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A Phase I Study of Pexidartinib, a Colony-Stimulating Factor 1 Receptor Inhibitor, in Asian Patients with Advanced Solid Tumors
Investigational New Drugs https://doi.org/10.1007/s10637-019-00745-z PHASE I STUDIES A phase I study of pexidartinib, a colony-stimulating factor 1 receptor inhibitor, in Asian patients with advanced solid tumors Jih-Hsiang Lee1 & Tom Wei-Wu Chen2 & Chih-Hung Hsu2,3 & Yu-Hsin Yen2 & James Chih-Hsin Yang2,3 & Ann-Lii Cheng2,3 & Shun-ichi Sasaki4 & LiYin (Lillian) Chiu5 & Masahiro Sugihara4 & Tomoko Ishizuka4 & Toshihiro Oguma4 & Naoyuki Tajima4 & Chia-Chi Lin2,6 Received: 15 January 2019 /Accepted: 7 February 2019 # The Author(s) 2019 Summary Background Pexidartinib, a novel, orally administered small-molecule tyrosine kinase inhibitor, has strong selectivity against colony- stimulating factor 1 receptor. This phase I, nonrandomized, open-label multiple-dose study evaluated pexidartinib safety and efficacy in Asian patients with symptomatic, advanced solid tumors. Materials and Methods Patients received pexidartinib: cohort 1, 600 mg/d; cohort 2, 1000 mg/d for 2 weeks, then 800 mg/d. Primary objectives assessed pexidartinib safety and tolerability, and determined the recommended phase 2 dose; secondary objectives evaluated efficacy and pharmacokinetic profile. Results All11patients(6males,5 females; median age 64, range 23–82; cohort 1 n = 3; cohort 2 n = 8) experienced at least one treatment-emergent adverse event; 5 experienced at least one grade ≥ 3 adverse event, most commonly (18%) for each of the following: increased aspartate aminotransfer- ase, blood alkaline phosphatase, gamma-glutamyl transferase, and anemia. Recommended phase 2 dose was 1000 mg/d for 2 weeks and800mg/dthereafter.Pexidartinibexposure,areaundertheplasmaconcentration-timecurvefromzeroto8h(AUC0-8h), and maximum observed plasma concentration (Cmax) increased on days 1 and 15 with increasing pexidartinib doses, and time at Cmax (Tmax) was consistent throughout all doses. -
07052020 MR ASCO20 Curtain Raiser
Media Release New data at the ASCO20 Virtual Scientific Program reflects Roche’s commitment to accelerating progress in cancer care First clinical data from tiragolumab, Roche’s novel anti-TIGIT cancer immunotherapy, in combination with Tecentriq® (atezolizumab) in patients with PD-L1-positive metastatic non- small cell lung cancer (NSCLC) Updated overall survival data for Alecensa® (alectinib), in people living with anaplastic lymphoma kinase (ALK)-positive metastatic NSCLC Key highlights to be shared on Roche’s ASCO virtual newsroom, 29 May 2020, 08:00 CEST Basel, 7 May 2020 - Roche (SIX: RO, ROG; OTCQX: RHHBY) today announced that new data from clinical trials of 19 approved and investigational medicines across 21 cancer types, will be presented at the ASCO20 Virtual Scientific Program organised by the American Society of Clinical Oncology (ASCO), which will be held 29-31 May, 2020. A total of 120 abstracts that include a Roche medicine will be presented at this year's meeting. "At ASCO, we will present new data from many investigational and approved medicines across our broad oncology portfolio," said Levi Garraway, M.D., Ph.D., Roche's Chief Medical Officer and Head of Global Product Development. “These efforts exemplify our long-standing commitment to improving outcomes for people with cancer, even during these unprecedented times. By integrating our medicines and diagnostics together with advanced insights and novel platforms, Roche is uniquely positioned to deliver the healthcare solutions of the future." Together with its partners, Roche is pioneering a comprehensive approach to cancer care, combining new diagnostics and treatments with innovative, integrated data and access solutions for approved medicines that will both personalise and transform the outcomes of people affected by this deadly disease. -
Daiichi Sankyo Group Value Report 2019
