DOCSLIB.ORG

Preclinical Discovery of Ixabepilone, a Highly Active Antineoplastic Agent

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Preclinical Discovery of Ixabepilone, a Highly Active Antineoplastic Agent Cancer Chemother Pharmacol (2008) 63:157–166 DOI 10.1007/s00280-008-0724-8 ORIGINAL ARTICLE Preclinical discovery of ixabepilone, a highly active antineoplastic agent Francis Y. F. Lee · Robert Borzilleri · Craig R. Fairchild · Amrita Kamath · Richard Smykla · Robert Kramer · Gregory Vite Received: 30 November 2007 / Accepted: 26 February 2008 / Published online: 18 March 2008 © Springer-Verlag 2008 Abstract The epothilones and their analogs constitute a These favorable preclinical characteristics have since novel class of antineoplastic agents, produced by the myxo- translated to the clinic. Ixabepilone has shown promising bacterium Sorangium cellulosum. These antimicrotubule phase II clinical eYcacy and acceptable tolerability in a agents act in a similar manner to taxanes, stabilizing micro- wide range of cancers, including heavily pretreated and tubules and resulting in arrested tumor cell division and drug-resistant tumors. Based on these results, a randomized apoptosis. Unlike taxanes, however, epothilones and their phase III trial was conducted in anthracycline-pretreated or analogs are macrolide antibiotics, with a distinct tubulin resistant and taxane-resistant metastatic breast cancer to binding mode and reduced susceptibility to a range of com- evaluate ixabepilone in combination with capecitabine. mon tumor resistance mechanisms that limit the eVective- Ixabepilone combination therapy showed signiWcantly supe- ness of taxanes and anthracyclines. While natural rior progression-free survival and tumor responses over epothilones A and B show potent antineoplastic activity in capecitabine alone. vitro, these eVects were not seen in preclinical in vivo mod- els due to their poor metabolic stability and unfavorable Keywords Antimicrotubule · III-Tubulin · Epothilone · pharmacokinetics. A range of epothilone analogs was syn- Multidrug resistance · Preclinical thesized, therefore, with the aim of identifying those with more favorable characteristics. Here, we describe the pre- clinical characterization and selection of ixabepilone, a Introduction semi-synthetic epothilone B analog, among many other epothilone analogs. Ixabepilone demonstrated superior pre- Since the clinical antitumor activity of the taxanes was dis- clinical characteristics, including high metabolic stability, covered in the 1990s, the rationale for using microtubule- low plasma protein binding and low susceptibility to multi- stabilizing agents in the treatment of cancer is undisputed drug resistance protein-mediated eZux, all of which were [1]. Taxanes are clinically active against a wide range of predictive of potent in vivo cell-killing activity. Ixabepilone tumor types, and play a key role in the treatment of both also demonstrated in vivo antitumor activity in a range of primary and metastatic breast cancer [2]. However, resis- human tumor models, several of which displayed resistance tance to cytotoxic drugs (including taxanes) is common, to commonly used agents such as anthracyclines and taxanes. and results in reduced response rates and ultimate disease progression in most patients with metastatic cancer [3]. While some tumors display intrinsic resistance to chemo- F. Y. F. Lee · R. Borzilleri · C. R. Fairchild · A. Kamath · therapeutic drugs, and thus show no response, others are R. Smykla · R. Kramer · G. Vite Bristol-Myers Squibb Pharmaceutical Research Institute, initially responsive to chemotherapy, but subsequently Princeton, NJ, USA develop acquired resistance. Both intrinsic and acquired resistance lead to a requirement for alternative treatment F. Y. F. Lee (&) options [3]. Bristol-Myers Squibb Co., P.O. Box 4000, K22-03, Princeton, NJ, USA A major mechanism by which tumors display resistance e-mail: [email protected] to commonly used agents such as taxanes and anthracyclines 123 158 Cancer Chemother Pharmacol (2008) 63:157–166 is through overexpression of multidrug resistance (MDR) development and selection of a particular epothilone proteins including P-glycoprotein (P-gp) and multidrug analog, BMS-247550 (ixabepilone), a semi-synthetic analog resistance-associated protein (MRP)-1 [4]. Overexpression of natural epothilone B that has shown phase II clinical activ- of these eZux pump proteins causes retention of sub-thera- ity in a wide range of tumor types, including those heavily peutic concentrations of drug