Primary:

To determine the maximum tolerated dose (MTD) of SAR3419 according to the dose limiting toxicities (DLTs) observed when administered as single agent every 3 weeks in patients with relapsed or refractory B-cell NHL.

Secondary:

To characterize the global safety profile. To evaluate the pharmacokinetic (PK) profile of SAR3419 in the proposed dosing schedule.

To assess the potential immunogenicity of SAR3419. To assess preliminary evidence of anti-lymphoma activity in patients with evaluable disease.

The Study Drug:

SAR3419 is designed to stop tumor growth and kill cancer cells by binding to CD19 molecules on the surface of lymphoma cells.

Screening Tests:

Before you can start treatment on this study, you will have "screening tests" to help the doctor decide if you are eligible to take part in this study. The following tests will be performed:

• Your complete medical history will be recorded
• You will have a physical exam including measurement of vital signs (blood pressure, heart rate, temperature, and breathing rate).
• Blood (about 3 tablespoons) will be drawn for routine tests.
• Urine will be collected for routine tests.
• Women who are able to have children must have a negative blood (one teaspoon) pregnancy test.
• You will have an electrocardiogram (ECG -- a test that measures the electrical activity of the heart).
• You will have a bone marrow aspirate. To collect a bone marrow aspirate, an area of the hip or chest bone is numbed with anesthetic, and a small amount of bone marrow is withdrawn through a large needle. To collect a bone marrow biopsy, an area of the hip or chest bone is numbed with anesthetic, and a small amount of bone marrow and bone is withdrawn through a large needle.
• You will have x-rays, positron emission tomography (PET) scans, and computerized tomography (CT) scans of the neck, chest, abdomen, and pelvis, to check the status of the disease.

Eye exams:

You will be asked if you have any problem with your vision and your doctor will use several different tests to examine your eyes before you receive the study drug. You will have a visual acuity test slit lamp and dilated exam, the Schirmer's test, pachymetry and topography tests.

You will be given eye drops throughout these tests to make your pupils bigger so the study staff can a better view of the internal structures of your eyes.

Visual Acuity Test:

A visual acuity test will be done. A chart will be held about 20 feet away from you and you will cover 1 of your eyes. There will be lines of letters on the chart going form large to small. You will try to read out the smallest line of letters that you can. This test will be done on each eye. This test will cause no discomfort.

Slit Lamp Exam:

Nothing will touch your eyes during the slit lamp exam. The slit lamp is a microscope that the eye doctor will use to look at your eyes. The doctor will slide the microscope toward your face until it is about 4-5 inches from your eye. You may blink during the procedure, unless the doctor asks you to keep still for a few seconds at a time. You may also be asked to move your eyes in certain directions so that different parts of your eyes can be looked at. The exam will take less than 5 minutes for each eye.

Schirmer's Test:

This test will be done to learn if your eyes produces enough tears to keep them moist. A small strip of filter paper will be placed inside the corners of your lower eyelids. You will close your eyes for 5 minutes. The paper will then be removed and the amount of moisture will be measured. The test is performed without any eye drops and then with eye drops.

Pachymetry Test:

You will have a pachymetry test to measure the thickness of your cornea (the clear part of the eye's protective covering). This test will take about a minute to complete after you are given eye drops.

Topography Test:

A topography test will be performed to measure the shape of your cornea. You will be seated in front of a machine, with head positioned in the chin-rest. An image of the front of the eye will be photographed and the computer will use the image to make a printout of the corneal shape. Nothing will touch your eyes. This test will take about a minute to complete.

Study Drug Dose Level:

If you are found to be eligible to take part in this study, you will be assigned to a dose level of SAR3419 based on when you joined this study. Three (3) to 6 participants will be enrolled at each dose level. The first group of participants will receive the lowest dose level. Each new group will receive a higher dose than the group before it, if no intolerable side effects were seen. This will continue until the highest tolerable dose of SAR3419 is found.

Study Drug Administration:

You will receive SAR3419 through a needle in your vein on Day 1 of each study cycle. Each "study cycle" is 21 days. The SAR3419 infusions will range from 30 minutes to 4 hours, depending on the dose level you will receive. About 30 minutes before starting the infusion, you will receive the following medications to prevent allergic reactions: diphenhydramine and acetaminophen. During and after infusion of SAR3419, your doctor will watch you for any side effects. Your doctor may add medications to help treat side effects and will discuss any medications and their risks and benefits with you.

