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Purpose:Tepotinib is an oral, potent, highly selective MET inhibitor. This first-in-man phase I trial investigated the MTD of tepotinib to determine the recommended phase II dose (RP2D).Patients and Methods:Patients received tepotinib orally according to one of three dose escalation regimens (R) on a 21-day cycle: R1, 30–400 mg once daily for 14 days; R2, 30–315 mg once daily 3 times/week; or R3, 300–1,400 mg once daily. After two cycles, treatment could continue in patients with stable disease until disease progression or unacceptable toxicity. The primary endpoint was incidence of dose-limiting toxicity (DLT) and treatment-emergent adverse events (TEAE). Secondary endpoints included safety, tolerability, pharmacokinetics, pharmacodynamics, and antitumor effects.Results:One hundred and forty-nine patients received tepotinib (R1: n = 42; R2: n = 45; R3: n = 62). Although six patients reported DLTs [one patient in R1 (115 mg), three patients in R2 (60, 100, 130 mg), two patients in R3 (1,000, 1,400 mg)], the MTD was not reached at the highest tested dose of 1,400 mg daily. The RP2D of tepotinib was established as 500 mg once daily, supported by translational modeling data as sufficient to achieve ≥95% MET inhibition in ≥90% of patients. Treatment-related TEAEs were mostly grade 1 or 2 fatigue, peripheral edema, decreased appetite, nausea, vomiting, and lipase increase. The best overall response in R3 was partial response in two patients, both with MET overexpression.Conclusions:Tepotinib was well tolerated with clinical activity in MET-dysregulated tumors. The RP2D of tepotinib was established as 500 mg once daily. MET abnormalities can drive tumorigenesis. This first-in-man trial demonstrated that the potent, highly selective MET inhibitor tepotinib can reduce or stabilize tumor burden and is well tolerated at doses up to 1,400 mg once daily. An RP2D of 500 mg once daily, as determined from translational modeling and simulation integrating human population pharmacokinetic and pharmacodynamic data in tumor biopsies, is being used in ongoing clinical trials.

Supplementary information showing details of study criteria, bioasssays, preclinical modelling, PK data, safety and efficacy.

Pan-proteasome inhibitors (pPIs) significantly improve outcomes in patients with multiple myeloma; however, their indiscriminate inhibition of multiple proteasome and immunoproteasome subunits causes diverse toxicities, including thrombocytopenia. We investigated the mechanisms underlying the platelet depletion induced by the pPIs bortezomib, carfilzomib, and ixazomib. An established thrombocytopenia model was adapted for each compound (bortezomib, ixazomib, and carfilzomib) to compare the following two pharmacodynamic mechanisms: a reversible inhibition of new progenitor cell formation (the myelosuppression model) and a reversible effect on the function of megakaryocytes to bud new platelets (platelet formation model). Bortezomib, ixazomib, and carfilzomib plasma concentration profiles and platelet counts were extracted from the literature. Pharmacokinetic (PK) and thrombocytopenia models were developed to predict the PK of these drugs and to describe their effects on proliferating cells and platelet budding. The PK models reproduced the exposure of the three compounds at steady state well compared with those reported in the literature. Both the platelet formation and myelosuppression models seemed able to describe the platelet depletion caused by bortezomib, ixazomib, and carfilzomib. Estimated structural parameters in the myelosuppression model were in the range of the values reported in the literature, whereas the mean transit time estimated with the platelet formation model was 3-fold to 10-fold higher than the highest reported value. The model of drug-induced myelosuppression yielded estimates of structural parameters in the range of those previously reported. The platelet formation model captured the temporal variation reported in clinical studies.

A central question in drug discovery is how to select drug candidates from a large number of available compounds. This analysis presents a model-based approach for comparing and ranking combinations of radiation and radiosensitizers. The approach is quantitative and based on the previously-derived Tumor Static Exposure (TSE) concept. Combinations of radiation and radiosensitizers are evaluated based on their ability to induce tumor regression relative to toxicity and other potential costs. The approach is presented in the form of a case study where the objective is to find the most promising candidate out of three radiosensitizing agents. Data from a xenograft study is described using a nonlinear mixed-effects modeling approach and a previously-published tumor model for radiation and radiosensitizing agents. First, the most promising candidate is chosen under the assumption that all compounds are equally toxic. The impact of toxicity in compound selection is then illustrated by assuming that one compound is more toxic than the others, leading to a different choice of candidate.

