Evaluation of the effect of erenumab on migraine-specific questionnaire in patients with chronic and episodic migraine.

Erenumab is a fully human anti-canonical calcitonin gene-related peptide receptor monoclonal antibody approved for migraine prevention. The Migraine-Specific Quality-of-Life Questionnaire (MSQ) is a 14-item patient-reported outcome instrument that measures the impact of migraine on health-related quality of life. Erenumab data from four phase II/III clinical trials were used to develop an item response theory (IRT) model within a nonlinear mixed effects framework, (i) evaluate the MSQ item information with respect to patient disability, (ii) characterize the longitudinal progression of the MSQ, and (iii) quantify the effect of erenumab on the MSQ in patients with migraine. The majority (80%) of information was found to be contained in 9 out of 14 items, extending the current knowledge on the reliability of the MSQ as a psychometric tool. Simulations across three MSQ domains show significant improvement from baseline, exceeding minimally important differences. Overall, the IRT model platform developed herein allows for systematic quantification of the effect of erenumab on the MSQ in patients with migraine.

Post hoc analysis of clinical trial data and pharmacokinetic data to assess wearing-off of erenumab within monthly treatment cycle.

BACKGROUND: Treatment wearing-off has been reported for calcitonin gene-related peptide-pathway monoclonal antibodies, including erenumab, specifically in the last week of the monthly dosing cycle. OBJECTIVE: We sought to determine the consistency of erenumab effect throughout the monthly treatment cycle. METHODS: In this post hoc analysis of four pivotal double-blind, randomized controlled studies of erenumab in episodic and chronic migraine, we assessed wearing-off based on change in weekly migraine days at week 4 versus average over weeks 1-3 in each monthly dosing cycle. Analyses were conducted at each monthly dosing cycle in all patients, in responders (≥50% reduction in weekly migraine days), and in consistent responders (response in ≥2monthly cycles). RESULTS: There was no evidence of wearing-off in the full study populations of two global studies (N = 946 and N = 656) and two Japan studies (N = 475 and N = 261). In the full study population, mean change in weekly migraine days at week 4 compared with the average over week 1-3 ranged from 0.15 days improvement to 0.19 days worsening in the placebo group and 0.08 days improvement to 0.20 days worsening in the erenumab groups. A subgroup of responders experienced wearing-off, but the extent of wearing-off did not differ between erenumab and placebo groups. The mean change in weekly migraine days at week 4 compared with the average over weeks 1-3 ranged from 0.34 to 0.61 days worsening in the placebo group and 0.27 to 0.78 days worsening in the erenumab groups. Few patients had persistent wearing-off in ≥2 consecutive monthly treatment cycles. For erenumab-treated responders, serum erenumab concentrations were similar among patients experiencing wearing-off and those maintaining response. CONCLUSION: No systematic wearing-off with erenumab was identified. Further research is needed to determine if wearing-off reported for some patients in clinical practice reflects a true treatment response pattern or normal fluctuations in migraine frequency.

Non-human primates in the PKPD evaluation of biologics: Needs and options to reduce, refine, and replace. A BioSafe White Paper.

Monoclonal antibodies (mAbs) deliver great benefits to patients with chronic and/or severe diseases thanks to their strong specificity to the therapeutic target. As a result of this specificity, non-human primates (NHP) are often the only preclinical species in which therapeutic antibodies cross-react with the target. Here, we highlight the value and limitations that NHP studies bring to the design of safe and efficient early clinical trials. Indeed, data generated in NHPs are integrated with in vitro information to predict the concentration/effect relationship in human, and therefore the doses to be tested in first-in-human trials. The similarities and differences in the systems defining the pharmacokinetics and pharmacodynamics (PKPD) of mAbs in NHP and human define the nature and the potential of the preclinical investigations performed in NHPs. Examples have been collated where the use of NHP was either pivotal to the design of the first-in-human trial or, inversely, led to the termination of a project prior to clinical development. The potential impact of immunogenicity on the results generated in NHPs is discussed. Strategies to optimize the use of NHPs for PKPD purposes include the addition of PD endpoints in safety assessment studies and the potential re-use of NHPs after non-terminal studies or cassette dosing several therapeutic agents of interest. Efforts are also made to reduce the use of NHPs in the industry through the use of in vitro systems, alternative in vivo models, and in silico approaches. In the case of prediction of ocular PK, the body of evidence gathered over the last two decades renders the use of NHPs obsolete. Expert perspectives, advantages, and pitfalls with these alternative approaches are shared in this review.

