DOCSLIB.ORG

Targeted Therapies in B-Cell Non-Hodgkin Lymphomas

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Targeted Therapies in B-Cell Non-Hodgkin Lymphomas REVIEW Targeted therapies in B-cell non-Hodgkin lymphomas The incidence of non-Hodgkin lymphomas has risen in recent years. Although several chemotherapy regimens are efficacious in non-Hodgkin lymphoma, the addition of targeted therapies has become an indispensable part of their treatment. Monoclonal antibodies directed against lymphocytes in different stages of maturation have changed the treatment paradigm for lymphoma. Since these antibodies bind with high affinity to cell surface antigens, they target malignant cells and spare normal tissue, thereby causing less nonspecific toxicity. Rituximab, a monoclonal antibody directed against CD20, was the first antibody to be US FDA-approved for the treatment of lymphoma. Several clinical trials are ongoing that will help to establish the role of targeted agents in the treatment of non-Hodgkin lymphoma. This review provides a summary of targeted agents already approved or in clinical trials for the treatment of non-Hodgkin lymphoma. KEYWORDS: mAbs monoclonal antibodies non-Hodgkin lymphoma Sapna Khubchandani & radioimmunoconjugates rituximab targeted therapies Myron S Czuczman† †Author for correspondence: Roswell Park Cancer Institute, Non-Hodgkin lymphomas (NHLs) are increas- include: DLBCL and its variants, Burkitt lym- Elm and Carlton Streets, ing in incidence and will be diagnosed in more phoma, PTCL, immunodeficiency-associated Buffalo, NY 14263, USA than 55,000 individuals this year alone [1,2]. The lymphoproliferative disorder, precursor B lym- Tel.: +1 716 845 3221 13 most frequent clinical classes recognized in phoblastic leukemia/lymphoma, and precursor Fax: +1 716 845 3894 the lymphoma classification include diffuse T lymphoblastic leukemia/lymphoma [5]. myron.czuczman@ large B-cell lymphoma (DLBCL), follicular roswellpark.org lymphoma (FL), small lymphocytic lymphoma Diffuse large B-cell lymphoma (SLL) mantle cell lymphoma (MCL), periph- Anti-CD20 antibody: rituximab eral T-cell lymphoma (PTCL), marginal B-cell Diffuse large B-cell lymphoma is the most fre- lymphoma of mucosa associated lymphoid tis- quently diagnosed NHL [3]. Cyclophosphamide, sue (MALT), primary mediastinal large B-cell adriamycin, vincristine and prednisone admin- lymphoma, anaplastic large T/null cell lym- istered every 21 days (CHOP-21) used to be the phoma, lymphoblastic lymphoma, Burkitt-like ‘gold standard’ of upfront therapy for DLBCL lymphoma, marginal zone B-cell lymphoma of and resulted in an overall survival of 30–40% the nodal type, lymphoplasmacytic lymphoma at 5 years [6,7]. The addition of rituximab, a and Burkitt lymphoma [3]. therapeutic antibody directed against a pan The ultimate goal of any tumor therapy B-cell antigen CD20, altered the treatment involves the destruction of tumor cells by target- paradigm for DLBCL. Rituximab is a chi- ing tumor-specific surface or intracellular prop- meric anti-CD20 human IgG1 monoclonal erties and thereby sparing normal tissue [4]. In antibody US FDA-approved for treatment of NHL, monoclonal antibodies binding to anti- DLBCL. Phase II studies of rituximab with gens specific to lymphocytes in different stages CHOP (R-CHOP) demonstrated safety in of maturation have recently changed the treat- patients with DLBCL [8,9]. This led to sev- ment paradigms for this disease. Some of the eral prospective, randomized Phase III stud- antigens being targeted include CD20, CD22, ies. In a landmark study of R-CHOP versus CD19, CD37 and CD80 on B-cell surface; and CHOP in previously untreated elderly patients CD52, CD4, CD3 and CD8 on T cells [4]. with DLBCL, the French study group Groupe d’Etude des Lymphomes de l’Adulte (GELA) Antibody-targeted therapy in demonstrated a 7-year progression-free sur- aggressive lymphomas vival of 52% for R-CHOP-21 versus 29% for Aggressive lymphomas are