DOCSLIB.ORG

Multiple Myeloma Therapies What Lies in the Future?

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Multiple Myeloma Therapies What Lies in the Future? Multiple Myeloma Therapies What lies in the future? Parameswaran Hari MD, MS Chief , Hematology Oncology Medical College of Wisconsin Conflict of Interest Am a consultant or advisor and grant recipient from virtually every company that works in the Myeloma field Framework for Newly Diagnosed MM—Patient Treatment Plan Eligibility for Transplant: Co-morbidities PS Age Transplant Candidate Not Transplant Candidate Induction Therapy Induction therapy Stem Cell Harvest Maintenance or extended therapy phase ASCT (early vs delayed) Consolidation and/or Maintenance MAINTENANCE AFTER TRANSPLANT: A MUST! CALGB IFM 2005-02 REF:https://www.fda.gov/drugs/informationondrugs/approveddrugs/ucm542791.htm TRANSPLANT STUDIES IN MM (NOVEL ERA) Study Author Year N ISS III High risk Follow-up Induction Conditioning SDT Maintenance cytogenetics (months) regimen (HDT +SDT) LEN (till GIMEMA RV- Palumbo 2014 273 23.6% 28.8% 51.2 Rd Mel 200 x 2 MPR progression) MM –PI-209 TRANSPLANT for MM– Continues to remain standard vs. None LEN + P vs. LEN RV-MM-EMN- Gay F 2015 256 29% 21.8% 52 Rd MEL 200 x 2 CRD (till 441 progression) IFM/DFCI Attal M 2015 700 18% 12.8% 44 RVD MEL 200 RVD x 8 LEN x 1 year 2009 LEN till EMN02/HO95 Cavo M 2016 1192 21% 25% 26 CyBorD MEL 200 x 1 or 2 VMP x 4 progression MINIMAL RESIDUAL DISEASE AND TRANSPLANT ARMS MRD negativity (%) HDT (EARLY) 79% SDT (DELAYED) 65% Attal et al. NEJM 2017 Minimal Residual Disease: New Definitions for CR 12 S.S. Patient Newly diagnosed 1 x 10 Disease burden CR 1 x 108 Stringent CR 1 x 104 Molecular/flow CR Sequencing CR True Cure? 0.0 FDA Approved MRD testing VACCINE POST TRANSPLANT(CTN 1401) TREATMENT MILESTONES IN MULTIPLE MYELOMA Kenneth C. Anderson Clin Cancer Res 2016;22:5419-5427 11 Prehistory Myeloma • Multiple myeloma has probably been present as a Four cases of possible multiple myeloma human disease for centuries. were found in Native American skeletons • There is evidence that multiple myeloma might date from 200 to 900AD. back to the time of the ancient Egyptians. Xray and skull 25 yrold female Indian with lytic lesions. Estimated to be from 200 to 900 AD. Anticancer Res.1999; Vol;19(5B):4273-7 Bull NY Acad Med. 1974; Vol 50. p 447-458. Clinical Trials ………………. MAKING MYELOMA History New Drugs – Are they Chemotherapy? CD38 ANTIBODIES TRANSPLANT INELGIBILBE- WHAT IS NEW? CAN WE MOVE DARATUMUMAB UPFRONT? INDUCTION TRANSPLANT CONSOLIDATION MAINTENANCE STEM CELL Dara-VRD X 2 Dara +LEN Dara-VRD x4 TRANSPLANT MMY2004 RANDOMZIED PHASE II TRIAL RANDOMIZE VRD x4 STEM CELL TRANSPLANT VRD X2 LEN ALCYONE STUDY DESIGN VMP × 9 cycles (n = 356) Bortezomib: 1.3 mg/m2 SC Cycle 1: twice weekly Cycles 2-9: once weekly Melphalan: 9 mg/m2 PO on Days 1-4 Primary endpoint: Key eligibility criteria: Prednisone: 60 mg/m2 PO on Days 1-4 •PFS •Transplant- ineligible Secondary endpoints: NDMM Follow-up for •ECOG 0-2 PD and •ORR •Creatinine clearance survival •≥VGPR rate ≥40 mL/min D-VMP × 9 cycles (n = 350) D •≥CR rate • –5 No peripheral Cycles 10+ •MRD (NGS; 10 ) neuropathy grade ≥2 Daratumumab: 16 mg/kg IV •OS 1:1 Randomization (N 1:1= 706)Randomization •Safety Cycle 1: once weekly 16 mg/kg IV Cycles 2-9: every 3 weeks + Every 4 weeks: Same VMP schedule until PD Stratification factors Statistical analyses •ISS (I vs II vs III) • 360 PFS events: 85% power for • Cycles 1-9: 6-week cycles •Region (EU vs other) 8-month PFS improvementa • Cycles 10+: 4-week cycles •Age (<75 vs ≥75 years) • Interim analysis: ~216 PFS events ECOG, Eastern Cooperative Oncology Group; ISS, International Staging System; EU, European Union; SC, subcutaneously; PO, orally; D, daratumumab; IV, intravenously; PD, progressive