Catumaxomab 50micrograms/0.5ml solution for infusion pre-filled syringes

BACKGROUND: Peritoneal carcinomatosis (PC) represents an unfavourable prognostic factor for patients with gastric cancer (GC). Intraperitoneal treatment with the bispecific and trifunctional antibody catumaxomab (EpCAM, CD3), in addition to systemic chemotherapy, could improve elimination of PC. METHODS: This prospective, randomised, phase II study investigated the efficacy of catumaxomab followed by chemotherapy (arm A, 5-fluorouracil, leucovorin, oxaliplatin, docetaxel, FLOT) or FLOT alone (arm B) in patients with GC and PC. Primary endpoint was the rate of macroscopic complete remission (mCR) of PC at the time of second diagnostic laparoscopy/laparotomy prior to optional surgery. RESULTS: Median follow-up was 52 months. Out of 35 patients screened, 15 were allocated to arm A and 16 to arm B. mCR rate was 27% in arm A and 19% in arm B (p = 0.69). Severe side effects associated with catumaxomab were nausea, infection, abdominal pain, and elevated liver enzymes. Median progression-free (6.7 vs. 5.4 months, p = 0.71) and overall survival (13.2 vs. 13.0 months, p = 0.97) were not significantly different in both treatment arms. CONCLUSIONS: Addition of catumaxomab to systemic chemotherapy was feasible and tolerable in advanced GC. Although the primary endpoint could not be demonstrated, results are promising for future investigations integrating intraperitoneal immunotherapy into a multimodal treatment strategy.

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In this paper, we discuss a response adaptive randomization method, and why it should be used in clinical trials for rare diseases compared to a randomized controlled trial with equal fixed randomization. The developed method uses a patient's biomarkers to alter the allocation probability to each treatment, in order to emphasize the benefit to the trial population. The method starts with an initial burn-in period of a small number of patients, who with equal probability, are allocated to each treatment. We then use a regression method to predict the best outcome of the next patient, using their biomarkers and the information from the previous patients. This estimated best treatment is assigned to the next patient with high probability. A completed clinical trial for the effect of catumaxomab on the survival of cancer patients is used as an example to demonstrate the use of the method and the differences to a controlled trial with equal allocation. Different regression procedures are investigated and compared to a randomized controlled trial, using efficacy and ethical measures.

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// Jürgen Borlak 1 , Florian Länger 2 , Reinhard Spanel 1, 3 , Georg Schöndorfer 4 , Christian Dittrich 5 1 Centre for Pharmacology and Toxicology, Hannover Medical School, Hannover, Germany 2 Department of Pathology, Hannover Medical School, Hannover, Germany 3 Institute of Pathology, Viersen, Germany 4 Clinical Development, Fresenius Biotech GmbH, München, Germany 5 Applied Cancer Research – Institution for Translational Research Vienna (ACR-ITR VIEnna) and Ludwig Boltzmann Institute for Applied Cancer Research (LBI-ACR VIEnna), Center for Oncology and Hematology, Kaiser Franz Josef-Spital, Vienna, Austria Correspondence to: Jürgen Borlak, email: Borlak.Juergen@mh-hannover.de Keywords: catumaxomab, acute liver failure (ALF), idiosyncratic drug hepatotoxicity, epithelial cell adhesion molecule EpCAM Received: November 18, 2015      Accepted: March 18, 2016      Published: April 4, 2016 ABSTRACT The immunotherapeutic catumaxomab targets EpCAM positive cancers and is approved for the treatment of peritoneal carcinomatosis. To assess the safety of intravenous applications a phase 1 clinical trial was initiated. Treatment of EpCAM positive tumor patients with catumaxomab caused dose dependent hepatitis as evidenced by significant elevations in serum alanine- and aspartate aminotransferases, bilirubin, γGT and induction of the acute phase C-reactive protein (CRP) and the cytokines IL6 and IL8. The first patient receiving 10μg catumaxomab experienced fatal acute liver failure which led to the termination of the study. Immmunopathology revealed catumaxomab to bind via its Fc-fragment to FcγR-positive Kupffer cells to stimulate CRP, chemokine and cytokine release. The observed CD3+T-cell margination at activated hepatic macrophages exacerbated T-cell mediated cytotoxicity. Strikingly, the combined Kupffer/T-cell responses against liver cells did not require hepatocytes to be EpCAM-positive. Catumaxomab’s off-target activity involved T-cell mediated lysis of the granzyme B cell death pathway and the molecular interaction of hepatic sinusoidal macrophages with T-cells induced cytolytic hepatitis. Although the bile ducts were surrounded by densely packed lymphocytes these rarely infiltrated the ducts to suggest an intrahepatic cholestasis as the cause of hyperbilirubinaemia. Lastly, evidence for the programming of memory T-cells was observed with one patient that succumbed to his cancer six weeks after the last catumaxomab infusion. In conclusion, our study exemplifies off-target hepatotoxicity with molecularly targeted therapy and highlights the complexities in the clinical development of immunotherapeutic antibodies.