potentially cur- CHOP-21 (p < 0.001), and an overall survival of able with chemotherapy. These lymphomas 53% for R-CHOP-21 versus 36% for CHOP-21 10.2217/THY.09.19 © 2009 Future Medicine Ltd Therapy (2009) 6(3), 371–380 ISSN 1475-0708 371 REVIEW Khubchandani & Czuczman Targeted therapies in B-cell non-Hodgkin lymphomas REVIEW (p = 0.004). Benefit was observed in patients carmustine–cytarabine, etoposide, melphalan with low risk, as well as high-risk, International (BEAM) high-dose therapy and autologous Prognostic Index [10]. stem cell transplant [18]. The Intergroup/Eastern Cooperative Oncology Group trial (ECOG 4494) [11,12] Anti-CD20-based also demonstrated that the addition of rituxi- radioimmunoconjugates mab to CHOP-21 or CHOP-14 significantly One approach to improve the cytotoxic poten- improves the outcome of elderly patients with tial of monoclonal antibodies is to attach them aggressive B-cell lymphomas. In the analysis of to radionuclides to form a radioimmunoconju- this study, R-CHOP significantly decreased the gate. Experience with radioimmunotherapy in risk of treatment failure compared with CHOP NHL is largely limited to the relapsed, refractory alone (hazard ratio: 0.64; 95% CI: 0.47–0.85; settings. Currently, two drugs are registered in p = 0.003) with an estimated failure-free sur- the USA: 90Y-ibritumomab tiuxetan (Zevalin®, vival of 52% for R-CHOP and 39% for CHOP. Genentech [CA, USA] and BiogenIDEC The second random assignment in responders to [MA, USA]) and 131I-tositumomab (Bexxar®; maintenance rituximab failed to demonstrate a GlaxoSmithKline [Middlesex, UK]). benefit after R-CHOP at the initial report and Ibritumomab, a murine anti-CD20 antibody, at follow up in 5.5 years. is labeled to Yttrium-90 to form 90Y-ibritumomab A Canadian population study confirmed the tiuxetan. Unlabeled rituximab is infused prior to overall survival advantage of R-CHOP versus the radiolabeled product to improve biodistribu- CHOP [13]. This was a retrospective study of tion. A nonrandomized multicenter Phase II study patients in the pre-rituximab era treated with was conducted to study the safety and efficacy of a CHOP-like chemotherapy versus the post- single dose of this drug in patients with relapsed/ rituximab era where patients were treated with refractory DLBCL who were not candidates for rituximab 24–72 h after each CHOP infusion. stem cell transplant. The ORR to 90Y-ibritumomab The recently published RICOVER-60 study tiuxetan was 19% in patients who were previously by the German High Grade Lymphoma Study treated with rituximab [19]. The ORR was 52% in Group (DSHNHL) treated elderly patients with patients who failed induction therapy and 53% aggressive lymphomas with 6–8 cycles of CHOP- in patients who relapsed after complete remis- 14 or R-CHOP-14 (time interval between courses sion (CR). The median progression-free survival/ of 14 days) [14]. The best results were seen with overall survival was 5.9 months/21.4 months R-CHOP-14, with event-free survival and overall in those for whom induction therapy failed, survival of 67 and 78%, respectively. 3.5 months/22.4 months in patients who relapsed The Mabthera International Trial (MINT) after CR and 1.6 months/4.6 months in patients study was an international trial in young newly who were treated with chemotherapy and rituxi- diagnosed good-risk patients with DLBCL [15]. mab, respectively. Two patients died of cerebral This study demonstrated that the addition of hemorrhage associated with grade 4 thrombocy- rituximab to six courses of CHOP or CHOP- topenia; 43% patients experienced grade 3 or 4 like chemotherapy improved 3-year event-free hematological toxicities. survival to 79% (95% CI: 75–83) versus 59%, In a Phase I/II trial of 90 Y-ibritumomab (95% CI: 54–64) and increased 3-year sur- tiuxetan the ORR was 43% in patients with vival to 93% (95% CI: 90–95) versus 84% intermediate-grade histology [20]. In long-term (95% CI: 80–88). follow-up, 58% of patients with DLBCL