disease; PFS, progression-free survival; ORR, overall response rate; VGPR, very good partial response; CR, complete response; MRD, minimal residual disease; NGS, next-generation sequencing; OS, overall survival. a8-month PFS improvement over 21-month median PFS of VMP. EFFICACY:PFS • Median (range) follow-up: 16.5 (0.1-28.1) months 12-month PFSa 18-month PFSa 100 87% 80 72% 76% D-VMP 60 Median: not reached 40 50% VMP Median: 18.1 months % surviving without progression without % surviving 20 HR, 0.50 (95% CI, 0.38-0.65; P <0.0001) 0 0 3 6 9 12 15 18 21 24 27 Months No. at risk VMP 356 303 276 261 231 127 61 18 2 0 D-VMP 350 322 312 298 285 179 93 35 10 0 50% reduction in the risk of progression or death in patients receiving D-VMP HR, hazard ratio; CI, confidence interval. aKaplan-Meier estimate. 21 QUIZ Walgreens Enema Syringe Relapsed, Refractory Disease: New Agents CURREN TREAMENTS OPTIONS-- for relapse • DARATUMAB-REVLIMID-DEXAMETHASONE • DARATUMUMAB-VELCADE-DEXAMETHASONE • DARATUMUMAB-POMALIDOMIDE-DEXAMETHASONE • CARFILZOMOB-REVLIMID-DEXAMETAHSONE • ELOTUZUMAB-REVLIMID-DEXAMETHASONE • IXAZOMIB-REVLIMID-DEXAMETAHSONE Prevention Trials Phases of Clinical Trials Diagnostic Trials Screening Trials Quality of Life Trials • Phase I studies primarily concerned with assessing the drug's safety. How much can be safely given? • Phase II test for efficacy. How well does the drug work in this disease? • Phase III – How well does the new drug compare against standard treatment? Don’t wait for other people – Jump in Not all trials succeed …….. MAN – O - GRAM SELINEXOR . Exportin 1 (XPO1) is the nuclear exporter for the majority of tumor suppressor proteins (TSPs), the glucocorticoid receptor (GR), and eIF4E-bound oncoprotein mRNAs . Selinexor is a first-in-class XPO1 inhibitor that induces nuclear retention and activation of TSPs and the GR in the presence of steroids and suppresses oncoprotein expression SELINEXOR: EFFICACY ORR CBR VGPR PR MR Category N (%) (%) (%) (%) (%) Overall 78 16 (21%) 26 (33%) 4 (5%) 12 (15%) 10 (13%) Quad 48 10 (21%) 14 (29%) 2 (4%) 8 (17%) 4 (8%) Refractory Penta 30 6 (20%) 12 (40%) 2 (7%) 4 (13%) 6 (20%) Refractory 6 Doses / 51 10 (20%) 15 (29%) 3 (6%) 7 (14%) 5 (10%) Month 8 Doses / 27 6 (22%) 11 (41%) 1 (4%) 5 (19%) 5 (19%) Month Vogl DT, et al. Blood. 2016;128:491. VENETOCLAX • Venetoclax induces cell death in multiple myeloma (MM) cell lines and primary samples, particularly those positive for the translocation t(11;14), which correlates with higher ratios of 1,2 BCL2 to MCL1 and BCL2 to BCL2L1 (BCL-XL) mRNA 1. Touzeau C, et al. Leukemia. 2014;28(1):210-212. 2. Punnoose E, et al. Mol Cancer Ther. 2016;15(5):1132-1144. VENETOCLAX: EFFICACY 5 0 T im e to P ro g re s s io n D u ra tio n o f O v e ra ll R e s p o n s e sC R C R V G P R P R 1 0 0 A ll P a tie n ts 1 0 0 A ll P a tie n ts O R R 4 0 % t(1 1 ;1 4 ) t(1 1 ;1 4 ) 4 0 d s t 4% e n o n -t(1 1 ;1 4 ) n o n -t(1 1 ;1 4 ) s n 7 5 7 5 s e i e t r a 1 0 % g P 3 0 o 5 0 r 5 0 f P o t e O R R 2 1 % o g N a 2 5 2 5 t 2 0 3% 1 3 % % n e 4% c r 0 e 0 P 1 0 8% 0 2 4 6 8 1 0 1 2 1 4 1 6 1 8 2 0 2 2 2 4 0 2 4 6 8 1 0 1 2 1 4 1 6 1 8 2 0 2 2 2 4 O R R 6 % 1 3 % M o n th s s in c e firs t d o s e M o n th s s in c e fir s t re s p o n s e 3% 6% 3% N o . a t ris k 6 6 3 3 2 7 2 0 1 6 9 3 1 1 1 1 1 1 4 1 4 1 3 1 3 9 3 2 1 1 1 1 0 N o . a t ris k 3 0 2 0 1 9 1 7 1 3 7 2 1 1 1 1 1 1 2 1 2 1 1 1 1 8 3 2 1 1 1 1 A ll P a t ie n t s t( 1 1 ; 1 4 ) n o n - t ( 1 1 ; 1 4 ) N o . a t ris k 3 6 1 3 8 3 3 2 1 2 2 2 2 1 N = 6 6 n = 3 0 n = 3 6 Kumar S, et al. Blood. 