In vitro and clinical investigations to determine the drug-drug interaction potential of entrectinib, a small molecule inhibitor of neurotrophic tyrosine receptor kinase (NTRK).

Background Entrectinib is a CNS-active, potent inhibitor of tyrosine receptor kinases A/B/C, ROS1 and anaplastic lymphoma kinase approved for use in patients with solid tumors. We describe the in vitro and clinical studies investigating potential entrectinib drug-drug interactions. Methods In vitro studies with human biomaterials assessed the enzymes involved in entrectinib metabolism, and whether entrectinib modulates the activity of the major cytochrome P450 (CYP) enzymes or drug transporter P-glycoprotein. Clinical studies investigated the effect of a strong CYP3A4 inhibitor (itraconazole) and inducer (rifampin) on single-dose entrectinib pharmacokinetics. The effect of entrectinib on sensitive probe substrates for CYP3A4 (midazolam) and P-glycoprotein (digoxin) were also investigated. Results Entrectinib is primarily metabolized by CYP3A4. In vitro, entrectinib is a CYP3A4/5 inhibitor (IC50 2 µM) and a weak CYP3A4 inducer. Entrectinib inhibited P-glycoprotein (IC50 1.33 µM) but is a poor substrate. In healthy subjects, itraconazole increased entrectinib Cmax and AUC by 73% and 504%, respectively, and rifampin decreased entrectinib Cmax and AUC by 56% and 77%, respectively. Single dose entrectinib did not affect midazolam AUC, although Cmax decreased by 34%. Multiple dose entrectinib increased midazolam AUC by 50% and decreased Cmax by 21%. Single dose entrectinib increased digoxin AUC and Cmax by 18% and 28%, respectively, but did not affect digoxin renal clearance. Conclusions Entrectinib is a CYP3A4 substrate and is sensitive to the effects of coadministered moderate/strong CYP3A4 inhibitors and strong inducers, and requires dose adjustment. Entrectinib is a weak inhibitor of CYP3A4 and P-glycoprotein and no dose adjustments are required with CYP3A4/P- glycoprotein substrates.Registration Number (Study 2) NCT03330990 (first posted online November 6, 2017) As studies 1 and 3 are phase 1 trials in healthy subjects, they are not required to be registered.

Characterization of the pharmacokinetics of entrectinib and its active M5 metabolite in healthy volunteers and patients with solid tumors.

BACKGROUND: Entrectinib is an oral, CNS-active, potent inhibitor of tyrosine receptor kinases A/B/C, tyrosine kinase ROS proto-oncogene 1, and anaplastic lymphoma kinase approved for use in patients with solid tumors. We describe 3 clinical studies, including one investigating the single/multiple dose pharmacokinetics of entrectinib in patients and two studies in healthy volunteers investigating the absorption/distribution/metabolism/excretion (ADME) of entrectinib, its relative bioavailability, and effect of food on pharmacokinetics. METHODS: The patient study is open-label with dose-escalation and expansion phases. Volunteers received entrectinib (100-400 mg/m2, and 600-800 mg) once daily with food in continuous 28-day cycles. In the ADME study, volunteers received a single oral dose of [14C]entrectinib 600 mg. In the third study, volunteers received single doses of entrectinib 600 mg as the research and marketed formulations in the fasted state (Part 1), and the marketed formulation in the fed and fasted states (Part 2). Entrectinib and its major active metabolite M5 were assessed in all studies. RESULTS: Entrectinib was absorbed in a dose-dependent manner with maximum concentrations at ~4 h postdose and an elimination half-life of ~20 h. Entrectinib was cleared mainly through metabolism and both entrectinib and metabolites were eliminated mainly in feces (minimal renal excretion). At steady-state, the M5-to-entrectinib AUC ratio was 0.5 (with 600 mg entrectinib research formulation in patients). The research and marketed formulations were bioequivalent and food had no relevant effect on pharmacokinetics. CONCLUSIONS: Entrectinib is well absorbed, with linear PK that is suitable for once-daily dosing, and can be taken with or without food.

Role of obinutuzumab exposure on clinical outcome of follicular lymphoma treated with first-line immunochemotherapy.

