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Entrectinib (Interim Monograph)
Entrectinib (interim monograph) DRUG NAME: Entrectinib SYNONYM(S): RXDX-1011, NMS-E6282 COMMON TRADE NAME(S): ROZLYTREK® CLASSIFICATION: molecular targeted therapy Special pediatric considerations are noted when applicable, otherwise adult provisions apply. MECHANISM OF ACTION: Entrectinib is an orally administered, small molecule, multi-target tyrosine kinase inhibitor which targets tropomyosin- related kinase (Trk) proteins TrkA, TrkB, and TrkC, proto-oncogene tyrosine-protein kinase ROS (ROS1) and anaplastic lymphoma kinase (ALK). TrkA, TrkB, and TrkC are receptor tyrosine kinases encoded by the neurotrophic tyrosine receptor kinase (NTRK) genes NTRK1, NTRK2, and NTRK3, respectively. Fusion proteins that include Trk, ROS1, or ALK kinase domains drive tumorigenic potential through hyperactivation of downstream signalling pathways leading to unconstrained cell proliferation. By potently inhibiting the Trk kinases, ROS1, and ALK, entrectinib inhibits downstream signalling pathways, cell proliferation and induces tumour cell apoptosis.3-5 PHARMACOKINETICS: Oral Absorption bioavailability = 55%; Tmax = 4-6 hours; Tmax delayed 2 h by high-fat, high-calorie food intake Distribution highly bound to human plasma proteins cross blood brain barrier? yes volume of distribution 551 L (entrectinib); 81.1 L (M5) plasma protein binding >99% (entrectinib and M5) Metabolism primarily metabolized by CYP 3A4 active metabolite(s) M5 inactive metabolite(s) M11 Excretion primarily via hepatic clearance urine 3.06% feces 82.9% (36% as unchanged entrectinib, 22% as M5) terminal half life 20 h (entrectinib); 40 h (M5) clearance 19.6 L/h (entrectinib); 52.4 L/h (M5) Elderly no clinically significant difference Children comparable pharmacokinetics of entrectinib and M5 in adults and children Ethnicity no clinically significant difference Adapted from standard reference3,4 unless specified otherwise. -
Tyrosine Kinase Inhibitors Ameliorate Autoimmune Encephalomyelitis in a Mouse Model of Multiple Sclerosis
J Clin Immunol DOI 10.1007/s10875-011-9579-6 Tyrosine Kinase Inhibitors Ameliorate Autoimmune Encephalomyelitis in a Mouse Model of Multiple Sclerosis Oliver Crespo & Stacey C. Kang & Richard Daneman & Tamsin M. Lindstrom & Peggy P. Ho & Raymond A. Sobel & Lawrence Steinman & William H. Robinson Received: 23 February 2011 /Accepted: 5 July 2011 # Springer Science+Business Media, LLC 2011 Abstract Multiple sclerosis is an autoimmune disease of development of disease and treat established disease in a the central nervous system characterized by neuroinflam- mouse model of multiple sclerosis. In vitro, imatinib and mation and demyelination. Although considered a T cell- sorafenib inhibited astrocyte proliferation mediated by the mediated disease, multiple sclerosis involves the activation tyrosine kinase platelet-derived growth factor receptor of both adaptive and innate immune cells, as well as (PDGFR), whereas GW2580 and sorafenib inhibited resident cells of the central nervous system, which macrophage tumor necrosis factor (TNF) production medi- synergize in inducing inflammation and thereby demyelin- ated by the tyrosine kinases c-Fms and PDGFR, respec- ation. Differentiation, survival, and inflammatory functions tively. In vivo, amelioration of disease by GW2580 was of innate immune cells and of astrocytes of the central associated with a reduction in the proportion of macro- nervous system are regulated by tyrosine kinases. Here, we phages and T cells in the CNS infiltrate, as well as a show that imatinib, sorafenib, and GW2580—small mole- reduction in the levels of circulating TNF. Our findings cule tyrosine kinase inhibitors—can each prevent the suggest that GW2580 and the FDA-approved drugs imatinib and sorafenib have potential as novel therapeu- : : : tics for the treatment of autoimmune demyelinating O. -
