A PHASE II STUDY OF ANTI-CD20 MONOCLONAL ANTIBODY (RITUXIMAB) THERAPY FOR PATIENTS WITH REFRACTORY OR RELAPSED PRIMARY CENTRAL NERVOUS SYSTEM LYMPHOMA (PCNSL)

Protocol Version: November 3, 2004

Purpose of Study

Primary Objective

• Determine the radiographic response proportion in patients with refractory or recurrent PCNSL to Rituximab when given as an intravenous infusion once weekly for 2 cycles.

Secondary Objectives

• Determine the time to progression free and overall survival of patients treated with Rituximab when given as an intravenous infusion once weekly for 2 cycles.
• Establish the toxicity profile of Rituximab in this patient population.

Eligibility Criteria

Inclusion Criteria

1. Patients must be at least 18 years of age.
2. Primary central nervous system lymphoma confirmed histologically by ONE of the following ways (all histologic material must be reviewed at enrolling institution and be within 30 days of first treatment):
   1. Brain biopsy or resection. All patients with a histologic diagnosis of non-Hodgkin’s B-cell lymphoma by brain biopsy or resection.
   2. CSF Cytology. All patients with positive cytology (CSF) or immunohistochemical diagnosis of monoclonality (CSF) with or without measurable intracranial disease.
   3. Vitreal biopsy. All patients with histologic confirmation of vitreal lymphoma with measurable intracranial tumor.
3. Patients must have a measurable (> 1 cm in diameter) progressive or recurrent tumor on MRI or CT imaging within -14 days of starting treatment.
4. Patients must be able to provide written informed consent.
5. Patients must have the following tests performed as part of a pre-treatment evaluation prior to starting treatment:
   1. CT chest-abdomen and pelvis with contrast to rule out systemic lymphoma.
   2. Lumbar Puncture for CNS cytology/flow cytometry (if deemed safe by the treating oncologist) to screen for leptomeningeal lymphoma.
   3. Ophthalmology evaluation with slit lamp examination is required to screen for ocular lymphoma.  If there is uveitis detected on ophthalmic examination vitreal aspiration/biopsy for cytopathology and flow cytometry is strongly recommended to definitively screen for the presence of ocular lymphoma.
   4. HIV serology must be performed and must be negative.  Patients must have a negative HIV serology due to the distinct clinical course of PCNSL in immunosuppressed patients and the potential drug interactions with antiviral regimens.
6. Patients must have progressed through the first line of treatment (chemotherapy and/or radiation) or have relapsed after initial successful treatment
7. Absolute neutrophil count ³1500/mm³, platelets ³ 100,000/mm³, hemoglobin concentration > 9.0 g/dl, creatinine < 1.5mg/dL, total bilirubin <1.5 mg/dl, transaminases < 4 times above the upper limits of the institutional normal.
8. Patients must have recovered from toxicity of prior therapy. An interval of at least 3 months must have elapsed since the completion of the most recent course of radiation therapy while at least 3 weeks must have elapsed since the completion of a non-nitrosourea containing chemotherapy regimen and at least 6 weeks since the completion of a nitrosourea containing chemotherapy regimen.
9. Patients must not be pregnant or breast-feeding. All patients with the potential for pregnancy should be counseled and requested to follow acceptable birth control methods to avoid conception for up to 12 months after the completion of treatment.  These patients are excluded because no information on this agent exists with regard to safety for a fetus or breast-feeding infant. 
10. Patients must have a Karnofsky performance status of > 60%.
11. No other serious concurrent infection or other medical illness should be present which would jeopardize the ability of the patient to receive the chemotherapy outlined in this protocol with reasonable safety.
12. Patients must have no concurrent malignancy except curatively treated basal or squamous cell carcinoma of the skin or carcinoma in situ.  Patients with prior malignancies must be disease-free for > five years.
13. Patients must be able to comply with prescribed medical care.
14. Patients’ brain biopsy must demonstrate the presence of CD 20 on cell surface.
15. Patients must have a mini mental status examination (MMSE) score ³ 15.

 Exclusion Criteria

1. Patients who have had prior treatment with an investigational drug, biological, or therapeutic device within 90 days of starting treatment with Rituximab.