2016;128:488. BCMA – THE NEW TARGET BCMA expressed on normal and malignant plasma cells • Promotes MM cell survival BCMA-targeted therapies, including CAR T cells, show pre-clinical and early clinical activity in myeloma Penn/Novartis CART-BCMA cells • Autologous T cell product • Human anti-BCMAscFv • CD3ζ /41BB stimulatory domains • Lentiviral vector • CD3/CD28 bead-stimulated manufacturing Tai et al, Blood 2014; Carpenter et al, Clin Can Res 2013; Tai et al, Blood 2016; Ali et al, Blood 2016; Cohen et al, ASH 2016, #1147; Lin et al, EHA 2017; Fan et al ASCO 2017, #LBA3001; Singh R et al. submitted 2017 Pagel, J JAMA Oncol 2017 BCMA CAR-T Ali SA, et al. Blood. 2016;128:1688-1700. 37 TUMOR RESPONSE 6 • *15 U 17/18 (94%) ORR, 10/18 (56%) 14 CR at active doses 11 • 9/10 evaluable patients MRD 800 x10 800 negative *12 † *21 • Durable ongoing responses over *18 6 1 year *16 *13 PD • Responses continue to improve *10 U as late as month 15 (VGPR to CR) 450 x10 450 7 PD *9 • Median PFS not reached in active 8 dose cohorts – 4 patients progressed 19 PD – Median follow up 40 weeks 6 *20 17 PD 4 † CR/sCR VGPR PR 150 x10 150 *6 U 5 Stable PD MRD- Disease 6 *3 PD † Deceased U Unconfirmed MRD+ *2 PD † † response 1 PD † High Tumor Burden (>50% Bone Marrow Involvement) 50 x 10 50 * 0 4 8 12 16 20 24 28 32 36 40 44 48 52 56 60 64 68 72 Patient 12 died of cardiopulmonary arrest Weeks on Study Patient 4 died of MDS following discontinuation 38 SELECT TREATMENT EMERGENT TOXICITIES • No dose-limiting toxicities (DLTs) observed in Dose Escalation Patients dose escalation (N = 21)1 • Cytopenias mostly related to Cy/Flu lymphodepletion Overall Grade 3 or higher Preferred Term – Recovery to Grade < 3 cytopenias by n (%) n (%) Month 2 following infusion: • ANC ≥ 1000/mm3 – 70% of patients Cytokine release syndrome 15 (71) 2 (10) • PLT ≥ 75/mm3 – 75% of patients Neurotoxicity2 5 (24) 0 • 5 deaths Neutropenia 18 (86) 18 (86) – 3 due to disease progression at 50 × 106 dose Thrombocytopenia 11 (52) 9 (43) – 2 in patients treated at active doses in CR Anemia 14 (67) 12 (57) at the time of death (cardiac arrest, MDS following discontinuation) • 1Data cut-off of October 2, 2017 14 patients experienced 1 or more SAEs 2Neurotoxicity includes the preferred terms: depressed level of consciousness, confusional state, bradyphrenia, somnolence
Load more

Recommended publications
  • Predictive QSAR Tools to Aid in Early Process Development of Monoclonal Antibodies
    Predictive QSAR tools to aid in early process development of monoclonal antibodies John Micael Andreas Karlberg Published work submitted to Newcastle University for the degree of Doctor of Philosophy in the School of Engineering November 2019 Abstract Monoclonal antibodies (mAbs) have become one of the fastest growing markets for diagnostic and therapeutic treatments over the last 30 years with a global sales revenue around $89 billion reported in 2017. A popular framework widely used in pharmaceutical industries for designing manufacturing processes for mAbs is Quality by Design (QbD) due to providing a structured and systematic approach in investigation and screening process parameters that might influence the product quality. However, due to the large number of product quality attributes (CQAs) and process parameters that exist in an mAb process platform, extensive investigation is needed to characterise their impact on the product quality which makes the process development costly and time consuming. There is thus an urgent need for methods and tools that can be used for early risk-based selection of critical product properties and process factors to reduce the number of potential factors that have to be investigated, thereby aiding in speeding up the process development and reduce costs. In this study, a framework for predictive model development based on Quantitative Structure- Activity Relationship (QSAR) modelling was developed to link structural features and properties of mAbs to Hydrophobic Interaction Chromatography (HIC) retention times and expressed mAb yield from HEK cells. Model development was based on a structured approach for incremental model refinement and evaluation that aided in increasing model performance until becoming acceptable in accordance to the OECD guidelines for QSAR models.