And High-Dose Cyclophosphamide
141-146 6/6/06 13:01 Page 141 ONCOLOGY REPORTS 16: 141-146, 2006 141 Different mechanisms for anti-tumor effects of low- and high-dose cyclophosphamide YASUHIDE MOTOYOSHI1,2, KAZUHISA KAMINODA1,3, OHKI SAITOH1, KEISUKE HAMASAKI2, KAZUHIKO NAKAO3, NOBUKO ISHII3, YUJI NAGAYAMA1 and KATSUMI EGUCHI2 Departments of 1Medical Gene Technology, Atomic Bomb Disease Institute; 2Division of Immunology, Endocrinology and Metabolism, Department of Medical and Dental Sciences, and 3Division of Clinical Pharmaceutics and Health Research Center, Nagasaki University Graduate School of Biomedical Sciences, 1-12-4 Sakamoto, Nagasaki 852-8501, Japan Received February 3, 2006; Accepted April 7, 2006 Abstract. It is known that, besides its direct cytotoxic effect appear to be highly crucial in a clinical setting of combined as an alkylating chemotherapeutic agent, cyclophosphamide chemotherapy and immunotherapy for cancer treatment. also has immuno-modulatory effects, such as depletion of CD4+CD25+ regulatory T cells. However, its optimal concen- Introduction tration has not yet been fully elucidated. Therefore, we first compared the effects of different doses of cyclophosphamide Chemotherapy and immunotherapy are generally regarded on T cell subsets including CD4+CD25+ T cells in mice. as unrelated or even mutually exclusive in cancer treatment, Cyclophosphamide (20 mg/kg) decreased the numbers of because chemotherapy kills not only target cancer cells but splenocytes, CD4+ and CD8+ T cells by ~50%, while a decline also immune cells, inducing systemic immune suppression in CD4+CD25+ T cell number was more profound, leading to and dampening the therapeutic efficacy of immunotherapy. the remarkably lower ratios of CD4+CD25+ T cells to CD4+ In this regard, however, cyclophosphamide appears an T cells. -
Intratumoral Immunotherapy for Early Stage Solid Tumors
Author Manuscript Published OnlineFirst on February 18, 2020; DOI: 10.1158/1078-0432.CCR-19-3642 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. 1 Intratumoral immunotherapy for early-stage solid tumors 2 3 Wan Xing Hong1,2*, Sarah Haebe2,3*, Andrew S. Lee4,5, C. Benedikt Westphalen3,6,7, 4 Jeffrey A. Norton1,2, Wen Jiang8, Ronald Levy2# 5 6 1. Department of Surgery, Stanford University School of Medicine 7 2. Stanford Cancer Institute, Division of Oncology, Department of Medicine, Stanford University 8 3. Department of Medicine III, University Hospital, LMU Munich, Germany 9 4. Department of Pathology, Stanford University School of Medicine 10 5. Shenzhen Bay Labs, Cancer Research Institute, Shenzhen, China 11 6. Comprehensive Cancer Center Munich, Munich, Germany 12 7. Deutsches Konsortium für Translationale Krebsforschung (DKTK), DKTK Partner Site Munich, 13 Germany 14 8. Department of Radiation Oncology, The University of Texas Southwestern Medical Center, Dallas, 15 Texas, USA 16 * These authors contributed equally to this work 17 # Correspondence: [email protected]. 18 CCSR 1105, Stanford, California 94305-5151 19 (650) 725-6452 (office) 20 21 Running title: Intratumoral immunotherapy for early-stage solid tumors 22 23 24 Conflict of Interest 25 Dr. Ronald Levy serves on the advisory boards for Five Prime, Corvus, Quadriga, BeiGene, GigaGen, 26 Teneobio, Sutro, Checkmate, Nurix, Dragonfly, Abpro, Apexigen, Spotlight, 47 Inc, XCella, 27 Immunocore, Walking Fish. 28 Dr. Benedikt Westphalen is on the advisory boards for Celgene, Shire/Baxalta Rafael Pharmaceuticals, 29 Redhill and Roche. He receives research support from Roche. -
Press Release
