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Lazertinib is a potent, irreversible, brain-penetrant, mutant-selective, and wild type-sparing third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor indicated for advanced non-small cell lung cancer (NSCLC). The study aimed to evaluate the effects of food and race on the pharmacokinetics (PK) of lazertinib from a healthy volunteer trial and PK data from NSCLC patients with EGFR mutation.An open-label, single-dose, two-period, single-sequence crossover study was conducted in healthy subjects with two race groups (non-Asian and Asian). Subjects orally received a single dose of lazertinib 240 mg in fasted and fed state (high-fat meal) in each period separated by a 21-day washout. An open-label, multicenter, phase 1/2 study was conducted in Asian and non-Asian patients with NSCLC. Patients were given oral lazertinib 20-320 mg once daily in fasted state continuously in 21-day cycles. PK parameters were evaluated using non-compartmental analysis.A total of 24 healthy subjects (12 non-Asians and 12 Asians) and 52 NSCLC patients (22 non-Asians and 30 Asians) were evaluated. The change in the overall systemic exposure of lazertinib at fed state was less than 15%. Non-Asians showed 58-76% of the systemic exposure than Asians in healthy subjects. In contrast, there were no significant differences in systemic exposure by race both after single and multiple doses among NSCLC patients.Lazertinib can be taken with or without food considering the comparable systemic exposures related to food. Although effect of race was not consistent across studies, there was no evidence for dose adjustment based on race.

PURPOSE Non–small-cell lung cancer (NSCLC) with epidermal growth factor receptor ( EGFR) exon 20 insertion (Exon20ins) mutations exhibits inherent resistance to approved tyrosine kinase inhibitors. Amivantamab, an EGFR-MET bispecific antibody with immune cell–directing activity, binds to each receptor's extracellular domain, bypassing resistance at the tyrosine kinase inhibitor binding site. METHODS CHRYSALIS is a phase I, open-label, dose-escalation, and dose-expansion study, which included a population with EGFR Exon20ins NSCLC. The primary end points were dose-limiting toxicity and overall response rate. We report findings from the postplatinum EGFR Exon20ins NSCLC population treated at the recommended phase II dose of 1,050 mg amivantamab (1,400 mg, ≥ 80 kg) given once weekly for the first 4 weeks and then once every 2 weeks starting at week 5. RESULTS In the efficacy population (n = 81), the median age was 62 years (range, 42-84 years); 40 patients (49%) were Asian, and the median number of previous lines of therapy was two (range, 1-7). The overall response rate was 40% (95% CI, 29 to 51), including three complete responses, with a median duration of response of 11.1 months (95% CI, 6.9 to not reached). The median progression-free survival was 8.3 months (95% CI, 6.5 to 10.9). In the safety population (n = 114), the most common adverse events were rash in 98 patients (86%), infusion-related reactions in 75 (66%), and paronychia in 51 (45%). The most common grade 3-4 adverse events were hypokalemia in six patients (5%) and rash, pulmonary embolism, diarrhea, and neutropenia in four (4%) each. Treatment-related dose reductions and discontinuations were reported in 13% and 4% of patients, respectively. CONCLUSION Amivantamab, via its novel mechanism of action, yielded robust and durable responses with tolerable safety in patients with EGFR Exon20ins mutations after progression on platinum-based chemotherapy.

Introduction: Lazertinib is a potent, irreversible, brain-penetrant, mutant-selective, and wild-type–sparing third-generation EGFR tyrosine kinase inhibitor (TKI), creating a wide therapeutic index. Cardiovascular adverse events (AEs), including QT prolongation, decreased left ventricular ejection fraction (LVEF), and heart failure, have emerged as potential AEs with certain EGFR TKI therapies. Methods: Cardiac safety of lazertinib was evaluated in TKI-tolerant adults with EGFR mutation-positive locally advanced or metastatic NSCLC receiving lazertinib (20–320 mg/d). QT intervals corrected with Fridericia’s formula (QTcF) prolongation, time-matched concentration-QTcF relationship, change of LVEF, and cardiac failure-associated AEs were evaluated. The clinical findings were supplemented by the following three preclinical studies: an in vitro hERG inhibition assay, an ex vivo isolated perfused rabbit heart study, and an in vivo telemetry-instrumented beagle dog study. Results: Preclinical evaluation revealed little to no physiological effect on the basis of electrocardiogram, electrophysiological, proarrhythmic, and hemodynamic parameters. Clinical evaluation of 181 patients revealed no clinically relevant QTcF prolongation by centralized electrocardiogram in any patient and at any dose level. The predicted magnitude of QTcF value increase at maximum steady-state plasma concentration for the therapeutic dose of lazertinib (240 mg/d) was 2.2 msec (upper bound of the two-sided 90% confidence interval: 3.6 msec). No patient had clinically relevant LVEF decrease (i.e., minimum postbaseline LVEF value of

Strong evidence exists supporting the important role T cells play in the immune response against tumors. Still, the ability to initiate tumor-specific immune responses remains a challenge. Recent clinical trials suggest that bispecific antibody-mediated retargeted T cells are a promising therapeutic approach to eliminate hematopoietic tumors. However, this approach has not been validated in solid tumors. PF-06671008 is a dual-affinity retargeting (DART®)-bispecific protein engineered with enhanced pharmacokinetic properties to extend in vivo half-life, and designed to engage and activate endogenous polyclonal T cell populations via the CD3 complex in the presence of solid tumors expressing P-cadherin. This bispecific molecule elicited potent P-cadherin expression-dependent cytotoxic T cell activity across a range of tumor indications in vitro, and in vivo in tumor-bearing mice. Regression of established tumors in vivo was observed in both cell line and patient-derived xenograft models engrafted with circulating human T lymphocytes. Measurement of in vivo pharmacodynamic markers demonstrates PF-06671008-mediated T cell activation, infiltration and killing as the mechanism of tumor inhibition.

The Ras family of genes are highly conserved across species and play an integral role in cell signaling. KRAS belongs to this family of genes that function as switches cycling between guanosine diphosphate (GDP)-bound OFF state or guanosine triphosphate (GTP)-bound ON state. When the homeostasis between the GDP- or GTP-bound states is disrupted, cell proliferation and signaling proceeds unchecked. Wild-type KRAS appears to function as a tumor suppressor gene, but mutated KRAS imparts an especially recalcitrant and a highly lethal cancer phenotype. Despite almost four decades of intense research, no therapies have been successful in targeting mutant KRAS. In part this is due to the small structure of the protein, which does not present scaffolds that can be readily targeted to render the molecule in an inactive conformation. The manifold interactions of KRAS with effector proteins and a host of posttranslational modifications appear to magnify the impact on cell signaling and allow for redundant pathways that can overcome attempts to silence the effects of the mutation. It is thought that KRAS mutations are not sufficient to activate a cancer; typically, another trigger is needed. This trigger might differ between different organs and is not fully understood. An understanding of the structure, function, signaling, and mutations can help advance the quest for a therapy for this elusive target.