Immunogenicity of erenumab: A pooled analysis of six placebo-controlled trials with long-term extensions.

BACKGROUND: Immunogenicity of erenumab, a human anti-calcitonin gene-related peptide receptor monoclonal antibody developed for migraine prevention, has been evaluated throughout clinical development. METHODS: Integrated post hoc analysis assessing immunogenicity of erenumab across six clinical trials in patients with episodic and chronic migraine (N = 2985). Anti-erenumab antibody incidence and potential impact on pharmacokinetics, efficacy, and safety were evaluated in short-term (double-blind treatment phase 12-24 weeks) and long-term (double-blind treatment phase plus extensions of up to 5 years) analyses. RESULTS: Anti-erenumab binding antibody incidence was low with few patients developing neutralizing antibodies. Antibody responses were mostly transient with low magnitude. Binding antibodies developed as early as 2-4 weeks after the first dose; the majority developed within the first 6 months and very few after the first year. Serum concentrations of erenumab in antibody-positive patients were generally lower than, but within the range of, antibody-negative patients. There was no impact of anti-erenumab antibodies on erenumab efficacy or safety with no differences between antibody-positive and antibody-negative patients in change in monthly migraine days or adverse event rates. CONCLUSIONS: This pooled analysis showed that immunogenicity had no meaningful clinical impact on efficacy or safety of erenumab in patients with migraine.Clinical Trial Registration: ClinicalTrials.gov, NCT01952574; ClinicalTrials.gov, NCT02456740; Clinicaltrials.gov NCT02483585; Clinicaltrials.gov, NCT02174861; Clinicaltrials.gov, NCT02630459; Clinicaltrials.gov, NCT03812224.

Influence of Renal Function on Pharmacokinetics, Pharmacodynamics, and Safety of a Single Dose of Romosozumab.

We evaluated the pharmacokinetics, pharmacodynamics, and safety of a single subcutaneous dose of romosozumab 210 mg, a monoclonal antibody against sclerostin, in an open-label, parallel-group study in participants with severe (stage 4) renal impairment (RI; n = 8) or end-stage renal disease requiring hemodialysis (ESRD-RH; n = 8), or healthy participants with normal renal function (n = 8). Compared with the group with normal renal function, the mean romosozumab exposure was 31% and 43% higher as measured by maximum observed serum concentration and area under the concentration-time curve, respectively, in the severe RI group and similar to those in the ESRD-RH group. For all 3 groups, the maximum mean percent increase in procollagen type 1 N terminal propeptide and decrease in serum C-telopeptide levels from baseline were observed on day 15. Changes in procollagen type 1 N terminal propeptide and serum C-telopeptide were of similar patterns in all 3 groups. The single dose of romosozumab 210 mg was well tolerated. Adverse events (AEs) were reported for 13 patients (7 patients with severe RI and 6 with ESRD-RH), with no deaths, AEs, or serious AEs leading to withdrawal. The incidence of subjects with postbaseline transient decreases in serum calcium (severe RI, n = 1; ESRD-RH, n = 5) and increases in intact parathyroid hormone (severe RI, n = 7; ESRD-RH, n = 7; healthy, n = 3) were greater in severe RI and ESRD-RH groups than in the healthy group. All reported events of hypocalcemia (severe RI, n = 1; ESRD-RH, n = 4) were asymptomatic. These results support the use of romosozumab without dose adjustment in patients with severe RI or ESRD-RH.

Pharmacokinetic Drug-Drug Interaction Study of Omecamtiv Mecarbil With Amiodarone and Digoxin in Healthy Subjects.