AIMS: Obinutuzumab (G) is a humanized type II, Fc-glycoengineered anti-CD20 monoclonal antibody used in various indications, including patients with previously untreated front-line follicular lymphoma. We investigated sources of variability in G exposure and association of progression-free survival (PFS) with average concentration over induction (CmeanIND ) in front-line follicular lymphoma patients treated with G plus chemotherapy (bendamustine, CHOP, or CVP) in the GALLIUM trial. METHODS: Individual exposures (CmeanIND ) were obtained from a previously established population pharmacokinetic model updated with GALLIUM data. Multivariate Cox proportional hazard models and univariate Kaplan-Meier plots investigated relationships of PFS with exposure and other potential prognostic factors. RESULTS: Overall, G exposure was lower in high body-weight patients and in males, and slightly lower in patients with high baseline tumour burden. Analysis of clinical outcomes showed that variability in G exposure did not impact PFS in G-bendamustine-treated patients; PFS was inferior in males and patients with FCGR2a/2b T232 T low-affinity receptor variant, and superior in patients with FCGR2a/2b I232T variant. In G-CHOP/CVP arms, PFS improved with increasing CmeanIND (hazard ratio = 1.74 and 0.394 at 5th and 95th percentile compared to median CmeanIND ) and was inferior in patients with high baseline tumour size and B symptoms. CONCLUSIONS: It remains unclear whether for G-CHOP/CVP patients lower G exposure is a consequence of adverse disease biology and/or resistance to chemotherapy backbone (higher clearance in nonresponder patients, as demonstrated for rituximab) rather than being the cause of poorer clinical outcome. A study with >1 dose level of G could help resolve this uncertainty.

Phase Ib study evaluating safety and clinical activity of the anti-HER3 antibody lumretuzumab combined with the anti-HER2 antibody pertuzumab and paclitaxel in HER3-positive, HER2-low metastatic breast cancer.

Purpose To investigate the safety and clinical activity of comprehensive human epidermal growth factor receptor (HER) family receptor inhibition using lumretuzumab (anti-HER3) and pertuzumab (anti-HER2) in combination with paclitaxel in patients with metastatic breast cancer (MBC). Methods This phase Ib study enrolled 35 MBC patients (first line or higher) with HER3-positive and HER2-low (immunohistochemistry 1+ to 2+ and in-situ hybridization negative) tumors. Patients received lumretuzumab (1000 mg in Cohort 1; 500 mg in Cohorts 2 and 3) plus pertuzumab (840 mg loading dose [LD] followed by 420 mg in Cohorts 1 and 2; 420 mg without LD in Cohort 3) every 3 weeks, plus paclitaxel (80 mg/m2 weekly in all cohorts). Patients in Cohort 3 received prophylactic loperamide treatment. Results Diarrhea grade 3 was a dose-limiting toxicity of Cohort 1 defining the maximum tolerated dose of lumretuzumab when given in combination with pertuzumab and paclitaxel at 500 mg every three weeks. Grade 3 diarrhea decreased from 50% (Cohort 2) to 30.8% (Cohort 3) with prophylactic loperamide administration and omission of the pertuzumab LD, nonetheless, all patients still experienced diarrhea. In first-line MBC patients, the objective response rate in Cohorts 2 and 3 was 55% and 38.5%, respectively. No relationship between HER2 and HER3 expression or somatic mutations and clinical response was observed. Conclusions Combination treatment with lumretuzumab, pertuzumab and paclitaxel was associated with a high incidence of diarrhea. Despite the efforts to alter dosing, the therapeutic window remained too narrow to warrant further clinical development. TRIAL REGISTRATION: on ClinicalTrials.gov with the identifier NCT01918254 first registered on 3rd July 2013.

CSF1R inhibition with emactuzumab in locally advanced diffuse-type tenosynovial giant cell tumours of the soft tissue: a dose-escalation and dose-expansion phase 1 study.

