DOCSLIB.ORG

Phase I Clinical Trial of Selinexor in Combination with Daunorubicin

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Phase I Clinical Trial of Selinexor in Combination with Daunorubicin Published OnlineFirst October 21, 2019; DOI: 10.1158/1078-0432.CCR-19-2169 CLINICAL CANCER RESEARCH | CLINICAL TRIALS: TARGETED THERAPY Phase I Clinical Trial of Selinexor in Combination with Daunorubicin and Cytarabine in Previously Untreated Poor-Risk Acute Myeloid Leukemia Kendra Sweet1, Rami Komrokji1, Eric Padron1, Christopher L. Cubitt2, Joel G. Turner3, Junmin Zhou4, Alan F. List1, David A. Sallman1, Jana L. Dawson5, Daniel M. Sullivan3, Julio Chavez1, Bijal D. Shah1, and Jeffrey E. Lancet1 ABSTRACT ◥ Purpose: Induction chemotherapy results in complete and recommended phase II dose of selinexor were the primary remission (CR) rates of 20% to 50% among patients with endpoints. poor-risk AML. Selinexor is an oral selective inhibitor of Results: Twenty-one patients with poor-risk AML were nuclear export with promising single-agent activity. By inhi- enrolled. All 21 patients were included in the safety evaluations biting the primary export protein, XPO1, selinexor localizes and survival analyses (4 in each of 2 cohorts; 13 in the expansion); and activates tumor suppressor proteins in the nucleus and 8 (53%) of the 19 patients evaluable for response achieved CR/CRi. inhibits DNA damage repair, rationalizing combination with MTD was not reached. Selinexor 80 mg (orally, twice weekly) was DNA-damaging agents. used in the expansion phase. The most common grade 3/4 Patients and Methods: This was a single-arm phase I nonhematologic treatment-emergent adverse events were febrile clinical trial of selinexor combined with cytarabine and dau- neutropenia (67%), diarrhea (29%), hyponatremia (29%), and norubicin (7þ3). Dose escalation was selinexor alone (3þ3) sepsis (14%). At median follow-up (28.9 months), 38% of patients with an expansion at the MTD. Cohorts 1 and 2 received 60 were alive. Median overall survival was 10.3 months. and 80 mg orally, respectively, twice weekly during induction. Conclusions: Selinexor plus 7þ3 is a safe regimen for patients Consolidation cycles ( 2) with selinexor at induction dose with newly diagnosed poor-risk AML and warrants further inves- plus 5þ2 were allowed for patients who achieved CR. MTD tigation in a larger clinical trial. Introduction the inactivation of TSPs, allowing malignant cells to evade apopto- sis (3). XPO1 is overexpressed in AML cells, and increased levels of Acute myeloid leukemia (AML) is a clonal hematopoietic disorder XPO1 are inversely correlated with overall survival (OS) in patients characterized by a block in myeloid differentiation and aberrant with AML (4). proliferation of immature myeloid progenitors. An inherent feature Selective inhibitors of nuclear export (SINE) compounds are orally of these self-renewing leukemia-initiating cells is their resistance to bioavailable small molecules that function by covalently binding to chemotherapy, which contributes to disease relapse (1). Nuclear– cysteine 528 in the cargo-binding pocket of the XPO1 protein. This cytoplasmic protein transport is required to maintain normal intra- prevents XPO1 from binding to the nuclear export signal of proteins, cellular signaling and cell-cycle regulation (2). Exportin 1 (XPO1/ thereby preventing the loading and nuclear export of cargo proteins. CRM1) is the sole nuclear export protein responsible for the cyto- The resulting nuclear retention, accumulation, and activation of TSPs plasmic translocation of nearly all tumor suppressor proteins (TSP) restore the tumor suppressor function, leading to apoptosis and cell- and growth regulators, including p53, p21, p27, forkhead box O3 cycle arrest of tumor cells, as well as forced differentiation of myeloid (FOXO3), and nucleophosmin 1 (NPM1). This nuclear export leads to blasts. These effects are seen in bulk tumor cells and leukemia- initiating cells (1, 5–8). Another client of XPO1 is the protein topo- isomerase IIa. Cytoplasmic localization of topoisomerase IIa is a well- 1Department of Malignant Hematology, H. Lee Moffitt Cancer Center and documented mechanism of chemotherapy resistance in multiple Research Institute, Tampa, Florida. 