Steady-state Cmin Research Articles

Phase Ib trial of erdafitinib (E) combined with enfortumab vedotin (EV) following platinum and PD-1/L1 inhibitors for metastatic urothelial carcinoma (mUC) with FGFR2/3 genetic alterations (GAs).

625 Background: Erdafitinib (E) is a treatment option in mUCpatients with somatic FGFR2/3 GAs after progression on platinum-based chemotherapy (PBC). Enfortumab Vedotin (EV) is approved as a single agent to treat mUC patients following prior PBC and PD1/L1 inhibitors or as second-line therapy for cisplatin-ineligible patients. Retrospective studies suggest that the activity of EV is not compromised by FGFR2/3 GAs. E and EV have different mechanisms of activity, and toxicities are mostly non-overlapping. Hence, there is rationale to evaluate the feasibility of combination E + EV, to overcome the difficulties of resistance and sequencing agents in mUC patients with FGFR2/3 GAs. Methods: This is an ongoing, single arm, multicenter, dose-escalation and expansion study of combination E + EV evaluating the safety, tolerability, pharmacokinetics (PK), and antitumor activity in patients with mUC harboring somatic FGFR2/3 GAs who have progressed after PBC and/or PD1/L1 inhibitor therapies. Dose escalation phase aims to identify the maximum tolerable dose and recommended phase 2 dose of EV at dose levels of 1 mg/kg and 1.25 mg/kg in combination with E at 8 mg/day as shown in the table. Preliminary safety, PK, and efficacy data for Dose Level (DL) 1 and 2 are presented in this abstract. Results: As of data cutoff, based on 3+3 design, total 8 patients are enrolled and finished dose limiting toxicity (DLT) period (1st cycle). Six patients were enrolled in DL1 with 1 DLT (skin rash) and 2 patients in DL2. The most common treatment-related adverse events (TRAE) included hyperphosphatemia (88%), mucositis (88%), hypercalcemia (75%), high AST (75%), hand foot syndrome (75%), peripheral neuropathy (75%), alopecia (63%), diarrhea (63%), hypoalbuminemia (63%) and hypomagnesemia (63%). Grade 3 TRAE included hand foot syndrome (50%), anemia (17%), rash (17%), anorexia (17%) and paronychia (17%). One patient developed grade 4 Stevens-Johnson syndrome related to EV which subsequently improved. PK data are available for all 6 subjects in DL1. The average steady-state Cmin of E and monomethyl auristatin E (MMAE) was 1430 ± 639 ng/mL and 1.4 ± 0.9 ng/mL, respectively, and the average Cmax of MMAE was 3.9 ± 0.9 ng/mL at DL1. All 8 patients are evaluable for response, and best response is partial response in all. Detailed safety and additional efficacy data will be presented. Conclusions: Combination E + EV is feasible and preliminarily exhibits antitumor activity. Dose escalation is ongoing to identify the MTD or recommended dose for expansion of the trial. Clinical trial information: NCT04963153 . [Table: see text]

Physiologically based pharmacokinetic modeling of daptomycin dose optimization in pediatric patients with renal impairment.

Background and Objective: Daptomycin is used to treat Gram-positive infections in adults and children and its dosing varies among different age groups. We focused on the pharmacokinetics of daptomycin in children with renal impairment, which has not been evaluated. Methods: A physiologically based pharmacokinetic (PBPK) model of daptomycin was established and validated to simulate its disposition in healthy populations and adults with renal impairment, along with a daptomycin exposure simulated in pediatric patients with renal impairment. Results: The simulated PBPK modeling results for various regimens of intravenously administered daptomycin were consistent with observed data according to the fold error below the threshold of 2. The Cmax and AUC of daptomycin did not differ significantly between children with mild-to-moderate renal impairment and healthy children. The AUC increased by an average of 1.55-fold and 1.85-fold in severe renal impairment and end-stage renal disease, respectively. The changes were more significant in younger children and could reach a more than 2-fold change. This scenario necessitates further daptomycin dose adjustments. Conclusion: Dose adjustments take into account the efficacy and safety of the drug; however, the steady-state Cmin of daptomycin may be above 24.3 mg/L in a few instances. We recommend monitoring creatine phosphokinase more than once a week when using daptomycin in children with renal impairment.

Ongoing Results of a Phase 1B/2 Dose-Escalation and Cohort-Expansion Study of the Selective, Noncovalent, Reversible Bruton'S Tyrosine Kinase Inhibitor, Vecabrutinib, in B-Cell Malignancies

Ongoing Results of a Phase 1B/2 Dose-Escalation and Cohort-Expansion Study of the Selective, Noncovalent, Reversible Bruton'S Tyrosine Kinase Inhibitor, Vecabrutinib, in B-Cell Malignancies

Vancomycin drug monitoring in infants with CoNS sepsis-target attainment, microbiological response and nephrotoxicity.

To characterize residual vancomycin concentrations (Cmin) and assess the relationships between Cmin, the risk of nephrotoxicity and persistent CoNS sepsis. In this 5-year retrospective study among infants treated with vancomycin, the primary outcome was the proportion of those with a steady state Cmin between 10 and 20 mg/L. The secondary outcomes were nephrotoxicity and persistent CoNS sepsis. Of 120 infants included, the median first steady state Cmin was 12.4 mg/L and 77 (64%) had a Cmin between 10 and 20 mg/L. Six percent developed nephrotoxicity. This risk was not associated with Cmin. Of the 30 infants with CoNS sepsis, 17 (57%) had persistent bacteremia, and this risk did not correlate significantly with Cmin, CoNS minimal inhibitory concentration (MIC) for vancomycin, or Cmin/MIC. The majority of infants achieved targeted levels of vancomycin, but persistent bacteremia was common. We did not identify a Cmin threshold associated with nephrotoxicity, nor with microbiological clearance.

Pharmacokinetic (PK) and exposure-response (ER) analysis of pertuzumab (P) in patients (pts) with HER2-positive metastatic gastroesophageal junction and gastric cancer (mGEJC/GC).

2564Background: The phase 2a, dose-finding JOSHUA study reported increased P clearance (CL; 37% lower P steady-state Cmin [Cmin,ss]) in pts with HER2+ mGEJC/GC vs metastatic breast cancer (MBC). Ba...