Press Release Daiichi Sankyo and AstraZeneca Announce Global Development and Commercialization Collaboration for Daiichi Sankyo’s HER2 Targeting Antibody Drug Conjugate [Fam-] Trastuzumab Deruxtecan (DS-8201) Collaboration combines Daiichi Sankyo’s scientific and technological excellence with AstraZeneca’s global experience and resources in oncology to accelerate and expand the potential of [fam-] trastuzumab deruxtecan as monotherapy and combination therapy across a spectrum of HER2 expressing cancers AstraZeneca to pay Daiichi Sankyo up to $6.90 billion in total consideration, including $1.35 billion upfront payment and up to an additional $5.55 billion contingent upon achievement of future regulatory and sales milestones as well as other contingencies Companies to share equally development and commercialization costs as well as profits worldwide from [fam-] trastuzumab deruxtecan with Daiichi Sankyo maintaining exclusive rights in Japan Daiichi Sankyo is expected to book sales in U.S., certain countries in Europe, and certain other markets where Daiichi Sankyo has affiliates; AstraZeneca is expected to book sales in all other markets worldwide, including China, Australia, Canada and Russia Tokyo, Munich and Basking Ridge, NJ – (March 28, 2019) – Daiichi Sankyo Company, Limited (hereafter, Daiichi Sankyo) announced today that it has entered into a global development and commercialization agreement with AstraZeneca for Daiichi Sankyo’s lead antibody drug conjugate (ADC), [fam-] trastuzumab deruxtecan (DS-8201), currently in pivotal development for multiple HER2 expressing cancers including breast and gastric cancer, and additional development in non-small cell lung and colorectal cancer. Daiichi Sankyo and AstraZeneca will jointly develop and commercialize [fam-] trastuzumab deruxtecan as a monotherapy or a combination therapy worldwide, except in Japan where Daiichi Sankyo will maintain exclusive rights. -
Alectinib Provides a New Option for ALK-Positive NSCLC Patients After Progression on Crizotinib See Commentary on Page 239
Community Translations Edited by Jame Abraham, MD, FACP Alectinib provides a new option for ALK-positive NSCLC patients after progression on crizotinib See Commentary on page 239 n December 2015, alectinib became the third ALK inhibitor approved by the United States Food and What’s new, what’s important IDrug Administration for the treatment of non-small- The US Food and Drug Administration approved alectinib to cell lung cancer (NSCLC) that displays rearrangements of treat patients with metastatic ALK-positive non-small-cell lung the anaplastic lymphoma kinase (ALK) gene. Alectinib is cancer whose disease had progressed or who could not toler- a second-generation small molecule inhibitor of the ALK ate treatment with crizotinib. In clinical trials, alectinib showed a protein that joins ceritinib in providing a useful treatment partial response of 38%-44% and an average progression-free option for patients who have progressed on crizotinib, as survival of 11.2 months. In all, 61% of patients experienced a a result of its ability to target crizotinib-resistant mutant complete or partial reduction in their brain metastatic lesions, forms of the ALK protein. Alectinib also displays enhanced with a progression-free survival of of 9.1 months. The recom- penetrance of the blood-brain barrier, which improves ef- mended dose is 600 mg orally twice daily. cacy against central nervous system (CNS) metastases. The most common side effects are fatigue, constipation, swell- Te FDA awarded alectinib accelerated approval on the ing (edema), and muscle pain (myalgia). Treatment with alec- basis of 2 phase 2, single-arm clinical trials in patients tinib may cause sunburn when patients are exposed to sunlight, with ALK-positive NSCLC who had progressed on and pregnant women should be notifed of the possible risk to crizotinib therapy, a group of patients who have few avail- the fetus, and to use contraception throughout treatment and for able treatment options. -
