A phase 2 study of patupilone in patients with metastatic castration-resistant prostate cancer previously treated with docetaxel: Canadian Urologic Oncology Group study P07a

N., Kim; Beardsley, Emma Kate; Eigl, Bernhard J.; Venner, Peter; Hotte, S. J.; Winquist, Eric; Ko, Yu Chieh; Sridhar, Srikala S.; Weber, Dirk; Saad, Fred

doi:10.1093/annonc/mdr336

Cited by 32 publications

(13 citation statements)

References 15 publications

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“…The PSA response rate and PFS observed in our sagopilone study are comparable to those reported for ixabepilone and patupilone (Galsky et al , 2005; Hussain et al , 2005; Chi et al , 2012). Differences between these compounds are more evident in the toxicity profiles: neutropenia and neuropathy associated with ixabepilone (Galsky et al , 2005; Hussain et al , 2005), diarrhoea associated with patupilone (Chi et al , 2012), and neuropathy associated with sagopilone.…”

Section: Discussionsupporting

confidence: 86%

“…Efforts have been directed towards evaluating the role of epothilones in metastatic CRPC, and to date two epothilones, ixabepilone and patupilone, have been investigated for the treatment of this disease (Galsky et al , 2005; Hussain et al , 2005, 2009; Chi et al , 2012). In a phase II study, weekly patupilone (2.5 mg m −2 ) showed minimal activity in patients with PC (Hussain et al , 2009), although response improved with 3-weekly patupilone (8 mg m −2 ) in a second phase II study (Chi et al , 2012). More robust activity was seen with ixabepilone, although this was not significantly different from that observed with docetaxel (Galsky et al , 2005; Hussain et al , 2005).…”

Section: Discussionmentioning

confidence: 99%

“…Differences between these compounds are more evident in the toxicity profiles: neutropenia and neuropathy associated with ixabepilone (Galsky et al , 2005; Hussain et al , 2005), diarrhoea associated with patupilone (Chi et al , 2012), and neuropathy associated with sagopilone. Patupilone may present an alternative to cabazitaxel, but perhaps only for patients with significant residual haematological toxicity following docetaxel.…”

Section: Discussionmentioning

confidence: 99%

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Phase II study of first-line sagopilone plus prednisone in patients with castration-resistant prostate cancer: a phase II study of the Department of Defense Prostate Cancer Clinical Trials Consortium

et al. 2012

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Background:Preclinical studies in prostate cancer (PC) models demonstrated the anti-tumour activity of the first fully synthetic epothilone, sagopilone. This is the first study to investigate the activity and safety of sagopilone in patients with metastatic castration-resistant PC (CRPC).Methods:Chemotherapy-naïve patients with metastatic CRPC received sagopilone (one cycle: 16 mg m−2 intravenously over 3 h q3w) plus prednisone (5 mg twice daily). The primary efficacy evaluation was prostate-specific antigen (PSA) response rate (⩾50% PSA reduction confirmed ⩾28 days apart). According to the Simon two-stage design, ⩾3 PSA responders were necessary within the first 13 evaluable patients for recruitment to continue until 46 evaluable patients were available.Results:In all, 53 patients received ⩾2 study medication cycles, with high compliance. Mean individual dose was 15.1±1.4 mg m−2 during initial six cycles, mean dose intensity 94±9%. The confirmed PSA response rate was 37%. Median overall progression-free survival was 6.4 months. The most commonly reported adverse events (>10% of patients) were peripheral neuropathy (94.3%), fatigue (54.7%) and pain in the extremities (47.2%). Sagopilone was associated with very little haematological toxicity.Conclusion:This study shows that first-line sagopilone has noteworthy anti-tumour activity and a clinically significant level of neuropathy for patients with metastatic chemotherapy-naïve CRPC.