2Department of Translational Research, H. myeloma and AML (9). Selinexor (KPT-330) is a SINE compound Lee Moffitt Cancer Center and Research Institute, Tampa, Florida. 3Department that has been extensively studied in laboratories by using AML cell of Blood and Marrow Transplant and Cellular Immunotherapy, H. Lee Moffitt lines, AML patient cells, and mouse models. Selinexor is reported to 4 Cancer Center and Research Institute, Tampa, Florida. Department of Immu- block XPO1, leading to nuclear retention of cargo proteins, including nology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida. 5Department of Experimental Therapeutics, H. Lee Moffitt Cancer Center and TSPs, and restore their functions. Selinexor also restores topoisom- Research Institute, Tampa, Florida. erase IIa in the nucleus and synergistically sensitizes cells to topo- isomerase II inhibitors, such as idarubicin, daunorubicin, etoposide, Note: Supplementary data for this article are available at Clinical Cancer Research Online (http://clincancerres.aacrjournals.org/). and mitoxantrone (3, 6, 10). The nuclear retention of topoisomerase IIa causes downregulation of DNA repair proteins, such as Rad51 and Corresponding Author: Kendra L. Sweet, H. Lee Moffitt Cancer Center and Research Institute, 12902 USF Magnolia Drive, Tampa, FL 33612. Phone: 813-745- Chk1, and results in increased lethal DNA double-strand breaks in the 6841; Fax: 813-745-3071; E-mail: kendra.sweet@moffitt.org presence of topoisomerase II inhibitors (10). When given sequentially with chemotherapy, selinexor appears to synergize with many DNA- Clin Cancer Res 2019;XX:XX–XX damaging agents (including idarubicin, daunorubicin, mitoxantrone, doi: 10.1158/1078-0432.CCR-19-2169 etoposide, and fludarabine), especially when the selinexor exposure Ó2019 American Association for Cancer Research. precedes that of the other drugs. Preclinical studies completed at our AACRJournals.org | OF1 Downloaded from clincancerres.aacrjournals.org on September 24, 2021. © 2019 American Association for Cancer Research. Published OnlineFirst October 21, 2019; DOI: 10.1158/1078-0432.CCR-19-2169 Sweet et al. Selinexor was given 2 hours before daunorubicin on days 1 and 3 on the Translational Relevance basis of preclinical studies, suggesting that selinexor sensitizes leuke- This clinical trial studied a group of patients with AML with very mic blasts to chemotherapy (3). During the dose escalation phase, poor-risk disease. Treatment options for these patients are limited patients who did not receive at least 5 doses of selinexor, in the absence and are often ineffective. The preclinical rationale for the combi- of a dose-limiting toxicity (DLT), were replaced. nation of drugs used was strong. This is the first clinical trial Reinduction was permitted for patients with residual leukemia seen completed using this combination in this clinical setting, and the on a day 21 bone marrow biopsy, provided a 50% reduction in the results are encouraging. The safety profile of this treatment com- total blast count from baseline was observed. Reinduction consisted of bination was acceptable for this particular group of patients, and administration of daunorubicin (45 mg/m2/day) on days 1 and 2 and the clinical responses suggest that the combination therapy may be cytarabine (100 mg/m2/day) as a continuous intravenous infusion on more effective than standard chemotherapy regimens alone. The days 1 through 5 (5þ2 regimen). Selinexor was given at the same dose results of this clinical trial justify a larger clinical trial with this as induction on days 1, 3, 8, and 10. On day 1, selinexor was given combination therapy. 