BACKGROUND: Diffuse-type tenosynovial giant cell tumour (dt-GCT) of the soft tissue (alternatively known as pigmented villonodular synovitis), an orphan disease with unmet medical need, is characterised by an overexpression of colony-stimulating factor 1 (CSF1), and is usually caused by a chromosomal translocation involving CSF1. CSF1 receptor (CSF1R) activation leads to the recruitment of CSF1R-expressing cells of the mononuclear phagocyte lineage that constitute the tumor mass in dt-GCT. Emactuzumab (RG7155) is a novel monoclonal antibody that inhibits CSF1R activation. We have assessed the safety, tolerability and activity of emactuzumab in patients with Dt-GCT of the soft tissue. METHODS: In this phase 1, first-in-human dose-escalation and dose-expansion study, eligible patients were aged 18 years or older with dt-GCT of the soft tissue with locally advanced disease or resectable tumours requiring extensive surgery, an Eastern Cooperative Oncology Group performance status of 1 or less, measurable disease according to Response Evaluation Criteria In Solid Tumors version 1.1, and adequate end-organ function. Patients with GCT of the bone were not eligible. Patients received intravenous emactuzumab at 900 mg, 1350 mg, or 2000 mg every 2 weeks in the dose-escalation phase and at the optimal biological dose in a dose-expansion phase. The primary objective was to evaluate the safety and tolerability of emactuzumab, and to determine the maximum tolerated dose or optimal biological dose. All treated patients were included in the analyses. Expansion cohorts are currently ongoing. This study is registered with ClinicalTrials.gov, number NCT01494688. FINDINGS: Between July 26, 2012, and Oct 21, 2013, 12 patients were enrolled in the dose-escalation phase. No dose-limiting toxicities were noted in the dose-escalation cohort; on the basis of pharmacokinetic, pharmacodynamic, and safety information, we chose a dose of 1000 mg every 2 week for the dose-expansion cohort, into which 17 patients were enrolled. Owing to different cutoff dates for safety and efficacy readouts, the safety population comprised 25 patients. Common adverse events after emactuzumab treatment were facial oedema (16 [64%] of 25 patients), asthenia (14 [56%]), and pruritus (14 [56%]). Five serious adverse events (periorbital oedema, lupus erythematosus [occurring twice], erythema, and dermohypodermitis all experienced by one [4%] patient each) were reported in five patients. Three of the five serious adverse events-periorbital oedema (one [4%]), lupus erythematosus (one [4%]), and dermohypodermitis (one [4%])-were assessed as grade 3. Two other grade 3 events were reported: mucositis (one [4%]) and fatigue (one [4%]). 24 (86%) of 28 patients achieved an objective response; two (7%) patients achieved a complete response. INTERPRETATION: Further study of dt-GCT is warranted and different possibilities, such as an international collaboration with cooperative groups to assure appropriate recruitment in this rare disease, are currently being assessed. FUNDING: F Hoffmann-La Roche.

Effects of high-density lipoprotein elevation with cholesteryl ester transfer protein inhibition on insulin secretion.

RATIONALE: High-density lipoprotein cholesterol elevation via cholesteryl ester transfer protein (CETP) inhibition represents a novel therapy for atherosclerosis, which also may have relevance for type 2 diabetes mellitus. OBJECTIVE: The current study assessed the effects of a CETP inhibitor on postprandial insulin, ex vivo insulin secretion, and cholesterol efflux from pancreatic ß-cells. METHODS AND RESULTS: Healthy participants received a daily dose of CETP inhibitor (n=10) or placebo (n=15) for 14 days in a randomized double-blind study. Insulin secretion and cholesterol efflux from MIN6N8 ß-cells were determined after incubation with treated plasma. CETP inhibition increased plasma high-density lipoprotein cholesterol, apolipoprotein AI, and postprandial insulin. MIN6N8 ß-cells incubated with plasma from CETP inhibitor-treated individuals (compared with placebo) exhibited an increase in both glucose-stimulated insulin secretion and cholesterol efflux over the 14-day treatment period. CONCLUSIONS: CETP inhibition increased postprandial insulin and promoted ex vivo ß-cell glucose-stimulated insulin secretion, potentially via enhanced ß-cell cholesterol efflux.

PBPK Modeling of Entrectinib and Its Active Metabolite to Derive Dose Adjustments in Pediatric Populations Co-Administered with CYP3A4 Inhibitors.

Physiologically based pharmacokinetic (PBPK) models of entrectinib and its equipotent metabolite, M5, were established in healthy adult subjects and extrapolated to pediatric patients to predict increases in steady-state systemic exposure on co-administration of strong and moderate CYP3A4 inhibitors (itraconazole at 5 mg/kg, erythromycin at 7.5-12.5 mg/kg and fluconazole at 3-12 mg/kg, respectively). Adult model establishment involved the optimization of fraction metabolized by CYP3A4 (0.92 for entrectinib and 0.98 for M5) using data from an itraconazole DDI study. This model captured well the exposure changes of entrectinib and M5 seen in adults co-administered with the strong CYP3A4 inducer rifampicin. In pediatrics, reasonable prediction of entrectinib and M5 pharmacokinetics in ≧2 year olds was achieved when using the default models for physiological development and enzyme ontogenies. However, a two to threefold misprediction of entrectinib and M5 exposures was seen in <2 year olds which may be due to missing mechanistic understanding of gut physiology and/or protein binding in very young children. Model predictions for ≧2 year olds showed that entrectinib AUC(0-t) was increased by approximately sevenfold and five to threefold by strong and high-moderate and low-moderate CYP3A4 inhibitors, respectively. Based on these victim DDI predictions, dose adjustments for entrectinib when given concomitantly with strong and moderate CYP3A4 inhibitors in pediatric subjects were recommended. These simulations informed the approved entrectinib label without the need for additional clinical pharmacology studies.

