Phase II trial of CV301 vaccine combined with atezolizumab in advanced urothelial carcinoma.

CV301 comprises recombinant poxviruses, Modified Vaccinia Ankara (MVA) and Fowlpox (FPV), encoding CEA, MUC-1, and co-stimulatory Molecules (TRICOM) ICAM-1, LFA-3, and B7-1. MVA-BN-CV301 is used for priming and FPV-CV301 is used for boosting. A Phase 2, single-arm trial was designed to evaluate CV301 plus atezolizumab as first-line treatment for cisplatin-ineligible advanced urothelial carcinoma (aUC) (Cohort 1) or progressing after platinum chemotherapy (Cohort 2). MVA-CV301 was given subcutaneously (SC) on Days 1 and 22 and FPV-CV301 SC from day 43 every 21 days for 4 doses, then tapered gradually over up to 2 years. Atezolizumab 1200 mg IV was given every 21 days. The primary endpoint was objective response rate (ORR). Overall, 43 evaluable patients received therapy: 19 in Cohort 1; 24 in Cohort 2; nine experienced ≥ Grade 3 therapy-related adverse events. In Cohort 1, one had partial response (PR) (ORR 5.3%, 90% CI 0.3, 22.6). In Cohort 2, 1 complete response and 1 PR were noted (ORR 8.3%, 90% CI 1.5, 24.0). The trial was halted for futility. Patients exhibiting benefit demonstrated T-cell response to CEA and MUC-1. The trial illustrates the challenges in the development of vaccines, which should be guided by robust preclinical data.

An antibody against IL-5 reduces numbers of esophageal intraepithelial eosinophils in children with eosinophilic esophagitis.

BACKGROUND & AIMS: The role of interleukin (IL)-5 in the pathogenesis of eosinophilic esophagitis (EoE) has been established in animal models; anti-IL-5 therapy has been reported to be effective in adults. We investigated whether IL-5 has a role in accumulation of esophageal eosinophils in children with EoE and whether therapy with mepolizumab, an antibody against IL-5, reduces the number of esophageal intraepithelial eosinophils in children with EoE. METHODS: We performed an international, multicenter, double-blind, randomized, prospective study of 59 children with EoE, defined as baseline peak count of esophageal intraepithelial eosinophils of ≥ 20 in at least 1 high-power field (hpf). Patients received an infusion every 4 weeks (a total of 3 infusions) of 0.55, 2.5, or 10 mg/kg mepolizumab. No placebo group was used. RESULTS: Baseline peak and mean esophageal intraepithelial eosinophil counts were (mean ± SE) 122.5 ± 8.78 and 39.1 ± 3.63 per hpf, respectively. Four weeks after the third infusion, peak eosinophil counts were <5 per hpf in 5 of 57 children (8.8%); we did not observe differences among groups given different doses of mepolizumab. Reduced peak and mean eosinophil counts, to <20 per hpf, were observed in 18 of 57 (31.6%) and 51 of 57 (89.5%) children, respectively. Peak and mean esophageal intraepithelial eosinophil counts decreased significantly to 40.2 ± 5.17 and 9.3 ± 1.25 per hpf, respectively (P < .0001). An analysis to evaluate predictors of response associated a higher mean baseline esophageal intraepithelial eosinophil count with a greater reduction in mean count (P < .0001). CONCLUSIONS: IL-5 is involved in the pathogenesis of EoE in children. Mepolizumab, an antibody against IL-5, reduces esophageal eosinophilic inflammation in these patients.

A randomized, double-blind, placebo-controlled study to assess efficacy and safety of 0.5 mg and 1 mg alosetron in women with severe diarrhea-predominant IBS.

OBJECTIVE: Alosetron is indicated for women with chronic, severe diarrhea-predominant IBS (d-IBS) who have not responded adequately to conventional therapy. Constipation is the most common adverse event with alosetron treatment. Multiple dosing regimens were assessed in a randomized, double-blind, placebo-controlled study (S3B30040) to determine efficacy, tolerability, and evaluate constipation rate. METHODS: 705 women with severe d-IBS were randomized to placebo, alosetron 0.5 mg once daily, 1 mg once daily, or 1 mg twice daily for 12 wk. The primary end point was the proportion of week 12 responders (patients with moderate or substantial improvement in IBS symptoms) on the 7-point Likert Global Improvement Scale (GIS). Secondary end points were average rate of adequate relief of IBS pain and discomfort, and bowel symptom improvements. RESULTS: The proportion of GIS responders at week 12 (primary time point) was significantly greater in all alosetron groups compared with placebo (54/176 [30.7%], 90/177 [50.8%], 84/175 [48%], and 76/177 [42.9%] for placebo, 0.5, 1 mg once daily, and 1 mg twice daily alosetron groups, respectively; P< or = 0.02). Results were similar for the average adequate relief rate (treatment effects > or =12%, P< or = 0.038). Bowel symptoms were improved in all alosetron groups. Constipation was the most common adverse event (9%, 16%, and 19% patients in the 0.5 mg, 1 mg once daily, and 1 mg twice daily groups, respectively). One event of intestinal obstruction and one of ischemic colitis occurred in the 0.5 mg group, and one event of fecal impaction occurred in the 1 mg twice-daily group. All were self-limited and resolved without sequelae. CONCLUSION: Alosetron 0.5 mg and 1 mg once daily as well as 1 mg twice daily are effective in providing global improvement in IBS symptoms, adequate relief of IBS pain and discomfort, and improvement in bowel symptoms in women with severe d-IBS. Lower dosing regimens resulted in a decreased constipation rate.