2 hours before daunorubicin administration. Patients who achieved complete remission (CR) or CR with incom- plete blood count recovery (CRi) were allowed to receive up to 2 cycles of consolidation therapy, consisting of 5þ2 with selinexor given at the institution using AML cell lines and AML patient cells indicated strong same dose as induction on days 1, 3, 8, and 10. synergistic interactions between selinexor and daunorubicin, and these Patients were permitted to discontinue their participation in the data rationalized the development of this clinical trial (Supplementary study and proceed to allogeneic hematopoietic stem cell transplant Figs. S1 and S2; Supplementary Table S1). Several early-phase trials (HSCT) at any time after achieving CR/CRi. Patients who did not have studied selinexor in AML both as a single agent and in combi- undergo HSCT could subsequently receive maintenance therapy nation with chemotherapy and report encouraging results (6, 11–13). consisting of selinexor at the same dose as induction on days 1 and This phase I study (NCT02403310) was conducted to further assess 8 of a 21 day cycle for up to 17 cycles (12 months). the role of selinexor in patients with previously untreated, poor-risk Supportive care measures were established to manage side-effects. AML when administered in combination with cytarabine and dau- These included the use of prophylactic antibiotics, antifungal agents, norubicin. The aim of the study was to identify the MTD and the and antivirals. Nausea was managed with antiemetics as needed and, recommended phase II dose (RP2D) of selinexor and to assess the for some patients, nausea management consisted of empiric treatment safety profile and preliminary signals of efficacy with this combination. with olanzapine (5 mg) taken orally at bedtime beginning 24
Load more

Recommended publications
  • Bulletin L'académie Nationale De Médecine
    Tome 202 — Mai et Juin — N os 5-6 2018 BULLETIN DE L’ACADÉMIE NATIONALE DE MÉDECINE publié par MM. Daniel C, Secrétaire perpétuel et Jean François A , Secrétaire adjoint Rédacteur en chef : Professeur Jean-Noël F Adjointe à la Rédaction : Sibylle du C ACADÉMIE NATIONALE DE MÉDECINE 16, RUE BONAPARTE — 75272 PARIS CEDEX 06 http://www.academie-medecine.fr 2018 — Tome 202 — Mai-Juin — N os 5-6 Sommaire BULLETIN DE L’ACADÉMIE NATIONALE DE MÉDECINE publié par MM. Daniel C, Secrétaire perpétuel et Jean François A , Secrétaire adjoint Rédacteur en chef : Professeur Jean-Noël F Adjointe à la Rédaction : Sibylle du C sommaire Rapports 817 Rapport 18-03. Efficacité et effets indésirables des statines : évidences et polémiques Efficacy and side effects of statin therapy: a reappraisal Michel Komajda, au nom de la Commission IV (Maladies cardiovasculaires) 837 Rapport 18-04. La place de la France dans les essais cliniques à promotion industrielle Yvon Lebranchu (Rapporteur), Au nom d’un groupe de travail rattaché à la Commission II (Thérapeutique-Pharmacologie-Toxicologie-Médicaments et autres produits de santé) 859 Rapport 18-05. La biologie médicale face aux défis de l’évolution des besoins de santé Medical biology in the face of the evolution of health care needs Claude Dreux, François-Xavier Maquart (rapporteurs), au nom du groupe de travail inter-académique de l’Académie nationale de médecine et de l’Aca- démie nationale de Pharmacie. 873 Rapport 18-06. La demande d’une nouvelle orientation (rhumatologie) par l’établissement thermal de Vals-les-Bains Daniel Bontoux et Christian Roques 811 Académie nationale de Médecine Communiqué 883 À propos de la dépénalisation de la consommation de cannabis Jean-Pierre.
