the PK levels, acetyl-tubulin increases to a maximal level by 1-2 h after dosing compared to predose, and declines to basal level by >4 hr. As plasma levels increased with dose from 40 mg to 160 mg for ricolinostat so do the number of patients that have an increase in acetyl-tubulin such that at dose levels ≥80 mg all patients have a measurable increase in acetylated tubulin. Levels of acetyl-tubulin were similar at dose levels of 180 and 360 mg of ACY-241. Acetyl-histone levels were low- moderate at the 160 and 180 mg dose level for ricolinosat and ACY-241, respectively, and for ACY-241 increased with increasing exposure at doses > 180 mg similar to results observed in vitro by immunoblot analysis of MM cells treated with ACY-241. In conclusion, the PK and PD results suggest that both ricolinostat and ACY-241 have reached a pharmacologically relevant level of HDAC inhibition as determined by acetylated tubulin and histone at the clinical dose levels examined. Citation Format: David L. Tamang, Jeffery Supko, Kailash Bhol, Catherine Wheeler, Simon S. Jones, Min Yang. Tubulin hyper-acetylation in blood lymphocytes: pharmacodynamic (PD) biomarker for the selective histone deacetylase (HDAC) 6 inhibitors ricolinostat and ACY-241 in multiple myeloma (MM) patients. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3958.

Clinical Pharmacokinetics and Pharmacodynamics of Pwt-143, an Oral, Potent and Selective Inhibitor of Phosphatidylinositol 3-Kinase P110delta, Following Single Oral Administration to Healthy Volunteers

Background: The Phosphatidylinositol 3-Kinases p110δ isoform (P110δ PI3K) is hyperactive in B cell malignancies and is central to multiple signaling pathways that drive proliferation, survival, homing and retention of malignant cells in lymphoid tissue and bone marrow. PI3Kd inhibitors have demonstrated important clinical activity in various lymphoid malignancies, albeit with certain toxicities and PK limitations. PWT-143, comprised of a novel molecular scaffold that is distinctive from other known PI3Kd-selective inhibitors, is a potent and selective inhibitor of P110δ PI3K enzymatic activity. PWT-143 exhibits low nanomolar potency in cellular assays, as well as in a pre-clinical whole blood functional assay of basophil activity (poster presented at 54th ASH Annual Meeting, 2012). PWT-143 also demonstrated highly favorable pharmacokinetics from oral administration in preclinical experiments. Preclinical toxicology and safety pharmacology data supported initial clinical assessment of oral PWT-143 in healthy volunteers, consistent with its target selectivity profile. Here we report the initial PK and PD results of a single dose of oral PWT-143 in healthy volunteers.Methods: A flexible, adaptive first-in-human study was conducted using a Translational Pharmaceutics® platform which enables rapid real-time PK/PD analysis and GMP manufacture of drug products between dosing periods. Based on the NOAEL in rats and dogs, with a standard safety margin for a first-in-human study, the starting dose level was 10 mg, with higher doses and/or formulation adjustments to be selected, based on review of emerging safety, tolerability and pharmacokinetic data. Blood samples were collected at regular time intervals, and plasma concentrations of PWT-143 were measured using a validated liquid chromatography tandem mass spectrometry method. Blood samples were also collected for testing with a PD assay; specifically, basophil activation assessed via CD63 expression by flow cytometry following ex-vivo stimulation with an anti-FCeR1 monoclonal antibody.Results: To date, subjects (n=3/cohort) have been orally administered 10 mg and 30 mg of PWT-143, and escalation is continuing (n=6/cohort). The 10 mg and 30 mg doses resulted in up to 55 % and 80 % inhibition of basophil activation, respectively, within 4 hours of dosing. Both doses resulted in no reported Adverse Events nor clinically significant changes in vital signs, ECGs or safety laboratory assessments. The geometric mean Cmax and half-life were 3.9 ng/ml (range; 2.0-6.6 ng/ml) and 29 hours (range; 20-42 hours), respectively, following oral administration of 30 mg.Conclusions: Measurable plasma levels of PWT-143, as well as significant inhibition of basophil activation have been observed at the lowest planned dose levels. These findings suggest that PWT-143 is orally bioavailable and exhibits potent on-target activity in humans. PK results suggest daily dosing is achievable. Results from the completed study with all dose levels will be presented. DisclosuresNo relevant conflicts of interest to declare.

