appendix 3
relapse

Relapse following CR is defined as:
Peripheral Blood Counts o Presence of peripheral blasts. A bone marrow examination must be performed to confirm relapse. However, please note that the date of relapse is the first date at which the relapsed patient had: leukemic blasts in the peripheral blood smear, or >5% blasts in the bone marrow.  
Bone Marrow Aspirate or Biopsy o Presence of more than 5% blasts, not attributable to another cause (i.e. bone marrow regeneration).  
| Known Risks and Side Effects Related to the Clofarabine Include Those Which Are: Likely Less Likely Rare But Serious   |                                                                                                                                                                                                                                                                                                          |               |                               |
|------------------------------------------------------------------------------------------------------------------------|----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|---------------|-------------------------------|
|                                                                                                                       | A fast heartbeat which may  cause pain in the chest                                                                                                                                                                                                                                                      |               |                               |
|                                                                                                                       | A feeling of extreme tiredness  not relieved by sleep                                                                                                                                                                                                                                                    |               |                               |
|                                                                                                                       | A decrease in blood pressure                                                                                                                                                                                                                                                                             |               |                               |
|                                                                                                                       | Pain in the abdomen (belly)                                                                                                                                                                                                                                                                              |               |                               |
|                                                                                                                       | Constipation                                                                                                                                                                                                                                                                                             |               |                               |
|                                                                                                                       | Diarrhea                                                                                                                                                                                                                                                                                                 |               |                               |
|                                                                                                                       | Nausea and/or vomiting                                                                                                                                                                                                                                                                                   |               |                               |
|                                                                                                                       | Headache                                                                                                                                                                                                                                                                                                 |               |                               |
|                                                                                                                       | Fever which may also come  with shaking chills                                                                                                                                                                                                                                                           |               |                               |
|                                                                                                                       | Anxiety                                                                                                                                                                                                                                                                                                  |               |                               |
|                                                                                                                       | Fever with a low white blood  cell count which could mean  that you have an infection and  might require hospitalization  and treatment with antibiotics                                                                                                                                                 |               |                               |
|                                                                                                                       | Loss of appetite                                                                                                                                                                                                                                                                                         |               |                               |
|                                                                                                                       | Elevation in the blood of certain  enzymes found in the liver  which may mean the liver is not  working as well as normal                                                                                                                                                                                |               |                               |
|                                                                                                                       | Damage to the sac around the  heart which can lead a build-up  of fluid around the heart which  may be painful and affect the  ability of the heart to work  normally but in most cases is  only mild and temporary                                                                                      |               |                               |
|                                                                                                                       | Temporary change to the heart  such that it does not pump the  blood as well which may make  you tired, weak, feel short of  breath, and retain fluid                                                                                                                                                    |               |                               |
|                                                                                                                       | Skin rash with itching and  redness or inflammation                                                                                                                                                                                                                                                      |               |                               |
|                                                                                                                       | Infections including those  caused by bacteria, virus, and  fungus and can be found in the  lung, the blood, the skin and                                                                                                                                                                                |              | Fluid build-up in the tissues |
|                                                                                                                       | Pain or burning at the site of  the injection                                                                                                                                                                                                                                                            |               |                               |
|                                                                                                                       | Dizziness                                                                                                                                                                                                                                                                                                |               |                               |
|                                                                                                                       | Sleepiness                                                                                                                                                                                                                                                                                               |               |                               |
|                                                                                                                       | Tremor (shakiness usually  of the hands)                                                                                                                                                                                                                                                                 |               |                               |
|                                                                                                                       | Changes to your emotions  such that you feel  depressed, anxious, irritable  or confused                                                                                                                                                                                                                 |               |                               |
|                                                                                                                       | High blood pressure                                                                                                                                                                                                                                                                                      |               |                               |
|                                                                                                                       | Cough or shortness of  breath                                                                                                                                                                                                                                                                            |               |                               |
|                                                                                                                       | Reddening of the face with  feelings of warmth when the  drug is infusing                                                                                                                                                                                                                                |               |                               |
