ECOG-ACRINE5508

Cancer Research GroupVersion Date: June 20, 2014

NCI Update Date: December 8, 2014

Randomized Phase III Study of Maintenance Therapy with Bevacizumab, Pemetrexed, or a Combination of Bevacizumab and Pemetrexed Following Carboplatin, Paclitaxel and Bevacizumab for Advanced Non-Squamous NSCLC

Version Date: June 20, 2014
NCI Update Date: December 8, 2014

Informed Consent for Cancer Treatment Trials

This is a clinical trial, a type of research study. Your doctor will explain the clinical trial to you. Clinical trials include only people who choose to take part. Please take your time to make your decision about taking part. You may discuss your decision with your friends and family. You can also discuss it with your health care team. If you have any questions, you can ask your doctor for more explanation.

You are being asked to take part in this study because you have non-small cell lung cancer that has spread.

Why is this study being done?

The purpose of this study is to find out the best maintenance therapy for patients with advanced stage non-small cell lung cancer. Maintenance therapy is usually given after 4 cycles of standard chemotherapy (1 cycle = 21 days) to keep the disease under control for a longer duration. This study will compare the effects, good and/or bad, of bevacizumab, pemetrexed or the combination of the two agents when given as maintenance therapy.

How many people will take part in the study?

About 1495 people will take part in this study.

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

Your physician and his team will explain all the study-related procedures to you. All the treatments will be administered on an outpatient basis except under unusual circumstances.

At the beginning of the study, you will receive the standard combination of carboplatin, paclitaxel and bevacizumab for a maximum of 4 cycles of therapy (1 cycle= 21 days). If your cancer is under control after the 4thcycle, you will then be randomly assigned to receive therapy with bevacizumab alone, pemetrexed alone or the combination of the two agents as maintenance therapy. Approximately 300 patients will be included to each of the three treatment groups. The combination of carboplatin, paclitaxel and bevacizumab is approved by the FDA for the treatment of patients with your type of lung cancer. Pemetrexed is approved by the FDA for patients with advanced stage non-small cell lung cancer, either in combination with cisplatin in patients with previously untreated disease, or as a single agent in patients with progressive disease following prior chemotherapy. The combination of pemetrexed and bevacizumab is considered investigational for the purposes of this study.

Before you begin the study

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 doctor.

  • Routine physical examination
  • Complete blood count
  • Blood chemistry tests to check the liver and kidney functions
  • CT scan or MRI scan of the chest and upper abdomen
  • Positron emission tomogram (PET scan)
  • Electrocardiogram, if you have any risk factors for heart disease
  • Pregnancy test (if you are a woman of reproductive age).
  • Smoking Status
  • Urine test

Some of the above scans are not mandatory, if the clinical suspicion for the spread of the disease to the corresponding organ is very low.

During the study

If the exams, tests and procedures show that you can be in the study, and you choose to take part, then you will need the following tests and procedures. They are part of regular cancer care.

  • Routine physical examination
  • Complete blood count and blood chemistry tests will be done before initiation of each treatment course. This may be conducted at more frequent intervals if your physician finds them to be necessary.
  • CT scan or MRI will be performed every 2 cycles of therapy to see if your cancer is responding to therapy
  • During the maintenance phase, you will be asked to take folic acid tablets (on a daily basis) if you are being treated with pemetrexed (alone or in combination). If you are on Arm B or C, you will also be given vitamin B12 (before you start treatment and once every few months) as well as dexamethasone (twice a day for 3 days in a row).
  • Urine tests

Induction Therapy

At the beginning of the study, you will receive the standard combination of carboplatin, paclitaxel and bevacizumab for a maximum of 4 cycles of therapy (1 cycle= 21 days). This is called Induction Therapy. You will also receive pre-medications prior to receiving paclitaxel. Pre-medications are given to reduce side effects associated with chemotherapy medications such as nausea and vomiting.

Maintenance Therapy

After 4 cycles of therapy, if your cancer remains under control, you will be "randomized" into one of the study groups described below. Randomization means that you are put into a group by chance. 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 a one in three chance of being placed in any group. This is called Maintenance Therapy.

If you are in group 1 (often called "Arm A"), you will be treated with bevacizumab every 3 weeks. The treatment will be continued as long as your cancer is under control and you do not experience any intolerable side effects.

If you are in group 2 (often called "Arm B"), you will be treated with pemetrexed every 3 weeks. The treatment will be continued as long as your cancer is under control and you do not experience any intolerable side effects. You will also receive pre-medications prior to taking pemetrexed (folic acid, vitamin B12 and dexamethasone).

If you are group 3 (often called “Arm C”), you will be treated with bevacizumab and pemetrexed every 3 weeks. The treatment will be continued as long as your cancer is under control and you do not experience any intolerable side effects. You will also receive premedications prior to taking pemetrexed (folic acid, vitamin B12 and dexamethasone).

During the maintenance phase if you are being treated with pemetrexed (alone or in combination) you will be given the following: folic acid tablets on a daily basis, vitamin B12 injections one week before maintenance therapy and every 9 weeks after that and dexamethasone twice daily for 3 days starting one day before maintenance therapy.

