BackgroundClaudin 18.2 (CLDN18.2) is physiologically confined to gastric mucosa tight junctions; however, upon malignant transformation, perturbations in cell polarity lead to CLDN18.2 epitopes being exposed on the cancer cell surface. The first-in-class monoclonal antibody, zolbetuximab (formerly known as IMAB362), binds to CLDN18.2 and can induce immune-mediated lysis of CLDN18.2-positive cells.Patients and methodsPatients with advanced gastric, gastro-oesophageal junction (GEJ) or oesophageal adenocarcinomas with moderate-to-strong CLDN18.2 expression in ≥50% of tumour cells received zolbetuximab intravenously every 2 weeks for five planned infusions. At least three patients were enrolled in two sequential cohorts (cohort 1300 mg/m2; cohort 2600 mg/m2); additional patients were enrolled into a dose-expansion cohort (cohort 3600 mg/m2). The primary end point was the objective response rate [ORR: complete and partial response (PR)]; secondary end points included clinical benefit [ORR+stable disease (SD)], progression-free survival, safety/tolerability, and zolbetuximab pharmacokinetic profile.ResultsFrom September 2010 to September 2012, 54 patients were enrolled (cohort 1, n = 4; cohort 2, n = 6; cohort 3, n = 44). Three patients in cohort 1 and 25 patients in cohorts 2/3 received at least 5 infusions. Antitumour activity data were available for 43 patients, of whom 4 achieved PR (ORR 9%) and 6 (14%) had SD for a clinical benefit rate of 23%. In a subgroup of patients with moderate-to-high CLDN18.2 expression in ≥70% of tumour cells, ORR was 14% (n = 4/29). Treatment-related adverse events occurred in 81.5% (n = 44/54) patients; nausea (61%), vomiting (50%), and fatigue (22%) were the most frequent.ConclusionsZolbetuximab monotherapy was well tolerated and exhibited antitumour activity in patients with CLDN18.2-positive advanced gastric or GEJ adenocarcinomas, with response rates similar to those reported for single-agent targeted agents in gastric/GEJ cancer trials.ClinicalTrials.gov numberNCT01197885.

Altered histone deacetylase (HDAC) activity has been identified in several types of cancer. This study was designed to determine the safety and maximum tolerated dose (MTD) of valproic acid (VPA) as an HDAC inhibitor in cancer patients. Twenty-six pre-treated patients with progressing solid tumours were enrolled in dose-escalating three-patient cohorts, starting at a dose of VPA 30 mg kg À1 day À1 . VPA was administered as an 1-h infusion daily for 5 consecutive days in a 21-day cycle. Neurocognitive impairment dominated the toxicity profile, with grade 3 or 4 neurological side effects occurring in 8 out of 26 patients. No grade 3 or 4 haematological toxicity was observed. The MTD of infusional VPA was 60 mg kg À1 day À1 . Biomonitoring of peripheral blood lymphocytes demonstrated the induction of histone hyperacetylation in the majority of patients and downmodulation of HDAC2. Pharmacokinetic studies showed increased mean and maximum serum VPA concentrations 4120 and 4250 mg l À1 , respectively, in the 90 and 120 mg kg À1 cohorts, correlating well with the incidence of dose-limiting toxicity (DLT). Neurotoxicity was the main DLT of infusional VPA, doses up to 60 mg kg À1 day À1 for 5 consecutive days are well tolerated and show detectable biological activity. Further investigations are warranted to evaluate the effectivity of VPA alone and in combination with other cytotoxic drugs.

Background:The aim of this exploratory subgroup analysis of the fluorouracil, oxaliplatin, docetaxel (FLOT)65+ trial was to determine tolerability and feasibility of perioperative chemotherapy in elderly, potentially operable esophagogastric cancer patients.Methods:Patients aged ⩾65 with locally advanced esophagogastric adenocarcinoma were randomized to perioperative chemotherapy consisting of four pre- and four postoperative cycles of infusional 5-FU, leucovorin, and oxaliplatin (FLO) without or with docetaxel 50 mg m−2 (FLOT), every 2 weeks.Results:Forty-four patients with a median age of 70 years were randomized and 43 patients started preoperative chemotherapy (FLO, 22; FLOT, 21). Thirty-eight (86.4%) patients completed four cycles of preoperative chemotherapy and 32 (74.4%) proceeded to surgery, with 67.4% R0 resections on intent-to-treat analysis (90.1% of the 32 patients who underwent resection). Median overall survival was not reached and median progression-free survival (PFS) was 17.3 months. Compared with the FLO group, the FLOT group showed a trend towards an improved median PFS (21.1 vs 12.0 months; P=0.09), however, associated with increased chemotherapy related toxicity. No perioperative mortality was observed. Postoperative morbidity was observed in 46.9% of patients (FLO, 35.3% FLOT, 60%).Conclusion:Neoadjuvant FLO or FLOT may offer a reasonable chance of curative surgery in elderly patients with locally advanced resectable gastroesophageal cancer. However, the increase in side effects with the FLOT regimen and postoperative morbidity should be carefully considered when an intensive chemotherapy regimen is planned.