Background: Prostate-specific membrane antigen (PSMA) is a well-characterized target that is overexpressed selectively on prostate cancer cells. PSMA antibodydrug conjugate (ADC) is a fully human IgG1 monoclonal antibody conjugated to the microtubule disrupting agent monomethyl auristatin E (MMAE), which is designed to specifically bind PSMA-positive cells, internalize, and then release its cytotoxic payload into the cells. PSMA ADC has demonstrated potent and selective antitumor activity in preclinical models of advanced prostate cancer. A Phase 1 study was conducted to assess the safety, pharmacokinetics, and preliminary antitumor effects of PSMA ADC in subjects with treatment-refractory prostate cancer. Methods:In this first-in-man dose-escalation study, PSMA ADC was administered by intravenous infusion every three weeks to subjects with progressive metastatic Present address: William C. Olson, Regeneron Pharmaceuticals, Inc., 777 Old Saw Mill River Rd, Tarrytown, NY 10591. Present address: Robert J. Israel, Salix Pharmaceuticals, 400 Somerset Corporate Blvd, Bridgewater, NJ 08807. † Deceased PETRYLAK ET AL. | 3 605castration-resistant prostate cancer (mCRPC) who were previously treated with docetaxel chemotherapy. The primary endpoint was to establish a maximum tolerated dose (MTD). The study also examined the pharmacokinetics of the study drug, total antibody, and free MMAE. Antitumor effects were assessed by measuring changes in serum prostate-specific antigen (PSA), circulating tumor cells (CTCs), and radiologic imaging.Results: Fifty-two subjects were administered doses ranging from 0.4 to 2.8 mg/kg. Subjects had a median of two prior chemotherapy regimens and prior treatment with abiraterone and/or enzalutamide. Neutropenia and peripheral neuropathy were identified as important first-cycle and late dose-limiting toxicities, respectively. The dose of 2.5 mg/kg was determined to be the MTD. Pharmacokinetics were approximately dose-proportional with minimal drug accumulation. Reductions in PSA and CTCs in subjects treated with doses of ≥1.8 mg/kg were durable and often concurrent. Conclusions:In an extensively pretreated mCRPC population, PSMA ADC demonstrated acceptable toxicity. Antitumor activity was observed over dose ranges up to and including 2.5 mg/kg. The observed anti-tumor activity supported further evaluation of this novel agent for the treatment of advanced metastatic prostate cancer. K E Y W O R D Santibody-drug conjugate, Prostate cancer, prostate-specific membrane antigen

No abstract

OBJECTIVE:To determine why residents present certain cases and not others at morning report (MR) in an institution that permits residents the free choice of cases. DESIGN / PARTICIPANTS: Prospective survey of 10 secondand third-year residents assigned to the medical service. SETTING:A 241-bed teaching hospital with 55 categorical internal medicine residents. MEASUREMENTS AND MAIN RESULTS:Over a 4-week period, there were 194 admissions to the medical service on 18 call days preceding MR. Of these admissions, 30 (15%) were presented at MR. Cases were more likely to be presented if they were considered unusual or rare in presentation or incidence ( p ‫؍‬ .001), involved significant management issues ( p ‫؍‬ .001), or were associated with remarkable imaging studies or other visual material ( p ‫؍‬ .006). Residents were more likely to present cases in which they disagreed with attending physicians on management plans ( p ‫؍‬ .005). Overall, residents rated few admissions as having notable physical examination findings (29/194) or ethical or cost issues (6/194). Of the seven most common admitting diagnoses, representing 44% of admissions, residents did not present cases involving four of these diagnoses. CONCLUSIONS:Residents presented cases at MR that they felt were unique or rare in presentation or incidence for purposes of discussing management issues. Complete resident freedom in choosing MR cases may narrow the scope of MR and exclude common diagnoses and other issues of import such as medical ethics or economics. orning report (MR) is a universal component of internal medicine training. 1-3 Though there is wide variation in format, attendance, and timing, all MRs share the common goal of case presentation for purposes of educating resident physicians, monitoring patient care, and reviewing management decisions and their outcomes. As a teaching session, resident physicians rank the educational value of MR higher than other conferences or activities. 4 The case mix at MR varies with institution-specific practices and ranges from review of all recent admissions to the selection of cases deemed interesting by the admitting residents, chief residents, or attending physicians. In a recent survey of 286 internal medicine training programs, 75% limited MR presentations to two to four recent admissions, and presented cases were largely selected by the residents themselves. 1 Given that the case mix at MR forms the template for discussion of disease-specific etiology, presentation, and management, case choice determines or at least affects the educational value of MR. Frequent criticisms of MR have included its preoccupation with rare cases or cases selectively chosen to showcase sound management or overall knowledge on the part of the presenting residents. 5,6 Though previous investigations have detailed resident preferences for the number and type of cases, no reports, to our knowledge, have explored the reasons residents present certain cases and not others in an institution that permits the free choice of MR cases. 4 ...