Neutropenia is a common side-effect of oncology drugs. We aimed to study the impact of exposure and dosing schedule on neutropenia to guide selection of dosing schedules that minimize neutropenia potential while maintaining the desired minimum concentration (Cmin) required for target engagement. Dose, frequency and PK parameters were chosen for five hypothetical drugs of various half-lives to (1) achieve same exposure with continuous dosing and evaluate impact of 4 intermittent dosing schedules; and (2) achieve same nadir for continuous and intermittent dosing and evaluate impact on % time above Cmin, a surrogate assumed to indicate target engagement. Absolute neutrophil count (ANC) profiles were simulated using Friberg model, a widely used semi-mechanistic myelosuppression model, assuming drug concentration directly reduce the proliferation rate of stem cells and progenitor cells in proliferation compartment. The correlations between different PK measures and neutropenia metrics were explored. In (1), when the same daily dose was used, intermittent schedules offered better management of ANC nadir. The reduced average drug exposure with intermittent dosing led to lower% time above Cmin. In (2), when the dose was adjusted to achieve the same nadir, drugs with moderate half-life (8–48 h) showed similar % time above Cmin regardless of schedule, while continuous dosing was better for a short half-life (4 h). Area under the concentration curve (AUC) was highly correlated with neutropenia. In summary, continuous dosing, with the dose selected correctly, is most effective to maintain % time above Cmin while providing similar tolerability as intermittent dosing with a higher dose. But dose interruptions could be required to manage individual toxicities. Intermittent schedules, on the other hand, allow recovery of ANC, enabling more orderly schedules.

CD3 bispecific antibody constructs recruit cytolytic T cells to kill tumor cells, offering a potent approach to treat cancer. T cell activation is driven by the formation of a trimolecular complex (trimer) between drugs, T cells, and tumor cells, mimicking an immune synapse. A translational quantitative systems pharmacology (QSP) model is proposed for CD3 bispecific molecules capable of predicting trimer concentration and linking it to tumor cell killing. The model was used to quantify the pharmacokinetic (PK)/pharmacodynamic (PD) relationship of a CD3 bispecific targeting P-cadherin (PF-06671008). It describes the disposition of PF-06671008 in the central compartment and tumor in mouse xenograft models, including binding to target and T cells in the tumor to form the trimer. The model incorporates T cell distribution to the tumor, proliferation, and contraction. PK/PD parameters were estimated for PF-06671008 and a tumor stasis concentration (TSC) was calculated as an estimate of minimum efficacious trimer concentration. TSC values ranged from 0.0092 to 0.064 pM across mouse tumor models. The model was translated to the clinic and used to predict the disposition of PF-06671008 in patients, including the impact of binding to soluble P-cadherin. The predicted terminal half-life of PF-06671008 in the clinic was approximately 1 day, and P-cadherin expression and number of T cells in the tumor were shown to be sensitive parameters impacting clinical efficacy. A translational QSP model is presented for CD3 bispecific molecules, which integrates in silico, in vitro and in vivo data in a mechanistic framework, to quantify and predict efficacy across species. Electronic supplementary material The online version of this article (10.1208/s12248-019-0332-z) contains supplementary material, which is available to authorized users.

TPS3150 Background: Amivantamab, an epidermal growth factor receptor (EGFR)-MET bispecific antibody with immune cell-directing activity, targets activating/resistance EGFR mutations and MET mutations/amplifications. Amivantamab has demonstrated antitumor activity in patients (pts) with EGFR-mutant NSCLC and also in pts with EGFR tyrosine kinase inhibitor-resistant disease. The recommended phase 2 dose (RP2D) is 1050 mg (1400 mg, ≥80 kg) administered as intravenous (IV) infusions weekly (QW) for the first 28-day cycle and every other week (Q2W) thereafter. A subcutaneous (SC) formulation of amivantamab has the potential to reduce pt and physician burden by reducing administration time. The safety and pharmacokinetics (PK) of amivantamab administered SC ± recombinant human hyaluronidase (rHuPH20) will be evaluated. Methods: PALOMA is an ongoing phase 1b dose escalation study of amivantamab SC in pts with advanced solid tumors that may derive benefit from EGFR or MET-directed therapy (NCT04606381). Pts must have progressed on standard of care therapy for metastatic disease, be ineligible for, or have refused current standard therapies. The primary endpoints are trough concentration at the end of QW dosing and safety of SC administration. The objective of part 1 is to evaluate the feasibility, safety, and PK of SC administration of a low concentration (50 mg/mL) formulation of amivantamab alone (Ami-LC) or admixed with rHuPH20 (Ami-LC-MD). Approximately 8 pts will be enrolled to receive either 1050/1400 mg amivantamab SC using Ami-LC-MD (Cohort 1a) or Ami-LC (Cohort 1b) QW in cycle 1 and Q2W thereafter. The objective of part 2 is to evaluate the safety and PK of SC administration of a high concentration (160 mg/mL) formulation of amivantamab alone (Ami-HC) or with rHuPH20 (Ami-HC-CF) and to determine a dose, schedule, and formulation for SC administration that achieves similar exposure as observed at the RP2D of amivantamab IV, with acceptable safety. Pts enrolled in part 2 will initially receive 1050/1400 mg amivantamab SC using Ami-HC-CF in Cohort 2a or Ami-HC in Cohort 2b. ≤10 pts may be enrolled in either cohort. Additional cohorts of ≤10 pts may be enrolled to support dose, schedule, and formulation selection as guided by safety and PK observations in earlier cohorts. To mitigate infusion related reactions (IRR), medication with steroid, paracetamol, and antihistamine will be given pre-infusion and as clinically indicated post-infusion. Safety assessments include monitoring adverse events, laboratory abnormalities, vital signs, IRR, and injection site reactions. Blood samples will be collected to assess PK, pharmacodynamics, and immunogenicity. A Study Evaluation Team composed of investigators and sponsor representatives will review safety and PK data to make decisions about dose escalation and cohort expansion throughout the conduct of the study. Clinical trial information: NCT04606381.

A mechanism-based pharmacokinetic/pharmacodynamic (PK/PD) model was used for preclinical to clinical translation of inotuzumab ozogamicin, a CD22-targeting antibody-drug conjugate (ADC) for B cell malignancies including non-Hodgkin's lymphoma (NHL) and acute lymphocytic leukemia (ALL). Preclinical data was integrated in a PK/PD model which included (1) a plasma PK model characterizing disposition and clearance of inotuzumab ozogamicin and its released payload N-Ac-γ-calicheamicin DMH, (2) a tumor disposition model describing ADC diffusion into the tumor extracellular environment, (3) a cellular model describing inotuzumab ozogamicin binding to CD22, internalization, intracellular N-Ac-γ-calicheamicin DMH release, binding to DNA, or efflux from the tumor cell, and (4) tumor growth and inhibition in mouse xenograft models. The preclinical model was translated to the clinic by incorporating human PK for inotuzumab ozogamicin and clinically relevant tumor volumes, tumor growth rates, and values for CD22 expression in the relevant patient populations. The resulting stochastic models predicted progression-free survival (PFS) rates for inotuzumab ozogamicin in patients comparable to the observed clinical results. The model suggested that a fractionated dosing regimen is superior to a conventional dosing regimen for ALL but not for NHL. Simulations indicated that tumor growth is a highly sensitive parameter and predictive of successful outcome. Inotuzumab ozogamicin PK and N-Ac-γ-calicheamicin DMH efflux are also sensitive parameters and would be considered more useful predictors of outcome than CD22 receptor expression. In summary, a multiscale, mechanism-based model has been developed for inotuzumab ozogamicin, which can integrate preclinical biomeasures and PK/PD data to predict clinical response.