M3258 is an orally bioavailable, potent, selective, reversible inhibitor of the large multifunctional peptidase 7 (LMP7, β5i, PSMB8) proteolytic subunit of the immunoproteasome; a component of the cellular protein degradation machinery, highly expressed in malignant hematopoietic cells including multiple myeloma. Here we describe the fit-for-purpose PK/PD/efficacy modelling of M3258 based on preclinical data from several species. The inhibition of LMP7 activity (PD) and tumor growth (efficacy) were tested in human multiple myeloma xenografts in mice. PK and efficacy data were correlated yielding a free M3258 concentration of 45 nM for half-maximal tumor growth inhibition (KC

Tepotinib is a highly selective and potent MET inhibitor in development for the treatment of patients with solid tumors. Given the favorable tolerability and safety profiles up to the maximum tested dose in the first‐in‐human (FIH) trial, an efficacy‐driven translational modeling approach was proposed to establish the recommended phase II dose (RP2D). To study the in vivo pharmacokinetics (PKs)/target inhibition/tumor growth inhibition relationship, a subcutaneous KP‐4 pancreatic cell‐line xenograft model in mice with sensitivity to MET pathway inhibition was selected as a surrogate tumor model. Further clinical PK and target inhibition data (derived from predose and postdose paired tumor biopsies) from a FIH study were integrated with the longitudinal PKs and target inhibition profiles from the mouse xenograft study to establish a translational PK/pharmacodynamic (PD) model. Preclinical data showed that tumor regression with tepotinib treatment in KP‐4 xenograft tumors corresponded to 95% target inhibition. We therefore concluded that a PD criterion of sustained, near‐to‐complete (>95%) phospho‐MET inhibition in tumors should be targeted for tepotinib to be effective. Simulations of dose‐dependent target inhibition profiles in human tumors that exceeded the PD threshold in more than 90% of patients established an RP2D of tepotinib 500 mg once daily. This translational mathematical modeling approach supports an efficacy‐driven rationale for tepotinib phase II dose selection of 500 mg once daily. Tepotinib at this dose has obtained regulatory approval for the treatment of patients with non‐small cell lung cancer harboring MET exon 14 skipping.

Introduction: Poly (ADP-ribose) polymerase (PARP) and ataxia telangiectasia and Rad3-related (ATR) inhibitors target key DNA damage response (DDR) kinases. PARP inhibitors (PARPi) suppress the catalytic activity of PARP and trap PARP in a complex with damaged DNA, resulting in the accumulation of unrepaired single-strand breaks (SSBs) and stalled replication forks. Loss of ATR activity blocks cell cycle arrest induced by single-stranded DNA and sensitizes cancer cells to agents that induce DNA replication stress. Thus, PARP inhibition synergizes (through synthetic lethality) with concurrent ATR inhibition by inducing replication fork collapse, double-strand breaks (DSBs), and PARP-DNA complex formation, with simultaneous loss of intra-S and G2/M checkpoints and suppression of DNA-damage repair, leading to mitotic catastrophe. Four PARPi are currently approved for the treatment of various cancers and several ATR inhibitors (ATRi) are in clinical trials either as monotherapies or in combination with other chemotherapeutic agents. We developed and validated a semi-mechanistic quantitative systems pharmacology (QSP) model that represents the mechanisms of action of PARPi and ATRi with minimal parameters, which could be used to inform the optimization of combination regimens. Methods: A QSP model of a growing cancer cell population was developed by considering SSBs and DSBs, and parallel DNA repair pathways relying on PARP and ATR. PARPi and ATRi mediated saturable inhibitory effects on their respective DDR pathways, while PARP-DNA trapping was represented as an increased conversion rate from SSBs to DSBs. Phenotypic impairments of the DDR such as BRCA mutations were embedded as DDR pathway deficiencies. The model was calibrated using experimental data derived from rucaparib and talazoparib combination studies with gartisertib. Results: The calibrated model captured well the tumor-growth inhibition observed in the HBCx9 PDX model for rucaparib and gartisertib, either alone or in combination, over average daily doses ranging from 50 mg/kg to 200 mg/kg (QD/BID) of rucaparib and 1-3 mg/kg (QD/BIW/QD alternate weeks) of gartisertib. The model was also able to predict the wide range of responses (from shrinkage to progressive disease) observed in a panel of triple-negative breast cancer PDX models (BRCA-mutant and wild type) treated with talazoparib and gartisertib in combination. The complete DDR model utilized 9 variable parameters, and the mechanisms of action of PARP and ATR inhibition were described by 4 parameters each. Conclusion: This newly developed QSP model provides a framework that can be applied to optimize the dosing regimens of PARP and ATR inhibitor combinations and help with clinical dosing strategy. Citation Format: Claire C. Villette, Frances Brightman, Nathalie Dupuy, Astrid Zimmermann, Florianne Lignet, Frank T. Zenke, Nadia Terranova, Jayaprakasam Bolleddula, Samer El Bawab, Christophe Chassagnole. Development and validation of a quantitative systems pharmacology model for prediction of preclinical efficacy of PARP inhibitors rucaparib and talazoparib combined with the ATR inhibitor gartisertib (M4344). [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5699.