    [Show full text]
  • Phase I Study of Selinexor in Combination With
    Phase I study of selinexor in combination with dexamethasone, ifosfamide, carboplatin, etoposide chemotherapy in patients with relapsed or refractory peripheral T-cell or natural-killer/T-cell lymphoma by Tiffany Tang, Peter Martin, Nagavalli Somasundaram, Cindy Lim, Miriam Tao, Eileen Poon, Maica J.D. Yunon, Shu Q. Toh, Sean X. Yan, Mohamad Farid, Jason Y. Chan, and Soon T. Lim Haematologica 2020 [Epub ahead of print] Citation: Tiffany Tang, Peter Martin, Nagavalli Somasundaram, Cindy Lim, Miriam Tao, Eileen Poon, Maica J.D. Yunon, Shu Q. Toh, Sean X. Yan, Mohamad Farid, Jason Y. Chan, and Soon T. Lim. Phase I study of selinexor in combination with dexamethasone, ifosfamide, carboplatin, etoposide chemotherapy in patients with relapsed or refractory peripheral T-cell or natural-killer/T-cell lymphoma. Haematologica. 2020; 105:xxx doi:10.3324/haematol.2020.251454 Publisher's Disclaimer. E-publishing ahead of print is increasingly important for the rapid dissemination of science. Haematologica is, therefore, E-publishing PDF files of an early version of manuscripts that have completed a regular peer review and have been accepted for publication. E-publishing of this PDF file has been approved by the authors. After having E-published Ahead of Print, manuscripts will then undergo technical and English editing, typesetting, proof correction and be presented for the authors' final approval; the final version of the manuscript will then appear in print on a regular issue of the journal. All legal disclaimers that apply to the journal also pertain to this production process. Article type: Original Article Title: Phase I study of selinexor in combination with dexamethasone, ifosfamide, carboplatin, etoposide chemotherapy in patients with relapsed or refractory peripheral T-cell or natural- killer/T-cell lymphoma.
    [Show full text]
  • Selinexor (Xpovio™) (Updated November 2019)
    selinexor (Xpovio™) EOCCO POLICY Policy Type: PA/SP Pharmacy Coverage Policy: EOCCO086 Description Selinexor (Xpovio) is an oral nuclear export inhibitor. Length of Authorization Initial: Six months Renewal: 12 months Quantity Limits Product Name Dosage Form Indication Quantity Limit 80 mg tablet twice weekly carton 1 carton (32 tablets)/28 days 100 mg tablet once weekly carton 1 carton Relapsed or (20 tablets)/28 days 80 mg tablet once weekly carton refractory multiple 1 carton myeloma (MM) (16 tablets)/28 days selinexor 60 mg tablet once weekly carton 1 carton (Xpovio) (12 tablets)/28 days 40 mg tablet once weekly carton 1 carton (8 tablets)/28 days 60 mg tablet twice weekly carton Relapsed or 1 carton refractory diffuse (24 tablets)/28 days 40 mg tablet twice weekly carton large B-cell 1 carton lymphoma (DLBCL) (16 tablets)/28 days Initial Evaluation I. Selinexor (Xpovio) may be considered medically necessary when the following criteria are met: A. Member is 18 years of age or older; AND B. Medication is prescribed by, or in consultation with, a hematologist or oncologist; AND C. Not used in combination with any other oncology therapy unless outlined below; AND D. A diagnosis of multiple myeloma when ONE of the following are met: 1. The provider attests to the following: i. The member has received ONE, but no more than THREE previous therapies; AND 1 selinexor (Xpovio™) EOCCO POLICY a. Previous treatments included at least one of the following medications: i. Bortezomib (Velcade) ii. Carfilzomib (Kyprolis) iii. Ixazomib (Ninlaro) iv. Daratumumab (Darzalex) v. Immunomodulatory agent (e.g., lenalidomide, pomalidomide); AND b.
