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MabThera: Primary endpoints of phase III trial met two years early due to superior efficacy benefits in relapsed indolent non-Hodgkin's lymphoma
Roche has been informed that a phase III study1 evaluating the use of MabThera (rituximab) in patients with relapsed indolent non-Hodgkin’s lymphoma (NHL) has met its primary endpoints two years earlier than expected.
In the two-part trial, patients were randomly assigned to receive MabThera plus chemotherapy or chemotherapy alone as initial treatment, and responding patients were then randomly assigned to receive MabThera for two years as maintenance therapy, or no further treatment. A pre-planned interim analysis showed that MabThera was the best therapeutic option in both parts of the trial: MabThera plus chemotherapy was significantly more effective than chemotherapy alone as initial treatment, and patients subsequently treated with MabThera maintenance for two years had significantly better progression-free survival than those who received no further treatment.
“More than half of patients with relapsed indolent NHL are currently treated with chemotherapy alone. This large trial confirms that MabThera should be the standard of care for patients with relapsed indolent NHL” said William M. Burns, Head of Roche’s Pharmaceuticals Division. “Moreover, this is the third study in indolent NHL to confirm the benefits of MabThera maintenance treatment. Due to these impressive results more patients will now benefit from MabThera for a longer time.”
The Independent Data Monitoring Committee (IDMC) concluded that the trial met its primary endpoints (response rate and progression-free survival) earlier than planned. The IDMC recommended changing the objective of the trial to answer the question of whether MabThera maintenance therapy is beneficial for patients receiving MabThera plus chemotherapy as initial treatment. The trial in its original design was not powered to answer this question. Therefore, the trial protocol will be amended so that all patients receive MabThera plus chemotherapy as initial treatment, and responding patients then be randomly assigned to receive MabThera as maintenance therapy for two years, or no further treatment.
Non-Hodgkin’s lymphoma affects 1.5 million people worldwide. Indolent NHL, representing about 45% of NHL patients, is a slow developing but serious cancer of the lymphatic system. NHL is one of the fastest growing cancers and has grown in incidence by 80% since the early 1970s.i
About the study
The international cooperative group phase III trial was conducted in 18 countriesii and recruited patients with relapsed indolent NHL. Patients were randomised to receive either six cycles of MabThera in combination with cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) chemotherapy, or CHOP chemotherapy alone. Patients who responded to initial treatment were then randomised to prolonged MabThera treatment (maintenance therapy) or no further treatment. MabThera maintenance therapy consisted of one dose of MabThera every three months for two years. In this study, the primary endpoints were response rates and progression-free survival for the initial treatment and maintenance parts of the study, respectively. Progression-free survival was evaluated as the time from randomisation to disease progression or death.
About MabThera
MabThera is a therapeutic antibody that binds to a particular protein - the CD20 antigen - on the surface of normal and malignant B-cells. It then recruits the body's natural defences to attack and kill the marked B-cells. Stem cells (B-cell progenitors) in bone marrow lack the CD20 antigen, allowing healthy B-cells to regenerate after treatment and return to normal levels within several months.
MabThera is indicated as a single-agent treatment for relapsed or refractory indolent NHL, and received European approval in March 2002 for the treatment of aggressive NHL in combination with CHOP chemotherapy. MabThera is known as Rituxan in the United States, Japan and Canada. More than 370,000 patients have been treated with MabThera worldwide to date.
Genentech and Biogen Idec co-market MabThera in the United States, and Roche markets MabThera in the rest of the world, except Japan, where MabThera is co-marketed by Chugai and Zenyaku Kogyo Co. Ltd.
Roche in Oncology
Within the last five years the Roche Group has become the world’s leading provider of anti-cancer treatments, supportive care products and diagnostics. Its oncology business includes an unprecedented four marketed products with survival benefit: Herceptin, MabThera, Xeloda and Avastin, which has been launched in the US recently, treat a range of malignancies such as breast cancer, non-Hodgkin’s lymphoma and colorectal cancer. Other key products include NeoRecormon (anaemia in various cancer settings), Bondronat (prevention of skeletal events in breast cancer and bone metastases patients, hypercalcemia of malignancy), Kytril (chemotherapy and radiotherapy-induced nausea and vomiting) and Roferon-A (leukaemia, Kaposi's sarcoma, malignant melanoma, renal cell carcinoma). Roche’s cancer medicines generated sales of more than 6 billion Swiss francs in 2003.