Abstract B34: Coordinated delivery of anticancer drug combinations incorporating molecularly targeted agents provides markedly increased plasma drug exposure, decreased toxicity and increased efficacy in preclinical tumor models

Abstract Background: Coordinated delivery of established chemotherapy combinations at synergistic drug ratios via nano-scale delivery vehicles has provided marked improvements in efficacy both preclinically and clinically. Many molecularly targeted agent (MTA) combinations have experienced difficulties in achieving optimal target inhibition without inducing dose limiting toxicities. Here we report the application of CombiPlex® technology to combinations incorporating MTAs for which optimal therapeutic effects require simultaneous tumor cell exposure. Methods: Prodrugs conjugates were synthesized for the HSP90 inhibitor AUY922 (AUY), docetaxel (DOC), the MEK inhibitor selumetinib (SEL) and Akt inhibitor ipatasertib (IPA) using cholesterol as a hydrophobic anchor joined via hydrolysable linkers that regenerate the parent drugs upon cleavage. These prodrugs were co-formulated in hydrophobic prodrug nanoparticles (HPN) by rapid mixing in the presence of surface stabilizing block co-polymers. Formulation compositions were iteratively optimized to achieve prolonged plasma drug concentrations while coordinating the PK of the combined agents. The tolerability and efficacy of the HPN combinations were compared to the free drug combinations administered in their conventional formulations. Results: AUY and DOC anchored to cholesterol via a diglycolate linker could be stably co-formulated in HPNs with a mean diameter of ∼65nm using a range of surface stabilizing block co-polymers. Using PLA-PEG block co-polymers, HPN-associated drugs exhibited no early distribution phase and virtually identical PK for AUY and DOC with a plasma half-life in mice of >12hr. Plasma concentrations of both agents over 24h were 2- to 4-orders of magnitude higher than for the free drugs. Similar PK results were obtained with the SEL:IPA combination. Combined IV treatment with DOC and AUY as the conventional free drugs led to significant increases in toxicity such that the DOC dose had to be reduced by 67% and the AUY dose had to be reduced by 60%. In contrast, when co-formulated in HPNs, both drugs could be administered with only a 30% dose reduction. In human xenograft tumor models (taxane resistant as well as taxane sensitive), the HPN formulation of AUY:DOC provided increased tumor growth inhibition; quantitative analysis of tumor growth delay revealed a 5-fold increase in antitumor activity compared to the free drug combination in the HCT15 model. A range of AUY:DOC drug ratio HPN formulations were also tested to identify the optimally efficacious drug ratio. HPN formulations of SEL:IPA also displayed improved tolerability compared to the free drug combination, particularly in view of the lower bioavailability for the agents administered in their oral dosing forms, while providing significant antitumor efficacy. Conclusions: HPN-mediated coordinated delivery of drug combinations incorporating molecularly targeted agents can favorably shift the PK/PD profile resulting in an improved therapeutic index. Initial results suggest this may expand the utility of combinations that to date have been limited by toxicities associated with dosing regimens aimed at ensuring simultaneous and durable multi-target inhibition. Citation Format: Lawrence D. Mayer, Paul Tardi, Sherwin Xie, Barry Liboiron, Winnie Lui, Leon Wan. Coordinated delivery of anticancer drug combinations incorporating molecularly targeted agents provides markedly increased plasma drug exposure, decreased toxicity and increased efficacy in preclinical tumor models. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr B34.

Abstract 5144: Low dose sorafenib delays hepatocellular cancer (HCC) development in the woodchuck model of hepatitis B related HCC