    [Show full text]
  • Targeting CRM1 in AML (Presented at ESH – Budapest)
    Targeting CRM1 in AML Gert Ossenkoppele & colleagues VU University Medical Center Amsterdam Approved Treatment Options for AML Compared to Other Hematologic Malignancies US approvals EU approvals Subsequently withdrawn Non-Hodgkin Lymphoma Acute Lymphoblastic Leukemia Multiple Myeloma Chronic Lymphocytic Leukemia Chronic Myeloid Leukemia Acute Myeloid Leukemia 1995 2000 2005 2010 2015 1. NCI Drug Info. http://www.cancer.gov/cancertopics/druginfo. 2. EMA Drug Approvals. http://www.ema.europa.eu/ema/index.jsp?curl=pages/includes/medicines/medicines_landing_page.jsp&mid=. 3. FDA Drug Approvals. http://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm.. 3. NCCN clinical practice guidelines in oncology: acute myeloid leukemia. National Comprehensive Cancer Network website. V.2.2014. http://www.nccn.org/professionals/physician_gls/PDF/aml.pdf Selective Inhibitors of Nuclear Export(SINE) (SINE) • Cancer cells can inactivate their Tumor Suppressor Proteins (TSPs) via nuclear export • Exportin 1 (XPO1, CRM1) is the exclusive nuclear exporter of most TSPs • XPO1 is elevated in Acute Myeloid Leukemia (AML), Chronic Lymphocytic Leukemia (CLL), NHL and other malignancies • Selinexor (KPT-330) is a covalent, oral Selective Inhibitor of Nuclear Export (SINE) that blocks XPO1 Selinexor: Novel Anti-Cancer Agent: Restores Tumor Suppressors & Reduces Oncoproteins Cell Membrane CYTOPLASM Tumor Suppressors XPO-1 Tumor Suppressors p53 Par-4 PP2A pRB Nuclear Pore Complex p21 SINE IkB Nuclear Envelope BRCA1 p27 Tumor Suppressors elF4E (myc,bcl2) Selinexor:
    [Show full text]
  • Selinexor for the Treatment of Triple- Class Refractory Multiple Myeloma
    Karyopharm Therapeutics Inc. ODAC Briefing Document Selinexor (KPT-330) 26 February 2019 Meeting SELINEXOR FOR THE TREATMENT OF TRIPLE- CLASS REFRACTORY MULTIPLE MYELOMA FDA ADVISORY COMMITTEE MEETING BRIEFING DOCUMENT ONCOLOGIC DRUGS ADVISORY COMMITTEE MEETING DATE: 26 FEBRUARY 2019 For Public Disclosure 1 of 132 Karyopharm Therapeutics Inc. ODAC Briefing Document Selinexor (KPT-330) 26 February 2019 Meeting 1. Executive Summary Karyopharm Therapeutics, Inc (Karyopharm) is seeking approval of selinexor, an oral, first-in class, exportin 1 (XPO1) inhibitor, in combination with low-dose dexamethasone for the treatment of patients with relapsed refractory multiple myeloma (RRMM) who have received at least 3 prior therapies and whose disease is refractory to at least 1 proteasome inhibitor (PI), at least 1 immunomodulatory imide drug (IMiD), and an anti- CD38 monoclonal antibody (mAb). This disease is referred to as “triple-class refractory” multiple myeloma (MM), and patients with this disease have exhausted all treatment options known to be effective. Selinexor has a unique mechanism of action that offers a new pathway for treating RRMM by selectively inhibiting XPO1, reactivating tumor suppressing proteins, and inducing tumor cell apoptosis. It is a slowly reversible covalent inhibitor of XPO1 dosed orally twice weekly. Selinexor in combination with low-dose dexamethasone (Sel+dex) produces clinically meaningful responses in patients with triple-class refractory MM who have exhausted all effective treatment options. Karyopharm has submitted a New Drug Application (NDA) for selinexor using the Accelerated Approval regulatory pathway, which allows drugs for serious conditions that fill an unmet medical need to be approved based on a surrogate endpoint (overall response rate; ORR) that is reasonably likely to predict a clinical benefit.