2. Patients who have received prior treatment with rituximab.

3. Patients who are pregnant or breast-feeding.  These patients are excluded because no information on this agent exists with regard to safety for a fetus or breast-feeding infant.

4. Patients without MRI or CT evidence of measurable contrast enhancing residual disease are not eligible.

5. Patients with positive HIV serology.  These patients are excluded because of the poor natural history of AIDS related lymphoma and the excessive toxicities that are often associated with antineoplastic therapies in this patient population.

6. Patients testing positive for the hepatitis B virus (HBV) are ineligible.  Rituximab can cause HBV reactivation.

Treatment Schedule

This will be a two-stage, Phase II trial.   Fifteen patients will be enrolled in the first stage of accrual.  If 1 or more patients demonstrate a response among the first 15 patients, 10 additional patients will be entered.  Patients will receive Rituximab at a dose of 375 mg/m².  A Treatment Cycle (i.e., 28 days) will consist of 4 days (Days 1, 8, 15, 22) of Rituximab administration. Treatment of an individual patient will continue for a maximum 2 cycles or until patient experiences disease progression or unacceptable toxicity.

Sample Informed Consent

A Phase II Study of Anti-CD20 monoclonal Antibody (Rituximab) Therapy for Patients with Refractory or Relapsed Primary Central Nervous System Lymphoma (PCNSL)

This is a clinical trial (a type of research study). Clinical trials include only patients who choose to take part. Please take your time to make your decision. Discuss it with your friends and family.

You are being asked to take part in this study because you have Primary Central Nervous System Lymphoma (PCNSL) that has returned after you have received other therapy.

WHY IS THIS STUDY BEING DONE?

The purpose of this study is to find out if Rituximab is active against PCNSL.  Rituximab belongs to a new group of cancer drugs known as monoclonal antibodies. Monoclonal antibodies are used to try and destroy some types of cancer cells without causing much harm to normal cells. Rituximab is used to treat other types of lymphoma, but it is not approved by the FDA for the treatment of PCNSL. We also want to know what effects (good and bad) Rituximab has on you. 

In the past radiation therapy was the standard treatment for CNS lymphoma.  Radiation can cause the tumor to shrink or disappear but often the tumor returns later. In addition, the radiation therapy can hurt normal brain tissue. 

Other research studies have tested treating this tumor with chemotherapy instead of radiation. These studies suggest that chemotherapy may work better than radiation and may not cause brain injury.   However, the cancer often returns after treatment with chemotherapy.  We want to learn if Rituximab is good treatment for patients who’s CNS Lymphoma has returned after they have received other treatment.

HOW MANY PEOPLE WILL TAKE PART IN THE STUDY?

A minimum of 15 and a maximum of 25 people will take part in this study.

WHAT IS INVOLVED IN THE STUDY?

If you take part in this study, you will have the following tests and procedures:

Before participating in this study you will have a complete physical examination, blood and urine tests, an electrocardiogram, and CT scan of your chest and abdomen.  You will be tested for the hepatitis B virus (HBV).  If you are positive for HBV you will not be eligible to participate in this study.  You will also have a brain scan (MRI or CT scan), an eye exam, and a spinal tap before you begin treatment.  Primary central nervous system lymphoma is sometimes a complication of an infection with the human immunodeficiency virus (HIV).  HIV can cause acquired immunodeficiency syndrome (AIDS). Before joining this study you will have a blood test to see if you have this virus.  If this blood test shows that you may have HIV you will not be able to get treated on this study.  Instead you will receive counseling and be referred to an HIV specialist. This specialist will help you determine what treatment will be best for you. 

If you are eligible to join this study you will receive Rituximab through a vein (intravenously) once a week for up to 2 months.  You will be admitted to the hospital for the first dose in order to watch you more closely. After the first dose you will be treated in the outpatient clinic.  Each dose will take between two and three hours.  

During the first month that you are being treated your blood counts will be checked once each week. During the second month your blood counts will be checked every two weeks.  Other lab work will be done monthly to see if your body is tolerating the treatments.