Omecamtiv mecarbil (OM), a novel cardiac myosin activator, is being evaluated for the treatment of heart failure with reduced ejection fraction. In vitro studies demonstrate OM as a substrate and inhibitor of P-glycoprotein (P-gp), which can result in drug-drug interactions. Two phase 1, open-label studies assessed the effect of coadministration of OM (50-mg single dose) on the pharmacokinetics of digoxin (0.5-mg single dose; N = 15), a P-gp substrate, and the effect of coadministration of amiodarone (600-mg single dose), a P-gp inhibitor, on the pharmacokinetics of OM (50-mg single dose; N = 14) in healthy subjects. The ratios of the geometric least squares mean (90% confidence interval [CI]) of digoxin coadministered with OM vs digoxin alone for area under the plasma concentration-time curve (AUC) from time 0 to infinity, AUC from time 0 to the time of the last quantifiable concentration, and maximum observed plasma concentration were 1.06 (90%CI, 0.99-1.14), 1.06 (90%CI, 0.98-1.14), and 1.08 (90%CI, 0.92-1.26), respectively. The ratios of the geometric least squares mean of OM coadministered with amiodarone vs OM alone for AUC from time 0 to infinity, AUC from time 0 to the time of the last quantifiable concentration, and maximum observed plasma concentration were 1.21 (90%CI, 1.08-1.36), 1.21 (90%CI, 1.07-1.36), and 1.08 (90%CI, 0.96-1.22), respectively. In conclusion, OM coadministered with digoxin or amiodarone did not result in any clinically relevant pharmacokinetic drug-drug interactions.

Omecamtiv mecarbil does not prolong QTc intervals at therapeutic concentrations.

AIMS: Omecamtiv mecarbil (OM) is a novel selective cardiac myosin activator under investigation for the treatment of heart failure. This study aimed to evaluate the effect of therapeutic concentrations of OM on electrocardiogram (ECG) parameters and exclude a clinically concerning effect on the rate-corrected QT (QTc) interval. METHODS: In part A, 70 healthy subjects received a 25 mg oral dose of OM, and pharmacokinetics were assessed. Only subjects with maximum observed plasma concentration ≤ 350 ng/mL (n = 60) were randomized into part B, where they received a single oral dose of placebo, 50 mg OM and 400 mg moxifloxacin in a 3-period, 3-treatment, 6-sequence crossover study with continuous ECG collection. RESULTS: After a 50-mg dose of OM, mean placebo-corrected change from baseline QTcF (∆∆QTcF; Fridericia correction) ranged from -6.7 ms at 1 hour postdose to -0.8 ms at 4 hours postdose. The highest upper bound of the 1-sided 95% confidence interval (CI) was 0.7 ms (4 h postdose). Moxifloxacin resulted in a clear increase in mean ∆∆QTcF, with a peak value of 13.1 ms (90% CI: 11.71-14.57) at 3 hours; lower bound of the 1-sided 95% CI was > 5 ms at all of the 3 prespecified time points. Based on a concentration-QTc analysis, an effect on ∆∆QTcF exceeding 10 ms can be excluded up to OM plasma concentrations of ~800 ng/mL. There were no serious or treatment-emergent adverse events leading to discontinuation from the study. CONCLUSION: OM does not have a clinically relevant effect on the studied ECG parameters.

Pharmacokinetic/pharmacodynamic and safety study of a single dose of evolocumab 140 mg in healthy Chinese subjects.

OBJECTIVE: Evolocumab, a human monoclonal antibody that binds to proprotein convertase subtilisin/kexin type 9 (PCSK9), markedly reduces low-density lipoprotein cholesterol (LDL-C). Here we characterize the pharmacokinetics, pharmacodynamics, safety, and tolerability of evolocumab manufactured at a new site administered in healthy Chinese subjects. MATERIALS AND METHODS: This phase 1 study of a single subcutaneous 140-mg dose of evolocumab was conducted in healthy subjects of Chinese descent residing in Hong Kong. Subjects were followed through day 85. RESULTS: 20 subjects (all men) were enrolled. Mean (SD) age was 26.6 (8.5) years; baseline LDL-C was 2.4 (0.7) mmol/L. Mean (SD) evolocumab maximum serum concentration (Cmax) was 14.1 (5.0) µg/mL; area under the serum drug concentration-time curve from time 0 to time of last quantifiable concentration (AUClast) was 178 (80) day×µg/mL; AUC from time 0 to infinity (AUCinf) was 187 (80) day×µg/mL; terminal half-life was 5.95 (1.76) days; median time to reach Cmax (tmax) was 4.0 days. Maximum LDL-C decrease (-57.5%) was observed on day 15 and recovered to baseline by day 57. The most common adverse events (AEs) were nasal congestion (20%), oropharyngeal pain (15%), sneezing (15%), cough (10%), upper respiratory tract infection (10%), and diarrhea (10%). Most AEs were isolated incidences of mild severity, with no serious or treatment-related events. No anti-evolocumab antibodies were detected. CONCLUSION: A single 140-mg dose of evolocumab manufactured at the new site and administered in healthy Chinese subjects was associated with typical antibody pharmacokinetics, rapid and reversible decreases in LDL-C, and no new safety events.