had a response, with a median duration of response of Rituximab in salvage therapy 49.8 months [21]. In a Phase II trial of R-CHOP The standard of care for DLBCL with primary followed by Y-ibritumomab tiuxetan in high-risk refractory or recurrent disease typically involves patients (International Prognostic Index 2 and salvage therapy followed by high-dose therapy 3) the intent to treat overall survival was 63% with stem cell transplantation. In Phase II trials, and event-free survival was 59%. All patients the addition of rituximab to salvage chemother- who received ibritumomab tiuxetan remained apy regimens may improve the overall response relapse-free at a median of 21 months [22]. rate (ORR) with ifosfamide, carboplatin and Tositumomab is a murine monoclonal anti- etoposide (ICE) and dexamethasone, high- body that binds to CD20 and is radiolabeled dose cytarabine and cisplatin (DHAP) [16,17]. to Iodine-131. This has been evaluated in five Currently, a randomized Phase III study is studies in patients who are not candidates for comparing R-DHAP with R-ICE followed by stem cell transplantation and have undergone 372 Therapy (2009) 6(3) future science group REVIEW Khubchandani & Czuczman Targeted therapies in B-cell non-Hodgkin lymphomas REVIEW a median of four prior therapies [23]. A CR rate A US-based Phase II study of lenalidomide of 25% and an ORR of 39% has been observed monotherapy in relapsed or refractory aggres- at a median follow up of 19.4 months. The sive NHL demonstrated an ORR of 34% for median duration of response was 20 months and all patients and 24% for DLBCL patients, with median time to progression was 4.2 months in a median time-to-progression of approximately all patients. 7 months in responders [39]. A larger interna- A Phase I/II trial of tositumomab, in place of tional trial in the same relapsed aggressive B-cell total-body irradiation, in combination with high- lymphoma population has reached accrual and dose etoposide and cyclophosphamide followed preliminary results appear to validate the earlier, by autologous stem cell transplant demonstrated smaller Phase II study [40]. Lenalidomide was promising therapeutic outcomes [24].
Load more

Recommended publications
  • Fig. L COMPOSITIONS and METHODS to INHIBIT STEM CELL and PROGENITOR CELL BINDING to LYMPHOID TISSUE and for REGENERATING GERMINAL CENTERS in LYMPHATIC TISSUES
    (12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT) (19) World Intellectual Property Organization International Bureau (10) International Publication Number (43) International Publication Date Χ 23 February 2012 (23.02.2012) WO 2U12/U24519ft ft A2 (51) International Patent Classification: AO, AT, AU, AZ, BA, BB, BG, BH, BR, BW, BY, BZ, A61K 31/00 (2006.01) CA, CH, CL, CN, CO, CR, CU, CZ, DE, DK, DM, DO, DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, (21) International Application Number: HN, HR, HU, ID, IL, IN, IS, JP, KE, KG, KM, KN, KP, PCT/US201 1/048297 KR, KZ, LA, LC, LK, LR, LS, LT, LU, LY, MA, MD, (22) International Filing Date: ME, MG, MK, MN, MW, MX, MY, MZ, NA, NG, NI, 18 August 201 1 (18.08.201 1) NO, NZ, OM, PE, PG, PH, PL, PT, QA, RO, RS, RU, SC, SD, SE, SG, SK, SL, SM, ST, SV, SY, TH, TJ, TM, (25) Filing Language: English TN, TR, TT, TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, (26) Publication Language: English ZW. (30) Priority Data: (84) Designated States (unless otherwise indicated, for every 61/374,943 18 August 2010 (18.08.2010) US kind of regional protection available): ARIPO (BW, GH, 61/441,485 10 February 201 1 (10.02.201 1) US GM, KE, LR, LS, MW, MZ, NA, SD, SL, SZ, TZ, UG, 61/449,372 4 March 201 1 (04.03.201 1) US ZM, ZW), Eurasian (AM, AZ, BY, KG, KZ, MD, RU, TJ, TM), European (AL, AT, BE, BG, CH, CY, CZ, DE, DK, (72) Inventor; and EE, ES, FI, FR, GB, GR, HR, HU, IE, IS, ΓΓ, LT, LU, (71) Applicant : DEISHER, Theresa [US/US]; 1420 Fifth LV, MC, MK, MT, NL, NO, PL, PT, RO, RS, SE, SI, SK, Avenue, Seattle, WA 98101 (US).
