518. Model-informed Dose Selection of Dual Toll-like Receptor 7/8 Inhibitor Enpatoran (M5049) for the Treatment of COVID-19 Pneumonia

Abstract Background Enpatoran, formerly known as M5049, is a potential first-in-class small molecule antagonist of toll-like receptors (TLR) 7 and 8, which may prevent viral-associated hyperinflammatory response and progression to ‘cytokine storm’ in coronavirus disease 2019 (COVID-19) patients. The objective of this study was to leverage existing population pharmacokinetic/pharmacodynamic (popPK/PD) models for enpatoran to inform dose selection for an accelerated Phase II study in COVID-19 patients with pneumonia. Methods The popPK/PD models were based on plasma PK and PD biomarker (ex vivo-stimulated interleukin [IL]6 and interferon α [IFNα] secretion) data from the enpatoran first-in-human Phase I study in healthy participants (Port A, et al. Lupus Sci Med 2020;7(Suppl. 1): Abstract P135). A two-compartment model describing PK used a sigmoidal Emax model with proportional decrease from baseline characterizing the PD response across the investigated single and multiple daily dose range of 1–200 mg (N=72). Concentrations that inhibited 50% and 90% (IC50/IC90) of cytokine secretion were estimated and stochastic simulations were performed to assess target coverage under different dosing regimens. Results Simulations suggested that, to achieve maximal inhibition of IL-6 over time, enpatoran PK concentrations would be maintained above the IC90 throughout the dosing interval with doses of 100 mg and 50 mg twice daily in 90% and 30% of participants, respectively. In comparison, IFNα inhibition was predicted to be lower, with IC90 coverage in 60% and 8% of participants with twice daily doses of 100 mg and 50 mg enpatoran, respectively. Conclusion Utilization of existing popPK/PD models allowed for the accelerated development of enpatoran in COVID-19 to address an unprecedented global pandemic. Rational model-informed dose selection was supported by data from a Phase I study in which there were no safety concerns. Disclosures Lena Klopp-Schulze, PhD, Merck KGaA, Darmstadt, Germany (Employee) Jamie Shaw, BS, EMD Serono Research & Development Institute, Inc., Billerica, MA, USA (an affiliate of Merck KGaA, Darmstadt, Germany) (Employee) Jennifer Dong, PhD, EMD Serono Research & Development Institute, Inc., Billerica, MA, USA (an affiliate of Merck KGaA, Darmstadt, Germany) (Employee) Akash Khandelwal, PhD, Merck KGaA, Darmstadt, Germany (Employee, Shareholder) Elizabeth Adams, MD, BioNTech SE, Germany (Employee)EMD Serono Research & Development Institute, Inc., Billerica, MA, USA (an affiliate of Merck KGaA, Darmstadt, Germany)(employer at the time of study) (Employee) Dongzi Yu, MD, EMD Serono Research & Development Institute, Inc., Billerica, MA, USA (an affiliate of Merck KGaA, Darmstadt, Germany) (Employee) Kosalaram Goteti, PhD, EMD Serono Research & Development Institute, Inc., Billerica, MA, USA (an affiliate of Merck KGaA, Darmstadt, Germany) (Employee)Pfizer (Shareholder)

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Phase I study protocol for ex-vivo lentiviral gene therapy for the inherited skin disease, Netherton Syndrome

Human Gene Therapy Clinical Development ◽

10.1089/hum.2013.195 ◽

2013 ◽

pp. 150127063140004

Author(s):

Wei-Li Di ◽

Jemima E Mellerio ◽

Catina Bernadis ◽

John Harper ◽

Alya Abdul-Wahab ◽

...

Keyword(s):

Gene Therapy ◽

Phase I ◽

Study Protocol ◽

Skin Disease ◽

Phase I Study ◽

Ex Vivo ◽

Netherton Syndrome ◽

Lentiviral Gene Therapy

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Phase I Study of AVE9633, an AntiCD33-Maytansinoid Immunoconjugate, Administered as an Intravenous Infusion in Patients with Refractory/Relapsed CD33-Positive Acute Myeloid Leukemia (AML).