Study Visits:

You will be asked to visit the clinic at different times during the study. The following tests and procedures will be performed:

• You will have a physical exam on Day 1 of all cycles.
• You will have 3 ECGs on Day 1 of all cycles.
• You will be asked about any side effects you have experienced and any treatments you have had since your last visit on Day 1 of all cycles.
• Blood (about 3 tablespoons) will be drawn twice a week during Cycle 1 and at least weekly during all other cycles, for routine tests.
• Blood (about 5 tablespoons) will be drawn on Days 1, 2, 3, 5, 15, and 21 for PK testing during Cycle 1.
• On Day 1 of Cycle 2, your tears will be collected to check for toxins before you receive SAR3419 and 24 hours after the infusion. Your tears will be collected using the same procedure used in the Schirmer's Test. Blood (about 2 tablespoons) will also be drawn on Day 1 of Cycle 2 to compare the toxins in your blood and tears.
• For Cycles 2 and after, blood (about 4 ½ tablespoons) will be drawn on Days 1 and 21 (plus or minus 3 days) for routine tests.
• You will have a CT scan and PET scan performed to check the status of the disease, every 2 cycles.

If you have certain side effects in your eyes, the eye exams will be repeated when necessary.

You may be asked to return to the clinic between routine study visits, based on the results of your blood tests. Your study doctor or the sponsor may decide that another blood sample should be taken before the next study visit.

Length of Study:

If the disease does not get worse and no intolerable side effects occur, you may receive up to 6 cycles of SAR3419 over 5 months. You will be taken off-study if the disease gets worse or intolerable side effects occur.

Follow-up Visit:

About 6 weeks after your last dose of SAR3419, your will be asked to visit the clinic. The following tests and procedures will be performed:

• You will have a physical exam.
• You will have 3 ECG's.
• Blood (about 3 tablespoons) will be drawn for routine tests.
• Urine will be collected for routine tests.
• You will have a blood (about 1 teaspoon) pregnancy test.

This is an investigational study. SAR3419 is not FDA approved and it is not commercially available. All drugs to help allergic prevent reaction are FDA approved and commercially available. Up to 50 patients will take part in this multicenter study. Up to 50 will be enrolled at M. D. Anderson.

Inclusion Criteria:

1. Histologically confirmed CD19-positive non Hodgkin's lymphoma.
2. Relapsed or refractory after standard treatments and with no curative option with conventional therapy.
3. Bidimensionally measurable disease.
4. No evidence of cerebral or meningeal involvement by lymphoma.
5. Age >/= 18 years.
6. ECOG performance status 0 to 2.
7. Life expectancy of at least 3 months.
8. Signed informed consent form prior to enrollment.

Exclusion Criteria:

1. Burkitt's lymphoma, Lymphoblastic lymphoma, Chronic lymphocytic leukemia (Small lymphocytic lymphoma may be included).
2. Chemotherapy or radiation therapy or other investigational agents within 4 weeks prior to entering the study.
3. Previous radioimmunotherapy within 12 weeks.
4. Patient with active infections or HIV infection.
5. Known active viral hepatitis.
6. Known intolerance to infused protein products or maytansinoids (an anti-tumor medication that is a derivative of a natural plant).
7. Any serious active disease or co-morbid condition, which in the opinion of the principle investigator, will interfere with the safety or with compliance with the study.
8. Poor bone marrow reserve as defined by absolute neutrophil count < 1.5 x 10^9/L or platelets < 100 x 10^9/L.
9. Baseline QTc interval > 500 msec (determined as the median of three EKGs done within a 30-min period) (Grade >/= 3 NCI-CTC v3.0)
10. Poor organ function as defined by one of the following: a.) Total bilirubin > 1.5 x ULN (>3 x ULN for patients with liver involvement); b.) AST, ALT > 2.5 x ULN (> 5 x ULN for patients with liver involvement); c.) Serum creatinine > 2 x ULN and/or creatinine clearance < 60 mL/min
11. Pregnant or breast-feeding women (sexually active females of childbearing potential must have a negative serum or urine pregnancy test).
12. Refused to use effective birth control methods if applicable. Women that can have children must use a medically acceptable method of birth control while participating in the study (birth control pill, intrauterine device or injection of Depo-Provera) and for at least 30 days after the last dose of study medication..