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Section: Discussionsupporting

confidence: 86%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Phase II study of first-line sagopilone plus prednisone in patients with castration-resistant prostate cancer: a phase II study of the Department of Defense Prostate Cancer Clinical Trials Consortium

et al. 2012

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“…8) was approved for monotherapy against metastatic breast cancer by the FDA in 2007, and is currently in many trials from Phase I to Phase III against a variety of carcinomas. Although it reached Phase III trials with Novartis, epothilone B or patupilone was withdrawn from the Phase III level but it is currently in a number of Phase II trials under the auspices of Novartis, and recently, data from a recent Phase II trial was published demonstrating activity in prostate cancer [76]. Dehydelone (didehydroepothilone D) was in Phase II trials as late as 2008 (Fig.…”

Section: The Role Of Microorganisms In Drug Discoverymentioning

confidence: 99%

Natural products: A continuing source of novel drug leads

Cragg

Newman

2013

Biochimica et Biophysica Acta (BBA) - General Subjects

2,437

1,525

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1. Background Nature has been a source of medicinal products for millennia, with many useful drugs developed from plant sources. Following discovery of the penicillins, drug discovery from microbial sources occurred and diving techniques in the 1970s opened the seas. Combinatorial chemistry (late 1980s), shifted the focus of drug discovery efforts from Nature to the laboratory bench. 2. Scope of Review This review traces natural products drug discovery, outlining important drugs from natural sources that revolutionized treatment of serious diseases. It is clear Nature will continue to be a major source of new structural leads, and effective drug development depends on multidisciplinary collaborations. 3. Major Conclusions The explosion of genetic information led not only to novel screens, but the genetic techniques permitted the implementation of combinatorial biosynthetic technology and genome mining. The knowledge gained has allowed unknown molecules to be identified. These novel bioactive structures can be optimized by using combinatorial chemistry generating new drug candidates for many diseases. 4 General Significance: The advent of genetic techniques that permitted the isolation / expression of biosynthetic cassettes from microbes may well be the new frontier for natural products lead discovery. It is now apparent that biodiversity may be much greater in those organisms. The numbers of potential species involved in the microbial world are many orders of magnitude greater than those of plants and multi-celled animals. Coupling these numbers to the number of currently unexpressed biosynthetic clusters now identified (>10 per species) the potential of microbial diversity remains essentially untapped.

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“…Importantly, patupilone is also not affected by common tumor resistance mechanisms, including β-tubulin mutation and overexpression of drug efflux pumps 46–49. Its antitumor activity has been shown in several clinical trials with various tumor types, including prostate, ovarian, and colon cancers 50–53…”

Section: Mechanisms Of Action Of Mbasmentioning

confidence: 99%

Microtubule-targeting agents in oncology and therapeutic potential in hepatocellular carcinoma

Loong¹,

Park²

2014

OTT

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Abstract:In mammalian cells, microtubules are present both in interphase and dividing cells. In the latter, microtubules forming the mitotic spindle are highly dynamic and exquisitely sensitive to therapeutic inhibitors. Developed to alter microtubule function, microtubule-binding agents have been proven to be highly active as an anticancer treatment. Significant development of microtubule-binding agents has taken place in recent years, with newer anti-tubulin agents now showing novel properties of enhanced tumor specificity, reduced neurotoxicity, and insensitivity to chemoresistance mechanisms. Hepatocellular carcinoma remains one of the most difficult cancers to treat, with chemotherapies being relatively ineffective. There is now evidence to suggest that microtubule-binding agents may be effective in the treatment of hepatocellular carcinoma, especially when used in combination with mammalian target of rapamycin inhibitors. Preclinical models have suggested that the latter may be able to overcome resistance to microtubule binding agents. In this review article, recent developments of novel microtubule binding agents and their relevance to the treatment of hepatocellular carcinoma will be discussed.

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A phase 2 study of patupilone in patients with metastatic castration-resistant prostate cancer previously treated with docetaxel: Canadian Urologic Oncology Group study P07a

Abstract: Patupilone at 8 mg/m2 was tolerable, had antitumor activity, and was associated with symptomatic improvement in patients previously treated with docetaxel.

Cited by 32 publications

References 15 publications

Phase II study of first-line sagopilone plus prednisone in patients with castration-resistant prostate cancer: a phase II study of the Department of Defense Prostate Cancer Clinical Trials Consortium

Phase II study of first-line sagopilone plus prednisone in patients with castration-resistant prostate cancer: a phase II study of the Department of Defense Prostate Cancer Clinical Trials Consortium

Natural products: A continuing source of novel drug leads

Microtubule-targeting agents in oncology and therapeutic potential in hepatocellular carcinoma

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