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Larotaxel

larotaxel is a semi-synthetic derivative of the taxane 10-deacetylbaccatin III with potential antineoplastic activities. Larotaxel binds to tubulin, promoting microtubule assembly and stabilization and preventing microtubule depolymerization, thereby inhibiting cell proliferation. As it represents poor substrate for P-glycoprotein-related drug resistance mechanisms, this agent may be useful for treating multi-drug resistant tumors. Larotaxel penetrates the blood brain barrier. Check for active clinical trials or closed clinical trials using this agent. (NCI Thesaurus).

Current developer:    sanofi-aventis

Chemical structure:  The chemical structure of larotaxel is similar to that of docetaxel except there is a cyclopropane ring in the molecule of larotaxel:

Highlight on most recent research using larotaxel

Phase I study of larotaxel (XRP9881) with carboplatin in chemotherapy-naïve patients with stage IIIB or stage IV non-small cell lung cancer. (data published in 2010). PURPOSE: This primary objective of this phase I dose-escalation study was to define the maximum tolerated dose (MTD) and dose limiting toxicity (DLT) of larotaxel administered in combination with carboplatin in chemotherapy-naïve patients with advanced/metastatic non-small cell lung cancer (NSCLC). METHODS: Eighteen patients with stage IIIB or IV NSCLC, in cohorts of three to six evaluable patients, were to receive every 3 weeks: larotaxel beginning at 45 mg/m(2) administered as a 1-h infusion, followed after 30 min by carboplatin (area under the concentration-time curve (AUC) = 6 mg/mL × min, later AUC = 5) as a 1-h infusion. Dose escalation of larotaxel up to 90 mg/m(2) was permitted according to DLT occurrence. Patients received ondansetron as prophylactic anti-emetic premedication. RESULTS: In view of the toxicity encountered, the carboplatin dose was decreased for the later part of the study to AUC = 5 mg/mL × min. Eight of 18 treated patients experienced DLTs in the first cycle, including neutropenia and associated complications, diarrhea and fatigue. The MTD of the combination was defined as larotaxel 60 mg/m(2) with a carboplatin AUC of 6 mg/mL × min. Neutropenia, reported at grade 3/4 in 15/18 patients (83%), was the most common severe adverse event, reaching grade 4 in 14 patients (78%). Eleven patients (61%) experienced grade 3/4 non-hematological toxicity, predominantly dehydration, fatigue, infection, nausea and vomiting. One patient (6%) achieved a partial response and 11 (61%) had stable disease. CONCLUSIONS: The combination of larotaxel and carboplatin is feasible and shows modest activity in chemotherapy-naïve patients with advanced/metastatic NSCLC. The principal toxicity was grade 3/4 neutropenia. [source: Cancer Chemother Pharmacol. 2010 Jan;65(2):227-34. A phase I study of larotaxel (XRP9881) administered in combination with carboplatin in chemotherapy-naïve patients with stage IIIB or stage IV non-small cell lung cancer. Robert F, Harper K, Ackerman J, Gupta S. UAB Comprehensive Cancer Center, University of Alabama at Birmingham, 35294-3300, USA. pacorobertuab@cs.com].

Larotaxel: broadening the road with new taxanes. (data published in 2009). Significant advances in cancer treatment have been achieved with novel targeted and state-of-the-art treatments. While the targeted treatments have received much attention in recent years, the more 'traditional' chemotherapeutic agents continue to play an important role in several malignancies. Former taxanes such as docetaxel and paclitaxel, with their broad anticancer activity, have contributed significantly to the improved treatment of a number of neoplastic diseases. Unfortunately, until now, the achievements obtained with these compounds have been mitigated by clinical limitations such as acquired or intrinsic resistance of tumors, poor CNS activity, allergic reactions and unfavorable toxicity profiles. Larotaxel (RPR 109881A) is a taxane analogue with a broad spectrum of activity and different toxicity profile and with the possible advantages of surpassing some mechanisms of resistance and penetrating into the CNS. The development path of this drug, its core clinical data and future treatment perspectives are discussed in this article. [source: Expert Opin Investig Drugs. 2009 Aug;18(8):1183-9. Larotaxel: broadening the road with new taxanes. Metzger-Filho O, Moulin C, de Azambuja E, Ahmad A. Research Fellow, Jules Bordet Institute, 121, Bd. de Waterloo, 1000 Brussels, Belgium. otto.metzger@bordet.be].

Phase II trial of larotaxel (XRP9881) in patients with metastatic breast cancer who previously received taxane-based therapy.( Date published in 2008.).  BACKGROUND: Treatment options are limited for patients with refractory metastatic breast cancer (MBC). Larotaxel (XRP9881) is a novel taxoid with preclinical activity against taxane-resistant breast cancer. The current phase II trial of larotaxel was conducted in women with taxane-treated MBC. PATIENTS AND METHODS: Patients were stratified by response to prior taxane therapy (resistant or nonresistant). Larotaxel 90 mg/m(2) was administered as a 1-h infusion every 3 weeks. Patients were evaluated for tumor response every two cycles. A blinded external response review committee determined the overall response rate (ORR), duration of response (DOR), and time to progression (TtP) of the disease. Median survival time (MST) and safety were also evaluated. RESULTS: One hundred and thirty patients were treated. In the nonresistant group, the ORR was 42%; median DOR 5.3 months; median TtP 5.4 months; and MST 22.6 months. In the resistant group, the ORR was 19%; median DOR 5.0 months; median TtP 1.6 months; and MST 9.8 months. The most common grade 3/4 adverse events were neutropenia (82%), fatigue (15%), diarrhea (12%), febrile neutropenia (9%), neutropenic infection (8%), and sensory neuropathy (7%). CONCLUSIONS: Larotaxel has good activity, manageable toxicity, and a favorable therapeutic index in women with taxane-pretreated MBC. [source: Ann Oncol. 2008 Jul;19(7):1255-60. Epub 2008 Apr 1.Phase II multicenter study of larotaxel (XRP9881), a novel taxoid, in patients with metastatic breast cancer who previously received taxane-based therapy. Diéras V, Limentani S, Romieu G, Tubiana-Hulin M, Lortholary A, Kaufman P, Girre V, Besenval M, Valero V. Department of Medical Oncology, Institut Curie, Paris, France. veronique.dieras@curie.net. To download the free paper: http://annonc.oxfordjournals.org/content/19/7/1255.long]. 

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42. Tamas Nagykalnai; Laszlo Landherr; Edina Meszaros Treatment possibilities in breast cancer progressing after anthracyclines and/or taxanes. Magyar onkologia (2010), 54(1), 9-16. 

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45. Zatloukal Petr; Gervais Radj; Vansteenkiste Johan; Bosquee Leon; Sessa Christiana; Brain Etienne; Dansin Eric; Urban Thierry; Dohollou Nadine; Besenval Michele; Quoix Elisabeth Randomized multicenter phase II study of larotaxel (XRP9881) in combination with cisplatin or gemcitabine as first-line chemotherapy in nonirradiable stage IIIB or stage IV non-small cell lung cancer. Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer (2008), 3(8), 894-901. 

46. Dieras V; Limentani S; Romieu G; Tubiana-Hulin M; Lortholary A; Kaufman P; Girre V; Besenval M; Valero V Phase II multicenter study of larotaxel (XRP9881), a novel taxoid, in patients with metastatic breast cancer who previously received taxane-based therapy. Annals of oncology : official journal of the European Society for Medical Oncology / ESMO (2008), 19(7), 1255-60.