Abstract Introduction: The eastern woodchuck is an established model of human hepatitis B viral infection and spontaneously develops HCC in the context of chronic woodchuck hepatitis viral infection (WHV) at a median age of 24 months. In this translational model of angiogenesis driven HCC, we evaluated the impact of sorafenib on delaying HCC development. Methods: Woodchucks were bred and inoculated at birth with titered infectious WHV pools obtained from chronic WHV carriers. By 12 months of age, the rate of chronic WHV infection was >60%. Animals were trained to receive drug orally mixed in a liquid diet. After an initial single dose woodchuck PK study it was predicted that sorafenib given orally M-F at 2.5 mg/kg once daily or 5mg/kg daily would achieve exposure in woodchucks ∼ 2x IC50 and 5X IC50 for all targets of sorafenib. This is within the exposure achieved in humans where the starting dose achieves exposures that are ∼ 10-12X IC50. We hypothesized that for both long term tolerability and delaying of HCC development, lower doses maybe ideal. Viral titers of WHV DNA were serially assessed, PK exposure of sorafenib and serial ultrasound (USG) was done q2 weeks to assess HCC development. Six WHV+ animals of similar age per arm were randomized to Placebo (P), low or high dose sorafenib. Time to tumor development (TTD) was measured from start of therapy to first occurrence of at least one 2 cm HCC was confirmed on 2 serial USGs. Tumor volume of all tumors seen was assessed as tumor burden. Results: Median TTD was 393 days, 490 and 498 days in the P, low and high dose sorafenib groups respectively. No toxicity was seen and PK results showed exposures as predicted in the two sorafenib groups. The tumor burden adjusted for the duration of therapy was significantly lower in the low dose group than the high dose and P groups. We evaluated three possible mechansims for this delay in HCC. WHV titers decreased as tumor burden increased as viral replication halts when malignant transformation occurs. The delay in TTD was not secondary to an antiviral effect that is known in this model and in humans to delay HCC occurrence. Anti-angiogenic effect was measured on H/E following necropsy as tumor necrosis and involved 7% of the total tumor volume in low dose and 13% of total tumor volume in high dose animals and 0% in P animals. High dose sorafenib inhibited the ex-vivo mixed lymphocyte reaction of woodchuck PBMC whereas low dose sorafenib did not which mechanistically may explain the difference seen in tumor burden with low compared to high dose sorafenib. Conclusions: The delay in HCC by 100 days seen in woodchucks would translate into a 3-9 years delay in HCC occurrence in humans. The tolerability at low dose for over 2 years, lower tumor burden and differential immune effects seen at low dose vs higher dose have great translational significance in the light of the recently completed STORM trial. Support: Sorafenib: Bayer. Funding: ACS- MSRG 08-096-01-CCE Citation Format: Renuka V. Iyer, Sandra Sexton, Leslie Curtin, Gerald Fetterly, Orla Maguire, Hans Minderman, Ilia Toshkov, Bud Tennant, Alan Hutson, Donald L. Trump, Candace Johnson. Low dose sorafenib delays hepatocellular cancer (HCC) development in the woodchuck model of hepatitis B related HCC. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 5144. doi:10.1158/1538-7445.AM2015-5144

STARTRK-1: Phase 1/2a study of entrectinib, an oral Pan-Trk, ROS1, and ALK inhibitor, in patients with advanced solid tumors with relevant molecular alterations.

2596 Background: Entrectinib (formerly RXDX-101), a potent and selective small molecule inhibitor of TrkA/B/C, ROS1, and ALK kinases, has demonstrated early clinical activity when orally administered intermittently under fasting conditions (ASCO 2014). In this abstract, we report a companion Phase 1/2a trial of entrectinib administered daily in the fed state. Methods: Pts with advanced solid tumors with molecular alterations in NTRK1/2/3, ROS1 or ALK were treated daily with entrectinib in the fed state. Pts with asymptomatic untreated brain metastases were allowed; pts may have received prior TKI therapy. Endpoints include safety, RP2D, PK, and tumor response Results: Entrectinib was well tolerated across all dose levels. No DLTs or significant safety issues were reported from any cohort. Of 15 pts treated, the majority reported only G1 or G2 AEs. 3 pts reported > G3 AEs (each unrelated to entrectinib). 1 SAE (unrelated) has been reported. Entrectinib was readily absorbed with median Tmax of 4 hr at steady state. Steady state was reached within 7 days of dosing and the estimated t1/2 was approximately 17 hrs. There were dose proportional exposure increases with moderate accumulation (~2x or less) at steady state. 15 pts with various molecular alterations identified by local lab testing were treated in the following dose cohorts (mg/m2): 100 (N = 5), 200 (N = 5), 400 (N = 5). Summary of alterations of enrolled pts: NTRK (point mutation = 5; amplification = 1; rearrangement = 1); ROS1 (SNP = 1); ALK (SNP = 2; ampl = 1; rearr = 4). 3 pts with ALK-rearranged NSCLC failed at least 2 prior ALK inhibitors. No pts with ROS1 rearrangements have been treated. No objective responses observed to date. Conclusions: Entrectinib, administered daily in fed condition, is well tolerated. In STARTRK-1, there have been no responses at doses ≤ 200 mg/m2 (400 mg/m2 cohort recently opened). Doses ≥ 400 mg/m2 were associated with responses in the ALKA-372-001 Phase 1 study. Dose escalation will continue until the RP2D is identified. Thereafter, Phase 2a cohort expansion will begin enrolling pts with NTRK1/2/3, ROS1, or ALK molecular alterations to assess antitumor activity. Clinical trial information: NCT02097810.

