Protocol SPI-MGD-11-20112.10.0006

Informed Consent Form

Protocol Version: Amendment 2 26 November 2012

INFORMED CONSENT TO BE IN A RESEARCH STUDY

Study Title: A Randomized, Open-Label, Multi-Center, Phase 2 Study of Zevalin (ibritumomab tiuxetan) versus Zevalin and motexafin gadolinium in Patients with Rituximab-Refractory Low-grade or Follicular B-cell Non-Hodgkin’s Lymphoma

Protocol Number: SPI-MGD-11-201

Sponsor: Spectrum Pharmaceuticals, Inc.

Investigator: Gregory R. Favis, MD

Institution: Halifax Health

Center for Oncology

303 N. Clyde Morris Blvd.

Daytona Beach, FL 32114

Telephone Number: (386) 254-4212

After office hours: (386) 254-4212

Study Coordinator: Halifax Health

Center for Oncology

Clinical Trials Department

Telephone number: (386) 254-4213

This is a clinical trial, which is a type of research study. Your study doctor will explain the clinical study to you. This consent form describes the study in order to help you decide if you want to participate. This consent form will tell you what you will have to do during the study and the risks and benefits of the study. Clinical studies include only people who choose to take part. Before making a decision, it is important that you understand the reasons that this research is being done and what is involved. Please take your time to carefully read the following information and make your decision about taking part. If you wish, you may take home an unsigned copy of this consent form to think about and you may discuss your decision with your friends and family. You can also discuss it with your health care team. You should discuss your participation with anyone you choose in order to better understand this study and your options. If you have any questions, you can ask your study doctor for more explanation.

This consent form may contain words that you do not understand. You should ask your study doctor and other study staff members any questions you have about this research study. Do not sign this form unless the study doctor or study staff has answered your questions and you decide that you want to be part of this study.

Being in this study does not replace your regular medical care. You may change your mind about being in this study at any time. Your decision whether or not to take part in this study is entirely voluntary. If you decide not to take part in the study or decide to participate and later change your mind for any reason, you will not be penalized or lose any benefits to which you are otherwise entitled.

If you agree to take part in this study, you will be asked to sign this consent form. Once you sign it, we will give you a signed copy to keep for your records.

You are being asked to take part in this study because you have been diagnosed with low-grade or Follicular Non-Hodgkin’s Lymphoma and your disease has either relapsed (came back), or progressed (getting worse) either during or within 6 months of Rituxan (rituximab) therapy.

Why is this study being done?

The main purpose of this study is to gather information on the safety and effectiveness of the study drug regimens which includes 2 marketed drugs, Rituxan (rituximab) and Zevalin (Ibritumomab tiuxetan) plus one experimental drug called motexafin gadolinium(hereafter called MGD or Study Drug), compared with Rituxan and Zevalin only in subjects with Low-grade or Follicular B-cell Non-Hodgkin’s Lymphoma (NHL, a kind of blood cancer) that are refractory to (did not respond) or relapsed (disease came back) after treatment with Rituxan. An “experimental drug” is a drug that is being tested and is not approved for sale in the United States by the U.S. Food and Drug Administration (FDA).

If you are eligible to be in the study and you have signed this informed consent, you will be assigned to one of the two study groups, as follows:

Group One: (Control Group – Zevalin Arm)will receive Rituxan and Zevalin.

Group Two: (Experimental Group MGD –Zevalin Arm)will receive Rituxan, Zevalin, plus Motexafin Gadolinium (MGD) (the Study Drug),

The treatment groupswill last over 2 weeks.

All subjects will be followed for 12 weeks to see if there are any side effects.

Subjects will then be followed for 12 months for disease response.

Motexafin Gadolinium (MGD) (the study drug) is a chemo medication. It is a liquid andwill be injected into your vein. MGD works by causing certain tumor cells’ to “self-destruct” (a process called apoptosis or programmed cell death). Several clinical trials using MGD in combination with chemotherapy or radiotherapies for patients with metastasis (spead of the cancer to other areas of the body) from blood cancer and solid tumor showed patients had progression free disease for a longer time.

In a recent Phase 1 study in people with relapsed/refractory NHL, treatment of MGD in combination with Zevalin® in people that Rituxan treatment no longer works on their diseases, 86 percent of subjects felt better while 64 percent of lymphoma sizes decreased dramatically or disappeared. All effectiveness in the study was found within the first 4 weeks after combined treatment of MGD and Zevalin. The combination therapy had fewer side effects. The most observed side effect was abnormal blood count and was similar to treatment with Zevalin alone.

