Pharmacy & Therapeutics - December 2008 - (Page 720)

MEETING HIGHLIGHTS: Chemotherapy Foundation Symposium XXVI C/P did not result in any overlapping toxicities. Assessment of changes in circulating cytokines following the administration of talactoferrin alfa revealed a statistically significant increase in IL-8 concentrations in the single-agent studies. In the NSCLC combination study, baseline cytokine levels were similar in both groups. C/P administration was associated with a decrease in cytokine levels. Talactoferrin alfa administration resulted in a statistically significant protection from decreases in IL-8, IL-12, and GM-CSF concentrations, compared with the placebo plus C/P group. Oral talactoferrin alfa is a promising, well-tolerated anticancer agent that significantly improved survival in patients with refractory NSCLC and improved response rates when it was added to C/P in previously untreated patients with NSCLC. Phase 3 studies are being planned. Systemic ADH-1 at a dose of 4,000 mg on days 1 and 8, in combination with melphalan on day 1, was well tolerated and represents a targeted therapy approach to regionally advanced melanoma. Tumor responses, especially complete responses, exceeded expectations in this group of heavily pretreated patients. Further study of this agent is warranted. Overcoming Immunosuppression in Head and Neck Cancer with Citoplurikin (IRX-2) • Jeffrey S. Moyer, IRX Study Group, IRX Therapeutics, Inc., Farmingdale, N.Y. Significant suppression of the immune system is a consistent observation in patients with head and neck squamous cell carcinoma (HNSCC) and is associated with a poor prognosis. This finding supports the potential role for immunotherapy in this difficult-to-treat tumor type. IRX-2 (citoplurikin) is a biologic response modifier derived from phytohemagglutinin (PHA)-stimulated mononuclear cells. It is composed of low-dose cytokines that are administered in combination with cyclophosphamide (Cytoxan, Bristol-Myers Squibb), indomethacin (Indocin, Merck), and zinc. IRX-2 stimulates and activates immature dendritic cells; increases expression of CD83, CCR7 and MHC-II markers; and protects from tumor-induced T-cell apoptosis. A multicenter phase 2 trial was conducted to determine the feasibility, toxicity, and potential efficacy of a short-term, preoperative IRX-2 regimen in 27 previously untreated patients with resectable, advanced HNSCC of the oral cavity (n = 15), oropharynx (n = 8), larynx (n = 3), or hypopharynx (n = 1). The Study Group assessed tumor response, cellular immune modulation, and toxicity and compared outcomes with those of 81 matched controls. Sixty percent of patients had stage IV cancer, 30% had stage III, and 10% had stage II. The IRX-2 regimen consisted of cytoxan 300 mg/m2 IV on the first day, followed by bilateral perilymphatic injections of IRX2 (115 units of IL-2 equivalence bilateral daily for 10 doses) on days 4 and 5. Daily oral indomethacin, zinc, and omeprazole (Prilosec, AstraZeneca) were given on days 1 to 21. Planned definitive surgery was performed on or around day 22 (range, 22–47 days). The median follow-up period was 15 months. The results showed that acute toxicity from the IRX-2 regimen was minimal (below grade 2). Serious adverse events (grade 3 and 4) occurring within 30 days of IRX-2 therapy included aspiration pneumonia in three patients, asthma in one patient, wound infection in one patient, alcohol withdrawal in one patient, and upper respiratory infection in one patient. Objective tumor responses (less than a 12% decrease according to blinded reviews of computed tomography scans) were documented in 16% of patients. Overall, tumor size was either reduced or stable in 74% of patients. IRX-2 was associated with significant changes in tumor and lymph node lymphocytic infiltration. The estimated two-year overall survival rate was 72%, and disease-free survival was 67%. The IRX regimen appears to be feasible and well tolerated. The findings of increased tumor lymphocyte infiltration, fibrosis, and objective tumor responses, together with excellent overall survival data, provide a rationale for initiating a pivotal phase 3 study (INSPIRE) in the fourth quarter of 2008. I Systemic ADH-1 (Exherin) and Melphalan (Alkeran) for Isolated Limb Infusion in Advanced Extremity In-transit Melanoma • Douglas S. Tyler, Duke University Medical School, Durham, N.C. The use of melphalan (Alkeran, M-ILI, GlaxoSmithKline) in isolated limb infusion is a recently described and tolerated treatment for patients with in-transit melanoma (intralymphatic tumor dissemination) of the extremity. A 39% complete response rate in the cohort of treated patients was noted. ADH-1 (Exherin, Adherex) is a cyclic pentapeptide that disrupts N-cadherin adhesion complexes. When given systemically in a preclinical model of regional melphalan therapy, tumor responses improved markedly. A phase 1 dose-escalation study was performed to evaluate the safety, tolerability, pharmacokinetics, and anti-tumor activity of systemic ADH-1 with melphalan in patients with measurable in-transit melanoma of the extremity. The ADH-1 dose-escalation cohorts of three patients each received 1,000, 2,000, and 4,000 mg, administered systemically on days 1 and 8 in combination with standard-dose melphalan, corrected for ideal body weight, on day 1. The 4,000-mg ADH-1 cohort was expanded to include a total of 10 patients. N-cadherin immunohistochemical staining and quantitative polymerase chain reaction analysis were performed on pre-treatment tumor tissue. At three months, the investigators used RECIST (response evaluation criteria in solid tumors) to define patient responses. Sixteen patients, including six patients who had not responded to melphalan alone, were treated. No dose-limiting toxicities were observed. Common treatment-related grade 1/1 toxicities included dermatological events in 14 patients, pain in 13 patients, and nausea in five. Grade 3 toxicities included shortness of breath, hypertension, neutropenia, anemia, and elevated serum creatine phosphokinase (CPK) levels. Grade 4 toxicities included CPK elevation. At three months, eight of the16 patients had complete responses, two had partial responses, two had stable disease, and four had progressive disease. Pharmacokinetic analysis demonstrated increasing ADH-1 concentrations at each dose escalation and minimal variability in melphalan drug concentrations for all patients. 720 P&T® • December 2008 • Vol. 33 No. 12

Table of Contents Feed for the Digital Edition of Pharmacy & Therapeutics - December 2008

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

For optimal viewing of this digital publication, please enable JavaScript and then refresh the page. If you would like to try to load the digital publication without using Flash Player detection, please click here.