A phase II study of paclitaxel poliglumex in combination with transdermal estradiol for the treatment of metastatic castration-resistant prostate cancer after docetaxel chemotherapy.

Knight Cancer Institute, Oregon Health and Science University, 3303 SW Bond Ave., Portland, OR 97239, USA.
Anti-cancer drugs (Impact Factor: 2.23). 12/2009; 21(4):433-8. DOI: 10.1097/CAD.0b013e3283355211
Source: PubMed

ABSTRACT Taxanes remain the only agents to extend survival in castration-resistant metastatic prostate cancer, but their impact on the natural history of this disease is modest. We sought to test the hypothesis that increased delivery of taxane chemotherapy to the tumor through the use of a macromolecular polymer-drug conjugate of paclitaxel modulated by estradiol could extend the utility of this class of drugs. Patients with metastatic adenocarcinoma of the prostate who progressed despite standard hormonal therapy and after docetaxel-containing chemotherapy were treated with transdermal estradiol (0.2 mg/24 h) for 4 weeks followed by the same dose of transdermal estradiol and paclitaxel poliglumex (PPX; 150 mg/m intravenous) every 28 days. The primary objective was to determine the level of activity of the regimen measured using a fraction of patients who experienced a confirmed decline in serum prostate-specific antigen (PSA) of 50% or more. A two-stage phase II study designed to identify a response rate of > or =25% required three responders among 21 patients in the first stage. Twenty-one patients who received a median of two earlier chemotherapy regimens were enrolled in the trial between March 2007 and May 2008. During the estradiol-only treatment phase, no patient had a PSA decline in excess of 50% and lesser PSA declines that ranged from 8.8 to 34.1% were seen in five patients. No patients achieved a > or =50% PSA decline following the addition of PPX and there were no responses in measurable disease. The median time to progression was 4 weeks. In conclusion, this regimen of low-dose transdermal estradiol induction followed by PPX does not have activity in taxane pretreated patients with castration-resistant prostate cancer.

  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: The field of nanotechnology has exploded in recent years with diverse arrays of applications. Cancer therapeutics have recently seen benefit from nanotechnology with the approval of some early nanoscale drug delivery systems. A diversity of novel delivery systems are currently under investigation and an array of newly developed, customized particles have reached clinical application. Drug delivery systems have traditionally relied on passive targeting via increased vascular permeability of malignant tissue, known as the enhanced permeability and retention effect (EPR). More recently, there has been an increased use of active targeting by incorporating cell specific ligands such as monoclonal antibodies, lectins, and growth factor receptors. This customizable approach has raised the possibility of drug delivery systems capable of multiple, simultaneous functions, including applications in diagnostics, imaging, and therapy which is paving the way to improved early detection methods, more effective therapy, and better survivorship for cancer patients.
    Pharmaceutics 12/2011; 3(2):171-185.
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: The concept of utilizing polymers in drug delivery has been extensively explored for improving the therapeutic index of small molecule drugs. In general, polymers can be used as polymer-drug conjugates or polymeric micelles. Each unique application mandates its own chemistry and controlled release of active drugs. Each polymer exhibits its own intrinsic issues providing the advantage of flexibility. However, none have as yet been approved by the U.S. Food and Drug Administration. General aspects of polymer and nano-particle therapeutics have been reviewed. Here we focus this review on specific clinically relevant anticancer polymer paclitaxel therapeutics. We emphasize their chemistry and formulation, in vitro activity on some human cancer cell lines, plasma pharmacokinetics and tumor accumulation, in vivo efficacy, and clinical outcomes. Furthermore, we include a short review of our recent developments of a novel poly(L-g-glutamylglutamine)-paclitaxel nano-conjugate (PGG-PTX). PGG-PTX has its own unique property of forming nano-particles. It has also been shown to possess a favorable profile of pharmacokinetics and to exhibit efficacious potency. This review might shed light on designing new and better polymer paclitaxel therapeutics for potential anticancer applications in the clinic.
    Cancers. 03/2010; 3(1):17-42.
  • [Show abstract] [Hide abstract]
    ABSTRACT: In recent years, potential uses and therapeutic benefits of polymer anticancer therapeutics are enormous. Over the past decades, cancer is one of the leading causes of mortality in the world. Many clinically approved chemotherapeutics severely encountering potential challenges against deadly cancer. Moreover, safetyand efficacy of anticancer agents have been limited by undesirable pharmacokinetics and biodistribution in the body.To address these limitations, various polymer drug conjugations are being studied and developed to improve the antitumor efficacy. Among other therapeutics, polymer therapeutics are well established platforms that circumvent anticancer therapeutics from enzymatic metabolism via direct conjugation to therapeutic molecules. Interestingly, polymer therapeutics will meet an unmet need of small molecules. The knowledge is thatpolymer-drug conjugation can achieve desired pharmacokinetics and biodistribution propertiesof several anticancer drugs. The present review mainly enlightens the most recent preclinical and clinical studies include safety, stability, pharmacokinetic behavior and distribution of polymer therapeutics.
    Current Drug Metabolism 12/2014; · 3.49 Impact Factor