    [Show full text]
  • Modifications to the Harmonized Tariff Schedule of the United States to Implement Changes to the Pharmaceutical Appendix
    United States International Trade Commission Modifications to the Harmonized Tariff Schedule of the United States to Implement Changes to the Pharmaceutical Appendix USITC Publication 4208 December 2010 U.S. International Trade Commission COMMISSIONERS Deanna Tanner Okun, Chairman Irving A. Williamson, Vice Chairman Charlotte R. Lane Daniel R. Pearson Shara L. Aranoff Dean A. Pinkert Address all communications to Secretary to the Commission United States International Trade Commission Washington, DC 20436 U.S. International Trade Commission Washington, DC 20436 www.usitc.gov Modifications to the Harmonized Tariff Schedule of the United States to Implement Changes to the Pharmaceutical Appendix Publication 4208 December 2010 (This page is intentionally blank) Pursuant to the letter of request from the United States Trade Representative of December 15, 2010, set forth at the end of this publication, and pursuant to section 1207(a) of the Omnibus Trade and Competitiveness Act, the United States International Trade Commission is publishing the following modifications to the Harmonized Tariff Schedule of the United States (HTS) to implement changes to the Pharmaceutical Appendix, effective on January 1, 2011. Table 1 International Nonproprietary Name (INN) products proposed for addition to the Pharmaceutical Appendix to the Harmonized Tariff Schedule INN CAS Number Abagovomab 792921-10-9 Aclidinium Bromide 320345-99-1 Aderbasib 791828-58-5 Adipiplon 840486-93-3 Adoprazine 222551-17-9 Afimoxifene 68392-35-8 Aflibercept 862111-32-8 Agatolimod
    [Show full text]
  • New Biological Therapies: Introduction to the Basis of the Risk of Infection
    New biological therapies: introduction to the basis of the risk of infection Mario FERNÁNDEZ RUIZ, MD, PhD Unit of Infectious Diseases Hospital Universitario “12 de Octubre”, Madrid ESCMIDInstituto de Investigación eLibraryHospital “12 de Octubre” (i+12) © by author Transparency Declaration Over the last 24 months I have received honoraria for talks on behalf of • Astellas Pharma • Gillead Sciences • Roche • Sanofi • Qiagen Infections and biologicals: a real concern? (two-hour symposium): New biological therapies: introduction to the ESCMIDbasis of the risk of infection eLibrary © by author Paul Ehrlich (1854-1915) • “side-chain” theory (1897) • receptor-ligand concept (1900) • “magic bullet” theory • foundation for specific chemotherapy (1906) • Nobel Prize in Physiology and Medicine (1908) (together with Metchnikoff) Infections and biologicals: a real concern? (two-hour symposium): New biological therapies: introduction to the ESCMIDbasis of the risk of infection eLibrary © by author 1981: B-1 antibody (tositumomab) anti-CD20 monoclonal antibody 1997: FDA approval of rituximab for the treatment of relapsed or refractory CD20-positive NHL 2001: FDA approval of imatinib for the treatment of chronic myelogenous leukemia Infections and biologicals: a real concern? (two-hour symposium): New biological therapies: introduction to the ESCMIDbasis of the risk of infection eLibrary © by author Functional classification of targeted (biological) agents • Agents targeting soluble immune effector molecules • Agents targeting cell surface receptors
    [Show full text]
  • B-Cell Targets to Treat Antibody-Mediated Rejection In