External Evaluations (as of June 30,2019) ™ Daiichi Sankyo Group Value Report 2019 Value Daiichi Sankyo Group MSCI Japan Empowering Women Select Index THE INCLUSION OF DAIICHI SANKYO CO.,LTD. IN ANY MSCI INDEX, AND THE USE OF MSCI LOGOS, TRADEMARKS, SERVICE MARKS OR INDEX NAMES HEREIN, DO NOT CONSTITUTE A SPONSORSHIP, ENDORSEMENT OR PROMOTION OF DAIICHI SANKYO CO.,LTD. BY MSCI OR ANY OF ITS AFFILIATES. THE MSCI INDEXES ARE THE EXCLUSIVE PROPERTY OF MSCI. MSCI AND THE MSCI INDEX NAMES AND LOGOS ARE TRADE- MARKS OR SERVICE MARKS OF MSCI OR ITS AFFILIATES. “Eruboshi” Certification Mark “Kurumin” Certification Mark Logo given to Certified Health and Productivity Management Organization (White500) This report uses FSC® certified paper, which indicates that the paper used to print this Paper report was produced from properly managed forests. 3-5-1, Nihonbashi-honcho, Chuo-ku, Tokyo 103-8426, Japan This report was printed using 100% Inks biodegradable printing inks from vegetable Corporate Communications Department oil. Daiichi Sankyo Group Tel: +81-3-6225-1126 CSR Department The waterless printing method used for this Value Report 2019 Tel: +81-3-6225-1067 Printing report minimized the use and release of harmful liquid wastes. https://www.daiichisankyo.com/ Printed in Japan 005_7045687911909.indd 1 2019/09/27 18:22:19 Introduction Our Mission The Core Values and Commitments serve as the criteria for business activities and In addition, we have established the DAIICHI SANKYO Group Corporate Conduct Charter . decision-making used by executive officers and employees in working to fulfill Our Mission . This charter calls on us to fulfill our social responsibilities by acting with the highest ethical Our Corporate Slogan succinctly explains the spirit of Our Mission, Core Values and standards and a good social conscience appropriate for a company engaged in business Commitments. -
Fam-Trastuzumab Deruxtecan-Nxki Submitted by Daiichi
Dan Liang, PharmD Associate Director, Medical Information & Education Daiichi Sankyo, Inc. 211 Mount Airy Road Basking Ridge, NJ 07920 Phone: 908-992-7054 Email: [email protected] Date of request: July 9, 2020 NCCN Panel: Colon Cancer and Rectal Cancer On behalf of Daiichi Sankyo, Inc. and AstraZeneca Pharmaceuticals LP, I respectfully request the NCCN Guideline Panel for Colon and Rectal Cancers to review data from the clinical study1 in support of fam-trastuzumab deruxtecan-nxki, also known as T-DXd, as a monotherapy option for the treatment of patients with HER2-positive unresectable and/or metastatic colorectal cancer. Specific Changes: We respectfully ask the NCCN panel to consider the following: • COL-D1 through COL-D6 and REC-F1 through REC-F6, “Continuum of Care - Systemic Therapy for Advanced or Metastatic Disease” o Add “Fam-trastuzumab deruxtecan-nxki (HER2-positive and RAS and BRAF WT)” to the following: . COL-D1 and REC-F1: “Patient not appropriate for intensive therapy” . COL-D2 and REC-F2: “Previous oxaliplatin-based therapy without irinotecan” . COL-D3 and REC-F3: “Previous irinotecan-based therapy without oxaliplatin” . COL-D4 and REC-F4: “Previous treatment with oxaliplatin and irinotecan” . COL-D5 and REC-F5: “Previous therapy without irinotecan or oxaliplatin” . COL-D6 and REC-F6: “FOLFOX or CAPEOX or (FOLFOX or CAPEOX) + bevacizumab” • COL-D11 and REC-F11, “Systemic Therapy for Advanced or Metastatic Disease – Chemotherapy Regimens” o Add “Fam-trastuzumab deruxtecan-nxki 6.4 mg/kg IV on Day 1, cycled every 21 days” with a footnote: “fam-trastuzumab deruxtecan-nxki is approved for metastatic HER2-positive breast cancer at a different dose of 5.4 mg/kg IV on Day 1, cycled every 21 days” FDA Clearance: ENHERTU (fam-trastuzumab deruxtecan-nxki) is a HER2-directed antibody and topoisomerase inhibitor conjugate indicated for the treatment of adult patients with unresectable or metastatic HER2-positive breast cancer who have received two or more prior anti-HER2-based regimens in the metastatic setting. -
The Tumor Microenvironment and Overcoming Immune Escape Arsen Osipov1, May Tun Saung1, Lei Zheng1 and Adrian G
