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Article ; Online: Optimising the combination dosing strategy of abemaciclib and vemurafenib in BRAF-mutated melanoma xenograft tumours.

Tate, Sonya C / Burke, Teresa F / Hartman, Daisy / Kulanthaivel, Palaniappan / Beckmann, Richard P / Cronier, Damien M

2016 Volume 114, Issue 6, Page(s) 669–679

Abstract: Background: Resistance to BRAF inhibition is a major cause of treatment failure for BRAF-mutated metastatic melanoma patients. Abemaciclib, a cyclin-dependent kinase 4 and 6 inhibitor, overcomes this resistance in xenograft tumours and offers a ... ...

Abstract	Background: Resistance to BRAF inhibition is a major cause of treatment failure for BRAF-mutated metastatic melanoma patients. Abemaciclib, a cyclin-dependent kinase 4 and 6 inhibitor, overcomes this resistance in xenograft tumours and offers a promising drug combination. The present work aims to characterise the quantitative pharmacology of the abemaciclib/vemurafenib combination using a semimechanistic pharmacokinetic/pharmacodynamic modelling approach and to identify an optimum dosing regimen for potential clinical evaluation. Methods: A PK/biomarker model was developed to connect abemaciclib/vemurafenib concentrations to changes in MAPK and cell cycle pathway biomarkers in A375 BRAF-mutated melanoma xenografts. Resultant tumour growth inhibition was described by relating (i) MAPK pathway inhibition to apoptosis, (ii) mitotic cell density to tumour growth and, under resistant conditions, (iii) retinoblastoma protein inhibition to cell survival. Results: The model successfully described vemurafenib/abemaciclib-mediated changes in MAPK pathway and cell cycle biomarkers. Initial tumour shrinkage by vemurafenib, acquisition of resistance and subsequent abemaciclib-mediated efficacy were successfully captured and externally validated. Model simulations illustrate the benefit of intermittent vemurafenib therapy over continuous treatment, and indicate that continuous abemaciclib in combination with intermittent vemurafenib offers the potential for considerable tumour regression. Conclusions: The quantitative pharmacology of the abemaciclib/vemurafenib combination was successfully characterised and an optimised, clinically-relevant dosing strategy was identified.
MeSH term(s)	Aminopyridines/administration & dosage ; Animals ; Antineoplastic Combined Chemotherapy Protocols/administration & dosage ; Antineoplastic Combined Chemotherapy Protocols/pharmacokinetics ; Benzimidazoles/administration & dosage ; Biomarkers, Tumor/metabolism ; Cell Line, Tumor ; Drug Administration Schedule ; Drug Resistance, Neoplasm ; Humans ; Indoles/administration & dosage ; Indoles/pharmacokinetics ; Melanoma/drug therapy ; Melanoma/enzymology ; Melanoma/genetics ; Melanoma/metabolism ; Mice ; Models, Biological ; Mutation ; Proto-Oncogene Proteins B-raf/genetics ; Proto-Oncogene Proteins B-raf/metabolism ; Sulfonamides/administration & dosage ; Sulfonamides/pharmacokinetics ; Xenograft Model Antitumor Assays
Chemical Substances	5-(4-ethylpiperazin-1-ylmethyl)pyridin-2-yl)-(5-fluoro-4-(7-fluoro-3-isopropyl-2-methyl-3H-benzimidazol-5-yl)pyrimidin-2-yl)amine ; Aminopyridines ; Benzimidazoles ; Biomarkers, Tumor ; Indoles ; Sulfonamides ; vemurafenib (207SMY3FQT) ; BRAF protein, human (EC 2.7.11.1) ; Proto-Oncogene Proteins B-raf (EC 2.7.11.1)
Language	English
Publishing date	2016-03-15
Publishing country	England
Document type	Journal Article
ZDB-ID	80075-2
ISSN	1532-1827 ; 0007-0920
ISSN (online)	1532-1827
ISSN	0007-0920
DOI	10.1038/bjc.2016.40
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Article ; Online: Exposure-response relationship of olaratumab for survival outcomes and safety when combined with doxorubicin in patients with soft tissue sarcoma.