Entrectinib dose confirmation in pediatric oncology patients: pharmacokinetic considerations.

PURPOSE: Entrectinib is a central nervous system-active potent inhibitor of tropomyosin receptor kinase (TRK), with anti-tumor activity against neurotrophic NTRK gene fusion-positive tumors. This study investigates the pharmacokinetics of entrectinib and its active metabolite (M5) in pediatric patients and aims to understand whether the pediatric dose of 300 mg/m2 once daily (QD) provides an exposure that is consistent with the approved adult dose (600 mg QD). METHODS: Forty-three patients aged from birth to 22 years were administered entrectinib (250-750 mg/m2 QD) orally with food in 4-week cycles. Entrectinib formulations included capsules without acidulant (F1) and capsules with acidulant (F2B and F06). RESULTS: Although there was interpatient variability with F1, entrectinib and M5 exposures increased dose dependently. Lower systemic exposures were observed in pediatric patients receiving 400 mg/m2 QD entrectinib (F1) versus adults receiving either the same dose/formulation or the recommended flat dose of 600 mg QD (~ 300 mg/m2 for a 70 kg adult) due to suboptimal F1 performance in the pediatric study. The observed pediatric exposures following 300 mg/m2 QD entrectinib (F06) were comparable to those in adults receiving 600 mg QD. CONCLUSIONS: Overall, the F1 formulation of entrectinib was associated with lower systemic exposure in pediatric patients compared with the commercial acidulant formulation (F06). Systemic exposures achieved in pediatric patients with the F06 recommended dose (300 mg/m2) were within the known efficacious range in adults, confirming the adequacy of the recommended dose regimen with the commercial formulation.

Efficacy and safety exposure-response analyses of entrectinib in patients with advanced or metastatic solid tumors.

PURPOSE: Entrectinib is an anti-cancer agent that inhibits TRKA/B/C, ROS1, and ALK. Secondary pharmacokinetic (PK) exposure parameters for entrectinib derived from a previously described population PK model were used to characterize exposure-response relationships in patients treated with entrectinib. METHODS: Data were pooled from Phase 1 and 2 studies of entrectinib (600-800 mg/day in adults, 250-750 mg/m2/day in children) in 293 patients with NTRK-, ROS1-, or ALK-positive, locally advanced or metastatic tumors. Efficacy was evaluated by the changes in sum of target lesion diameters and best overall response defined by RECIST1.1. A longitudinal nonlinear mixed-effect model described the relationship between entrectinib exposure and tumor size data in patients with ROS1-positive non-small-cell lung cancer (NSCLC) or NTRK fusion-positive solid tumors. The relationship between exposure and treatment-emergent (TEAEs) or serious (SAEs) adverse events was assessed by logistic regression in all patients for whom secondary PK parameter estimates were derived. RESULTS: Among the 89 patients with evaluable efficacy data included in the exposure-efficacy analysis, 73% (65/89) achieved a complete or partial response. Entrectinib exposure distribution was similar in responders and non-responders. Model-described tumor shrinkage rates were 8-12 times greater than growth rates in both ROS-1-positive NSCLC patients and NTRK fusion-positive solid tumor patients, with no relationship between exposure and these rates. The probability of experiencing a Grade ≥ 3 TEAE or SAE increased with exposure, primarily at doses > 600 mg/day. CONCLUSION: These analyses supported that entrectinib at 600 mg/day provides an acceptable benefit-risk ratio in adults with NTRK-, ROS1-, or ALK-positive tumors, considered as rare disease.

Anti-CSF-1R emactuzumab in combination with anti-PD-L1 atezolizumab in advanced solid tumor patients naïve or experienced for immune checkpoint blockade.