Every 4 doses (4 weeks) will be considered a cycle.  You will have a brain scan after the first cycle.  If your tumor is the same size or smaller you will receive another cycle. The study will end after two cycles and another brain scan will be repeated at that time.  If the brain scan shows that your tumor is larger, you and your doctor will discuss other treatment options.  If this brain scan shows that the Rituximab has made a big difference in shrinking the size of your tumor an extra MRI will be done one month later to confirm this. If any of these brain scans show that the tumor is the same size or smaller you will return to the clinic every three months for follow up visits.  During these visits a brain scan will be done.  An eye exam will be done yearly.  During this time you and your doctor may decide to continue with Rituximab treatment “off study”. 

HOW LONG WILL I BE IN THE STUDY?

You will receive Rituximab for up to 2 months unless your tumor grows, or the side effects are too hard on you, or you desire to stop treatment.  The doctor may decide to take you off this study if he thinks it will be in your best interest, drug supply is insufficient, your condition worsens, or new information becomes available.

You can stop participating at any time. However, if you decide to stop participating in the study, we encourage you to talk to the researcher and your regular doctor first.

WHAT ARE THE RISKS OF THE STUDY?

While on the study, you are at risk for these side effects. You should discuss these with the researcher and/or your regular doctor. There also may be other side effects that we cannot predict. Other drugs will be given to make side effects less serious and uncomfortable.

Many side effects go away shortly after the Rituximab is stopped, but in some cases side effects can be serious or long lasting or permanent or fatal.

Likely Side Effects:

• Patients may experience drug hypersensitivity with Rituximab. This reaction can occur within seconds or minutes of receiving the drug.  It may include fever and chills during the initial infusion. Patients will receive medications before each treatment to try to prevent this type of reaction. 

• Rituximab may cause abnormal heart beats, abnormal heart rate and heart attack.  It may also cause changes in blood pressure (high or low blood pressure).  Some patients have experienced temporary low blood pressure while receiving Rituximab.  If you are being treated for high blood pressure the doctor may change the way you take your blood pressure medication.

• Rituximab may cause low white blood cell count, red blood cell count and platelet count.

• Rituximab may cause rash, hives, itching.

• Rituximab may cause fatigue, fever, chills, sweating or a general feeling of discomfort.

• Rituximab may also cause nausea, vomiting diarrhea and abdominal pain or cramping.

• Rituximab may cause, infection with or without fever.

• Rituximab may also cause low levels of calcium in the blood or abnormal liver functions or high blood sugar.

• Rituximab may also cause runny or stuffy nose, sinus and throat irritation, shortness of breath or cough, lung abnormalities, and low oxygen levels in the blood.

• Rituximab may cause dizziness, or seizures.

• Rituximab may also cause headache, muscle or bone or joint pain

Other Side Effects: 

• Rituximab may also cause anxiety, depression, agitation, sleepiness and balance difficulties.

• Rituximab may also cause internal swelling or swelling of your hands and feet.

• Rituximab may also cause flushing.

• Rituximab may also cause airway constriction or Acute Respiratory Distress Syndrome.

Reproductive risks: Because Rituximab may affect an unborn baby, you should not become pregnant or father a baby while on this study. You should not nurse a baby while on this study. If you are a female of childbearing potential you will be given a pregnancy test before you can join this protocol. If you are pregnant you will not be eligible to join this study. You will be required to use birth control for up to 12 months after ending treatment.  Ask your doctor about counseling and more information about preventing pregnancy.

For more information about risks and side effects, ask the researcher or contact ___________________________________________.

ARE THERE BENEFITS TO TAKING PART IN THE STUDY?

If you agree to take part in this study, there may or may not be direct medical benefit to you. We hope the information learned from this study will benefit other patients with PCNSL.

WHAT OTHER OPTIONS ARE THERE?

You do not have to join this clinical trial to get treatment for your brain tumor.  Instead of joining this study, you may choose to have standard radiation therapy or another type of chemotherapy. You may also be eligible for other research studies.  You can also choose to have no therapy at this time.  This means you would only receive care to help you feel more comfortable.  Please talk to your doctor about these and other options. You may continue to get care from your physician even if you do not take part in the study. 

WHAT ABOUT CONFIDENTIALITY?

This section tells you what information about you may be used and given out in this study and who may give and receive the information.  By signing this consent form, you agree that health information that identifies you may be used and/or given out as needed in this study. _________________ has a policy to protect health information that may identify you.  Federal and state laws also protect your privacy.  ______________________ has procedures in place to support these policies and laws.

a.  What information about you may be used or given out in this study?