Jones, Robin L / Mo, Gary / Baldwin, John R / Peterson, Patrick M / Ilaria, Robert L / Conti, Ilaria / Cronier, Damien M / Tap, William D

Cancer chemotherapy and pharmacology

2018 Volume 83, Issue 1, Page(s) 191–199

Abstract: Purpose: Olaratumab is a recombinant human IgG1 monoclonal antibody against PGDFRα. Olaratumab plus doxorubicin improved survivalversus doxorubicin in an open-label, randomised phase 2 soft tissue sarcoma (STS) trial. We characterised the olaratumab ... ...

Abstract	Purpose: Olaratumab is a recombinant human IgG1 monoclonal antibody against PGDFRα. Olaratumab plus doxorubicin improved survivalversus doxorubicin in an open-label, randomised phase 2 soft tissue sarcoma (STS) trial. We characterised the olaratumab exposure-response relationship for progression-free survival (PFS), overall survival (OS), and safety. Methods: PFS and OS data from the 133 patients enrolled in the phase 2 study were analysed using time-to-event modelling. The effect of olaratumab on PFS/OS was explored using the trough serum concentration after cycle 1 (C Results: PFS and OS were described by models with an exponential hazard function and inhibitory E Conclusions: PFS/OS benefits occurred without a rate change in TEAEs across quartiles. Maximum benefit in OS was achieved in the upper three quartiles and a potential of early disease progression in the lower quartile of olaratumab serum exposure. These results prompted a loading dose strategy in the ongoing phase 3 STS trial.
MeSH term(s)	Antibodies, Monoclonal/administration & dosage ; Antineoplastic Combined Chemotherapy Protocols/therapeutic use ; Doxorubicin/administration & dosage ; Follow-Up Studies ; Humans ; Prognosis ; Sarcoma/drug therapy ; Sarcoma/mortality ; Sarcoma/pathology ; Survival Rate
Chemical Substances	Antibodies, Monoclonal ; Doxorubicin (80168379AG) ; olaratumab (TT6HN20MVF)
Language	English
Publishing date	2018-11-08
Publishing country	Germany
Document type	Clinical Trial, Phase II ; Journal Article ; Multicenter Study ; Randomized Controlled Trial ; Research Support, Non-U.S. Gov't
ZDB-ID	6820-2
ISSN	1432-0843 ; 0344-5704 ; 0943-9404
ISSN (online)	1432-0843
ISSN	0344-5704 ; 0943-9404
DOI	10.1007/s00280-018-3723-4
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Zs.A 1420: Show issues

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Article ; Online: Population Pharmacokinetic Modeling of Olaratumab, an Anti-PDGFRα Human Monoclonal Antibody, in Patients with Advanced and/or Metastatic Cancer.

Mo, Gary / Baldwin, John R / Luffer-Atlas, Debra / Ilaria, Robert L / Conti, Ilaria / Heathman, Michael / Cronier, Damien M

Clinical pharmacokinetics

2017 Volume 57, Issue 3, Page(s) 355–365

Abstract: Background and objectives: Olaratumab is a recombinant human monoclonal antibody that binds to platelet-derived growth factor receptor-α (PDGFRα). In a randomized phase II study, olaratumab plus doxorubicin met its predefined primary endpoint for ... ...

