©2012 Schimanski et al; licensee BioMed Central Ltd.
LICC: L-BLP25 in patients with colorectal carcinoma after curative resection of hepatic metastases--a randomized, placebo-controlled, multicenter, multinational, double-blinded phase II trial
1First Deptartment of Internal Medicine, University Medical Center (UMC), University Hospital of Mainz, Mainz, Germany
2Department of General and Abdominal Surgery, Municipal Hospital of Karlsruhe, Karlsruhe, Germany
3Digestive Oncology Unit, University Hospital Gasthuisberg, Leuven, Belgium
4Third Department of Internal Medicine, University Medical Center (UMC), University Hospital of Salzburg, Salzburg, Austria
5Department of General and Abdominal Surgery, University Medical Center (UMC), University Hospital of Frankfurt, Frankfurt, Germany
6Onkologische Schwerpunktpraxis Eppendorf, Hamburg, Germany
7First Department of Internal Medicine, University Medical Center (UMC), University Hospital of Ulm, Ulm, Germany
8Center of Internal Medicine, Robert-Bosch Hospital, Stuttgart, Germany
9Med. Klinik Mitte, Hospital of Dortmund, Dortmund, Germany
10Third Department of Internal Medicine, University Hospital of Großhadern, Munich, Germany
11Department of Oncology, Antwerp University Hospital, Edegem, Belgium
12Department of Internal Medicine, Leopoldina Hospital, Schweinfurt, Germany
13Department of Internal Medicine, University Medical Center (UMC), University Hospital of Essen, Essen, Germany
14Oncologianova GmbH, Recklinghausen, Germany
15Outpatient center for hematology and oncology, Mühlheim an der Ruhr, Germany
16Department of General, Visceral and Transplantation Surgery, Campus Virchow Klinikum, Humboldt University, Berlin, Germany
17First Department of Internal Medicine, Kliniken Nordoberpfalz AG, Klinikum Weiden, Germany
18Outpatient center for hematology and oncology, Offenburg, Germany
19Institute of Medical Biometrics, Epidemiology and Informatics (IMBEI), University Medical Center (UMC), University Hospital of Mainz, Mainz, Germany
20iOMEDICO, Freiburg, Germany
21Department of General and Abdominal Surgery, University Medical Center (UMC), University Hospital of Mainz, Mainz, Germany
22First Dept. of Internal Medicine, University Medical Center (UMC), University Hospital of Mainz, Langenbeckstrasse 1, D-55131 Mainz, Germany
Received November 1, 2011; Accepted April 11, 2012.
This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0
), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
The recurrence risk after curatively intended resection of hepatic metastases in CRC patients ranges up to 70% [15
]. No generally accepted adjuvant or perioperative strategies are available, significantly reducing the recurrence rate or prolonging overall survival [9
]. According to the German S3 guideline, adjuvant chemotherapy after R0 resection of liver metastases can be considered, whereas neo-adjuvant chemotherapy prior to resection of liver metastases can be considered in reasonable exceptional cases [9
]. In contrast, R0 resectable metastases limited to the liver should be resected. In summary, the recommendation for neoadjuvant/adjuvant chemotherapy is currently not strong in Germany. As the majority of centers is located in Germany we decided to comply with the German guidelines, knowing that peri-operative chemotherapy is considered standard of care in some other countries.
Participating centers confirmed the acceptance of the protocol containing a placebo arm. The standard treatment of care after resection of liver metastases in the participating centers is to watch and wait. As a consequnce, the study offers a potentially effective verum treatment to two thirds of participating patients, which would not receive any treatment otherwise.
In addition, we accept patients treated in a neoadjuvant manner, if the neoadjuvant therapy has lasted 12 weeks or less. This is necessary, as some patients have been treated in a neoadjuvant setting, but the patients are presented for the study only post surgery. As a short chemotherapy does not interfere with the postoperative immune system capacity, we agreed to include those patients. A significant impact of neoadjuvant chemotherapy has not been proven so far. Thus, the ethics committee and the Paul-Ehrlich-Institute accepted inclusion criteria.
CRC is reported to have MUC1 expression in ~61% of pT1, 78% of pT2, 98% of pT3 and 90% of pT4 colorectal cancer samples and thus clearly correlates with invasiveness, being an optimal target for MUC1 based vaccination strategies after resection of hepatic metastases [34
]. In addition, MUC1 expression was found in 100% (56/56) of colorectal cancer liver metastases [35
]. A MUC1 expression of > 85% is expected in the study population analyzed, as the vast majority of metastatic cases will be pT3/pT4. It has been well discussed, that an engagement of the immune system might be the most successful therapeutic option to reduce micro-metastases and thus decreased recurrence rates and increase recurrence free survival time and overall survival time [36
L-BLP25 is designed to induce cellular cytotoxicity towards MUC1 expressing tumor cells. Doses of 1,000 μg have increased overall survival time in NSCLC patients from 13.3 months to 30.0 months in patients with stage IIIB disease without pleural effusion (HR 0.55) [38
]. A similar effect would be highly beneficial for patients after hepatic metastasectomy who have a high recurrence risk (70%) with a median time to recurrence of ~18-23 months [15
Thus, we aim to test L-BLP-25 vaccine in a randomized, placebo-controlled, multicenter, double blinded, safety/efficacy study in patients with metastatic CRC. Eligible patients will have had their primary tumor resected and will have undergone curative-intent resection of liver metastases (R0/R1) within the last 6 weeks. Since the percentage of colorectal cancers expressing MUC1 is very high, MUC1 testing results are not required prior to inclusion. Further, the significance of detection of MUC1 expression in a tumor sample is unclear, due to the fact that this may not mean that the tumor is truly negative for MUC1, patients whose tumors are not shown to be expressing MUC1 can be included into this study. Eligible patients will be randomized via IVRS to treatment with L-BLP-25 versus placebo (2:1). Treatment will be discontinued upon documented relapse or if subjects are free from relapse, treatment will be discontinued 3 years after first application.
The dose regimen and treatment schedule will be the same as those used in Trial EMR 63325-001 (worldwide phase III, START). Throughout the development of L-BLP25, a single low-dose of cyclophosphamide (300 mg/m2 to a maximum of 600 mg) has been administered prior to initiation of treatment with L-BLP25. The purpose is to overcome the immune suppression seen in cancer subjects and thus to enhance the development of an effective immune response to the MUC1 immunogen present in the vaccine.
We also decided to accept patients treated in a neo-adjuvant manner, if the neoadjuvant therapy has lasted 12 weeks or less. This became necessary, as some patients have been treated in a neo-adjuvant setting, but are presented for the study evaluation only post surgery. As a short chemotherapy seems not interfere with the postoperative immune system capacity, we agreed to include those patients in order to optimize accrual.
Patients in the investigational arm receive cyclophosphamide prior to immunotherapy, in an attempt to overcome the immune suppression seen in cancer subjects. Therefore, to maintain the double-blind design, subjects in the control arm will receive saline solution in the same calculated dose volume as that of cyclophosphamide.
The design and implementation of the current vaccination study in colorectal cancer is feasible. The study will provide recurrence-free and overall survival rates of groups in an unbiased fashion.