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Cabazitaxel
Description of Cabazitaxel: Cabazitaxel is a semi-synthetic derivative of the natural taxoid 10-deacetylbaccatin III with potential antineoplastic activity. Cabazitaxel binds to and stabilizes tubulin, resulting in the inhibition of microtubule depolymerization and cell division, cell cycle arrest in the G2/M phase, and the inhibition of tumor cell proliferation. Unlike other taxane compounds, this agent is a poor substrate for the membrane-associated, multidrug resistance (MDR), P-glycoprotein (P-gp) efflux pump and may be useful for treating multidrug-resistant tumors. In addition, cabazitaxel penetrates the blood-brain barrier (BBB). Check for active clinical trials or closed clinical trials using this agent. (NCI Thesaurus).
Cabazitaxel was developed by sanofi-aventis and was approved in 2010. JEVTANA (cabazitaxel injection) ® is a microtubule inhibitor indicated in combination with prednisone for the treatment of patients with hormone-refractory metastatic prostate cancer previously treated with a docetaxel-containing treatment regimen..
In a phase III trial with 755 men for the treatment of hormone-refractory prostate cancer, median survival was 15.1 months for patients receiving cabazitaxel versus 12.7 months for patients receiving mitoxantrone. Cabazitaxel was associated with more grade 3-4 neutropenia (81.7%) than mitoxantrone (58%). [source: http://en.wikipedia.org/wiki/Cabazitaxel]
According to Villanueva et al's review paper, Resistance represents a major obstacle to successful cancer treatment; therefore, the development of an agent that overcomes common mechanisms of resistance is a welcome advance. The efficacy of cabazitaxel in clinical studies is consistent with its preclinical profile, in which it has demonstrated activity in a number of chemotherapyresistant tumour models. The pharmacokinetic data for cabazitaxel demonstrated dose proportionality, with a high plasma clearance and a long terminal half-life. The very large volume of distribution at steady state suggests extensive penetration into tissues. Of interest, cabazitaxel is able to cross the blood-brain barrier in preclinical models.
Cabazitaxel is associated with a manageable and acceptable safety profile. Although, in the TROPIC trial, cabazitaxel treatment was associated with a higher number of deaths during the treatment period as a result of neutropenia and diarrhoea, mandatory provision of well structured contingency plans, including patient education, access to acute specialized care, haematopoietic growth factor support, antimicrobials and supportive care will help to mitigate against these adverse events. Future studies will assess whether a cabazitaxel dose of 20 mg/m2 every 3 weeks is associated with similar efficacy and safety to the 25 mg/m2 dose (PROSELICA), and a phase III trial will compare cabazitaxel with docetaxel and prednisone in patients with mCRPC not previously treated with chemotherapy.
Cabazitaxel is a very promising novel antineoplastic agent that has been approved in the US and Europe for the treatment of men with mCRPC whose disease has progressed following treatment with docetaxel-based chemotherapy. The emergence of this new chemotherapeutic agent is very encouraging in an era otherwise dominated by new, biological anticancer agents. (source: Villanueva C, Bazan F, Kim S, Demarchi M, Chaigneau L, Thiery-Vuillemin A, Nguyen T, Cals L, Dobi E, Pivot X. Cabazitaxel: a novel microtubule inhibitor. Drugs. 2011 Jul 9;71(10):1251-8.)
Chemical structure of cabazitaxel Comparing to the chemical structure of docetaxel, cabazitaxel has two more methyl groups. For this reason, cabazitaxel is also called dimethoxydocetaxel (see the following chemical structures).