This drug-interaction study evaluated the effect of omeprazole, a proton-pump inhibitor, on ibrutinib’s pharmacokinetics (PK) in healthy participants. This open-label, sequential-design study included 20 healthy adults aged 18–55 years. Ibrutinib (560 mg, single dose) was administered after an overnight fast alone on day 1 and with omeprazole on day 7. Omeprazole (40 mg) alone was administered on days 3–6, 1 h before breakfast; and after an overnight fast on day 7, followed by ibrutinib 2 h later. Blood was sampled on days 1 and 7 for up to 48 h postdose, and the standard PK parameters for ibrutinib and PCI-45227 were summarized using descriptive statistics. The effect of omeprazole on ibrutinib’s PK was determined by assessing geometric mean ratios (GMRs) and 90% CIs. Mechanistic modeling was performed using the BTK-receptor occupancy (RO) model. AUC48h and AUClast of ibrutinib plus omeprazole versus ibrutinib alone showed a modest decrease (GMR [90% CI] 98.3% [83.1–116.3] and 92.5% [77.8–109.9], respectively); Cmax decreased by 62.5% (GMR [90% CI] 37.5% [26.4–53.4]), with delayed tmax (1−2 h) and terminal half-life unaffected. Mean AUC for PCI-45227 (primary metabolite) was ~ 20% lower with ibrutinib plus omeprazole versus ibrutinib alone. Model predictions showed no impact of decreased Cmax on BTK target engagement. No new safety signals were identified with the use of ibrutinib in this study. The decrease in Cmax without a corresponding decrease in AUC by omeprazole was not clinically relevant for ibrutinib’s bioavailability. No dose adjustments are recommended during ibrutinib’s co-administration with omeprazole or other pH-altering agents.

The objective of this manuscript was to establish in vitro–in vivo correlation (IVIVC) between the in vitro efficacy and in vivo efficacy of antibody drug conjugates (ADCs), using a PK/PD modeling approach. Nineteen different ADCs were used to develop IVIVC. In vitro efficacy of ADCs was evaluated using a kinetic cell cytotoxicity assay. The cytotoxicity data obtained from in vitro studies was characterized using a novel mathematical model, parameter estimates from which were used to derive an in vitro efficacy matrix for each ADC, termed as ‘in vitro tumor static concentration’ (TSCin vitro). TSCin vitro is a theoretical concentration at continuous exposure of which the number of cells will neither increase nor decrease, compared to the initial cell number in the experiment. The in vivo efficacy of ADCs was evaluated using tumor growth inhibition (TGI) studies performed on human tumor xenograft bearing mice. The TGI data obtained from in vivo studies was characterized using a PK/PD model, parameter estimates from which were used to derive an in vivo efficacy matrix for each ADC, termed as ‘in vivo tumor static concentration’ (TSCin vivo). TSCin vivo is a theoretical concentration if one were to maintain in the plasma of a tumor bearing mouse, the tumor volume will neither increase nor decrease compared to the initial tumor volume. Comparison of the TSCin vitro and TSCin vivo values from 19 ADCs provided a linear and positive IVIVC. The Spearman’s rank correlation coefficient for TSCin vitro and TSCin vivo was found to be 0.82. On average TSCin vivo was found to be ~ 27 times higher than TSCin vitro. The reasonable IVIVC for ADCs suggests that in vitro efficacy data was correctly able to differentiate ADCs for their in vivo efficacy. Thus, IVIVC can be used as a tool to triage ADC molecules in the discovery stage, thereby preventing unnecessary scaling-up of ADCs and waste of time and resources. An ability to predict the concentration of ADC that is efficacious in vivo using the in vitro data can also help in optimizing the experimental design of preclinical efficacy studies. As such, the novel PK/PD modeling method presented here to establish IVIVC for ADCs holds promise, and should be evaluated further using diverse set of cell lines and anticancer agents.

Antibody-drug conjugates (ADCs) offer promise as a therapeutic modality that can potentially reduce the toxicities and poor therapeutic indices caused by the lack of specificity of conventional anticancer therapies. ADCs combine the potency of cytotoxic agents with the target selectivity of antibodies by chemically linking a cytotoxic payload to an antibody, potentially creating a synthetic molecule that will deliver targeted antitumor therapy that is both safe and efficacious. The ADC repertoire contains a range of payload molecules, antibodies, and linkers. Two ADC molecules, Kadcyla® and Adcetris®, have been approved by the FDA, and many more are currently in clinical development.

Protein arginine methyltransferase 5 (PRMT5), a type II methyltransferase, is responsible for symmetric arginine di-methylation of multiple cellular proteins involved in the regulation of cellular transcription. PRMT5 is involved in cellular processes such as survival, proliferation, and apoptosis, and an elevated tumor PRMT5 protein level has recently been correlated with poor survival of cancer patients. JNJ-64619178, a selective PRMT5 inhibitor, showed inhibition of cellular growth in several cell lines representing multiple cancer histologies in vitro. From this, a broad selection of xenograft models was chosen to demonstrate potent anti-tumor efficacy. Xenograft models representing small cell lung cancer (SCLC), non-small cell lung cancer (NSCLC), acute myeloid leukemia (AML), and non-Hodgkin lymphoma were chosen to demonstrate anti-tumor efficacy. Biologically significant tumor growth inhibition up to 99% was observed in both solid and hematological xenograft models, including an aggressive disseminated model of AML, with oral doses of 1 to 10 mg/kg, once daily. Importantly, continued inhibition of tumor growth was observed for several weeks following dosing cessation. Dosing of JNJ-64619178 results in inhibition of Sym-Arg di-methylation of SMD1/3 proteins, core components of the spliceosome in the tumor, and general Sym-Arg di-methylation of serum proteins. These serve as pharmacodynamic markers of PRMT5 inhibition in xenograft models. Potent and prolonged inhibition of SMD1/3 di-methylation was observed in the SCLC model, during and after the dosing period. This has led to the exploration of alternative dosing regimens preclinically. PRMT5 inhibitor JNJ-64619178 is currently being investigated in a Phase I clinical trial, based on its high selectivity and potency, favorable pharmacokinetics and safety properties, and strong preclinical efficacy and pharmacodynamic data. Citation Format: Hillary J. Millar, Dirk Brehmer, Tinne Verhulst, Nahor Haddish-Berhane, Tony Greway, Dana Gaffney, An Boeckx, Erika Van Heerde, Thomas Nys, Joseph Portale, Ulrike Philippar, Tongfei Wu, Sylvie Laquerre, Kathryn Packman. In vivo efficacy and pharmacodynamic modulation of JNJ-64619178, a selective PRMT5 inhibitor, in human lung and hematologic preclinical models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 950.