Roche is developing new tests which will have a significant impact on disease management for cancer patients in the future. With a broad portfolio of tumour markers for prostate, colorectal, liver, ovarian, breast, stomach, pancreas and lung cancer, as well as a range of molecular oncology tests, Roche will continue to be the leaders in providing cancer focused treatments and diagnostics.
Roche Oncology has four research sites (two in the US, Germany and Japan) and four Headquarter Development sites (two in the US, UK and Switzerland).
About Roche
Headquartered in Basel, Switzerland, Roche is one of the world’s leading innovation-driven healthcare groups. Its core businesses are pharmaceuticals and diagnostics. Roche is number one in the global diagnostics market and is the leading supplier of pharmaceuticals for cancer and a leader in virology and transplantation. As a supplier of products and services for the prevention, diagnosis and treatment of disease, the Group contributes on a broad range of fronts to improving people’s health and quality of life. Roche employs roughly 65,000 people in 150 countries. The Group has alliances and research and development agreements with numerous partners, including majority ownership interests in Genentech and Chugai.
1 European Organization for Research and Treatment of Cancer (EORTC) 20981
All trademarks used or mentioned in this release are legally protected.
Notes to editors:
i World Health Report 2000, World Health Organization, www.who.int.
ii Countries that participated in the study: Canada, Australia, The Netherlands, The UK, Norway, Slovenia, Slovakia, Belgium, Hungary, South Africa, Sweden, New Zealand, Denmark, Egypt, France, Switzerland, Italy, Poland.
MabThera
Your doctor has recommended a medication called MabThera as treatment for your Non Hodgkins Lymphoma (NHL). This information sheet provides a brief introduction to MabThera and explains the common side effects you may experience. This does not mean you will definitely get them. It is also possible you may experience a side effect not mentioned here. MabThera may be given in conjunction with chemotherapy so you should also refer to the specific information and advice sheet relating to these other drugs.
WHAT IS MABTHERA? It is not chemotherapy and it is not a hormone therapy. It is called a monoclonal antibody (Mab) and is one of the novel new cancer therapies which utilise the natural immune system (Immunotherapy). Cancers, grow mainly outside the control of the bodies normal regulatory systems (see what is cancer). Despite this they are sufficiently similar to the own bodies cells to escape the normal bodies defence mechanism against "foreign" attack, as a result they are able to hide from the bodies immune system. There are, however, some differences between cancer and normal body cells. These differences can be detected with sensitive laboratory tests.
In some types of NHL a protein is present on the cell surface (an antigen) called CD20. Over expression (making too much) of CD20 reflects an abnormality in the DNA of the cell - a tiny piece of DNA has moved from one chromosome called number 14 to number 18. This is called a translocation(14;18). This moves a cancer producing gene (previously locked out of harms way) into a position which turns the normal lymphoid cell into a cancerous lymphoma cell. This oncogene called bcl-2 is responsible for "over expressing" CD20. In some cases particularly the low grade follicular type of NHL there are hundreds more CD20 receptors on the cancer cells than the normal cells.
Technology now exists to make antibodies (the normal chemicals used by the immune system to detect and attack foreign particles in the body). These antibodies have been made to detect CD20 receptors. The antibody is therefore an anti-CD20 treatment called Rituximab or its commercial name MabThera. MabThera is indicated as a single-agent treatment for relapsed or refractory indolent NHL, and received European approval in March 2002 for the treatment of aggressive NHL in combination with CHOP chemotherapy. In September 2004, MabThera was also given a licence for the first line treatment of Follicular NHL in combination with CVP (Cyclophosphamide, vincristine and prednisolone) chemotherapy. The drug is known as Rituxan in the United States, Japan and Canada, and as MabThera in the rest of the world.
