Hyper-CVAD and Ponatinib in Ph-Positive and/or BCR-ABL Positive Acute Lymphoblastic Leukemia (ALL)

The goal of this clinical research study is to learn if intensive chemotherapy combined with ponatinib, followed by maintenance therapy, can help to control ALL with the Ph chromosome and/or BCR-ABL. The safety of this treatment will also be studied.

Study Drugs:

The intensive chemotherapy used in this study includes a combination of 7 chemotherapy drugs. These drugs include cyclophosphamide, vincristine, Adriamycin (doxorubicin), dexamethasone, methotrexate, cytarabine (Ara-C), and ponatinib. This is called hyper-CVAD. You may also receive rituximab. These chemotherapy drugs are designed to interfere with the multiplication of cancer cells, which may slow or stop their growth and spread throughout the body. This may cause the cancer cells to die.

The maintenance therapy used in this study includes a combination of 3 chemotherapy drugs. These drugs include vincristine, prednisone, and ponatinib.

Cytarabine is designed to insert itself into DNA (the genetic material of cells) and stop the DNA from repairing itself.

Cyclophosphamide is designed to interfere with the multiplication of cancer cells, which may slow or stop their growth and spread throughout the body. This may cause the cancer cells to die.

Ponatinib is designed to block a protein that cancer may need to grow, survive, or spread.

Dexamethasone, doxorubicin, methotrexate, and prednisone are each designed to stop or slow the growth of cancer cells, which may cause the cells to die.

Vincristine is designed to interfere with the multiplication of cancer cells, which may slow or stop their growth and spread throughout the body. This may cause the cancer cells to die.

Rituximab is designed to attach to leukemia cells, which may cause them to die.

Study Drug Administration:

If you are found to be eligible to take part in this study, you will receive intensive chemotherapy therapy and ponatinib followed by maintenance therapy. You will receive 2 kinds of intensive chemotherapy regimens (hyper-CVAD therapy and methotrexate plus cytarabine) that will alternate about every 3 weeks for a total of 8 cycles (4 courses of each regimen). Each study cycle is about 3-4 weeks.

Intensive Chemotherapy:

You may receive up to 8 cycles of intensive chemotherapy in the hospital (about 4 or 5 days as inpatient). For participants 60 years and older, you will receive the entire first course in the hospital (about 21 days), in a protected environment, until you have healthy recovery of your blood counts.

Hyper-CVAD: Cycles 1, 3, 5, and 7:

On Days 1-3 of Cycles 1, 3, 5, and 7, you will receive cyclophosphamide by vein over about 3 hours 2 times a day about every 12 hours. While you are receiving cyclophosphamide, you will receive mesna as a continuous infusion by a central venous catheter (CVC) starting about 1 hour before you receive cyclophosphamide and ending about 12 hours after the last dose of cyclophosphamide. Mesna is given to lower the risk of side effects. A CVC is a sterile flexible tube that will be placed into a large vein while you are under local anesthesia. Your doctor will explain this procedure to you in more detail, and you will be required to sign a separate consent form for this procedure.

On Days 1 and 11 of Cycles 1, 3, 5, and 7 (+/- 2 days), you will receive vincristine by vein over about 30 minutes.

On Day 4 of Cycles 1, 3, 5, and 7, you will receive doxorubicin by a CVC over 24-48 hours.

On Days 1-4 and 11-14 of Cycles 1, 3, 5, and 7 (+/- 2 days), you will take dexamethasone by mouth 1 time a day or by vein over 30 minutes.

On Days 1-14 of Cycle 1 and every day during Cycles 2-8, you will take ponatinib by mouth 1 time a day.

If the doctor thinks it is needed, on Days 1 and 11 of Cycles 1 and 3 and on Days 1 and 8 for Cycles 2 and 4, you will also receive rituximab by vein over several hours.

You will also receive methotrexate alternating with cytarabine by a spinal tap (intrathecally) to help lower the risk of the disease coming back in the fluid surrounding your brain. A spinal tap (also called a lumbar puncture) is when fluid surrounding the spinal cord is removed by inserting a needle into the lower back. The affected area is numbed with local anesthetic during the procedure. It can also be used to give chemotherapy. The number of doses you receive will depend on how many doses the study doctor thinks is needed. If you start with leukemia in the brain, it will be given 2 times a week until there is no leukemia present and then 1 time a week for 4 weeks. Occasionally, a sample of the fluid obtained from the spinal taps may be tested for leukemia. A sample will also be tested to see if it reaches the fluid around the brain.

