Performance evaluation in multicenter clinical trials: development of a model by the AIDS Clinical Trials Group.

The AIDS Clinical Trials Group (ACTG), supported by the National Institute of Allergy and Infectious Diseases (NIAID), is the largest federally funded program of AIDS clinical trials. It is a collaboration involving 59 institutions and affiliated clinical centers, known as AIDS Clinical Trials Units (ACTUs), NIAID staff, and a Statistical and Data Analysis Center (SDAC). An institutional evaluation tool was developed to evaluate ACTU performance, distinguish between clinical centers with superior performance and those not meeting standards, and assist NIAID in allocating funding based on performance. The evaluation tool was designed to reflect the many distinguishing features of ACTG study protocols and clinical trial centers in order to measure performance objectively. The evaluation focused on assessing the financial resources expended by the ACTU in recruiting, treating, and following study patients during the evaluation period; the number of women and minorities enrolled; and the ACTU's scientific contributions to the ACTG. To help quantify the ACTU's performance in enrolling study subjects, a formula was derived to assess the total effort required to screen, enroll, treat, and assess subjects participating in ACTG studies. A weighting system was developed for each study protocol to account for the variations in effort and resources required by the different protocols. Future directions in the ACTG evaluation process include strategies to evaluate performance in relation to quality of data and to determine ways in which the evaluation process can be used to enhance the achievement of programmatic goals.

Human antibody responses to components of the monoclonal antimelanoma antibody ricin A chain immunotoxin XomaZyme-MEL.

Human antibody responses to immunotoxin components were evaluated in 21 melanoma patients who were treated with XomaZyme-MEL, a murine monoclonal antimelanoma antibody-ricin A chain conjugate. Twenty of the 21 melanoma patients produced antibodies against ricin A chain, while 15 of 21 produced antibodies reactive with the murine monoclonal antibody component. Both IgM and IgG antibody responses were produced. Immunoglobulin responses were usually detected 1 to 2 weeks following initiation of therapy, with peak levels generally attained 2 to 4 weeks posttherapy. Titers of the anti-ricin A chain antibodies were generally higher than those of the antimurine monoclonal antibodies for the dose range tested. There was no clear correlation between the dose of immunotoxin administered and the antibody titer. By use of a competitive flow cytometry assay, antiidiotype responses were demonstrated in eight of 10 melanoma patients who had antimurine antibodies. Both the kinetics of appearance and the relative titers of the antiidiotype responses generally corresponded to the antimurine responses. The development of antimmunotoxin antibodies can reduce the therapeutic potential of immunotoxins through several mechanisms. The development of antibodies in a significant number of patients suggests that optimally effective, repeated courses of therapy will require some procedure for suppressing or abrogating the response against the immunotoxin.

Therapy of patients with malignant melanoma using a monoclonal antimelanoma antibody-ricin A chain immunotoxin.

We conducted a trial of a murine monoclonal antimelanoma antibody-ricin A chain immunotoxin (XOMAZYME-MEL) in 22 patients with metastatic malignant melanoma. The dose of immunotoxin administered ranged from 0.01 mg/kg daily for 5 days to 1 mg/kg daily for 4 days (total dose: 3.2 to 300 mg). Side effects observed in most patients were a transient fall in serum albumin with an associated fall in serum protein, weight gain, and fluid shifts resulting in edema. In addition, patients experienced mild to moderate malaise, fatigue, myalgia, decrease in appetite, and fevers. There was a transient decrease in voltage on electrocardiograms without clinical symptoms, change in serial echocardiograms or elevation of creatine phosphokinase MB isozyme levels. Symptoms consistent with mild allergic reactions were observed in three patients. The side effects were related to the dose of immunotoxin administered and were generally transient and reversible. Encouraging clinical results were observed, even after a single course of a low dose of immunotoxin. In addition, localization of antibody and A chain to sites of metastatic disease was demonstrated by immunoperoxidase staining of biopsy specimens. Additional studies are being conducted to continue the evaluation of safety and efficacy of immunotoxin therapy for malignancy.

Phase 1 immunolymphoscintigraphy with an In-111-labeled antimelanoma monoclonal antibody.

A phase 1 study was conducted using a monoclonal antimelanoma antibody-DTPA conjugate labeled with indium-111, for immunolymphoscintigraphy in patients with metastatic melanoma. The imaging agent, labeled with 1 mCi (37 MBq) In-111, was administered as an interstitial interdigital injection to six patients scheduled to undergo lymph node dissection for suspected metastatic malignant melanoma. No adverse effects were observed in any of the patients either during or after the infusion as determined by clinical and laboratory parameters. Antibodies to the murine immunoglobulin were produced in some patients. Regional lymph nodes were visualized whether tumor-bearing or not, and light microscopic autoradiography showed In-111 activity associated with histiocytes. One of two patients harboring both tumor-bearing and tumor-free lymph nodes exhibited preferential localization in tumor-bearing nodes. The authors conclude that this study demonstrates safety of the radiopharmaceutical and that further study is needed to improve its usefulness for diagnosis of lymph node metastases.

Transduction and plasmid deoxyribonucleic acid analysis in a multiply antibiotic-resistant strain of Staphylococcus epidermidis.

A genetic analysis of a multiply antibiotic-resistant strain of Staphylococcus epidermidis was performed. Experiments designed to show reversion of organisms to antibiotic susceptibility, as well as studies of the influence of ultraviolet irradiation of phage on the transduction frequencies of the resistance markers, indicated that determinants of chloramphenicol (cml), tetracycline (tet), and neomycin (neo) resistance are present on separate plasmids, but the streptomycin marker is chromosomal. In 2 to 6% of tetracycline-resistant transductants, co-transduction of cml was also observed. By using CsCl-dye density gradients followed by neutral sucrose gradients, the plasmids carrying cml, tet, and neo could be isolated and their molecular weights could be determined. The tetracycline plasmid is shown to be incompatible with one of the cryptic plasmids of a recipient strain.