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Background: 15-20% of all patients initially diagnosed with colorectal cancer develop metastatic disease and surgical resection remains the only potentially curative treatment available. Current 5-year survival following R0-resection of liver metastases is 28-39%, but recurrence eventually occurs in up to 70%. To date, adjuvant chemotherapy has not improved clinical outcomes significantly. The primary objective of the ongoing LICC trial (L-BLP25 In Colorectal Cancer) is to determine whether L-BLP25, an active cancer immunotherapy, extends recurrence-free survival (RFS) time over placebo in colorectal cancer patients following R0/R1 resection of hepatic metastases. L-BLP25 targets MUC1 glycoprotein, which is highly expressed in hepatic metastases from colorectal cancer. In a phase IIB trial, L-BLP25 has shown acceptable tolerability and a trend towards longer survival in patients with stage IIIB locoregional NSCLC.
Methods: This is a multinational, phase II, multicenter, randomized, double-blind, placebo-controlled trial with a sample size of 159 patients from 20 centers in 3 countries. Patients with stage IV colorectal adenocarcinoma limited to liver metastases are included. Following curative-intent complete resection of the primary tumor and of all synchronous/metachronous metastases, eligible patients are randomized 2:1 to receive either L-BLP25 or placebo. Those allocated to L-BLP25 receive a single dose of 300 mg/m2 cyclophosphamide (CP) 3 days before first L-BLP25 dose, then primary treatment with s.c. L-BLP25 930 mug once weekly for 8 weeks, followed by s.c. L-BLP25 930 mug maintenance doses at 6-week (years 1&2) and 12-week (year 3) intervals unless recurrence occurs. In the control arm, CP is replaced by saline solution and L-BLP25 by placebo. Primary endpoint is the comparison of recurrence-free survival (RFS) time between groups. Secondary endpoints are overall survival (OS) time, safety, tolerability, RFS/OS in MUC-1 positive cancers. Exploratory immune response analyses are planned. The primary endpoint will be assessed in Q3 2016. Follow-up will end Q3 2017. Interim analyses are not planned.
Discussion: The design and implementation of such a vaccination study in colorectal cancer is feasible. The study will provide recurrence-free and overall survival rates of groups in an unbiased fashion. Trial Registration EudraCT Number 2011-000218-20
(1) Background: Refractory acute graft-versus-host disease (R-aGvHD) remains a leading cause of death after allogeneic stem cell transplantation. Survival rates of 15% after four years are currently achieved; deaths are only in part due to aGvHD itself, but mostly due to adverse effects of R-aGvHD treatment with immunosuppressive agents as these predispose patients to opportunistic infections and loss of graft-versus-leukemia surveillance resulting in relapse. Mesenchymal stromal cells (MSC) from different tissues and those generated by various protocols have been proposed as a remedy for R-aGvHD but the enthusiasm raised by initial reports has not been ubiquitously reproduced.
(2) Methods: We previously reported on a unique MSC product, which was generated from pooled bone marrow mononuclear cells of multiple third-party donors. The products showed dose-to-dose equipotency and greater immunosuppressive capacity than individually expanded MSCs from the same donors. This product, MSC-FFM, has entered clinical routine in Germany where it is licensed with a national hospital exemption authorization. We previously reported satisfying initial clinical outcomes, which we are now updating. The data were collected in our post-approval pharmacovigilance program, i.e., this is not a clinical study and the data is high-level and non-monitored.
(3) Results: Follow-up for 92 recipients of MSC-FFM was reported, 88 with GvHD ≥°III, one-third only steroid-refractory and two-thirds therapy resistant (refractory to steroids plus ≥2 additional lines of treatment). A median of three doses of MSC-FFM was administered without apparent toxicity. Overall response rates were 82% and 81% at the first and last evaluation, respectively. At six months, the estimated overall survival was 64%, while the cumulative incidence of death from underlying disease was 3%.
(4) Conclusions: MSC-FFM promises to be a safe and efficient treatment for severe R-aGvHD.
BACKGROUND: Adjuvant chemotherapy (ACT) for breast cancer improves relapse-free survival (BCRFS) and overall survival. Differences in terms of efficacy and toxicity could partly be explained by the significant interpatient variability in pharmacokinetics which cannot be captured by dosing according to body surface area. Consequently, tailored dosing was prospectively evaluated in the PANTHER trial.
PATIENTS AND METHODS: PANTHER is a multicenter, open-label, randomized phase III trial which compared tailored, dose-dense (DD) epirubicin/cyclophosphamide (E/C) and tailored docetaxel (D) (tDD) with standard interval 5-fluorouracil/E/C and D. The primary end point was BCRFS and the primary efficacy analysis has been previously published. In this secondary analysis, we aimed to retrospectively explore the concept of dose tailoring. Our two hypotheses were that BCRFS would not vary depending on the cumulative administered epirubicin dose; and that dose tailoring would lead to appropriate dosing and improved outcomes for obese patients, who are known to have worse prognosis and increased toxicity after DD ACT.
RESULTS: Patients treated with tDD had similar BCRFS regardless of the cumulative epirubicin dose (P = 0.495), while obese patients in this group [body mass index (BMI) ≥30] had improved BCRFS compared with nonobese ones (BMI <30) [hazard ratio (HR) = 0.51, 95% confidence interval (CI) 0.30-0.89, P = 0.02]. Moreover, tDD was associated with improved BCRFS compared with standard treatment only in obese patients (HR = 0.49, 95% CI 0.26-0.90, P = 0.022) but not in nonobese ones (HR = 0.79, 95% CI 0.60-1.04, P = 0.089). The differences were not formally statistically significant (P for interaction 0.175). There were no differences in terms of toxicity across the epirubicin dose levels or the BMI groups.
CONCLUSIONS: Dose tailoring is a feasible strategy that can potentially improve outcomes in obese patients without increasing toxicity and should be pursued in further clinical studies.