Abstract	Background and objectives: Olaratumab is a recombinant human monoclonal antibody that binds to platelet-derived growth factor receptor-α (PDGFRα). In a randomized phase II study, olaratumab plus doxorubicin met its predefined primary endpoint for progression-free survival and achieved a highly significant improvement in overall survival versus doxorubicin alone in patients with advanced or metastatic soft tissue sarcoma (STS). In this study, we characterize the pharmacokinetics (PKs) of olaratumab in a cancer patient population. Methods: Olaratumab was tested at 15 or 20 mg/kg in four phase II studies (in patients with nonsmall cell lung cancer, glioblastoma multiforme, STS, and gastrointestinal stromal tumors) as a single agent or in combination with chemotherapy. PK sampling was performed to measure olaratumab serum levels. PK data were analyzed by nonlinear mixed-effect modeling techniques using NONMEM Results: The PKs of olaratumab were best described by a two-compartment PK model with linear clearance (CL). Patient body weight was found to have a significant effect on both CL and central volume of distribution (V Conclusion: The PKs of olaratumab were best described by a model with linear disposition. Patient body weight and tumor size were found to be significant covariates. The PKs of olaratumab were not affected by immunogenicity or chemotherapeutic agents.
MeSH term(s)	Adult ; Aged ; Aged, 80 and over ; Antibodies, Monoclonal/administration & dosage ; Antibodies, Monoclonal/pharmacokinetics ; Antineoplastic Agents/administration & dosage ; Antineoplastic Agents/pharmacokinetics ; Antineoplastic Combined Chemotherapy Protocols/administration & dosage ; Antineoplastic Combined Chemotherapy Protocols/pharmacokinetics ; Body Weight ; Disease-Free Survival ; Dose-Response Relationship, Drug ; Doxorubicin/administration & dosage ; Female ; Humans ; Male ; Middle Aged ; Models, Biological ; Neoplasm Metastasis ; Neoplasms/drug therapy ; Neoplasms/pathology ; Nonlinear Dynamics ; Receptor, Platelet-Derived Growth Factor alpha/antagonists & inhibitors ; Survival Rate ; Time Factors ; Young Adult
Chemical Substances	Antibodies, Monoclonal ; Antineoplastic Agents ; Doxorubicin (80168379AG) ; Receptor, Platelet-Derived Growth Factor alpha (EC 2.7.10.1) ; olaratumab (TT6HN20MVF)
Language	English
Publishing date	2017-08-07
Publishing country	Switzerland
Document type	Clinical Trial, Phase II ; Comparative Study ; Journal Article ; Randomized Controlled Trial ; Research Support, Non-U.S. Gov't
ZDB-ID	197627-8
ISSN	1179-1926 ; 0312-5963
ISSN (online)	1179-1926
ISSN	0312-5963
DOI	10.1007/s40262-017-0562-0
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Zs.A 1246: Show issues

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Article ; Online: A Population Pharmacokinetic and Pharmacodynamic Analysis of Abemaciclib in a Phase I Clinical Trial in Cancer Patients.

Tate, Sonya C / Sykes, Amanda K / Kulanthaivel, Palaniappan / Chan, Edward M / Turner, P Kellie / Cronier, Damien M

Clinical pharmacokinetics

2017 Volume 57, Issue 3, Page(s) 335–344

Abstract: Background and objectives: Abemaciclib, a dual inhibitor of cyclin-dependent kinases 4 and 6, has demonstrated clinical activity in a number of different cancer types. The objectives of this study were to characterize the pharmacokinetics of abemaciclib ...

Abstract	Background and objectives: Abemaciclib, a dual inhibitor of cyclin-dependent kinases 4 and 6, has demonstrated clinical activity in a number of different cancer types. The objectives of this study were to characterize the pharmacokinetics of abemaciclib in cancer patients using population pharmacokinetic (popPK) modeling, and to evaluate target engagement at clinically relevant dose levels. Methods: A phase I study was conducted in cancer patients which incorporated intensive pharmacokinetic sampling after single and multiple oral doses of abemaciclib. Data were analyzed by popPK modeling, and patient demographics contributing to pharmacokinetic variability were explored. Target engagement was evaluated by combining the clinical popPK model with a previously developed pre-clinical pharmacokinetic/pharmacodynamic model. Results: The pharmacokinetic analysis incorporated 4012 plasma concentrations from 224 patients treated with abemaciclib at doses ranging from 50 to 225 mg every 24 h and 75 to 275 mg every 12 h. A linear one-compartment model with time- and dose-dependent relative bioavailability (F Conclusion: The proportion of abemaciclib pharmacokinetic variability that can be attributed to patient demographics is negligible, and as such there are currently no dose adjustments recommended for adult patients of different sex, age, or body weight. Trial registration: NCT01394016 (ClinicalTrials.gov).
MeSH term(s)	Adult ; Aged ; Aged, 80 and over ; Aminopyridines/administration & dosage ; Aminopyridines/pharmacokinetics ; Aminopyridines/pharmacology ; Antineoplastic Agents/administration & dosage ; Antineoplastic Agents/pharmacokinetics ; Antineoplastic Agents/pharmacology ; Benzimidazoles/administration & dosage ; Benzimidazoles/pharmacokinetics ; Benzimidazoles/pharmacology ; Biological Availability ; Body Weight ; Cyclin-Dependent Kinase 4/antagonists & inhibitors ; Cyclin-Dependent Kinase 6/antagonists & inhibitors ; Dose-Response Relationship, Drug ; Drug Administration Schedule ; Female ; Humans ; Male ; Middle Aged ; Models, Biological ; Neoplasms/drug therapy ; Neoplasms/pathology ; Sex Factors ; Young Adult
Chemical Substances	5-(4-ethylpiperazin-1-ylmethyl)pyridin-2-yl)-(5-fluoro-4-(7-fluoro-3-isopropyl-2-methyl-3H-benzimidazol-5-yl)pyrimidin-2-yl)amine ; Aminopyridines ; Antineoplastic Agents ; Benzimidazoles ; CDK4 protein, human (EC 2.7.11.22) ; CDK6 protein, human (EC 2.7.11.22) ; Cyclin-Dependent Kinase 4 (EC 2.7.11.22) ; Cyclin-Dependent Kinase 6 (EC 2.7.11.22)
Language	English
Publishing date	2017-05-24
Publishing country	Switzerland
Document type	Clinical Trial, Phase I ; Journal Article ; Multicenter Study ; Research Support, Non-U.S. Gov't
ZDB-ID	197627-8
ISSN	1179-1926 ; 0312-5963
ISSN (online)	1179-1926
ISSN	0312-5963
DOI	10.1007/s40262-017-0559-8
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Article ; Online: Pharmacokinetics of doxorubicin following concomitant intravenous administration of olaratumab (IMC-3G3) to patients with advanced soft tissue sarcoma.