A Phase 1, Randomized, Double-Blind, Single-Dose, Placebo-Controlled Safety, Tolerability, And Pharmacokinetic/Pharmacodynamic Study Of Evolocumab In Healthy Chinese Subjects.

PURPOSE: Evolocumab is a human monoclonal antibody that reduces circulating low-density lipoprotein cholesterol (LDL-C) by inhibiting proprotein convertase subtilisin/kexin type 9 (PCSK9). Data on evolocumab pharmacokinetics and pharmacodynamics are derived mostly from Caucasian populations. The objectives of this study were to characterize the single-dose pharmacokinetic and pharmacodynamic parameters, safety, and tolerability of evolocumab in healthy Chinese subjects. SUBJECTS AND METHODS: This was a phase 1, randomized, double-blind, placebo-controlled study (CTR20150465). Two parallel cohorts were randomized 5:1 to receive single subcutaneous injections of either evolocumab (140 mg or 420 mg) or placebo. Pharmacokinetics, pharmacodynamics, and safety were evaluated through day 85. The primary endpoints were maximum concentration (Cmax) and area under the drug concentration-time curve from time 0 to time of last quantifiable concentration (AUClast). RESULTS: Thirty-six men (median age 26) were enrolled to receive evolocumab 140 mg (n=15), evolocumab 420 mg (n=15), or placebo (n=6). After 140 mg and 420 mg evolocumab, mean (SD) Cmax was 13.8 (3.6 µg/mL and 67.6 (15.2) µg/mL, respectively, and mean (SD) AUClast was 166 (55) day·µg/mL and 1110 (274) day·µg/mL, respectively. LDL-C declined reversibly, with reductions of 70% at 140 mg and 71% at 420 mg. Maximum effects on LDL-C and PCSK9 levels were reached by day 15 and 24 hrs, respectively, at 140 mg, and by day 22 and 4 hrs, respectively, at 420 mg. No serious adverse events occurred and the overall incidence of treatment-emergent adverse events was similar for evolocumab and placebo: 26.7% (140 mg) and 33.3% (placebo); 66.7% (420 mg) and 66.7% (placebo). CONCLUSION: In this population of healthy Chinese subjects, single 140 mg and 420 mg doses of evolocumab exhibited nonlinear kinetics and more than dose-proportional increases in exposure, were associated with up to 71% reduction in LDL-C, and demonstrated a safety profile similar to placebo.

Biodistribution, shedding, and transmissibility of the oncolytic virus talimogene laherparepvec in patients with melanoma.

BACKGROUND: Talimogene laherparepvec (T-VEC) is an intralesionally delivered, modified herpes simplex virus type-1 oncolytic immunotherapy. The biodistribution, shedding, and potential transmission of T-VEC was systematically evaluated during and after completion of therapy in adults with advanced melanoma. METHODS: In this phase 2, single-arm, open-label study, T-VEC was administered into injectable lesions initially at 106 plaque-forming units (PFU)/mL, 108 PFU/mL 21 days later, and 108 PFU/mL every 14 (±3) days thereafter. Injected lesions were covered with occlusive dressings for ≥1 week. Blood, urine, and swabs from exterior of occlusive dressings, surface of injected lesions, oral mucosa, anogenital area, and suspected herpetic lesions were collected throughout the study. Detectable T-VEC DNA was determined for each sample type; infectivity was determined for all swabs with detectable T-VEC DNA. FINDINGS: Sixty patients received ≥1 dose of T-VEC. During cycles 1-4, T-VEC DNA was detected in blood (98·3% of patients, 36·7% of samples), urine (31·7% of patients, 3·0% of samples) and swabs from injected lesions (100% of patients, 57·6% of samples), exterior of dressings (80% of patients,19·5% of samples), oral mucosa (8·3% of patients, 2·5% of samples), and anogenital area (8·0% of patients, 1·1% of samples). During the safety follow-up period, T-VEC DNA was only detected on swabs from injected lesions (14% of patients, 5.8% of samples). T-VEC DNA was detected in 4/37 swabs (3/19 patients) of suspected herpetic lesions. Among all samples, only those from the surface of injected lesions tested positive for infectivity (8/740 [1·1%]). Three close contacts reported signs and symptoms of suspected herpetic origin; however, no lesions had detectable T-VEC DNA. INTERPRETATION: Using current guidelines, T-VEC can be administered safely to patients with advanced melanoma and is unlikely to be transmitted to close contacts with appropriate use of occlusive dressings. FUND: This study was funded by Amgen Inc.: ClinicalTrials.gov, NCT02014441.

