Catumaxomab

Catumaxomab is a trifunctional rat-mouse hybrid monoclonal antibody (IgG2) directed against the epithelial cell adhesion molecule (EpCAM) and the CD3 antigen. EpCAM is present on most carcinomas, and CD3 is part of the T-cell receptor on mature T-cells. A third functional binding site in the Fc region interacts with accessory immune cells through Fc-gamma receptors. The antibody is infused into the peritoneal cavity and acts locally.

Mechanism of Action

• Three-way binding: catumaxomab binds EpCAM on tumour cells, CD3 on T-cells and Fc-gamma receptors on accessory immune cells (DrugBank names macrophages and natural killer cells), bringing the three cell types into close contact.
• Concerted immune reaction: T-cell activation, T-cell-mediated killing through the granzyme/perforin system, antibody-dependent cell-mediated cytotoxicity, complement-dependent cytotoxicity and phagocytosis. The result is destruction of tumour cells in the peritoneal cavity, which removes a major cause of malignant ascites.
• Cytokine release: binding to immune and tumour cells starts the release of pro-inflammatory and cytotoxic cytokines, which underlies the cytokine-release symptoms seen during and after infusion.
• Preclinical activity: in vitro, tumour cells with low and high EpCAM expression were killed regardless of the primary tumour type. In a mouse model of ovarian carcinoma with human mononuclear cells, intraperitoneal treatment delayed tumour development.

Pharmacokinetics

• Absorption: given into the peritoneal cavity, catumaxomab is immediately available at its target site.
• Distribution: it distributes in ascites fluid, the site of action. In a study of 13 patients given the four infusions over 6 hours each, mean and median ascites Cmax were 7,122 and 3,270 pg/mL. Residual antibody that is not bound to target cells reaches the circulation intact: geometric mean plasma Cmax was 0.5 ng/mL (range 0–2.3) and AUC 1.7 day·ng/mL. Variability between patients is high because ascites volume and tumour cell burden differ.
• Metabolism and elimination: as for endogenous IgG, mainly proteolytic catabolism throughout the body, not primarily through the kidneys or liver. For the systemic fraction the geometric mean apparent terminal half-life is 2.5 days (range 0.7–17.5).
• Special populations: no studies have been conducted.

• Malignant ascites: intraperitoneal treatment of malignant ascites in adults with EpCAM-positive carcinomas who are not eligible for further systemic anticancer therapy.

• Hypersensitivity to catumaxomab or to any of the excipients.
• Hypersensitivity to murine (rat and/or mouse) proteins.

The most common reactions are pyrexia (62%), abdominal pain (42%), nausea (41%) and vomiting (38%). The most serious are systemic inflammatory response syndrome and hepatic failure. The frequencies come from an integrated analysis of 11 studies in 517 patients (4 studies in malignant ascites, 7 in other cancers; 293 patients had 6-hour and 224 had 3-hour infusions), so some listed terms come from settings outside malignant ascites, including intraoperative use.

Very common (≥1/10): cytokine release syndrome; abdominal pain, nausea, vomiting, diarrhoea; pyrexia, chills, fatigue, pain; increased C-reactive protein.

Common (≥1/100 to <1/10): infection; anaemia, leukocytosis, lymphopenia; systemic inflammatory response syndrome, hypersensitivity; decreased appetite, dehydration, hypokalaemia, hyponatraemia, hypoalbuminaemia, hyperglycaemia, hypocalcaemia, hypoproteinaemia; anxiety; dizziness; tachycardia; hypertension, hypotension, flushing, hot flush; dyspnoea, hypoxia, pleural effusion; abdominal discomfort, abdominal distension, upper abdominal pain, gastro-oesophageal reflux disease, sub-ileus, flatulence; hyperbilirubinaemia, cholangitis; allergic dermatitis, rash, erythema, hyperhidrosis, pruritus; back pain, myalgia, arthralgia; haematuria, proteinuria; asthenia, inflammation, oedema, chest pain, influenza-like illness, malaise, peripheral oedema; raised ALT, AST, alkaline phosphatase, gamma-glutamyltransferase, body temperature, neutrophil and white cell counts, creatinine, urea, amylase, creatine phosphokinase, platelet count, hepatic enzymes and procalcitonin; decreased haemoglobin, total protein and blood potassium; weight decreased.