Abstract CT144: Preclinical and clinical studies and modeling and simulation to identify phase II dose for cerdulatinib: a dual SYK/JAK inhibitor for the treatment of B-cell malignancies

Abstract Background. Subsets of B cell lymphomas appear to rely on B-cell receptor (BCR) and/or cytokine JAK/STAT signaling for survival. SYK is upstream of BTK, PI3Kδ, and PLCγ2 on the BCR signaling pathway, and thus a potential therapeutic target. Additional survival support appears to be mediated by cytokine-induced JAK/STAT pathways. Cerdulatinib is a dual SYK/JAK inhibitor being evaluated in patients with relapsed/refractory B cell malignancies in a dose escalation study. Patient PK and PD parameters indicated nonlinearity at doses above 30 mg QD. Exposure at the 45 mg dose was 3-fold higher than at 30 mg QD. As the dose was further increased up to 100 mg QD, the Cssmax and AUC values plateaued. PD results also appeared to plateau achieving approximately 50-90% target inhibition in peripheral blood assays at steady-state Cmin to Cmax, respectively. The target therapeutic exposure for oncology, based on pre-clinical models, is a Cssmin >1.5uM which would lead to >90% SYK/JAK inhibition at the trough concentration Objective. Pre-clinical and clinical PK/PD relationships and correlations between SYK/JAK inhibition and tumor response will be presented. A physiological-based PK (PBPK) model was developed to elucidate the relationship between dose, dosing schedule, and exposure. The goal of developing a PBPK model was to provide a strategy to increase exposure in patients to therapeutic target levels. Methods. This is a 3+3 dose escalation study with 28-day cycles and doses studied from 15 mg to 100 mg QD, and up to 45 mg BID. PK, PD, and safety were monitored. SYK and JAK inhibition was determined by multiple whole blood assays measuring signaling via the B cell antigen receptor, IL2, IL4, IL6, and GM-CSF. Serum markers of tumor burden - CCL3, CCL4, and other markers of inflammation, were also measured. Physiochemical parameters and in vitro ADME parameters were used to construct a PBPK model. Results. Exposure correlated well with PD and tumor responses in the dose escalation study. Low pH dependent solubility was identified as the rate-limiting factor in increasing plasma concentrations. The PBPK model predicted BID dosing would result in significantly higher plasma levels. The Cssmin concentration of QD doses from 40 to 100 mg QD was ∼0.70 uM while for the 45 mg BID dose for the first 3 patients the Cssmin was ∼1.5 uM. Complete target inhibition at this Cssmin was achieved with good tolerability. Conclusions. The preliminary PBPK model identified the pH dependent low solubility of cerdulabinib as the rate-limiting factor of absorption with increasing doses. Subsequent evaluation of 45 mg BID doses in patients provided higher Cmin, Cmax, and AUC values for all patients treated at this dose level and PD markers indicated complete inhibition of both pathways. We are now enrolling additional patients at this dose, in preparation for selecting our final phase II dose. Citation Format: Janet M. Leeds, Greg Coffey, Anjali Pandey, Pam B. Conley, Karen Rowland Yeo, Alice B. Ke, John T. Curnutte, Glenn Michelson. Preclinical and clinical studies and modeling and simulation to identify phase II dose for cerdulatinib: a dual SYK/JAK inhibitor for the treatment of B-cell malignancies. [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 CT144.

Phase 3 pharmacokinetics and safety study of a posaconazole tablet formulation in patients at risk for invasive fungal disease.

BACKGROUND Antifungal prophylaxis with a new oral tablet formulation of posaconazole may be beneficial to patients at high risk for invasive fungal disease. A two-part (Phase 1B/3) study evaluated posaconazole tablet pharmacokinetics (PK) and safety. METHODS Patients with neutropenia following chemotherapy for haematological malignancy or recipients of allogeneic HSCT receiving prophylaxis or treatment for graft-versus-host disease received 300 mg posaconazole (as tablets) once daily (twice daily on day 1) for up to 28 days without regard to food intake. Weekly trough PK sampling was performed during therapy, and a subset of patients had sampling on days 1 and 8. Cmin-evaluable subjects received ≥6 days of dosing, and were compliant with specified sampling timepoints. Steady-state PK parameters, safety, clinical failure and survival to day 65 were assessed. ClinicalTrials.gov, NCT01777763; EU Clinical Trials Register, EUDRA-CT 2008-006684-36. RESULTS Two hundred and ten patients received 300 mg posaconazole (as tablets) once daily. Among Cmin-evaluable subjects (n = 186), steady-state mean Cmin was 1720 ng/mL (range = 210-9140). Steady-state Cmin was ≥700 ng/mL in 90% of subjects with 5% (10 of 186) 500 ng/mL and only one patient (<1%) had a pCavg <500 ng/mL.

Clinical and Correlative Results of a Phase 1 Study of Cerdulatinib (PRT062070) a Dual SYK/JAK Inhibitor in Patients with Relapsed/Refractory B Cell Malignancies