in tumor cells, which results pretreated with, and/or resistant to, prior therapies [16–26]. in a lack of eYcacy. In some tumors that are intrinsically resistant to chemotherapy, expression of MDR proteins reXects the constitutive expression of these proteins by the Epothilones and their analogs: a novel class tissues from which the tumors are derived (for example, of antineoplastic agents liver and kidney). However, in tumors derived from tissue types that do not express MDR proteins physiologically, Epothilones are 16-member macrolides with unique anti- treatment with chemotherapy can induce expression of bacterial and antifungal activity. Preclinical experiments these proteins. This results in acquired resistance to the have shown that natural epothilones A and B have potent chemotherapy agent used, in addition to drugs of the same antineoplastic activity against a wide range of tumor cell class and, on occasion, of diVerent classes [3]. In the case lines in vitro [14, 27]. This is particularly true for epothi- of the taxanes, at least one other mechanism of drug resis- lone B, which showed greater in vitro activity when com- tance is known to exist: the overexpression of the III-tubu- pared with epothilone A [28, 29]. However, this promising lin isoform in preference to the II isoform reduces the in vitro activity of these natural epothilones did not trans- eYcacy of taxanes, as these drugs speciWcally target the II late into robust in vivo preclinical antitumor eYcacy [30]. isoform [5–8]. This was due to the poor metabolic stability and unfavor- In recent years, there has been a great deal of interest able pharmacokinetic properties of natural epothilones seen among the oncology community in targeted agents. It is in rodent models. Synthetic and semi-synthetic epothilone now widely acknowledged that agents such as trastuzumab analogs were, therefore, developed, with the aim of yield- (which targets HER2 in breast cancer) and bevacizumab ing more favorable preclinical characteristics that would (which targets VEGF to inhibit angiogenesis in a range of lead to improved in vivo activity [31, 32]. This was possi- solid tumors) have the potential beneWts of at least compa- ble due to the fact that epothilones have a structure of only rable eYcacy and reduced side-eVects compared with cyto- moderate complexity, and are amenable to total and semi- toxic agents. However, targeted therapies are only eVective synthesis. A range of semisynthetic analogs was developed in subsets of patients with tumors expressing the target and tested by Bristol–Myers Squibb in order to identify molecule, hence it is likely that cytotoxic agents will candidates with a superior eYcacy and safety proWle versus remain important in the treatment of cancer, either in com- epothilone B. Of these, ixabepilone is an analog rationally bination with other agents [as seen clinically with paclitaxel designed for high in vivo eYcacy, good metabolic stability, in combination with bevacizumab in trials of non-small cell low protein binding and increased water solubility. The lac- lung carcinoma (NSCLC)] or second-line to other therapies tone oxygen is replaced with nitrogen, resulting in the lac- [9, 10]. There is, therefore, a pressing need for the develop- tam compound (Fig. 1b). SigniWcantly, this lactam ring is ment of novel antineoplastic agents that are able to over- not susceptible to hydrolysis by esterases, conferring meta- come major mechanisms of tumor drug resistance. bolic stability on ixabepilone. Because of its improved Natural epothilones and their analogs are a novel class of water solubility, ixabepilone has a reduced requirement in antineoplastic agents, produced by the myxobacterium its formulation for the solubilizing agent cremophor, an Sorangium cellulosum [11, 12]. Like the taxanes, epothil- agent that has been associated with hypersensitivity ones promote tumor cell death by stabilizing microtubules reaction in patients. and inducing apoptosis [13]. However, as macrolide antibi- otics, the epothilones are structurally unrelated to taxanes and have a distinct tubulin-binding mode. Moreover, unlike Preclinical evaluation of ixabepilone taxanes and anthracyclines, epothilones have low suscepti- bility to multiple mechanisms of tumor cell resistance, In order to be of clinical value, an epothilone analog must: including MDR, III-tubulin overexpression and -tubulin (1) be eYcacious, resulting in clinically meaningful mutations [8, 14, 15]. responses at practical concentrations; (2) have an accept- The potential for reduced susceptibility to common able safety proWle; and (3) be readily available through mechanisms of tumor resistance led to preclinical and scalable synthesis. clinical evaluation of natural epothilones A–F (Fig. 1a), While the in vitro cytotoxicity/activity of the drug may and a wide range of synthetic and semi-synthetic analogs of give some indication of how potent the drug will be in vivo, these agents. This review will describe the preclinical this is not always the case (as seen for natural epothilones B 123 Cancer Chemother Pharmacol (2008) 63:157–166 159 Fig. 1 a Structures of natural a R epothilones A–F and b the semi-