Protein arginine methyltransferase 5 (PRMT5) is an epigenetic enzyme with oncogenic properties. JNJ-64619178 (JNJ178) is a potent, selective, structurally unique PRMT5 inhibitor with good preclinical efficacy in inhibiting the growth of hematologic and solid tumor cell lines. Toxicology studies showed that JNJ178 decreased reticulocytes and neutrophils in rats and dogs. The objectives of translational modeling and simulation were to understand the exposure-response relationship of both safety and efficacy and provide guidance to the first-in-human clinical development of JNJ178. Experimental data for the PK/PD (Pharmacokinetics/Pharmacodynamics) modeling included: plasma concentration after single dose of JNJ178 in non-tumor bearing mice, plasma concentration and PD markers of dimethylation of arginine (%SDMA in plasma and %SMD1/3-Me2 in tumor, respectively) after multiple doses (1 to 10 mg/kg) QD (once daily) of JNJ178 in H1048 (human small cell lung carcinoma) xenografts, and tumor volume in four xenograft mouse models (A427, human lung carcinoma; H441, human lung adenocarcinoma; H520, human squamous cell lung carcinoma; and H1048). Plasma PK were first described by a standard two-compartment model and used as a driver of PD and tumor volume (efficacy). Plasma and tumor PD were modeled using an indirect response model. A hybrid tumor growth coupled with transit compartment mediated tumor killing model was used to fit the tumor volume data. To predict the safety profile of JNJ178, lifespan based indirect response model for erythropoiesis and Friberg myelosuppression model were used to simulate hemoglobin and neutrophil kinetics in human. The PK/PD model described the data well and validated the hypothesis that PD is driven by trough concentration. Based on the exposure-response relationship from the four xenograft models, the trough concentration needed to achieve tumor stasis for mouse was determined. In addition, the level of inhibition in tumor and plasma PD marker that was associated with tumor stasis was identified. Together with human PK parameters scaled using allometry, the dose range needed to achieve target therapeutic exposure for a typical human subject was predicted. Simulation results from erythropoiesis and Friberg myelosuppression models informed the optimal doing schedules for certain dose levels that would allow hematological toxicity to be manageable with 1.0 x 109/L neutrophil counts at all times. Overall, a translational modeling and simulation approach that considers safety and efficacy has been instrumental in the design of the first-in-human clinical development of PRMT5 inhibitor JNJ178 regarding selection of dose and schedule. Citation Format: Yue Guo, Nahor Haddish-Berhane, Hillary J. Millar, Tinne Verhulst, Tony Greway, Junguo Zhou, Loeckie DeZwart, Dana Gaffney, Joseph Portale, Dirk Brehmer, An Boeckx, Erika Van Heerde, Daniele Ouellet. Translational efficacy and safety modeling and simulation to support the clinical development of JNJ-64619178, a PRMT5 inhibitor [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3905.

9009 Background: JNJ-372 binds EGFR and cMet to block ligand binding, promote receptor degradation, and trigger antibody-dependent cellular cytotoxicity in models of EGFR-mutated (EGFRm) NSCLC. Here we describe the ongoing phase 1 safety, pharmacokinetics (PK), and activity of JNJ-372 in patients (pts) with NSCLC, including 3rd generation tyrosine kinase inhibitor (3GTKI)-relapsed EGFRm NSCLC and EGFR Exon20ins disease. Methods: Pts received JNJ-372 (140–1400 mg) IV weekly for the first 28-day cycle and biweekly thereafter. 1050–1400 mg doses are being explored in dose expansion. Blood samples were collected for PK analyses. Efficacy by investigator per RECIST v1.1 in pts with EGFRm NSCLC treated at ≥700 mg is presented. Tumors were characterized by next-generation sequencing of circulating tumor (ct)DNA and/or tumor tissue. Results: As of 17 Jan 2019, 116 enrolled pts with NSCLC were treated. Median age was 63 years, 38% were male, 77% were Asian, and 97% had EGFR mutations. Mean duration of treatment was 3.8 months, longest exposure was 20 cycles. The PK data set included pts from Korea (77%) and the US (23%). At the 1050 mg dose, 72% of pts achieved average concentrations above the EC90 based on preclinical models. Adverse events (AEs; ≥20%) were rash (59%), infusion related reaction (58%), paronychia (28%), and constipation (22%). Additional EGFR/cMet-related AEs include stomatitis (17%), pruritis (15%), peripheral edema (11%), and diarrhea (7%). Grade ≥3 AEs were reported in 34% (8% treatment-related) with dyspnea (6%) and pneumonia (3%) most frequently observed. Among response-evaluable pts, 25/88 (28%) achieved best timepoint response of partial response (PR). 10/47 pts with prior 3GTKI therapy had best timepoint response of PR (6 confirmed), including 4 with C797S, 1 with cMet amplification, and 5 without identifiable EGFR/cMet-dependent resistance. 6/20 pts with Exon20ins had best timepoint response of PR (3 confirmed). Conclusions: JNJ-372 has a manageable safety profile consistent with EGFR and cMet inhibition. Preliminary responses were achieved in 3GTKI-relapsed disease, including C797S and cMet amplification, and Exon20ins disease; enrollment in dose expansion is ongoing. Clinical trial information: NCT02609776.

A bispecific immunomodulatory biotherapeutic molecule (P-cadherin LP-DART) based on the Dual Affinity Re-Targeting (DART) scaffold has been developed as a potential antitumor treatment showing efficacy in preclinical testing. A minimal anticipated biological effect level (MABEL) approach was applied to project the first-in-human (FIH) dose, because of its immune agonistic properties following target engagement. The pharmacological activity of P-cadherin LP-DART is driven by binding to both P-cadherin on the tumor cells and CD3 on T cells. Therefore, the concentration of the tri-molecular synapse formed between drug, T cell, and tumor cell, rather than drug concentration, is responsible for efficacy. A mechanistic pharmacokinetic/pharmacodynamic (PK/PD)-driven approach was explored to understand the exposure-response relationship based on the synapse concentration to project the MABEL dose. Orthogonal approaches including PK-driven and receptor occupancy calculations were also investigated. This study showcases the application of PK/PD modeling in immune-oncology, and could potentially be implemented for other bispecific biotherapeutics.

Glucokinase is a key regulator of glucose homeostasis, and small molecule allosteric activators of this enzyme represent a promising opportunity for the treatment of type 2 diabetes. Systemically acting glucokinase activators (liver and pancreas) have been reported to be efficacious but in many cases present hypoglycaemia risk due to activation of the enzyme at low glucose levels in the pancreas, leading to inappropriately excessive insulin secretion. It was therefore postulated that a liver selective activator may offer effective glycemic control with reduced hypoglycemia risk. Herein, we report structure-activity studies on a carboxylic acid containing series of glucokinase activators with preferential activity in hepatocytes versus pancreatic β-cells. These activators were designed to have low passive permeability thereby minimizing distribution into extrahepatic tissues; concurrently, they were also optimized as substrates for active liver uptake via members of the organic anion transporting polypeptide (OATP) family. These studies lead to the identification of 19 as a potent glucokinase activator with a greater than 50-fold liver-to-pancreas ratio of tissue distribution in rodent and non-rodent species. In preclinical diabetic animals, 19 was found to robustly lower fasting and postprandial glucose with no hypoglycemia, leading to its selection as a clinical development candidate for treating type 2 diabetes.

