DOCSLIB.ORG

Day Dosing of the Proteasome Inhibitor Carfilzomib in Patients with Relapsed Or Refractory Multiple Myeloma Or Lymphoma

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Day Dosing of the Proteasome Inhibitor Carfilzomib in Patients with Relapsed Or Refractory Multiple Myeloma Or Lymphoma Published OnlineFirst July 3, 2012; DOI: 10.1158/1078-0432.CCR-11-3007 Clinical Cancer Cancer Therapy: Clinical Research A Phase I Single-Agent Study of Twice-Weekly Consecutive- Day Dosing of the Proteasome Inhibitor Carfilzomib in Patients with Relapsed or Refractory Multiple Myeloma or Lymphoma Melissa Alsina1, Suzanne Trudel2, Richard R. Furman3, Peter J. Rosen5, Owen A. O'Connor4, Raymond L. Comenzo6, Alvin Wong7, Lori A. Kunkel8, Christopher J. Molineaux9, and Andre Goy10 Abstract Purpose: Carfilzomib is a next-generation, selective, proteasome inhibitor with clinical activity in relapsed and/or refractory multiple myeloma. The objectives of this phase I study were to establish the safety, tolerability, pharmacokinetic, and pharmacodynamic profiles of escalating doses of carfilzomib in patients with relapsed or refractory hematologic malignancies. Experimental design: Carfilzomib (doses ranging from 1.2–27 mg/m2) was administered i.v. on 2 consecutive days for 3 weeks of a 4-week cycle. Single-agent dose escalation (n ¼ 37) was followed by a dose- expansion phase (n ¼ 11) that comprised 2 cohorts (carfilzomib or carfilzomib þ dexamethasone). During dose expansion, carfilzomib was administered starting with 20 mg/m2 during the first week (days 1, 2) and then escalated to 27 mg/m2 thereafter. Results: A maximum tolerated dose (MTD) was not reached during dose escalation. Dosing in the expansion cohort was well tolerated. Adverse events were manageable and primarily of grade I or II. The main hematologic adverse events of grade III were anemia and thrombocytopenia. Notably, there were no observations of grade III or more peripheral neuropathy. Carfilzomib was cleared rapidly with an elimination half-life of less than 30 minutes but still induced dose-dependent inhibition of the 20S chymotrypsin-like proteasome activity. At doses of 15 to 27 mg/m2, there was evidence of activity among patients with multiple myeloma and with non-Hodgkin lymphoma. Conclusions: Escalated dosing of carfilzomib on a schedule of 2 consecutive days for 3 weeks of a 4- week cycle was tolerable and showed promising activity. This dose regimen has been selected for ongoing and future clinical studies, including PX-171-003A1 and the pivotal trial ASPIRE. Clin Cancer Res; 18(17); 4830–40. Ó2012 AACR. Introduction The 20S proteasome is a central regulator of the Authors' Affiliations: 1H. Lee Moffitt Cancer and Research Center, Tampa, cellular homeostasis through its function in ubiquitin- 2 Florida; University of Toronto Princess Margaret Hospital, Toronto, dependent turnover of proteins regulating signal trans- Ontario, Canada; 3Weill Cornell Medical College; 4NYU Clinical Cancer Center, New York, New York; 5Tower Cancer Research Foundation, Bev- duction, cell-cycle progression, apoptosis, survival, and erly Hills, California; 6Tufts University, Boston, Massachusetts; 7Onyx stress response pathways. Cancer cells seem to be par- 8 9 Pharmaceuticals, South San Francisco; Independent Consultant; CJM ticularly dependent upon these proteasome-regulated Consulting, San Francisco, California; and 10John Theurer Cancer Center, Hackensack, New Jersey pathways (1–4). The 3 proteolytic activities of the 20S proteasome core include chymotrypsin-like, trypsin- Note: Supplementary data for this article are available at Clinical Cancer Research Online (http://clincancerres.aacrjournals.org/). like, and caspase-like activities (5). The chymotrypsin- like activity is critical to cell survival and is a target of the Prior presentation of this study: Presented in abstract form at the 49th Annual Meeting of the American Society of Hematology, 2007. clinically available proteasome inhibitors (6). The pro- teasome was initially validated as a therapeutic target in Corresponding Author: Melissa Alsina, H. Lee Moffitt Cancer and Research Center, The University of South Florida, 12902 Magnolia Drive, multiple myeloma (7, 8) with the U.S. approval of Tampa, FL 33612. Phone: 813-745-6886; Fax: 813-745-6732; E-mail: bortezomib (Velcade, Millennium Pharmaceuticals). melissa.alsina@moffitt.org Carfilzomib (formerly PR-171; Onyx Pharmaceuticals) is a doi: 10.1158/1078-0432.CCR-11-3007 next-generation proteasome