BACKGROUND: This phase 1b study (NCT02323191) evaluated the safety, antitumor activity, pharmacokinetics, and pharmacodynamics of colony-stimulating factor-1 receptor-blocking monoclonal antibody (mAb) emactuzumab in combination with the programmed cell death-1 ligand (PD-L1)-blocking mAb atezolizumab in patients with advanced solid tumors naïve or experienced for immune checkpoint blockers (ICBs). METHODS: Emactuzumab (500-1350 mg flat) and atezolizumab (1200 mg flat) were administered intravenously every 3 weeks. Dose escalation of emactuzumab was conducted using the 3+3 design up to the maximum tolerated dose (MTD) or optimal biological dose (OBD). Extension cohorts to evaluate pharmacodynamics and clinical activity were conducted in metastatic ICB-naive urothelial bladder cancer (UBC) and ICB-pretreated melanoma (MEL), non-small cell lung cancer (NSCLC) and UBC patients. RESULTS: Overall, 221 patients were treated. No MTD was reached and the OBD was determined at 1000 mg of emactuzumab in combination with 1200 mg of atezolizumab. Grade ≥3 treatment-related adverse events occurred in 25 (11.3%) patients of which fatigue and rash were the most common (14 patients (6.3%) each). The confirmed objective response rate (ORR) was 9.8% for ICB-naïve UBC, 12.5% for ICB-experienced NSCLC, 8.3% for ICB-experienced UBC and 5.6% for ICB-experienced MEL patients, respectively. Tumor biopsy analyses demonstrated increased activated CD8 +tumor infiltrating T lymphocytes (TILs) associated with clinical benefit in ICB-naïve UBC patients and less tumor-associated macrophage (TAM) reduction in ICB-experienced compared with ICB-naïve patients. CONCLUSION: Emactuzumab in combination with atezolizumab demonstrated a manageable safety profile with increased fatigue and skin rash over usual atezolizumab monotherapy. A considerable ORR was particularly seen in ICB-experienced NSCLC patients. Increase ofCD8 +TILs under therapy appeared to be associated with persistence of a TAM subpopulation.

Entrectinib in children and young adults with solid or primary CNS tumors harboring NTRK, ROS1, or ALK aberrations (STARTRK-NG).

BACKGROUND: Entrectinib is a TRKA/B/C, ROS1, ALK tyrosine kinase inhibitor approved for the treatment of adults and children aged ≥12 years with NTRK fusion-positive solid tumors and adults with ROS1 fusion-positive non-small-cell lung cancer. We report an analysis of the STARTRK-NG trial, investigating the recommended phase 2 dose (RP2D) and activity of entrectinib in pediatric patients with solid tumors including primary central nervous system tumors. METHODS: STARTRK-NG (NCT02650401) is a phase 1/2 trial. Phase 1, dose-escalation of oral, once-daily entrectinib, enrolled patients aged <22 years with solid tumors with/without target NTRK1/2/3, ROS1, or ALK fusions. Phase 2, basket trial at the RP2D, enrolled patients with intracranial or extracranial solid tumors harboring target fusions or neuroblastoma. Primary endpoints: phase 1, RP2D based on toxicity; phase 2, objective response rate (ORR) in patients harboring target fusions. Safety-evaluable patients: ≥1 dose of entrectinib; response-evaluable patients: measurable/evaluable baseline disease and ≥1 dose at RP2D. RESULTS: At data cutoff, 43 patients, median age of 7 years, were response-evaluable. In phase 1, 4 patients experienced dose-limiting toxicities. The most common treatment-related adverse event was weight gain (48.8%). Nine patients experienced bone fractures (20.9%). In patients with fusion-positive tumors, ORR was 57.7% (95% CI 36.9-76.7), median duration of response was not reached, and median (interquartile range) duration of treatment was 10.6 months (4.2-18.4). CONCLUSIONS: Entrectinib resulted in rapid and durable responses in pediatric patients with solid tumors harboring NTRK1/2/3 or ROS1 fusions.

Population pharmacokinetic analysis of entrectinib in pediatric and adult patients with advanced/metastatic solid tumors: support of new drug application submission.

PURPOSE: Entrectinib (ROZLYTREK®) is a CNS-active, potent, and selective inhibitor of ROS1, TRK A/B/C, and ALK kinase activity. It was recently approved for the treatment of ROS1-positive non-small cell lung cancer and NTRK gene fusion-positive solid tumors. The main objective of this analysis was to characterize the pharmacokinetics (PK) of entrectinib and its main active metabolite, M5. METHODS: A total of 276 cancer patients receiving oral entrectinib were included in the analysis. A model-based population approach was used to characterize the PK profiles of both entities using NONMEM® 7.4. A joint model captures the PK of both entrectinib and M5. The effects of pH modifiers, formulation, weight, age, and sex on model parameters were assessed. Model performance was evaluated using visual predictive checks (VPCs). RESULTS: The absorption of entrectinib was best described using a sequential zero- and first-order absorption model and the disposition with one-compartment model for each entity with linear elimination. Moderate-to-high between-patient variability was estimated in model parameters (from 30.8% for the apparent clearance of entrectinib to 122% for the first-order absorption rate constant). Theory-based allometric scaling using body weight on clearances and volumes and a 28% lower relative bioavailability of the F1 formulation in pediatric patients were retained in the model. The VPC confirmed the good predictive performance of the PopPK model. CONCLUSIONS: A robust population PK model was built and qualified for entrectinib and M5, describing linear PK for both entities. This model was used to support the ROZLYTREK® new drug application.