Load more

Recommended publications
  • In Vivo Evaluation of Ixabepilone (BMS247550), a Novel Epothilone B Derivative, Against Pediatric Cancer Models Jennifer K
    Cancer Therapy: Preclinical In vivo Evaluation of Ixabepilone (BMS247550), A Novel Epothilone B Derivative, against Pediatric Cancer Models Jennifer K. Peterson,1Chandra Tucker,1Edward Favours,1PamelaJ. Cheshire,1Jeremy Creech,1 Catherine A. Billups,2 Richard Smykla,3 Francis Y.F. Lee,3 and Peter J. Houghton1 Abstract Purpose:Vinca alkaloids, agents that cause depolymerization of microtubules, are highly active in treatment of many pediatric cancers. In contrast, taxanes, agents that stabilize microtubules, are far less effective against the same cancer types.The purpose of the current study was to evaluate the antitumor activity of ixabepilone, an epothilone B derivative representing a new class of microtubule-stabilizing antimitotic agent in a wide variety of pediatric solid tumor models. Experimental Design: Ixabepilone was administered i.v. every 4 days for three doses to scid mice bearing s.c. human rhabdomyosarcoma (three lines), neuroblastoma (four),Wilms’ tumors (six), osteosarcoma (four), or brain tumors (seven).Tumor diameters were measured weekly, and tumor growth or regressions were determined. Pharmacokinetic studies were done following a single administration of drug at the maximum tolerated dose (MTD) level (10 mg/kg). Results: At the MTD (10 mg/kg), ixabepilone induced objective responses (all tumors in a group achieved z50% volume regression) in three of three rhabdomyosarcoma lines, three of five neuroblastomas, six of seven Wilms’ tumor models, two of six osteosarcoma, and four of eight brain tumor models. However, the dose-response curve was steep with only 2 of 19 tumors models regressing (z50%) at 4.4 mg/kg. In comparison, paclitaxel administered at the MTD on the same schedule failed to induce objective regressions of three tumor lines that were highly sensitive to treatment with ixabepilone.
    [Show full text]
  • Management of Brain and Leptomeningeal Metastases from Breast Cancer
    International Journal of Molecular Sciences Review Management of Brain and Leptomeningeal Metastases from Breast Cancer Alessia Pellerino 1,* , Valeria Internò 2 , Francesca Mo 1, Federica Franchino 1, Riccardo Soffietti 1 and Roberta Rudà 1,3 1 Department of Neuro-Oncology, University and City of Health and Science Hospital, 10126 Turin, Italy; [email protected] (F.M.); [email protected] (F.F.); riccardo.soffi[email protected] (R.S.); [email protected] (R.R.) 2 Department of Biomedical Sciences and Human Oncology, University of Bari Aldo Moro, 70121 Bari, Italy; [email protected] 3 Department of Neurology, Castelfranco Veneto and Treviso Hospital, 31100 Treviso, Italy * Correspondence: [email protected]; Tel.: +39-011-6334904 Received: 11 September 2020; Accepted: 10 November 2020; Published: 12 November 2020 Abstract: The management of breast cancer (BC) has rapidly evolved in the last 20 years. The improvement of systemic therapy allows a remarkable control of extracranial disease. However, brain (BM) and leptomeningeal metastases (LM) are frequent complications of advanced BC and represent a challenging issue for clinicians. Some prognostic scales designed for metastatic BC have been employed to select fit patients for adequate therapy and enrollment in clinical trials. Different systemic drugs, such as targeted therapies with either monoclonal antibodies or small tyrosine kinase molecules, or modified chemotherapeutic agents are under investigation. Major aims are to improve the penetration of active drugs through the blood–brain barrier (BBB) or brain–tumor barrier (BTB), and establish the best sequence and timing of radiotherapy and systemic therapy to avoid neurocognitive impairment. Moreover, pharmacologic prevention is a new concept driven by the efficacy of targeted agents on macrometastases from specific molecular subgroups.