inhibitor that is structurally and Ó2012 American Association for Cancer Research. mechanistically distinct from boronate-based proteasome 4830 Clin Cancer Res; 18(17) September 1, 2012 Downloaded from clincancerres.aacrjournals.org on September 27, 2021. © 2012 American Association for Cancer Research. Published OnlineFirst July 3, 2012; DOI: 10.1158/1078-0432.CCR-11-3007 Phase I Carfilzomib Safety and Antitumor Activity inhibition over extended periods of time, whereas borte- Translational Relevance zomib cannot (7). The activity of the reversible proteasome inhibitor In human tumor xenograft studies, potent antitumor bortezomib in preclinical and clinical studies validated activity was seen when carfilzomib was administered on the proteasome as a therapeutic target in patients with a a weekly schedule of days (D) 1 and 2 (9). Notably, the subset of hematologic malignancies including multiple antitumor efficacy of carfilzomib delivered on 2 consecutive myeloma. While subsequent incorporation of bortezo- days was greater than that of bortezomib administered on mib into the treatment paradigm for multiple myeloma its clinical dosing schedule (biweekly, D1/D4) in the has had a favorable impact on the course of disease, same models. Readministration of carfilzomib before resistance emerges in a significant proportion of patients, full recovery of proteasome activity resulted in optimal and painful peripheral neuropathy can severely limit antitumor activity, supporting the hypothesis that pro- treatment. Carfilzomib is a next-generation, irreversible longed proteasome inhibition (i.e., >48 hours) enhances proteasome inhibitor with increased selectivity for the antitumor activity in vivo. proteasome’s chymotrypsin-like active site. This second Collectively, these findings led to the design of 2 separate phase I study shows that carfilzomib is active and well phase I studies. In the first study (PX-171-001), carfilzomib tolerated on a dosing schedule of 2 consecutive days for 3 was administered to patients with relapsed or refractory of 4 weeks in patients with relapsed and refractory hematologic malignancies on a 2-week cycle, with doses up hematologic malignancies, particularly multiple myelo- to 20 mg/m2 given daily for 5 consecutive days, followed by ma. These data support the further development of 9 days of rest (14). A dose of 15 mg/m2 was established as carfilzomib and provide the basis for the dosing schedule the maximum tolerated dose (MTD) on this schedule and used in ongoing phase II and III clinical evaluation in produced promising preliminary responses in patients with multiple myeloma and other malignancies. multiple myeloma and Waldenstrom’s€ macroglobulinemia (14). In the present study (PX-171-002), carfilzomib was administered in a 4-week cycle (D1/2, D8/9, D15/16, inhibitors such as bortezomib (9–11). Although both target followed by 12 days of rest). It was hypothesized that this the proteasome’s chymotrypsin-like activity, their mechan- regimen could display improved tolerability while still isms of action and selectivity differ due to their pharmaco- providing prolonged proteasome inhibition and disease phores and peptide sequences (6). Carfilzomib exhibits a control in patients with advanced hematologic malignan- high degree of specificity for the catalytic N-terminal threo- cies. The safety, tolerability, and pharmacokinetic/pharma- nine residues in each of the proteolytic active sites within the codynamic profile from this study are presented herein. proteasome (9, 10). The peptide portion of the carfilzomib confers a high degree of selectivity for chymotrypsin-like Patients and Methods activity over the other 2 active sites of the proteasome (9). In contrast, boronate proteasome inhibitors such as borte- Human patient protection and clinical trial zomib, originally developed as potent serine protease inhi- registration bitors, retain some cross-reactivity against other proteases The protocol, informed consent, and other relevant study (11, 12). documentation were approved by the appropriate Institu- Another important distinction between carfilzomib and tional Review Boards before patient enrollment. All parti- bortezomib is the stability of interaction of carfilzomib with cipants provided written informed consent in accordance the proteasome. Bortezomib is a slowly reversible inhibitor with federal and local institutional guidelines. This trial was of the proteasome, and recovery from inhibition results registered at www.clinicaltrials.gov