    [Show full text]
  • Annexes to the Annual Report of the European Medicines Agency 2014
    Annexes to the annual report of the European Medicines Agency 2014 Table of contents Annex 1 – Members of the Management Board ............................................................................. 2 Annex 2 – Members of the Committee for Medicinal Products for Human Use ................................... 4 Annex 3 – Members of the Pharmacovigilance Risk Assessment Committee ...................................... 6 Annex 4 – Members of the Committee for Medicinal Products for Veterinary Use ............................... 8 Annex 5 – Members of the Committee on Orphan Medicinal Products ............................................ 10 Annex 6 – Members of the Committee on Herbal Medicinal Products .............................................. 12 Annex 07 – Committee for Advanced Therapies .......................................................................... 14 Annex 8 – Members of the Paediatric Committee ........................................................................ 16 Annex 9 – Working parties and working groups .......................................................................... 18 Annex 10 – CHMP opinions in 2014 on medicinal products for human use ...................................... 22 Annex 11 – CVMP opinions in 2014 on medicinal products for veterinary use .................................. 36 Annex 12 – COMP opinions in 2014 on designation of orphan medicinal products ............................ 41 Annex 13 – HMPC European Union herbal monographs in 2014....................................................
    [Show full text]
  • Selinexor) for the Treatment of Patients with Relapsed Or Refractory Multiple Myeloma
    July 5, 2019 Karyopharm Announces FDA Approval of XPOVIOTM (selinexor) for the Treatment of Patients with Relapsed or Refractory Multiple Myeloma This information is intended to notify the press release issued on July 3 (ET) by Karyopharm Therapeutics Inc. Please click http://investors.karyopharm.com/press-releases for the original press release distributed by Karyopharm. 1st paragraph of the press release: (NEWTON, Mass., July 3, 2019) -- Karyopharm Therapeutics Inc. (Nasdaq: KPTI), an oncology- focused pharmaceutical company, today announced that the U.S. Food and Drug Administration (FDA) has approved oral XPOVIOTM (selinexor), a nuclear export inhibitor, in combination with dexamethasone for the treatment of adult patients with relapsed or refractory multiple myeloma (RRMM) who have received at least four prior therapies and whose disease is refractory to at least two proteasome inhibitors, at least two immunomodulatory agents, and an anti-CD38 monoclonal antibody. This indication is approved under accelerated approval based on response rate. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial. The ongoing, randomized Phase 3 BOSTON study evaluating selinexor in combination with Velcade® (bortezomib) and low-dose dexamethasone will serve as the confirmatory trial. The FDA’s Accelerated Approval Program was developed to allow for expedited approval of drugs that treat serious conditions and that fill an unmet medical need. About the Ono and Karyopharm Collaboration In October 2017, Ono Pharmaceutical Co., Ltd. concluded an exclusive license agreement with Karyopharm Therapeutics Inc. for the development and commercialization of Selinexor, their first-in- class oral XPO1 (Exportin 1) inhibitor, and Eltanexor/KPT-8602, a second-generation oral XPO1 inhibitor, for all oncology indications exclusively in Japan, South Korea, Taiwan, Hong Kong and ASEAN countries.
    [Show full text]
  • Weekly Selinexor, Bortezomib and Dexamethasone (Svd)
    Weekly Selinexor, Bortezomib and Dexamethasone (SVd) Versus Twice Weekly Bortezomib and Dexamethasone (Vd) in Patients with Multiple Myeloma (MM) After 1–3 Prior Therapies: Initial Results of the Phase 3 BOSTON Study Meletios A. Dimopoulos1, Sosana Delimpasi2, Maryana Simonova3, Ivan Spicka4, Ludek Pour5, Iryna Kriachok6, Maria Gavriatopoulou7, Halyna Pylypenko8, Holger W. Auner9, Xavier Leleu10, Vadim Doronin11, Polina Kaplan12, Roman Hajek13, Benjamin Reuben14, Tuphan Kanti Dolai15, Dinesh Kumar Sinha16, Melina Arazy17, Paul G. Richardson18, Nizar J. Bahlis19, Sebastian Grosicki20 1National and Kapodistrian University of Athens School of Medicine, Athens, Greece; 2General Hospital Evangelismos, Athens, Greece; 3Institute of Blood Pathology & Transfusion Medicine of National Academy of Medical Sciences of