    [Show full text]
  • Use of Vacuum Therapy in Access Port Catheter Extravasation of Vesicant Cytotoxic Agents
    Journal of Lung, Pulmonary & Respiratory Research Case Report Open Access Use of vacuum therapy in access port catheter extravasation of vesicant cytotoxic agents Abstract Volume 5 Issue 4 - 2018 Extravasation of vesicant cytotoxic is a severe complication of chemotherapy. Alejandro Gabriel Da Lozzo,1 Alberto Daniel Although access port catheters are used to reduce extravasation, rates up to 4.7% have Giménez Conca,2 Sung Ho Hyon,3 María been reported. Complications can be severe with tissue necrosis or even organ failure 2 and death. The principal cause is needle malpositioning. Treatment mostly includes Paula Cardenas 1 immediate explantation of the port and subcutaneous lavage. We report two cases: Thoracic Surgery, Hospital Italiano de Buenos Aires, Argentina 2Hematology, Hospital Italiano de Buenos Aires, Argentina one with conservative treatment with port explant and local wound care and another 3Minimally Invasive Surgery, Hospital Italiano de Buenos Aires, patient with aggressive treatment that included port explant, lavage and use of vacuum Argentina therapy to complete suction of any remnant vesicant cytotoxic. Alejandro Gabriel Da Lozzo, Thoracic Keywords: cytotoxic, extravasation, vacuum therapy, breast edema, surgical lavage Correspondence: Surgery, General Surgery Service, Hospital Italiano de Buenos Aires, Argentina, Tel +54 911 34375357, Email [email protected] Received: July 19, 2018 | Published: August 06, 2018 Introduction so nursing care protocols based in patient safety with early warning are encouraged, especially with high risk drug administration. The Access port catheters have been successfully employed in cancer principal cause of extravasation is needle malpositioning or secondary 1 therapy since first described in the 1980s. They provide a way to disconnection between the needle and the port.4 Cytotoxic drugs are administer drugs when peripheral venous access is not available classified based upon their potential for local toxicity (Table 1).
    [Show full text]
  • Ixabepilone and Eribulin Mesylate: Two Novel Agents Approved for the Chemotherapeutic Treatment of Metastatic Breast Cancer
    Review: Clinical Trial Outcomes Ixabepilone and eribulin mesylate: two novel agents approved for the chemotherapeutic treatment of metastatic breast cancer Clin. Invest. (2013) 3(4), 385–394 While the majority of breast cancer patients present with early stage Yael S Zack & Linda T Vahdat* disease, 40% of these patients will eventually progress to metastatic Division of Hematology and Oncology, disease. Resistance to existing chemotherapeutic agents continues to Department of Medicine, Weill Cornell Medical pose a challenge in the management of these patients. This review College, 425 East 61St, NY, 10065, USA will analyze the two most recently approved chemotherapy drugs for *Author for correspondence: Tel.: +1 212 821 0644 the treatment of breast cancer; ixabepilone and eribulin mesylate. Fax: +1 212 821 0758 Ixabepilone is a semisynthetic analog of epothilone B, and is thought to E-mail: [email protected] overcome taxane resistance via disruption to microtubule homeostasis. Two Phase III studies, one by Rugo et al. and the other by Thomas et al., showed improvement in progression-free survival with the combination of ixabepilone and capecitabine to approximately 6 months compared with 4.2 months in the capecitabine-alone group in both trials. These resulted in ixabepilone being approved for use alone or in combination with capecitabine for the treatment of locally advanced or metastatic breast cancer after failure of an anthracycline and a taxane in either the adjuvant or the metastatic setting. The drug has been shown to have activity even in heavily pretreated patients who have received at least two prior chemotherapy regimens for the treatments of metastatic disease.