as NCT00150462. from a combination of the off-rate from the enzyme and de novo synthesis of new proteasomes. In contrast, proteasome Eligibility criteria inhibition by carfilzomib is mechanistically irreversible (9, Patients 18 years or more of age with histologically 10) as it involves the formation of 2 covalent bonds; new confirmed multiple myeloma, non–Hodgkin lymphoma protein synthesis is therefore required for the recovery of (NHL), Waldenstrom’s€ macroglobulinemia, or Hodgkin cellular proteasome activity. Consequently, proteasome lymphoma (HL), and treatment-refractory or relapsed dis- inhibition with carfilzomib is sustained over a longer period ease after 2 or more prior therapies were eligible for the of time than with bortezomib (9). study. Other key eligibility criteria included Eastern Coop- Mechanistic differences between carfilzomib
Load more

Recommended publications
  • The Application of a Characterized Pre-Clinical
    THE APPLICATION OF A CHARACTERIZED PRE-CLINICAL GLIOBLASTOMA ONCOSPHERE MODEL TO IN VITRO AND IN VIVO THERAPEUTIC TESTING by Kelli M. Wilson A dissertation submitted to Johns Hopkins University in conformity with the requirements for the degree of Doctor of Philosophy Baltimore, Maryland March, 2014 ABSTRACT Glioblastoma multiforme (GBM) is a lethal brain cancer with a median survival time (MST) of approximately 15 months following treatment. A serious challenge facing the development of new drugs for the treatment of GBM is that preclinical models fail to replicate the human GBM phenotype. Here we report the Johns Hopkins Oncosphere Panel (JHOP), a panel of GBM oncosphere cell lines. These cell lines were validated by their ability to form tumors intracranially with histological features of human GBM and GBM variant tumors. We then completed whole exome sequencing on JHOP and found that they contain genetic alterations in GBM driver genes such as PTEN, TP53 and CDKN2A. Two JHOP cell lines were utilized in a high throughput drug screen of 466 compounds that were selected to represent late stage clinical development and a wide range of mechanisms. Drugs that were inhibitory in both cell lines were EGFR inhibitors, NF-kB inhibitors and apoptosis activators. We also examined drugs that were inhibitory in a single cell line. Effective drugs in the PTEN null and NF1 wild type cell line showed a limited number of drug targets with EGFR inhibitors being the largest group of cytotoxic compounds. However, in the PTEN mutant, NF1 null cell line, VEGFR/PDGFR inhibitors and dual PIK3/mTOR inhibitors were the most common effective compounds.
    [Show full text]
  • Options for the Treatment of Gemcitabine-Resistant Advanced Pancreatic Cancer
    JOP. J Pancreas (Online) 2010 Mar 5; 11(2):113-123. REVIEW Options for the Treatment of Gemcitabine-Resistant Advanced Pancreatic Cancer Ioannis Gounaris, Kamarul Zaki, Pippa Corrie Oncology Centre, Cambridge University Hospitals NHS Trust. Cambridge, United Kingdom Summary Context Pancreatic cancer is noteworthy in that the number of patients dying from the disease is roughly equal to the number diagnosed. For more than a decade, gemcitabine has constituted the standard of care for the palliative treatment of the majority of patients who present with metastatic or relapsed disease, although the survival gains are limited. Despite a median survival of less than 6 months, there is a significant proportion of advanced pancreatic cancer patients who progress on gemcitabine that remains fit and these patients are candidates for second-line treatment. Methods The OVID MEDLINE database was searched from 1950 to present using the MeSH terms “pancreatic neoplasms”, “drug treatment” and “gemcitabine”. After excluding non-relevant results, 31 published studies were identified. These results were supplemented by searching the last three (2007-2009) American Society of Clinical Oncology (ASCO) Proceedings of Annual Meetings for studies published only in abstract form and reviewing reference lists of published articles. Results and discussion The evidence for second line treatments of metastatic pancreatic cancer consists mostly of single arm, small phase II studies. Oxaliplatin-fluoropyrimidine combinations appear promising and have shown increased survival compared to best supportive care. As the molecular pathways governing pancreatic cancer are unravelled, novel targeted therapies may offer the greatest promise for this disease either given alone, combined with one another, or with cytotoxic agents.