Rituxan and Zevalin are commercial medications (already approved by FDA) that are currently used in the treatment of follicular non-Hodgkin’s lymphoma.

Rituximab (Rituxan®) will be given as part of the study drug treatment plan. Rituximab is an anti-CD-20 monoclonal antibody therapy. It is a biological therapy and is not a chemotherapy medication. It comes in a liquid form that is given into your vein. It works by killing blood cells that have multiplied abnormally. Rituximab is approved by the Food and Drug administration (FDA) and is now used as a single treatment of lymphoma that is stable.

Zevalin is a radioimunotherapy. This involves treating your lymphoma with a monoclonal antibody that has been attached to a radioactive charge. A monoclonal antibody uses the body’s own immune cells to kill cancer cells. The radioactive material called Yttrium 90 is attached to an antibody. This allows radiation to be brought straight to cancer cells that the antibody attaches to. This type of therapy uses both the antibody’s and radioactive material’s good effects. The charge gives off gamma radiation which helps to destroy more cancer cells. The levels of radiation arelow enough that you do not have to take special precautions after you have the facility where the drug is given.

The Sponsor of this study is Spectrum Pharmaceuticals, Inc.

How many people will take part in the study?

About 100subjects (50 in each group) will take part in this study.

What will happen if I take part in this research study?

Before you begin this research study, your doctor will perform tests to determinethat you have this disease and it is safe for you to participate in this clinical study. This is called the screening period and lasts up to 14 days. Before you begin these tests, you will need to sign this informed consent form.

You will need to have the following exams, tests or procedures to find out if you can be in the study. These exams, tests or procedures are part of regular cancer care and may be done even if you do not join the study. If you have had some of them recently, they may not need to be repeated. This will be up to your study doctor.

Screening Period

  • Evaluation of your disease:

The study doctor will perform CAT (CT) scans of the chest, abdomen, pelvis and neck if needed and possibly PETor PET/CT scans within 6 weeks before randomization to assess the extent of your disease. A blood test may also be performed to look for abnormal cells in your blood.

  • A PET Scan / PET/CTScanis a computerized image that looks at the activity of tumor cells in your entire body. It requires injection of a special marker into your vein, such as sugar (glucose) combined with a low-dose of radioactive substance (a tracer). A camera records the tracer’s signal as it travels through your body.
  • A CT Scan is a study using x-rays to look at one part of your body. It may be done with or without contrast. Contrastmeans that dye is injected into your vein to increase the differences between normal and abnormal tissues.
  • Screening Health and Medication Questions: You will be asked questions about your health, your medical history, your cancer history, your smoking history and the medications you currently take.
  • Vital Signs: Your study doctor, or other licensed health professional, will record your vital signs (blood pressure, heart rate and temperature), and measure your height and weight.
  • Physical Exam: The study doctor will evaluate your body and its functions. The study doctor will also gather information about your current health status by asking you questions about your symptoms, if any, medical history and lifestyle.
  • Blood testing: Blood will be drawn from a vein for blood count and other tests. Each blood draw will amount to abouthalf of a tablespoon.
  • A complete blood count will be performed to tell whether you have enough red blood cells to carry oxygen or white blood cells to fight infection.
  • A blood chemistry test will tell whether your liver and kidneys are working properly and whether your blood minerals are within normal range
  • .Hepatitis testing (for viruses that cause liver disease). [Note: You may not participate in the study if you test positive for hepatitis. Positive information will be reported to the state health authorities and counseling and treatment will be discussed
  • Pregnancy Testing: If you are female, your blood will be tested to see if you are pregnant. You will only have pregnancy testing if you are a woman and can have children. The study doctor or study staff will tell you if the pregnancy test results are positive. If the test is positive, you will not be able to take part in this study. The results of the pregnancy testing must be negative in order for you to be in the study.
  • Electrocardiogram: is a noninvasive test that is used to detect underlying heart conditions by measuring the electrical activity of the heart to test if your heart is working properly. 12 ECG leads (wires) will be attached to your body in standard locations (hands, legs and front of the chest). A small amount of gel will be applied to the skin. This will allow the electrical impulses of the heart to be more easily transmitted to the ECG leads.
  • Bone Marrow Aspiration/Biopsy: A bone marrow aspiration/biopsy will be performed for all randomized subjects to confirm that your bone marrow is able to make enough white blood cells, red blood cells and platelets. A bone marrow biopsy will be taken by a needle from your hip bone. The area will be numbed prior to the procedure to prevent pain.
  • Possible Flow Cytometry: A method for analyzing or closely studying cells or particles one at a time and then generating data (information) about the characteristics (features) of the sample materials. This method is routinely used to look for cancer cells in the blood.