Background: Background: Subsets of B cell lymphomas demonstrate a reliance on B-cell receptor (BCR) and/or cytokine JAK/STAT signaling for survival. SYK is positioned upstream of BTK, PI3Kδ, and PLCγ2 on the BCR signaling pathway, making it a potential therapeutic target. Additional survival support appears to be mediated by cytokine-induced JAK/STAT pathways, which can be activated by tumor autocrine signaling loops or by pro-inflammatory cytokines originating from non-malignant infiltrating leukocytes present in the tumor microenvironment. Pre-clinical models demonstrate broad anti-tumor activity with combined SYK and JAK inhibition relative to selective inhibition of these targets alone.Methods: This is a 3+3 dose escalation study with 28-day cycles and doses studied ranging from 15mg to 65mg once daily. PK, PD, and safety were monitored. Clinial response was assessed by standard criteria. The level of inhibition of SYK and JAK was determined by multiple whole blood assays measuring signaling via BCR and receptors for the B-cell antigen, IL2, IL4, IL6, and GM-CSF. Serum markers of tumor burden - CCL3, CCL4, and other markers of inflammation, were also measured.Results: A total of 36 patients (pt) with CLL/SLL or B cell NHL were dosed. Median age was 67 years (range 23-85) and median prior therapies (tx) was 3 (range 1-8). Treatment emergent AEs of ≥ grade 3 observed deemed related to study drug were: neutropenia (n=2), anemia (n=1), and pneumocystis pneumonia (grade 5, n=1) at 30mg; anemia, AST increase, hypotension, thrombocytopenia (n=1 for each), and fatigue (n=2) at 45mg; anemia, neutropenia, abdominal pain, pneumonia, and fatigue (n=1 for each) at 50mg, and diarrhea and fatigue (n=1 for each) at 65mg. The patient with grade 3 AST had tumor progression to the liver. No dose-limiting toxicities (DLT) have been reported to date and cerdulatinib is generally well tolerated. Saturating inhibition of SYK and JAK in circulating lymphocytes (>80% inhibition) and serum inflammation markers (e.g., β2M,CRP, CCL4; 50-90% inhibition) occurs at plasma concentrations achieved at Cmin of the 40mg dose ( 0.6-1µM) at steady state. At the 65mg dose, these parameters were 80-90% inhibited on day 1 of cycle 1 indicating a more immediate effect compared to lower doses. At the 65mg dose, steady state Cmin and Cmax concentrations are approximately 1 and 2µM, respectively, sufficient to induce apoptosis in the majority of B cell lymphoma cell lines tested. PK is suitable for once daily dosing with a half-life of 12-16 hours and a 2:1 peak-trough ratio. Partial responses (n=4) were observed at 30mg in a pt with del 17p CLL who had relapsed after 6 prior tx; at 45mg a pt with CLL who had received 4 prior tx, and another pt with FL who had received 3 prior tx; and at 65mg in a pt with a transformed DLBCL (MYC, BCL2, and BCL6 expression by IHC) who had relapsed approximately 1 year after 1 prior tx. Responses occurred after 2 cycles of tx. Seven total patients have remained on cerdulatinib for over 200 days, including 2 who have been on for a year or more.Conclusions: Cerdulatinib continues to demonstrate a favorable PK profile and good tolerability at high levels of SYK and JAK inhibition. The clinical responses seen to date support further development and dose escalation continues to identify the MTD. Phase II expansion cohorts are open or planned for CLL, FL, aggressive NHL (DLBCL), and a combination with rituximab. DisclosuresMichelson:Portola Pharmaceuticals Inc: Employment, Equity Ownership, Research Funding. Pandey:Portola Pharmaceuticals Inc: Employment. Birrell:Portola Pharmaceuticals Inc: Employment. Coffey:Portola Pharmaceuticals Inc: Employment, Equity Ownership, Research Funding. Leeds:Portola Pharmaceuticals Inc: Employment. Curnutte:Portola Pharmaceuticals Inc: Employment.

Predicting Cerdulatinib Therapeutic Concentrations in Patients with Relapsed/Refractory B Cell Malignancies Using Preclinical Models and Clinical PK/PD and Tumor Response Correlates

▪Background: Preclinical data and early clinical studies demonstrate a reliance on B cell antigen receptor (BCR) signaling and/or cytokine-induced JAK/STAT signaling for survival of subsets of B cell malignancies. Increased serum concentrations of several cytokines are observed in CLL and NHL and predict a more aggressive disease progression (Yan, X. J., et al, 2011; Mahadevan, D., et al, 2009; el Far. M., et al, 2004; Lai, R., et al, 2002; Fayed, L., et al, 2001). The source of these cytokines may be derived from the tumor itself in an autocrine stimulation fashion, or from non-tumor leukocytes which have mounted an ineffective immune response within the tumor microenvironment. Experimentally, IL4 has been shown to promote the survival of CLL B cells in culture and protect them from death by treatment with fludarabine and chlorambucil (Steele, A.J., et al, 2010). The mechanism underlying this survival support appears to be cytokine-induced up-regulation of BCL2 family members (Castejon, R., et al, 1999; Jewell, A.P., et al, 1994; Panayiotidis, P., et al, 1993; Dancescu, M., et al, 1992). Combined SYK/JAK inhibition may therefore represent a powerful strategy to treat B cell malignancies. Cerdulatinib is a reversible ATP competitive inhibitor of SYK, JAK1, JAK3, and TYK2 that is currently in clinical development for the treatment of relapsed/refractory B cell lymphoma and leukemia. We review here cerdulatinib preclinical and clinical pharmacodynamic/pharmacokinetic relationships to tumor response in treated patients.Methods: Inhibition of SYK- and JAK-dependent and independent signaling was determined by intracellular phospho-flow following stimulation of human whole blood with various agonists against BCR and cytokine receptors. Anti-tumor activities of cerdulatinib and other selective inhibitors of BCR and JAK/STAT pathways were evaluated in fourteen DLBCL cell lines by CellTiter Glo, caspase 3 induction, and cell cycle arrest. In vivo anti-inflammatory activity of cerdulatinib was determined using the rat collagen induced arthritis model. The effective concentrations pre-clinically were compared to cerdulatinib-induced SYK and JAK inhibition, anti-inflammatory activity, and anti-tumor activity following oral dosing in relapsed/refractory CLL and NHL patients.Results: Cerdulatinib demonstrated broad anti-tumor activity in DLBCL cell lines, relative to other targeted agents. In a panel of 14 cell lines representing both ABC and GCB subtypes, 9 underwent apoptosis and an additional 2 underwent cell cycle arrest. Cooperative effects of SYK and JAK inhibition were observed in 4 of the cell lines, whereas 3 cell lines were sensitive to SYK but not JAK inhibition, and 1 cell line was sensitive to JAK but not SYK inhibition. Three of the 14 cell lines were resistant to cerdulatinib. Apoptosis was induced in the majority of DLBCL cell lines at 2 µM (achieved at clinical doses ≥40 mg). In healthy whole blood ex vivo spiking experiments, cerdulatinib selectively inhibited BCR/SYK and cytokine (IL2, IL4, IL6) JAK/STAT signaling with IC50's ranging from 0.2-0.9 µM (achieved at clinical doses of 15 mg-40 mg). Inflammation and joint destruction in the rat collagen-induced arthritis model was arrested at 0.3 µM average plasma concentration (achieved at clinical doses ≥30 mg). In cancer patients receiving cerdulatinib once daily, plasma concentrations above 2 µM have been safely achieved, while maintaining steady-state Cmin of ~1 µM. Following oral dosing in patients, SYK and JAK pathways were inhibited with similar potency as was observed in healthy volunteer ex vivo spiking experiments with >90% inhibition of SYK and JAK safely achieved for multiple cycles of therapy. Tumor response as measured by CT scan strongly correlated with percent inhibition of SYK and JAK signaling in patient-derived whole blood, and percent inhibition of serum markers of inflammation (e.g., β2M, CRP, IL10, VCAM1, sTNFR, CCL3).Conclusion: Once daily oral dosing of cerdulatinib at 40-65 mg achieves steady-state plasma concentrations in the 1-2µM range (trough to peak), which is sufficient to block SYK/JAK signaling, inflammatory mechanisms, and affect tumor viability both in DLBCL cell lines and in patients. We conclude that these exposure levels are sufficient to begin testing the clinical potential of cerdulatinib. We will begin enrolling phase Ib/IIa expansion cohorts this year. DisclosuresCoffey:Portola Pharmaceuticals Inc: Employment, Equity Ownership, Research Funding. Feng:Portola Pharmaceuticals: Employment, Equity Ownership, Research Funding. Michelson:Portola Pharmaceuticals Inc: Employment, Equity Ownership, Research Funding. Leads:Portola Pharmaceuticals: Employment, Equity Ownership, Research Funding. Curnutte:Portola Pharmaceuticals, Inc.: Employment; 3-V Biosciences: Equity Ownership; Sea Lane Biotechnologies: Consultancy. Pandey:Portola Pharmaceuticals Inc: Employment. Conley:Portola Pharmaceuticals, Inc.: Employment.