    [Show full text]
  • LEUKEMIA CHEMOTHERAPY REGIMENS (Part 1 of 2) the Selection, Dosing, and Administration of Anti-Cancer Agents and the Management of Associated Toxicities Are Complex
    LEUKEMIA CHEMOTHERAPY REGIMENS (Part 1 of 2) The selection, dosing, and administration of anti-cancer agents and the management of associated toxicities are complex. Drug dose modifications and schedule and initiation of supportive care interventions are often necessary because of expected toxicities and because of individual patient variability, prior treatment, and comorbidities. Thus, the optimal delivery of anti-cancer agents requires a healthcare delivery team experienced in the use of such agents and the management of associated toxicities in patients with cancer. The chemotherapy regimens below may include both FDA-approved and unapproved uses/regimens and are provided as references only to the latest treatment strategies. Clinicians must choose and verify treatment options based on the individual patient. REGIMEN DOSING Acute Myeloid Leukemia (AML) Induction Therapy Cytarabine (Cytosar-U; ARA-C) + Days 1–3: An anthracycline (eg, daunorubicin at least 60mg/m2/day IV, an anthracycline idarubicin 10–12mg/m2/day IV, or mitoxantrone 10–12mg/m2/day IV), plus (daunorubicin [Cerubidine], Days 1–7: Cytarabine 100–200mg/m2/day continuous IV infusion. idarubicin [Idamycin], OR mitoxantrone [Novantrone])1, 2 Days 1–3: An anthracycline (eg, daunorubicin 45mg/m2/day IV, idarubicin 12mg/m2/day IV, or mitoxantrone 12mg/m2/day IV), plus Days 1–7: Cytarabine 100mg/m2/day continuous IV infusion. Intermediate-dose cytarabine3 Cycle 1 Days 1–7: Cytarabine 200mg/m2/day continuous IV infusion, plus Days 5–6: Idarubicin 12mg/m2/day IV. Cycle 2 Days 1–6: Cytarabine 1,000mg/m2 continuous IV infusion for 3 hrs twice daily, plus Days 3, 5 and 7: Amsacrine 120mg/m2/day.
    [Show full text]
  • (DAC) Followed by Clofarabine, Idarubicin, and Cytarabine (CIA) in Acute Leukemia 2012-1064
    2012-1064 September 02, 2014 Page 1 Protocol Page Phase I/II Study of Decitabine (DAC) followed by Clofarabine, Idarubicin, and Cytarabine (CIA) in Acute Leukemia 2012-1064 Core Protocol Information Short Title Decitabine followed by Clofarabine, Idarubicin, and Cytarabine in Acute Leukemia Study Chair: Nitin Jain Additional Contact: Allison Pike Jeannice Y. Theriot Leukemia Protocol Review Group Department: Leukemia Phone: 713-745-6080 Unit: 428 Full Title: Phase I/II Study of Decitabine (DAC) followed by Clofarabine, Idarubicin, and Cytarabine (CIA) in Acute Leukemia Protocol Type: Standard Protocol Protocol Phase: Phase I/Phase II Version Status: Terminated 01/12/2018 Version: 12 Submitted by: Jeannice Y. Theriot--4/26/2017 2:13:38 PM OPR Action: Accepted by: Melinda E. Gordon -- 5/1/2017 7:55:15 AM Which Committee will review this protocol? The Clinical Research Committee - (CRC) 2012-1064 September 02, 2014 Page 2 Protocol Body Phase I/II Study of Decitabine (DAC) followed by Clofarabine, Idarubicin, and Cytarabine (CIA) in Acute Leukemia 1. OBJECTIVES Phase I Primary: To determine the maximal tolerated dose (MTD) of clofarabine to be used in portion II of the study Phase II Primary: To determine the response rate of the DAC-CIA regimen Secondary: A) To determine the toxicity of the combination regimen B) To determine the disease-free survival (DFS) and overall survival (OS) rates 2. RATIONALE 2.1 Acute Myelogenous Leukemia Acute myelogenous leukemia (AML) is the most common acute leukemia in adults. It is estimated that 13,780 men and women will be diagnosed with and 10,200 men and women will die of acute myeloid leukemia in the year 2012.1 AML is a disease with a poor prognosis with a 5-year survival of only around 30%.2,3 Certain subgroups of AML have a particularly worse Page 1 of 34 outcome such as patients with relapsed and/or refractory AML and AML arising from antecedent myelodysplastic syndrome (MDS) or myeloproliferative neoplasms (MPNs).