Osipov et al. Journal for ImmunoTherapy of Cancer (2019) 7:224 https://doi.org/10.1186/s40425-019-0667-0 REVIEW Open Access Small molecule immunomodulation: the tumor microenvironment and overcoming immune escape Arsen Osipov1, May Tun Saung1, Lei Zheng1 and Adrian G. Murphy1,2* Abstract Immunotherapy has led to a paradigm shift in the treatment of many advanced malignancies. Despite the success in treatment of tumors like non-small cell lung cancer (NSCLC) and melanoma, checkpoint inhibition-based immunotherapy has limitations. Many tumors, such as pancreatic cancer, are less responsive to checkpoint inhibitors, where patients tend to have a limited duration of benefit and where clinical responses are more robust in patients who are positive for predictive biomarkers. One of the critical factors that influence the efficacy of immunotherapy is the tumor microenvironment (TME), which contains a heterogeneous composition of immunosuppressive cells. Myeloid-derived suppressor cells (MDSCs) and tumor-associated macrophages (TAMs) alter the immune landscape of the TME and serve as facilitators of tumor proliferation, metastatic growth and immunotherapy resistance. Small molecule inhibitors that target these components of the TME have been developed. This special issue review focuses on two promising classes of immunomodulatory small molecule inhibitors: colony stimulating factor-1 receptor (CSF-1R) and focal adhesion kinase (FAK). Small molecule inhibitors of CSF-1R reprogram the TME and TAMs, and lead to enhanced T-cell-mediated tumor eradication. FAK small molecule inhibitors decrease the infiltration MDSCs, TAMs and regulatory T-cells. Additionally, FAK inhibitors are implicated as modulators of stromal density and cancer stem cells, leading to a TME more conducive to an anti-tumor immune response. -
Antibody–Drug Conjugates
Published OnlineFirst April 12, 2019; DOI: 10.1158/1078-0432.CCR-19-0272 Review Clinical Cancer Research Antibody–Drug Conjugates: Future Directions in Clinical and Translational Strategies to Improve the Therapeutic Index Steven Coats1, Marna Williams1, Benjamin Kebble1, Rakesh Dixit1, Leo Tseng1, Nai-Shun Yao1, David A. Tice1, and Jean-Charles Soria1,2 Abstract Since the first approval of gemtuzumab ozogamicin nism of activity of the cytotoxic warhead. However, the (Mylotarg; Pfizer; CD33 targeted), two additional antibody– enthusiasm to develop ADCs has not been dampened; drug conjugates (ADC), brentuximab vedotin (Adcetris; Seat- approximately 80 ADCs are in clinical development in tle Genetics, Inc.; CD30 targeted) and inotuzumab ozogami- nearly 600 clinical trials, and 2 to 3 novel ADCs are likely cin (Besponsa; Pfizer; CD22 targeted), have been approved for to be approved within the next few years. While the hematologic cancers and 1 ADC, trastuzumab emtansine promise of a more targeted chemotherapy with less tox- (Kadcyla; Genentech; HER2 targeted), has been approved to icity has not yet been realized with ADCs, improvements treat breast cancer. Despite a clear clinical benefit being dem- in technology combined with a wealth of clinical data are onstrated for all 4 approved ADCs, the toxicity profiles are helping to shape the future development of ADCs. In this comparable with those of standard-of-care chemotherapeu- review, we discuss the clinical and translational strategies tics, with dose-limiting toxicities associated with the mecha- associated with improving the therapeutic index for ADCs. Introduction in antibody, linker, and warhead technologies in significant depth (2, 3, 8, 9). Antibody–drug conjugates (ADC) were initially designed to leverage the exquisite specificity of antibodies to deliver targeted potent chemotherapeutic agents with the intention of improving Overview of ADCs in Clinical Development the therapeutic index (the ratio between the toxic dose and the Four ADCs have been approved over the last 20 years (Fig. -
Tanibirumab (CUI C3490677) Add to Cart