    [Show full text]
  • Psoriasis and the New Biologic Agents: Interrupting a T-AP Dance
    Review Synthèse Psoriasis and the new biologic agents: interrupting a T-AP dance Scott R.A. Walsh, Neil H. Shear Abstract corticosteroids, tar, anthralin, calcipotriol or tazarotene be- come cumbersome to apply as lesional surface area increases. PSORIASIS IS AN IMMUNE-MEDIATED SKIN DISEASE in which chronic T- Furthermore, potential side effects of these therapies increase cell stimulation by antigen-presenting cells (APC) occurs in the with the level of application. Nevertheless, topical treatment skin. This interplay between the T-cell and APC has been likened remains an adjunct in more severe disease to limit the re- to a “T-AP dance” where specific steps must occur in sequence to quirement for more aggressive therapies. Phototherapy is a result in T-cell activation and the disease phenotype; otherwise T- popular option in the treatment of more widespread disease. cell anergy would occur. Several novel engineered proteins de- However, ultraviolet light is generally only available in larger signed to block specific steps in immune activation (biologic treatment centres, requires a major time commitment (2–3 agents) have demonstrated efficacy in the treatment of psoriasis. times per week for many months) and can be associated with These agents include fusion proteins, monoclonal antibodies and an increased risk of cutaneous neoplasms.6 For moderate to recombinant cytokines. These medications act at specific steps during the T-AP dance either to inhibit T-cell activation, costimu- severe disease, oral systemic immunosuppressives such as lation and subsequent proliferation of T-cells, lead to immune de- methotrexate and cyclosporine or oral retinoids are generally viation or induce specific cytokine blockades.
    [Show full text]
  • Siplizumab Induces NK Cell Fratricide Through Antibody-Dependent Cell
    ORIGINAL RESEARCH published: 11 February 2021 doi: 10.3389/fimmu.2021.599526 Siplizumab Induces NK Cell Fratricide Through Antibody- Dependent Cell-Mediated Cytotoxicity Christian Binder 1,2*, Felix Sellberg 1,2, Filip Cvetkovski 2, Stefan Berg 2, Erik Berglund 2,3 and David Berglund 1,2 1 Department of Immunology, Genetics and Pathology, Section of Clinical Immunology, Uppsala University, Uppsala, Sweden, 2 Research and Development, ITB-Med AB, Stockholm, Sweden, 3 Division of Transplantation Surgery, Department of Clinical Science, Intervention and Technology (CLINTEC), Karolinska Institute and Karolinska University Hospital, Stockholm, Sweden The glycoprotein CD2 is expressed on T and NK cells and contributes to cell-cell conjugation, agonistic signaling and actin cytoskeleton rearrangement. CD2 has Edited by: previously been shown to have an important function in natural NK cell cytotoxicity but Carsten Watzl, to be expendable in antibody-mediated cytotoxicity. Siplizumab is a monoclonal anti-CD2 Leibniz Research Centre for Working fi Environment and Human Factors IgG1 antibody that is currently undergoing clinical trials in the eld of transplantation. This (IfADo), Germany study investigated the effect of CD2 binding and Fc g receptor binding by siplizumab (Fc- Reviewed by: active) and Fc-silent anti-CD2 monoclonal antibodies in allogeneic mixed lymphocyte John Pradeep Veluchamy, reaction and autologous lymphocyte culture. Further, induction of NK cell fratricide and VU University Medical Center, Netherlands inhibition of natural cytotoxicity as well as antibody-dependent cytotoxicity by these Kerry S. Campbell, agents were assessed. Blockade of CD2 via monoclonal antibodies in the absence of Fc g Fox Chase Cancer Center, United States receptor binding inhibited NK cell activation in allogeneic mixed lymphocyte reaction.