    [Show full text]
  • Patient Benefit and Risk in Anticancer Drug Development: a Systematic Review of the Ixabepilone Trial Portfolio
    medRxiv preprint doi: https://doi.org/10.1101/19003467; this version posted August 1, 2019. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC 4.0 International license . Patient Benefit and Risk in Anticancer Drug Development: A Systematic Review of the Ixabepilone Trial Portfolio Benjamin Carlislea, James Mattinaa, Tiger Zhenga, Jonathan Kimmelmana* aStudies of Translation, Ethics and Medicine (STREAM) Biomedical Ethics Unit McGill University 3647 Peel Street Montreal QC H3A 1X1 1 Corresponding author, Email: [email protected], Telephone: 514-398- 6980, Fax: 514-398-8349 NOTE: This preprint reports new research that has not been certified1 by peer review and should not be used to guide clinical practice. medRxiv preprint doi: https://doi.org/10.1101/19003467; this version posted August 1, 2019. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC 4.0 International license . Abstract OBJECTIVE: To describe the patient burden and benefit, and the dynamics of trial success in the development of ixabepilone—a drug that was approved in the US but not in Europe. DATA SOURCES: Trials were captured by searching Embase and MEDLINE on July 27, 2015. STUDY SELECTION: Inclusion: 1) primary trial reports, 2) interventional trials, 3) human subjects, 4) phase 1 to phase 3, 5) trials of ixabepilone in monotherapy or combination therapy of 6) pre-licensure cancer indications.
    [Show full text]
  • 22065S006 Ixempra
    Clinical Review Amir H. Shahlaee MD sNDA 22065, S-006 Ixempra® (ixabepilone) CLINICAL REVIEW Application Type Pediatric Exclusivity Determination Application Number(s) sNDA 22-065/S-006 Priority or Standard Priority Submit Date(s) 1/14/2011 Received Date(s) 1/18/2011 PDUFA Goal Date 7/14/2011 extended to 10/18/2011 Division / Office DDOP/OODP Reviewer Name(s) Amir Shahlaee, MD CDTL Ke Liu, MD, PhD Review Completion Date 9/9/2011 Established Name Ixabepilone (Proposed) Trade Name Ixempra® Therapeutic Class Microtubule inhibitor Applicant Bristol-Myers Squibb Formulation(s) Intravenous Injection Dosing Regimen Not applicable Indication(s) None Intended Population(s) None 1 Reference ID: 3020673 Clinical Review Amir H. Shahlaee MD sNDA 22065, S-006 Ixempra® (ixabepilone) Table of Contents 1 RECOMMENDATIONS/RISK BENEFIT ASSESSMENT ......................................... 6 1.1 Recommendation on Regulatory Action ............................................................. 6 1.2 Risk Benefit Assessment.................................................................................... 6 1.3 Recommendations for Postmarket Risk Evaluation and Mitigation Strategies ... 7 1.4 Recommendations for Postmarket Requirements and Commitments ................ 7 2 INTRODUCTION AND REGULATORY BACKGROUND ........................................ 8 2.1 Product Information ............................................................................................ 8 2.2 Tables of Currently Available Treatments for Proposed Indications ..................