To Give or Not to Give PK Results: An Ethical Dilemma for Researchers & Regulators in Uganda

To Give or Not to Give PK Results: An Ethical Dilemma for Researchers & Regulators in Uganda

Abstract 2908: A first-in-human phase I study of SAR650984, a humanized anti-CD38 antibody in patients with CD38+ hematological malignancies: Preliminary PK and PD results of escalation phase

Abstract SAR650984 is a novel humanized monoclonal antibody specifically targeting the CD38. , A phase 1 dose escalation study is being conducted in patients with confirmed CD38+ hematological malignancies to determine safety of SAR650984, to establish the MTD and the biologically active dose, and to characterize the PK and PD after repeated IV administration. Methods: The study design was composed of 2 parts. The first one was an accelerated phase with 1 to 3 patients per dose cohort from 0.0001 mg/kg to 0.1 mg/kg and the second phase includes 3 to 7 patients per dose cohort between 0.3 and 20 mg/kg every 2 weeks. An additional 6 patient cohort was added at 10 mg/kg every week. Results: 34 out of the 39 treated patients were Relapsed Refractory Multiple Myeloma (MM) patients. SAR650984 was well tolerated. Overall Response Rate (CR + PR) for dosing cohorts of ≥1mg/kg is 32% (2 MR, 5 PR, 2 CR of 28). Pharmacodynamics were evaluated by measuring CD38 density and its occupancy by the drug in bone marrow on cancer cells, using a validated quantitative flow cytometry method. This parameter has been correlated with the dose and exposure levels. Receptor Occupancy (RO) could be detected starting from the 1 mg/kg dose. From 5 mg/kg dose level, preliminary results demonstrated receptor occupancy greater than 70% (maximum observed: 97.7%). From 0.0001 to 0.01 mg/kg doses, no or limited PK parameters could be calculated. The PK profile was not linear with a decrease in clearance when the dose was increased suggesting target mediated clearance. Based on individual modeling, a moderate to high variability (CV% = 49 to 130%) was observed on estimated systemic total clearance, regardless of the dose group. At the10 mg/kg Q2W, the shape of the PK profile suggests saturation of the target. All MM patients (N=6) at cycle 1 had SAR650984 plasma trough levels consistently above the 10 µg/ml level which is associated with anti-tumor activity in mouse xenograft studies (Cssmin of the lowest pharmacological active dose). At 20 mg/kg Q2W, in 2/3 MM patients, SAR650984 plasma trough levels from cycle 2 were above the concentration needed to eradicate the tumor (129 µg/mL) in the same animal model, based on the Simeoni et al modelling approach. These preliminary phase 1 safety and efficacy results are associated with a favorable PK/PD profile and justify the progression of the program to phase 2. NCT : NCT01084252 Citation Format: Marie-Laure L. Ozoux, Hélène Guillemin, Marie-Hélène H. Pascual, Sylvaine Cartot-Cotton, Christine Veyrat-Follet, Delphine Valente, Maxime Moulard, Christine Mauriac, Antoine Deslandes, Dorothee Semiond. A first-in-human phase I study of SAR650984, a humanized anti-CD38 antibody in patients with CD38+ hematological malignancies: Preliminary PK and PD results of escalation phase. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2908. doi:10.1158/1538-7445.AM2014-2908

Phase II clinical trial of PM00104 (Zalypsis®) in urothelial carcinoma patients progressing after first-line platinum-based regimen

This exploratory phase II clinical trial evaluated the antitumor activity, safety profile and pharmacokinetics of PM00104 (Zalypsis(®)) 3 mg/m(2) 1 h every 3-week intravenous infusion in patients with advanced and/or metastatic urothelial carcinoma progressing after first-line platinum-based chemotherapy. The primary efficacy end point was the disease control rate (DCR), defined as the percentage of patients with confirmed objective response or progression-free at 3 months, according to the response evaluation criteria in solid tumors. In a first stage (n = 19 patients evaluable for efficacy), only one patient achieved DCR (stable disease as best response and progression-free survival of 3.1 months). According to the 2-stage design used, the primary efficacy objective was unmet, and therefore, the trial was finalized without opening the second stage. The most common adverse events related to PM00104 were fatigue, anorexia, nausea, troponin I increase and neutropenia, which were transient and manageable with dose modifications or administration delays. Mean PK results (Cmax = 48.57 μg/l and area under the curve (AUC) = 154.97 h μg/l) were similar to those observed in a previous phase I trial evaluating the same dose and schedule. Few troponin I concentrations were higher than 0.10 ng/ml, and none of them were related to parameters of PM00104 exposure such as AUC or Cmax. No recommendation is given for further evaluation of PM00104 as single-agent treatment of patients with pretreated advanced and/or metastatic urothelial carcinoma. No new safety signals were observed.