5/17/2018 NCI Metathesaurus Contains Exact Match Begins With Name Code Property Relationship Source ALL Advanced Search NCIm Version: 201706 Version 2.8 (using LexEVS 6.5) Home | NCIt Hierarchy | Sources | Help Suggest changes to this concept Tanibirumab (CUI C3490677) Add to Cart Table of Contents Terms & Properties Synonym Details Relationships By Source Terms & Properties Concept Unique Identifier (CUI): C3490677 NCI Thesaurus Code: C102877 (see NCI Thesaurus info) Semantic Type: Immunologic Factor Semantic Type: Amino Acid, Peptide, or Protein Semantic Type: Pharmacologic Substance NCIt Definition: A fully human monoclonal antibody targeting the vascular endothelial growth factor receptor 2 (VEGFR2), with potential antiangiogenic activity. Upon administration, tanibirumab specifically binds to VEGFR2, thereby preventing the binding of its ligand VEGF. This may result in the inhibition of tumor angiogenesis and a decrease in tumor nutrient supply. VEGFR2 is a pro-angiogenic growth factor receptor tyrosine kinase expressed by endothelial cells, while VEGF is overexpressed in many tumors and is correlated to tumor progression. PDQ Definition: A fully human monoclonal antibody targeting the vascular endothelial growth factor receptor 2 (VEGFR2), with potential antiangiogenic activity. Upon administration, tanibirumab specifically binds to VEGFR2, thereby preventing the binding of its ligand VEGF. This may result in the inhibition of tumor angiogenesis and a decrease in tumor nutrient supply. VEGFR2 is a pro-angiogenic growth factor receptor -
Advances in Epidermal Growth Factor Receptor Specific Immunotherapy: Lessons to Be Learned from Armed Antibodies
www.oncotarget.com Oncotarget, 2020, Vol. 11, (No. 38), pp: 3531-3557 Review Advances in epidermal growth factor receptor specific immunotherapy: lessons to be learned from armed antibodies Fleury Augustin Nsole Biteghe1,*, Neelakshi Mungra2,*, Nyangone Ekome Toung Chalomie4, Jean De La Croix Ndong5, Jean Engohang-Ndong6, Guillaume Vignaux7, Eden Padayachee8, Krupa Naran2,* and Stefan Barth2,3,* 1Department of Radiation Oncology and Biomedical Sciences, Cedars-Sinai Medical, Los Angeles, CA, USA 2Medical Biotechnology & Immunotherapy Research Unit, Institute of Infectious Disease and Molecular Medicine, Faculty of Health Sciences, University of Cape Town, Cape Town, South Africa 3South African Research Chair in Cancer Biotechnology, Department of Integrative Biomedical Sciences, Faculty of Health Sciences, University of Cape Town, Cape Town, South Africa 4Sun Yat-Sen University, Zhongshan Medical School, Guangzhou, China 5Department of Orthopedic Surgery, New York University School of Medicine, New York, NY, USA 6Department of Biological Sciences, Kent State University at Tuscarawas, New Philadelphia, OH, USA 7Arctic Slope Regional Corporation Federal, Beltsville, MD, USA 8Department of Physiology, University of Kentucky, Lexington, KY, USA *These authors contributed equally to this work Correspondence to: Stefan Barth, email: [email protected] Keywords: epidermal growth factor receptor (EGFR); recombinant immunotoxins (ITs); targeted human cytolytic fusion proteins (hCFPs); recombinant antibody-drug conjugates (rADCs); recombinant antibody photoimmunoconjugates (rAPCs) Received: May 30, 2020 Accepted: August 11, 2020 Published: September 22, 2020 Copyright: © 2020 Biteghe et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. -
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. -
Phase Ib Study of the Combination of Pexidartinib (PLX3397), a CSF-1R Inhibitor, and Paclitaxel in Patients with Advanced Solid
TAM0010.1177/1758835919854238Therapeutic Advances in Medical OncologyR Wesolowski, N Sharma 854238research-article20192019 Therapeutic Advances in Medical Oncology Original Research Ther Adv Med Oncol Phase Ib study of the combination of 2019, Vol. 11: 1 –13 DOI:https://doi.org/10.1177/1758835919854238 10.1177/ pexidartinib (PLX3397), a CSF-1R inhibitor, 1758835919854238https://doi.org/10.1177/1758835919854238 © The Author(s), 2019. Article reuse guidelines: and paclitaxel in patients with advanced sagepub.com/journals- solid tumors permissions Robert Wesolowski, Neelesh Sharma, Laura Reebel, Mary Beth Rodal, Alexandra Peck, Brian L. West, Adhirai Marimuthu, Paul Severson, David A. Karlin, Afshin Dowlati, Mai H. Le, Lisa M. Coussens and Hope S. Rugo Abstract Purpose: To evaluate the safety, recommended phase II dose (RP2D) and efficacy of pexidartinib, a colony stimulating factor receptor 1 (CSF-1R) inhibitor, in combination with weekly paclitaxel in patients with advanced solid tumors. Patients and Methods: In part 1 of this phase Ib study, 24 patients with advanced solid tumors received escalating doses of pexidartinib with weekly