Scheme 1: chemical structures of cabazitaxel and docetaxel
Cabazitaxel: Drug Description JEVTANA (cabazitaxel) is an antineoplastic agent belonging to the taxane class. It is prepared by semi-synthesis with a precursor extracted from yew needles. The chemical name of cabazitaxel is (2α,5β;,7β;,10β;,13α)-4-acetoxy-13-({(2R,3S)-3[(tertbutoxycarbonyl) amino]-2-hydroxy-3-phenylpropanoyl}oxy)-1-hydroxy-7,10-dimethoxy-9oxo-5,20-epoxytax-11-en-2-yl benzoate – propan-2-one(1:1). Cabazitaxel is a white to off-white powder with a molecular formula of C45H57NO14•C3H6O and a molecular weight of 894.01 (for the acetone solvate) / 835.93 (for the solvent free). It is lipophilic, practically insoluble in water and soluble in alcohol. JEVTANA (cabazitaxel) Injection 60 mg/1.5 mL is a sterile, non-pyrogenic, clear yellow to brownish-yellow viscous solution and is available in single-use vials containing 60 mg cabazitaxel (anhydrous and solvent free) and 1.56 g polysorbate 80. Each mL contains 40 mg cabazitaxel (anhydrous) and 1.04 g polysorbate 80. DILUENT for JEVTANA is a clear, colorless, sterile, and non-pyrogenic solution containing 13% (w/w) ethanol in water for injection, approximately 5.7 mL. JEVTANA requires two dilutions prior to intravenous infusion. JEVTANA injection should be diluted only with the supplied DILUENT for JEVTANA, followed by dilution in either 0.9% sodium chloride solution or 5% dextrose solution.
Cabazitaxel: Mechanism of Action The taxanes act by binding to microtubules, cytoskeletal polymers composed of α-tubulin and β-tubulin heterodimers. The binding of taxanes to tubulin promotes the stabilization of GDP-bound tubulin in the microtubule resulting in inhibition of disassembly and prevention of subsequent mitosis and cell division. Derived from the bark of yew trees, in 1992, paclitaxel was the first taxane approved by the Food and Drug Administration (FDA) as an anti-neoplastic agent. Docetaxel, a semisynthetic analog with increased potency, was approved by the FDA in 1996 for the treatment advanced breast cancer and later in 2004 for the treatment of metastatic CRPC. These earlier generation taxanes have high substrate affinity for the ATP-dependent drug efflux pump P-glycoprotein 1 (P-gp1). Therefore, P-gp1 is thought to account for, at least in part, both inherent and acquired resistance to these agents.
Cabazitaxel, also known as XRP6258, is a semi-synthetic taxane from a
single diastereoisomer of 10-deacetyl baccatin III, and derived from the
needles of various Taxus species. By binding to tubulin, cabazitaxel
inhibits microtubule depolymerization and cell division, resulting in
cell cycle arrest. This compound was selected for clinical testing due
to its poor affinity for ATP-dependent drug efflux pump P-gp1, and its
greater blood-brain barrier penetration compared to paclitaxel and
docetaxel. Cabazitaxel has also demonstrated superior in vitro
cytotoxicity compared to docetaxel in several murine and human cancer
cell lines. (source: Clinical Development of Cabazitaxel for the
Treatment of Castration-Resistant Prostate Cancer . Che-Kai Tsao, Sonia
Seng, William K. Oh, and Matthew D. Galsky
Highlight on most recent research using cabazitaxel