Sodium-glucose co-transporter-2 (SGLT2) inhibitors are an emerging class of agents for use in the treatment of type 2 diabetes mellitus (T2DM). Inhibition of SGLT2 leads to improved glycemic control through increased urinary glucose excretion (UGE). In this study, a biologically based pharmacokinetic/pharmacodynamic (PK/PD) model of SGLT2 inhibitor-mediated UGE was developed. The derived model was used to characterize the acute PK/PD relationship of the SGLT2 inhibitor, dapagliflozin, in rats. The quantitative translational pharmacology of dapagliflozin was examined through both prospective simulation and direct modeling of mean literature data obtained for dapagliflozin in healthy subjects. Prospective simulations provided time courses of UGE that were of consistent shape to clinical observations, but were modestly biased toward under prediction. Direct modeling provided an improved characterization of the data and precise parameter estimates which were reasonably consistent with those predicted from preclinical data. Overall, these results indicate that the acute clinical pharmacology of SGLT2 inhibitors in healthy subjects can be reasonably well predicted from preclinical data through rational accounting of species differences in pharmacokinetics, physiology, and SGLT2 pharmacology. Because these data can be generated at the earliest stages of drug discovery, the proposed model is useful in the design and development of novel SGLT2 inhibitors. In addition, this model is expected to serve as a useful foundation for future efforts to understand and predict the effects of SGLT2 inhibition under chronic administration and in other patient populations.

PRMT5 is a type II methyltransferase that symmetrically di-methylates arginine residues on proteins involved in signal transduction and cellular transcription. For example, PRMT5 acts as the enzymatic machinery of the methylosome complex, crucial for spliceosome assembly and activity. Although not frequently mutated or amplified in tumors, an elevated PRMT5 protein level that leads to higher methylosome activity and promotes epithelial–mesenchymal transition, has recently been correlated with a poor survival of cancer patients. The PRMT5 inhibitor JNJ-64619178 has been selected as a clinical candidate based on its high selectivity and potency, paired with favorable oral pharmacokinetics and safety properties. JNJ-64619178 binds simultaneously to the SAM- and protein substrate- binding pockets of the PRMT5/MEP50 complex with a pseudo-irreversible mode-of-action. Chemical proteomics, methylomics and RNA-sequencing analyses of PRMT5 inhibitor treated cell line samples support the current biological understanding of PRMT5 as a regulator of alternative splicing events. JNJ-64619178 showed potent and broad inhibition of cellular growth, observed in several cell line panels that represent diverse cancer histologies. Ongoing investigations will explore the potential synthetic lethal correlation between PRMT5 inhibition and cancer driver pathways, including those addicted to altered splicing. Oral administration of JNJ-64619178 resulted in efficient inhibition of di-methylation of SMD1/3 proteins, components of the splicing machinery and direct substrates of the methylosome, in several human NSCLC and SCLC cancer mouse xenograft models. JNJ-64619178 demonstrated dose-dependent tumor growth inhibition and regression in several human NSCLC and SCLC cancer mouse xenograft models with sustained blockage of tumor re-growth after dosing cessation. In summary, JNJ-64619178 has a favorable pre-clinical profile supporting clinical testing in patients with lung cancer and other malignancies. Citation Format: Tongfei Wu, Hillary Millar, Dana Gaffney, Lijs Beke, Geert Mannens, Petra Vinken, Ivan Sommers, Jan-Willem Thuring, Weimei Sun, Christopher Moy, Vineet Pande, Junguo Zhou, Nahor Haddish-Berhane, Mark Salvati, Sylvie Laquerre, Matthew V. Lorenzi, Dirk Brehmer. JNJ-64619178, a selective and pseudo-irreversible PRMT5 inhibitor with potent in vitro and in vivo activity, demonstrated in several lung cancer models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4859.

10 páginas, 2 tablas, 5 figuras, The methodology of dynamic optimal experimental design was applied to estimate the thermal conductivity and the volumetric heat capacity of conduction heated foods simultaneously. For this purpose, a hotwire probe was used to generate heat in the thermal center of a food product. The temperature response was measured at a specified location inside the food. In order to minimize the effect of experimental input errors on the estimates, the information content of the measured temperature profiles was maximized. Optimal (dynamic) heat generation profiles as well as an optimal location to measure the temperature response in the food product were computed based on modern global optimization algorithms. These heating profiles were implemented and it was shown that the methodology guarantees an optimal regime for simultaneous parameter estimation. Pulse heating with two peaks – one at the beginning and one at the end of the experiment – was found to be an optimal heating profile. The optimal measurement position was located at some distance from, and close to, the heating probe. The mathematical and numerical outcomes of the applied methodology were interpreted in a physical context. Validation experiments with a food simulator (Tylose) were done, and coefficients of variation of 4% and 2% were obtained for the thermal conductivity and volumetric heat capacity, respectively., The authors gratefully acknowledge the F.W.O. for funding this research. Authors Banga and Moles acknowledge financial support from the Spanish Government (MEC AGL2004-05206-C02-01/ALI) and Xunta de Galicia (PGIDIT05PXIC40201PN).

Existing treatments of IBD adopt targeted oral drug delivery route for delivering bioactive agents more efficiently and with fewer side effects. However, the complex and dynamic luminal environment of the GIT and major intra/inter patient variability greatly affects treatment, resulting in variable clinical response in patients. Mathematical simulation model can be employed to consider the complex luminal environment to asses the performance of drug delivery systems for clinical efficacy. The objective of this paper was to evaluate existing targeted oral drug delivery system for the treatment of IBD subject to inter/intra patient luminal variability using in silico experiments employing previously developed mathematical model. Simulation results indicated that the average small intestinal drug release was 44+/-19% and 48+/-21% for healthy and UC subjects, respectively. The systemic absorption of drug approached 10-25% in healthy controls and 16-32% in UC subjects. Calculated drug release from the simulations for different scenario of pH and TT had a good agreement with the clinical in vivo data (13-36% and 17-35% for healthy and UC subjects, respectively). This agreement was also true for 5-ASA and its metabolite (N-acetyl-5-ASA) recovery in the colon. The computational model has a high degree of agreement with data obtained from literature. Physicians can use characteristic performance curves of different delivery systems produced in silico to select a delivery system that would work best for their patients based upon the patient's pH and transit time profiles. It also could be used by the pharmaceutical industry to improve their medicine efficacy by altering the design.

Although ion-exchange resins have been used widely as drug delivery systems, their exact release kinetics has not been reported yet. Usually only the rate-limiting step has been taken into account and the rest of the steps have been ignored as instantaneous processes. To investigate the exact release kinetics of polymer-coated drug/ion-exchange resin complexes for sustained drug delivery, the results of new mathematical modeling were compared with experimental results. Drug/resin complexes with a model drug, dextromethorphan, were prepared and used as cores for fluid-bed coating. An aqueous colloidal dispersion of poly(vinyl acetate) was applied for the coating. A comprehensive mathematical model was developed using a mechanistic approach by considering diffusion, swelling, and ion-exchange processes solved by numerical techniques. The rate-limiting factor of the uncoated resin particles was diffusion through the core matrix. Similarly, in the coated particles the rate-limiting factor was diffusion through the coating membrane. The mathematical model has captured the phenomena observed during experimental evaluations and the release dynamics from uncoated and coated (at different coat levels) particles were predicted accurately (maximum RMSE 2.4%). The mathematical model is a useful tool to theoretically evaluate the drug release properties from coated ion-exchange complexes thus can be used for design purposes.