|                                                                                                                       | Sore throat                                                                                                                                                                                                                                                                                              |               |                               |
|                                                                                                                       | Inflammation and/or sores  in the mouth (and/or throat  and /or esophagus, the tube  that leads from the mouth to  the stomach) that may make  swallowing difficult and are  painful (painful mouth  sores)                                                                                              |               |                               |
|                                                                                                                       | Pain including back or arm  or leg pain                                                                                                                                                                                                                                                                  |               |                               |
|                                                                                                                       | Enlarged liver which could  lead to an elevation in the  blood of bilirubin which is  found in the liver and if  present in large amounts can  lead to a yellow appearing  skin (jaundice)                                                                                                               |               |                               |
|                                                                                                                       | Weight loss                                                                                                                                                                                                                                                                                              |               |                               |
|                                                                                                                       | Aches and pains in the  muscles and joints                                                                                                                                                                                                                                                               |               |                               |
|                                                                                                                       | Bleeding from the bladder  or gums                                                                                                                                                                                                                                                                       |               |                               |
|                                                                                                                       | Fluid build-up in the lungs                                                                                                                                                                                                                                                                              |              | The rapid death of large  numbers of tumor cells  which can cause the  potassium and  phosphate salts and the  uric acid in the blood to  rise quickly and this  could lead to a lifethreatening irregular  heart beat or damage to  the kidneys.                               |
|                                                                                                                       | Severe loss of water  from the body  (dehydration) which if  untreated may cause low  blood pressure and  severe loss of salts such  as sodium and  potassium from the body  and could lead to the  kidneys failing which  could be life-threatening                                                     |               |                               |
|                                                                                                                       | Capillary leak  syndrome: A condition  in which fluid and  proteins leak out of tiny  blood vessels and flow  into surrounding tissues,  resulting in dangerously  low blood pressure.  Capillary leak syndrome  may lead to multiple  organ failure such as  kidney, heart or liver  failure and shock. |               |                               |
|                                                                                                                       | Inflammation of the  pancreas (an organ in  the abdomen which  produces insulin and  certain digestive  chemicals) which may  affect the function of the                                                                                                                                                 |               |                               |
| Bridging Study Version 5.0                                                                                             | Confidential                                                                                                                                                                                                                                                                                             | Page 49 of 52 |                               |  
APPENDIX 4  
  
Known and Expected Toxicities of Study Treatment  
| Known Risks and Side Effects Related to the Clofarabine Include Those Which Are: Likely Less Likely Rare But Serious   |                                                                                                                                                                                                                                                                                                |                                                                                                                   |                                                                                    |
|------------------------------------------------------------------------------------------------------------------------|------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|-------------------------------------------------------------------------------------------------------------------|------------------------------------------------------------------------------------|
| other places in the body                                                                                               |                                                                                                                                                                                                                                                                                                |                                                                                                                   |                                                                                    |
|                                                                                                                       | Bloody nose                                                                                                                                                                                                                                                                                    |                                                                                                                   |                                                                                    |
|                                                                                                                       | Fewer white blood cells, red  blood cells and platelets in the  blood o a low number of white  blood cells can make it  easier to get infections o a low number of red blood  cells can make you feel tired  and weak o a low number of platelets  causes you to bruise and  bleed more easily | that can make you feel short  of breath                                                                           |                                                                                    |
|                                                                                                                       | Severe rash with redness  and pain on the palms of the  hand and soles of the feet                                                                                                                                                                                                             |                                                                                                                   |                                                                                    |
|                                                                                                                       | Red spots on the skin from  low platelets                                                                                                                                                                                                                                                      |                                                                                                                   |                                                                                    |
|                                                                                                                       | High levels of uric acid in  the blood which could  damage the kidneys                                                                                                                                                                                                                         |                                                                                                                   |                                                                                    |
|                                                                                                                       | Increased levels of a  chemical (creatinine) in the  blood which could mean  kidney damage                                                                                                                                                                                                     | pancreas and which may  cause pain in the  abdomen (belly) which  can be severe and may  increase the blood sugar |                                                                                    |
| Known Risks and Side Effects Related to Cyclophosphamide Include Those Which Are: Likely Less Likely Rare But Serious  |                                                                                                                                                                                                                                                                                                |                                                                                                                   |                                                                                    |
|                                                                                                                       | Loss of appetite                                                                                                                                                                                                                                                                               |                                                                                                                   |                                                                                    |
|                                                                                                                       | Nausea                                                                                                                                                                                                                                                                                         |                                                                                                                   |                                                                                    |