    [Show full text]
  • Drug Name Plate Number Well Location % Inhibition, Screen Axitinib 1 1 20 Gefitinib (ZD1839) 1 2 70 Sorafenib Tosylate 1 3 21 Cr
    Drug Name Plate Number Well Location % Inhibition, Screen Axitinib 1 1 20 Gefitinib (ZD1839) 1 2 70 Sorafenib Tosylate 1 3 21 Crizotinib (PF-02341066) 1 4 55 Docetaxel 1 5 98 Anastrozole 1 6 25 Cladribine 1 7 23 Methotrexate 1 8 -187 Letrozole 1 9 65 Entecavir Hydrate 1 10 48 Roxadustat (FG-4592) 1 11 19 Imatinib Mesylate (STI571) 1 12 0 Sunitinib Malate 1 13 34 Vismodegib (GDC-0449) 1 14 64 Paclitaxel 1 15 89 Aprepitant 1 16 94 Decitabine 1 17 -79 Bendamustine HCl 1 18 19 Temozolomide 1 19 -111 Nepafenac 1 20 24 Nintedanib (BIBF 1120) 1 21 -43 Lapatinib (GW-572016) Ditosylate 1 22 88 Temsirolimus (CCI-779, NSC 683864) 1 23 96 Belinostat (PXD101) 1 24 46 Capecitabine 1 25 19 Bicalutamide 1 26 83 Dutasteride 1 27 68 Epirubicin HCl 1 28 -59 Tamoxifen 1 29 30 Rufinamide 1 30 96 Afatinib (BIBW2992) 1 31 -54 Lenalidomide (CC-5013) 1 32 19 Vorinostat (SAHA, MK0683) 1 33 38 Rucaparib (AG-014699,PF-01367338) phosphate1 34 14 Lenvatinib (E7080) 1 35 80 Fulvestrant 1 36 76 Melatonin 1 37 15 Etoposide 1 38 -69 Vincristine sulfate 1 39 61 Posaconazole 1 40 97 Bortezomib (PS-341) 1 41 71 Panobinostat (LBH589) 1 42 41 Entinostat (MS-275) 1 43 26 Cabozantinib (XL184, BMS-907351) 1 44 79 Valproic acid sodium salt (Sodium valproate) 1 45 7 Raltitrexed 1 46 39 Bisoprolol fumarate 1 47 -23 Raloxifene HCl 1 48 97 Agomelatine 1 49 35 Prasugrel 1 50 -24 Bosutinib (SKI-606) 1 51 85 Nilotinib (AMN-107) 1 52 99 Enzastaurin (LY317615) 1 53 -12 Everolimus (RAD001) 1 54 94 Regorafenib (BAY 73-4506) 1 55 24 Thalidomide 1 56 40 Tivozanib (AV-951) 1 57 86 Fludarabine
    [Show full text]
  • Corporate Overview May 2017
    Corporate Overview May 2017 DEVELOPING PRECISION MEDICINES TO TREAT CANCER Forward Looking Statements This presentation contains forward-looking statements. Such statements include, but are not limited to, statements regarding our research, pre-clinical and clinical development activities, plans and projected timelines for tipifarnib, KO- 947 and KO-539, plans regarding regulatory filings, our expectations regarding the relative benefits of our product candidates versus competitive therapies, and our expectations regarding the therapeutic and commercial potential of our product candidates. The words “believe,” “may,” “will,” “estimate,” “promise,” “plan”, “continue,” “anticipate,” “intend,” “expect,” “potential” and similar expressions (including the negative thereof), are intended to identify forward-looking statements. Because such statements are subject to risks and uncertainties, actual results may differ materially from those expressed or implied by such forward-looking statements. Risks that contribute to the uncertain nature of the forward-looking statements include: our future preclinical studies and clinical trials may not be successful; the U.S. Food and Drug Administration (FDA) may not agree with our interpretation of the data from clinical trials of our product candidates; we may decide, or the FDA may require us, to conduct additional clinical trials or to modify our ongoing clinical trials; we may experience delays in the commencement, enrollment, completion or analysis of clinical testing for our product candidates, or significant issues regarding the adequacy of our clinical trial designs or the execution of our clinical trials may arise, which could result in increased costs and delays, or limit our ability to obtain regulatory approval; our product candidates may not receive regulatory approval or be successfully commercialized; unexpected adverse side effects or inadequate therapeutic efficacy of our product candidates could delay or prevent regulatory approval or commercialization; we may not be able to obtain additional financing.
