Paclitaxel poliglumex and carboplatin as first-line therapy in ovarian, peritoneal or fallopian tube cancer: A phase I and feasibility trial of the Gynecologic Oncology Group

Section of Gynecologic Oncology, Fox Chase Cancer Center, Philadelphia, PA 19111-2497, USA.
Gynecologic Oncology (Impact Factor: 3.77). 06/2008; 110(3):329-35. DOI: 10.1016/j.ygyno.2008.05.008
Source: PubMed


To estimate the maximum tolerated dose (MTD) of paclitaxel poliglumex (PPX) in combination with carboplatin in patients with chemotherapy-naive ovarian, primary peritoneal or fallopian tube cancer, and to assess the feasibility of administering multiple cycles of this regimen.
The first 11 patients were treated in a standard 3 + 3 dose-seeking design, with carboplatin held constant at area under the curve (AUC) of 6 and PPX at 225, 175 or 135 mg/m(2). Pharmacokinetics of PPX and carboplatin were evaluated during this dose-seeking component of the trial. MTD was defined by acute dose-limiting toxicities (DLT) in the first cycle. Twenty additional evaluable patients were treated at the estimated MTD to assess the feasibility of this regimen over >or=4cycles.
PPX at 225 mg/m(2) resulted in DLT in 2/3 patients, and was de-escalated first to 175 mg/m(2) and then to 135 mg/m(2). PPX slowly hydrolyzed to paclitaxel and did not alter the pharmacokinetics of carboplatin. DLT within the first 4-cycles were observed in 3 patients (15%) treated at the MTD: neutropenia > 2weeks (2), febrile neutropenia (1). Nineteen patients (95%) experienced grade 4 neutropenia. Sixteen patients (80%) had at least one episode of grade 3 thrombocytopenia. Three patients (15%) had grade 2 and one had grade 3 peripheral neuropathy. Complete response by CA-125 was 75%.
The recommended dose of PPX of 135 mg/m(2) with carboplatin (AUC = 6) in newly diagnosed ovarian cancer was feasible for multiple cycles, but hematologic toxicity was greater compared with standard carboplatin and 3-hour paclitaxel.

Download full-text


Available from: Cecilia Allievi, Mar 26, 2015
  • Source
    • "It was first extracted from the Yew tree in the US in 1971 and, by 1992, received approval from the US Food and Drug Administration (FDA) for clinical use. Today, paclitaxel has proved effective for the treatment of many types of cancers, such as ovarian [1] [2] [4] [5], breast [1] [5] [6], lung [7] [8], esophageal [9], and liver cancers [10]. Unique activities of paclitaxel are that it binds to β-tubulin in the microtubule specifically and reversibly with a stoichiometry of almost one (relative to the α,βtubulin dimer) [11] [12], inhibits cell division, blocks cell mitosis, stabilizes cytoplasmic microtubules , and induces the formation of the characteristic microtubule bundles in cells [13]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Although tremendous progress has been made in basic cancer biology and in the development of novel cancer treatments, cancer remains a leading cause of death in the world. The etiopathogenesis of cancer is complex. Besides genetic predisposition, known environmental factors associated with cancer are: diet, lifestyle, and environmental toxins. Toxicity of drugs and eventual relapse of cancers contribute to high cancer death rates. Current therapeutic interventions for cancer- surgery, chemotherapy, radiotherapy, thermotherapy, etc. are far from being curative for many forms of cancer. Chemotherapy, in particular, though the most commonly used cancer treatment, is usually associated with side effects with varying degrees of severity. The purpose of this brief review is to assemble current literature on some crude drugs and to focus on their beneficial roles and drug targets in cancer therapy and chemo-prevention. Although their pharmacological mechanisms and biochemical roles in cancer biology and tumor chemo-prevention are not fully understood, crude drugs are believed to have nutriceutical effects upon cancer patients.
    Full-text · Article · Jan 2011 · International Journal of Clinical and Experimental Medicine
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Cytotoxic chemotherapeutic agents are the mainstay of anti-cancer therapy. Improvements in the therapeutic ratio of cytotoxic anti-cancer drugs remain a major unmet need as these agents are limited by toxicity to normal organs and relatively modest anti-tumor efficacy as a result of lack of specificity. Cytotoxic drugs target rapidly dividing cells in normal tissues with similar effects to those in tumor tissue. One approach to overcoming these deficiencies is to chemically conjugate cytotoxic molecules such as paclitaxel to a macromolecular carrier. This creates new chemical entities that enhance distribution to tumor tissues, render hydrophobic agents water soluble, potentially decrease toxicity to normal organs, and enhance efficacy. Our group has focused on covalently linking cytotoxic agents to a macromolecular peptide polymer, poly-l-glutamic acid (PGA). PGA was selected for its large number of potential binding sites, high aqueous solubility, lack of immunogenicity, and its biodegradability. This chapter focuses on the developmental challenges associated with polymer therapeutics, using as an example, CT-2103, generically named paclitaxel poliglumex. Sections are devoted to chemistry, manufacturing, and controls specifically addressing development of characterization methods and release specifications for this complex molecule; preclinical pharmacology and toxicology; pharmacokinetics and metabolism including an interaction with estradiol; and clinical development through Phase III trials. A brief review of a second PGA conjugate with camptothecin, CT-2106, is also included.
    Full-text · Article ·
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: These data describing the preclinical and early clinical development of CT-2103 demonstrate the feasibility of using polyglutamic acid homopolymers to create macromolecular cytotoxic drug conjugates. PG has the characteristics of an ideal polymeric drug carrier including biodegradability, the ability to solubilise hydrophobic agents even at high loading, stability in circulation, and apparent lack of immunogenicity. Preliminary clinical data indicate that CT-2103 is well tolerated by short infusion and has what appears to be reduced toxicity to neural tissue and hair follicles compared with paclitaxel delivered in the standard formulation. In preclinical studies, the MTD was approximately twice that of standard paclitaxel and the antitumour efficacy in was improved. Preliminary clinical data from Phase II studies indicate that the MTD will be higher than that of paclitaxel and that CT-2103 has activity, even in patients who have failed prior taxane therapy. The potentially enhanced efficacy and apparently reduced toxicity of CT-2103 can be predominantly ascribed to its improved distribution to tumour tissue through the EPR effect and the reduced exposure of normal tissues. Taken together, these data suggest that PG is an excellent polymeric backbone for the delivery of oncologic therapeutics and is likely to improve the therapeutic indices of a number of other agents. A second PG conjugate designated CT-2106, a PG camptothecin with an interposed glycine linker, will enter clinical trials shortly.
    Full-text · Article · Feb 2003 · Advances in Experimental Medicine and Biology
Show more