A multi-scale mathematical model for drug release of oral targeted drug delivery systems was developed and applied to a commercially available delayed release tablet (Asacol®) that delivers 5-aminosalicyclic acid (5-ASA) to the colon. Underlying physical and biochemical principles governing the involved processes (diffusion and dissolution) were employed to develop the mathematical description. Finite element formulation was used to numerically solve the model equations. Molecular dynamics (MD) simulations were used to predict macro-scale transport properties of the drug and the biologic fluid. The effect of pH variability in the gastrointestinal tract environment on the dissolution of the polymeric enteric coating was investigated using the Monte Carlo method. The direct coupling method employed (MD) predicted a sufficiently accurate diffusion coefficient (5.7 × 10− 6 cm2 s− 1) of the drug molecules in reasonable (3 h) computation times. The model was validated using experimental data from in vitro dissolution experiments and provided accurate prediction of the drug release from the delivery system (root mean square error of 5%). The amount of drug entering the systemic circulation, computed from the predicted drug release in varying pH environments in the small bowel, was 15–24%. This range was in good agreement with clinical in vivo data (13–36%) obtained from literature. This research shows that in silico experiments using mechanistic models and stochastic approaches can be used for drug design and optimization and as a decision making tool for physicians.

Antibody-drug conjugates (ADCs) offer promise as a therapeutic modality that can potentially reduce the toxicities and poor therapeutic indices caused by the lack of specificity of conventional anticancer therapies. ADCs combine the potency of cytotoxic agents with the target selectivity of antibodies by chemically linking a cytotoxic payload to an antibody, potentially creating a synthetic molecule that will deliver targeted antitumor therapy that is both safe and efficacious. The ADC repertoire contains a range of payload molecules, antibodies, and linkers. Two ADC molecules, Kadcyla® and Adcetris®, have been approved by the FDA, and many more are currently in clinical development.

The objectives of this investigation were as follows: (a) to validate a mechanism-based pharmacokinetic (PK) model of ADC for its ability to a priori predict tumor concentrations of ADC and released payload, using anti-5T4 ADC A1mcMMAF, and (b) to analyze the PK model to find out main pathways and parameters model outputs are most sensitive to. Experiential data containing biomeasures, and plasma and tumor concentrations of ADC and payload, following A1mcMMAF administration in two different xenografts, were used to build and validate the model. The model performed reasonably well in terms of a priori predicting tumor exposure of total antibody, ADC, and released payload, and the exposure of released payload in plasma. Model predictions were within two fold of the observed exposures. Pathway analysis and local sensitivity analysis were conducted to investigate main pathways and set of parameters the model outputs are most sensitive to. It was discovered that payload dissociation from ADC and tumor size were important determinants of plasma and tumor payload exposure. It was also found that the sensitivity of the model output to certain parameters is dose-dependent, suggesting caution before generalizing the results from the sensitivity analysis. Model analysis also revealed the importance of understanding and quantifying the processes responsible for ADC and payload disposition within tumor cell, as tumor concentrations were sensitive to these parameters. Proposed ADC PK model provides a useful tool for a priori predicting tumor payload concentrations of novel ADCs preclinically, and possibly translating them to the clinic.

Objectives of the present investigation were: (1) to compare three literature reported tumor growth inhibition (TGI) pharmacodynamic (PD) models and propose an optimal new model that best describes the xenograft TGI data for antibody drug conjugates (ADC), (2) to translate efficacy of the ADC Trastuzumab-emtansine (T-DM1) from mice to patients using the optimized PD model, and (3) to apply the translational strategy to predict clinically efficacious concentrations of a novel in-house anti-5T4 ADC, A1mcMMAF. First, the performance of all four of the PD models (i.e. 3 literature reported + 1 proposed) was evaluated using TGI data of T-DM1 obtained from four different xenografts. Based on the estimates of the pharmacodynamic/pharmacokinetic (PK/PD) modeling, a secondary parameter representing the efficacy index of the drug was calculated, which is termed as the tumor static concentration (TSC). TSC values derived from all four of the models were compared with each other, and with literature reported values, to assess the performance of these models. Subsequently, using the optimized PK/PD model, PD parameters obtained from different cell lines, human PK, and the proposed translational strategy, clinically efficacious doses of T-DM1 were projected. The accuracy of projected efficacious dose range for T-DM1 was verified by comparison with the clinical doses. Aforementioned strategy was then applied to A1mcMMAF for projecting its efficacious concentrations in clinic. TSC values for A1mcMMAF, obtained by fitting TGI data from 4 different xenografts with the proposed PK/PD model, were estimated to range from 0.6 to 11.5 μg mL−1. Accordingly, the clinically efficacious doses for A1mcMMAF were projected retrospectively. All in all, the improved PD model and proposed translational strategy presented here suggest that appropriate correction for the clinical exposure and employing the TSC criterion can help translate mouse TGI data to predict first in human doses of ADCs.

To build a multiscale mechanism based pharmacokinetic–pharmacodynamic (PK/PD) model for antibody drug conjugates (ADCs), using brentuximab-vedotin as an example, for preclinical to clinical translation of ADC efficacy. Brentuximab-vedotin experimental data, collected from diverse publications, were employed in the following steps to build and validate the model: (1) characterization of ADC and payload PK at the cellular level, (2) characterization of payload PK in plasma and tumor tissue of xenograft mouse, (3) characterization of ADC PK in mouse plasma, (4) prediction of the tumor payload concentrations in xenograft mouse by integrating parameters obtained from steps 1–3 with the novel tumor disposition model for ADC, (5) characterization of preclinical brentuximab-vedotin tumor growth inhibition data using the novel PK/PD model, (6) characterization of ADC and payload PK in cancer patients, and (7) prediction of clinical responses of brentuximab-vedotin using the PK/PD model, by integrating PK parameters obtained from step 6, and translated mouse parameters from step 5; and comparing them with clinical trial results. The tumor disposition model was able to accurately predict xenograft tumor and plasma payload concentrations. PK/PD model predicted progression free survival rates and complete response rates for brentuximab-vedotin in patients were comparable to the observed clinical results. It is essential to understand and characterize the disposition of ADC and payload, at the cellular and physiological level, to predict the clinical outcome of ADC. A first of its kind mechanistic model has been developed for ADCs, which can integrate preclinical biomeasures and PK/PD data, to predict clinical response.