    [Show full text]
  • (12) United States Patent (10) Patent No.: US 8,911,786 B2 Desai Et Al
    US00891. 1786B2 (12) United States Patent (10) Patent No.: US 8,911,786 B2 Desai et al. (45) Date of Patent: Dec. 16, 2014 (54) NANOPARTICLE COMPRISING RAPAMYCIN A61K 45/06 (2013.01); A61K 47/42 (2013.01); AND ALBUMINAS ANTICANCERAGENT A61N 5/10 (2013.01); A61N 7700 (2013.01) (75) Inventors: Neil P. Desai, Los Angeles, CA (US); USPC ............ 424/491; 424/489: 424/490; 424/500 Patrick Soon-Shiong, Los Angeles, CA (58) Field of Classification Search (US); Vuong Trieu, Calabasas, CA (US) USPC .......... 424/465-489, 490, 491, 500: 514/19.3 See application file for complete search history. (73) Assignee: Abraxis Bioscience, LLC, Los Angeles, CA (US) (56) References Cited (*) Notice: Subject to any disclaimer, the term of this patent is extended or adjusted under 35 U.S. PATENT DOCUMENTS U.S.C. 154(b) by 344 days. 5,206,018 A * 4/1993 Sehgal et al. ................. 424,122 5,362.478 A 11/1994 Desai et al. (21) Appl. No.: 12/530,188 5.439,686 A 8, 1995 Desai et al. 5,498.421 A 3, 1996 Grinstaffet al. (22) PCT Filed: Mar. 7, 2008 5,505,932 A 4/1996 Grinstaffet al. 5,508,021 A 4/1996 Grinstaffet al. (86). PCT No.: PCT/US2O08/OO3O96 5,512,268 A 4/1996 Grinstaffet al. 5,540,931 A 7/1996 Hewitt et al. S371 (c)(1), 5,560,933 A 10/1996 Soon-Shiong et al. (2), (4) Date: Mar. 4, 2010 5,635,207 A 6/1997 Grinstaffet al. 5,639,473 A 6/1997 Grinstaffet al.
    [Show full text]
  • Spotlight Review
    Leukemia (2009) 23, 10–24 & 2009 Macmillan Publishers Limited All rights reserved 0887-6924/09 $32.00 www.nature.com/leu SPOTLIGHT REVIEW Bone marrow microenvironment and the identification of new targets for myeloma therapy K Podar, D Chauhan and KC Anderson Department of Medical Oncology, LeBow Institute for Myeloma Therapeutics, Dana Farber Cancer Institute, Jerome Lipper Multiple Myeloma Center, Harvard Medical School, Boston, MA, USA The development of multiple myeloma (MM) is a complex multi- Signaling cascades activated by cytokines, growth factors and/ step process involving both early and late genetic changes in or adhesion in MM cells include the Ras/Raf/MEK/MAPK- the tumor cell as well as selective supportive conditions by the k bone marrow (BM) microenvironment. Indeed, it is now well pathway, PI3K/Akt-pathway, the JAK/Stat3-pathway, the NF B- established that MM cell-induced disruption of the BM homeo- pathway and the Wnt-pathway. Promising intracellular targets stasis between the highly organized cellular and extracellular for novel therapies also include protein kinase C (PKC) and SPOTLIGHT compartments supports MM cell proliferation, survival, migra- heat-shock proteins (HSPs). Moreover, genomic profiling has tion and drug resistance through activation of various signaling now identified additional stage-specific intracellular targets, (for example, PI3K/Akt, JAK/Stat-, Raf/MEK/MAPK-, NFjB- and which are now under investigation as novel potential therapeutic Wnt-) pathways. Based on our enhanced understanding of the 2,4 functional importance of the MM BM microenvironment and its targets. inter-relation with the MM cell resulting in homing, seeding, Cell surface receptors include integrins, cadherins, selectins, proliferation and survival, new molecular targets have been syndecans, and the immunoglobulin superfamily of cell adhe- identified and derived treatment regimens in MM have already sion molecules including syndecan-1 (CD138), H-CAM (CD44), changed fundamentally during recent years.