    Muro et al. Int J Transplant Res Med 2016, 2:023 Volume 2 | Issue 2 International Journal of Transplantation Research and Medicine Commentary: Open Access B-Cell Targets to Treat Antibody-Mediated Rejection in Transplantation Manuel Muro1*, Santiago Llorente2, Jose A Galian1, Francisco Boix1, Jorge Eguia1, Gema Gonzalez-Martinez1, Maria R Moya-Quiles1 and Alfredo Minguela1 1Immunology Service, University Clinic Hospital Virgen de la Arrixaca, Spain 2Nephrology Service, University Clinic Hospital Virgen de la Arrixaca, Spain *Corresponding author: Manuel Muro, PhD, Immunology Service, University Clinic Hospital “Virgen de la Arrixaca”, Biomedical Research Institute of Murcia (IMIB), Murcia, Spain, Tel: 34-968-369599, E-mail: [email protected] Antibody-mediated rejection (AMR) in allograft transplantation APRIL (a proliferation-inducing ligand). These co-activation signals can be defined with a rapid increase in the levels of specific are required for B-cell differentiation into plasma cell and enhancing serological parameters after organ transplantation, presence of donor their posterior survival and are a key determinant of whether specific antibodies (DSAs) against human leukocyte antigen (HLA) developing B-cells will survive or die during the establishment molecules, blood group (ABO) antigens and/or endothelial cell of immuno-tolerance [5,6]. Important used agents commercially antigens (e.g. MICA, ECA, Vimentin, or ETAR) and also particular available are Tocilizumab (anti-IL6R) and Belimumab (BAFF). histological parameters [1,2]. If the AMR persists or progresses, the The receptors of BAFF and APRIL could also be important as treatment to eliminate the humoral component of acute rejection eventual targets, for example BAFF-R, TACI (transmembrane include three sequential steps: (a) steroid pulses, antibody removal activator and calcium modulator and cyclophyllin ligand interactor) (plasma exchange or immuno-adsorption) and high doses of and BCMA (B-cell maturation antigen).
    [Show full text]
  • Highlights from the Pan Pacific Lymphoma Conference
    October 2011 A SPECIAL MEETING REVIEW EDITION Volume 9, Issue 10, Supplement 24 Highlights From the Pan Pacific Lymphoma Conference August 15–19, 2011 Kauai, Hawaii Special Reporting on: • Aggressive T-Cell Lymphomas • Novel Agents With Activity in CLL/SLL • PTCL—Update on Novel Therapies • Agents Targeting the Stromal Elements of the Lymph Node • Inducing Apoptosis in Lymphoma Cells Through Novel Agents With Expert Commentary by: Bruce D. Cheson, MD Deputy Chief Division of Hematology-Oncology Head of Hematology Lombardi Comprehensive Cancer Center Georgetown University Hospital Washington, DC Eb: E W Th O N www.clinicaladvances.com ENGINEERING T H E N E X T GENERATION OF ANTIBODY-DRUG CONJUGATES 003203_sgncor_adcadvcaho_fa4.indd 2 8/25/11 11:13 AM An innovative approach to improving outcomes in patients with cancer Antibody-drug conjugates (ADCs) use a conditionally stable linker to combine the targeting specificity of monoclonal antibodies with the tumor-killing power of potent cytotoxic agents.1,2 This could allow potent drugs to be delivered directly to tumor cells with minimal systemic toxicity. Optimizing the parameters for clinical success Scientists at Seattle Genetics are focused on parameters critical to the effective performance of ADCs, including target antigen selection,3,4 linker stability5-7 and potent cytotoxic agents.4,7,8 Elements of an antibody-drug conjugate Linker ADCs link precision and Antibody attaches the cytotoxic agent to specific for a tumor-associated the antibody. Newer linker potency for greater activity
    [Show full text]
  • An Analysis of Toxicity and Response Outcomes from Dose