Abstract B27: A phase I dose escalation study of the MDM2 inhibitor DS-3032b in patients with advanced solid tumors and lymphomas

Abstract Background: Reactivation of the tumor suppressor functions of p53 by targeting its negative regulator mdm2 represents an attractive approach to treat cancers expressing wildtype functional p53. DS-3032b disrupts the interaction between p53 and mdm2, and has demonstrated anti-tumor activity preclinically. Here, we report results from the Dose Escalation part (Part 1) of our Phase I Trial in solid tumors and lymphomas which aimed to determine a tentative recommended Phase 2 dose (tRP2D) and characterize the safety, tolerability, pharmacokinetic (PK), and pharmacodynamic (PD) profiles of DS-3032b. Methods: DS-3032b dose was escalated using an accelerated titration followed by modified Continuous Reassessment Method and Escalation with Overdose Control design, from 15 mg through 30, 60, 120, 160, and 240 mg in a PO QD schedule in 21 of 28 days per cycle (QD 21/28). A 90 mg dose schedule of everyday administration (QD 28/28) had also been tested. Results: Thirty-one of 34 patients (pts) enrolled were evaluable for dose limiting toxicities (DLT). Of the 13 different tumors types enrolled, 77% were TP53 wildtype, with well-differentiated/de-differentiated (WD/DD) liposarcoma (LPS) being the most frequent (n = 13; 44%). The maximum tolerated dose (MTD) was determined to be 120 mg with 2/13 DLTs for the QD 21/28 schedule, which is currently being evaluated as the tRP2D in the Dose Expansion part (Part 2) of the study in more limited tumor types. The MTD was 90 mg with 1/9 DLT for the QD 28/28 schedule. The most common drug-related adverse events (AEs) were hematological (thrombocytopenia (Th) [68%], anemia [35%], neutropenia [29%] gastrointestinal (nausea [71%], vomiting [32%] and diarrhea [38%]), and fatigue [47%]. Prolonged Th resulting in &amp;gt;4 weeks dose interruption was seen in 8 pts, 2 were treated at the tRP2D. Bone marrow examination performed in selected pts revealed no dysplastic changes. A total of 6 pts experienced DLTs, all treated at MTD or higher. The 3 MTD DLTs were caused by Th that resulted in &amp;gt;1 week delay in starting Cycle 2. There was a moderate degree of inter-patient variability in PK exposure, with considerable overlap in exposures at the two MTDs (Cycle 1 Day 1 mean Cmax = 559.9 and 567.7 ng/mL, and mean AUC 0-24 = 8047.7 and 8629.3 ng*h/mL respectively for 120 and 90 mg doses). The steady state Cmin at MTDs exceeded the levels demonstrated as necessary for both disrupting MDM2-p53 interactions and showing antitumor activity preclinically. Induction of the PD biomarker MIC 1 in serum correlated with drug exposure. Twenty three pts were evaluable for tumor response. Most pts (20/26) experienced stable disease (SD) as the best tumor response though no pt had an objective response. The median progression free survival (mPFS) for all evaluable pts at 5.7 months, with 3 (1 carcinoid and 2 liposarcoma; all contain MDM2 amplification) still on study after receiving therapy for 12+, 20+, and 21+ cycles. The greatest tumor shrinkage and most durable SD were seen in pts with WD/DD LPS with mPFS of 6.3 months and 3-month PFS rate of 92%. Conclusions: DS-3032b shows an acceptable safety profile at the tRP2D of 120mg QD x 21/28. Preliminary evidence of clinical activity with prolonged PFS was seen in WD/DD LPS in which MDM2 is universally amplified, warranting further investigation in this disease. ClinicalTrials.gov Identifier: NCT01877382 Citation Format: Todd Bauer, David Hong, Neeta Somaiah, Charles Cai, Saeheum Song, Prasanna Kumar, Roohi Gajee, Michael Rosen, Jarema Kochan, Shuquan Chen, David Hyman, Tyler Masters, Funda Meric-Bernstam, Archie Tse, Patricia LoRusso, Amy Weise, Mrinal Gounder. A phase I dose escalation study of the MDM2 inhibitor DS-3032b in patients with advanced solid tumors and lymphomas. [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 B27.