Ukraine, Lviv, Ukraine; 4Charles University and General Hospital, Prague, Czech Republic; 5Fakultní Nemocnice Brno, Brno, Czech Republic; 6National Cancer Institution, Kiev, Ukraine; 7Alexandra Hospital, School of Medicine, National and Kapodistrian University of Athens, Athens, Greece; 8Department of Hematology, Cherkassy Regional Oncological Center, Cherkassy, Ukraine; 9Imperial College London, London, United Kingdom; 10Department of Hematology, CHU la Miletrie and Inserm CIC 1402, Poitiers, France; 11City Clinical Hospital #40, Moscow, Russian Federation; 12City Clinical Hospital#4, Dnipro, Ukraine; 13Department of Hemato-oncology, University Hospital Ostrava, University of Ostrava, Ostrava, Czech Republic; 14Kings College Hospital
    [Show full text]
  • The Potential of XPO1 Inhibitors As a Game Changer in Relapsed/Refractory Hematologic Malignancies
    Aging Pathobiology and Therapeutics 2020; 2(2):109-113 109 DOI: 10.31491/APT.2020.06.023 BRIEF Creative Commons 4.0 The potential of XPO1 inhibitors as a game changer in relapsed/refractory hematologic malignancies Henan Wanga, Jing Yanga, Liang Wanga,* a Department of Hematology, Beijing Tongren Hospital, Capital Medical University, Beijing 100730, China. Abstract XPO1 is a transporter receptor protein that transports leucine-rich proteins from the nucleus into the cyto- plasm through the nuclear pore complex. In hematologic malignancies, XPO1 is often overexpressed, leading to abnormal regulation of cell growth and apoptosis or abnormal cell cycle regulation. Therefore, XPO1 inhibi- tors can be used as targeted drugs to block the transport of overexpressed XPO1, thus treating hematologic malignancies. We summarized the use of XPO1 inhibitors in clinical studies according to different hematologic Keywords: XPO1 inhibitor, hematologic malignancies, selinexor, targeted therapy malignancies and reviewed their efficacy and toxicity. Introduction containing cargo and forms a ternary complex with RanGTP, passing through NPCs and entering the cyto- The nucleus is an organelle that coats genetic material plasm. The XPO1-cargo protein, which is driven by GTP with a double membrane, separating transcription in the hydrolysis, contains almost all tumor suppressor proteins nucleus from translation in the cytoplasm. To achieve (TSPs; such as p53, Rb, BRCA1/2, APC, and survivin), adequate cellular function, this spatial division in eukary- cell cycle regulatory proteins (such as p21, p27, and ga- otic cells requires selective and efficient bidirectional lactin-3), the glucocorticoid receptor (GR), and chemo- transport of specific proteins and mRNAs through nuclear therapy targets (such as DNA topoisomerase) [1-2].
    [Show full text]
  • A Phase 1 Study of Selinexor in Combination with Paclitaxel and Carboplatin in Patients with Advanced Ovarian Or Endometrial
    A Phase 1 Study of Selinexor in Combination with Paclitaxel and Carboplatin in Patients with Advanced Ovarian or Endometrial Cancers Makker V1, Martin M1, Zhou Q2, Iasonos A2, Cadoo K1, Grisham R1, Hyman DM1, O’Cearbhaill RE1, Snyder Charen A1, Tew WP1, Leitao MM3 , Bonafede M1, Boucicaut N1, Aghajanian C1 1 2 3 Poster 970P Gynecologic Medical Oncology Service Department of Biostatistics Department of Surgery, Memorial Sloan Kettering Cancer Center and Weill Cornell Medical College, New York, NY BACKGROUND METHODS RESULTS •This is a single-institution, open label, Phase I study. NCT02269293 This ongoing study has enrolled 16 patients (data cutoff: August 25, 2017) with Table 6: Tumor Response by RECIST 1.1 • XPO1 is a major nuclear export protein for tumor suppressor proteins •3+3 dose escalation design for each of 4 regimens. baseline characteristics shown in Table 2 and tumor genomic testing results of Patient ID Parameter Number 15 (%) (TSPs), including p53, p73, FOXO, pRB, BRCA1 and PP2A. •Patients with OC received 1 prior platinum therapy. EC/ECS pts in Table 3. All patients experienced an adverse event (AE). A summary 014 Complete Response 1 (6.7) • Selective Inhibitor of Nuclear Export (SINE) compounds inhibit XPO1, •Patients with EC and endometrial carcinosarcomas (ECS) could be of AEs is shown in Tables 4 & 5. Efficacy outcomes are summarized in Table 6 leading to nuclear retention of TSPs and selective tumor cell apoptosis. chemotherapy naïve or have received 1 prior platinum-based therapy. with an objective response rate of 73.3%. The duration of treatment and overall time 002, 004, 005, 006, 008, 009, Partial Response 10 (66.7) • Selinexor (S) is a first-in-class oral, covalent SINE compound.