    Brock et al. BMC Cancer (2021) 21:777 https://doi.org/10.1186/s12885-021-08440-0 RESEARCH ARTICLE Open Access Is more better? An analysis of toxicity and response outcomes from dose-finding clinical trials in cancer Kristian Brock1* ,VictoriaHomer1, Gurjinder Soul2, Claire Potter1,CodyChiuzan3 and Shing Lee3 Abstract Background: The overwhelming majority of dose-escalation clinical trials use methods that seek a maximum tolerable dose, including rule-based methods like the 3+3, and model-based methods like CRM and EWOC. These methods assume that the incidences of efficacy and toxicity always increase as dose is increased. This assumption is widely accepted with cytotoxic therapies. In recent decades, however, the search for novel cancer treatments has broadened, increasingly focusing on inhibitors and antibodies. The rationale that higher doses are always associated with superior efficacy is less clear for these types of therapies. Methods: We extracted dose-level efficacy and toxicity outcomes from 115 manuscripts reporting dose-finding clinical trials in cancer between 2008 and 2014. We analysed the outcomes from each manuscript using flexible non-linear regression models to investigate the evidence supporting the monotonic efficacy and toxicity assumptions. Results: We found that the monotonic toxicity assumption was well-supported across most treatment classes and disease areas. In contrast, we found very little evidence supporting the monotonic efficacy assumption. Conclusions: Our conclusion is that dose-escalation trials routinely use methods whose assumptions are violated by the outcomes observed. As a consequence, dose-finding trials risk recommending unjustifiably high doses that may be harmful to patients. We recommend that trialists consider experimental designs that allow toxicity and efficacy outcomes to jointly determine the doses given to patients and recommended for further study.
    [Show full text]
  • Monoclonal Antibody-Based Therapy As a New Treatment Strategy in Multiple Myeloma
    Leukemia (2012) 26, 199–213 & 2012 Macmillan Publishers Limited All rights reserved 0887-6924/12 www.nature.com/leu REVIEW Monoclonal antibody-based therapy as a new treatment strategy in multiple myeloma NWCJ van de Donk1, S Kamps1, T Mutis2 and HM Lokhorst1 1Department of Hematology, University Medical Center Utrecht, Utrecht, The Netherlands and 2Department of Clinical Chemistry and Hematology, University Medical Center Utrecht, Utrecht, The Netherlands The introduction of autologous stem cell transplantation the myeloma patients achieved a partial response (PR) or stable combined with the introduction of immunomodulatory drugs disease following rituximab therapy. All these patients expressed (IMiDs) and proteasome inhibitors has significantly improved CD20 on their myeloma cells.2 However, as only B15–20% of survival of multiple myeloma patients. However, ultimately the majority of patients will develop refractory disease, indicating all myeloma patients express CD20 on their bone marrow the need for new treatment modalities. In preclinical and clinical plasma cells, new targets for immunotherapy need to be studies, promising results have been obtained with several identified. The search for other targets has led to the develop- monoclonal antibodies (mAbs) targeting the myeloma tumor ment of mAbs targeting growth factor receptors or adhesion cell or the bone marrow microenvironment. The mechanisms molecules on myeloma cells. Other newly developed mAbs underlying the therapeutic efficacy of these mAbs include are directed against cellular or non-cellular components of the direct induction of tumor cell apoptosis via inhibition or activation of target molecules, complement-dependent cyto- bone marrow microenvironment, resulting in the neutraliza- toxicity and antibody-dependent cell-mediated cytotoxicity tion of growth factors, inhibition of angiogenesis, modulation (ADCC).