P356 Safety and PK results of a thorough QT/QTc (TQT) study of orally administered RPC1063, a novel, selective S1P1 receptor agonist

P356 Safety and PK results of a thorough QT/QTc (TQT) study of orally administered RPC1063, a novel, selective S1P1 receptor agonist

Abstract P2-16-22: A dose-finding phase lb study of BEZ235 in combination with paclitaxel in patients with HER2-negative, locally advanced or metastatic breast cancer

Abstract Background: The PI3K/Akt/mTOR pathway is the most frequently activated signaling pathway in breast cancer (BC). Activation of this pathway promotes tumor growth and progression, and resistance to anticancer therapies, including paclitaxel (PTX). BEZ235 is an oral, ATP-competitive inhibitor that targets class l PI3K and downstream effectors mTORC1/2. BEZ235 has shown antiproliferative, proapoptotic, and antiangiogenic activity in multiple preclinical cancer models. In a Ph I study, single-agent BEZ235 given twice daily (BID) showed preliminary signs of clinical activity. Methods: This was a multicenter, open-label Ph Ib/II study of daily, oral BEZ235 given BID in combination with weekly (QW) intravenous PTX in women with HER2-, metastatic or locally advanced BC (NCT01495247). For the Ph Ib part, the primary objective was to determine the maximum tolerated dose (MTD)/recommended Ph II dose (RP2D) of BEZ235 in combination with PTX based on dose-limiting toxicities (DLTs) using a 5-parameter adaptive Bayesian logistic regression model with overdose control. MTD was defined as the highest dose not causing medically unacceptable DLTs in >35% of pts during Cycle 1 (28 days). Secondary objectives included safety, preliminary activity, and PK. Safety was monitored by physical exams, vital signs, laboratory tests, weight, and cardiac health. AEs were assessed continuously by CTCAE v4.03. Tumor evaluations were performed at screening and every 8 wks after starting treatment, and assessed locally by RECIST v1.1. Results: As of April 12, 2013, 18 pts (mean age: 50 yr; 67% ≥4 prior lines of antineoplastic therapy) had been enrolled into Ph Ib. 13 pts received BEZ235 200 mg BID + PTX 80 mg/m2 QW. The dose level was then reduced to BEZ235 100 mg BID + PTX 80 mg/m2 QW (n = 5). Of 17 evaluable pts (12 at the 200-mg BID dose; 5 at the 100-mg BID dose), 6 (35%) developed ≥1 DLTs (5 [42%] at the 200-mg BID dose; 1 [20%] at the 100-mg BID dose): neutropenia (n = 3 [1 at the 100-mg BID dose]), stomatitis (n = 3), nausea (n = 2), and vomiting (n = 1). Of 18 pts, 12 have discontinued (6 due to disease progression; 4 AEs; 1 physician decision; 1 pt/guardian decision). Median duration of exposure to BEZ235 and PTX was 76 days each. The most common suspected study drug-related AEs included asthenia (78%), nausea (72%), neutropenia (72%), diarrhea (67%), stomatitis (61%), and decreased appetite (56%). Among 13 pts receiving BEZ235 200 mg BID, 2 (15%) achieved a PR, 4 (31%) had SD, and 4 (31%) had PD; all 5 pts receiving BEZ235 100 mg BID had SD. PK results showed large interpatient variability at both dose levels. Analysis of pAKT and p4EBP1 was performed on peripheral blood mononuclear cells collected from pts before treatment and 4 h following treatment (Cmax). PK/PD analysis did not provide evidence of a strong and consistent correlation between BEZ235 plasma concentrations and pAKT inhibition. Conclusions: The MTD/RP2D of BEZ235 in combination with PTX in pts with locally advanced or metastatic HER2- BC was not reached. Based on the observed overall safety profile, efficacy, variable PK, and PD data from the Ph Ib part of this study, further enrollment has stopped. The Ph II part of the study will not be conducted. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P2-16-22.