Ribavirin and abacavir drug interaction in HIV–HCV coinfected patients

To examine the impact of ribavirin and abacavir coadministration on hepatitis C virus (HCV) virological response and trough ribavirin plasma concentration (Cmin) in HIV-HCV coinfected patients. Pharmacokinetic substudy on patients from the ANRS CO-13 HEPAVIH cohort. Patients receiving ribavirin-pegylated interferon for whom a ribavirin steady state Cmin was prospectively determined were included. Rapid virological response (RVR), early virological response (EVR) and sustained virological response (SVR) as well as HCV-RNA decline were evaluated. Overall, 124 HIV-HCV coinfected patients (95% on antiretroviral therapy) were enrolled. Of these patients, 22% received abacavir. The overall median (interquartile range) ribavirin Cmin was 1.6 mg/l (1.2-2.2) with no statistical difference between abacavir users and nonusers [1.5 mg/l (0.99-2.1) and 1.7 (1.2-2.3), P = 0.15]. RVR and EVR were 52 and 72%, respectively. There was no difference observed in the proportion of abacavir users vs. nonusers achieving RVR (respectively 59 vs. 50%, P = 0.40) or EVR (72 vs. 73%, P = 0.94), or in the HCV-RNA decline at week 4 [-2.24 log(10) IU/ml, (-3.58; -0.81) and -1.27 (-2.8; -0.47) P = 0.28] or at week 12 [-1.76 log(10) IU/ml (-3.67; -0.35) and -1.85 (-3.13; -1.13) (P = 0.58)]. The SVR rate was 45% for abacavir users and 24% for abacavir nonusers, but the difference was not statistically significant (P = 0.059). In our study, there was no evidence that abacavir affected HCV treatment outcomes and the ribavirin Cmin was similar in abacavir users and nonusers, confirming the absence of pharmacokinetic interaction between abacavir and ribavirin. An abacavir-containing regimen is, therefore, a well tolerated treatment alternative for coinfected patients starting HCV treatment.

Exposure-response (E-R) analysis of rilotumumab (R, AMG 102) plus epirubicin/cisplatin/capecitabine (ECX) in patients (pts) with locally advanced or metastatic gastric or esophagogastric junction (G/EGJ) cancer.

2535 Background: R is an investigational, fully human monoclonal antibody to hepatocyte growth factor/scatter factor (HGF/SF), the only known MET receptor ligand. In a double-blind, placebo-controlled, phase 2 trial of 121 pts with G/EGJ cancer, R (7.5 or 15 mg/kg) + ECX showed trends for improved overall survival (OS) and progression-free survival (PFS) compared to ECX alone (placebo, P). Methods: E-R analyses were performed using pharmacokinetic (PK), biomarker, efficacy, and safety data. A population PK model was used to evaluate covariate effects (eg, demographics, ECX, and MET status) on R PK and predict individual R exposure (trough steady-state Cmin [C]). The effect of C on OS/PFS was evaluated with Kaplan-Meier estimates and Cox proportional hazards models. Covariate effects for OS/PFS were evaluated with multivariate analysis. The relationships between adverse events of interest (AEs), lab values, and C were analyzed with descriptive statistics and linear regression models. Results: R showed linear PKs that were unaffected by ECX or MET levels. Pts who received R + ECX were divided into low C (CL) and high C (CH) groups by the median C (94 µg/mL). Median PFS was 4.2, 4.5, and 6.9 months in the P, CL, and CH groups; median OS was 8.9, 9.5, and 13.3 months. Improved OS/PFS in CH and improved PFS in CH and CL groups (vs P) were seen after adjusting for baseline covariates. Pts with tumors that expressed high MET levels (METHigh: &gt; 50% cells positive) showed greater improvement in OS in the CH vs CL group. No improvement in OS was seen in METLow pts (CH and CL groups) compared to placebo (see Table). No relationship was seen between R exposure and AEs or lab values. Conclusions: Higher R exposure was associated with improved OS/PFS in METHigh pts without increased toxicity, supporting further study of R + ECX in G/EGJ cancer. [Table: see text]

A multicenter, randomized phase II study of rilotumumab (R) (AMG 102) or placebo (Pbo) plus mitoxantrone (M) and prednisone (P) in patients (pts) with previously treated castrate-resistant prostate cancer (CRPC).

115 Background: R is an investigational, fully human monoclonal antibody to hepatocyte growth factor (HGF) that prevents HGF binding to the c-Met receptor. We conducted a 3-arm, double-blind, randomized phase 2 study to examine the safety and estimate the efficacy of adding R to MP in CRPC pts. Methods: Eligible pts (≥ 18 years) had progressive CRPC, prior taxane-based chemotherapy, and ECOG PS ≤ 1. The primary endpoint was overall survival (OS). Secondary endpoints included progression-free survival (PFS), PSA response, pharmacokinetics (PK), and safety. Pts were randomized 1:1:1 to R (15 mg/kg IV Q3W) + MP (12 mg/m2 IV Q3W, 5 mg BID orally) [Arm A]; R (7.5 mg/kg IV Q3W) + MP [Arm B]; or Pbo + MP [Arm C] for up to 12 cycles. Results: 142 pts (Arms A/B/C: 45/48/49 pts) were enrolled between March 10, 2009 and December 2, 2009. Median age: 67/67/69 yrs; ECOG PS 1: 69/71/61%; progression during prior taxane therapy: 51/54/47%. Most common reason for discontinuation was disease progression (60/58/69%). Efficacy is shown in the table. R + MP showed no statistically significant difference in OS. Adverse events (AE) with ≥ 5% difference in Arms A + B vs C included peripheral edema, 24/8%; nausea, 44/35%; mucosal inflammation, 8/0%; rash, 8/0%; arthralgia, 16/8%; neutropenia, 16/8%. Grade 5 AE: cardiac arrest, pulmonary embolism, septic shock (1 each in Arm B). R showed linear PK with mean (SD) steady state Cmin of 251 (100) and 127 (35) μg/mL and Cmax of 609 (126) and 297 (75) μg/mL in Arms A and B. R did not affect PK of M. Conclusions: R + MP was well tolerated with no unexpected toxicities. R + MP showed no significant improvements in OS, PFS, and PSA response. [Table: see text]

S3-7: Everolimus for Postmenopausal Women with Advanced Breast Cancer: Updated Results of the BOLERO-2 Phase III Trial.