Uncommon (≥1/1,000 to <1/100): oral candidiasis, skin infection, herpes simplex, pneumonia, urinary tract infection and other localised infections; coagulopathy, leukopenia, neutropenia, thrombocytopenia, thrombocythaemia; fluid retention, hypoglycaemia, polydipsia, hypomagnesaemia; agitation, depression; syncope, tremor, paraesthesia, convulsion, lethargy, peripheral sensory neuropathy, polyneuropathy, dysgeusia; blurred vision; vertigo; sinus tachycardia, palpitations, arrhythmia, cardiac failure; pulmonary embolism, acute respiratory distress syndrome, bronchospasm, cough, hiccups, lung infiltration, respiratory distress or failure, tachypnoea, wheezing; abdominal cramps, dry mouth, paralytic ileus, impaired gastric emptying, ascites, peritonitis, small intestinal obstruction, haematemesis, stomatitis and other gastrointestinal complaints; cytolytic hepatitis, hepatic failure, cholestasis, abnormal hepatic function, toxic hepatitis, jaundice; night sweats, urticaria, palmar erythema, pruritic rash, skin reaction; bone pain, flank pain, musculoskeletal pain, pain in extremity; dysuria, leukocyturia, oliguria, renal failure (including acute), renal pain; pelvic pain; application site inflammation, catheter site pain, extravasation, injection site reaction, mucosal inflammation, thirst, general physical health deterioration; anastomotic complication, procedural pain, wound dehiscence; and further laboratory changes (for example raised bilirubin, transaminases, lipase, INR, prolonged activated thromboplastin time, decreased oxygen saturation, sodium and chloride).

Cytokine release syndrome occurred in 23% of patients in a re-analysis of the pivotal study and was mostly grade 1 or 2 (of 41 suspected episodes, 3 were grade 1, 27 grade 2, 10 grade 3 and 1 grade 4); pre-medication can reduce or prevent its symptoms. Systemic inflammatory response syndrome was reported in 2 of 203 patients exposed in the pivotal study; both cases were grade 4, required hospitalisation and ended treatment. Abdominal pain occurred in 38.9% of patients in the main study period, reached grade 3 or higher in 8.9% and settled with symptomatic treatment. Transient liver enzyme and bilirubin rises were common; 12 patients (5.6%) had ALT above 3 times the upper limit of normal with bilirubin above 2 times the upper limit, which was reversible in 10 of the 12. Safety with 3-hour and 6-hour infusions was broadly comparable, with more chills, hypotension, diarrhoea, fatigue, anaemia and pleural effusion after the 3-hour infusion.

• No interaction studies have been performed.
• Immune-interfering factors: administration is not recommended in the presence of factors that interfere with the immune system, in particular acute infections.
• Pre-medication: an analgesic, antipyretic and non-steroidal anti-inflammatory medicine is recommended before each infusion to prevent cytokine-release symptoms (see Administration and Dosage).

Korjuny must be given under the supervision of a physician experienced in the use of anti-cancer medicinal products. It is given as an intraperitoneal infusion only: never as an intraperitoneal bolus and never by any other route. The concentrate is diluted in sodium chloride 9 mg/mL (0.9%) solution for injection and infused at a constant rate with an adequate pump system, over at least 3 hours. Infusion times of 3 and 6 hours were studied, and 6 hours may be considered for the first dose depending on the patient’s health. An additional 500 mL of sodium chloride 0.9% is given before each infusion and 250 mL in parallel with it (see SmPC section 6.6 for dilution).

EpCAM Testing

In the clinical studies EpCAM expression was determined with a validated immunocytochemical assay on malignant ascites samples, with a positivity threshold of at least 400 EpCAM-positive cells per million analysed ascites cells. Where a CE-marked in vitro diagnostic device with the appropriate intended purpose is not available, alternative assays should be validated and show appropriate analytical performance.

Dosing Schedule

Four intraperitoneal infusions:

• Infusion 1: 10 micrograms on day 0.
• Infusion 2: 20 micrograms on day 3.
• Infusion 3: 50 micrograms on day 7.
• Infusion 4: 150 micrograms on day 10.

The interval between infusion days can be extended at the treating physician’s discretion to reduce the risk of adverse reactions, but the whole treatment period should not exceed 21 days.

Before Each Infusion

• Pre-medication to prevent cytokine-release symptoms, including an analgesic, an antipyretic and a non-steroidal anti-inflammatory medicine, is recommended. Side effects are treated as medically indicated and according to the current standard of care.
• Ascites drainage, at least until spontaneous flow stops or symptoms are relieved, is a prerequisite to keep circulation and kidney function stable.
• Blood volume, blood protein, blood pressure, pulse and renal function are assessed before each infusion. Hypovolaemia, hypoproteinaemia, hypotension, circulatory decompensation and acute renal impairment must be resolved first.