Pharmaceutics of Oral Anticancer Agents and Stimulants
Pharmaceutics of oral anticancer agents and stimulants Maikel Herbrink The research in this thesis was performed at the Departments of Pharmacy & Pharma- cology and Medical Oncology & Clinical Pharmacology of the Netherlands Cancer Insti- tute – Antoni van Leeuwenhoek hospital, Amsterdam, the Netherlands. Printing of this thesis was financially supported by: Netherlands Cancer Institute Chipsoft BV Pfizer BV ISBN: 978-90-393-6997-5 Design, lay-out and print Gildeprint, Enschede © Maikel Herbrink, 2018 Pharmaceutics of oral anticancer agents and stimulants Farmaceutisch onderzoek naar oraal toegediende antikankermiddelen en stimulantia (met een samenvatting in het Nederlands) Proefschrift ter verkrijging van de graad van doctor aan de Universiteit Utrecht op gezag van de rector magnificus, prof. dr. H.R.B.M. Kummeling, ingevolge het besluit van het college voor promoties in het openbaar te verdedigen op woensdag 27 juni 2018 des middags te 4.15 uur door Maikel Herbrink geboren op 2 februari 1990 te Groningen Promotoren: Prof. dr. J.H. Beijnen Prof. dr. J.H.M. Schellens Copromotor: Dr. B. Nuijen Contents Preface 9 Chapter 1: Introduction 15 1.1 Variability in bioavailability of small molecular tyrosine 17 kinase inhibitors Cancer Treat Rev. 2015 May;41(5):412-422 1.2 Inherent formulation issues of kinase inhibitors 51 J Control Release. 2016 Oct;239:118-127 1.3 High-tech drugs in creaky formulations 81 Pharm Res. 2017 Sep;34(9):1751-1753 Chapter 2: Pharmaceutical analysis of oral anticancer drug substances 89 2.1. Thermal study of pazopanib hydrochloride 91 J Therm Anal Calorim. 2017 Dec;130(3):1491-1499 2.2. -
AN ANTICANCER DRUG COCKTAIL of Three Kinase Inhibitors Improved Response to a DENDRITIC CELL–BASED CANCER VACCINE
Author Manuscript Published OnlineFirst on July 2, 2019; DOI: 10.1158/2326-6066.CIR-18-0684 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. 1 AN ANTICANCER DRUG COCKTAIL OF Three Kinase Inhibitors Improved Response to a DENDRITIC CELL–BASED CANCER VACCINE Jitao Guo1, Elena Muse1, Allison J. Christians1, Steven J. Swanson2, and Eduardo Davila1, 3, 4 1Division of Medical Oncology, Department of Medicine, University of Colorado, Anschutz Medical Campus, Aurora, Colorado, United States; 2Immunocellular Therapeutics Ltd., Westlake Village, California, United States; 3 Human Immunology and Immunotherapy Initiative, University of Colorado, Anschutz Medical Campus, Aurora, Colorado, United States; and 4University of Colorado Comprehensive Cancer Center, Aurora, Colorado, United States. Running Title: REPURPOSING ANTICANCER DRUGS FOR DC CANCER VACCINE Keywords: Dendritic cell; cancer vaccine; MK2206; NU7441; Trametinib Financial supports: This work was supported by R01CA207913, a research award from ImmunoCellular Therapeutics, VA Merit Award BX002142, University of Maryland School of Medicine Marlene and Stewart Greenebaum Comprehensive Cancer Center P30CA134274 and the University of Colorado Denver Comprehensive Cancer Center P30CA046934. Corresponding author: Dr. Eduardo Davila Mail stop 8117,12801 E. 17th Avenue, Aurora, CO 80045 Email: [email protected] Phone: (303) 724-0817; Fax:(303) 724-3889 Conflict of Interest Disclosures: These studies were partly funded by a grant from ImmunoCellular Therapeutics (IMUC). S.S. currently serves as SVP Research IMUC but the remaining authors declare no competing financial interests. Counts: Abstract, 242 words; Manuscript, 4523 words; Figures, 5; References,50. Downloaded from cancerimmunolres.aacrjournals.org on October 2, 2021. © 2019 American Association for Cancer Research. -
