Agents Available Under CTEP Collaborative Agreements for Clinical and Non-Clinical Studies 1 As of 7/28/2021
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The Impact of Immunological Checkpoint Inhibitors and Targeted Therapy on Chronic Pruritus in Cancer Patients
biomedicines Review The Impact of Immunological Checkpoint Inhibitors and Targeted Therapy on Chronic Pruritus in Cancer Patients Alessandro Allegra 1,* , Eleonora Di Salvo 2 , Marco Casciaro 3,4, Caterina Musolino 1, Giovanni Pioggia 5 and Sebastiano Gangemi 3,4 1 Division of Hematology, Department of Human Pathology in Adulthood and Childhood “Gaetano Barresi”, University of Messina, 98125 Messina, Italy; [email protected] 2 Department of Veterinary Sciences, University of Messina, 98125 Messina, Italy; [email protected] 3 School of Allergy and Clinical Immunology, Department of Clinical and Experimental Medicine, University of Messina, 98125 Messina, Italy; [email protected] (M.C.); [email protected] (S.G.) 4 Operative Unit of Allergy and Clinical Immunology, Department of Clinical and Experimental Medicine, University of Messina, 98125 Messina, Italy 5 Institute for Biomedical Research and Innovation (IRIB), National Research Council of Italy (CNR), 98164 Messina, Italy; [email protected] * Correspondence: [email protected]; Tel.: +39-090-221-2364 Abstract: Although pruritus may sometimes be a consequential situation to neoplasms, it more frequently emerges after commencing chemotherapy. In this review, we present our analysis of the chemotherapy treatments that most often induce skin changes and itching. After discussing conventional chemotherapies capable of inducing pruritus, we present our evaluation of new drugs such as immunological checkpoint inhibitors (ICIs), tyrosine kinase inhibitors, and monoclonal antibodies. Although ICIs and targeted therapy are thought to damage tumor cells, these therapies can modify homeostatic events of the epidermis and dermis, causing the occurrence of cutaneous toxicities in treated subjects. In the face of greater efficacy, greater skin toxicity has been reported for most of these drugs. -
MET Or NRAS Amplification Is an Acquired Resistance Mechanism to the Third-Generation EGFR Inhibitor Naquotinib
www.nature.com/scientificreports OPEN MET or NRAS amplifcation is an acquired resistance mechanism to the third-generation EGFR inhibitor Received: 5 October 2017 Accepted: 16 January 2018 naquotinib Published: xx xx xxxx Kiichiro Ninomiya1, Kadoaki Ohashi1,2, Go Makimoto1, Shuta Tomida3, Hisao Higo1, Hiroe Kayatani1, Takashi Ninomiya1, Toshio Kubo4, Eiki Ichihara2, Katsuyuki Hotta5, Masahiro Tabata4, Yoshinobu Maeda1 & Katsuyuki Kiura2 As a third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI), osimeritnib is the standard treatment for patients with non-small cell lung cancer harboring the EGFR T790M mutation; however, acquired resistance inevitably develops. Therefore, a next-generation treatment strategy is warranted in the osimertinib era. We investigated the mechanism of resistance to a novel EGFR-TKI, naquotinib, with the goal of developing a novel treatment strategy. We established multiple naquotinib-resistant cell lines or osimertinib-resistant cells, two of which were derived from EGFR-TKI-naïve cells; the others were derived from geftinib- or afatinib-resistant cells harboring EGFR T790M. We comprehensively analyzed the RNA kinome sequence, but no universal gene alterations were detected in naquotinib-resistant cells. Neuroblastoma RAS viral oncogene homolog (NRAS) amplifcation was detected in naquotinib-resistant cells derived from geftinib-resistant cells. The combination therapy of MEK inhibitors and naquotinib exhibited a highly benefcial efect in resistant cells with NRAS amplifcation, but the combination of MEK inhibitors and osimertinib had limited efects on naquotinib-resistant cells. Moreover, the combination of MEK inhibitors and naquotinib inhibited the growth of osimertinib-resistant cells, while the combination of MEK inhibitors and osimertinib had little efect on osimertinib-resistant cells. -
IGF System in Sarcomas: a Crucial Pathway with Many Unknowns to Exploit for Therapy