On Day 2 of Cycles 1, 2, 3, and 4 (+/- 2 days), you will receive intrathecal methotrexate.

On Day 7 of Cycles 1, 2, 3, and 4 (+/- 2 days), you will receive intrathecal cytarabine.

Methotrexate alternating with cytarabine by vein: Cycles 2, 4, 6, and 8 On Day 1 of Cycles 2, 4, 6 and 8, you will receive methotrexate by vein over about 24 hours (+/- 3 hours).

On Days 1-3 of Cycles 2, 4, 6, and 8, you will receive solumedrol by vein over less than 30 minutes about every 12 hours.

On Days 2 and 3 of Cycles 2, 4, 6, and 8, you will receive cytarabine by vein 2 times a day over about 3 hours each time.

On Days 2-5 of Cycles 2, 4, 6, and 8, you will receive leucovorin by vein over about 1 hour or by mouth every 6 hours beginning about 12 hours (+/- 2 hours) after you finish receiving methotrexate. Leucovorin is given to lower the risk of side effects such as mouth sores and kidney damage.

You will also receive filgrastim or pegfilgrastim after all cycles of Hyper-CVAD and methotrexate plus cytarabine. You will receive it either as injection just under your skin every day, or only once after chemotherapy, until you have healthy recovery of your white blood cells, which will be determined by the study doctor.

If the disease is responding to therapy and you have not had any intolerable side effects, you will continue on intensive chemotherapy for up to 8 courses, and you will then go to the maintenance therapy phase. You will be taken off this study if the disease gets worse or you have any intolerable side effects.

Maintenance Therapy:

Maintenance therapy, which will last for up to 2 years, will be given after you complete all 8 courses of intensive chemotherapy. Each maintenance cycle will be about 28 days.

On Day 1, you will receive vincristine by vein over about 30 minutes.

On Days 1-5, you will take prednisone by mouth.

You will take ponatinib as a single dose every day by mouth. You may continue to take ponatinib every day for as long as you are receiving benefit and you are not having intolerable side effects.

Post-Remission Therapy:

During Months 6 and 13, you may receive another course of hyper-CVAD, depending on how you are feeling and the status of the disease.

Your doses of all chemotherapy that is given in this study may be increased or decreased depending on your organ function and side effects. Throughout intensive chemotherapy and maintenance therapy, you will also receive other drugs, fluids, or blood products (such as antibiotics, antiemetics, antacids, saline, platelets, and plasma), including allopurinol (by mouth) or rasburicase (by vein), to help protect your body against tumor lysis syndrome. This is a condition brought on by the death of large tumors, which causes damage to kidneys.

Study Visits:

At each study visit, you will be asked how you are feeling and about any drugs you may be taking.

Before Day 1 of Cycle 2, you will have an ECG (+/- 2 days).

On Day 1 of Cycles 2-8, you will have a chest x-ray.

Blood (about 1 tablespoon) will be drawn for routine tests 1-2 times each week during Cycle 1, every 1-3 weeks during Cycles 2-8, and every 4-6 weeks during maintenance cycles.

You will have a bone marrow aspiration and/or biopsy (about 1 teaspoon) to check the status of the disease on Days 14 and 21 (+/- 5 days) of Cycle 1, and every 2-3 cycles during consolidation, then every 3-6 months during maintenance.

The blood draws for routine tests, bone marrow aspirations/biopsies, and ECGs may be repeated more often anytime the doctor thinks it is needed.

Length of Treatment:

You may receive the intensive chemotherapy for up to 8 cycles (about 8 months) and then maintenance therapy for up to 2 years. You may continue to take ponatinib as long as you are receiving benefit. You will no longer be able to take the study drugs if the disease gets worse, if intolerable side effects occur, or if you are unable to follow study directions.

Your participation on the study will be over once you have completed the follow-up.

Follow-up:

You will have a follow-up visit 30 days after your last dose of the study drugs. At this visit, you will be asked about any side effects you may be having. If you cannot make it to the clinic for this visit, it can be done over the phone with a member of the study staff. The phone call should last about 10 minutes.

This is an investigational study. Ponatinib is FDA approved to treat patients with certain types of leukemia. Its use in this study is investigational.

All other drugs used in this study are FDA approved and commercially available. Their use together in this study is investigational.

Up to 60 patients will take part in this study. All will be enrolled at MD Anderson.