Physiologically-Based Pharmacokinetic Modelling of Entrectinib Parent and Active Metabolite to Support Regulatory Decision-Making.

BACKGROUND AND OBJECTIVE: Entrectinib is a selective inhibitor of ROS1/TRK/ALK kinases, recently approved for oncology indications. Entrectinib is predominantly cleared by cytochrome P450 (CYP) 3A4, and modulation of CYP3A enzyme activity profoundly alters the pharmacokinetics of both entrectinib and its active metabolite M5. We describe development of a combined physiologically based pharmacokinetic (PBPK) model for entrectinib and M5 to support dosing recommendations when entrectinib is co-administered with CYP3A4 inhibitors or inducers. METHODS: A PBPK model was established in Simcyp® Simulator. The initial model based on in vitro-in vivo extrapolation was refined using sensitivity analysis and non-linear mixed effects modeling to optimize parameter estimates and to improve model fit to data from a clinical drug-drug interaction study with the strong CYP3A4 inhibitor, itraconazole. The model was subsequently qualified against clinical data, and the final qualified model used to simulate the effects of moderate to strong CYP3A4 inhibitors and inducers on entrectinib and M5 pharmacokinetics. RESULTS: The final model showed good predictive performance for entrectinib and M5, meeting commonly used predictive performance acceptance criteria in each case. The model predicted that co-administration of various moderate CYP3A4 inhibitors (verapamil, erythromycin, clarithromycin, fluconazole, and diltiazem) would result in an average increase in entrectinib exposure between 2.2- and 3.1-fold, with corresponding average increases for M5 of approximately 2-fold. Co-administration of moderate CYP3A4 inducers (efavirenz, carbamazepine, phenytoin) was predicted to result in an average decrease in entrectinib exposure between 45 and 79%, with corresponding average decreases for M5 of approximately 50%. CONCLUSIONS: The model simulations were used to derive dosing recommendations for co-administering entrectinib with CYP3A4 inhibitors or inducers. PBPK modeling has been used in lieu of clinical studies to enable regulatory decision-making.

Lack of effect of dalcetrapib on QT interval in healthy subjects following multiple dosing.

PURPOSE: Evaluate dalcetrapib's potential to prolong QT intervals in healthy subjects. METHODS: This was a single-center, randomized, active and placebo-controlled, six-sequence, three-period cross-over study. Participants [18-65 years; body mass index (BMI) 18-30 kg/m(2)] were randomized to daily doses of dalcetrapib 600 mg (therapeutic) or 3,900 mg (supratherapeutic) or to dalcetrapib-matched placebo for 7 days. On Day 8, subjects received single-dose moxifloxacin 400 mg (active control) or placebo, following the placebo or dalcetrapib, respectively. Electrocardiographic parameters were recorded on Days -1, 1, 7, and 8. The primary endpoint was the difference to placebo of time-matched change from baseline in the study-specific corrected QT interval (QTcS) at seven time-points within 24 h after dalcetrapib 3,900 mg on Day 7. An upper 95% confidence interval (CI) <10 ms confirmed the absence of a significant effect. Pharmacokinetic and lipid-related parameters were measured. RESULTS: Subjects (n = 49) were predominantly male (71%), and all were white, with a mean age of 45 years and mean BMI of 25 kg/m(2). For the primary analysis, the upper 95% CI for dalcetrapib 3,900 mg was <10 ms at all time-points. Similar findings were obtained for dalcetrapib 600 mg. Following the administration of moxifloxacin, the QTcS increased by >5 ms. At Day 7, exposure for dalcetrapib 3,900 mg was approximately eightfold higher than that for dalcetrapib 600 mg [mean area under the plasma concentration-time curve between time 0 and 24 h 68,500 vs. 8,280 ng*h/mL; mean peak concentration 6,810 vs. 861 ng/mL]. Cholesteryl ester transfer protein activity was inhibited by 30%, and high-density lipoprotein cholesterol increased by 26% for dalcetrapib 600 mg. Dalcetrapib was well tolerated. CONCLUSIONS: Dalcetrapib is not associated with QT interval prolongation, even at doses markedly greater than intended therapeutically.

Therapeutically-induced stable disease in oncology early clinical trials.