    [Show full text]
  • GRP78-Directed Immunotherapy in Relapsed Or Refractory Multiple Myeloma - Results from a Phase 1 Trial with the Monoclonal Immunoglobulin M Antibody PAT-SM6
    Plasma Cell Disorders ARTICLES GRP78-directed immunotherapy in relapsed or refractory multiple myeloma - results from a phase 1 trial with the monoclonal immunoglobulin M antibody PAT-SM6 Leo Rasche,1 Johannes Duell,1 Inês C. Castro,2 Valentina Dubljevic,3 Manik Chatterjee,1 Stefan Knop,1 Frank Hensel,2 Andreas Rosenwald,4 Hermann Einsele,1 Max S. Topp,1* and Stephanie Brändlein4* 1Department of Internal Medicine II, University Hospital Würzburg, Germany; 2Patrys GmbH, Würzburg, Germany; 3Patrys Ltd., Melbourne, Australia; and 4Institute of Pathology, University of Würzburg, Germany, and Comprehensive Cancer Center Mainfranken, Germany *MST and SB contributed equally to this work. ABSTRACT The primary objective of this phase 1 study was to evaluate the safety and tolerability of the anti-glucose regulated protein 78 monoclonal immunoglobulin M antibody PAT-SM6 in subjects with relapsed or refractory multiple myeloma. Twelve heavily pretreated patients received four intravenous infusions of PAT-SM6 at doses of 0.3, 1, 3, and 6 mg/kg within 2 weeks. Efficacy, pharmacokinetics and immunogenicity were followed up until the end of the trial (day 36). In addition, immune cell patterns in peripheral blood were assessed by flow cytometry and glu- cose regulated protein 78 expression status was evaluated in bone marrow specimens by immunohistochemistry and flow cytometry at screening. All doses administered were found to be safe and well tolerated; the maximum tolerated dose was not reached. The most common treatment emergent adverse event was leukopenia (grades 1 and 2) in eight out of the 12 multiple myeloma patients. Pharmacokinetic analysis demonstrated dose-proportional increases in drug serum concentration.
    [Show full text]
  • Monoclonal Antibody Therapy for Classical Hodgkin Lymphoma
    Review: Clinical Trial Outcomes Monoclonal antibody therapy for classical Hodgkin lymphoma Clin. Invest. (2013) 3(9), 899–910 Major advances in the treatment of B-cell lymphoma resulting from the Ewa Paszkiewicz-Kozik & introduction of a monoclonal antibody to the CD20 antigen 15 years Jan Walewski* ago have left Hodgkin lymphoma (HL) aside. This has changed with the Department of Lymphoid Malignancies, The success of the anti-CD30 antibody conjugated with an antitubulin agent, Maria Sklodowska–Curie Memorial Institute & Oncology Centre, 5 Roentgen Street, 02–781 brentuximab vedotin, recently approved for the treatment of adult Warsaw, Poland + patients with relapsed or refractory CD30 HL following autologous stem *Author for correspondence: cell transplantation (ASCT) or following at least two prior therapies when Tel.: +48 22 546 3248 ASCT or for which multi-agent chemotherapy is not a treatment option. Fax: +48 22 546 3250 The magnitude of clinical activity of the new antibody has also prompted E-mail: [email protected] research on biologic functions of the CD30 molecule, as well as exploring other potential targets present on multinucleated Reed–Sternberg cells and the surrounding inflammatory area for a range of antibodies. This article will review the accumulating clinical data on the use of monoclonal antibodies in the treatment of classical HL with focus on CD20 and CD30 targets. We describe possible mechanisms of action, efficacy and toxicity related to administration of rituximab, brentuximab vedotin, daclizumab and other antibodies investigated in Phase I and II trials for classical HL. Keywords: brentuximab vedotin • CD20 • CD25 • CD30 • daclizumab • Hodgkin lymphoma • monoclonal antibodies • rituximab The treatment of B-cell lymphoid malignancies was revolutionized 15 years ago by the advent of the monoclonal antibody to the CD20 antigen.
    [Show full text]
  • Ep 3178848 A1
    (19) TZZ¥__T (11) EP 3 178 848 A1 (12) EUROPEAN PATENT APPLICATION (43) Date of publication: (51) Int Cl.: 14.06.2017 Bulletin 2017/24 C07K 16/28 (2006.01) A61K 39/395 (2006.01) C07K 16/30 (2006.01) (21) Application number: 15198715.3 (22) Date of filing: 09.12.2015 (84) Designated Contracting States: (72) Inventor: The designation of the inventor has not AL AT BE BG CH CY CZ DE DK EE ES FI FR GB yet been filed GR HR HU IE IS IT LI LT LU LV MC MK MT NL NO PL PT RO RS SE SI SK SM TR (74) Representative: Cueni, Leah Noëmi et al Designated Extension States: F. Hoffmann-La Roche AG BA ME Patent Department Designated Validation States: Grenzacherstrasse 124 MA MD 4070 Basel (CH) (71) Applicant: F. Hoffmann-La Roche AG 4070 Basel (CH) (54) TYPE II ANTI-CD20 ANTIBODY FOR REDUCING FORMATION OF ANTI-DRUG ANTIBODIES (57) The present invention relates to methods of treating a disease, and methods for reduction of the formation of anti-drug antibodies (ADAs) in response to the administration of a therapeutic agent comprising administration of a Type II anti-CD20 antibody, e.g. obinutuzumab, to the subject prior to administration of the therapeutic agent. EP 3 178 848 A1 Printed by Jouve, 75001 PARIS (FR) EP 3 178 848 A1 Description Field of the Invention 5 [0001] The present invention relates to methods of treating a disease, and methods for reduction of the formation of anti-drug antibodies (ADAs) in response to the administration of a therapeutic agent.