Translational pharmacokinetic-pharmacodynamic analysis in the pharmaceutical industry: an IQ Consortium PK-PD Discussion Group perspective.

With inadequate efficacy being the primary cause for the attrition of drug candidates in clinical development, the need to better predict clinical efficacy earlier in the drug development process has increased in importance in the pharmaceutical industry. Here, we review current applications of translational pharmacokinetic-pharmacodynamic (PK-PD) modeling of preclinical data in the pharmaceutical industry, including best practices. Preclinical translational PK-PD modeling has been used in many therapeutic areas and has been impactful to drug development. The role of preclinical translational PK-PD modeling in drug discovery and development will continue to evolve and broaden, given that its broad implementation in the pharmaceutical industry is relatively recent and many opportunities still exist for its further application.

Motesanib with or without panitumumab plus FOLFIRI or FOLFOX for the treatment of metastatic colorectal cancer.

PURPOSE: This study assessed the safety, efficacy, and pharmacokinetics of motesanib, a multitargeted small molecule angiogenesis inhibitor, with and without panitumumab, in combination with FOLFIRI or FOLFOX in patients with metastatic colorectal cancer (mCRC). METHODS: This open-label, phase 1b, two-part, multicenter study in patients with mCRC and ≤1 prior treatment evaluated escalating doses (50, 75, 100, or 125 mg QD, 75 mg BID) of motesanib with panitumumab and chemotherapy (Part 1) and the target dose of motesanib with chemotherapy (Part 2). RESULTS: At 17 sites in the USA and Australia, 119 patients were enrolled between December 2004 and February 2010. In Part 1 [motesanib plus panitumumab/FOLFIRI (n = 36) or plus panitumumab/FOLFOX (n = 17)], all motesanib doses tested were tolerated and 125 mg QD was deemed the target dose. Following toxicity results for combination therapy in other trials, panitumumab was withdrawn from the study. Part 2 evaluated motesanib 125 mg with chemotherapy [FOLFIRI (n = 37); FOLFOX (n = 29)]. The primary endpoint, objective response rate in patients with measurable disease by RECIST, was 20 % overall and was higher among patients receiving first-line (27 % overall; FOLFOX, 24 %; FOLFIRI, 27 %) compared with second-line therapy (14 % overall; FOLFOX, 0 %; FOLFIRI, 20 %). The most common adverse events were diarrhea, nausea, fatigue, and hypertension. We observed a low rate of cholecystitis [3 of 119 (2.5 %)], a known adverse event of motesanib and other small molecule VEGF inhibitors. CONCLUSIONS: Motesanib 125 mg QD in combination with FOLFIRI or FOLFOX chemotherapy was tolerated and demonstrated modest efficacy in first-/second-line mCRC.

Preclinical pharmacokinetic/pharmacodynamic modeling and simulation in the pharmaceutical industry: an IQ consortium survey examining the current landscape.