paclitaxel (80 mg/m2). Pexidartinib was administered at 600 mg/day in cohort 1. For subsequent cohorts, the dose was increased by ⩽50% using a standard 3+3 design. In part 2, 30 patients with metastatic solid tumors were enrolled to examine safety, tolerability and efficacy of the RP2D. Pharmacokinetics and biomarkers were also assessed. Results: A total of 51 patients reported ≥1 adverse event(s) (AEs) that were at least possibly related to either study drug. Grade 3–4 AEs, including anemia (26%), neutropenia (22%), lymphopenia (19%), fatigue (15%), and hypertension (11%), were Correspondence to: Robert Wesolowski recorded in 38 patients (70%). -
Antibody–Drug Conjugates: the Last Decade
pharmaceuticals Review Antibody–Drug Conjugates: The Last Decade Nicolas Joubert 1,* , Alain Beck 2 , Charles Dumontet 3,4 and Caroline Denevault-Sabourin 1 1 GICC EA7501, Equipe IMT, Université de Tours, UFR des Sciences Pharmaceutiques, 31 Avenue Monge, 37200 Tours, France; [email protected] 2 Institut de Recherche Pierre Fabre, Centre d’Immunologie Pierre Fabre, 5 Avenue Napoléon III, 74160 Saint Julien en Genevois, France; [email protected] 3 Cancer Research Center of Lyon (CRCL), INSERM, 1052/CNRS 5286/UCBL, 69000 Lyon, France; [email protected] 4 Hospices Civils de Lyon, 69000 Lyon, France * Correspondence: [email protected] Received: 17 August 2020; Accepted: 10 September 2020; Published: 14 September 2020 Abstract: An armed antibody (antibody–drug conjugate or ADC) is a vectorized chemotherapy, which results from the grafting of a cytotoxic agent onto a monoclonal antibody via a judiciously constructed spacer arm. ADCs have made considerable progress in 10 years. While in 2009 only gemtuzumab ozogamicin (Mylotarg®) was used clinically, in 2020, 9 Food and Drug Administration (FDA)-approved ADCs are available, and more than 80 others are in active clinical studies. This review will focus on FDA-approved and late-stage ADCs, their limitations including their toxicity and associated resistance mechanisms, as well as new emerging strategies to address these issues and attempt to widen their therapeutic window. Finally, we will discuss their combination with conventional chemotherapy or checkpoint inhibitors, and their design for applications beyond oncology, to make ADCs the magic bullet that Paul Ehrlich dreamed of. Keywords: antibody–drug conjugate; ADC; bioconjugation; linker; payload; cancer; resistance; combination therapies 1. -
Trastuzumab and Paclitaxel in Patients with EGFR Mutated NSCLC That Express HER2 After Progression on EGFR TKI Treatment
www.nature.com/bjc ARTICLE Clinical Study Trastuzumab and paclitaxel in patients with EGFR mutated NSCLC that express HER2 after progression on EGFR TKI treatment Adrianus J. de Langen1,2, M. Jebbink1, Sayed M. S. Hashemi2, Justine L. Kuiper2, J. de Bruin-Visser2, Kim Monkhorst3, Erik Thunnissen4 and Egbert F. Smit1,2 BACKGROUND: HER2 expression and amplification are observed in ~15% of tumour biopsies from patients with a sensitising EGFR mutation who develop EGFR TKI resistance. It is unknown whether HER2 targeting in this setting can result in tumour responses. METHODS: A single arm phase II study was performed to study the safety and efficacy of trastuzumab and paclitaxel treatment in patients with a sensitising EGFR mutation who show HER2 expression in a tumour biopsy (IHC ≥ 1) after progression on EGFR TKI treatment. Trastuzumab (first dose 4 mg/kg, thereafter 2 mg/kg) and paclitaxel (60 mg/m2) were dosed weekly until disease progression or unacceptable toxicity. The primary end-point was tumour response rate according to RECIST v1.1. RESULTS: Twenty-four patients were enrolled. Nine patients were exon 21 L858R positive and fifteen exon 19 del positive. Median HER2 IHC was 2+ (range 1–3). For 21 patients, gene copy number by in situ hybridisation could be calculated: 5 copies/nucleus (n = 9), 5–10 copies (n = 8), and >10 copies (n = 4). An objective response was observed in 11/24 (46%) patients. Highest response rates were seen for patients with 3+ HER2 IHC (12 patients, ORR 67%) or HER2 copy number ≥10 (4 patients, ORR 100%). Median tumour change in size was 42% decrease (range −100% to +53%).