Villalobos, Victor M / Mo, Gary / Agulnik, Mark / Pollack, Seth M / Rushing, Daniel A / Singh, Arun / Van Tine, Brian A / McNaughton, Rhian / Decker, Rodney L / Zhang, Wei / Shahir, Ashwin / Cronier, Damien M

Cancer medicine

2019 Volume 9, Issue 3, Page(s) 882–893

Abstract: Background: Olaratumab, a fully human monoclonal antibody, selectively binds to human platelet-derived growth factor receptor alpha and blocks ligand binding. This study assessed the effect of olaratumab on the pharmacokinetics (PK) of doxorubicin and ... ...

Abstract	Background: Olaratumab, a fully human monoclonal antibody, selectively binds to human platelet-derived growth factor receptor alpha and blocks ligand binding. This study assessed the effect of olaratumab on the pharmacokinetics (PK) of doxorubicin and the safety of olaratumab alone and in combination with doxorubicin. Methods: This open-label randomized phase 1 trial enrolled 49 patients ages 27 to 83 with metastatic or locally advanced soft tissue sarcoma (STS). Patients participated in 21-day treatment cycles (up to 8) until they met discontinuation criteria. In cycles 1 and 2, patients received olaratumab (15 mg/kg in Part A, 20 mg/kg in Part B) and doxorubicin (75 mg/m Results: PK properties of doxorubicin administered alone or in combination with olaratumab (15 or 20 mg/kg) were similar for AUC(0-t Conclusions: Olaratumab at 15 or 20 mg/kg before doxorubicin infusion had no clinically relevant effect on systemic exposure to doxorubicin compared with doxorubicin alone in patients with metastatic or locally advanced STS.
MeSH term(s)	Adult ; Aged ; Aged, 80 and over ; Antibodies, Monoclonal/administration & dosage ; Antibodies, Monoclonal/adverse effects ; Antineoplastic Combined Chemotherapy Protocols/administration & dosage ; Antineoplastic Combined Chemotherapy Protocols/adverse effects ; Antineoplastic Combined Chemotherapy Protocols/pharmacokinetics ; Disease Progression ; Doxorubicin/administration & dosage ; Doxorubicin/adverse effects ; Doxorubicin/pharmacokinetics ; Drug Interactions ; Female ; Humans ; Infusions, Intravenous ; Male ; Middle Aged ; Neoplasm Staging ; Sarcoma/diagnosis ; Sarcoma/drug therapy ; Sarcoma/mortality ; Sarcoma/pathology
Chemical Substances	Antibodies, Monoclonal ; Doxorubicin (80168379AG) ; olaratumab (TT6HN20MVF)
Language	English
Publishing date	2019-12-10
Publishing country	United States
Document type	Clinical Trial, Phase I ; Journal Article ; Randomized Controlled Trial ; Research Support, Non-U.S. Gov't
ISSN	2045-7634
ISSN (online)	2045-7634
DOI	10.1002/cam4.2728
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Article ; Online: Phase II study of olaratumab with paclitaxel/carboplatin (P/C) or P/C alone in previously untreated advanced NSCLC.