The application of modeling and simulation techniques is increasingly common in preclinical stages of the drug discovery and development process. A survey focusing on preclinical pharmacokinetic/pharmacodynamics (PK/PD) analysis was conducted across pharmaceutical companies that are members of the International Consortium for Quality and Innovation in Pharmaceutical Development. Based on survey responses, ~68% of companies use preclinical PK/PD analysis in all therapeutic areas indicating its broad application. An important goal of preclinical PK/PD analysis in all pharmaceutical companies is for the selection/optimization of doses and/or dose regimens, including prediction of human efficacious doses. Oncology was the therapeutic area with the most PK/PD analysis support and where it showed the most impact. Consistent use of more complex systems pharmacology models and hybrid physiologically based pharmacokinetic models with PK/PD components was less common compared to traditional PK/PD models. Preclinical PK/PD analysis is increasingly being included in regulatory submissions with ~73% of companies including these data to some degree. Most companies (~86%) have seen impact of preclinical PK/PD analyses in drug development. Finally, ~59% of pharmaceutical companies have plans to expand their PK/PD modeling groups over the next 2 years indicating continued growth. The growth of preclinical PK/PD modeling groups in pharmaceutical industry is necessary to establish required resources and skills to further expand use of preclinical PK/PD modeling in a meaningful and impactful manner.

Population pharmacokinetic modeling of motesanib and its active metabolite, M4, in cancer patients.

Motesanib is a small molecule and potent multikinase inhibitor with antiangiogenic and antitumor activity. Population pharmacokinetic (POPPK) modeling of motesanib and M4, an active metabolite, was performed to assess sources of variability in cancer patients. The analysis included data collected from 451 patients from 8 clinical trials with oral doses of motesanib ranging from 25 to 175 mg, either once daily or twice daily. The POPPK analyses were performed using nonlinear mixed-effect models with a sequential approach. Covariate effects of demographics and other baseline characteristics were assessed with stepwise covariate modeling. A 2-compartment model with food effect on absorption parameters fitted the PK data of motesanib well. The effects albumin and sex on apparent clearance (CL/F) of motesanib were statistically significant. The albumin effect was more important but remained below a 25% difference. A 1-compartment model fitted PK data of M4 well. Effects of race (Asian vs non-Asian) and dosing frequency were identified as statistically significant covariates on the CL/F of M4. The maximum effect of albumin would result in less than 25% change in motesanib CL/F and as such would not warrant any dosing adjustment. However, faster elimination of M4 in Asian patients requires further investigation.

Anticancer activity of the type I insulin-like growth factor receptor antagonist, ganitumab, in combination with the death receptor 5 agonist, conatumumab.

Agents targeting the insulin-like growth factor receptor type 1 (IGF1R) have shown antitumor activity. Based on the evidence for interaction between the IGF-1 and TRAIL pathways, we hypothesized that the combination of ganitumab (monoclonal antibody to IGF1R) with the pro-apoptotic death receptor 5 agonist, conatumumab, might increase antitumor response. Ganitumab and conatumumab were tested in combination in a Colo-205 xenograft model. Part 1 of the clinical study was a phase Ib program of three doses of conatumumab (1, 3, 15 mg/kg) in combination with 18 mg/kg ganitumab to determine the maximum tolerated dose (MTD) in patients with advanced solid tumors. Part 2 was conducted in six cohorts with advanced non-small cell lung cancer (squamous or non-squamous histology), colorectal cancer, sarcoma, pancreatic cancer, or ovarian cancer, treated at the recommended doses of the combination. The combination was significantly more active in the Colo-205 xenograft model than either single agent alone (p < 0.0015). In part 1 of the clinical study, no dose-limiting toxicities were observed and the MTD of conatumumab was 15 mg/kg in combination with 18 mg/kg ganitumab. In part 2, 78 patients were treated and there were no objective responses but 28 patients (36 %) had stable disease (median 46 days, range 0-261). The combination was well-tolerated with no new toxicities. In conclusion, the combination of ganitumab and conatumumab was well-tolerated but had no objective responses in the population tested. The successful future application of this combination of antitumor mechanisms may rely on the identification of predictive biomarkers.

FLT3 and CDK4/6 inhibitors: signaling mechanisms and tumor burden in subcutaneous and orthotopic mouse models of acute myeloid leukemia.