When I am finished with study treatment

You will be continued on the maintenance therapy as long as the cancer is under control. Your physician may take you off the study if you experience severe side effects. After completion of the study, you will be treated with appropriate standard treatment options by your treating physician. There will not be any tests conducted following completion of the study. However, you will be followed up every 3 months as part of routine standard cancer care for the first 2 years after the study, and then every 6 months for 2-5 years after the study. If you change physicians, your original physician or his associate might call you to obtain follow up information over the phone.

Study chart

During the first part of the study, you will receive carboplatin, paclitaxel and bevacizumab every 3 weeks (Induction Therapy). Each 3-week period is referred to as a cycle. Treament will be repeated every 3 weeks for a total of 4 cycles. After the 4th cycle, if your cancer is under control, you will be entered to the second part of the study, referred to as Maintenance Therapy. You will receive Maintenance Therapy every 3 weeksin this study. The chart below shows what will happen to you during Cycle 1 and future treatment cycles as explained previously. The left-hand column shows the day in the cycle and the right-hand column tells you what to do on that day.

Cycle 1 of first part of the study (induction therapy)

Day / What You Do
Within 72 hrs prior to starting study /
  • Get routine blood tests

Day 1 /
  • You will be seen by your physician and have a routine physical exam
  • Urine test
  • Receive chemotherapy by IV

Days 1 – 21 /
  • Report any new symptoms or medical problems to your physician

Cycles 2, 3 & 4 (induction therapy)

Day / What You Do
Day 1 /
  • Get routine blood tests, urine test and physical exam within 72 hours before starting each new cycle (more if your doctor tells you to)
  • Receive chemotherapy by IV

Days 1 – 21 /
  • Report any new symptoms or medical problems to your physician

End of Cycles 2 and 4 /
  • Get routine CT scans or MRIs (more if your doctor tells you to)

Cycle 1 of second part of study (maintenance therapy) (applies only if you are eligible for randomization)

Day / What You Do
Within 72 hrs prior to starting study /
  • Get routine blood tests

Day 1 /
  • You will be seen by your physician and have a routine physical exam
  • Urine test (Arms 1/A and 3/C only)
  • Receive chemotherapy by IV

Days 1 – 21 /
  • Report any new symptoms or medical problems to your physician

Future cycles (maintenance therapy)

Day / What You Do
Day 1 /
  • Get routine blood tests, urine test (Arms 1/A and 3/C only) and physical exam within 72 hours before starting each new cycle (more if your doctor tells you to)
  • Receive chemotherapy by IV

Days 1 – 21 /
  • Report any new symptoms or medical problems to your physician

End of Every 3rdCycle (3, 6, 9, 12…) /
  • Get routine CT scans or MRIs (more if your doctor tells you to)

Premedication tables

Pemetrexed (If you are randomized to therapy with pemetrexed (alone or in combination)

Folic acid / Start taking folic acid tablets once a day starting one week before your first treatment with pemetrexed and ending 21 days after the last dose of pemetrexed.
Vitamin B12 / Will be given by an injection in your muscle approximately 1 week before your first treatment with pemetrexed and repeated every 3 cycles of therapy (1 cycle= 21 days) until the end of treatment.
Dexamethasone / Take dexamethasone twice daily for 3 days in a row, starting one day before your treatment with pemetrexed for each cycle.

Paclitaxel:*

Dexamethasone / You will take dexamethasone 12 and then 6 hours prior to treatment with paclitaxel by mouth OR you will get dexamethasone by IV one hour or less before treatment with paclitaxel.
Diphenhydramine / You will get diphenhydramine by IV one hour or less before treatment with paclitaxel.
Cimetidine / You will get cimetidine by IV one hour or less before treatment with paclitaxel.

*You may get other similar premedicated drugs in place of the ones described above.

Study plan

Another way to find out what will happen to you during the study is to read the chart below. Start reading at the top and read down the list, following the lines and arrows.


How long will I be in the study?

During the initial part of the study, you will be treated for a maximum of 4 courses. If your cancer gets worse or if your side effects become too severe, you will be taken off study and your physician will discuss appropriate alternative treatment options. If your cancer is under control after the 4th course, you will be asked to take the maintenance therapy as long as your cancer remains under control. This could last for several months or even longer than a year. After you are finished takingthe maintenance therapy, the doctor will ask you to visit the office for follow-up exams every 3 months for 2 years after the study, and every 6 months from 2-5 years after the study.

Can I stop being in the study?

Yes. You can decide to stop at any time. Tell the doctor if you are thinking about stopping or decide to stop. He will tell you how to stop safely.

It is important to tell the doctor if you are thinking about stopping so any risks from thetreatment regimencan be evaluated by your doctor. Another reason to tell your doctor that you are thinking about stopping is to discuss what follow-up care and testing could be most helpful for you.

The doctor may stop you from taking part in this study at any time if he believes it is in your best interest; if you do not follow the study rules; or if the study is stopped.

What side effects or risks can I expect from being in the study?

If you choose to take part in this study, there is a risk that:

  • You may lose time at work or home and spend more time in the hospital or doctor’s office than usual
  • You may be asked sensitive or private questions which you normally do not discuss
  • The study drug(s)/study approach may not be better, and could possibly be worse, than the usual approach for your cancer.