Background: This open-label, phase 1 trial (NCT02316197) aimed to determine the maximum-tolerated dose (MTD) and/or recommended phase 2 dose (RP2D) of peposertib (formerly M3814), a DNA-dependent protein kinase (DNA-PK) inhibitor in patients with advanced solid tumours. Secondary/exploratory objectives included safety/tolerability, pharmacokinetic/pharmacodynamic profiles and clinical activity. Methods: Adult patients with advanced solid tumours received peposertib 100–200 mg once daily or 150–400 mg twice daily (BID) in 21-day cycles. Results: Thirty-one patients were included (median age 66 years, 61% male). One dose-limiting toxicity, consisting of mainly gastrointestinal, non-serious adverse events (AEs) and long recovery duration, was reported at 300 mg BID. The most common peposertib-related AEs were nausea, vomiting, fatigue and pyrexia. The most common peposertib-related Grade 3 AEs were maculopapular rash and nausea. Peposertib was quickly absorbed systemically (median Tmax 1.1–2.5 h). The p-DNA-PK/t-DNA-PK ratio decreased consistently in peripheral blood mononuclear cells 3–6 h after doses ≥100 mg. The best overall response was stable disease (12 patients), lasting for ≥12 weeks in seven patients. Conclusions: Peposertib was well-tolerated and demonstrated modest efficacy in unselected tumours. The MTD was not reached; the RP2D was declared as 400 mg BID. Further studies, mainly with peposertib/chemo-radiation, are ongoing. Clinical trial registration: NCT02316197, SCOPUS: ar.j, info:eu-repo/semantics/published

© 2017 ASCPT. Radiotherapy is one of the major therapy forms in oncology, and combination therapies involving radiation and chemical compounds can yield highly effective tumor eradication. In this paper, we develop a tumor growth inhibition model for combination therapy with radiation and radiosensitizing agents. Moreover, we extend previous analyses of drug combinations by introducing the tumor static exposure (TSE) curve. The TSE curve for radiation and radiosensitizer visualizes exposure combinations sufficient for tumor regression. The model and TSE analysis are then tested on xenograft data. The calibrated model indicates that the highest dose of combination therapy increases the time until tumor regrowth 10-fold. The TSE curve shows that with an average radiosensitizer concentration of 1.0μg/mL the radiation dose can be decreased from 2.2 Gy to 0.7 Gy. Finally, we successfully predict the effect of a clinically relevant treatment schedule, which contributes to validating both the model and the TSE concept.

