Ruxolitinib in GvHD (RIG) study: a multicenter, randomized phase 2 trial to determine the response rate of Ruxolitinib and best available treatment (BAT) versus BAT in steroid-refractory acute graft-versus-host disease (aGvHD) (NCT02396628).

BACKGROUND: Graft-versus-Host Disease (GvHD) causes significant morbidity and mortality in patients after allogeneic stem cell transplantation. Donor T-cells cause inflammation and tissue damage in GvHD target organs such as liver, gut and skin. Cytokine receptor associated kinases JAK1 and JAK2 are critical for inflammatory cytokine response in GvHD. Ruxolitinib is a small molecule inhibitor of JAK1 and JAK2. Preliminary data indicated substantial clinical activity in patients with steroid-refractory (SR) acute and chronic GvHD. METHODS: The RIG-study is an investigator-initiated open-label, multicenter, prospective randomized controlled two-arm phase 2 study, comparing the efficacy of ruxolitinib and best available treatment (BAT) versus BAT in steroid-refractory acute GvHD (SR-aGvHD). Patients with acute skin, intestinal or liver GvHD > grade 1 and failure of previous treatment are eligible. The trial aims to include 160 patients who will be randomized in a 1:1 ratio and stratified by GvHD grade (≤ grade 3 versus grade 4) and number of previous immunosuppressive treatments (≤ 3 versus ≥4). The primary endpoint is the overall response rate at day 28, defined as: Improvement of at least one stage in the severity of acute GvHD in one organ without deterioration in any other organ, or disappearance of any GvHD signs from all organs without requirement for new systemic immunosuppressive treatment. Secondary objectives include time to response, overall survival, event-free survival, non-relapse mortality (NRM), failure-free survival, graft failure rates, quality of life and changes in serum levels of pro-inflammatory cytokines and GvHD-related biomarkers. DISCUSSION: This randomized prospective trial will provide further evidence if the retrospectively collected data demonstrating activity of ruxolitinib for SR-aGvHD can be reproduced. A major advantage of ruxolitinib might be the limited and predictable toxicity profile compared to other immunosuppressive therapies that mainly includes viral reactivation and cytopenias. This trial will establish candidate biomarkers to predict and monitor responses to ruxolitinib. As a next step ruxolitinib might be tested upfront against steroids or in a preemptive manner to prevent GvHD to occur. TRIAL REGISTRATION: NCT02396628 (registration date 17.07.2015); DRKS00007939 (registration date 26.03.2015).

ESOPEC: prospective randomized controlled multicenter phase III trial comparing perioperative chemotherapy (FLOT protocol) to neoadjuvant chemoradiation (CROSS protocol) in patients with adenocarcinoma of the esophagus (NCT02509286).

BACKGROUND: Recent randomized controlled trials comparing neoadjuvant chemoradiation plus surgery or perioperative chemotherapy plus surgery with surgery alone showed significant survival benefits for combined modality treatment of patients with localized esophageal adenocarcinoma. However, head-to-head comparisons of neoadjuvant chemoradiation and perioperative chemotherapy applying contemporary treatment protocols are lacking. The present trial was initiated to obtain valid information whether neoadjuvant chemoradiation or perioperative chemotherapy yields better survival in the treatment of localized esophageal adenocarcinoma. METHODS/DESIGN: The ESOPEC trial is an investigator-initiated multicenter prospective randomized controlled two-arm trial, comparing the efficacy of neoadjuvant chemoradiation (CROSS protocol: 41.4Gy plus carboplatin/paclitaxel) followed by surgery versus perioperative chemotherapy and surgery (FLOT protocol: 5-FU/leucovorin/oxaliplatin/docetaxel) for the curative treatment of localized esophageal adenocarcinoma. Patients with cT1cN + cM0 and cT2-4acNxcM0 esophageal and junctional adenocarcinoma are eligible. The trial aims to include 438 participants who are centrally randomized to one of the two treatment groups in a 1:1 ratio stratified by N-stage and study site. The primary endpoint of the trial is overall survival assessed with a minimum follow-up of 36 months. Secondary objectives are progression-free survival, recurrence-free survival, site of failure, postoperative morbidity and mortality, duration of hospitalization as well as quality of life. DISCUSSION: The ESOPEC trial compares perioperative chemotherapy according to the FLOT protocol to neoadjuvant chemoradiation according to the CROSS protocol in multimodal treatment of non-metastasized recectable adenocarcinoma of the esophagus and the gastroesophageal junction. The goal of the trial is identify the superior protocol with regard to patient survival, treatment morbidity and quality of life. TRIAL REGISTRATION: NCT02509286 (July 22, 2015).

Prognostic factors for survival in patients with unresectable pancreatic cancer.

OBJECTIVES: In patients with unresectable pancreatic cancer, estimation of individual prognosis is essential to provide the most suitable biliary stent (self-expanding metal stent or plastic stent). The aim of the current study was to determine prognostic factors for survival in patients with unresectable pancreatic cancer after initial biliary drainage. PATIENTS AND METHODS: The current study included 278 patients with unresectable pancreatic cancer. Prognostic factors for survival were analyzed using the Cox proportional hazards model, the Kaplan-Meier survival estimator, and the Wilcoxon test for difference in survival. RESULTS: In univariate analysis, advanced T stage according to the TNM classification (P = 0.021, Wald test) and the presence of distant metastases (P = 0.001, Wald test) were predictive factors for shorter survival. However, in multivariate analysis, the presence of distant metastasis was the only independent prognostic factor. The median survival time after initial biliary drainage was 3.1 and 6.6 months in patients with and without the presence of distant metastases, respectively. CONCLUSIONS: The presence of distant metastases was identified as the only independent prognostic factor for survival after initial biliary drainage. A self-expanding metal stent should be systematically chosen for patient without distant metastases, whereas polyethylene plastic stents should be preferred in patients with distant metastases.

Chemotherapy-induced nausea and vomiting in the treatment of gastrointestinal tumors and secondary prophylaxis with aprepitant.

BACKGROUND: Chemotherapy-induced nausea and vomiting (CINV) belongs to the most feared side-effects of cancer treatment. Its incidence during chemotherapy of gastrointestinal tumors (GITs) with highly and moderately emetogenic regimens is not well documented. It is also unknown whether aprepitant, a neurokinin-1 receptor antagonist, can be used as secondary antiemetic prophylaxis in case of CINV during cycle 1. PATIENTS AND METHODS: Patients with GITs who were treated with highly and moderately emetogenic chemotherapy received standard antiemetic prophylaxis including a 5-hydroxytryptamine-3 receptor antagonist and dexamethasone. In case of CINV > grade 1 (National Cancer Institute classification) during the first chemotherapy course, aprepitant was additionally administered with further cycles. RESULTS: We screened 109 patients. 16 patients (15%) experienced acute and/or delayed CINV. Features associated with CINV were low-dose cisplatin-containing chemotherapy (15/16 patients), female gender (11/16 patients), abstinence to alcohol (11/16 patients) and former emesis gravidarum (11/16 patients). 11 patients who got further courses of the same chemotherapy received aprepitant. 7 are fully assessable for response. 5 of 7 patients had a complete protection from CINV (71%) and 1 patient had improved symptoms. CONCLUSIONS: In the majority of cases, primary standard antiemetic prophylaxis provided adequate protection against CINV. In case of failure to primary prophylaxis, secondary prophylaxis with aprepitant showed a high efficacy against CINV.