Monitoring After Infusion

Patients stay under close medical supervision for at least 24 hours after the first infusion and for at least 6 hours after the later infusions; a longer hospital stay is at the treating physician’s discretion.

Special Populations

• Hepatic impairment: no dose adjustment in mild to moderate impairment. Patients with severe impairment, more than 70% of the liver replaced by metastases, or portal vein thrombosis or obstruction have not been investigated and are treated only after a thorough benefit/risk evaluation.
• Renal impairment: no dose adjustment in mild impairment. Moderate to severe impairment has not been studied, so treatment is considered only after a thorough benefit/risk evaluation.
• Children and adolescents: safety and efficacy under 18 years have not been established; no data are available.

Cytokine Release Syndrome

Binding of catumaxomab to immune and tumour cells triggers the release of pro-inflammatory and cytotoxic cytokines. Symptoms reported during and after infusion include fever, hypotension, gastrointestinal symptoms, headache, myalgia, arthralgia, tachycardia, chills, respiratory symptoms, skin symptoms and fatigue. Despite pre-medication they can reach grade 4. Patients are told to seek immediate medical attention if signs of cytokine release occur at any time, and it is treated as medically indicated.

Systemic Inflammatory Response Syndrome

Isolated cases (fever, increased heart rate and respiratory rate, abnormal leukocyte count) have occurred during and after treatment. Patients are told to seek immediate medical attention if signs appear, and it is treated as medically indicated.

Infections

Administration is not recommended in the presence of factors that interfere with the immune system, particularly acute infections. Patients are monitored for signs of infection before and after each infusion and treated appropriately.

Liver and Kidney Function

Transient liver enzyme rises after infusion are common and mostly improve soon after the last dose. In rare cases catumaxomab-related drug-induced liver injury or hepatitis may occur and can lead to hepatic failure, including fatal outcome, so patients are closely monitored for clinically significant liver test changes. Catumaxomab is not eliminated through the kidneys.

Abdominal Pain

Abdominal pain is common. It is transient and considered partly a consequence of the intraperitoneal route.

Performance Status and Body Mass Index

In the pivotal study, patients with a Karnofsky performance score below 60 or a body mass index below 17 or above 40 kg/m² were not investigated. Treating them is at the physician’s discretion.

Patient Card

The prescriber discusses the risks with the patient and gives a patient card to carry at all times. It describes the common signs and symptoms of cytokine release syndrome and systemic inflammatory response syndrome and when to seek medical attention.

Pregnancy, Breastfeeding and Fertility

• Women of childbearing potential: Korjuny is not recommended in women of childbearing potential who are not using contraception.
• Pregnancy: not recommended; data are limited or absent, and animal studies are insufficient for reproductive toxicity.
• Breastfeeding: it is unknown whether catumaxomab or its metabolites pass into human milk. A decision is made whether to stop breastfeeding or to abstain from treatment, weighing the benefit of each.
• Fertility: no data are available.

Excipients

Each pre-filled syringe contains 21.6 micrograms (10 micrograms syringe) or 108 micrograms (50 micrograms syringe) of polysorbate 80, which may cause allergic reactions. The product contains less than 1 mmol sodium (23 mg) per dose unit, but the amount infused is higher because of the sodium chloride used for dilution and in parallel with each infusion.

Effect on Driving

Korjuny has a minor influence on the ability to drive and use machines. Patients with infusion-related symptoms should not drive or use machines until they pass.

Store in a refrigerator at 2–8 °C. Do not freeze. Keep in the original package to protect from light. As a refrigerated product it must stay in the cold chain from dispatch until the administering hospital uses it. For storage after dilution, see Shelf Life.

• Unopened: 3 years.
• After dilution: the prepared infusion solution is physically and chemically stable for 48 hours at 2–8 °C and for 24 hours at a temperature not above 25 °C. From a microbiological point of view it should be used immediately; otherwise in-use times and conditions are the responsibility of the user and would normally not exceed 24 hours at 2–8 °C, unless dilution took place under controlled and validated aseptic conditions.

Prescription only (Rx): a medicinal product subject to restricted medical prescription. Treatment is given under the supervision of a physician experienced in anti-cancer medicinal products, as an intraperitoneal infusion with monitoring in hospital afterwards, so Korjuny is supplied to the hospital or clinic that administers it, kept at 2–8 °C. Korjuny 10 micrograms comes in a blue-coded carton with 3 pre-filled syringes and 5 cannulas, and Korjuny 50 micrograms in a red-coded carton with 4 pre-filled syringes and 5 cannulas; not all pack sizes may be marketed.