61 1 Journal of Molecular C Mancarella and Targeting IGF system in sarcoma 61:1 T45–T60 Endocrinology K Scotlandi THEMATIC REVIEW 40 YEARS OF IGF1 IGF system in sarcomas: a crucial pathway with many unknowns to exploit for therapy Caterina Mancarella and Katia Scotlandi Experimental Oncology Lab, CRS Development of Biomolecular Therapies, Orthopaedic Rizzoli Institute, Bologna, Italy Correspondence should be addressed to K Scotlandi: [email protected] This paper forms part of a special section on 40 Years of IGF1. The guest editors for this section were Derek LeRoith and Emily Gallagher. Abstract The insulin-like growth factor (IGF) system has gained substantial interest due to its Key Words involvement in regulating cell proliferation, differentiation and survival during anoikis f sarcomas and after conventional and targeted therapies. However, results from clinical trials have f IGF system been largely disappointing, with only a few but notable exceptions, such as trials targeting f targeted therapy sarcomas, especially Ewing sarcoma. This review highlights key studies focusing on IGF f clinical trials signaling in sarcomas, specifically studies underscoring the properties that make this system an attractive therapeutic target and identifies new relationships that may be exploited. This review discusses the potential roles of IGF2 mRNA-binding proteins (IGF2BPs), discoidin domain receptors (DDRs) and metalloproteinase pregnancy-associated plasma protein-A (PAPP-A) in regulating the IGF system. Deeper investigation of these novel regulators of the IGF system may help us to further elucidate the spatial and temporal control of the IGF Journal of Molecular axis, as understanding the control of this axis is essential for future clinical studies. -
Therapeutic Targeting of the IGF Axis
cells Review Therapeutic Targeting of the IGF Axis Eliot Osher and Valentine M. Macaulay * Department of Oncology, University of Oxford, Oxford, OX3 7DQ, UK * Correspondence: [email protected]; Tel.: +44-1865617337 Received: 8 July 2019; Accepted: 9 August 2019; Published: 14 August 2019 Abstract: The insulin like growth factor (IGF) axis plays a fundamental role in normal growth and development, and when deregulated makes an important contribution to disease. Here, we review the functions mediated by ligand-induced IGF axis activation, and discuss the evidence for the involvement of IGF signaling in the pathogenesis of cancer, endocrine disorders including acromegaly, diabetes and thyroid eye disease, skin diseases such as acne and psoriasis, and the frailty that accompanies aging. We discuss the use of IGF axis inhibitors, focusing on the different approaches that have been taken to develop effective and tolerable ways to block this important signaling pathway. We outline the advantages and disadvantages of each approach, and discuss progress in evaluating these agents, including factors that contributed to the failure of many of these novel therapeutics in early phase cancer trials. Finally, we summarize grounds for cautious optimism for ongoing and future studies of IGF blockade in cancer and non-malignant disorders including thyroid eye disease and aging. Keywords: IGF; type 1 IGF receptor; IGF-1R; cancer; acromegaly; ophthalmopathy; IGF inhibitor 1. Introduction Insulin like growth factors (IGFs) are small (~7.5 kDa) ligands that play a critical role in many biological processes including proliferation and protection from apoptosis and normal somatic growth and development [1]. IGFs are members of a ligand family that includes insulin, a dipeptide comprised of A and B chains linked via two disulfide bonds, with a third disulfide linkage within the A chain. -
Systematic Review: Targeting HER2 in Bladder Cancer