Abstract Background: The mTOR pathway is constitutively activated in hormone-resistant advanced breast cancer (ABC). In phase II trials, everolimus (EVE) showed promising efficacy both as monotherapy and in combination with endocrine therapy in patients with estrogen receptor-positive (ER+) ABC. This double-blind, placebo-controlled, phase III study evaluated EVE plus exemestane (EXE) in patients with ER+ ABC refractory to letrozole or anastrozole. Patients and Methods: Eligible patients were randomized (2:1) to EXE (25 mg/day) with EVE (10 mg/day) or with matching placebo. The primary endpoint was progression-free survival (PFS). Secondary endpoints included overall survival, response rate, quality of life (QoL), and safety. Results: 724 patients were randomized (485: EVE+EXE; 239: EXE). Baseline characteristics were well balanced; median age was 62 years, 56% had visceral involvement, and 84% had documented benefit from previous endocrine therapy, which included letrozole or anastrozole (100%), tamoxifen (48%), fulvestrant (16%), and chemotherapy for advanced disease (25%). This analysis is based on 457 events and median follow-up of 12.5 months. PFS by investigator assessment showed a hazard ratio (HR) of 0.44 (95% CI: 0.36−0.53) and a median duration of 7.4 (EVE+EXE) vs 3.2 months (EXE) (P&amp;lt;1 × 10−16) and 12-month estimate of 31% vs 10%. PFS by central assessment showed an HR of 0.36 (95% CI: 0.28−0.45) and a median duration of 11.0 (EVE+EXE) vs 4.1 months (EXE) (P&amp;lt;1 × 10−16) and 12-month estimate of 48% vs 18%. Response rates and clinical benefit rate were also higher for EVE+EXE (12.0% vs 1.3% and 50.5% vs 25.5%). A total of 138 patients died; 17.3% in the EVE+EXE arm and 22.6% in the EXE arm. The most common grade 3/4 adverse events were stomatitis (8% vs 1%), anemia (7% vs 1%), hyperglycemia (5% vs &amp;lt; 1%), dyspnea (4% vs 1%), and fatigue (4% vs 1%) for the EVE+EXE and EXE groups, respectively. Grade 3 pneumonitis was observed in patients receiving EVE (3% vs 0%). No difference in time to deterioration of QoL was observed. EVE increased EXE steady-state Cmin and Cmax levels by 45% and 64%, respectively, with no difference in estradiol levels. Serum markers of bone resorption and bone formation increased in the EXE arm and generally decreased in the EVE+EXE arm. Conclusion: The addition of EVE to EXE is associated with significant and sustained prolongation of PFS. Adverse events were higher in the combination arm but manageable by dose interruption and/or reduction and did not affect QoL. EVE in combination with an aromatase inhibitor is a promising therapeutic option for women with hormone receptor-positive advanced breast cancer. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr S3-7.

Posaconazole Plasma Concentrations in Critically Ill Patients

Posaconazole is an azole antifungal agent with a broad spectrum of activity and a manageable side-effect profile. Although the pharmacokinetics of posaconazole have been described in healthy volunteers who received the drug by means of a nasogastric tube or with nutritional supplements, the pharmacokinetics of posaconazole have not been reported in critically ill patients. Twenty-seven patients in the general intensive care unit managed according to standard protocols were randomly allocated to dose regimens of either 400 mg twice daily or 200 mg 4 times daily. Plasma samples were collected for pharmacokinetic analysis after the first dose and at steady-state. Posaconazole plasma concentrations were compared with suggested effect targets for prophylaxis and treatment. Mean Cmin steady-state plasma concentrations of posaconazole were low for both regimens (306 and 137 ng/mL for 400 mg twice daily and 200 mg 4 times daily regimens, respectively), as was total exposure to posaconazole in each group [area under the concentration-time curve (AUC0-t) for first dose: 761 and 299 μg·h/L]. Only 17% of patients achieved steady-state Cmin posaconazole plasma concentrations above the suggested target for prophylaxis, and only one patient had a Cmin posaconazole concentration that exceeded the suggested target for treatment effect. Systemic exposure to posaconazole seemed to be subtherapeutic in most patients in this cohort. Poor absorption of posaconazole due to drug interactions may explain the low systemic exposure; however, further investigation is necessary. These data suggest that there is a need for an intraveneous formulation of the drug if it is to be used effectively in critically ill patients, and therapeutic drug monitoring is an essential tool in this setting to identify patients with low systemic exposure to prevent therapeutic failure.

A first-in-human phase I study of U3-1287 (AMG 888), a HER3 inhibitor, in patients (pts) with advanced solid tumors.

3026 Background: Human epidermal growth factor receptor 3 (HER3) is a key dimerization partner for the HER family and activates oncogenic signaling pathways. Its overexpression in many solid tumors has been linked to poor prognosis. U3-1287 (AMG 888) is a fully human anti-HER3 monoclonal antibody with demonstrated anticancer activity in preclinical models. This study had 2 parts: based on the observed tolerability of ≤20 mg/kg and pharmacokinetics (PK) study from the dose-escalation phase (part 1), 9, 14, and 20 mg/kg Q2W dosages were given in the dose-expansion phase (part 2). Methods: Pts with non–small cell lung cancer (NSCLC) and other refractory solid tumors thought to express HER3 were eligible. Study assessments included adverse event (AE) rates, PK, and tumor response (per modified RECIST and overall metabolic tumor response by EORTC). Human antihuman antibody (HAHA) responses were measured to assess immunogenicity. Results: Part 2 data (as of 9/24/10) are reported. Pts (N=31) with head and neck (1 pt), breast (1), ovary (1), cecum/appendix (1), colorectal cancer (CRC, 10), and NSCLC (17) tumor types were given 9 (n=10), 14 (n=2), and 20 mg/kg (n=19) of U3-1287 (AMG 888). Pts had a median (range) of 5 (2–10) prior chemotherapy regimens. 11 serious AEs were reported in 10 pts; none were attributable to U3-1287 (AMG 888). 16 pts (51.6%) experienced AEs ≥ grade (Gr) 3, with 1 Gr 5 dyspnea and 1 Gr 4 hypoglycemia. Two AEs ≥ Gr 3 were considered drug-related: Gr 3 anemia and Gr 3 rash. Gr 1/2 drug-related AEs in ≥10% of pts were fatigue, diarrhea, and nausea. Of 21 pts assessed, no HAHA responses were observed (by 21 days postdose). PK analysis (n=15) showed that steady state is reached after 3 dosing cycles for pts receiving 9, 14, or 20 mg/kg. Mean steady state Cmin was >10-fold greater than the threshold concentration required for 90% HER3 inhibition in xenograft models. Eight pts (6 NSCLC, 2 CRC) had a best response of stable disease at or beyond day-70 visit. One pt (NSCLC, 20 mg/kg) had significant tumor shrinkage (26.3%) and partial metabolic response by FDG-PET scan. Conclusions: U3-1287 (AMG 888) is well tolerated, with an absence of detectable HAHA responses. Part 2 data support 9–20 mg/kg Q2W dosage for future studies.