FLT3(ITD) subtype acute myeloid leukemia (AML) has a poor prognosis with currently available therapies. A number of small molecule inhibitors of FLT3 and/or CDK4/6 are currently under development. A more complete and quantitative understanding of the mechanisms of action of FLT3 and CDK4/6 inhibitors may better inform the development of current and future compounds that act on one or both of the molecular targets, and thus may lead to improved treatments for AML. In this study, we investigated in both subcutaneous and orthotopic AML mouse models, the mechanisms of action of three FLT3 and/or CDK4/6 inhibitors: AMG925 (Amgen), sorafenib (Bayer and Onyx), and quizartinib (Ambit Biosciences). A composite model was developed to integrate the plasma pharmacokinetics of these three compounds on their respective molecular targets, the coupling between the target pathways, as well as the resulting effects on tumor burden reduction in the subcutaneous xenograft model. A sequential modeling approach was used, wherein model structures and estimated parameters from upstream processes (e.g. PK, cellular signaling) were fixed for modeling subsequent downstream processes (cellular signaling, tumor burden). Pooled data analysis was employed for the plasma PK and cellular signaling modeling, while population modeling was applied to the tumor burden modeling. The resulting model allows the decomposition of the relative contributions of FLT3(ITD) and CDK4/6 inhibition on downstream signaling and tumor burden. In addition, the action of AMG925 on cellular signaling and tumor burden was further studied in an orthotopic tumor mouse model more closely representing the physiologically relevant environment for AML.

TRAIL receptor agonist conatumumab with modified FOLFOX6 plus bevacizumab for first-line treatment of metastatic colorectal cancer: A randomized phase 1b/2 trial.

BACKGROUND: In patients with previously untreated metastatic colorectal cancer (mCRC), we conducted a phase 1b/randomized phase 2 trial to define the safety, tolerability, and efficacy of mFOLFOX6 plus bevacizumab (mFOLFOX6/bev) with conatumumab, an investigational, fully human monoclonal IgG1 antibody that specifically activates death receptor 5 (DR5). METHODS: Twelve patients were enrolled in a phase 1b open-label dose-escalation trial of conatumumab with mFOLFOX6/bev; thereafter, 190 patients were randomized 1:1:1 to receive mFOLFOX6/bev in combination with 2 mg/kg conatumumab, 10 mg/kg conatumumab, or placebo. Therapy cycles were repeated every 2 weeks until disease progression or the occurrence of unacceptable toxicity. RESULTS: In phase 1b, conatumumab with mFOLFOX6/bev was tolerated without apparent added toxicity over mFOLFOX6/bev alone. In phase 2, conatumumab with mFOLFOX6/bev did not confer a benefit in progression-free survival when compared with placebo with mFOLFOX6/bev. Toxicity was similar in all treatment arms. Following treatment, similar increases in circulating caspase-3 levels were observed in all arms. CONCLUSIONS: Conatumumab with mFOLFOX6/bev did not offer improved efficacy over the same chemotherapy with placebo in first-line treatment of patients with mCRC. These data do not support further development of conatumumab in advanced CRC.

The effect of different dosing regimens of motesanib on the gallbladder: a randomized phase 1b study in patients with advanced solid tumors.

BACKGROUND: Gallbladder toxicity, including cholecystitis, has been reported with motesanib, an orally administered small-molecule antagonist of VEGFRs 1, 2 and 3; PDGFR; and Kit. We assessed effects of motesanib on gallbladder size and function. METHODS: Patients with advanced metastatic solid tumors ineligible for or progressing on standard-of-care therapies with no history of cholecystitis or biliary disease were randomized 2:1:1 to receive motesanib 125 mg once daily (Arm A); 75 mg twice daily (BID), 14-days-on/7-days-off (Arm B); or 75 mg BID, 5-days-on/2-days-off (Arm C). Primary endpoints were mean change from baseline in gallbladder size (volume by ultrasound; independent review) and function (ejection fraction by CCK-HIDA; investigator assessment). RESULTS: Forty-nine patients received ≥1 dose of motesanib (Arms A/B/C, n = 25/12/12). Across all patients, gallbladder volume increased by a mean 22.2 cc (from 38.6 cc at baseline) and ejection fraction decreased by a mean 19.2% (from 61.3% at baseline) during treatment. Changes were similar across arms and appeared reversible after treatment discontinuation. Three patients had cholecystitis (grades 1, 2, 3, n = 1 each) that resolved after treatment discontinuation, one patient developed grade 3 acute cholecystitis requiring cholecystectomy, and two patients had other notable grade 1 gallbladder disorders (gallbladder wall thickening, gallbladder dysfunction) (all in Arm A). Two patients developed de novo gallstones during treatment. Twelve patients had right upper quadrant pain (Arms A/B/C, n = 8/1/3). The incidence of biliary "sludge" in Arms A/B/C was 39%/36%/27%. CONCLUSIONS: Motesanib treatment was associated with increased gallbladder volume, decreased ejection fraction, biliary sludge, gallstone formation, and infrequent cholecystitis. TRIAL REGISTRATION: ClinicalTrials.gov NCT00448786.