    [Show full text]
  • Drug Treatments in Psoriasis
    Drug Treatments in Psoriasis Authors: David Gravette, Pharm.D. Candidate, Harrison School of Pharmacy, Auburn University; Morgan Luger, Pharm.D. Candidate, Harrison School of Pharmacy, Auburn University; Jay Moulton, Pharm.D. Candidate, Harrison School of Pharmacy, Auburn University; Wesley T. Lindsey, Pharm.D., Associate Clinical Professor of Pharmacy Practice, Drug Information and Learning Resource Center, Harrison School of Pharmacy, Auburn University Universal Activity #: 0178-0000-13-108-H01-P | 1.5 contact hours (.15 CEUs) Initial Release Date: November 29, 2013 | Expires: April 1, 2016 Alabama Pharmacy Association | 334.271.4222 | www.aparx.org | [email protected] SPRING 2014: CONTINUING EDUCATION |WWW.APARX.Org 1 EducatiONAL OBJECTIVES After the completion of this activity pharmacists will be able to: • Outline how to diagnose psoriasis. • Describe the different types of psoriasis. • Outline nonpharmacologic and pharmacologic treatments for psoriasis. • Describe research on new biologic drugs to be used for the treatment of psoriasis as well as alternative FDA uses for approved drugs. INTRODUCTION depression, and even alcoholism which decreases their quality of Psoriasis is a common immune modulated inflammatory life. It is uncertain why these diseases coincide with one another, disease affecting nearly 17 million people in North America and but it is hypothesized that the chronic inflammatory nature of Europe, which is approximately 2% of the population. The highest psoriasis is the underlying problem. frequencies occur in Caucasians
    [Show full text]
  • Modifications to the Harmonized Tariff Schedule of the United States To
    U.S. International Trade Commission COMMISSIONERS Shara L. Aranoff, Chairman Daniel R. Pearson, Vice Chairman Deanna Tanner Okun Charlotte R. Lane Irving A. Williamson 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 the Dominican Republic- Central America-United States Free Trade Agreement With Respect to Costa Rica Publication 4038 December 2008 (This page is intentionally blank) Pursuant to the letter of request from the United States Trade Representative of December 18, 2008, set forth in the Appendix hereto, and pursuant to section 1207(a) of the Omnibus Trade and Competitiveness Act, the Commission is publishing the following modifications to the Harmonized Tariff Schedule of the United States (HTS) to implement the Dominican Republic- Central America-United States Free Trade Agreement, as approved in the Dominican Republic-Central America- United States Free Trade Agreement Implementation Act, with respect to Costa Rica. (This page is intentionally blank) Annex I Effective with respect to goods that are entered, or withdrawn from warehouse for consumption, on or after January 1, 2009, the Harmonized Tariff Schedule of the United States (HTS) is modified as provided herein, with bracketed matter included to assist in the understanding of proclaimed modifications. The following supersedes matter now in the HTS. (1). General note 4 is modified as follows: (a). by deleting from subdivision (a) the following country from the enumeration of independent beneficiary developing countries: Costa Rica (b).