    [Show full text]
  • Assessment Report
    28 January 2021 EMA/CHMP/95252/2021 Committee for Medicinal Products for Human Use (CHMP) Assessment report Nexpovio International non-proprietary name: selinexor Procedure No. EMEA/H/C/005127/0000 Note Assessment report as adopted by the CHMP with all information of a commercially confidential nature deleted. Official address Domenico Scarlattilaan 6 ● 1083 HS Amsterdam ● The Netherlands Address for visits and deliveries Refer to www.ema.europa.eu/how-to-find-us Send us a question Go to www.ema.europa.eu/contact Telephone +31 (0)88 781 6000 An agency of the European Union © European Medicines Agency, 2021. Reproduction is authorised provided the source is acknowledged. Table of contents 1. Background information on the procedure .............................................. 8 1.1. Submission of the dossier ...................................................................................... 8 1.2. Steps taken for the assessment of the product ....................................................... 10 2. Scientific discussion .............................................................................. 12 2.1. Problem statement .......................................................................................... 12 2.1.1. Disease or condition ......................................................................................... 12 2.1.2. Epidemiology .................................................................................................. 12 2.1.3. Biologic features .............................................................................................
    [Show full text]
  • Selinexor, Lenalidomide and Dexamethasone (Srd) for Patients with Relapsed/Refractory and Newly Diagnosed Multiple Myeloma
    Selinexor, Lenalidomide and Dexamethasone (SRd) for Patients with Relapsed/Refractory and Newly Diagnosed Multiple Myeloma Darrell J White MD1, Richard LeBlanc MD FRCPC2, Muhamed Baljevic MD3, Nizar Bahlis MD4, Suzanne Lentzsch MD PhD5, Christopher P Venner MD6, Cristina Gasparetto MD7, Christine I Chen MD8, Brea C. Lipe MD9, Sascha A Tuchman MD10, Heather J. Sutherland MD PhD11, Rami Kotb MD12, Michael Sebag MD PhD13, Natalie Scott Callander MD14, William I. Bensinger MD15, Adriana C. Rossi MD16, Noa Biran17, Heidi Sheehan18, Dane Van Domelen PhD18, Tianjun Zhou MD PhD18, Kazuharu Kai MD PhD18, Jatin Shah MD18, Sharon Shacham PhD MBA18, Michael G. Kauffman MD PhD18, Gary J. Schiller MD19 1Queen Elizabeth II Health Sciences Centre and Dalhousie University, Halifax, NS; 2 Maisonneuve-Rosemont Hospital, University of Montreal, QC, Canada; 3Department of Internal Medicine, Division of Oncology and Hematology, University of Nebraska Medical Center, Omaha, NE; 4Charbonneau Cancer Research Institute, Calgary, AB, Canada; 5Division of Hematology/Oncology, Columbia University, New York, NY; 6Cross Cancer Institute, Edmonton, AB; 7Duke University Cancer Center, Durham, NC; 8Princess Margaret Cancer Centre, Toronto, ON; 9University of Rochester, Rochester, NY; 10University of North Carolina, Chapel Hill, NC; 11Vancouver General Hospital, Vancouver, BC; 12Cancer Care Manitoba, Winnipeg, MB; 13McGill University Health Centre, Montréal, QC; 14University of Wisconsin, Carbone Cancer Center, Madison, WI; 15Swedish Cancer Institute, Seattle, WA; 16NYPH
    [Show full text]