Tubulin Hyper-Acetylation In Blood Lymphocytes: Pharmacodynamic (PD) Biomarker For The Selective Histone Deacetylase (HDAC) 6 Inhibitor ACY-1215 In Multiple Myeloma (MM) Patients

IntroductionHDACs are a family of enzymes that remove acetyl groups from proteins and are involved in many key cellular processes, including apoptosis, cell cycle arrest and angiogenesis. Nonselective HDAC inhibitors has shown promise in treating MM in combination with standard therapies such as proteasome inhibitors (PIs) [1]. However, nonselective HDAC inhibitors have been of limited utility due to adverse effects. HDAC6 is a Class IIb enzyme found in the cytoplasm that is intimately involved in cytoskeletal remodeling and vesicle transport associated with degradation of misfolded protein through the regulation of the acetylation status of α-tubulin. Recent work [2, 3] suggests that selectively inhibiting HDAC6 in MM is an important therapeutic modality as part of a combination therapy with PIs and immunomodulatory agents (IMiDs) and may minimize toxicity due to Class I HDAC inhibition. ACY-1215 is a novel HDAC6-selective small molecule inhibitor that has been shown to be effective in reducing tumor burden in preclinical animal models of MM, and the anti-tumor activities correlate with increased levels of acetyl-tubulin, a HDAC6 specific substrate, in blood and tumor cells. ACY-1215 has now advanced to phase I clinical trials as a combination agent for the treatment of relapsed and refractory MM. A clinical PD biomarker for HDAC6 inhibition is critical to demonstrate that therapeutic plasma levels of ACY-1215 also increase the HDAC6 specific biomarker, acetylated tubulin, versus the Class I HDAC biomarker, acetylated histones. In addition HDAC6 inhibition is expected to be well-tolerated and dose limiting toxicity may not be reached implying continued dose escalation in phase 1 may not be warranted if there is a suitable increase in the PD HDAC6 biomarker. We describe the development of a clinical PD biomarker of HDAC6 inhibition, acetylated α-tubulin, to determine when blood levels of ACY-1215 are reached that give a specific increase in the biomarker versus acetylated histones. MethodsAssay sensitivity, dynamic range and reproducibility have been established using peripheral whole blood from healthy donors and MM patients incubated with ACY-1215 ex vivo. In the clinic, peripheral blood is collected at up to six different PK matched time points after drug administration.Lymphocytes were assessed for tubulin and histone hyper-acetylation by flow cytometry using specific antibodies that recognize acetyl groups in the context of the specific protein targets. ACY-1215 plasma concentration was also determined in the peripheral blood by an appropriate bioanalytical method. More than 50 MM patients have been enrolled in two separate clinical trials and received escalating oral ACY-1215 doses from 40 mg to 240 mg. The ACY-100 study is composed of two parts, ACY-1215 monotherapy and combination therapy with both bortezomib and dexamethasone. A second study, ACE-MM-101, examines ACY-1215 in combination with lenalidomide and dexamethasone. Results & ConclusionPatients in ACY-100 and ACE-MM-101 clinical trials have shown elevated tubulin hyper-acetylation in peripheral blood lymphocytes as ACY-1215 dose increases from 40 mg to 240 mg. ACY-1215 plasma concentration reaches a maximal level (Cmax) 1 hr after administration. An apparent exposure plateau was reached at dose levels >160 mg where Cmax reached 1.2 - 1.8 µM. Correlating to the PK levels, the PD biomarker acetyl-tubulin increases to a maximal level 1 hr after dosing compared to predose, and declines to basal level by >4 hr with an apparent lag period compared to plasma levels of ACY-1215. Acetyl-histone levels were not significantly changed at these doses indicating a predominant HDAC6 selective effect. As plasma levels increased with dose from 40 mg to 160 mg so do the number of patients that have a measurable increase in acetyl-tublin such that at dose levels ≥80 mg all patients have a measurable increase in acetylated tubulin. In conclusion the clinical PK and PD results, comparing to prior preclinical studies [4], suggest that ACY-1215 has reached a pharmacologically relevant level of HDAC6 inhibition at clinical doses ≥80 mg. These results will aid in the determination of the recommend phase 2 dose of ACY-1215 in combination with PIs and IMiDs. Disclosures:Tamang:Acetylon Pharmaceuticals, Inc: Employment, Equity Ownership. Jones:Acetylon Pharmaceuticals, Inc: Employment, Equity Ownership. Yang:Acetylon Pharmaceuticals, Inc: Employment, Equity Ownership. Supko:Acetylon: Research Funding.