    [Show full text]
  • I Regulations
    23.2.2007 EN Official Journal of the European Union L 56/1 I (Acts adopted under the EC Treaty/Euratom Treaty whose publication is obligatory) REGULATIONS COUNCIL REGULATION (EC) No 129/2007 of 12 February 2007 providing for duty-free treatment for specified pharmaceutical active ingredients bearing an ‘international non-proprietary name’ (INN) from the World Health Organisation and specified products used for the manufacture of finished pharmaceuticals and amending Annex I to Regulation (EEC) No 2658/87 THE COUNCIL OF THE EUROPEAN UNION, (4) In the course of three such reviews it was concluded that a certain number of additional INNs and intermediates used for production and manufacture of finished pharmaceu- ticals should be granted duty-free treatment, that certain of Having regard to the Treaty establishing the European Commu- these intermediates should be transferred to the list of INNs, nity, and in particular Article 133 thereof, and that the list of specified prefixes and suffixes for salts, esters or hydrates of INNs should be expanded. Having regard to the proposal from the Commission, (5) Council Regulation (EEC) No 2658/87 of 23 July 1987 on the tariff and statistical nomenclature and on the Common Customs Tariff (1) established the Combined Nomenclature Whereas: (CN) and set out the conventional duty rates of the Common Customs Tariff. (1) In the course of the Uruguay Round negotiations, the Community and a number of countries agreed that duty- (6) Regulation (EEC) No 2658/87 should therefore be amended free treatment should be granted to pharmaceutical accordingly, products falling within the Harmonised System (HS) Chapter 30 and HS headings 2936, 2937, 2939 and 2941 as well as to designated pharmaceutical active HAS ADOPTED THIS REGULATION: ingredients bearing an ‘international non-proprietary name’ (INN) from the World Health Organisation, specified salts, esters or hydrates of such INNs, and designated inter- Article 1 mediates used for the production and manufacture of finished products.
    [Show full text]
  • Siplizumab, an Anti-CD2 Monoclonal Antibody, Induces a Unique Set of Immune Modulatory Effects Compared to Alemtuzumab and Rabbit Anti-Thymocyte Globulin in Vitro
    ORIGINAL RESEARCH published: 11 November 2020 doi: 10.3389/fimmu.2020.592553 Siplizumab, an Anti-CD2 Monoclonal Antibody, Induces a Unique Set of Immune Modulatory Effects Compared to Alemtuzumab and Rabbit Anti-Thymocyte Globulin In Vitro 1,2 1,2 2 2,3 Edited by: Christian Binder *, Felix Sellberg , Filip Cvetkovski , Erik Berglund 1,2 Michael Loran Dustin, and David Berglund University of Oxford, United Kingdom 1 Section of Clinical Immunology, Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Reviewed by: Sweden, 2 Research and Development, ITB-Med AB, Stockholm, Sweden, 3 Department of Clinical Science, Intervention and Carla Baan, Technology (CLINTEC), Division of Transplantation Surgery, Karolinska Institute and Karolinska University Hospital, Erasmus University Rotterdam, Stockholm, Sweden Netherlands Takashi MaruYama, National Institutes of Health (NIH), Antibodies are commonly used in organ transplant induction therapy and to treat United States autoimmune disorders. The effects of some biologics on the human immune system *Correspondence: Christian Binder remain incompletely characterized and a deeper understanding of their mechanisms of [email protected] action may provide useful insights for their clinical application. The goal of this study was to contrast the mechanistic properties of siplizumab with Alemtuzumab and rabbit Anti- Specialty section: Thymocyte Globulin (rATG). Mechanistic assay systems investigating antibody-dependent This article was submitted to T Cell Biology, cell-mediated cytotoxicity, antibody-dependent cell phagocytosis and complement- a section of the journal dependent cytotoxicity were used to characterize siplizumab. Further, functional effects Frontiers in Immunology of siplizumab, Alemtuzumab, and rATG were investigated in allogeneic mixed lymphocyte Received: 07 August 2020 Accepted: 14 October 2020 reaction.