    [Show full text]
  • (INN) for Biological and Biotechnological Substances
    INN Working Document 05.179 Update 2013 International Nonproprietary Names (INN) for biological and biotechnological substances (a review) INN Working Document 05.179 Distr.: GENERAL ENGLISH ONLY 2013 International Nonproprietary Names (INN) for biological and biotechnological substances (a review) International Nonproprietary Names (INN) Programme Technologies Standards and Norms (TSN) Regulation of Medicines and other Health Technologies (RHT) Essential Medicines and Health Products (EMP) International Nonproprietary Names (INN) for biological and biotechnological substances (a review) © World Health Organization 2013 All rights reserved. Publications of the World Health Organization are available on the WHO web site (www.who.int ) or can be purchased from WHO Press, World Health Organization, 20 Avenue Appia, 1211 Geneva 27, Switzerland (tel.: +41 22 791 3264; fax: +41 22 791 4857; e-mail: [email protected] ). Requests for permission to reproduce or translate WHO publications – whether for sale or for non-commercial distribution – should be addressed to WHO Press through the WHO web site (http://www.who.int/about/licensing/copyright_form/en/index.html ). The designations employed and the presentation of the material in this publication do not imply the expression of any opinion whatsoever on the part of the World Health Organization concerning the legal status of any country, territory, city or area or of its authorities, or concerning the delimitation of its frontiers or boundaries. Dotted lines on maps represent approximate border lines for which there may not yet be full agreement. The mention of specific companies or of certain manufacturers’ products does not imply that they are endorsed or recommended by the World Health Organization in preference to others of a similar nature that are not mentioned.
    [Show full text]
  • Ep 3321281 A1
    (19) TZZ¥¥ _ __T (11) EP 3 321 281 A1 (12) EUROPEAN PATENT APPLICATION (43) Date of publication: (51) Int Cl.: 16.05.2018 Bulletin 2018/20 C07K 14/79 (2006.01) A61K 38/40 (2006.01) A61K 38/00 (2006.01) A61K 38/17 (2006.01) (2006.01) (2006.01) (21) Application number: 17192980.5 A61K 39/395 A61K 39/44 C07K 16/18 (2006.01) (22) Date of filing: 03.08.2012 (84) Designated Contracting States: • TIAN, Mei Mei AL AT BE BG CH CY CZ DE DK EE ES FI FR GB Coquitlam, BC V3J 7E6 (CA) GR HR HU IE IS IT LI LT LU LV MC MK MT NL NO • VITALIS, Timothy PL PT RO RS SE SI SK SM TR Vancouver, BC V6Z 2N1 (CA) (30) Priority: 05.08.2011 US 201161515792 P (74) Representative: Gowshall, Jonathan Vallance Forresters IP LLP (62) Document number(s) of the earlier application(s) in Skygarden accordance with Art. 76 EPC: Erika-Mann-Strasse 11 12746240.6 / 2 739 649 80636 München (DE) (71) Applicant: biOasis Technologies Inc Remarks: Richmond BC V6X 2W8 (CA) •This application was filed on 25.09.2017 as a divisional application to the application mentioned (72) Inventors: under INID code 62. • JEFFERIES, Wilfred •Claims filed after the date of receipt of the divisional South Surrey, BC V4A 2V5 (CA) application (Rule 68(4) EPC). (54) P97 FRAGMENTS WITH TRANSFER ACTIVITY (57) The present invention is related to fragments of duction of the melanotransferrin fragment conjugated to human melanotransferrin (p97). In particular, this inven- a therapeutic or diagnostic agent to a subject.
    [Show full text]