Efficacy, PK and Safety Results of Clinical Study Of Recombinant Fusion Protein Linking Coagulation Factor IX With Albumin (rIX-FP) In Previously Treated Patients With Hemophilia B

BackgroundThe standard of care for patients with severe hemophilia B is replacement treatment with Factor IX (FIX) 2-3 times a week. A fusion protein genetically linking recombinant human coagulation FIX with recombinant human albumin (rIX-FP) was developed with the aim to extend the half-life of FIX. In the completed Phase I pharmacokinetic study, the mean half-life of rIX-FP was found to be over 5 times longer than the subjects' previous FIX. Thus, rIX-FP has potential to prevent bleedings for longer periods, allowing reduction in the frequency of injections compared to standard FIX and to reduce the number of injections required to treat a single bleed. AimsThis was a Phase I/II open-label, multicenter study of rIX-FP in previously treated patients 12-65 years of age with severe hemophilia B (FIX ≤ 2%). The study evaluated the safety and efficacy of rIX-FP, including prevention of bleeding episodes during weekly prophylaxis of rIX-FP. MethodsAfter completion of a 14-day rIX-FP pharmacokinetic assessment, 13 subjects in the prophylaxis arm received weekly prophylaxis of rIX-FP for approximately 11 months, and 4 subjects in the on-demand arm received rIX-FP upon occurrence of bleeding events. The treatment doses were initially selected based upon the pharmacokinetic profile of rIX-FP and subject's bleeding phenotype, and doses could be adjusted at the Investigator's discretion. ResultsSeventeen subjects were enrolled from hemophilia treatment centers in Israel and Bulgaria; the mean age was 26 years (range 13 to 46 years). Following a single injection of 25 IU/kg rIX-FP (n=13), the mean FIX activity level was 3.75% and 2.67% above baseline at Day 7 and Day 14, respectively, and the mean half-life of rIX-FP was 95 hours (comparable to the previously reported Phase I data).Over the 11 month treatment period, rIX-FP demonstrated a good safety profile with a total of over 700 EDs. The treatment was well tolerated and no FIX inhibitor formation was observed. There was no AE considered to be related to treatment with rIX-FP. No subject was withdrawn from the study due to safety concerns or lack of hemostatic efficacy.All 13 prophylaxis subjects were successfully maintained on a weekly routine regimen of rIX-FP for the entire duration of the study, with annualized spontaneous bleeding rates of 1.255 and 1.134 (mean and median respectively). Furthermore, three prophylaxis subjects who received only on-demand treatment prior to study entry had greater than 80% reduction in the annualized bleeding rate compared to their annualized bleeding rate prior to study entry. All bleeding events were treated successfully with ≤ 2 injections of rIX-FP, with approximately 90% of bleeds treated with a single injection of rIX-FP. The mean weekly consumption of rIX-FP was reduced markedly compared to the subjects' weekly consumption of the previous FIX product. ConclusionThis Phase I/II study demonstrated the clinical efficacy of rIX-FP for once weekly routine prophylaxis to prevent spontaneous bleeding episodes and for the treatment of bleeding episodes. In addition, rIX-FP showed an excellent safety and an improved PK profile over currently marketed factor IX products. Disclosures:Lubetsky:CSL Behring: Investigator for CSL clinical trial of rIX-FP Other. Lissitchkov:CSL Behring: Investigator for CSL Behring clinical trial of rIX-FP Other. Santagostino:CSL Behring: Honoraria, Investigator for CSL Behring clinical trial of rIX-FP Other, Research Funding, Speakers Bureau. Jotov:CSL Behring: sub-investigator for CSL Begring trial of rIX-FP Other. Barazani-Brutman:CSL Behring: study coordinator for CSL Behring rIX-FP trials Other. Voigt:CSL Behring: Employment. Moises:CSL Behring: Employment. Jacobs:CSL Behring: Employment. Martinowitz:CSL Behring: Honoraria, Investigator for CSL rIX-FP trials Other, Speakers Bureau.

Targeting p53 mutant ovarian cancer: Phase I results of the WEE1 inhibitor MK-1775 with carboplatin plus paclitaxel in patients (pts) with platinum-sensitive, p53-mutant ovarian cancer (OC).