Gerber, David E / Swanson, Paul / Lopez-Chavez, Ariel / Wong, Lucas / Dowlati, Afshin / Pennell, Nathan A / Cronier, Damien M / Qin, Amy / Ilaria, Robert / Cosaert, Jan / Shahir, Ashwin / Baggstrom, Maria Q

Lung cancer (Amsterdam, Netherlands)

2017 Volume 111, Page(s) 108–115

Abstract: Background: In non-small cell lung cancer (NSCLC), platelet-derived growth factor receptor (PDGFR) mediates angiogenesis, tissue invasion, and tumor interstitial pressure. Olaratumab (IMC-3G3) is a fully human anti-PDGFRα monoclonal antibody. This Phase ...

Abstract	Background: In non-small cell lung cancer (NSCLC), platelet-derived growth factor receptor (PDGFR) mediates angiogenesis, tissue invasion, and tumor interstitial pressure. Olaratumab (IMC-3G3) is a fully human anti-PDGFRα monoclonal antibody. This Phase II study assessed safety and efficacy of olaratumab+paclitaxel/carboplatin (P/C) versus P/C alone for previously untreated advanced NSCLC. Materials and methods: Patients received up to six 21-day cycles of P 200mg/m Results: 131 patients were: 67 with olaratumab+P/C and 64 with P/C; 74% had nonsquamous NSCLC. Median PFS was similar between olaratumab+P/C and P/C (4.4 months each) (HR 1.29; 95% CI [0.86-1.93]; p=0.21). Median OS was similar between olaratumab+P/C (11.8 months) and P/C (11.5 months) (HR 1.04; 95% CI [0.68-1.57]; p=0.87). Both arms had similar toxicity profiles. All evaluable cases were PDGFR-negative by immunohistochemistry. Tumor stroma PDGFR expression was evaluable in 23/131 patients, of which 78% were positive. Conclusions: The addition of olaratumab to P/C did not result in significant prolongation of PFS or OS in advanced NSCLC. Olaratumab studies in other patient populations, including soft tissue sarcoma (NCT02783599), pancreatic cancer (NCT03086369), and pediatric malignancies (NCT02677116) are underway.
MeSH term(s)	Aged ; Antibodies, Monoclonal/administration & dosage ; Antineoplastic Combined Chemotherapy Protocols/adverse effects ; Antineoplastic Combined Chemotherapy Protocols/therapeutic use ; Carcinoma, Non-Small-Cell Lung/drug therapy ; Carcinoma, Non-Small-Cell Lung/mortality ; Carcinoma, Non-Small-Cell Lung/pathology ; Combined Modality Therapy ; Drug Administration Schedule ; Female ; Humans ; Lung Neoplasms/drug therapy ; Lung Neoplasms/mortality ; Lung Neoplasms/pathology ; Male ; Middle Aged ; Neoplasm Staging ; Paclitaxel/administration & dosage ; Remission Induction ; Survival Analysis ; Treatment Outcome
Chemical Substances	Antibodies, Monoclonal ; Paclitaxel (P88XT4IS4D) ; olaratumab (TT6HN20MVF)
Language	English
Publishing date	2017-07-18
Publishing country	Ireland
Document type	Clinical Trial, Phase II ; Journal Article ; Multicenter Study ; Randomized Controlled Trial ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	632771-0
ISSN	1872-8332 ; 0169-5002
ISSN (online)	1872-8332
ISSN	0169-5002
DOI	10.1016/j.lungcan.2017.07.009
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Zs.A 2135: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular Jg. 1995 - 2021: Lesesall (1.OG) ab Jg. 2022: Lesesaal (EG)
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Article ; Online: Phase 2 study of tabalumab, a human anti-B-cell activating factor antibody, with bortezomib and dexamethasone in patients with previously treated multiple myeloma.