HOW DOES MABTHERA WORK? Research has shown that 95% of patients with low grade follicular lymphoma over express CD20. The higher grades of NHL are the less likely it is to have CD20 receptors (see classification of lymphomas). In any case, before treatment, this can be measured on a sample of lymphoma in the original biopsy ( a further biopsy is usually not required). If the NHL does over express CD20 down the microscope it will stain brightly compared the normal cells (see left picture). In these patients it is then possible to give MabThera to attack the lymphoma cells which still remain in the body. In the body the MabThera finds the cancer cells wherever they may be hiding and sticks to the CD20 receptor. It then enhances the tumour response in a number of ways:
It triggers a self destruct mechanism within the cell (apoptosis).
It also encourages the bodies normal immune cells to attack the tumour.
They condition the cancer cell to be more sensitive to chemotherapy.
HOW IS MABTHERA GIVEN? Techniques may vary but the most commonly used technique is as an infusion into a vein in the hand or arm through a small plastic tube called a cannula. The infusion rate may vary on how it is tolerated but on the first occasion it is at least 4-5 hours. This is usually given as a day case. The dose is calculated by the height & weight of the patient (then converted into surface area). The recommended dose is 375mg/meter squared once a week for 4 infusions if given as monotherapy and 8 if given with chemotherapy. Occasionally, as with all protein based drugs it is possible to get an allergic reaction. The nurses will therefore be checking how you are feeling and measuring your breathing, pulse and blood pressure blood regularly. Sometimes, in response to mild reaction, it may have to be slowed down over several hours. Rarely if there allergic reaction is prominent it has to be stopped altogether. To avoid a mild reaction often paracetamol and an antihistamine (e.g. piriton) are given before the infusion.
ARE THERE ANY SIDE EFFECTS? When given with chemotherapy the side effect normally relate to the chemotherapy. Mabthera is usually well tolerated. It has a major advantage over chemotherapy by not damaging the bone marrow. It does have some mild side effects of its own:-
Infusion related reaction:
Fever, chills and rigors, throat irritation, a runny nose, flushing or pain in the sites of the tumours. These are usually mild but can be distressing in some patients. They usually occur 30 minutes to 2 hours after starting the infusion and are more common the faster the infusion . These symptoms can be diminished by taking a paracetamol and an anti-histamine. The nurse will monitor your pulse and blood pressure during the infusion.
If the reaction is severe (rare) there may be associated with dizziness, wheezing or a sensation of throat swelling which may be associated with a drop in blood pressure. In this case, the infusion will be slowed down or even stopped and the reaction can be treated with intravenous steroids. Severe infusion reactions are more likely if there high tumour burden (very advanced bulk disease) In these cases there has very rarely been fatalities.
Other potential side effects:
Rarely patients have experience mild nausea or even vomiting but these only last a few hours.
MabThera does not damage the heart but if a patient has a pre-existing heart problem such as heart failure or angina there infusion reaction could make this worse and should be used in caution.
This medicine should only be used during pregnancy where the advantages to the individual outweigh the potential risks. Seek medical advice from your doctor.
There is no information available about the safety of this medicine during breastfeeding. For this reason, the manufacturer states that it should not be used during breastfeeding. Seek medical advice from your doctor.
Specific information is also supplied in the drug packaging. Alternatively contact Cancer Bacup on 0808 8001234 or the Lymphoma association
Rituximab (Mabthera®)
What is rituximab?
Monoclonal antibodies
What it looks like
How it is given
Possible side effects
Additional information
References
What is rituximab?
Rituximab (pronounced ri tucks i mab) belongs to a group of cancer drugs known as monoclonal antibodies. It is used to treat several types of non-Hodgkin’s lymphoma.
Rituximab can be given on its own to people who cannot have chemotherapy because of the potential side effects, or to those whose lymphoma has come back after chemotherapy. It can also be given in combination with chemotherapy as the first treatment for people who have high-grade lymphoma that is at an advanced stage when first diagnosed.