Finite element mathematical model for drug release of oral targeted drug delivery systems was developed and applied to a commercially available delayed release dosage form (Asacol®) that delivers 5-aminosalicyclic acid (5-ASA) to the colon. To account for the dissolving and deforming dosage form as it transits the gastrointestinal tract, an Arbitrary Lagrangian-Eulerian (ALE) approach was employed. The effect of regional variability of GIT conditions (pH and transit time) on the dissolution of the delayed release coating and, in turn, on drug release was addressed using Monte-Carlo stochastic approach for healthy and diseased (UC) subjects. The model was validated using experimental data from in vitro dissolution experiments and provided accurate prediction of the drug release from the dosage form (Root Mean Square Error of 5%).Stochastic simulation results indicated that the average small intestinal drug release was 44±19% and 48±21% for healthy and UC subjects, respectively. The systemic absorption of the released drug was estimated to be 10-25% in healthy controls and 11-28% in UC subjects. These results are in good agreement with the clinical in vivo data (13-36% and 17-35% for healthy and UC subjects, respectively). This agreement was also true for 5-ASA and its metabolite (N-acetyl-5-ASA) recovery in the colon. The model can be used for design and optimization of broad range of new and existing targeted and controlled release formulations to the distal intestine and colon.

The purpose of this study was to develop a physiologically based simulation tool that is able to predict local as well as systemic bioavailability of 5-aminosalicylic acid (5-ASA)-targeted delivery formulations using the existing understanding of the transport and metabolism mechanisms of 5-ASA. The model accounts for active and passive transcellular transport (absorptive and efflux), passive paracellular transport, intestinal biotransformation, and systemic metabolism and clearance. The intestinal physiology was represented by transverse segments for ileum and proximal colon and longitudinal compartments for the microphysiology of the intestinal tissue. The tool, equipped with an optimization routine that enables tuning model parameters, was developed in Matlab and uses a user-friendly graphical interface for data input and output. Physiologic and kinetic model parameters were estimated either from literature monolayer transport studies using nonlinear curve fitting or obtained directly from the literature. 5-ASA clinical pharmacokinetic profiles of a once-daily (one 4-g/day dose) and twice-daily (two 2-g/day doses) dosing regimen were used to partially calibrate and validate the model, respectively. Simulation results showed that drug C(max) in the gut mucosal layers reached a higher level and was achieved sooner than in the systemic blood level. The computed relative local bioavailability with respect to the systemic bioavailability was 0.063. With use of the model, the relative local bioavailability of different formulations can be established for fast performance verification of new preparations based on measured systemic bioavailability. These types of models play a critical role in designing such preparations and rapidly assessing their effectiveness and will foster efficient experimental designs, saving time and resources.

Multiscale computational modeling of drug delivery systems (DDS) is poised to provide predictive capabilities for the rational design of targeted drug delivery systems, including multi-functional nanoparticles. Realistic, mechanistic models can provide a framework for understanding the fundamental physico-chemical interactions between drug, delivery system, and patient. Multiscale computational modeling, however, is in its infancy even for conventional drug delivery. The wide range of emerging nanotechnology systems for targeted delivery further increases the need for reliable in silico predictions. This review will present existing computational approaches at different scales in the design of traditional oral drug delivery systems. Subsequently, a multiscale framework for integrating continuum, stochastic, and computational chemistry models will be proposed and a case study will be presented for conventional DDS. The extension of this framework to emerging nanotechnology delivery systems will be discussed along with future directions. While oral delivery is the focus of the review, the outlined computational approaches can be applied to other drug delivery systems as well.

Introduction: Previously we have shown the utility of Fluorescent Molecular Tomography (FMT) imaging in evaluating bio-distribution of biologics. P-cadherin LP-DART is a bi-specific Dual Affinity Re-Targeting (DART®) molecule targeting CD3 expressed on T-cells and P-cadherin expressed on tumors. In this study we evaluated the bio-distribution and tumor targeting of P-cadherin LP-DART using FMT imaging in a colorectal xenograft model. Methods: NSG or athymic nude mice with subcutaneous HCT-116 xenografts were used. Studies that included engraftment of T-cells received either PBMNCs or T-cells isolated from healthy human volunteers. Bio-distribution studies were initiated when the tumors reached 300-500 mm3. P-cadherin LP-DART or a negative control-DART (non-targeted domain x CD3 binding domain) was conjugated with a near-infrared fluorophore VivoTag680XL (VT680), and the labeling efficiency was determined by spectrophotometer. T-cells used in trafficking studies were labeled with CellVue815. Cell surface P-cadherin expression and P-cadherin LP-DART binding was determined by flow cytometry. T-cell activity was measured with cytotoxic T-lymphocyte (CTL) assays. FMT imaging was performed longitudinally post injection of labeled bi-specifics. Data was analyzed using TrueQuant software. Plasma and tissues were collected for PK analysis by ELISA or histology. Results: VT680 conjugation to P-cadherin LP-DART did not significantly affect the binding to P-cadherin, whereas CD3 binding was decreased. In vivo FMT imaging revealed high levels of P-cadherin LP-DART accumulation in the tumors. The in vivo kinetics revealed that the peak accumulation in tumors was 96hrs post-injection. At 240hrs post-injection, there was still measurable P-cadherin LP-DART detected in tumors. Ex vivo imaging showed 20-25 fold increase in accumulation of P-cadherin LP-DART compared to negative control DART. Comparison of P-cadherin LP-DART accumulation between PBMNC engrafted and non-engrafted model showed no significant difference in quantity or kinetics. There was no significant difference in the kinetics of elimination in the whole-body, heart or liver between P-cadherin LP-DART or negative control. Ex vivo comparison of accumulation in various organs showed no difference between P-cadherin LP-DART or negative control. Cell trafficking studies with CellVue labeled T-cells showed the co-localization of T-cells and P-cadherin LP-DART in tumors. Conclusion: FMT imaging showed that P-cadherin LP-DART specifically targeted HCT-116 tumors. Cell trafficking studies showed that engrafted T-cells accumulated in tumors. This study shows the utility of FMT in bio-distribution studies of biologics and in vivo cell trafficking. Citation Format: Anand Giddabasappa, Vijay Gupta, Timothy S. Fisher, John David, Norberg Rand, Allison Rohner, Justin Cohen, Tracey Clark, Nahor Haddish-Berhane, Adam Root, Chad May. Bio-distribution and tumor targeting of a P-cadherin x CD3 bi-specific redirected T-cell molecule using fluorescence molecular tomography imaging. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 5111. doi:10.1158/1538-7445.AM2015-5111