    [Show full text]
  • Natural Products. a History of Success and Continuing Promise for Drug Discovery and Development
    Natural Products. A History of Success and Continuing Promise for Drug Discovery and Development Gordon M. Cragg NIH Special Volunteer [email protected] David J. Newman Natural Products Branch Developmental Therapeutics Program National Cancer Institute EARLY DOCUMENTATION OF USE OF MEDICINAL PLANTS http://www.nlm.nih.gov/hmd/collections/archives/index.html • Mesopotamian ~2,600 B. C. E. • Egyptian ~ 1,800 B. C. E. • Chinese – ~1,100 B. C. E. and continuing • Indian ~ 1,000 B. C. E. and continuing • Greek ~ 500 B. C. E. Greco-Roman expertise preserved and coordinated with other traditions by Islamic cultures during the Dark Ages ~ 400-1,100 CE Avicenna. Persian pharmacist, physician, poet, philosopher author: canon medicinae – “final codification of Greco-Roman medicine” Great Moments in Pharmacy Collection APhA Traditional Medicine and Drug Discovery • 80% of the world population resides in developing countries • 80% of people in developing countries utilize plants to meet their primary health care needs • Global pop. ca. 7 billion ca. 4.5 billion people utilize plants to meet their primary health care needs Farnsworth NR, et al. Medicinal Plants in Therapy. Bull. W.H.O. 63:965-981 (1985) Fabricant and Farnsworth, EnViron. Health Perspect. 109, 69-75 (2001) Cordell and Clovard, J. Nat. Prod., 75, 514-525 (2012) Norman Farnsworth 1800s. Discovery of some active principles of major herbal preparations Newman and Cragg. Natural Product Chemistry for Drug Discovery, eds. Buss and Butler, M. S., Royal Soc. Chem., Cambridge, 2010, pp. 3-27 European chemists (apothecaries) revolutionized drug discovery and development. 1817. Sertϋrner reports isolation of morphine from Papaver somniferum.
    [Show full text]
  • Chemotherapy and Polyneuropathies Grisold W, Oberndorfer S Windebank AJ European Association of Neurooncology Magazine 2012; 2 (1) 25-36
    Volume 2 (2012) // Issue 1 // e-ISSN 2224-3453 Neurology · Neurosurgery · Medical Oncology · Radiotherapy · Paediatric Neuro- oncology · Neuropathology · Neuroradiology · Neuroimaging · Nursing · Patient Issues Chemotherapy and Polyneuropathies Grisold W, Oberndorfer S Windebank AJ European Association of NeuroOncology Magazine 2012; 2 (1) 25-36 Homepage: www.kup.at/ journals/eano/index.html OnlineOnline DatabaseDatabase FeaturingFeaturing Author,Author, KeyKey WordWord andand Full-TextFull-Text SearchSearch THE EUROPEAN ASSOCIATION OF NEUROONCOLOGY Member of the Chemotherapy and Polyneuropathies Chemotherapy and Polyneuropathies Wolfgang Grisold1, Stefan Oberndorfer2, Anthony J Windebank3 Abstract: Peripheral neuropathies induced by taxanes) immediate effects can appear, caused to be caused by chemotherapy or other mecha- chemotherapy (CIPN) are an increasingly frequent by different mechanisms. The substances that nisms, whether treatment needs to be modified problem. Contrary to haematologic side effects, most frequently cause CIPN are vinca alkaloids, or stopped due to CIPN, and what symptomatic which can be treated with haematopoetic taxanes, platin derivates, bortezomib, and tha- treatment should be recommended. growth factors, neither prophylaxis nor specific lidomide. Little is known about synergistic neu- Possible new approaches for the management treatment is available, and only symptomatic rotoxicity caused by previously given chemo- of CIPN could be genetic susceptibility, as there treatment can be offered. therapies, or concomitant chemotherapies. The are some promising advances with vinca alka- CIPN are predominantly sensory, duration-of- role of pre-existent neuropathies on the develop- loids and taxanes. Eur Assoc Neurooncol Mag treatment-dependent neuropathies, which de- ment of a CIPN is generally assumed, but not 2012; 2 (1): 25–36. velop after a typical cumulative dose. Rarely mo- clear.