Monoclonal antibodies
Monoclonal antibodies are used to try to destroy some types of cancer cells while causing little harm to normal cells. They recognise certain proteins that are found on the surface of particular cancer cells. The monoclonal antibody recognises the protein and ‘locks’ on to it (like a key in a lock). This may then trigger the body’s immune system to attack the cancer cells and can sometimes cause the cells to destroy themselves.
Rituximab locks on to a protein called CD20 which is found on the surface of one of the main types of normal white blood cells (B-cell lymphocytes). It is also present on the surface of most of the abnormal B-cell lymphocytes which occur in most types of non-Hodgkin’s lymphoma. Rituximab attacks both abnormal (malignant) and normal B-cell lymphocytes. However, the body quickly replaces any normal white blood cells which are damaged, so the risk of side effects from this is very small.
What it looks like
Rituximab is a clear fluid after being diluted.
How it is given
Rituximab is given as a drip (infusion) through a fine tube (cannula) inserted into the vein. Some people can have an allergic reaction to rituximab; to reduce the risk of this the first dose is given slowly over a number of hours. You will be given some antihistamines and steroids before the treatment is given, to help prevent any reaction. If you do have a reaction the infusion can be stopped and started again when the symptoms are over. You may need to stay in hospital overnight for the first treatment so that you can be monitored. After that, rituximab can usually be given in the outpatients department and over a shorter period of time.
When used by itself, rituximab is usually given weekly over a period of four weeks. The treatment may be repeated later if needed.
If rituximab is being used with chemotherapy it is given with each course of chemotherapy.
Possible side effects
Each person’s reaction to a cancer drug is unique. Some people have very few side effects, while others may experience more. We have outlined the most common side effects. However, we have not included those that are very rare and therefore extremely unlikely to affect you. If you notice any effects that you think may be due to the drug but which are not listed in the factsheet, please discuss them with your doctor or nurse.
The side effects of rituximab are generally mild and some of these can be reduced with medicines. Side effects can begin during the first dose of the drug and may continue for a few hours afterwards, but are usually milder with following doses.
The most common side effects are decribed below:
Flu-like symptoms These can include a high temperature, chills, weakness, muscle aches, tiredness, dizziness and headaches. They can occur while the rituximab is being given, but do not usually last long.
Low blood pressure This may happen during the infusion, so your blood pressure will usually be regularly checked. People who normally take medicines to lower their blood pressure may be advised by the doctor to take these at least 12 hours before rituximab is given.
Feeling sick (nausea) and occasional vomiting There are now very effective anti-sickness drugs to prevent or greatly reduce nausea and vomiting. If the sickness is not controlled, or continues, tell your doctor. He or she can prescribe other anti-sickness drugs that may be more effective.
Tumour pain Some people may experience mild pain in the parts of the body where they have cancer. Painkillers can be given to relieve this.
Allergic reactions You may have a slight allergic reaction to rituximab. Signs of this include skin rashes and itching, a feeling of swelling in the tongue or throat, irritation of the nasal passages, wheezing, a cough and breathlessness. You will be monitored closely during your treatment, but let your nurse or doctor know if you have any of these symptoms. To help reduce the chance of developing an allergic reaction, antihistamines can be given before the infusion. The infusion can also be slowed down or stopped until the reaction is over.
Flushing You may experience a sudden warmth in your face and some redness or darkening of the face. This can happen for a short period of time during the infusion.
Additional information
Rituximab may worsen heart problems in people who already have these. For this reason it is used with caution in anyone who has heart disease.
References
This section has been compiled using information from a number of reliable sources including:
Martindale: The Complete Drug Reference (33rd edition), Eds. Sweetman et al. Pharmaceutical Press, 2002.
British National Formulary (48th edition). British Medical Association and Royal Pharmaceutical Society of Great Britain, September 2004.
Full guidance on rituximab for aggressive non-Hodgkin’s lymphoma. National Institute for Clinical Excellence (NICE), September 2003.
Full guidance on rituximab for follicular non-Hodgkin’s lymphoma. National Institute for Clinical Excellence (NICE), March 2002.
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