FLT3 Inhibitors in Acute Myeloid Leukemia Mei Wu1, Chuntuan Li2 and Xiongpeng Zhu2*
Wu et al. Journal of Hematology & Oncology (2018) 11:133 https://doi.org/10.1186/s13045-018-0675-4 REVIEW Open Access FLT3 inhibitors in acute myeloid leukemia Mei Wu1, Chuntuan Li2 and Xiongpeng Zhu2* Abstract FLT3 mutations are one of the most common findings in acute myeloid leukemia (AML). FLT3 inhibitors have been in active clinical development. Midostaurin as the first-in-class FLT3 inhibitor has been approved for treatment of patients with FLT3-mutated AML. In this review, we summarized the preclinical and clinical studies on new FLT3 inhibitors, including sorafenib, lestaurtinib, sunitinib, tandutinib, quizartinib, midostaurin, gilteritinib, crenolanib, cabozantinib, Sel24-B489, G-749, AMG 925, TTT-3002, and FF-10101. New generation FLT3 inhibitors and combination therapies may overcome resistance to first-generation agents. Keywords: FMS-like tyrosine kinase 3 inhibitors, Acute myeloid leukemia, Midostaurin, FLT3 Introduction RAS, MEK, and PI3K/AKT pathways [10], and ultim- Acute myeloid leukemia (AML) remains a highly resist- ately causes suppression of apoptosis and differentiation ant disease to conventional chemotherapy, with a me- of leukemic cells, including dysregulation of leukemic dian survival of only 4 months for relapsed and/or cell proliferation [11]. refractory disease [1]. Molecular profiling by PCR and Multiple FLT3 inhibitors are in clinical trials for treat- next-generation sequencing has revealed a variety of re- ing patients with FLT3/ITD-mutated AML. In this re- current gene mutations [2–4]. New agents are rapidly view, we summarized the preclinical and clinical studies emerging as targeted therapy for high-risk AML [5, 6]. on new FLT3 inhibitors, including sorafenib, lestaurtinib, In 1996, FMS-like tyrosine kinase 3/internal tandem du- sunitinib, tandutinib, quizartinib, midostaurin, gilteriti- plication (FLT3/ITD) was first recognized as a frequently nib, crenolanib, cabozantinib, Sel24-B489, G-749, AMG mutated gene in AML [7]. -
Rheumatic Immune-Related Adverse Events—A Consequence of Immune Checkpoint Inhibitor Therapy
biology Review Rheumatic Immune-Related Adverse Events—A Consequence of Immune Checkpoint Inhibitor Therapy Anca Bobircă 1,†, Florin Bobircă 2,†, Ioan Ancuta 1,†, Alesandra Florescu 3, Vlad Pădureanu 4,* , 5, 6, 7 8 Dan Nicolae Florescu *, Rodica Pădureanu * , Anca Florescu and Anca Emanuela Mus, etescu 1 Department of Internal Medicine and Rheumatology, Carol Davila University of Medicine and Pharmacy, 050474 Bucharest, Romania; [email protected] (A.B.); [email protected] (I.A.) 2 Department of General Surgery, Carol Davila University of Medicine and Pharmacy, 050474 Bucharest, Romania; fl[email protected] 3 Department of Rheumatology, Emergency Clinical County Hospital of Craiova, 200642 Craiova, Romania; [email protected] 4 Department of Internal Medicine, University of Medicine and Pharmacy of Craiova, 200349 Craiova, Romania 5 Department of Gastroenterology, University of Medicine and Pharmacy of Craiova, 200349 Craiova, Romania 6 Department of Internal Medicine, Emergency Clinical County Hospital of Craiova, 200642 Craiova, Romania 7 Department of Internal Medicine and Rheumatology, Dr. I Cantacuzino Hospital, 030167 Bucharest, Romania; anca-teodora.fl[email protected] 8 Department of Rheumatology, University of Medicine and Pharmacy of Craiova, 200349 Craiova, Romania; [email protected] * Correspondence: [email protected] (V.P.); dan.fl[email protected] (D.N.F.); [email protected] (R.P.) † All these authors contributed equally to this work. Citation: Bobirc˘a,A.; Bobirc˘a,F.; Ancuta, I.; Florescu, A.; P˘adureanu, Simple Summary: Cancer therapy has evolved over the years, immunotherapy being the most used V.; Florescu, D.N.; P˘adureanu, R.; for untreatable malignant tumors. Immune checkpoint inhibitors decrease the ability of tumor cells Florescu, A.; Mus, etescu, A.E. -