Bintrafusp alfa, a first-in-class bifunctional fusion protein composed of the extracellular domain of the TGF-βRII receptor (TGF-β "trap") fused to a human IgG1-blocking PD-L1, showed a manageable safety profile and clinical activity in phase I studies in patients with heavily pretreated advanced solid tumors. The recommended phase 2 dose (RP2D) was selected based on integration of modeling, simulations, and all available data. A 1,200-mg every 2 weeks (q2w) dose was predicted to maintain serum trough concentration (Ctrough ) that inhibits all targets of bintrafusp alfa in circulation in > 95% of patients, and a 2,400-mg every 3 weeks (q3w) dose was predicted to have similar Ctrough . A trend toward an association between exposure and efficacy variables and a relatively stronger inverse association between clearance and efficacy variables were observed. Exposure was either weakly or not correlated with probability of adverse events. The selected intravenous RP2D of bintrafusp alfa is 1,200 mg q2w or 2,400 mg q3w.

Purpose: Tepotinib is an oral, potent, highly selective MET inhibitor. This first-in-man phase I trial investigated the MTD of tepotinib to determine the recommended phase II dose (RP2D). Patients and Methods: Patients received tepotinib orally according to one of three dose escalation regimens (R) on a 21-day cycle: R1, 30–400 mg once daily for 14 days; R2, 30–315 mg once daily 3 times/week; or R3, 300–1,400 mg once daily. After two cycles, treatment could continue in patients with stable disease until disease progression or unacceptable toxicity. The primary endpoint was incidence of dose-limiting toxicity (DLT) and treatment-emergent adverse events (TEAE). Secondary endpoints included safety, tolerability, pharmacokinetics, pharmacodynamics, and antitumor effects. Results: One hundred and forty-nine patients received tepotinib (R1: n = 42; R2: n = 45; R3: n = 62). Although six patients reported DLTs [one patient in R1 (115 mg), three patients in R2 (60, 100, 130 mg), two patients in R3 (1,000, 1,400 mg)], the MTD was not reached at the highest tested dose of 1,400 mg daily. The RP2D of tepotinib was established as 500 mg once daily, supported by translational modeling data as sufficient to achieve ≥95% MET inhibition in ≥90% of patients. Treatment-related TEAEs were mostly grade 1 or 2 fatigue, peripheral edema, decreased appetite, nausea, vomiting, and lipase increase. The best overall response in R3 was partial response in two patients, both with MET overexpression. Conclusions: Tepotinib was well tolerated with clinical activity in MET-dysregulated tumors. The RP2D of tepotinib was established as 500 mg once daily. MET abnormalities can drive tumorigenesis. This first-in-man trial demonstrated that the potent, highly selective MET inhibitor tepotinib can reduce or stabilize tumor burden and is well tolerated at doses up to 1,400 mg once daily. An RP2D of 500 mg once daily, as determined from translational modeling and simulation integrating human population pharmacokinetic and pharmacodynamic data in tumor biopsies, is being used in ongoing clinical trials.

Evofosfamide is a cytotoxic small-molecule prodrug preferentially activated under hypoxic conditions. The cytotoxicity of evofosfamide impacted the generation of in vitro drug-drug interaction (DDI) data, especially in vitro induction results. Therefore, a novel physiologically based pharmacokinetic (PBPK) approach was used, which involved available in vitro and clinical data of evofosfamide and combined it with induction data from the prototypical cytochrome P450 (CYP)3A inducer rifampicin. The area under the concentration-time curve (AUC) ratios of midazolam were above 0.80, indicating that induction of CYP3A by evofosfamide administered weekly is unlikely to occur in humans. Moreover, static and PBPK modeling showed no clinically relevant inhibition via CYP2B6, CYP2D6, and CYP3A4. In conclusion, PBPK models were used to supplement in vitro information of a cytotoxic compound. This approach may set a precedent for future studies of cytotoxic drugs, potentially reducing the need for clinical DDI studies and providing more confidence in the clinical use of approved cytotoxic compounds for which DDI information is sparse.

