Safety, pharmacokinetics, and antitumor activity of the anti-CEACAM5-DM4 antibody-drug conjugate tusamitamab ravtansine (SAR408701) in patients with advanced solid tumors: first-in-human dose-escalation study.

BACKGROUND: Tusamitamab ravtansine (SAR408701) is an antibody-drug conjugate composed of a humanized monoclonal antibody that binds carcinoembryonic antigen-related cell adhesion molecule-5 (CEACAM5) and a cytotoxic maytansinoid that selectively targets CEACAM5-expressing tumor cells. In this phase I dose-escalation study, we evaluated the safety, pharmacokinetics, and preliminary antitumor activity of tusamitamab ravtansine in patients with solid tumors. PATIENTS AND METHODS: Eligible patients were aged ≥18 years, had locally advanced/metastatic solid tumors that expressed or were likely to express CEACAM5, and had an Eastern Cooperative Oncology Group Performance Status of 0 or 1. Patients were treated with ascending doses of tusamitamab ravtansine intravenously every 2 weeks (Q2W). The first three dose levels (5, 10, and 20 mg/m2) were evaluated using an accelerated escalation protocol, after which an adaptive Bayesian procedure was used. The primary endpoint was the incidence of dose-limiting toxicities (DLTs) during the first two cycles, graded using National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) v4.03 criteria. RESULTS: Thirty-one patients received tusamitamab ravtansine (range 5-150 mg/m2). The DLT population comprised 28 patients; DLTs (reversible grade 3 microcystic keratopathy) occurred in three of eight patients treated with tusamitamab ravtansine 120 mg/m2 and in two of three patients treated with 150 mg/m2. The maximum tolerated dose was identified as 100 mg/m2. Twenty-two patients (71%) experienced ≥1 treatment-related treatment-emergent adverse event (TEAE), seven patients (22.6%) experienced ≥1 treatment-related grade ≥3 TEAE, and three patients (9.7%) discontinued treatment due to TEAEs. The most common TEAEs were asthenia, decreased appetite, keratopathy, and nausea. Three patients had confirmed partial responses. The mean plasma exposure of tusamitamab ravtansine increased in a dose-proportional manner from 10 to 150 mg/m2. CONCLUSIONS: Tusamitamab ravtansine had a favorable safety profile with reversible, dose-related keratopathy as the DLT. Based on the overall safety profile, pharmacokinetic data, and Bayesian model recommendations, the maximum tolerated dose of tusamitamab ravtansine was defined as 100 mg/m2 Q2W.

[Translational research and Cancer Plan]. / Recherche translationnelle et plan Cancer.

The French Cancer Plan 2003-2007 has made translational research central to its research programme, to ensure the care-research continuum and the quickest application possible for the most recent discoveries, for the patients' benefit. This is a new field of research, still little-known or ill-understood. A working group, composed of physicians and researchers from academic research and industrial research, sought to define translational research in cancerology and define the issues at stake in it. Translational research needs to develop in close connection with the patients in order to enable a bi-directional flow of knowledge from cognitive research toward medical applications and from observations made on patients toward cognitive research. Placed under the aegis of the French National Cancer Institute and Leem Research, the group has put forth a strategy for implementing translational research in cancerology in France to make it attractive, competitive and efficient and to foster the development of public-private partnerships.

Induction of type III secretion in Shigella flexneri is associated with differential control of transcription of genes encoding secreted proteins.

Shigella, the etiological agent of human bacillary dysentery, invades the colonic epithelium where it induces an intense inflammatory response. Entry of Shigella into epithelial cells involves a type III secretion machinery, encoded by the mxi and spa operons, and the IpaA-D secreted proteins. In this study, we have identified secreted proteins of 46 and 60 kDa as the products of virA and ipaH9.8, respectively, the latter being a member of the ipaH multigene family. Inactivation of virA did not affect entry into epithelial cells. Using lacZ transcriptional fusions, we found that transcription of virA and four ipaH genes, but not that of the ipaBCDA and mxi operons, was markedly increased during growth in the presence of Congo red and in an ipaD mutant, two conditions in which secretion through the Mxi-Spa machinery is enhanced. Transcription of the virA and ipaH genes was also transiently activated upon entry into epithelial cells. These results suggest that transcription of the virA and ipaH genes is regulated by the type III secretion machinery and that a regulatory cascade differentially controls transcription of genes encoding secreted proteins, some of which, like virA, are not required for entry.

Approaching the RSV season with a nursing plan of action.

As the statistics show with year-in, year-out regularity, during November through March in the United States, approximately 90,000 infants and young children will be hospitalized with a severe lower respiratory infection attributable to the respiratory syncytial virus (RSV). This virus, discovered only as recently as 1956, appears to be ubiquitous, infecting virtually 100% of children by age 4. For most of them the resulting illness will be mild and easily vanquished by an intact immune system. For some, however, RSV infection confers considerable morbidity, and these infants and children are the concern of the symposium held in conjunction with Pediatric Nursing's 11th annual conference. The symposium addressed several aspects of RSV infection: Who is at risk and should be hospitalized? How can nurses contribute to the care of hospitalized patients? Are there environmental risks to health-care personnel from ribavirin aerosol, the antiviral treatment approved for RSV infection? Are there special considerations for mechanically ventilated patients? Speakers generally concluded that symptomatic treatment and antiviral therapy with ribavirin aerosol can reduce severe morbidity in severely infected patients with minimal occupation risk to health-care personnel.

Severe invasive group A streptococcal infections in Ontario, Canada: 1987-1991.

During the past few years, there has been an apparent increase in serious infections due to group A streptococci (GAS) worldwide. We describe our experience with severe invasive GAS infections in Ontario, Canada, during the past 5 years (February 1987 through December 1991). A case was defined as the isolation of GAS from blood or normally sterile tissue in association with hypotension (systolic blood pressure, < 90 mm Hg). Fifty cases were identified in patients ranging in age from 4 to 100 years (median age, 47 years); 29 (58%) of the patients died. A primary focus of infection was identified in 38 cases (76%), with soft tissue being the site involved most frequently (68%). No focus of infection was found in 12 patients, and 36 patients (72%) were bacteremic. Complications included acute respiratory distress syndrome (21 of 50), acute renal failure (20 of 50), hypocalcemia (19 of 24), elevated creatinine kinase values (21 of 27), coagulation abnormalities (15 of 21), and hepatitis (15 of 24). Eleven cases (22%) were nosocomial; one of these was secondary to another nosocomial case. Thirty-three isolates were available for M and T typing and for determination of the presence of the genes for streptococcal pyrogenic exotoxin (SPE). The most frequent types were M1T1 (10) and M12/T12 (8). Twelve isolates possessed the speA gene, and 16 isolates had the speC gene. Only three isolates possessed both speA and speC. All isolates possessed the speB gene.