5518 Background: MK-1775 is a highly selective, investigational oral tyrosine kinase inhibitor of WEE1, which regulates G2 cell cycle checkpoint. Functional p53 mutation impairs G1 checkpoint; hence, targeting G2 checkpoint with MK-1775 in p53 mutants should induce synthetic lethality. Methods: Pts with platinum-sensitive disease-recurrent OC who had measurable disease (RECIST 1.1) with loss of function (LOF) p53 mutations by Roche AmpliChip were eligible. All pts received MK-1775 225mg twice daily (BID) D1-D3 (5 doses) plus carboplatin AUC5 + paclitaxel 175mg/m2 every 21 days (CP) for 6 cycles. The objective for the phase I run-in portion of the study was to determine the recommended phase II dose based on safety data. A Toxicity Probability Interval method [Ji et al, Clin Trials 2010; 7(6):653-63] would determine if additional lower doses should be explored. A randomized phase II portion, assessing the efficacy of the combination vs placebo, would start if ≥5 radiological responses and <5 dose-limiting toxicities (DLTs) were observed among the first 13 pts. Results: Of 76 pts screened (26 wt, 43 mutant [24 nonfunctional], 7 undetermined), 19 women had LOF p53 mutations and were eligible. Fifteen consented and were enrolled in the Phase I: median age was 57 (range 38-77); ECOG 0:1 ratio 9:6 pts. Three DLTs were observed: G3 febrile neutropenia, G4 neutropenia, and G4 thrombocytopenia. Diarrhea (84.6%), nausea (76.9%), and fatigue (76.9%) were the most common adverse events (AEs). Seven of 13 pts completed treatment (2 ongoing). Three pts discontinued due to AEs and 3 patients withdrew consent prior to completing treatment. Of 14 evaluable pts by RECIST 1.1 there were 11 partial responses (PRs; 6 confirmed, 5 unconfirmed) and 3 had stable disease; 7 pts were evaluable by CA125 with 3 complete responses and 4 PRs. MK-1775 PK results were similar to those reported for monotherapy studies. Conclusions: The combination of MK-1775 225mg BID x 5 doses with CP is well tolerated, with a preliminary radiological response rate of 78.6%, and has met the safety and efficacy bar for randomized phase II assessment in part 2 of the study. Clinical trial information: NCT01357161.

Abstract 2089: NT113, a potent and selective pan-ErbB inhibitor, is efficacious in vivo and has high brain penetrance.

Abstract Background: The ErbB family of receptor tyrosine kinases EGFR (ErbB1), Her2 (ErbB2) and ErbB4 (Her4) function to transduce signals across the cell membrane in a wide variety of epithelial cells. ErbB dimerization results in the phosphorylation of intracellular tyrosine residues, activating diverse signaling pathways. These downstream pathways culminate in a variety of cellular responses, including cell growth, proliferation, differentiation and migration. In addition, interactions between ErbB receptors provide a mechanism for signal differentiation and amplification. Dysregulation of ErbB mediated signaling confers a growth advantage, and can result in cellular transformation and/or increased tumor metastatic potential. ErbB family members have been well validated cancer targets. Both antibodies and small molecule kinase inhibitors targeting individual ErbB receptors or both ErbB1/ErbB2 together have been approved for the treatment of human cancers. In addition, some ErbB targeting agents are in late stages of clinical testing. A large fraction of glioblastoma multiforme (GBM, the most common and malignant primary brain tumor) harbors EGFRvIII activating mutation, and may represent an especially appropriate subgroup of this cancer for treatment with ErbB inhibitors. Results: NT113 is a potent and selective pan-ErbB family kinase inhibitor. It also inhibits known mutant EGFRs resistant to first generation EGFR inhibitors, including the T790M gate keeper mutant. NT113 inhibited proliferation of ErbB kinase driven cell lines, and GBM cell lines harboring EGFRvIII mutations. NT113 showed excellent oral PK in mouse and rat. rat, iv CL = 6.3 L/h/Kg, oral t1/2 = 15 h, F = 70%; mouse iv CL = 1.4 L/h/Kg, oral t1/2 = 16h, F = 100%. Importantly, NT113 showed significant brain exposure in rat oral PK studies, with brain/plasma ratio > 4 at 2, 4 and 24 hr time points, while afatinib brain level was not detectable at all 3 time points. If these PK results are maintained in human patients, it may lead to significant clinical activity. Longer half life would allow the drug to better permeate into tumor, while the brain penetrance is favorable for insuring the clinical activity of NT113 for CNS cancer, as well as for brain metastasis of NSCLC and breast cancers. In vivo, NT113 displayed excellent activities in NT87 gastric cancer xenograft models, and in NCI-H1975 (T790M gate keeper mutation) NSCLC xenograft models. In an intracrania GBM xenograft model with EGFRvIII mutation, NT113 completely suppressed the growth of tumor, and significantly prolonged the life span of the mice after two weeks of oral dosing. Conclusion: NT113 appears to be a promising best-in-class agent for treating cancers whose growth is driven by both wild type and mutant ErbB. It is currently undergoing IND enabling studies. Citation Format: Wang Shen, Harry Pedersen, Dennis Brown, Jackie Walling, David James, Tomoko Ozawa. NT113, a potent and selective pan-ErbB inhibitor, is efficacious in vivo and has high brain penetrance. [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 2089. doi:10.1158/1538-7445.AM2013-2089