New clinical trial results: cabazitaxel (XRP6258) plus capecitabine in patients with metastatic breast cancer progressing after anthracycline and taxane treatment.: Most patients with metastatic breast cancer (MBC) progress after chemotherapy. Cabazitaxel (XRP6258) is a new taxoid that is active in chemotherapy-resistant tumour cell lines. The objectives of this phase I/II study were to assess the maximum tolerated dose (MTD), safety profile, pharmacokinetics, and activity of cabazitaxel plus capecitabine in patients with MBC who had been previously treated with taxanes and anthracyclines. RESULTS: Thirty-three patients were enrolled and treated (15 in part I; 18 in part II). Cabazitaxel 20mg/m(2) plus capecitabine 1000mg/m(2) was the MTD. Pharmacokinetic analysis showed no apparent drug-drug interaction. In all patients, the main grade 3-4 toxicities were asthenia (n=5), hand-foot syndrome (n=5), neutropenia (n=21), neutropenic infection (n=1), and neutropenic colitis (n=1). One patient had febrile neutropenia. Antitumour activity was observed at all dose-levels with two complete responses, five partial responses (PRs), and 20 disease stabilisations (seven unconfirmed PR). At the MTD, 21 patients were evaluable for efficacy. The ORR was 23.8% (95% CI: 8.2-47.2%). The median response duration was 3.1months (95% CI: 2.1-8.4months), with four of five lasting for more than 3months. Median time to progression was 4.9months. CONCLUSIONS: Cabazitaxel combined with capecitabine is active, has a safety profile consistent with a taxane plus capecitabine combination and warrants further investigation in patients with MBC. [source: Eur J Cancer. 2011 May;47(7):1037-45. ]
Phase III trial of cabazitaxel for the treatment of metastatic castration-resistant prostate cancer. For patients with metastatic castration-resistant prostate cancer (mCRPC), the current standard of care is chemotherapy involving the tubulin-binding taxane docetaxel. However, as the tumor cells become resistant to docetaxel-based therapy, disease progression is inevitable, and until recently there was no further available treatment beyond palliative care. In June 2010, cabazitaxel, a next-generation taxane, was approved by the US FDA for the treatment of mCRPC that has progressed after docetaxel therapy. This article describes the background and rationale of cabazitaxel's development and the clinical study program that led to its FDA approval, focusing on the Phase III TROPIC trial that demonstrated the efficacy of cabazitaxel plus prednisone in the treatment of mCRPC. Future development of this therapy and others under investigation is discussed. [source: Future Oncol. 2011 Apr;7(4):497-506.]
Cabazitaxel for the treatment of prostate cancer. Prostate cancer is a frequently diagnosed male cancer. In men presenting locally advanced or metastatic disease, the mainstay of treatment is hormonal suppression. Despite the castrate levels of testosterone, with time, prostate cancer gradually evolves into a castration-refractory state. Chemotherapeutic agents are able to influence the natural history of metastatic castration-resistant prostate cancer. Docetaxel is a clinically relevant, FDA-approved taxane. Today, it is the first-line chemotherapeutic agent in castration-refractory prostate cancer (CRPC). There is no standard second-line chemotherapeutic regimen. Areas covered: This review provides information on the efficacy of cabazitaxel as a second-line treatment for CRPC. The medline database was searched for clinical trials on chemotherapeutical treatment options of castration-resistant prostate cancer. All available data on the efficacy of cabazitaxel are summarized. Expert opinion: New treatment strategies for castration-resistant prostate cancer should primarily focus on quality of life. In this view, vaccination therapy seems promising because of the acceptable level of toxicity. However, more research is needed to prove their efficacy in the treatment of castration-resistant prostate cancer. Cabazitaxel seems to be a promising second-line therapy in CRPC. [source: Expert Opin Pharmacother. 2011 Apr;12(6):977-82.]