A randomized phase 2 study of paclitaxel and carboplatin with or without conatumumab for first-line treatment of advanced non-small-cell lung cancer.

INTRODUCTION: This study evaluated the efficacy, safety, and pharmacokinetics of conatumumab combined with paclitaxel-carboplatin (PC) as first-line treatment for advanced non-small-cell lung cancer (NSCLC). METHODS: Patients (aged >18 years) with previously untreated advanced or recurrent NSCLC were randomized 1:1:1 (stratified by Eastern Cooperative Oncology Group performance status and disease stage) to receive up to six 3-week cycles of PC combined with conatumumab (arm 1, 3 mg/kg; arm 2, 15 mg/kg) or placebo (arm 3) every 3 weeks. The primary endpoint was progression-free survival (PFS). This study is registered with ClinicalTrials.gov (NCT00534027). RESULTS: Between August 8, 2007 and April 9, 2009, 172 patients were randomized (arm 1, n = 57; arm 2, n = 56; arm 3, n = 59). Median PFS was 5.4 months (95% confidence interval [CI] 4.1-6.3) in arm 1 (hazard ratio [HR] 0.84 [95% CI 0.57-1.24]; p = 0.41), 4.8 months (95% CI 3.2-6.5) in arm 2 (HR 0.93 [0.64-1.35]; p = 0.57), and 5.5 months (95% CI 4.3-5.7) in arm 3. There was an interaction between tumor histology and the effect of conatumumab on PFS (squamous HR 0.47 [0.23-0.94]; nonsquamous HR 1.08 [0.74-1.57]; interaction p = 0.039).The most common grade of three or more adverse events were neutropenia, anemia, and thrombocytopenia. There was no evidence of pharmacokinetic interactions between conatumumab and PC. Of 158 patients assessable for FCGR3A polymorphisms, conatumumab treatment was associated with a trend toward longer overall survival (HR 0.72 [0.43-1.23]) among V-allele carriers (V/V or F/V; n = 54) but not among F-allele homozygotes (n = 34; HR 1.37 [0.66-2.86]). CONCLUSION: Although well tolerated, the addition of conatumumab to PC did not improve outcomes in unselected patients with previously untreated advanced NSCLC.

Intracellular-signaling tumor-regression modeling of the pro-apoptotic receptor agonists dulanermin and conatumumab.

Dulanermin (rhApo2L/TRAIL) and conatumumab bind to transmembrane death receptors and trigger the extrinsic cellular apoptotic pathway through a caspase-signaling cascade resulting in cell death. Tumor size time series data from rodent tumor xenograft (COLO205) studies following administration of either of these two pro-apoptotic receptor agonists (PARAs) were combined to develop a intracellular-signaling tumor-regression model that includes two levels of signaling: upstream signals unique to each compound (representing initiator caspases), and a common downstream apoptosis signal (representing executioner caspases) shared by the two agents. Pharmacokinetic (PK) models for each drug were developed based on plasma concentration data following intravenous and/or intraperitoneal administration of the compounds and were used in the subsequent intracellular-signaling tumor-regression modeling. A model relating the PK of the two PARAs to their respective and common downstream signals, and to the resulting tumor burden was developed using mouse xenograft tumor size measurements from 448 experiments that included a wide range of dose sizes and dosing schedules. Incorporation of a pro-survival signal--consistent with the hypothesis that PARAs may also result in the upregulation of pro-survival factors that can lead to a reduction in effectiveness of PARAs with treatment--resulted in improved predictions of tumor volume data, especially for data from the long-term dosing experiments.