Blood ◽

10.1182/blood.v108.11.4548.4548 ◽

2006 ◽

Vol 108 (11) ◽

pp. 4548-4548 ◽

Cited By ~ 1

Author(s):

Francis Giles ◽

Rodica Morariu-Zamfir ◽

John Lambert ◽

Srdan Verstovsek ◽

Deborah Thomas ◽

...

Keyword(s):

Phase I ◽

Dose Level ◽

Disulfide Bonds ◽

Phase I Study ◽

Dose Range ◽

Microtubule Assembly ◽

Treatment Schedule ◽

Specific Tumor ◽

M Phase ◽

Grade 3

Abstract AVE9633 is an immunoconjugate created by conjugation of the cytotoxic maytansinoid, DM4, to the monoclonal IgG1 antibody, huMy9-6 (average of 3.5 molecules of DM4 per antibody). The huMy9-6 antibody is a humanized version of a murine monoclonal antibody, My9-6, which is specific for the CD33 antigen expressed on the surface of myeloid cells, including the majority of cases of AML. Because CD33 has little expression outside the hematopoietic system, it represents an attractive target for antibody-based therapy in patients with AML. The humanized antibody, huMy9-6, binds to the CD33 antigen with an apparent KD in the range of 10−10 M. Maytansinoids are anti-mitotics that inhibit tubulin polymerization and microtubule assembly, inhibiting cells during the G2/M phase of the mitotic cycle. In order to link maytansinoids to antibodies via disulfide bonds, a new thiol-containing maytansinoid (DM4) was synthesized. Attachment of potent maytansinoids to an antibody via disulfide bonds provides a satisfactory stability in the bloodstream. After the conjugate is bound at the specific tumor site it is internalized and the cytotoxic agent is released within the target cell. A phase I study of AVE9633 is being conducted in patients with refractory/relapsed CD33+ AML. The study regimen consists of AVE9633 IV infusion on Day 1 of a 3 weeks cycle. To date dose levels of 15 (N=3), 30 (N=5), 50 (N=4), 75 (N=4), 105 (N=2), 200 (N=3) and 260 (N=1) mg/m2 have been investigated. Hypersensitivity reactions during perfusion were noted, requiring prophylaxis with steroids. No other AVE9633- attributable extramedullary Grade 3 AE has been observed to date. Free DM4, measured by LC/MS/MS was detectable from the 75 mg/m2 dose level; its Cmax (at the end of infusion) increased from 10 ng/mL at the 75 mg/m2 dose level to 70 ng/mL at 200 mg/m2. Neither AVE9633-associated myelosuppression nor responses have been noted. Using Flow Cytometry Assay on peripheral blasts and monocytes, total saturation and down regulation of CD33 were observed following administration of doses ≥ 30 mg/m2. AVE9633 exposure (measuring, by ELISA method, all antibodies containing at lease one molecule of DM4) increased proportionally with the administered dose in the dose range 15 to 200 mg/m2. Updated PK results and potential explanations for the lack of efficacy using this treatment schedule will be presented.

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Pharmacodynamically guided dose selection of PF-00337210, a VEGFR2 tyrosine kinase (TK) inhibitor, in a phase I study.

Journal of Clinical Oncology ◽

10.1200/jco.2010.28.15_suppl.3033 ◽

2010 ◽

Vol 28 (15_suppl) ◽

pp. 3033-3033

Author(s):

G. Liu ◽

P. LoRusso ◽

E. I. Heath ◽

J. Y. Bruce ◽

A. M. Traynor ◽

...

Keyword(s):

Tyrosine Kinase ◽

Phase I ◽

Phase I Study ◽

Dose Selection ◽

Selection Of

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Human pharmacokinetic (PK) characterization of the novel dual-action anti-HER3/EGFR antibody MEHD7945A (MEHD) in patients with refractory/recurrent epithelial tumors.

Journal of Clinical Oncology ◽

10.1200/jco.2012.30.15_suppl.2567 ◽

2012 ◽

Vol 30 (15_suppl) ◽

pp. 2567-2567 ◽

Cited By ~ 1

Author(s):

Manuel Hidalgo ◽

Antonio Calles ◽

Dejan Juric ◽

Rodrigo Dienstmann ◽

Desamparados Roda Perez ◽

...