RATIONALE: The RECIST guideline defines four categories of response to treatment for cancer patients according to post-baseline changes in tumor burden, hence ignoring disease history. However, if left untreated, tumors grow exponentially, implying that pretreatment changes in tumor size are key to thoroughly assess efficacy. We present a model-based approach to estimate the rates of changes in tumor mass, before and after treatment onset. METHODS: Sixty-eight patients were eligible for the analysis of tumor size data from a Phase 1 study evaluating the effect of emactuzumab. In addition to tumor size measured at baseline and every six weeks during treatment, a pre-baseline measurement was gathered for each patient. A longitudinal regression model was used to estimate the rates of tumor size change before and after treatment onset. RESULTS: The median pre-treatment tumor growth exponential rate was equal to 0.022 month-1, corresponding to a tumor size doubling time of 4 months, and the on-treatment median tumor shrinkage exponential rate was equal to 0.001 month-1. Among sixteen patients categorized as stable disease per RECIST, only five had similar slopes before and after treatment while nine actually improved. One patient in particular had a therapeutically induced stabilization of the disease. CONCLUSION: Our analysis emphasizes the importance of collecting pre-baseline scans to distinguish therapeutically induced stable disease from cases where the tumor growth is not perturbed by treatment.

Physiologically Based Absorption Modelling to Explore the Impact of Food and Gastric pH Changes on the Pharmacokinetics of Entrectinib.

Entrectinib is a potent and selective tyrosine kinase inhibitor (TKI) of TRKA/B/C, ROS1, and ALK with both systemic and CNS activities, which has recently received FDA approval for ROS1 fusion-positive non-small cell lung cancer and NTRK fusion-positive solid tumors. This paper describes the application of a physiologically based biophamaceutics modeling (PBBM) during clinical development to understand the impact of food and gastric pH changes on absorption of this lipophilic, basic, molecule with reasonable permeability but strongly pH-dependent solubility. GastroPlus™ was used to develop a physiologically based pharmacokinetics (PBPK) model integrating in vitro and in silico data and dissolution studies and in silico modelling in DDDPlus™ were used to understand the role of self-buffering and acidulant on formulation performance. Models were verified by comparison of simulated pharmacokinetics for acidulant and non-acidulant containing formulations to clinical data from a food effect study and relative bioavailability studies with and without the gastric acid-reducing agent lansoprazole. A negligible food effect and minor pH-dependent drug-drug interaction for the market formulation were predicted based on biorelevant in vitro measurements, dissolution studies, and in silico modelling and were confirmed in clinical studies. These outcomes were explained as due to the acidulant counteracting entrectinib self-buffering and greatly reducing the effect of gastric pH changes. Finally, sensitivity analyses with the verified model were applied to support drug product quality. PBBM has great potential to streamline late-stage drug development and may have impact on regulatory questions.

PK/PD Mediated Dose Optimization of Emactuzumab, a CSF1R Inhibitor, in Patients With Advanced Solid Tumors and Diffuse-Type Tenosynovial Giant Cell Tumor.

Targeted biological therapies may achieve maximal therapeutic efficacy at doses below the maximum tolerated dose (MTD); therefore, the search for the MTD in clinical studies may not be ideal for these agents. Emactuzumab is an investigational monoclonal antibody that binds to and inhibits the activation of the cell surface colony-stimulating factor-1 receptor. Here, we show how modeling target-mediated drug disposition coupled with pharmacodynamic end points was used to optimize the dose of emactuzumab without defining an MTD. The model could be used to recommend doses across different disease indications. The approach recommended an optimal biological dose of emactuzumab for dosing every 2 weeks (q2w) ≥ 900 mg, approximately three-fold lower than the highest dose tested clinically. The model predicted that emactuzumab doses ≥ 900 mg q2w would achieve target saturation in excess of 90% over the entire dosing cycle. Subsequently, a dose of 1,000 mg q2w was used in the extension phase of a phase I study of emactuzumab in patients with advanced solid tumors or diffuse-type tenosynovial giant cell tumor. Clinical data from this study were consistent with model predictions. The model was also used to predict the optimum dose of emactuzumab for use with dosing every 3 weeks, enabling dosing flexibility with respect to comedications. In summary, this work demonstrates the value of quantitative clinical pharmacology approaches to dose selection in oncology as opposed to traditional MTD methods.

Phase Ib study of anti-CSF-1R antibody emactuzumab in combination with CD40 agonist selicrelumab in advanced solid tumor patients.