The drugs used in this study may affect how different parts of your body work such as your liver, kidneys, heart, and blood. The study doctor will be testing your blood and will let you know if changes occur that may affect your health.

There is also a risk that you could have side effects from the study drug(s)/study approach.

Here are important points about side effects:

  • The study doctors do not know who will or will not have side effects.
  • Some side effects may go away soon, some may last a long time, or some may never go away.
  • Some side effects may interfere with your ability to have children.
  • Some side effects may be serious and may even result in death.

Here are important points about how you and the study doctor can make side effects less of a problem:

  • Tell the study doctor if you notice or feel anything different so they can see if you are having a side effect.
  • The study doctor may be able to treat some side effects.
  • The study doctor may adjust the study drugs to try to reduce side effects.

The tables below show the most common and the most serious side effects that researchers know about. There might be other side effects that researchers do not yet know about. If important new side effects are found, the study doctor will discuss these with you.

Possible Side Effects of Carboplatin and Paclitaxel (Table Version Date: October 8, 2013)

COMMON, SOME MAY BE SERIOUS
In 100 people receiving Carboplatin and Paclitaxel, more than 20 and up to 100 may have:
  • Hair loss
  • Infection, especially when white blood cell count is low
  • Anemia which may cause tiredness, or may require blood transfusions
  • Bruising, bleeding
  • Diarrhea, nausea, vomiting, constipation
  • Sores in mouth which may cause difficulty swallowing
  • Changes in taste
  • Allergic reaction which may cause rash, low blood pressure, wheezing, shortness of breath, swelling of the face or throat
  • Pain
  • Muscle weakness
  • Numbness and tingling in fingers and toes

OCCASIONAL, SOME MAY BE SERIOUS
In 100 people receiving Carboplatin and Paclitaxel, from 4 to 20 may have:
  • Heart attack or heart failure which may cause shortness of breath, swelling of ankles, and tiredness
  • Abnormal heartbeat
  • A tear or a hole in the stomach which may cause belly pain or that may require surgery
  • Damage to the lungs which may cause shortness of breath
  • Blood clot which may cause swelling, pain, shortness of breath

RARE, AND SERIOUS
In 100 people receiving Carboplatin and Paclitaxel, 3 or fewer may have:
  • Changes in vision
  • Damage to organs which may cause hearing and balance problems

Possible Side Effects of Bevacizumab(Table Version Date: August 1, 2013):

COMMON, SOME MAY BE SERIOUS
In 100 people receiving bevacizumab, more than 20 and up to 100 may have:
  • High blood pressure which may cause headache or blurred vision

OCCASIONAL, SOME MAY BE SERIOUS
In 100 people receiving bevacizumab, from 4 to 20 may have:
  • Anemia which may require blood transfusion
  • Low white cell count that may increase the risk of infection
  • Infection, including collection of pus in the belly or rectum
  • Abnormal heartbeat which may cause palpitations or fainting
  • Pain in the belly, rectum, chest, joints, muscles, or tumor
  • Low appetite, constipation, diarrhea, heartburn, nausea, vomiting, or dehydration
  • Internal bleeding which may cause black tarry stool, blood in vomit, coughing up of blood, or blood in urine
  • Bleeding from other sites, including the vagina or nose
  • Blockage of internal organs which may cause vomiting or inability to pass stool
  • Sores in mouth
  • Allergic reaction during or after infusion of bevacizumab which may cause fever, chills, rash, itching, hives, low blood pressure, wheezing, shortness of breath, swelling of the face or throat
  • Delay in healing of wounds or spontaneous opening of wounds
  • Weight loss, tiredness, or dizziness
  • Damage to the jawbone which may cause loss of teeth
  • Headache
  • Numbness, tingling, or pain in the fingers or toes
  • Hoarseness, stuffy nose, or cough
  • Blood clot in limbs or lungs which may cause swelling, pain, or shortness of breath
  • Leakage of protein in the urine, which can rarely lead to damage to the kidney

RARE, AND SERIOUS
In 100 people receiving bevacizumab, 3 or fewer may have:
  • Clots in the arteries, causing stroke (which may cause paralysis or weakness) or heart attack (which may cause chest pain or shortness of breath). This risk is significantly increased in patients who are elderly or with history of diabetes
  • Heart failure which may cause shortness of breath, swelling of ankles, or tiredness
  • Bowel perforation (a tear in the bowel) that can cause pain or bleeding and require surgery to repair
  • A tear or hole (fistula) in internal organs such as the nose, throat, lungs, esophagus, rectum, or vagina. These conditions may cause serious infections or bleeding and require surgery to repair
  • Flesh-eating bacteria syndrome, an infection in the deep layers of skin
  • Bleeding in the tumor, brain, belly, or lungs which may cause confusion, blood in stool or coughing up blood
  • Brain damage which may cause headache, seizure, blindness (also known as Reversible Posterior Leukoencephalopathy Syndrome)
  • Kidney damage which may require dialysis

Additional Notes on Possible Side Effects for Bevacizumab: