DOCSLIB.ORG

Treatment of Relapsed and Refractory Multiple Myeloma

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Treatment of Relapsed and Refractory Multiple Myeloma Multiple myeloma Treatment of relapsed and refractory multiple myeloma S. Lonial ABSTRACT Department of Hematology and Treatment options and outcomes for patients with relapsed myeloma have dramatically changed Medical Oncology, Winship Cancer over the past ten years due in large part to the availability of novel agents such as bortezomib, thalido- Institute, Emory University School of mide and lenalidomide. These have now been incorporated into the treatment approach for newly Medicine, Atlanta, GA, USA diagnosed patients and also raise questions about bow best to manage patients who relapse. In addi- tion to existing and approved agents, several others have recently been or are soon to be approved, as Correspondence: well as new classes of agents in phase III trials that are likely to not only improve long-term outcomes, Sagar Lonial but that will also complicate treatment algorithms. We will review data on the optimal use of existing E-mail: [email protected] approaches for relapsed disease, as well as new agents under development for relapsed and refractory myeloma. Acknowledgments Sagar Lonial is supported by funding Learning goals from the Richard and Annelly Deets At the conclusion of this activity, participants should understand: Fund for Multiple Myeloma. - when a patient needs therapy for relapsed myeloma; - how best to use available treatment options for managing relapsed myeloma; Hematology Education: - which are the new agents under development and how to use them for the management of relapsed the education program for the and refractory myeloma. annual congress of the European Hematology Association 2013;7:216-226 Introduction myeloma with the highest chance of response and good tolerance for any given patient. Multiple myeloma (MM) is a clonal plasma cell malignancy characterized by bone, renal, How to define relapse hematologic, and often neurological complica- tions.1 The overall survival for patients with symptomatic myeloma has dramatically Response criteria in myeloma represent an improved over the last decade due to the broad evolving work in progress. While the defini- use of high-dose therapy and autologous trans- tion of complete response (CR) continues to plant for suitable patients, as well as the avail- become more and more stringent, the defini- ability of novel agents whose mechanisms of tion of relapse or progression has been rela- action are distinctly different from alkylators tively constant. Relapse from a CR is defined or steroids. However, even with these as reappearance of the serum or urinary para- advances, most patients will eventually die of protein, of 5% or over bone marrow plasma complications associated with the develop- cells, new lytic bone lesions/soft tissue plas- ment of resistant disease.2 Plasma cells spend macytomas, an increase in size of residual their time in the marrow microenvironment bone lesions, and/or development of hypercal- supported by autocrine and paracrine secretion cemia (corrected serum calcium >11.5 mg/dL) of growth factors such as IL-6, TNFα, IGF-1 not attributable to another cause.5 Following and VEGF,3 as well as direct interaction of the the increased depth of response seen with new bone marrow microenvironment with plasma therapies, the ‘CR penalty’ was addressed by cells via integrins and cell adhesion molecules allowing patients who have achieved a CR to which promote growth and inhibit apoptosis.4 be defined as relapsed when they develop a However, the practical delivery of anti-myelo- protein of at least 0.5 gm/dL rather than the ma therapy in the context of relapsed or refrac- historical definition of immunofixation nega- tory disease is a constantly evolving area of tive to immunofixation positive.6 Criteria for research, and one which needs to take into progressive disease (PD) when a CR has not consideration factors of clinical importance. been achieved include new or expanding bone These include: i) which diseasevs setting the lesions, hypercalcemia, and a more than 25% patient comes to us in (early . late); ii) dis- increase in either serum monoclonal parapro- ease specific biology (standard- or high-risk); tein concentration, 24-h urinary light chain iii) prior therapies; and iv) prior toxicities excretion, or plasma cells within a bone mar- from therapy. Through clinical integration of row. Relapsed MM refers to the circumstance these factors, a treatment strategy can be wherein a patient treated to the point of maxi- defined for patients with relapsed or refractory mal response experiences PD, whereas refrac- Hematology Education: the education program for the annual congress of the European Hematology Association | 2013; 7(1) | 216 | Stockholm, Sweden, June 13-16, 2013 tory MM refers to a clinical scenario