Keyword(s):

Phase I ◽

Phase I Study ◽

Population Analysis ◽

Demographic Data ◽

Single Agent ◽

Compartment Model ◽

Individual Variability ◽

Study Patient ◽

Epithelial Tumors ◽

Dual Action

2567 Background: MEHD is a novel dual-action human IgG1 antibody that blocks ligand binding to HER3 and EGFR, and elicits antibody-dependent cell-mediated cytotoxicity (ADCC). MEHD demonstrates single-agent activity in a broad panel of tumor models, including models resistant to anti-HER3 or anti-EGFR treatment alone. The objective of this analysis was to characterize the PK of MEHD associated with body weight (BW)-based dosing used in a phase I study in patients with epithelial tumors and to evaluate the potential for using fixed dosing in future studies. Methods: Preliminary non-compartmental and population PK analyses were performed using patient data from the dose-escalation stage [1, 4, 10, 15, 22, and 30 mg/kg every two weeks (q2w)] and expansion stage (14 mg/kg q2w) of the phase I study. Patient demographic data and other relevant clinical covariates were evaluated in the population analysis. PK simulation of 1000 subjects with a log-normal BW distribution was performed to compare the inter-individual variability of MEHD exposure following fixed or BW-based dosing. Results: As expected,MEHD exhibited nonlinear PK. In the noncompartmenal analysis, the apparent clearance (CL) decreased in a dose-dependent fashion (about 40 to 9.9 mL/day/kg from 1 to 30 mg/kg) and approached linearity at doses >10 mg/kg (q2w). In the population analysis, the PK profile of MEHD was well described by a two compartment model with linear and nonlinear clearance. The target-mediated clearance was consistent with that of anti-EGFR antibodies. The nonspecific CL and central volume of distribution (V1) values were approximately 6 mL/day/kg and 52.4 mL/kg, respectively. BW had a moderate effect on V1, but not on CL. PK simulations suggest that, compared with BW-based dosing, fixed dosing would result in less inter-individual variability in MEHD exposure. Both 1100 mg q2w or 1650 mg q3w of MEHD achieve the targeted therapeutic exposure. Conclusions: The dual-action antibody MEHD demonstrated PK consistent with anti-EGFR antibodies. Fixed dosing of MEHD on an every 2 or 3 week schedule is supported.

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Pharmacokinetic Profile of a 2-Month Dose Regimen of Aripiprazole Lauroxil: A Phase I Study and a Population Pharmacokinetic Model

CNS Drugs ◽

10.1007/s40263-017-0447-7 ◽

2017 ◽

Vol 31 (7) ◽

pp. 617-624 ◽

Cited By ~ 10

Author(s):

Marjie L. Hard ◽

Richard J. Mills ◽

Brian M. Sadler ◽

Angela Y. Wehr ◽

Peter J. Weiden ◽

...

Keyword(s):

Phase I ◽

Dose Regimen ◽

Phase I Study ◽

Population Pharmacokinetic Model ◽

Pharmacokinetic Model ◽

Pharmacokinetic Profile ◽

Population Pharmacokinetic

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Assessment of the nlmixr R-package for population pharmacokinetic modeling: A metformin case study

10.22541/au.163630727.72118368/v1 ◽

2021 ◽

Author(s):

Wen Yao Mak ◽

Qing Xi Ooi ◽

Cintia Cruz ◽

Irene Looi ◽

Kah Hay Yuen ◽

...