• Drug: Cyclophosphamide
  300 mg/m^2 by vein over 3 hours every 12 hrs for 6 doses days 1,2,3 (total dose 1800mg/m2) for Odd Courses 1,3,5,7.
  Other Names:

  • Cytoxan
  • Neosar
• Drug: Mesna
  600 mg/m^2 by vein continuous infusion daily for 24 hours for Odd Courses 1,3,5,7.
  Other Name: Mesnex
• Drug: Doxorubicin
  50 mg/m2 by vein over 24 hrs via central venous catheter on Day 4 of Odd Courses 1,3,5,7.
  Other Names:

  • Doxorubicin Hydrochloride
  • Adriamycin PFS
  • Adriamycin RDF
  • Rubex
• Drug: Vincristine

  2 mg by vein on day 1 and day 11 of Odd Courses 1,3,5,7.

  Maintenance Therapy Starting Dose: 2 mg by vein on day 1 approximately every 28 days for 24 months.

• Drug: Dexamethasone
  40 mg by vein or by mouth daily on days 1-4 and days 11-14 of Odd Courses 1,3,5,7.
  Other Name: Decadron
• Drug: Ponatinib

  Odd Courses 1,3,5,7: 45 mg by mouth daily days 1-14 for Course 1. For subsequent courses 3, 5, and 7, 70 mg by mouth daily.

  Even Courses 2,4,6,8: 45 mg by mouth daily.

  Maintenance Therapy Starting Dose: 45 mg by mouth daily as tolerated for 24 months.

• Drug: G-CSF (Filgrastim)
  Even and Odd Courses: 10 mcg/kg subcutaneously daily (or 5mcg/kg twice daily) until post-nadir granulocytes >1.0 x 109/L.
  Other Names:

  • Filgrastim
  • NeupogenTM
• Drug: Rituximab

  Odd Courses: 375 mg/m2 by vein on days 1 and 11 of Cycles 1 and 3 for patients with CD20 expression (>20% by flow cytometry).

  Even Courses: 375 mg/m2 by vein on days 1 and 8 of cycles 2 and 4 for patients with CD20 expression (>20% by flow cytometry).

  Other Name: Rituxan
• Drug: Methotrexate

  12 mg intrathecally (6mg via Ommaya reservoir) on day 2 for Odd Courses.

  200 mg/m2 by vein over 2 hours (+ 1 hr) followed by 800 mg/m2 over 22 hours on day 1 for Even Courses.

• Drug: Cytarabine

  CNS prophylaxis: 100 mg intrathecally day 7 for Even and Odd Courses.

  Even Course 2,4,6,8: 3g/m2 by vein over 3 hours every 12 hours for 4 doses on days 2, 3.

  Other Names:

  • Ara-C
  • Cytosar
  • DepoCyt
  • Cytosine Arabinosine Hydrochloride
• Drug: Solu-medrol ( Methyl Prednisolone)
  50 mg by vein every 12 hours for 6 doses days 1-3 of Even Course 2,4,6,8.
  Other Names:

  • Depo-Medrol
  • Medrol
  • Methyl Prednisolone
• Drug: Citrovorum (Leucovorin)
  Even Courses 2,4,6,8 on Days 2 - 5: Rescue 50 mg by vein or mouth followed by 15 mg by vein or by mouth every 6 hours for 8 doses beginning 12 hours post Methotrexate completion, i.e. approximately 36 hours from start of Methotrexate.
  Other Names:

  • Leucovorin
  • Wellcovorin
• Drug: Prednisone
  Maintenance Therapy Starting Dose: 200 mg by mouth daily days 1-5 approximately every 28 days with vincristine for 24 months.
• Drug: Pegfilgrastim (Neulasta)

  Even Courses: Neulasta may replace G-CSF at a dose of 6 mg subcutaneously on Day 5.

  Odd Courses: Neulasta may replace G-CSF at 6 mg subcutaneously on Day 4.

  Other Names:

  • NeulastaTM
  • PEG-G-CSF

• Experimental: Hyper-CVAD + Ponatinib
  Hyper-CVAD Odd courses 1, 3, 5, 7. Cyclophosphamide 300 mg/m^2 by vein (IV) every 12 hours for 6 doses Days 1-3; Vincristine 2 mg IV Day 1 and Day 11; Doxorubicin (Adriamycin) 50 mg/m^2 continuous IV Day 4; Dexamethasone 40 mg IV/orally/day Days 1-4 and days 11-14; Methotrexate 12 mg intrathecally (6mg via Ommaya reservoir) on Day 2; Cytarabine 100 mg intrathecally Day 7; and Ponatinib 45 mg orally daily days 1-14 for Course 1 then 70 mg daily other odd courses. Pegfilgrastim (Neulasta) may replace G-CSF at 6 mg subcutaneously on Day 4.
  Interventions:

