Pharmacy & Therapeutics - December 2008 - (Page 719)

MEETING HIGHLIGHTS: Chemotherapy Foundation Symposium XXVI continued from page 714 MK-0457, unlike the other multi-kinase inhibitors, has activity in patients with T315I, an imatinib-resistant mutation of high importance. Homoharringtonine. The anticancer agent Myelostat (Stragen) belongs to the plant alkaloid family of drugs. The elimination of the T315I clone and a cytogenetic response have been reported in some patients. Summary. Studies of other inhibitors, such as PHA-739358, AP-24534, and DCC-2036, are expected to begin shortly. Each agent that was described in this section offers hope in cases of treatment failure with imatinib. The major challenges are to prevent the development of imatinib resistance and to find ways to eradicate all evidence of disease in all patients. below 10 ng/ml). Overall, the initial clinical evaluation of T-DM1 has demonstrated that this agent was well tolerated at the maximum tolerated dose of 3.6 mg/kg every three weeks or at 2.4 mg/kg per week. T-DM1 is now in phase 2 studies in combination with other agents. Oral Talactoferrin, an Immunomodulatory Agent for Non–Small-Cell Lung Cancer • Giuseppi Giaccone, National Cancer Institute, Bethesda, Md. Talactoferrin alfa (Agennix), an orally active immunomodulatory protein, acts at the gut and at gut-associated lymphoid tissue (GALT) through a novel mechanism of dendritic cell recruitment and activation. Following oral administration, this agent is transported by M cells into the small intestinal Peyer’s patches, where it recruits circulating immature dendritic cells to GALT and induces their maturation. Maturation of dendritic cells in the presence of tumor antigens and lymphoid effector cells induces a strong systemic innate and adaptive immune response mediated by anti-cancer natural killer (NK) cells. CD8+ lymphocytes and NK T cells result in the activation of tumor-draining lymph nodes, cellular infiltration of distant tumors, and tumor cell death. A phase 2 double-blind, placebo-controlled study was conducted in 100 adults with locally advanced or metastatic (stage IIIB/IV) non–small-cell lung cancer (NSCLC) who had not responded to first-line platinum-based chemotherapy or second-line chemotherapy. The primary endpoint was overall survival. Talactoferrin alfa at a dose of 1.5 g twice daily or placebo was administered for up to three 14-week cycles (12 weeks on, two weeks off). All patients were included in the intent-to-treat (ITT) analysis. In another phase 2 study conducted in India, the primary endpoint was response rate in 110 chemotherapynaive patients with locally advanced stage IIIB or IV NSCLC. The former trial met its primary endpoint with a 65% increase (2.4 months) in median overall survival from 3.7 months for the placebo arm to 6.1 months for the treated arm. The effect of talactoferrin alfa was also observed in prognostically relevant subsets. The six-month survival rate in the ITT population increased from 28% to 49% (P = 0.0272) with a trend toward improved progression-free sur vival. The treated patients experienced fewer adverse events than those receiving placebo, a difference that was statistically significant. In another study of the previously untreated patients, talactoferrin alfa was administered for up to three six-week cycles (five weeks on, one week off) in combination with up to six three-week cycles of carboplatin/paclitaxel (C/P, or Taxol/ Carbo). Patients showed improvement in response rates compared with those receiving placebo. The addition of oral talactoferrin alfa to C/P improved response rates more than placebo plus C/P by 15% in the ITT population (27% vs. 42%, respectively) and by 18% in the evaluable patients (29% vs. 47%, respectively; P = 0.05, one-tailed test). Positive trends were observed in secondary efficacy endpoints, including progression-free survival and overall survival. Talactoferrin alfa was well tolerated, and no drug-related adverse effects were reported. Adding talactoferrin alfa to Trastuzumab–DM1 Conjugate for HER-2–Positive Breast Cancer • Ian E. Krop, Dana-Farber Cancer Institute, Boston, Mass. The introduction of trastuzumab (Herceptin, Genentech) and lapatinib (Tykerb, GlaxoSmithKline) into clinical practice has resulted in significant improvement in outcomes for women with HER-2–positive breast cancer. However, neither drug is perfect; de novo and acquired resistance to both agents remains an important clinical problem and new agents are needed to overcome therapeutic resistance. Trastuzumab (T)-DM1 (T-DM1) is a first in its class HER-2 antibody–drug conjugate (ADC) in the development for HER-2–positive breast cancer. T-DM1 combines trastuzumab’s HER-2–-blocking activity with a targeted delivery of a highly potent anti-microtubule agent (DM1) to HER-2–expressing cells. DM1 binds to tubulin competitively with vinca alkaloids but 20 to 100 times more potently than vincristine. DM1 is covalently attached to trastuzumab via a stable, non-reducible multiple-component condensation (MCC) linker molecule, which has been engineered to potentially enhance the therapeutic window of DM1 by minimizing systemic exposure to free DM1 and improving tumor exposure to T-DM1. A monoclonal antibody is linked with a cytotoxic agent to destroy tumor cells but minimize the impact on normal tissue. T-DM1 is the first antibody–drug conjugate with an MCC linker to be evaluated in clinical practice. In a phase 1 study, T-DM1 was evaluated either weekly or every three weeks in 24 patients who had received previous therapy for metastasis. In the every-three-week cohort, the dose-limiting toxicity was grade 4 thrombocytopenia in twothirds of patients at 4.8 mg/kg. In the weekly cohort, the doselimiting toxicity was grade 2 or 3 thrombocytopenia, which prevented re-treatment at day 8 in two of three patients at 2.9 mg/kg. The maximum tolerated dose was identified as 3.6 mg/kg every three weeks or 2.4 mg/kg per week. In both schedules, thrombocytopenia at the maximum tolerated dose was generally grade 1 or 2 and was reversible. Other common toxicities included transaminase elevations, fatigue, and headache, all of which were mild events of grade 1 or 2. There was no cardiac toxicity. The half-life of T-DM1 was two to four days, and concentrations of free DM1 were low (a peak concentration of Vol. 33 No. 12 • December 2008 • P&T® 719

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Pharmacy & Therapeutics - December 2008 Contents Editorial Medication Errors Prescription: Washington New Drugs/Drug News/ New Medical Devices Drug Forecast Interpreting Estimates of Treatment Effects Chemotherapy Foundation Symposium XXVI: Innovative Cancer Therapy for Tomorrow Third Annual Onmark National Payor/Provider Forum Fourth Annual Ophthalmic Drug Development and Delivery Summit Classification and Pharmacological Management Of Obesity CE Test and Forms Season’s Greetings: Thanks to Our Readers and Reviewers

Pharmacy & Therapeutics - December 2008

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