Keyword(s):

Compartment Model ◽

Stochastic Simulations ◽

Population Pharmacokinetic ◽

Parameter Estimates ◽

Mixed Effect ◽

Flip Flop ◽

Final Model ◽

Elimination Phase ◽

Transit Compartment ◽

Terminal Elimination Phase

Aim: nlmixr offers first-order conditional estimation with or without interaction (FOCE or FOCEi) and stochastic approximation estimation-maximisation (SAEM) to fit nonlinear mixed-effect models (NLMEM). We modelled metformin’s population pharmacokinetics with flip-flop characteristics within nlmixr framework and investigated SAEM and FOCEi’s performance with respect to bias, precision, and robustness. Method: Compartmental pharmacokinetic models were fitted. The final model was determined based on the lowest objective function value and visual inspection of goodness-of-fit plots. To examine flip-flop pharmacokinetics, k_a values of a typical concentration-time profile based on the final model were perturbed and changes in the steepness of the terminal elimination phase were evaluated. The bias and precision of parameter estimates were compared between SAEM and FOCEi using stochastic simulations and estimations. For robustness, parameters were re-estimated as the initial estimates were perturbed 100-times and resultant changes evaluated. Results: A one-compartment model with transit compartment for absorption best described the data. At low n, Stirling’s approximation of n! over-approximated plasma concentration unlike the log-gamma function. Flip-flop pharmacokinetics were evident as the steepness of the terminal elimination phase changed with k_a. Mean rRMSE for fixed-effect parameters was 0.932. When initial estimates were perturbed, FOCEi estimates of k_a and food effect on k_a appeared bimodal and were upward biased. Discussion: nlmixr is reliable for NLMEM even if flip-flop is present but caution should be exercised when using Stirling’s approximation for n! in the transit compartment model. SAEM was marginally superior to FOCEi in bias and precision, but SAEM was superior against initial estimate perturbations.

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Pharmacokinetics of rivaroxaban in children using physiologically based and population pharmacokinetic modelling: an EINSTEIN-Jr phase I study

Thrombosis Journal ◽

10.1186/s12959-018-0185-1 ◽

2018 ◽

Vol 16 (1) ◽

Cited By ~ 11

Author(s):

Stefan Willmann ◽

Kirstin Thelen ◽

Dagmar Kubitza ◽

Anthonie W. A. Lensing ◽

Matthias Frede ◽

...

Keyword(s):

Phase I ◽

Phase I Study ◽

Population Pharmacokinetic ◽

Pharmacokinetic Modelling ◽

Population Pharmacokinetic Modelling ◽

Physiologically Based

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A phase I study of dovitinib (TKI258) in Japanese patients with advanced solid tumors.

Journal of Clinical Oncology ◽

10.1200/jco.2012.30.15_suppl.3088 ◽

2012 ◽

Vol 30 (15_suppl) ◽

pp. 3088-3088

Author(s):

Hiroya Takiuchi ◽

Masahiro Gotoh ◽

Motoki Yoshida ◽

Takayuki Kii ◽

Keishi Yamashita ◽

...

Keyword(s):

Phase I ◽

Disease Progression ◽

Solid Tumors ◽

Phase I Study ◽

Kinase Inhibitor ◽

Performance Status ◽

Dose Range ◽

Japanese Patients ◽

Advanced Solid Tumors ◽

Grade 3

3088^ Background: Dovitinib is a tyrosine kinase inhibitor with demonstrated inhibitory activity against FGFRs, VEGFRs, and PDGFRs in vivo. Based on responses observed in renal cell carcinoma, breast cancer, AML, melanoma, and multiple myeloma in clinical studies in the West, we investigated dovitinib in Japanese patients (pts). Methods: This multicenter phase I study determined the maximum tolerated dose (MTD) of dovitinib based on the occurrence of dose-limiting toxicity (DLT) in Japanese pts with advanced solid tumors. Following a 2-day pharmacokinetic (PK) run-in period, dovitinib was administered orally once daily on a 5-days-on/2-days-off schedule in 28-day cycles until disease progression or withdrawal. The planned dose range was 100-600 mg/day. A 2-parameter Bayesian logistic regression model based on the principle of escalation with overdose control was used to estimate the MTD. Results: In total, 28 pts received dovitinib: 100 mg (n = 3), 200 mg (n = 3), 300 mg (n = 7), 400 mg (n = 9), and 500 mg (n = 6). The median age was 58.5 years (range, 30-76); 16 of 28 pts (57%) were male. All pts had stage IV disease, with an ECOG performance status of 0 or 1. Pts completed a median of 3 cycles. One pt is currently ongoing in the study (peritoneal adenocarcinoma, 400-mg cohort, cycle 19), 23 discontinued due to disease progression, and 4 discontinued due to adverse events (AEs). All DLTs were grade 3: anorexia (n = 1; 300 mg), nausea/vomiting (n = 1; 400 mg), liver function disorder (n = 1; 400 mg), and increased alanine transaminase (n = 1; 500 mg). The most common grade 3/4 AEs (occurring in >10% of pts) suspected to be related to study drug were lymphopenia (18%), neutropenia (14%), abnormal hepatic function (14%), decreased white blood cell count (14%), decreased appetite (14%), and hypertension (14%). Best responses were confirmed partial response in 1 pt (4%; peritoneal adenocarcinoma, 400-mg cohort), stable disease in 9 pts (32%), and progressive disease in 10 pts (36%). No treatment-related deaths have been reported. Safety and PK parameters were comparable to those of non-Japanese pts in the global study. Conclusions: The study has completed enrollment. Dovitinib was found to be tolerable at doses up to 500 mg, which was declared as the MTD in Japanese pts.