Introduction: Strong evidence exists supporting the important role T-cells play in the immune response against tumors. Still, the ability to initiate tumor specific immune responses remains a challenge. We have developed a Dual-Affinity Re-Targeting (DART®) protein engineered with enhanced pharmacokinetic properties to extend in vivo half-life, and designed to engage and activate endogenous polyclonal T cell populations via the CD3 complex in the presence of P-cadherin expressing tumors. We designate this bispecific redirecting T-cell molecule as P-cadherin LP-DART. P-cadherin up-regulation has been reported in various tumors, including breast, gastric, endometrial, colorectal and pancreatic cancers, and is correlated with poor survival of patients. Methods: The P-cadherin LP-DART was stably expressed by CHO cells and purified to homogeneity via standard antibody-purification methods. Functional in vitro studies were performed with a panel of human cancer cell lines and human T cells isolated from healthy donors. In vivo tumor growth inhibition studies were performed in immunodeficient athymic nude or NOD-scid IL2Rgammanull (NSG) mice bearing human tumor cell line- or patient derived-xenografts and human T-cells, and treated with P-cadherin LP-DART. Results: P-cadherin LP-DART exhibited binding to a broad panel of cancer cell lines expressing various levels of endogenous cell surface P-cadherin, and comparable binding to a number of human donor derived T-cells expressing CD3. In the presence of T-cells, this bispecific molecule elicited P-cadherin expression level dependent cytotoxic T-lymphocyte (CTL) responses against the different tumor cell lines, and induced antigen dependent T-cell activation and cytokine release. P-cadherin LP-DART also demonstrated potent in vivo anti-tumor activity against implanted tumor xenografts. Significant tumor growth inhibition was observed across a range of potential indications that express P-cadherin. Measurement of in vivo pharmacodynamic markers support P-cadherin LP-DART mediated CTL infiltration and killing as the mechanism of tumor inhibition. Conclusions: P-cadherin LP-DART displays potent in vitro and in vivo redirected T-cell activity against a broad panel of cancer cell lines expressing a range of cell surface P-cadherin levels. These data support further investigation of P-cadherin LP-DART as a potential novel therapeutic treatment for cancers expressing P-cadherin. Citation Format: Timothy S. Fisher, Adam Root, Bryan Peano, Allison Rohner, Justin Lucas, Mark Elliott, Konstantinos Tsaparikos, Hui Wang, Jonathan Golas, Maria Gavriil, Susan Benard, Tao He, Tracey Clark, Nahor Haddish-Berhane, Ralph Alderson, Yinhua Yang, Syd Johnson, Paul Moore, Lioudmila Tchistiakova, Hans-Peter Gerber, Chad May. Bispecific redirected T-cell immunotherapy targeting P-cadherin expressing tumors. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2476. doi:10.1158/1538-7445.AM2015-2476

The objective of the present study is to include coating thickness non-uniformity in the development of a drug release model using coated ion-exchange pellets through the use of stochastic approaches. Drug release from ion-exchange resins was described using a Nernst–Plank model. Complexes of a model drug (dextromethorphan) and Dowex® 50WX4-200 were prepared using a modified batch method and coated with Kollicoat® SR 30D polymer. The deterministic model, validated using experimental drug release profiles for different coating thicknesses at 0%, 10%, 15%, 20% (w/w), was in agreement with the experimental data with a maximum root mean square error (RMSE) of 2.4%. An arbitrary Lagrangian–Eulerian approach was pursued to develop models of spherical pellets with non-uniform coating thicknesses. The Monte Carlo method was used to simulate the effect of the level of coating deformity on the cumulative drug release profile. Considering the co-existence of equal percentages of deformed and undeformed pellets in a batch, the cumulative release profile can vary by approximately ±6% as a result of coating non-uniformity. The release profile obtained for a model of an arbitrary pellet with an actual non-uniform coating profile was in good agreement with the average release profile for the models of the theoretical randomly deformed pellets. The developed mathematical model is a useful tool to evaluate and predict release profiles of polymer coated ion-exchange resin complexes.

Antibody-drug conjugates (ADCs) represent a promising therapeutic modality for the clinical management of cancer. We sought to develop a novel ADC that targets 5T4 (TPBG), an oncofetal antigen expressed on tumor-initiating cells (TICs), which comprise the most aggressive cell population in the tumor. We optimized an anti-5T4 ADC (A1mcMMAF) by sulfydryl-based conjugation of the humanized A1 antibody to the tubulin inhibitor monomethylauristatin F (MMAF) via a maleimidocaproyl linker. A1mcMMAF exhibited potent in vivo anti-tumor activity in a variety of tumor models and induced long-term regressions for up to 100 days after the last dose. Strikingly, animals showed pathological complete response in each model. In a non-small cell lung cancer patient-derived xenograft in which 5T4 is preferentially expressed on the less differentiated tumor cells, A1mcMMAF treatment resulted in sustained tumor regressions and reduced TIC frequency. These results highlight the potential of ADCs that target the most aggressive cell populations within tumors. An optimized pharmacokinetic/pharmacodynamic (PK/PD) model of tumor growth and drug kill was used to characterize the ADC concentration response relationship in mouse. A holistic secondary parameter, tumor static concentration (TSC), was derived from model parameters to quantify efficacy and support early clinical trial design. Tumor static concentrations [80% confidence] of A1mcMMAF ranged from 1.1[0.9 -1.4] μg/ml to 11.6 [9.6 - 14.1] μg/ml across tumor models. For comparison, in the clinic T-DM1 has an average concentration of 14 μg/ml at an efficacious dose of 3.6 mg/kg Q3wk (HER+ breast cancer) (Krop et al. 2010) and Brentuximab-vedotin has an average concentration of 3.65 μg/ml at an efficacious dose of 1.8 mg/kg Q 3wk (HL/ ALCL) (Younes et al. 2010). Taken together, the preclinical data established a promising therapeutic index that supports clinical testing of A1mcMMAF. Expression analysis profiling using clinical and preclinical data indicated that lung and breast tumors demonstrated differentially high expression of 5T4 in comparison to normal tissues. An IHC assay developed in house confirmed the hypothesis that a broad range of 5T4 expression was measurable in NSCLC patient tumor samples. Additionally, we developed an assay that measures 5T4 expression on circulating tumor cells (CTCs) and used this assay to measure and characterize a broad range of 5T4 expression in CTCs obtained from the blood of NSCLC patients. We intend to deploy these co-developed immunoassays to guide A1mcMMAF clinical development. Citation Format: Puja Sapra, Marc Damelin, Kimberly Marquette, Kenneth G. Geles, Jonathon Golas, Maureen Dougher, Bitha Narayanan, Andreas Giannakou, Kiran Khandke, Russell Dushin, Elana Ernstoff, Judy Lucas, Mauricio Leal, George Hu, Alison Betts, Nahor Haddish-Berhane, Eric Powell, Steven Pirie-Shepherd, Christopher O'Donnell, Lioudmila Tchistiakova, Hans-Peter Gerber, Dena Marrinucci, Eric Tucker. Preclinical development and translational research on a novel antibody-drug conjugate that targets 5T4, an oncofetal antigen expressed on tumor-initiating cells. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4752. doi:10.1158/1538-7445.AM2013-4752

Glucokinase is a key regulator of glucose homeostasis and small molecule activators of this enzyme represent a promising opportunity for the treatment of Type 2 diabetes. Several glucokinase activators have advanced to clinical studies and demonstrated promising efficacy; however, many of these early candidates also revealed hypoglycemia as a key risk. In an effort to mitigate this hypoglycemia risk while maintaining the promising efficacy of this mechanism, we have investigated a series of substituted 2-methylbenzofurans as “partial activators” of the glucokinase enzyme leading to the identification of N,N-dimethyl-5-(2-methyl-6-((5-methylpyrazin-2-yl)-carbamoyl)benzofuran-4-yloxy)pyrimidine-2-carboxamide as an early development candidate.