Mediator-associated kinases CDK8/19 are context-dependent drivers or suppressors of tumorigenesis. Their inhibition is predicted to have pleiotropic effects, but it is unclear whether this will impact on the clinical utility of CDK8/19 inhibitors. We discovered two series of potent chemical probes with high selectivity for CDK8/19. Despite pharmacodynamic evidence for robust on-target activity, the compounds exhibited modest, though significant, efficacy against human tumor lines and patient-derived xenografts. Altered gene expression was consistent with CDK8/19 inhibition, including profiles associated with super-enhancers, immune and inflammatory responses and stem cell function. In a mouse model expressing oncogenic beta-catenin, treatment shifted cells within hyperplastic intestinal crypts from a stem cell to a transit amplifying phenotype. In two species, neither probe was tolerated at therapeutically-relevant exposures. The complex nature of the toxicity observed with two structurally-differentiated chemical series is consistent with on-target effects posing significant challenges to the clinical development of CDK8/19 inhibitors. DOI: http://dx.doi.org/10.7554/eLife.20722.001, eLife digest Healthy cells in the human body can become cancerous if they gain genetic mutations that allow them to rapidly grow and divide. Some types of cancer respond better to drug treatments than others and tumors often develop resistance to a particular drug treatment after a while. Because of this, researchers are always searching for new molecules to develop into anticancer drugs. Recently, a team of researchers identified some small molecules that could inactivate two closely related proteins called CDK8 and CDK19. CDK8 is essential for the WNT signaling pathway – which enables cells to communicate with one another – and has been extensively studied in various cancers. Previous studies indicate that this protein can either promote or inhibit the growth of tumors, depending on the type and stage of the cancer. Furthermore, CDK8 regulates a type of molecular switch called a “super-enhancer”, which controls the activity of many genes. In contrast, the role of CDK19 in cells was not as well understood. Here Clarke, Ortiz-Ruiz et al. investigated whether two different classes of small molecules that target CDK8 and CDK19 (referred to as “prototype CDK8/19 drugs”) could inhibit the growth of cancers, and whether they have any harmful side effects on healthy cells. For the experiments, human cancer cells were implanted into mice. Treating these mice with prototype CDK8/19 drugs inhibited the activity of CDK8 and CDK19 in the cancer cells and slowed the growth of colorectal tumors. A type of blood cancer called acute myeloid leukaemia was particularly sensitive to the drugs. However, Clarke, Ortiz-Ruiz et al. also observed that the prototype drugs altered the activity of many genes with roles in healthy tissues such as immune, bone and stem cells. Further experiments in mice and cells grown in the laboratory confirmed that these prototype drugs have adverse effects on healthy intestinal and bone marrow stem cells and trigger changes to immune cells. These concerning side effects were also evident when the prototype drugs were tested in rats and dogs. Furthermore, the experiments indicate that there is not a suitable range of doses of these drugs in which the therapeutic benefits outweigh the toxic side effects. Clarke, Ortiz-Ruiz et al. conclude that the clinical development of CDK8/19 drugs will be extremely challenging and that their prototype drugs would not currently be suitable for use as cancer treatments. However, the small molecules they describe will be important probes in research to study exactly how CDK8/19 regulate gene activity in both healthy cells and cancers. DOI: http://dx.doi.org/10.7554/eLife.20722.002