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Phase I study of OKT3 x hu3F8 bispecific antibody (GD2Bi) armed T cells (GD2BATs) in GD2-positive tumors.

Journal of Clinical Oncology ◽

10.1200/jco.2019.37.15_suppl.2533 ◽

2019 ◽

Vol 37 (15_suppl) ◽

pp. 2533-2533 ◽

Cited By ~ 2

Author(s):

Maxim Yankelevich ◽

Shakeel Modak ◽

Roland Chu ◽

Daniel W. Lee ◽

Archana Thakur ◽

...

Keyword(s):

T Cells ◽

Phase I ◽

Phase I Study ◽

Residual Disease ◽

Ex Vivo ◽

Autologous Blood ◽

Maximum Tolerated Dose ◽

Clinical Activity ◽

Minor Response

2533 Background: With the proven success of anti-GD2 monoclonal antibodies in eradicating minimal residual disease in neuroblastoma (NB), exploiting antibody based anti-GD2 in T cell mediated strategies has potential to combat higher disease burden and improve patient outcome. We hypothesized that arming of ex vivo expanded and activated, autologous, blood derived T cells (ATC) with chemically heteroconjugated GD2Bi should redirect them to target NB. In vitro, ATC coated (armed) with 50 ng/106 cells of GD2Bi exhibited specific killing of NB and osteosarcoma (OS) cell lines. Methods: In this phase I study (NCT02173093), patients with GD2-positive tumors received 8, biweekly infusions of GD2BATs + daily low-dose IL-2 and biweekly granulocyte-macrophage colony stimulating factor (GM-CSF). The study followed the standard 3+3 design with dose levels of 40, 80, and 160 x 106 GD2BATs/kg/infusion. Results: Twelve patients (NB = 7, OS = 3, Desmoplastic Small Round Cell Tumor = 2) were enrolled from 11/2013 to 12/2017 and 9 completed therapy. Adequate ATCs could not be grown in one patient and two patients did not complete 8 infusions because of rapid disease progression. Infusions were given in outpatient settings. All patients developed a mild, dose-independent and manageable form of cytokine release syndrome with grades 2-3 fevers/chills, headaches and occasional hypotension for up to 48 hours after infusion. No patients developed significant pain. Maximum tolerated dose was not reached. Evidence of activity was seen in several patients including one patient with OS who had a PET response, one patient with NB who had complete bone marrow response (this patient had remained progression free for 2.5 years after completion of infusions), and another NB patient who had a minor response on MIBG scan. Four patients with NB are currently alive after additional therapies at 12, 14, 18, and 47 months post BAT infusions. Conclusions: Autologous T cells from heavily pretreated patients could be expanded ex vivo to large numbers, armed with GD2Bi, cryopreserved and thawed for safe IV administration up to total dose of 1.28x109/kg. Ongoing phase II arm of the trial will focus on evaluation of clinical activity of GD2BATs in patients with NB. Clinical trial information: NCT02173093.

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