Raje, Noopur S / Moreau, Philippe / Terpos, Evangelos / Benboubker, Lotfi / Grząśko, Norbert / Holstein, Sarah A / Oriol, Albert / Huang, Shang-Yi / Beksac, Meral / Kuliczkowski, Kazimierz / Tai, Datchen F / Wooldridge, James E / Conti, Ilaria / Kaiser, Christopher J / Nguyen, Tuan S / Cronier, Damien M / Palumbo, Antonio

British journal of haematology

2017 Volume 176, Issue 5, Page(s) 783–795

Abstract: In this double-blind, Phase 2 study, 220 patients with relapsed/refractory multiple myeloma were randomly assigned 1:1:1 to receive placebo (N = 72), tabalumab 100 mg (N = 74), or tabalumab 300 mg (N = 74), each in combination with dexamethasone 20 mg ... ...

Abstract	In this double-blind, Phase 2 study, 220 patients with relapsed/refractory multiple myeloma were randomly assigned 1:1:1 to receive placebo (N = 72), tabalumab 100 mg (N = 74), or tabalumab 300 mg (N = 74), each in combination with dexamethasone 20 mg and subcutaneous bortezomib 1·3 mg/m
MeSH term(s)	Adult ; Aged ; Antibodies, Monoclonal/administration & dosage ; Antineoplastic Combined Chemotherapy Protocols/adverse effects ; Antineoplastic Combined Chemotherapy Protocols/therapeutic use ; Bortezomib/administration & dosage ; Dexamethasone/administration & dosage ; Disease-Free Survival ; Double-Blind Method ; Female ; Humans ; Male ; Middle Aged ; Multiple Myeloma/complications ; Multiple Myeloma/drug therapy ; Multiple Myeloma/mortality ; Salvage Therapy/methods ; Treatment Outcome
Chemical Substances	Antibodies, Monoclonal ; Bortezomib (69G8BD63PP) ; Dexamethasone (7S5I7G3JQL) ; tabalumab (PQP8VH3MJW)
Language	English
Publishing date	2017-03
Publishing country	England
Document type	Clinical Trial, Phase II ; Journal Article ; Multicenter Study ; Randomized Controlled Trial
ZDB-ID	80077-6
ISSN	1365-2141 ; 0007-1048
ISSN (online)	1365-2141
ISSN	0007-1048
DOI	10.1111/bjh.14483
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Uh III Zs.182: Show issues

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Article: Phase 1 Study of Tabalumab, a Human Anti-B-Cell Activating Factor Antibody, and Bortezomib in Patients with Relapsed/Refractory Multiple Myeloma.

Raje, Noopur S / Faber, Edward A / Richardson, Paul G / Schiller, Gary / Hohl, Raymond J / Cohen, Adam D / Forero, Andres / Carpenter, Susan / Nguyen, Tuan S / Conti, Ilaria / Kaiser, Christopher J / Cronier, Damien M / Wooldridge, James E / Anderson, Kenneth C

Clinical cancer research : an official journal of the American Association for Cancer Research

2016 Volume 22, Issue 23, Page(s) 5688–5695

Abstract: Purpose: Tabalumab, a human mAb that neutralizes B-cell-activating factor (BAFF), demonstrated antitumor activity in xenograft models of multiple myeloma. Here we report on a phase I study of relapsed/refractory multiple myeloma patients in which the ... ...

Abstract	Purpose: Tabalumab, a human mAb that neutralizes B-cell-activating factor (BAFF), demonstrated antitumor activity in xenograft models of multiple myeloma. Here we report on a phase I study of relapsed/refractory multiple myeloma patients in which the primary objective was to identify a tolerable and potentially efficacious dose of tabalumab when combined with bortezomib. Experimental design: Forty-eight patients were enrolled; 20 to the dose-escalation cohort, and 28 to cohort expansion in which a dose of 100 mg of tabalumab was evaluated. All patients had received either prior bortezomib or an immunomodulatory drug; the median number of prior therapies was 3. Bortezomib was administered intravenously on days 1, 4, 8, and 11 of a 21-day schedule. Tabalumab was given every 21 days for 3 cycles, then every 42 days thereafter. Results: The most common grade 3/4 toxicities included thrombocytopenia, neutropenia, pneumonia, and peripheral sensory neuropathy. There were no dose-limiting toxicities, and the maximum tolerated dose was not reached. Pharmacokinetic data suggested serum exposure increased in a greater than dose-proportional manner up to a dose of 100 mg. Out of 46 evaluable patients, 20 had confirmed responses. The median time to progression (9 patients censored) was 4.8 months, and the median response duration (4 patients censored) was 7.2 months. Conclusions: A dose of 100 mg tabalumab in combination with bortezomib was well tolerated and active and is currently under further investigation. Clin Cancer Res; 22(23); 5688-95. ©2016 AACR.
Language	English
Publishing date	2016-12-01
Publishing country	United States
Document type	Journal Article
ZDB-ID	1225457-5
ISSN	1557-3265 ; 1078-0432
ISSN (online)	1557-3265
ISSN	1078-0432
DOI	10.1158/1078-0432.CCR-16-0201
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Zs.A 4223: Show issues