Randomization: You will be randomly assigned into one of the two study groups described above. Randomization means that you are put into one of the two groups by 50/50 chance. This process is called randomization and is like flipping a coin. A computer program will place you in one of the study groups. Neither you nor your doctor can choose the group you will be in. You will have an equal chance of being placed in either of the 2 groups.

Group One: (Control Group – Zevalin Arm)will receive Rituxan and Zevalin.

Group Two: (Experimental Group MGD –Zevalin Arm)will receive Rituxan, Zevalin, plus Motexafin Gadolinium (MGD) (the Study Drug),

During the study …

If the exams, tests and procedures show that you can be in the study, and you choose to participate, then you will need the following tests and procedures.

Week 1, Day 1

  • Vital signs
  • Pregnancy testing, if needed
  • Blood testing: Your blood will be collected every week for 12 weeks to obtain a complete blood count to tell whether you have enough red blood cells to carry oxygen or white blood cells to fight infection.
  • Review of medications: Your doctor will ask you questions about all the medications that you are currently taking or have stopped taking, your medical history and your health.

Study Drug Day 1:

Control Group (Zevalin arm): you will receive an infusion of rituximab which will take up to 4 hours.

Experimental Group (MGD-Zevalin arm): you will receive an infusion of Motexafin gadolinium (MGD) by intravenous (IV) infusion in your vein over one hour. After waiting one hour you will receive asecond infusion of rituximab which will take up to 4 hours.

You should plan on spending most of the day in the out patient infusion clinic at HalifaxHealthCenter for Oncology. You will be assessed for side effects throughout the infusions.

Assessment of side effects:After having received the first dose of your study drug you will be asked by your doctor or the study staff about any side effects you are experiencing, difficulties you may be having which may or may not be related to the study drug treatment. This assessment of side effects will continue as long as you are receiving study treatment or throughout the follow-up period whichever is longer. (These assessments are are considered ‘standard of care’ for subjects who are treated with Zevalin treatment alone.)

Week 1, Days 2 to 4

  • Vital signs
  • Review of medications: Your doctor will ask you questions about all the medicationsthat you are currently taking or have stopped taking, your medical history and your health.
  • Study Drug (Days 2 – 4):

Control Group (Zevalin Arm):

  • You will not receive any drugs.

Experimental Group (MGD-Zevalin Arm):

  • You will receive an infusion of Motexafin gadolinium by intravenous (IV) infusion in your vein over one hour each day.
  • Assessment of side effects: After having received your study drug, you will be asked by your doctor or the study staff about any side effects you are experiencing, difficulties you may be having which may or may not be related to the study drug treatment. This assessment of side effects will continue as long as you are receiving study treatment or throughout the follow-up period whichever is longer.

Week 2, Day 8

  • Vital signs
  • Physical Exam
  • Pregnancy testing, if applicable
  • Blood testing: Your blood will be collected every week for 12 weeks to obtain a complete blood count to tell whether you have enough red blood cells to carry oxygen or white blood cells to fight infection.
  • Review of medications: Your doctor will ask you questions about all the medications that you are currently taking or have stopped taking, your medical history and your health.

Study Drug(Day 8):

Control Group (Zevalin Arm): You will receive:

  • a second rituximab infusion which will take up to 4 hours.
  • This will be given in the out patient infusion clinic at HalifaxHealthCenter for Oncology
  • Four hours after the second infusion of rituximab, you will receive a short 10 minute infusion of Zevalin, in theHalifaxHealthCenter for Oncology Radiation Therapy Department.
  • You will be assessed for side effects throughout both infusions.
  • You should plan on spending most of the day at HalifaxHealthCenter for Oncology.

Experimental Group (MGD-Zevalin Arm): You will receive:

  • an infusion of Motexafin gadolinium by intravenous (IV) infusion in your vein over one hour.
  • After waiting one hour after the infusion, you will receive a second infusion of rituximab which will take up to 4 hours.
  • Within four hours after the second infusion of rituximab, you will receive a short 10 minute infusion of Zevalin in the HalifaxHealthCenter for Oncology Radiation Therapy Department.
  • You should plan on spending most of the day at HalifaxHealthCenter for Oncology.
  • You will be assessed for side effects throughout the infusions.
  • Assessment of side effects: After having received your study drug you will be asked by your doctor or the study staff about any side effects you are experiencing, difficulties you may be having which may or may not be related to the study drug treatment. This assessment of side effects will continue as long as you are receiving study treatment or throughout the follow-up period whichever is longer.

Week 2, (Days 9-11)