A Randomized Crossover Study to Determine Relative Bioequivalence of Tenofovir, Emtricitabine, and Efavirenz (Atripla) Fixed-Dose Combination Tablet Compared With a Compounded Oral Liquid Formulation Derived From the Tablet

A Randomized Crossover Study to Determine Relative Bioequivalence of Tenofovir, Emtricitabine, and Efavirenz (Atripla) Fixed-Dose Combination Tablet Compared With a Compounded Oral Liquid Formulation Derived From the Tablet

Dasatinib Exposure and Relationship to Efficacy and Safety In Patients with Newly Diagnosed Chronic Myeloid Leukemia In Chronic Phase (CML-CP)

AbstractAbstract 4938 Introduction:Dasatinib 100 mg once daily (QD) has superior efficacy compared with imatinib in patients with newly diagnosed CML-CP, as demonstrated by a randomized phase 3 trial in this setting (CA180-056/DASISION; Kantarjian et al, N Engl J Med 2010;362:2260-70). Exposure-efficacy response was characterized by examining the relationship between weighted time-averaged dasatinib concentration (wCavg) and the probability of achieving a confirmed complete cytogenetic response (cCCyR; defined as CCyR detected in 2 consecutive assessments), the primary endpoint of DASISION. Exposure-safety response was characterized by describing the relationship between dasatinib trough concentration (Cmin) and occurrence of pleural effusion in DASISION. Methods:wCavg and Cmin were determined by a population pharmacokinetic (PPK) model that described concentration-time data from 235 subjects in DASISION. wCavg was calculated within the treatment duration up to the time of cCCyR or discontinuation (whichever occurred earlier) excluding dose interruptions. The probability of cCCyR was described by a logistic regression model with respect to Cavg and the following covariates as predictors: cumulative duration of dose interruption (calculated as a percentage of the overall treatment duration [Pintr] until cCCyR or discontinuation, whichever occurred earlier), age, gender, and race. The relationship of Cmin to the hazard of pleural effusion (any grade) was characterized using a Cox proportional-hazards model that also examined the following covariates: age, gender, race, history of cardiac disease, and dasatinib treatment status (first line/after prior imatinib). Results:Concentration-time data for dasatinib were described by a linear two-compartment PPK model with first-order absorption. No statistically significant or clinically relevant differences in dasatinib PK were found between patients with newly diagnosed disease or those with prior imatinib therapy. Within the limited range of exposure produced by dasatinib 100 mg QD treatment and measured in the analysis dataset, the probability of achieving cCCyR in patients with newly diagnosed CML-CP was similar irrespective of dasatinib wCavg: high rates of cCCyR (>70% by 12 months) were observed across the exposure range. The probability of cCCyR decreased by 14% for each doubling in duration of dose interruption (Pintr; p<0.01). Among analyzed patients, pleural effusion (any grade) was reported in 10% of patients at 1 year in the DASISION trial. The risk of pleural effusion increased with dasatinib steady-state Cmin (hazard ratio of 1.1 for every unit increase of Cmin; 95% confidence interval [CI]: 1.04–1.17; p<0.01) and age (hazard ratio of 2.01 for every decade increase in life; 95% CI: 1.73–2.34; p<0.01). Conclusions:These analyses show that the probability of cCCyR in patients with newly diagnosed CML-CP was similarly high across the exposure range/wCavg produced by dasatinib 100 mg QD treatment. Cmin and age are associated with the risk of pleural effusion.AnalysisPredictorMedian (5th–95th percentiles)Odds/hazard ratio coefficient (95% CI)P-valueCCyRPintr (%)11.5 (0–27.7)0.86 (0.81–0.92)<0.001Pleural effusionCmin (ng/mL)1.69 (0–7.09)1.10 (1.04–1.17)0.002Age (years)56 (27–73)2.01 (1.73–2.34)<0.001CCyR = odds ratio (logistic regression); pleural effusion = hazard ratio (Cox proportional hazards).CCyR coefficients are with respect to log2 of predictor variable; log2 Pintr increases by 1 unit for each doubling in value.Pleural effusion coefficients are with respect to Cmin and age/10; age/10 coefficient increases by 1 unit for each additional 10 years. Disclosures:Wang: Bristol-Myers Squibb: Employment. Off Label Use: First-line treatment of CML with dasatinib. Agrawal: Bristol-Myers Squibb: Employment. Damokosh: Bristol-Myers Squibb: Employment, Equity Ownership. Roy: Bristol-Myers Squibb: Employment, Equity Ownership.