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Article: Semi-mechanistic pharmacokinetic/pharmacodynamic modeling of the antitumor activity of LY2835219, a new cyclin-dependent kinase 4/6 inhibitor, in mice bearing human tumor xenografts.

Tate, Sonya C / Cai, Shufen / Ajamie, Rose T / Burke, Teresa / Beckmann, Richard P / Chan, Edward M / De Dios, Alfonso / Wishart, Graham N / Gelbert, Lawrence M / Cronier, Damien M

Clinical cancer research : an official journal of the American Association for Cancer Research

2014 Volume 20, Issue 14, Page(s) 3763–3774

Abstract: Purpose: Selective inhibition of cyclin-dependent kinases 4 and 6 (CDK4/6) represents a promising therapeutic strategy. However, despite documented evidence of clinical activity, limited information is available on the optimal dosing strategy of CDK4/6 ... ...

Abstract	Purpose: Selective inhibition of cyclin-dependent kinases 4 and 6 (CDK4/6) represents a promising therapeutic strategy. However, despite documented evidence of clinical activity, limited information is available on the optimal dosing strategy of CDK4/6 inhibitors. Here, we present an integrated semi-mechanistic pharmacokinetic/pharmacodynamic model to characterize the quantitative pharmacology of LY2835219, a CDK4/6 inhibitor, in xenograft tumors. Experimental design: LY2835219 plasma concentrations were connected to CDK4/6 inhibition and cell-cycle arrest in colo-205 human colorectal xenografts by incorporating the biomarkers, phospho-(ser780)-Rb, topoisomerase II α, and phosphohistone H3, into a precursor-dependent transit compartment model. This biomarker model was then connected to tumor growth inhibition (TGI) by: (i) relating the rate of tumor growth to mitotic cell density, and (ii) incorporating a concentration-dependent mixed cytostatic/cytotoxic effect driving quiescence and cell death at high doses. Model validation was evaluated by predicting LY2835219-mediated antitumor effect in A375 human melanoma xenografts. Results: The model successfully described LY2835219-mediated CDK4/6 inhibition, cell-cycle arrest, and TGI in colo-205, and was validated in A375. The model also demonstrated that a chronic dosing strategy achieving minimum steady-state trough plasma concentrations of 200 ng/mL is required to maintain durable cell-cycle arrest. Quiescence and cell death can be induced by further increasing LY2835219 plasma concentrations. Conclusions: Our model provides mechanistic insight into the quantitative pharmacology of LY2835219 and supports the therapeutic dose and chronic dosing strategy currently adopted in clinical studies.
MeSH term(s)	Administration, Oral ; Aminopyridines/pharmacokinetics ; Aminopyridines/therapeutic use ; Animals ; Antineoplastic Agents/pharmacokinetics ; Antineoplastic Agents/therapeutic use ; Benzimidazoles/pharmacokinetics ; Benzimidazoles/therapeutic use ; Biomarkers, Tumor/metabolism ; Cell Line, Tumor ; Cyclin-Dependent Kinase 4/antagonists & inhibitors ; Cyclin-Dependent Kinase 6/antagonists & inhibitors ; Humans ; Inhibitory Concentration 50 ; Mice, Nude ; Protein Kinase Inhibitors/pharmacokinetics ; Protein Kinase Inhibitors/therapeutic use ; Tumor Burden/drug effects ; Xenograft Model Antitumor Assays
Chemical Substances	5-(4-ethylpiperazin-1-ylmethyl)pyridin-2-yl)-(5-fluoro-4-(7-fluoro-3-isopropyl-2-methyl-3H-benzimidazol-5-yl)pyrimidin-2-yl)amine ; Aminopyridines ; Antineoplastic Agents ; Benzimidazoles ; Biomarkers, Tumor ; Protein Kinase Inhibitors ; CDK4 protein, human (EC 2.7.11.22) ; CDK6 protein, human (EC 2.7.11.22) ; Cyclin-Dependent Kinase 4 (EC 2.7.11.22) ; Cyclin-Dependent Kinase 6 (EC 2.7.11.22)
Language	English
Publishing date	2014-05-21
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	1225457-5
ISSN	1557-3265 ; 1078-0432
ISSN (online)	1557-3265
ISSN	1078-0432
DOI	10.1158/1078-0432.CCR-13-2846
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Article ; Online: Phase 1/2 study of ocaratuzumab, an Fc-engineered humanized anti-CD20 monoclonal antibody, in low-affinity FcγRIIIa patients with previously treated follicular lymphoma.