Cabazitaxel: a novel second-line treatment for metastatic castration-resistant prostate cancer. Until recently, patients with castration-resistant prostate cancer (CRPC) had limited therapeutic options once they became refractory to docetaxel chemotherapy, and no treatments improved survival. This changed in June 2010 when the Food and Drug Administration (FDA) approved cabazitaxel as a new option for patients with CRPC whose disease progresses during or after docetaxel treatment. For most of these patients, cabazitaxel will now replace mitoxantrone (a drug that was FDA-approved because of its palliative effects) as the treatment of choice for docetaxel-refractory disease. The approval of cabazitaxel was based primarily on the TROPIC trial, a large (n = 755) randomized Phase III study showing an overall median survival benefit of 2.4 months for men with docetaxel-pretreated metastatic CRPC receiving cabazitaxel (with prednisone) compared to mitoxantrone (with prednisone). Cabazitaxel is a novel tubulin-binding taxane that differs from docetaxel because of its poor affinity for P-glycoprotein (P-gp), an ATP-dependent drug efflux pump. Cancer cells that express P-gp become resistant to taxanes, and the effectiveness of docetaxel can be limited by its high substrate affinity for P-gp. Preclinical and early clinical studies show that cabazitaxel retains activity in docetaxel-resistant tumors, and this was confirmed by the TROPIC study. Common adverse events with cabazitaxel include neutropenia (including febrile neutropenia) and diarrhea, while neuropathy was rarely observed. Thus, the combination of cabazitaxel and prednisone is an important new treatment option for men with docetaxel-refractory metastatic CRPC, but this agent should be administered cautiously and with appropriate monitoring (especially in men at high risk of neutropenic complications). [source: Drug Des Devel Ther. 2011 Mar 10;5:117-24.]
Cabazitaxel for the treatment of castration-resistant prostate cancer: Treatment with docetaxel-based chemotherapy results in improved survival in patients with metastatic castration-resistant prostate cancer. However, all patients eventually develop progressive disease associated with poor outcomes. In this article, we discuss the available second-line therapeutic options following docetaxel, with a special focus on cabazitaxel, which is the first agent to yield extended survival as second-line therapy following docetaxel. Cabazitaxel, a novel semi-synthetic taxane, is effective even in docetaxel-resistant model systems. Recently, results of the Phase III TROPIC trial demonstrated improved survival with cabazitaxel plus prednisone compared with mitoxantrone and prednisone in patients with progressive metastatic castration-resistant prostate cancer, following prior docetaxel, which led to approval by the US FDA. (See: Future Oncol. 2011 Jan;7(1):15-24.).
Cabazitaxel fills one of the gaps in the treatment of prostate cancer: Prostate cancer is the second most frequently diagnosed cancer in men and the fifth most common cancer overall. Globally, more than 900,000 new cases of prostate cancer will be diagnosed in 2010 and more than 260,000 will, unfortunately, die from the disease. In the US, an estimated 217,000 new cases of prostate cancer and 32,000 deaths are expected this year. Definitive therapy (surgery or radiation) is highly effective, but if the tumor escapes the gland, treatment options are limited. For this population of patients, androgen suppression is the cornerstone of initial therapy. Furthermore, progression to castration resistant prostate cancer (CRPC) is inevitable. The current front-line treatment for patients with CRPC is the chemotherapeutic agent docetaxel (administered every 3 weeks). Until now, it is the only agent that has been shown to prolong survival in CRPC. The approval trial for docetaxel found a median overall survival of 19.2 months for patients receiving docetaxel plus prednisone compared to 16.3 months for patients receiving mitoxantrone plus prednisone (p=0.0094). Mitoxantrone plus prednisone is often utilized for its palliative benefits, but two randomized trials failed to demonstrate a survival advantage. (see Cancer Biol Ther. 2011 Jan 12;10(12):1233-4.).
1: Guancial EA, Taplin ME. Case Report: Responses to
Cabazitaxel in Metastatic Castration-Resistant Prostate Cancer After
Extensive Docetaxel Treatment. Clin Genitourin Cancer. 2011 Aug 2. [Epub
ahead of print] PubMed PMID: 21816687.
Cabazitaxel related patents: 1. Billot, Pascal; Dufraigne, Marielle; Elmaleh,
Hagit; Guiliani, Alexandre; Mangin, Fabrice; Rortais, Patricia; Zaske,
Lionel. Crystalline forms of dimethoxy docetaxel and methods for
preparing same. PCT Int. Appl. (2009), 16pp.; Chemical Indexing
Equivalent to 151:181550 (FR). CODEN: PIXXD2 WO 2009115655 A2 20090924
CAN 151:366528 AN 2009:1165562 |
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