    [Show full text]
  • Phase I Trial of Siplizumab in CD-2 Positive Lymphoproliferative Disease
    Phase I Trial of Siplizumab in CD-2 Positive Lymphoproliferative Disease J E Janik1, D O’Mahony1, JC Morris1, L Moses1, D O’Hagan1, W Gao1, M A Stetler-Stevenson1, M Taylor2, L Hammershaimb2 T Waldmann1 1National Cancer Institute, Bethesda, Maryland 2MedImmune Oncology, Inc., Gaithersburg, MD Target for Receptor-directed Therapy CD25 CD2 (IL-2Rα) Malignant CD52 CD122 (IL-2R/IL-15Rβ) or Activated T Cell CD3 CD30 CD4 CD2 • Sheep red blood cell receptor • Binds to LFA3 • Highly expressed on T and NK cells Background • Siplizumab is a humanized IgG1 kappa class monoclonal antibody that binds to the CD2 receptor on human T- and NK-cells. • In an animal model of adult T-cell leukemia/lymphoma (ATL)-fifty percent of animals survived tumor challenge after 4 weeks of siplizumab treatment and the life-span of tumor bearing animals treated for six months was equivalent to that of animals not challenged with tumors. Preclinical Studies of MEDI-507 in ATL Model Zhang, Blood 102:284-8, 2003 Primary Objectives • Determine the maximum tolerated dose (MTD) of MEDI-507 administered to patients with CD2-positive lymphoproliferative disorders. • Determine the safety and tolerability of MEDI-507 in this patient population. Secondary Objectives • Estimate the time course of MEDI-507 saturation of CD2 binding sites in peripheral blood and tumor aspirates. • Determine the serum pharmacokinetics of MEDI-507. • Estimate the time course of T-cell and NK-cell depletion after MEDI-507. • Estimate the time course of T-cell and NK-cell recovery after MEDI-507. • Explore the antitumor activity of MEDI-507 with regard to response rate, time to progression, and overall survival.
    [Show full text]
  • (12) United States Patent (10) Patent No.: US 8,741,861 B2 Mann (45) Date of Patent: Jun
    USOO8741861 B2 (12) United States Patent (10) Patent No.: US 8,741,861 B2 Mann (45) Date of Patent: Jun. 3, 2014 (54) METHODS OF NOVEL THERAPEUTIC McLaughlin et al. Pulmonary arterial hypertension, 2006, Circula CANDDATE DENTIFICATION THROUGH tion, 1.14:1417-1431).* GENE EXPRESSION ANALYSIS IN Vidal et al. Making sense of antisense, 2005, European Journal of VASCULAR-RELATED DISEASES Cancer, 41:2812-18.* Barst et al. Diagnosis and Differential Assessment of pulmonary (75) Inventor: David M. Mann, San Diego, CA (US) arterial hypertension, 2004, Journal of the American College of Car diology, vol.43, No. 12, Supplement S. p. 40S-47S.* (73) Assignee: Vascular Biosciences, San Diego, CA Esau et al., WO 2005/013901 A2, only pp. 1-250 are included.* (US) Chan and Loscalzo, “Pathogenic Mechanisms of Pulmonary Arterial Hypertension.” (2007) Journal of Molecular and Cellular Cardiology (*) Notice: Subject to any disclaimer, the term of this 44:14-30. patent is extended or adjusted under 35 Geracietal., “Gene Expression Patterns in the Lungs of Patients with U.S.C. 154(b) by 177 days. Primary Pulmonary Hypertension: A Gene Microarray Analysis.” (2001) Circulation Research 88:555-562. (21) Appl. No.: 12/934,950 Giaid and Saleh, “Reduced Expression of Endothelial Nitric Oxide Synthase in the Lungs of Patients with Pulmonary Hypertension.” (22) PCT Filed: Mar. 27, 2009 (1995) New England Journal of Medicine 333:214-221. Hoshikawa et al., “Hypoxia Induces Different Genes in the Lungs of (86). PCT No.: PCT/US2O09/038685 Rats Compared with Mice.” (2003) Physiological Genomics 12:209 219. S371 (c)(1), Kwapiszewska et al., “Expression Profiling of Laser-Microdissected (2), (4) Date: Dec.