Bladder Cancer 5 (2019) 1–12 1 DOI 10.3233/BLC-180196 IOS Press Systematic Review Systematic Review: Targeting HER2 in Bladder Cancer Vadim S. Koshkina, Peter O’Donnellb,EvanY.Yuc and Petros Grivasd,∗ aDepartment of Medicine, Division of Hematology and Oncology, University of California San Francisco, CA, USA bDepartment of Medicine, Section of Hematology/Oncology, University of Chicago, Chicago, IL, USA cDepartment of Medicine, Division of Oncology, Clinical Research Director, Fred Hutchinson Cancer Research Center, University of Washington, Seattle Cancer Care Alliance, Seattle, WA, USA dDepartment of Medicine, Division of Oncology, University of Washington, Seattle Cancer Care Alliance, Seattle, WA, USA Received 23 August 2018 Accepted 22 November 2018 Abstract. Background: HER2 (ErbB2) is a receptor of the Human Epidermal Growth Factor Receptor (HER) family whose role in oncogenesis of numerous malignancies is well described. Drugs targeting HER2 are currently approved in breast and gastroesophageal cancers while pan-HER targeting agents are being evaluated in multiple malignancies. HER2 genomic alterations are commonly described in urothelial cancer and multiple trials have assessed the efficacy of anti-HER2 agents in both muscle-invasive and metastatic urothelial carcinoma. Objective: To review prospective clinical trials of therapeutic agents with HER2–targeting activity in patients with bladder cancer. Methods: A systematic search of PubMed, ASCO abstracts and Clinicaltrials.gov was performed to identify studies of HER2–targeting agents in bladder cancer. Reported results from prospective trials were reviewed and summarized. Results: Eleven prospective clinical trials with reported results were identified that investigated activity of trastuzumab, lapatinib, neratinib, afatinib, or autologous cellular immunotherapy, (DN24–02), in various bladder cancer treatment settings. -
Primary and Acquired Resistance to Immunotherapy in Lung Cancer: Unveiling the Mechanisms Underlying of Immune Checkpoint Blockade Therapy
cancers Review Primary and Acquired Resistance to Immunotherapy in Lung Cancer: Unveiling the Mechanisms Underlying of Immune Checkpoint Blockade Therapy Laura Boyero 1 , Amparo Sánchez-Gastaldo 2, Miriam Alonso 2, 1 1,2,3, , 1,2, , José Francisco Noguera-Uclés , Sonia Molina-Pinelo * y and Reyes Bernabé-Caro * y 1 Institute of Biomedicine of Seville (IBiS) (HUVR, CSIC, Universidad de Sevilla), 41013 Seville, Spain; [email protected] (L.B.); [email protected] (J.F.N.-U.) 2 Medical Oncology Department, Hospital Universitario Virgen del Rocio, 41013 Seville, Spain; [email protected] (A.S.-G.); [email protected] (M.A.) 3 Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), 28029 Madrid, Spain * Correspondence: [email protected] (S.M.-P.); [email protected] (R.B.-C.) These authors contributed equally to this work. y Received: 16 November 2020; Accepted: 9 December 2020; Published: 11 December 2020 Simple Summary: Immuno-oncology has redefined the treatment of lung cancer, with the ultimate goal being the reactivation of the anti-tumor immune response. This has led to the development of several therapeutic strategies focused in this direction. However, a high percentage of lung cancer patients do not respond to these therapies or their responses are transient. Here, we summarized the impact of immunotherapy on lung cancer patients in the latest clinical trials conducted on this disease. As well as the mechanisms of primary and acquired resistance to immunotherapy in this disease. Abstract: After several decades without maintained responses or long-term survival of patients with lung cancer, novel therapies have emerged as a hopeful milestone in this research field. -
Clinical Development of FGFR3 Inhibitors for the Treatment of Urothelial Cancer
Bladder Cancer 5 (2019) 87–102 87 DOI 10.3233/BLC-180205 IOS Press Review Clinical Development of FGFR3 Inhibitors for the Treatment of Urothelial Cancer Tony Ibrahima, Marco Gizzib, Ratislav Bahledac and Yohann Loriota,d,∗ aD´epartement de M´edecine Oncologique, Gustave Roussy, Universit´e Paris-Sud, Universit´e Paris-Saclay, Villejuif, France bDepartment of Medical Oncology. Grand Hˆopital de Charleroi, Charleroi, Belgium cDrug Development Department (DITEP), Gustave Roussy, Villejuif France dInserm 981, Universit´e Paris-Sud, Universit´e Paris Saclay, Villejuif, France Received: 29 November 2018 Accepted: 4 March 2019 Abstract. The fibroblast growth factor receptor 3 (FGFR3) plays critical roles in driving oncogenesis of a subset of patients with urothelial carcinomas (UC). Growing evidence from preclinical studies suggests that FGFR3 inhibition can reduce proliferation and survival in vitro and in vivo models of FGFR3-altered UC. Early clinical trials investigating selective FGFR3 inhibitor have reported preliminary signs of antitumor activity in advanced UC patients with selected FGFR3 mutations or fusions. Currently, phase 3 trials with erdafitinib and rogaratinib are enrolling patients with known FGFR3 alterations. Future combinations with targeted therapies or immune checkpoint inhibitors may increase the efficacy of selective FGFR3 inhibitors. Herein, we discuss current clinical development of FGFR3 inhibitors as well as unsolved questions with regards to patient selection, management of toxicities and mechanisms of resistance to selective FGFR3 inhibitors. Keywords: Urothelial cancer, bladder cancer, fibroblast growth factor 3, tyrosine kinase INTRODUCTION the treated patients [1–11]. Innovative strategies aim- ing to improve metastatic UC treatment efficacy have Metastatic urothelial carcinoma (UC) is frequent learned from targeted therapies in solid tumors such and has a poor prognosis. -
The Role of Single Arm Trials in Oncology Drug Development EMA-ESMO Workshop on Single-Arm Trials for Cancer Drug Market Access 30Th June 2016
The role of Single Arm Trials in Oncology Drug Development EMA-ESMO Workshop on single-arm trials for cancer drug market access 30th June 2016 Gideon Blumenthal, MD Office of Hematology and Oncology Products U.S. Food and Drug Administration Challenges with “newparadigm” with Challenges Challenges ROS1 MET PTEN+ PTEN+ Targeted KRAS Therapy N=50 p53 with “oldparadigm” - 200 LKB1 ??? ORR Magnitude, Durable Large EGFR ALK N=800 R - 1200 1. Feasibility of screening/enrolling pts for RCT? for pts screening/enrolling of Feasibility 1. 2. Equipoise Lost? Equipoise 2. Platinum doublet Platinum Platinum doublet Platinum + drug X EFFECT CLINICALLY DETECTION “FAILURE” HIGHRISK 30 ) % ( 25 s n Patients with TARGET Gene events by category (%) o i t 0 25 50 75 100 a r 20 e All t l a Common (5% or greater) e 15 Intermediate (2−5%) n e g Rare (Less than 2%) T 10 2 E G R A 5 T 0 3 1 3 4 5 1 2 4 L 2 1 2 2 3 3 1 1 7 1 1 2 1 2 2 1 1 4 1 1 3 1 1 4 4 2 2 6 1 6 2 1 1 1 4 1 L 4 2 2 2 1 1 2 1 1 1 3 1 3 1 1 3 3 1 2 2 2 2 1 L 2 4 5 L 1 1 1 1 2 3 6 F T T T F F A A S P S A B S K K A B B A S A A A A R N C R R R C R R G O Q M I I 5 L L L 1 L 1 L − F T T T T F F T T P 2 A B A S A A K B B B K 1 K A B X L K V 2 K K P 3 V K E K T S V V P B K 1 A H H R H E H R E D H D R 1 H H C R N D D D R R R H H D D H C H D A OR F T A B A A Y O A K C E P R Y R A M M R A T D W O R I K M L B 2 P X K 2 B 2 2 A 3 C K T E T T L A T T C K K A B N Z F F F F N B B A B A A A S 3 N H H C M C R R N N A C N D S S S E N R A S S N S V C D N A R T C C F D R D C R F N N D R N D R R B O S P R A R N R A -
2017 Immuno-Oncology Medicines in Development
2017 Immuno-Oncology Medicines in Development Adoptive Cell Therapies Drug Name Organization Indication Development Phase ACTR087 + rituximab Unum Therapeutics B-cell lymphoma Phase I (antibody-coupled T-cell receptor Cambridge, MA www.unumrx.com immunotherapy + rituximab) AFP TCR Adaptimmune liver Phase I (T-cell receptor cell therapy) Philadelphia, PA www.adaptimmune.com anti-BCMA CAR-T cell therapy Juno Therapeutics multiple myeloma Phase I Seattle, WA www.junotherapeutics.com Memorial Sloan Kettering New York, NY anti-CD19 "armored" CAR-T Juno Therapeutics recurrent/relapsed chronic Phase I cell therapy Seattle, WA lymphocytic leukemia (CLL) www.junotherapeutics.com Memorial Sloan Kettering New York, NY anti-CD19 CAR-T cell therapy Intrexon B-cell malignancies Phase I Germantown, MD www.dna.com ZIOPHARM Oncology www.ziopharm.com Boston, MA anti-CD19 CAR-T cell therapy Kite Pharma hematological malignancies Phase I (second generation) Santa Monica, CA www.kitepharma.com National Cancer Institute Bethesda, MD Medicines in Development: Immuno-Oncology 1 Adoptive Cell Therapies Drug Name Organization Indication Development Phase anti-CEA CAR-T therapy Sorrento Therapeutics liver metastases Phase I San Diego, CA www.sorrentotherapeutics.com TNK Therapeutics San Diego, CA anti-PSMA CAR-T cell therapy TNK Therapeutics cancer Phase I San Diego, CA www.sorrentotherapeutics.com Sorrento Therapeutics San Diego, CA ATA520 Atara Biotherapeutics multiple myeloma, Phase I (WT1-specific T lymphocyte South San Francisco, CA plasma cell leukemia www.atarabio.com -