  • Drug: Cyclophosphamide
  • Drug: Mesna
  • Drug: Doxorubicin
  • Drug: Vincristine
  • Drug: Dexamethasone
  • Drug: Ponatinib
  • Drug: G-CSF (Filgrastim)
  • Drug: Rituximab
  • Drug: Methotrexate
  • Drug: Cytarabine
  • Drug: Pegfilgrastim (Neulasta)
• Experimental: Methotrexate + Cytarabine + Ponatinib
  Even courses 2,4, 6, and 8. Methotrexate 12 mg intrathecally (6 mg via Ommaya reservoir); Cytarabine 3 g/m^2 IV every 12 hours for 4 doses Days 2 + 3; Ponatinib 45 mg orally/day; Citrovorum (Leucovorin) rescue 50 mg by vein or by mouth followed by 15 mg by vein or by mouth every 6 hours for 8 doses beginning 12 hours post Methotrexate completion. Pegfilgrastim (Neulasta) may replace G-CSF at a dose of 6 mg subcutaneously on Day 5.
  Interventions:

  • Drug: Ponatinib
  • Drug: G-CSF (Filgrastim)
  • Drug: Rituximab
  • Drug: Methotrexate
  • Drug: Cytarabine
  • Drug: Solu-medrol ( Methyl Prednisolone)
  • Drug: Citrovorum (Leucovorin)
  • Drug: Pegfilgrastim (Neulasta)
• Experimental: Maintenance Therapy

  Maintenance chemotherapy with vincristine, and prednisone for approximately 24 months.

  Vincristine 2 mg by vein on day 1 approximately every 28 days for 24 months. Ponatinib 45 mg by mouth daily as tolerated for 24 months. Prednisone 200 mg by mouth daily days 1-5 approximately every 28 days with vincristine for 24 months.

  Interventions:

  • Drug: Vincristine
  • Drug: Ponatinib
  • Drug: Prednisone

Inclusion Criteria:

1. Diagnosis of one of the following: a) Previously untreated Ph-positive ALL [either t(9;22) and/or bcr-abl positive] (includes patients initiated on first course of hyper-CVAD before cytogenetics known); b) Previously treated Ph-positive ALL, after 1-2 courses of chemotherapy with or without other TKIs 1) If they achieved CR, they are assessable only for event-free and overall survival, or 2) If they failed to achieve CR, they are assessable for CR, event-free, and overall survival.
2. Age >/= 18 years
3. Performance status </= 2 (ECOG Scale, Appendix E)
4. Adequate liver function (bilirubin </= 3.0 mg/dl, unless considered due to tumor), and renal function (creatinine </= 3.0 mg/dl, unless considered due to tumor)
5. Adequate cardiac function as assessed clinically by history and physical examination
6. Signed informed consent

Exclusion Criteria:

1. Active serious infection not controlled by oral or intravenous antibiotics
2. Treatment with any investigational antileukemic agents or chemotherapy agents in the last 7 days before study entry, unless full recovery from side effects has occurred or patient has rapidly progressive disease judged to be life-threatening by the investigator
3. Active secondary malignancy other than skin cancer (e.g., basal cell carcinoma or squamous cell carcinoma) that in the investigator's opinion will shorten survival to less than 1 year
4. Active Grade III-V cardiac failure as defined by the New York Heart Association Criteria (Appendix H); a) Uncontrolled angina, or MI within 6 months, b) Diagnosed or suspected congenital long QT syndrome, c) Any history of clinically significant ventricular arrhythmias (such as ventricular tachycardia, ventricular fibrillation, or Torsades de pointes), d) Prolonged QTc interval on pre-entry electrocardiogram (> 470 msec) unless corrected after electrolyte replacement, e) Patients currently taking drugs that are generally accepted to have a risk of causing Torsades de Pointes (unless these can be changed to acceptable alternatives)
5. Prior history of treatment with ponatinib
6. Pregnant and lactating women will not be eligible; women of childbearing potential should have a negative pregnancy test prior to entering on the study and be willing to practice methods of contraception. Women do not have childbearing potential if they have had a hysterectomy or are postmenopausal without menses for 12 months. In addition, men enrolled on this study should understand the risks to any sexual partner of childbearing potential and should practice an effective method of birth control
7. History of significant bleeding disorder unrelated to cancer, including: a) Diagnosed congenital bleeding disorders (e.g., von Willebrand's disease), b) Diagnosed acquired bleeding disorder within one year (e.g., acquired anti-factor VIII antibodies)
8. Patients with documented significant pleural or pericardial effusions unless they are thought to be secondary to their leukemia