New drugs: Sipuleucel-T, cabazitaxel, and collagenase clostridium histolyticum

Abstract

Antineoplastic agents sipuleucel-T Prostate cancer is the second most common type of cancer in men in the United States, following skin cancer. In 2009, almost 200,000 new cases of prostate cancer were diagnosed. The treatment of prostate cancer may include surgery, radiation, and/or medications (e.g., androgen deprivation therapy). Although hormonal treatment has been effective in many men, metastatic disease may often become resistant to this therapy, and a regimen based on docetaxel (e.g., Taxotere) has been the only treatment that has been demonstrated to prolong survival in men with hormone refractory prostate cancer. Sipuleucel-T (Provenge—Dendreon) is an autologous cellular immunotherapy that is also designated as a therapeutic vaccine. The preparation of the product initially requires the collection of a patient’s peripheral blood mononuclear cells using a leukapheresis procedure approximately 3 days before the infusion date. The product contains these cells, including antigen-presenting cells (APCs), that have been activated in a culture medium with a recombinant human protein, PAP-GM-CSF, that consists of prostatic acid phosphatase (PAP; an antigen expressed in most prostate cancers) linked to granulocyte-macrophage colony-stimulating factor (GM-CSF; an immune cell activator). The active components of sipuleucel-T are autologous APCs and PAP-GM-CSF. During culture, the APCs can bind with and process the recombinant antigen into small peptides that are then displayed on the surface of the APCs. Although the mechanism of action is not completely understood, the product is designed to induce an immune response targeted against PAP. Sipuleucel-T is administered by intravenous infusion and is indicated for the treatment of asymptomatic or minimally symptomatic metastatic castration-resistant (hormone-refractory) prostate cancer. Its effectiveness was demonstrated in placebo-controlled studies in which those in the control group also underwent leukapheresis procedures but received autologous peripheral blood mononuclear cells that had not been activated. Although the times to disease progression for the two groups did not differ enough to be considered statistically significant, the median survival was significantly longer in the group of patients receiving sipuleucel-T (25.8 months vs. 21.7 months in the largest study). The most important risk experienced with the use of sipuleucel-T is acute infusion reactions consisting of responses such as fever, chills, dyspnea, nausea, fatigue, hypertension, and/or tachycardia. Most of these events were mild to moderate in severity, but in the controlled studies, approximately 4% of patients experienced severe (grade 3) reactions. To reduce the potential for acute infusion reactions, patients should be premedicated orally with acetaminophen and an antihistamine such as diphenhydramine approximately 30 minutes before administration of the drug. The most frequently reported adverse events included chills (53%), fatigue (41%), fever (31%), back pain (30%), nausea (22%), joint ache (20%), and headache (18%). Treatment with sipuleucel-T was discontinued in 2% of patients as a result of adverse events. Because sipuleucel-T is designed to stimulate the immune system, the concurrent use of an immunosuppressive agent (e.g., systemic corticosteroids) or chemotherapy may reduce the effectiveness of the new drug. The concomitant use of these agents has not been studied, but patients already being treated with an immunosuppressive agent should be evaluated to determine whether it is appropriate to discontinue or reduce the dosage of this medication before treatment with sipuleucel-T. The recommended course of treatment with sipuleucel-T is three doses, administered at approximately 2-week intervals. Approximately 3 days before each dose, the patient’s immune cells are collected using a leukapheresis procedure. The cells are sent to a center at which they are mixed with PAPGM-CSF. The product is supplied in an infusion bag in a special insulated polyurethane container that is placed in a cardboard shipping box and sent to the provider for infusion administration. The infusion bag should remain in the insulated container until the time of administration. Each dose of sipuleucel-T contains a minimum of 50 million autologous CD54+ cells activated with PAP-GMCSF in Lactated Ringer’s Injection. The product is supplied as a suspension in an infusion bag containing a volume of 250 mL. The medication is for autologous use only, and before infusion, the patient’s identity must be matched with the patient identifiers on the infusion bag and the pertinent form provided with the product. Sipuleucel-T is administered via intravenous infusion over a period of approximately 60 minutes until the entire volume has been infused. A cell filter should not be used. Although premedication may reduce the occurrence and severity of infusion reactions, patients should be observed for at least 30 minutes following each infusion. If an acute