An Open-Label, Positron Emission Tomography Study to Assess Adenosine A2A Brain Receptor Occupancy of Vipadenant (BIIB014) at Steady-State Levels in Healthy Male Volunteers

Adenosine A2A receptor antagonists are potential new treatments for Parkinson disease. We used positron emission tomography (PET) of the A2A receptor radiotracer, [C]SCH442416, to assess binding of the novel A2A antagonist, vipadenant (previously known as BIIB014), to human brain A2A receptors and to investigate the relationship among dose, steady-state plasma levels, and receptor occupancy. We used PET to compare [C]SCH442416 uptake before and after blockade with daily oral vipadenant (2.5-100 mg/d for 10 or 11 days) in healthy volunteers (n = 15). We estimated receptor occupancy in brain regions of interest, particularly the putamen, by kinetic modeling of PET data. We estimated the dose, minimal plasma concentration at steady state (Cmin), and area under the plasma concentration curve (AUC0-tau) at the steady state required for saturation (> or =90% receptor occupancy) using Bayesian Emax and logistic regression models. The estimated receptor occupancy of vipadenant in the brain regions of interest varied from 74% to 94% at the lowest daily dose (2.5 mg) and reached saturation in all regions at 100 mg. In the putamen, the estimated minimal daily dose, steady-state Cmin, and steady-state AUC0-tau required for receptor saturation were 10.2 mg (interquartile range, 28%), 0.097 microg/mL (27%), and 6 microg h/mL (21%), respectively. This study provides the first evidence that vipadenant occupies A2A receptors in the human brain. Receptor occupancy was related to both dose and plasma levels of vipadenant. These results, coupled with previous efficacy results in animals, justify continued development of vipadenant as a potential treatment for Parkinson disease.

Comparison of Steady-State Imatinib (IM) Trough Levels, Clinical Response, and Safety Between Caucasian and Asian Patients with Chronic Lyeloid Leukemia in Chronic Phase (CML-CP) Treated with 400mg and 800mg Daily Doses of IM in the Tyrosine Kinase Inhibitor Optimization and Selectivity (TOPS) Study.

Abstract Abstract 1127 Poster Board I-149 Background In the TOPS study, IM trough levels (Cmin) were collected from different race groups, mainly Caucasian and Asian, but also Black and others. Inter-ethnic differences in the PK of a drug are known to be important factors accounting for inter-individual variation in drug responsiveness. This analysis reports the comparison between Caucasian and Asian CML patients (pts) treated at doses of 400 mg QD and 400 mg bid (800 mg daily) of IM Cmin on Day 29 of initial treatment, clinical response, safety and tolerability. Methods Steady state IM Cmin on Day 29 and clinical response and safety data obtained during the first 12 months (mos) of treatment were obtained from pts randomized 2:1 to 800 mg or 400 mg daily IM. The steady-state Cmin was defined as predose concentration collected approximately within ±3 hours of the scheduled dosing time on Day 29. The associations of race with the rates of major molecular response (MMR) and complete cytogenetic response (CCyR) were evaluated. Correlation of IM exposure with clinical response (MMR and CCyR) was assessed by grouping pts into quartiles based on their measured IM Cmin levels at Day 29. The safety endpoint for each pt was the presence or absence of an adverse event (AE) of grade 3 or higher in the first 12 mos from the first dose. Results IM Cmin levels were available from 229 pts in TOPS including 54 Caucasians, 18 Asians, and 14 Black and others at 400 mg (total 86) and 103 Caucasians, 29 Asians, and 11 Black and others at 800 mg (total 143). For the first 12 mos, the means of the average dose intensities for Asian (mean [range], 362 [267-400] in 400 mg and 666 [226-800] in 800 mg) were not significantly different from Caucasian (386 [204-597] in 400 mg and 666 [289-800] in 800 mg) (P=0.070 and P=0.995 for the 400 mg and 800 mg arms, respectively). Mean (± SD) of IM Cmin levels (ng/mL) with respect to race are shown in Table 1. IM Cmin was slightly over-proportional to dose and showed large interpatient variability (CV=42-60%) for both dose groups regardless of the race group. In the lower quartile Cmin group (Cmin&lt;1290 ng/mL), the differences in CCyR and MMR rates between Asian and Caucasian pts were significant (P=0.031 and P=0.022 respectively), which was probably due to a higher rate of dose interruptions in the 1st 12 mos in Asian pts. A definitive conclusion cannot be drawn due to the small number of Asian pts. Occurrences of at least one grade 3 or 4 adverse event were found to be significantly higher in Asian pts (69% and 75% in the 1st 6 and 12 mos respectively) compared to Caucasian pts (53% and 57% in the 1st 6 and 12 mos respectively) (P=0.028 and P=0.008 respectively). Conclusion The results of this analysis from TOPS show that IM Cmin levels were similar between Caucasian and Asian CML pts in each treatment arm. There were no major differences in efficacy, as measured by MMR and CCyR rates by 12 mos, between Asian and Caucasian pts. There were no unexpected differences in patterns of AEs between Caucasian and Asian pts; however, occurrences of one or more grade 3 AEs were higher in Asian. Further analysis on a larger group of CML pts will be needed to evaluate the impact of AE rate differences between Caucasian and Asian pts. Disclosures Kim: Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Wyeth: Research Funding. Granvil:Novartis: Employment. Demirhan:Novartis: Employment. Reynolds:Novartis: Employment. Jin:Novartis: Employment. Wang:Novartis: Employment, Equity Ownership. Baccarani:Novartis Pharma: Consultancy, Honoraria, Research Funding, Speakers Bureau; Bristol-Mayer Squibb: Consultancy, Honoraria, Research Funding, Speakers Bureau. Cortes-Franco:Novartis: Honoraria, Research Funding, Speakers Bureau; Wyeth: Honoraria, Research Funding, Speakers Bureau; BMS: Honoraria, Research Funding, Speakers Bureau. Druker:OHSU patent #843 - Mutate ABL Kinase Domains: Patents &amp; Royalties; MolecularMD: Equity Ownership; Roche: Consultancy; Cylene Pharmaceuticals: Consultancy; Calistoga Pharmaceuticals: Consultancy; Avalon Pharmaceuticals: Consultancy; Ambit Biosciences: Consultancy; Millipore via Dana-Farber Cancer Institute: Patents &amp; Royalties; Novartis, ARIAD, Bristol-Myers Squibb: Research Funding. Hughes:Bristol-Myers Squibb: Advisor, Honoraria, Research Funding; Novartis: Advisor, Honoraria, Research Funding. Guilhot:Novartis: Consultancy, Honoraria, Research Funding; BMS: Consultancy, Honoraria.