    [Show full text]
  • Figure Chemotherapy Sequencing Chart
    6-Manchini_Cover 6/23/143:25PMPage20 2 0 l *Foll F i J First Chemotherapy Agent g o Y u o Vi Trastuzumab Topotecan Temsiro Streptozocin Rituximab Doxor D Pentostatin Pemetrexed Panitumumab Pac D Da Pac Oxa Mitoxantrone Mitomycin Methotrexate Mesna Cyclo D Dacarbazine Cytarabine C Mel Mechlorethamine Leucovorin C Ixabep Irinotecan Ifosfamide C Carboplatin Bl Bevacizumab Idar Gemcitabine Vinorelbine Vincristine Fluorourac Fl Etoposide Epir Be Y - u w SITE I isplatin etuximab armustine oxor ocetaxel actinomycin - r SAME u n e SITE COM n u e published guide published r THERAPEUTIC THERAPEUTIC d b o D p l l l N u d n u n i i i mycin arabine lastine U platin h taxel (Abraxane) taxel taxel b O amustine or b p u u a PLICATION alan icin i C icin N T T h b b l u D one l C os icin (Liposomal) icin icin l h b i R OMPATIBLE mus E o icin e U p i S l P h f G (5-FU) TED m A amide LI H TIBLE o N e t E h m e l i nes a r a t o p l y o S g Benda mustine Benda mustine e y q O u n Bevacizumab Bevacizumab e n c c o i l n o Bleo mycin Bleo mycin g g T1 y C ND ND ND ND ND , T h P Carbop latin C2 Carbop latin a h r a t r m Carmustine Carmustine R a c E y Cetuximab Cetuximab V G1 T1 P1 C1 I PD/T l N PD E , T T .
    [Show full text]
  • IXEMPRA Label
    HIGHLIGHTS OF PRESCRIBING INFORMATION ----------------------------CONTRAINDICATIONS------------------------------- These highlights do not include all the information needed to use ® ® • Hypersensitivity to drugs formulated with Cremophor EL (4). IXEMPRA safely and effectively. See full prescribing information for • Baseline neutrophil count <1500 cells/mm3 or a platelet count ® <100,000 cells/mm3 (4). IXEMPRA . • Patients with AST or ALT >2.5 x ULN or bilirubin >1 x ULN must not be treated with IXEMPRA in combination with capecitabine (4). ® IXEMPRA Kit (ixabepilone) for Injection, for intravenous infusion only ------------------------WARNINGS AND PRECAUTIONS----------------------- Initial U.S. Approval: 2007 • Peripheral Neuropathy: Monitor for symptoms of neuropathy, primarily sensory. Neuropathy is cumulative, generally reversible and should be WARNING: TOXICITY IN HEPATIC IMPAIRMENT managed by dose adjustment and delays (2.2, 5.1). See full prescribing information for complete boxed warning. • Myelosuppression: Primarily neutropenia. Monitor with peripheral blood ® IXEMPRA in combination with capecitabine must not be given to cell counts and adjust dose as appropriate (2.2, 5.2). patients with AST or ALT >2.5 x ULN or bilirubin >1 x ULN due to • Hypersensitivity reaction: Must premedicate all patients with an H1 increased risk of toxicity and neutropenia-related death. (4, 5.3) antagonist and an H2 antagonist before treatment (2.3, 5.4). • Fetal harm can occur when administered to a pregnant woman. Women ---------------------------RECENT
    [Show full text]
  • Study Protocol and Statistical Analysis Plan