M3258 is an orally bioavailable, potent, selective, reversible inhibitor of the large multifunctional peptidase 7 (LMP7, β5i, PSMB8) proteolytic subunit of the immunoproteasome; a crucial component of the cellular protein degradation machinery, which is highly expressed in malignant hematopoietic cells including multiple myeloma. M3258 was previously shown to deliver strong in vivo preclinical efficacy in multiple myeloma xenograft models, as well as a more benign non-clinical safety profile compared to approved pan-proteasome inhibitors, exemplified by a lack of effects on the central and peripheral nervous systems and cardiac and respiratory organs. Here we describe preclinical PK/PD and PK/efficacy modelling which led to a prediction of the PK profile, and the efficacious and safe dose ranges of M3258 in human which were used to guide the design of the phase I dose-escalation trial of M3258 in >3 line relapsed/refractory multiple myeloma (RRMM) patients. Mouse, rat, dog and monkey PK, plasma protein binding and intrinsic clearance data were used to estimate a half-life of approximately 6 hours for M3258 in human. The human total clearance and volume of distribution for M3258 were predicted to be 0.033 L/h/kg and 0.28 L/kg, respectively, whilst oral bioavailability was estimated to be above 80%. LMP7 proteolytic activity was assessed as a PD readout in human multiple myeloma tumor cells xenografted to mice as well as in dog peripheral blood mononuclear cells (PBMCs). A strong PK/PD relationship was observed for M3258 across both species. LMP7 inhibition by M3258 also correlated strongly with anti-tumor efficacy in multiple myeloma xenografts, with maximal efficacy observed at M3258 exposure delivering sustained inhibition of tumor LMP7 activity. Quantitative PK/PD/efficacy modeling predicted the biologically efficacious dose (BED) of M3258 upon oral application to be between 10 - 90 mg daily in human. By incorporating data from nonclinical safety studies, these data suggest an attractive human PK profile of M3258, enabling oral application, as well as an improved human therapeutic index compared to approved pan-proteasome inhibitors. M3258 is being investigated in a phase I, first-in-man, 2-part, open label clinical study designed to determine the safety, tolerability, PK, PD and early signs of efficacy of M3258 as a single agent (dose-escalation) and co-administered with dexamethasone (dose-expansion) in participants with RRMM whose disease has progressed following > 3 prior lines of therapy and for whom no effective standard therapy exists. Integration of these data will guide the selection of the BED for potential further clinical development of M3258. Disclosures Lignet: Merck Healthcare KGaA: Employment. Esdar:Merck Healthcare KGaA: Employment. Friese-Hamim:Merck Healthcare KGaA: Employment. Becker:Merck Healthcare KGaA: Employment, Other: Holding shares with a value below 1000-USD. Drouin:EMD Serono Research and Development Institute: Employment. El Bawab:Merck Healthcare KGaA: Employment. Goodstal:EMD Serono Research and Development Institute: Employment. Gimmi:Merck Healthcare KGaA: Employment. Haselmayer:Merck Healthcare KGaA: Employment. Jährling:Merck Healthcare KGaA: Employment. Sanderson:Merck Healthcare KGaA: Employment. Sloot:Merck Healthcare KGaA: Employment. Stinchi:Merck Healthcare KGaA: Employment. Victor:Merck Healthcare KGaA: Employment. Walter:Merck Healthcare KGaA: Employment. Rohdich:Merck Healthcare KGaA: Employment.

e14514 Background: MSB11455 is a proposed biosimilar to the currently licensed pegfilgrastim (Neulasta). This phase I study (NCT03251248) assessed the pharmacokinetic (PK)/pharmacodynamic (PD) bioequivalence of MSB11455 to Neulasta. Methods: Healthy volunteers were randomized to one of two crossover sequences, MSB11455/Neulasta or Neulasta/MSB11455. Subjects received a single subcutaneous dose of either MSB11455 or Neulasta (both 6 mg/0.6 mL) on Day 1 of each study period. Samples for PK/PD analysis were taken predose and up to Day 16 postdose. Immunogenicity samples were taken predose and up to Day 84 postdose. Safety was assessed throughout the study. Results: 244 subjects were randomized and received both treatments. For all primary PK/PD parameters 90% repeated confidence intervals of the geometric mean ratio of MSB11455 versus Neulasta were within the pre-defined equivalence range (80.00%–125.00%): AUC0–∞ (96.59, 112.82), AUC0–last (97.29, 113.96), Cmax (97.13, 114.99), Emax (98.74, 102.39) and AUE0–t (97.30, 100.23). Safety and tolerability as well as immunogenicity were comparable between treatment sequences. No filgrastim-specific neutralizing antibodies were detected in either treatment sequence. Conclusions: PK/PD equivalence of MSB11455 and pegfilgrastim was demonstrated with comparable immunogenicity, safety, and tolerability. This study supports the biosimilarity of MSB11455 to Neulasta. Clinical trial information: NCT03251248.