    [Show full text]
  • A Phase I, Pharmacokinetic, and Biological Study of The
    Vol. 9, 4761–4771, October 15, 2003 Clinical Cancer Research 4761 A Phase I, Pharmacokinetic, and Biological Study of the Farnesyltransferase Inhibitor Tipifarnib in Combination with Gemcitabine in Patients with Advanced Malignancies Amita Patnaik,1 S. Gail Eckhardt, the pharmacokinetic behavior of each agent administered Elzbieta Izbicka, Anthony A. Tolcher, alone and together. The proportions of unfarnesylated and Lisa A. Hammond, Chris H. Takimoto, farnesylated HDJ2, a chaperone protein that undergoes far- nesylation, were measured in peripheral blood mononuclear Garry Schwartz, Heather McCreery, cells. Andrew Goetz, Masataka Mori, Kazutoyo Terada, Results: Nineteen evaluable patients were treated with Lou Gentner, Mary-Ellen Rybak, 74 courses of tipifarnib/gemcitabine (mg/mg/m2). Myelosup- Henry Richards, Steven Zhang, and pression was the principal toxicity. Dose-limiting myelosup- Eric K. Rowinsky pression occurred in 2 of 5 patients at the 300/1000 dose level, whereas 2 of 11 evaluable patients at the 200/1000 dose Institute for Drug Development, Cancer Therapy and Research Center, San Antonio, Texas 78229 [A. P., S. G. E., E. I., A. A. T., level experienced dose-limiting toxicity. There was no evi- L. A. H., C. H. T., H. M., A. G., E. K. R.]; Brooke Army Medical dence of clinically relevant pharmacokinetic interactions Center, San Antonio, Texas 78234-6200 [G. S.]; Kumamoto between tipifarnib and gemcitabine. Inhibition of farnesyla- University School of Medicine, Kumamoto, Japan 860-8556 [M. M., tion of HDJ2, a potential surrogate for Ras and/or other K. T.]; and Johnson and Johnson Pharmaceutical Research and potentially relevant farnesylated proteins, was demon- Development, Titusville, New Jersey 08560 [L.
    [Show full text]
  • (12) Patent Application Publication (10) Pub. No.: US 2009/0226431 A1 Habib (43) Pub
    US 20090226431A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2009/0226431 A1 Habib (43) Pub. Date: Sep. 10, 2009 (54) TREATMENT OF CANCER AND OTHER Publication Classification DISEASES (51) Int. Cl. A 6LX 3/575 (2006.01) (76)76) InventorInventor: Nabilabil Habib,Habib. Beirut (LB(LB) C07J 9/00 (2006.01) Correspondence Address: A 6LX 39/395 (2006.01) 101 FEDERAL STREET A6IP 29/00 (2006.01) A6IP35/00 (2006.01) (21) Appl. No.: 12/085,892 A6IP37/00 (2006.01) 1-1. (52) U.S. Cl. ...................... 424/133.1:552/551; 514/182: (22) PCT Filed: Nov.30, 2006 514/171 (86). PCT No.: PCT/US2O06/045665 (57) ABSTRACT .."St. Mar. 6, 2009 The present invention relates to a novel compound (e.g., 24-ethyl-cholestane-3B.5C,6C.-triol), its production, its use, and to methods of treating neoplasms and other tumors as Related U.S. Application Data well as other diseases including hypercholesterolemia, (60) Provisional application No. 60/741,725, filed on Dec. autoimmune diseases, viral diseases (e.g., hepatitis B, hepa 2, 2005. titis C, or HIV), and diabetes. F2: . - 2 . : F2z "..., . Cz: ".. .. 2. , tie - . 2 2. , "Sphagoshgelin , , re Cls Phosphatidiglethanolamine * - 2 .- . t - r y ... CBs .. A . - . Patent Application Publication Sep. 10, 2009 Sheet 1 of 16 US 2009/0226431 A1 E. e'' . Phosphatidylcholine. " . Ez'.. C.2 . Phosphatidylserias. * . - A. z' C. w E. a...2 .". is 2 - - " - B 2. Sphingoshgelin . Cls Phosphatidglethanglamine Figure 1 Patent Application Publication Sep. 10, 2009 Sheet 2 of 16 US 2009/0226431 A1 Chile Phosphater Glycerol Phosphatidylcholine E.