|                                                                                                                       | Vomiting                                                                                                                                                                                                                                                                                       |                                                                                                                   |                                                                                    |
|                                                                                                                       | Fewer white blood  cells in the blood. - a low number of  white blood  cells may make  it easier to get  infections.                                                                                                                                                                           |                                                                                                                   |                                                                                    |
|                                                                                                                       | Hair loss                                                                                                                                                                                                                                                                                      |                                                                                                                   |                                                                                    |
|                                                                                                                       | Decreased ability of  the body to fight  infection                                                                                                                                                                                                                                             |                                                                                                                   |                                                                                    |
|                                                                                                                       | Absence or  decrease in the  number of sperm  which may be  temporary or  permanent which  may decrease the  ability to have  children                                                                                                                                                         |                                                                                                                  | Abnormal hormone function which  may lower the level of salt in the blood          |
|                                                                                                                       | Abdominal pain                                                                                                                                                                                                                                                                                 |                                                                                                                   |                                                                                    |
|                                                                                                                       | Diarrhea                                                                                                                                                                                                                                                                                       |                                                                                                                   |                                                                                    |
|                                                                                                                       | Fewer red blood cells and platelets in  the blood - a low number of red blood cells  may make you feel tired and weak. - a low number of platelets may  cause you to bruise and bleed more  easily.                                                                                            |                                                                                                                   |                                                                                    |
|                                                                                                                       | Bleeding and inflammation of the  urinary bladder                                                                                                                                                                                                                                              |                                                                                                                   |                                                                                    |
|                                                                                                                       | Absence or decrease monthly periods  which may be temporary or permanent  and which may decrease the ability to  have children                                                                                                                                                                 |                                                                                                                   |                                                                                    |
|                                                                                                                       | Temporary blurred vision                                                                                                                                                                                                                                                                       |                                                                                                                   |                                                                                    |
|                                                                                                                       | Nasal stuffiness with IV infusions                                                                                                                                                                                                                                                             |                                                                                                                   |                                                                                    |
|                                                                                                                       | Skin rash                                                                                                                                                                                                                                                                                      |                                                                                                                   |                                                                                    |
|                                                                                                                       | Darkening of areas of the skin and  finger nails                                                                                                                                                                                                                                               |                                                                                                                   |                                                                                    |
|                                                                                                                       | Slow healing of wounds                                                                                                                                                                                                                                                                         |                                                                                                                   |                                                                                    |
|                                                                                                                       | Infections                                                                                                                                                                                                                                                                                     |                                                                                                                  | Heart muscle damage  which may occur with  very high doses and  which may be fatal |
|                                                                                                                       | Abnormal heart rhythms                                                                                                                                                                                                                                                                         |                                                                                                                   |                                                                                    |
|                                                                                                                       | Damage and scarring of  lung tissue which may  make you short of breath                                                                                                                                                                                                                        |                                                                                                                   |                                                                                    |
|                                                                                                                       | A new cancer or leukemia  resulting from this  treatment.                                                                                                                                                                                                                                      |                                                                                                                   |                                                                                    |
|                                                                                                                       | Damage or scarring of  urinary bladder tissue                                                                                                                                                                                                                                                  |                                                                                                                   |                                                                                    |