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Peritoneal metastasis, also known as peritoneal carcinomatosis (PC), is a refractory cancer that is typically resistant to conventional therapies. The typical treatment for PC is a combination of cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC). Recently, research in this area has seen significant advances, particularly in immunotherapy as an alternative therapy for PC, which is very encouraging. Catumaxomab is a trifunctional antibody intraperitoneal (IP) immunotherapy authorized in Europe that can be used to diminish malignant ascites by targeting EpCAM. Intraperitoneal (IP) immunotherapy breaks immunological tolerance to treat peritoneal illness. Increasing T-cell responses and vaccination against tumor-associated antigens are two methods of treatment. CAR-T cells, vaccine-based therapeutics, dendritic cells (DCs) in combination with pro-inflammatory cytokines and NKs, adoptive cell transfer, and immune checkpoint inhibitors are promising treatments for PC. Carcinoembryonic antigen-expressing tumors are suppressed by IP administration of CAR-T cells. This reaction was strengthened by anti-PD-L1 or anti-Gr1. When paired with CD137 co-stimulatory signaling, CAR-T cells for folate receptor cancers made it easier for T-cell tumors to find their way to and stay alive in the body.

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OBJECTIVE: Systemic lupus erythematosus (SLE) patients are at risk during the COVID-19 pandemic, yet the underlying molecular mechanisms remain incompletely understood. This study sought to analyze the potential molecular connections between COVID-19 and SLE, employing a bioinformatics approach to identify effective drugs for both conditions. METHODS: The data sets GSE100163 and GSE183071 were utilized to determine share differentially expressed genes (DEGs). These DEGs were later analyzed by various bioinformatic methods, including functional enrichment, protein-protein interaction (PPI) network analysis, regulatory network construction, and gene-drug interaction construction. RESULTS: A total of 50 common DEGs were found between COVID-19 and SLE. Gene ontology (GO) functional annotation revealed that "immune response," "innate immune response," "plasma membrane," and "protein binding" were most enriched in. Additionally, the pathways that were enriched include "Th1 and Th2 cell differentiation." The study identified 48 genes/nodes enriched with 292 edges in the PPI network, of which the top 10 hub genes were CD4, IL7R, CD3E, CD5, CD247, KLRB1, CD40LG, CD7, CR2, and GZMK. Furthermore, the study found 48 transcription factors and 8 microRNAs regulating these hub genes. Finally, four drugs namely ibalizumab (targeted to CD4), blinatumomab (targeted to CD3E), muromonab-CD3 (targeted to CD3E), and catumaxomab (targeted to CD3E) were found in gene-drug interaction. CONCLUSION: Four possible drugs that targeted two specific genes, which may be beneficial for COVID-19 patients with SLE.

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