Combination therapies are widely accepted as a cornerstone for treatment of different cancer types. A tumor growth inhibition (TGI) model is developed for combinations of cetuximab and cisplatin obtained from xenograft mice. Unlike traditional TGI models, both natural cell growth and cell death are considered explicitly. The growth rate was estimated to 0.006 h−1 and the natural cell death to 0.0039 h−1 resulting in a tumor doubling time of 14 days. The tumor static concentrations (TSC) are predicted for each individual compound. When the compounds are given as single-agents, the required concentrations were computed to be 506 mg · mL−1 and 56 ng · mL−1 for cetuximab and cisplatin, respectively. A TSC curve is constructed for different combinations of the two drugs, which separates concentration combinations into regions of tumor shrinkage and tumor growth. The more concave the TSC curve is, the lower is the total exposure to test compounds necessary to achieve tumor regression. The TSC curve for cetuximab and cisplatin showed weak concavity. TSC values and TSC curves were estimated that predict tumor regression for 95% of the population by taking between-subject variability into account. The TSC concept is further discussed for different concentration-effect relationships and for combinations of three or more compounds.

Objectives: To evaluate the dose/exposure/target inhibition/tumor growth relationship of MSC2156119J, an orally administered, reversible, ATP-competitive, highly potent and selective c-Met receptor tyrosine kinase inhibitor, in order to determine the recommended phase II dose (RP2D) for the program. Methods: Interim pharmacokinetic (PK) and biomarker (PD) data, i.e. plasma concentrations and c-Met inhibition in tumor biopsies from an ongoing first-in-human (FIM) solid tumor trial of MSC2156119J, were analyzed using the population modeling approach. The exposure/target inhibition relationship established in rich sampled KP-4 xenografted mice was utilized as prior information to develop the human model. Model-based simulations of the c-Met inhibition profiles in humans, aiming for a level that achieved tumor regression in mice, helped to determine the biologically active dose of MSC2156119J. Results: During the FIM study, the maximum tolerated dose of MSC2156119J was not reached at a dose of 1,400 mg/day. Instead, a biologically active dose was selected as the RP2D, based on a translational modeling approach that integrated the quantitative relationship between dose, exposure, and target as well as tumor inhibition in humans and in a preclinical model. In KP-4 xenografted mice, tumor c-Met inhibition (quantified as normalized phosphorylated c-Met expression [pMET]) was described by a turnover full inhibitory Imax model, and tumor growth inhibition was best described by the Simeoni model. Simulations demonstrated that nearly complete pMET inhibition (≥95%) is required for tumor stasis or even regression. In the FIM study, a one-compartment linear model with an absorption transit compartment best described the PK of MSC2156119J at doses of 30-700 mg. The turnover model developed from mice data was applied to evaluate the level of c-Met inhibition in paired human tumor biopsies (taken pre- and on-treatment). System turnover parameters for pMET were set equal to those estimated in mice, while the treatment potency (1/IC50 of the inhibition of build-up) of MSC2156119J in humans was found to be 1.7-fold higher than that in mice. Assuming a 30% inter-individual variability in IC50, human simulations suggested that a 500-mg once-daily dose regimen of MSC2156119J could achieve continuous pMET inhibition of ≥95% in 90% of the population. The model and simulation will be confirmed using additional PK data and further tumor biopsies. Conclusions: c-Met inhibition in human tumor lesions was described by a turnover model developed in KP-4 xenografted mice. Using this translational modeling and simulation approach and human PK and target inhibition data from paired tumor biopsies, a biologically active dose of 500 mg was proposed as the RP2D for MSC2156119J. This dose achieves continuous pMET inhibition of ≥95% in 90% of the population and has been adopted for the current development program for MSC2156119J. Citation Format: Wenyuan Xiong, Samer El Bawab, Friedhelm Bladt, Michael Meyring, Manfred Klevesath, Gerald Falchook, David Hong, Andreas Johne, Pascal Girard. Model-based phase II dose selection of c-Met inhibitor MSC2156119J. [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 4510. doi:10.1158/1538-7445.AM2015-4510