in which a patient is patients who did not have a transplant as part of their ini- either unresponsive to current therapy or progresses within tial treatment, or for patients with long duration of remis- 60 days of last treatment. It is important to recall that sion following transplant, salvage autologous transplant ‘patients with refractory disease’ has historically referred could be considered. Incorporation of patient- or treat- to patients who were resistant to dexamethasone and alky- ment-related AEs (existing cytopenias, neuropathy, or lators and, given the short duration of response to both thrombosis) should also play a part in the choice of agents alone, patients often developed refractory disease. More in the relapsed disease setting. For patients with more recently, the availability of different classes of agents advanced relapse, or with aggressive disease biology, the including proteasome inhibitors and immunomodulatory use of combinations of agents or novel agents in combina- agents, the generic term ‘refractory’ requires more speci- tion with cytotoxic agents may be a more appropriate ficity. Currently, the term ‘refractory’ requires a descrip- approach. Even among patients with aggressive relapse, tion of what the patient is refractory to, i.e. steroids, borte- the use of salvage transplant has a role if cytopenias are zomib or lenalidomide. In addition, there may be biologi- limiting treatment options, as long as some form of main- cal differences between patients who areversus defined as refrac- tenance therapy is used afterwards in an effort to stave off tory by progression on treatment those who early or rapid relapse. Disease biology can also influence progress within 60 days of stopping therapy and, as such, the choice of therapy for relapsed/refractory MM, and reg- they should be specified when base-line patients’ charac- imens including bortezomib or lenalidomide are preferred teristics are described in clinical trials. Patients who fail to in individuals with the higher risk t(4;14) disease as well achieve any response to induction therapy (< minimal as the use of some form of maintenance therapy, which response, MR) and then progress on therapy are an espe- appears to be of greater importance among patients with cially challenging category of patients with primary biologically defined high-risk disease. Importantly, the refractory myeloma.7 optimal therapy of patients with deletion of 17p (p53), As we now have more tools with which to approach who usually derived short benefit from available therapies relapsed disease, the decision as to when to treat this con- outcomes, is not known at this time and thus for these tinues to be an issue. The current International Myeloma patients aggressive combination therapy with aggressive Working Group guidelines (IMWG) state that patients maintenance treatment may be warranted.9,10 More sophis- should be observed until they develop symptomatic ticated biological correlatives for the selection of treat- relapse (the same criteria used to differentiate smoldering ment are obviously desirable but are not currently avail- myeloma from symptomatic myeloma). This raises the able for routine clinical practice. issue of differences between patientsversus with biochemical Interestingly, most of the novel combination approaches relapse (blood or urine protein only) those patients in MM explored to date have reliably produced response with symptomatic relapse (new evidence of end organ in the majority of patients, and CR/nCR is not uncommon. damage according to the CRAB criteria). Most clinical tri- One unresolved question in MM therapy is whether use of als require patients to have symptomatic relapse prior to combinations of novel agents to achieve high response study entry, and it is clear that there are patients who can rates is better than the sequential use of these agents alone have long-term low-level disease burden and who do not or with corticosteroids. Emerging data from large phase III require therapy. Early initiation of salvage therapy in those studies suggest that progression-free survival is superior patients would not necessarily offer benefit, while there with a 3-drug combination compared with a doublet, but may be others with high risk or aggressive relapse for so far no survival improvement has been noted.11 Several whom waiting till there is evidence of end organ damage currently ongoing phase III trials are evaluating a similar may ultimately limit the efficacy of therapy. At this point, comparison (lenalidomide/dexamethasone +/- carfil- it remains prudent to observe patients who have ‘biochem- zomib, lenalidomide/dexamethasone +/- elotuzumab, ical relapse’ only, unless there are other factors (prior his- bortezomib/dexamethasone +/- panobinostat) and
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]
  • 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.
    [Show full text]