Comparative Efficacy and Safety of Lorlatinib and Alectinib for ALK
cancers Systematic Review Comparative Efficacy and Safety of Lorlatinib and Alectinib for ALK-Rearrangement Positive Advanced Non-Small Cell Lung Cancer in Asian and Non-Asian Patients: A Systematic Review and Network Meta-Analysis Koichi Ando 1,2,* , Ryo Manabe 1, Yasunari Kishino 1, Sojiro Kusumoto 1, Toshimitsu Yamaoka 3 , Akihiko Tanaka 1, Tohru Ohmori 1,4 and Hironori Sagara 1 1 Division of Respiratory Medicine and Allergology, Department of Medicine, Showa University School of Medicine, 1-5-8 Hatanodai, Shinagawa-ku, Tokyo 142-8666, Japan; [email protected] (R.M.); [email protected] (Y.K.); [email protected] (S.K.); [email protected] (A.T.); [email protected] (T.O.); [email protected] (H.S.) 2 Division of Internal Medicine, Showa University Dental Hospital Medical Clinic, Senzoku Campus, Showa University, 2-1-1 Kita-senzoku, Ohta-ku, Tokyo 145-8515, Japan 3 Advanced Cancer Translational Research Institute, Showa University, 1-5-8 Hatanodai, Shinagawa-ku, Tokyo 142-8555, Japan; [email protected] 4 Department of Medicine, Division of Respiratory Medicine, Tokyo Metropolitan Health and Hospitals Corporation, Ebara Hospital, 4-5-10 Higashiyukigaya, Ohta-ku, Tokyo 145-0065, Japan * Correspondence: [email protected]; Tel.: +81-3-3784-8532 Citation: Ando, K.; Manabe, R.; Kishino, Y.; Kusumoto, S.; Yamaoka, Simple Summary: The treatment of anaplastic lymphoma kinase (ALK) rearrangement-positive T.; Tanaka, A.; Ohmori, T.; Sagara, H. (ALK-p) advanced non-small cell lung cancer (NSCLC) remains a challenge. -
Dual Targeting of HER2-Positive Cancer with Trastuzumab Emtansine and Pertuzumab: Critical Role for Neuregulin Blockade in Antitumor Response to Combination Therapy
Published OnlineFirst October 4, 2013; DOI: 10.1158/1078-0432.CCR-13-0358 Clinical Cancer Cancer Therapy: Clinical Research See related article by Gwin and Spector, p. 278 Dual Targeting of HER2-Positive Cancer with Trastuzumab Emtansine and Pertuzumab: Critical Role for Neuregulin Blockade in Antitumor Response to Combination Therapy Gail D. Lewis Phillips1, Carter T. Fields1, Guangmin Li1, Donald Dowbenko1, Gabriele Schaefer1, Kathy Miller5, Fabrice Andre6, Howard A. Burris III8, Kathy S. Albain9, Nadia Harbeck10, Veronique Dieras7, Diana Crivellari11, Liang Fang2, Ellie Guardino3, Steven R. Olsen3, Lisa M. Crocker4, and Mark X. Sliwkowski1 Abstract Purpose: Targeting HER2 with multiple HER2-directed therapies represents a promising area of treatment for HER2-positive cancers. We investigated combining the HER2-directed antibody–drug con- jugate trastuzumab emtansine (T-DM1) with the HER2 dimerization inhibitor pertuzumab (Perjeta). Experimental Design: Drug combination studies with T-DM1 and pertuzumab were performed on cultured tumor cells and in mouse xenograft models of HER2-amplified cancer. In patients with HER2- positive locally advanced or metastatic breast cancer (mBC), T-DM1 was dose-escalated with a fixed standard pertuzumab dose in a 3þ3 phase Ib/II study design. Results: Treatment of HER2-overexpressing tumor cells in vitro with T-DM1 plus pertuzumab resulted in synergistic inhibition of cell proliferation and induction of apoptotic cell death. The presence of the HER3 ligand, heregulin (NRG-1b), reduced the cytotoxic activity of T-DM1 in a subset of breast cancer lines; this effect was reversed by the addition of pertuzumab. Results from mouse xenograft models showed enhanced antitumor efficacy with T-DM1 and pertuzumab resulting from the unique antitumor activities of each agent.