Ganjoo, Kristen N / de Vos, Sven / Pohlman, Brad L / Flinn, Ian W / Forero-Torres, Andres / Enas, Nathan H / Cronier, Damien M / Dang, Nam H / Foon, Kenneth A / Carpenter, Susan P / Slapak, Christopher A / Link, Brian K / Smith, Mitchell R / Mapara, Markus Y / Wooldridge, James E

Leukemia & lymphoma

2014 Volume 56, Issue 1, Page(s) 42–48

Abstract: This phase 2 study assessed the safety and efficacy of ocaratuzumab, a humanized anti-CD20 monoclonal antibody. Fifty patients with previously treated follicular lymphoma (FL) and a low-affinity genotype of FcγRIIIa received ocaratuzumab 375 mg/m(2) ... ...

Abstract	This phase 2 study assessed the safety and efficacy of ocaratuzumab, a humanized anti-CD20 monoclonal antibody. Fifty patients with previously treated follicular lymphoma (FL) and a low-affinity genotype of FcγRIIIa received ocaratuzumab 375 mg/m(2) weekly for 4 weeks. Grade 3/4/5 adverse events (AEs) were reported in 11/1/1 patients, respectively. Serious AEs were reported by 11/50 patients, and three discontinued due to AEs. One patient died from aspiration pneumonia due to possibly drug-related nausea and vomiting. Investigator-assessed response rate was 30% (15/50), including four complete responses (CR), three CR unconfirmed (CRu) and eight partial responses (PR). Investigator-assessed median Progression-free survivial (PFS) was 38.3 weeks. Ocaratuzumab's pharmacokinetic profile was similar to that reported for rituximab. Lymphocyte subset analysis showed significant, selective reduction of B-cells during and after ocaratuzumab treatment. Ocaratuzumab at this dose and schedule is active and well tolerated in patients with previously treated FL with low affinity FcγRIIIa genotypes. ClinTrials registry number: NCT00354926.
MeSH term(s)	Adult ; Aged ; Aged, 80 and over ; Alleles ; Antibodies, Monoclonal, Humanized/pharmacology ; Antibodies, Monoclonal, Humanized/therapeutic use ; Antineoplastic Agents/pharmacology ; Antineoplastic Agents/therapeutic use ; Female ; Heterozygote ; Humans ; Lymphoma, Follicular/drug therapy ; Lymphoma, Follicular/metabolism ; Lymphoma, Follicular/mortality ; Lymphoma, Follicular/pathology ; Male ; Middle Aged ; Neoplasm Staging ; Polymorphism, Single Nucleotide ; Receptors, IgG/genetics ; Receptors, IgG/metabolism ; Retreatment ; Treatment Outcome
Chemical Substances	AME 133 ; Antibodies, Monoclonal, Humanized ; Antineoplastic Agents ; FCGR3A protein, human ; Receptors, IgG
Language	English
Publishing date	2014-07-14
Publishing country	United States
Document type	Case Reports ; Clinical Trial, Phase I ; Journal Article ; Multicenter Study ; Research Support, Non-U.S. Gov't
ZDB-ID	1042374-6
ISSN	1029-2403 ; 1042-8194
ISSN (online)	1029-2403
ISSN	1042-8194
DOI	10.3109/10428194.2014.911859
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