BACKGROUND: This phase Ib study evaluated the safety, clinical activity, pharmacokinetics, and pharmacodynamics (PD) of emactuzumab (anti-colony stimulating factor 1 receptor monoclonal antibody (mAb)) in combination with selicrelumab (agonistic cluster of differentiation 40 mAb) in patients with advanced solid tumors. METHODS: Both emactuzumab and selicrelumab were administered intravenously every 3 weeks and doses were concomitantly escalated (emactuzumab: 500 to 1000 mg flat; selicrelumab: 2 to 16 mg flat). Dose escalation was conducted using the product of independent beta probabilities dose-escalation design. PD analyzes were performed on peripheral blood samples and tumor/skin biopsies at baseline and on treatment. Clinical activity was evaluated using investigator-based and Response Evaluation Criteria In Solid Tumors V.1.1-based tumor assessments. RESULTS: Three dose-limiting toxicities (all infusion-related reactions (IRRs)) were observed at 8, 12 and 16 mg of selicrelumab together with 1000 mg of emactuzumab. The maximum tolerated dose was not reached at the predefined top doses of emactuzumab (1000 mg) and selicrelumab (16 mg). The most common adverse events were IRRs (75.7%), fatigue (54.1%), facial edema (37.8%), and increase in aspartate aminotransferase and creatinine phosphokinase (35.1% both). PD analyzes demonstrated an increase of Ki67+-activated CD8+ T cells accompanied by a decrease of B cells and the reduction of CD14Dim CD16bright monocytes in peripheral blood. The best objective clinical response was stable disease in 40.5% of patients. CONCLUSION: Emactuzumab in combination with selicrelumab demonstrated a manageable safety profile and evidence of PD activity but did not translate into objective clinical responses. TRIALREGISTRATION NUMBER: NCT02760797.

A continuous-time multistate Markov model to describe the occurrence and severity of diarrhea events in metastatic breast cancer patients treated with lumretuzumab in combination with pertuzumab and paclitaxel.

PURPOSE: To inform lumretuzumab and pertuzumab dose modifications in order to decrease the incidence, severity, and duration of the diarrhea events in metastatic breast cancer patients treated with a combination therapy of lumretuzumab (anti-HER3) in combination with pertuzumab (anti-HER2) and paclitaxel using quantitative clinical pharmacology modeling approaches. METHODS: The safety and pharmacokinetic (PK) data from three clinical trials (lumretuzumab monotherapy n = 47, pertuzumab monotherapy n = 78, and the combination therapy of lumretuzumab, pertuzumab and paclitaxel n = 35) were pooled together to develop a continuous-time discrete states Markov model describing the dynamics of the diarrhea events. RESULTS: The model was able to capture the time course of different severities of diarrhea reasonably well. The effect of lumretuzumab and pertuzumab was well described by an Emax function indicating an increased rate of transition from moderate to mild or more severe diarrhea with higher doses. The concentration needed to trigger or worsen diarrhea episodes was estimated to be 120-fold lower in combination therapy compared to monotherapy, suggesting strong synergy between the two monoclonal antibodies. The prophylactic effect of loperamide in a subset of patients was also well captured by the model with a clear tendency to reduce the occurrence of diarrhea events. CONCLUSIONS: This work shows that PK-toxicity modeling provides insight into how the severity of key adverse events evolves over time and highlights the potential use to support decision making in drug development.

Mechanistic Investigations of Diarrhea Toxicity Induced by Anti-HER2/3 Combination Therapy.

Combination of targeted therapies is expected to provide superior efficacy in the treatment of cancer either by enhanced antitumor activity or by preventing or delaying the development of resistance. Common challenges in developing combination therapies include the potential of additive and aggravated toxicities associated with pharmacologically related adverse effects. We have recently reported that combination of anti-HER2 and anti-HER3 antibodies, pertuzumab and lumretuzumab, along with paclitaxel chemotherapy in metastatic breast cancer, resulted in a high incidence of diarrhea that ultimately limited further clinical development of this combination. Here, we further dissected the diarrhea profile of the various patient dose cohorts and carried out in vitro investigations in human colon cell lines and explants to decipher the contribution and the mechanism of anti-HER2/3 therapeutic antibodies to intestinal epithelium malfunction. Our clinical investigations in patients revealed that while dose reduction of lumretuzumab, omission of pertuzumab loading dose, and introduction of a prophylactic antidiarrheal treatment reduced most severe adverse events, patients still suffered from persistent diarrhea during the treatment. Our in vitro investigations showed that pertuzumab and lumretuzumab combination treatment resulted in upregulation of chloride channel activity without indication of intestinal barrier disruption. Overall, our findings provide a mechanistic rationale to explore alternative of conventional antigut motility using medication targeting chloride channel activity to mitigate diarrhea of HER combination therapies. Mol Cancer Ther; 17(7); 1464-74. ©2018 AACR.