    [Show full text]
  • Chronic Myelogenous Leukemia: a Review and Update of Current and Future Therapy
    International Journal of Pharmacy and Pharmaceutical Sciences ISSN- 0975-1491 Vol 8, Issue 7, 2016 Review Article CHRONIC MYELOGENOUS LEUKEMIA: A REVIEW AND UPDATE OF CURRENT AND FUTURE THERAPY ANKIT ASHOKKUMAR DARJI, PRAFUL D. BHARADIA HNGU University Ph. D. Student Email: [email protected] Received: 08 Apr 2016 Revised and Accepted: 17 May 2016 ABSTRACT Leukemia is a cancer of marrow and blood, which is a clonal myeloproliferative disease, characterized by the presence of oncogenic Philadelphia chromosome, formed by a reciprocal translocation between chromosomes 9 and 22, resulting in the novel chimeric oncoprotein BCR/ABL. Chronic leukemia typically progresses slowly and permits the growth of greater numbers of more developed cells. If the cell change takes place in a type of marrow cell that normally goes on to form red blood cells, some kinds of white blood cells and platelets, the leukemia is called “myeloid. Therapy for chronic myeloid leukemia depends on the stage of CML patient. After diagnosis and confirmation of CML positive patient, treatment available for patients includes imatinib that is an early diagnosed treatment for CML but after some duration of time, it may lead to resistance to imatinib treatment. Dasatinib, nilotinib, bosutinib & ponatinib can be used for the treatment of CML as secondary treatments. Ponatinib is also found effective against T315i mutation patients. Omacetaxine mepesuccinate can be given with a mechanism of action independent of tyrosine kinase inhibition. Clinical trial for development of advanced therapy, which includes combination therapy and newer developed a treatment against CML are going on. It is required to develop better drug therapy, which will not cause genetical mutation and drug resistant.
    [Show full text]
  • Spectrum Pharmaceuticals Appoints Steven M. Fruchtman, MD, an Industry Veteran, As Vice President of Clinical Development
    Spectrum Pharmaceuticals Appoints Steven M. Fruchtman, MD, an Industry Veteran, as Vice President of Clinical Development ● Dr. Fruchtman Is a Hematologist/Oncologist With a Proven Track Record in Clinical Research ® ● Joins Spectrum From Allos Therapeutics, Where He Led Development of FOLOTYN For Hematologic and Oncologic Indications; Leading to FDA Approval of FOLOTYN in Relapsed and Refractory Peripheral T-Cell Lymphoma ● Previously, Dr. Fruchtman Was At Novartis, Where He Was Responsible For The Development of Panobinostat For Hematologic and Oncologic Indications, and Proleukin For Renal Cell and Melanoma; and Ortho Biotech Products, a Division of Johnson & Johnson, Where He Led The Development of Doxil® and Others IRVINE, Calif--(BUSINESS WIRE)-- Spectrum Pharmaceuticals (NasdaqGS: SPPI), a biotechnology company with fully integrated commercial and drug development operations with a primary focus in oncology, today announced the appointment of Steven M. Fruchtman, MD, to the position of Vice President of Clinical Development. Dr. Fruchtman will report directly to George Tidmarsh, MD, PhD, the Company's Chief Scientific Officer and Head of Research and Development Operations, and will provide the strategic planning and leadership necessary for managing the Company's clinical development of belinostat, ZEVALIN® and its other pipeline products. "We are pleased to announce the appointment of Dr. Fruchtman as our Vice President of Clinical Development," said Rajesh C. Shrotriya, M.D., Chairman, Chief Executive Officer, and President of Spectrum Pharmaceuticals. "Steve comes to us from Allos Therapeutics, where he spearheaded the development of FOLOTYN. He was instrumental in the presentation of the FOLOTYN data to the ODAC panel that recommended and ultimately received FDA approval in relapsed/refractory Peripheral T-Cell Lymphoma.
    [Show full text]