New ADC Shrinks HER2-Positive Tumors
Published OnlineFirst August 2, 2019; DOI: 10.1158/2159-8290.CD-NB2019-089 NEWS IN BRIEF he says, “I can’t cancer, and 17 had HER2-low HR- fathom that cost.” negative breast cancer. The remaining Cytoplasm –Elie Dolgin n 47 patients had gastric, urothelial, or endometrial tumors. Eye-related side effects were again New ADC prevalent: 71% of patients were Shrinks affected by problems such as conjunc- tivitis, keratitis, and dry eye. These Nuclear pore HER2- adverse effects have been seen with complex Positive other ADCs—although they haven’t Tumors been described with T-DM1—but the mechanism remains unclear, says A novel co-author Philippe Aftimos, MD, of Nucleus antibody–drug the Jules Bordet Institute and the Free conjugate (ADC) University of Brussels in Belgium. Tumor suppressor protein Selective inhibitor of triggers responses nuclear export inhibitor The ADC produced partial + eiF4E-bound mRNA in patients with Regulatory factor XPO1 responses in 33% of the patients with HER2-expressing HER2-positive metastatic breast breast cancer Selinexor is a selective inhibitor of nuclear export. By blocking XPO1, it cancer; 28% with HER2-low, HR- prevents molecular cargo from moving through the nuclear pore complex, and other solid positive metastatic breast cancer; and causing cell-cycle arrest, apoptosis, and other antitumor activity. (Courtesy tumors, a phase I 40% with HER2-low, HR-negative of Karyopharm Therapeutics; modified with permission.) clinical trial metastatic breast cancer. The median indicates (Lancet progression-free survival for these Oncol 2019;20:1124–35). The drug commonly experienced side effects three groups was 7.6 months, such as thrombocytopenia, hypona- could become a new treatment for 4.1 months, and 4.9 months, respec- tremia, anemia, and nausea. -
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%). -
ASCO Virtual • 41 Patient Data (N~70) • Final Results Scientific Program • Incl
A YEAR OF CLINICAL, REGULATORY & COMMERCIAL PROGRESS Corporate Presentation April 7, 2021 Nasdaq / AIM: HCM Safe Harbor Statement & Disclaimer The performance and results of operations of the HUTCHMED Group contained within this presentation are historical in nature, and past performance is no guarantee of future results. This presentation contains forward-looking statements within the meaning of the “safe harbor” believes that the publications, reports, surveys and third-party clinical data are reliable, HUTCHMED has provisions of the U.S. Private Securities Litigation Reform Act of 1995. These forward-looking statements not independently verified the data and cannot guarantee the accuracy or completeness of such data. can be identified by words like “will,” “expects,” “anticipates,” “future,” “intends,” “plans,” “believes,” You are cautioned not to give undue weight to this data. Such data involves risks and uncertainties and “estimates,” “pipeline,” “could,” “potential,” “first-in-class,” “best-in-class,” “designed to,” “objective,” are subject to change based on various factors, including those discussed above. “guidance,” “pursue,” or similar terms, or by express or implied discussions regarding potential drug candidates, potential indications for drug candidates or by discussions of strategy, plans, expectations Nothing in this presentation or in any accompanying management discussion of this presentation or intentions. You should not place undue reliance on these statements. Such forward-looking constitutes, nor is it intended to constitute or form any part of: (i) an invitation or inducement to engage statements are based on the current beliefs and expectations of management regarding future events, in any investment activity, whether in the United States, the United Kingdom or in any other jurisdiction; and are subject to significant known and unknown risks and uncertainties.