Information that identifies you and relates to your health or medical condition may be used or given out in this study.  Information that identifies you can include your name, address, telephone number, date of birth, Social Security number and other details about you.  Information that relates to your health or medical condition includes:

Information obtained from the activities and procedures outlined in this consent form, which may include:

i)  things done to see if you can join this study, such as physical examinations, blood and urine tests and any other information that you share with us, including information about your health history and your family health history; and

ii)  information obtained during the study, such as how you respond to the study activities or procedures, information we learn in study visits, phone calls, surveys, physical examinations, blood and urine tests, x-rays and other tests and any other medical information we learn from you as a participant in this study.

b.  Who may use and give out information about you?

Some people may see your health information and may give out your health information during this study.  These include the researcher and the research staff, the institutional review boards and their staff, legal counsel, audit and compliance staff, officers of the organization and other people who need to see the information to help this study or make sure it is being done as it should.

c.  Who may see your health information?

Other organizations may see your health information during this study.  These include:

• Governmental entities that have the right to see or review your health information, such as the Office of Human Research Protections and the Food and Drug Administration
• Doctors and staff at other places that are participating in this study
• The pharmaceutical sponsor, IDEC Pharmaceuticals, Inc.
• The sponsor of this study and people that the sponsor my contract with for this study.  The name of the sponsor is CTEP/NCI.
• The Contract Research Organization.  The name of the CRO is Theradex.
• The Data Safety Monitoring Board
• An outside institutional review board
• NABTT CNS Consortium

d.  Why will this information be used and given out?

Your information will be used and given out to carry out this study and to evaluate the results of this study.

e.  What if you decide not to give your permission to use and give out your health information?

You do not have to give your permission to use or give out your health information.  However, if you do not give permission, you may not participate in this study.

f.  May you withdraw or cancel your permission?

You may cancel your agreement to allow your health information to be used or given out at any time by sending a written notice to the Institutional Review Board Office, __________________________________.  If you do this, you are leaving this study.  If you leave this study, no new health information about you will be gathered after that date.  However, information gathered before that date may be used or given out if it is needed for this study or any follow-up for this study.

g.  Is your health information protected after it has been given to others?

If your health information is given to someone not covered by these policies and laws, that information may no longer be protected, and may be used or given out without your permission.

h.  Does this consent form have an end date?

This authorization to use and give out health information continues until the end of this study and any necessary data analysis follow-up activities for this study. 

A)  What is the role of the IRB?

Research studies involving human volunteers are reviewed by an Institutional Review Board (IRB).  The IRB is made up of doctors, nurses, scientists, non-scientists and people from the community.  The IRB is responsible for protecting participant’s rights.

WHAT ARE THE COSTS?

Taking part in this study may lead to added costs to you or your insurance company. Rituximab is a commercially available drug and will be billed to your insurance company. Please ask about any expected added costs or insurance problems. 

In the case of injury or illness resulting from this study, emergency medical treatment is available. This care will be provided at the usual charge. No funds have been set aside to compensate you in the event of injury. You or your insurance company will be charged for continuing medical care and/or hospitalization.

You will receive no payment for taking part in this study.

WHAT ARE MY RIGHTS AS A PARTICIPANT?

Taking part in this study is voluntary. You may choose not to take part or may leave the study at any time. Leaving the study will not result in any penalty or loss of benefits to which you are entitled. 

We will tell you about new information that may affect your health, welfare, or willingness to stay in this study. 

WHOM DO I CALL IF I HAVE QUESTIONS OR PROBLEMS?

For questions about the study or a research-related injury, contact the researcher __________________ (NAME{S}) at     __________________ (TELEPHONE NUMBER) .

For questions about your rights as a research participant, contact the__________________ (NAME OF CENTER) Institutional Review Board (which is a group of people who review the research to protect your rights) at __________________ (TELEPHONE NUMBER).

WHERE CAN I GET MORE INFORMATION?

You may call the NCI's Cancer Information Service at 1 800 4 CANCER (1 800 422 6237) or TTY: 1 800 332 8615

        Visit the NCI's Web sites

            cancerTrials: comprehensive clinical trials information

            http://cancertrials.nci.nih.gov.

            CancerNet: accurate cancer information including PDQ

            http://cancernet.nci.nih.gov.