    Ixabepilone CA163-157 TMHRI BMS-247550 Clinical Protocol Version: 8 TMHRI IRB#T 0908-0265T BMS Protocol #: CA163-157 ICE Trial RANDOMIZED OPEN-LABEL NEO-ADJUVANT PHASE II STUDY COMPARING IXABEPILONE (I) Vs IXABEPILONE PLUS CETUXIMAB (IC) IN TRIPLE NEGATIVE BREAST CANCER PATIENTS (ICE) VERSION: 8.0 DATE: 8/9/2012 PHASE: II IND Number: 104,307 Jenny Chang, MD. Director, Methodist Cancer Center The Methodist Hospital/Weill Cornell University 6445 Main Street, P21-341 Houston Texas, 77030 Phone: 713-441-0681 Fax: 713-793-1642 [email protected] Date: 08/09/2012 V. 8 TMHRI&BMS Page 1 of 83 Ixabepilone CA163-157 TMHRI BMS-247550 Clinical Protocol Version: 8 STUDY SUMMARY Title: Randomized open-label neo-adjuvant phase II study comparing ixabepilone (I) vs. ixabepilone plus cetuximab (IC) in Triple negative breast cancer patients Objectives: Primary Objective: 1. To determine the pathologic complete response rate (pCR) (breast and axilla) of Ixabepilone versus Ixabepilone when combined with cetuximab in patients with invasive breast adenocarcinoma T1N1-N3M0 or T2-4 N0-3M0 disease who are Triple negative and who are candidates for preoperative chemotherapy. Secondary Objective(s): 1. To evaluate overall objective response rate in both treatment groups. 2. To assess toxicity of each regimen. Exploratory Objectives: 1. To correlate the expression of biomarkers such as PTEN, EGFR and EGFR-pathway associated genes (including, but not limited to, TGF-, CRYAB, NRAS, KRAS, AKT3, PTEN, MEK1 and KRAS amplicon genes) with the objective clinical and pathologic response. 2. To potentially explore other gene/protein expression patterns, mutations and gene/chromosomal copy number alterations related to sensitivity or resistance to ixabepilone, other anti-microtubule agents and cetuximab.
    [Show full text]
  • Provincial Systemic Therapy Program
    July 2014 Volume 17, Number 7 For Health Professionals Who Care For Cancer Patients Inside This Issue: . Editor’s Choice – New Programs: Fludarabine, . List of New and Revised Protocols, Provincial Pre‐ Cyclophosphamide and Rituximab in CLL (LYFCR), 3‐Day Printed Orders and Patient Handouts – New: Etoposide, Ifosfamide with Mesna in Advanced Soft Tissue UHNNAVCAP, LYFCR, SAAVIME3; Revised: BRAJACTG, or Bony Sarcoma (SAAVIME3) BRAJACTT, UBRAJDAC, BRAVTR, CNAJTZRT, CNTEMOZ, . Provincial Systemic Therapy Program – Chinese and CNTEMOZMD, GICAPIRI, GIENDO2, GIFOLFIRI, Punjabi Translated Protocol Patient Handouts UGIPNEVER, GOBEP, GOCXCRT, GOOVVIN, UGUAXIT, GUBPWRT, HLHETCSPA, ULKATOATRA, ULKATOP, . Cancer Drug Manual – New: Lambrolizumab (Interim); ULUAVCRIZ; New Translated Protocol Patient Revised: Etoposide, Pazopanib, Temozolomide; Change in Handouts (Chinese & Punjabi): GIEFUPRT, GIFUART, Terminology to Non‐DEHP from Non‐PVC: Cabazitaxel, GIFUPART, GIGAIRT, GIRCRT Docetaxel, Etoposide, Ixabepilone, Paclitaxel, Temsirolimus, Teniposide . Website Resources and Contact Information . Benefit Drug List – New: LYFCR, SAAVIME3 EDITOR’S CHOICE NEW PROGRAMS The Provincial Systemic Therapy Program has approved the following programs effective 01 July 2014: Lymphoma: Fludarabine, Cyclophosphamide and Rituximab for Chronic Lymphocytic Leukemia (CLL) (LYFCR) – The BCCA Lymphoma Tumour Group has introduced this new treatment program for CLL patients with high‐ risk disease (e.g. deletion in chromosome 11 [11q deletion]) who are young and fit. Currently, the treatment standard for CLL in British Columbia is fludarabine and rituximab (LYFLUDR). This regimen balances efficacy with tolerability in most CLL patients, whose median age of diagnosis is 72 years and many of whom may have comorbidities. Phase III data have shown that in patients who are young and fit, the combination of fludarabine, cyclophosphamide and rituximab is associated with a higher response rate compared to fludarabine and cyclophosphamide alone (65% vs.
    [Show full text]