    [Show full text]
  • Population Pharmacokinetics of Siplizumab (MEDI-507) Implications for Dosing E
    Population Pharmacokinetics of Siplizumab (MEDI-507) Implications for Dosing E. Gibiansky, PhD1; J. Janik, MD2; D. Mahony, MD2; K. Kaucic, MD1; L. Hammershaimb, MD1; G. Robbie, PhD1 1 MedImmune, Inc., Gaithersburg, MD, USA; 2 Metabolism Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA Abstract T-Cell Depletion Data IMPLICATIONS FOR DOSING ◗ Data too sparse for pharmacokinetic/pharmacokinetic (PK/PD) ◗ “Target-mediated” elimination is governed by Objectives: Siplizumab (MEDI-507), a humanized IgG1k class modeling. monoclonal antibody, which targets CD2 expressing T- and • Availability and affinity to target NK-cells, is being evaluated in an ongoing open-label • Efficient depetion of CD4+ and CD8+ T cells in peripheral • Distribution of drug to target outside blood phase I dose-escalation trial in patients with CD2-positive blood at all doses ◗ According to T-cell depletion data drug rapidly kills cells lymphoproliferative diseases. The aim of this report is to • All PD measurements collected at peak effect in blood. describe a population pharmacokinetic model of siplizumab • No PD measurements at trough or between doses ◗ Continued rapid elimination in the absence of target cells and simulations of alternative doses/regimens performed for in blood suggests optimization of dosing. Scaled observed T-cell counts. • presence of target cells in tissues Methods: 490 serum siplizumab samples were collected Predicted serum concentration. • distribution/elimination of drug outside of blood from 25 patients who received 0.4–4.8 mg/kg of siplizumab as ID=6 Cohort=2 1–3 consecutive daily doses every 14 days for 1–8 cycles. 8 g IMPLICATION To maximize drug effect, maintain serum concentrations The population pharmacokinetic analysis was performed using 6 NONMEM.
    [Show full text]
  • 1 Abbreviated Title: Siplizumab/EPOCH-R in T/NK NHL NCI Protocol #: 09C0065 H Version Date: 11/21/2018 NCT Number: NCT01445535 P
    Abbreviated Title: Siplizumab/EPOCH-R in T/NK NHL NCI Version Date: 11/21/2018 Abbreviated Title: Siplizumab/EPOCH-R in T/NK NHL NCI Protocol #: 09C0065 H Version Date: 11/21/2018 NCT Number: NCT01445535 Phase I Trial of Siplizumab and Dose-Adjusted EPOCH-Rituximab (DA-EPOCH-R) in T and NK-Cell Lymphomas NCI Principal Investigator: Wyndham H. Wilson, M.D., Ph.D. A-F Lymphoid Malignancies Branch (LYMB) Center for Cancer Research (CCR) National Cancer Institute (NCI) National Institutes of Health (NIH) Building 10, Room 4N115 Bethesda, MD 20892 Phone: 240-760-6092 Email: [email protected] Investigational Agent: Drug Name: Siplizumab IND Number: 103970 – IND withdrawn 01-22-2013 Sponsor: Dr. Thomas Waldmann Manufacturer: MedImmune Commercial Agents: Etoposide, Prednisone, Vincristine, Cyclophosphamide, Doxorubicin, Rituximab 1 Abbreviated Title: Siplizumab/EPOCH-R in T/NK NHL NCI Version Date: 11/21/2018 PRÉCIS Background: x The clinical outcome for patients with T-cell non-Hodgkin’s lymphoma is significantly inferior to the outcome of patients with B-cell non-Hodgkin’s lymphoma. In most reports less than 20% of patients with T cell lymphoid malignancies remain free of disease at 5 years. x The combination of alemtuzumab and EPOCH chemotherapy was evaluated in patients with chemotherapy naïve aggressive T and NK cell lymphoid malignancy. Dose-limiting bone marrow toxicity prevented escalation of the alemtuzumab dose. x Siplizumab is a humanized monoclonal antibody directed at CD2 that demonstrated activity in the treatment of relapsed/refractory T cell lymphoma, suggesting further development by combining with chemotherapy for untreated patients. Siplizumab caused EBV lymphoproliferative disease in patients treated with a weekly schedule of administration.
    [Show full text]
  • INN Working Document 05.179 Update 2011
    INN Working Document 05.179 Update 2011 International Nonproprietary Names (INN) for biological and biotechnological substances (a review) INN Working Document 05.179 Distr.: GENERAL ENGLISH ONLY 2011 International Nonproprietary Names (INN) for biological and biotechnological substances (a review) Programme on International Nonproprietary Names (INN) Quality Assurance and Safety: Medicines Essential Medicines and Pharmaceutical Policies (EMP) International Nonproprietary Names (INN) for biological and biotechnological substances (a review) © World Health Organization 2011 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; email: [email protected]). Requests for permission to reproduce or translate WHO publications – whether for sale or for noncommercial 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]