|                                                                                                                       | Severe allergic reaction  which can be life  threatening with shortness  of breath, low blood  pressure, rapid heart rate  chills and fever                                                                                                                                                    |                                                                                                                   |                                                                                    |
|                                                                                                                       | Infertility which is the  inability to have children                                                                                                                                                                                                                                           |                                                                                                                   |                                                                                    |  
  
| Known Risks and Side Effects Related to Etoposide Include Those Which Are: Likely Less Likely Rare But Serious   |                     |               |                  |    |                     |
|------------------------------------------------------------------------------------------------------------------|---------------------|---------------|------------------|----|---------------------|
|                                                                                                                 | Nausea and vomiting |              | Loss of appetite |   | Damage to the liver |
| Bridging Study Version 5.0                                                                                       | Confidential        | Page 50 of 52 |                  |    |                     |  
| Known Risks and Side Effects Related to Etoposide Include Those Which Are: Likely Less Likely Rare But Serious   |                                                                                                                                                                                                                                                                                          |    |                                                                                                                                            |
|------------------------------------------------------------------------------------------------------------------|------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|----|--------------------------------------------------------------------------------------------------------------------------------------------|
|                                                                                                                 | Hair loss                                                                                                                                                                                                                                                                                |    |                                                                                                                                            |
|                                                                                                                 | A feeling of weakness or  tiredness                                                                                                                                                                                                                                                      |    |                                                                                                                                            |
|                                                                                                                 | Fewer red and white  blood cells and platelets  in the blood o a low number of red  blood cells can make  you feel tired and  weak o a low number of  white blood cells can  make it easier to get  infections o a low number of  platelets causes you  to bruise and bleed  more easily |   | Decreased blood pressure  during the infusion which  may require treatment                                                                 |
|                                                                                                                 | Rashes                                                                                                                                                                                                                                                                                   |    |                                                                                                                                            |
|                                                                                                                 | Diarrhea                                                                                                                                                                                                                                                                                 |    |                                                                                                                                            |
|                                                                                                                 | Pain in the abdomen                                                                                                                                                                                                                                                                      |    |                                                                                                                                            |
|                                                                                                                 | Mouth sores                                                                                                                                                                                                                                                                              |    |                                                                                                                                            |
|                                                                                                                 | Tingling sensation or loss  of sensation in fingers or  toes                                                                                                                                                                                                                             |    |                                                                                                                                            |
|                                                                                                                 | A feeling of extreme  tiredness or weakness                                                                                                                                                                                                                                              |    |                                                                                                                                            |
|                                                                                                                 | The finger or toe nails may  loosen from their nail beds                                                                                                                                                                                                                                 |    |                                                                                                                                            |
|                                                                                                                 | Inflammation of the vein  through which the  medication was given                                                                                                                                                                                                                        |    |                                                                                                                                            |
|                                                                                                                 | Chest pain                                                                                                                                                                                                                                                                               |   | Severe allergic reaction which can  be life threatening with shortness  of breath, low blood pressure,  rapid heart rate, chills and fever |
|                                                                                                                 | A new cancer or leukemia  resulting from this treatment                                                                                                                                                                                                                                  |    |                                                                                                                                            |
|                                                                                                                 | Severe rashes which can result in  loss of skin and damage to  mucous membranes                                                                                                                                                                                                          |    |                                                                                                                                            |
|                                                                                                                 | Absence or decrease monthly  periods which may be temporary  or permanent and which may  decrease the ability to have  children                                                                                                                                                          |    |                                                                                                                                            |
|                                                                                                                 | Damage to the heart muscle  which may make you feel tired,  weak, feel short of breath, and  retain fluid                                                                                                                                                                                |    |                                                                                                                                            |  
  
There also may be other side effects that we cannot predict. Many side effects go away shortly after the drugs are stopped, but in some cases side effects can be serious, longlasting, or permanent. Other drugs may be given to make side effects less serious and uncomfortable.
appendix 5
bridging therapy roadmap

| Drug                     | Route                 | Dosage    | Days   |
|--------------------------|-----------------------|-----------|--------|
| Clofarabine              | IV over 2 hours       | 20 mg/m2  | 1-5    |
| Etoposide (ETOP)         | IV over 2 hours       | 100 mg/m2 | 1-5    |
| Cyclophosphamide (CYCLO) | IV over 30 to 60 mins | 300 mg/m2 | 1-5    |
appendix 5
drugs given in this order

Clofarabine 20 mg/m2IV over 2 hours followed by Etoposide 100 mg/m2IV over 2 hours followed by Cyclophosphamide 300 mg/m2IV as a 30-60 minute infusion  
Ht ____________ Wt. ___________ **BSA ___________**  
| Date     | Date            | Day      | Clofarabine   |
|----------|-----------------|----------|---------------|
| Due      | Given           | ETOP     | CYCLO         |
| ______mg | ______mg        | ______mg |               |
| 1        | ______mg        | ______mg | ______mg      |
| 2        | ______mg        | ______mg | ______mg      |
| 3        | ______mg        | ______mg | ______mg      |
| 4        | ______mg        | ______mg | ______mg      |
| 5        | ______mg        | ______mg | ______mg      |
| 6-28     | No Chemotherapy |          |               |