Patient case: 4-year-old female with leukemia; genetic feature: ABL1

Clinical trial: Study of the Combination of Inotuzumab Ozogamycin (CMC-544) With Low-intensity Chemotherapy in Patients With Acute Lymphoblastic Leukemia (ALL)

Summary: The goal of the Phase I part of this clinical research study is to test 2 dose levels of the drug inotuzumab ozogamycin to find the highest tolerable dose that can be given in combination with chemotherapy. The goal of Phase II is to learn if inotuzumab ozogamycin given in combination with chemotherapy can help to control acute lymphoblastic leukemia (ALL). The safety of the study drugs will also be studied.
  Participants in this study are at least 60 years of age and have newly diagnosed ALL or have refractory-relapsed ALL regardless of age.
  Inotuzumab ozogamycin is designed to attach to a protein that is often found in leukemia cells. This may cause the cancer cells to die.
  Rituximab is designed to attach to cancer cells and damage them, which may cause the cells to die.
  Hyper-CVD includes a combination of cyclophosphamide, vincristine, dexamethasone, methotrexate, Ara-C (cytarabine), and Neulasta (pegfilgrastim). The maintenance therapy used in this study is called POMP, which includes a combination of mercaptopurine, methotrexate, vincristine, and prednisone. 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.

Detailed description: Study Groups:
  If participant is found to be eligible to take part in this study, participant will be assigned to a study group based on when you join this study. One (1) group of 6 participants will be enrolled in the Phase I portion of the study, and 1 group of up to 60 participants will be enrolled in Phase II.
  The Phase I group will receive the lowest dose level of inotuzumab ozogamycin. The Phase II group will receive a higher dose of inotuzumab ozogamycin, if no intolerable side effects were seen.
  All participants will receive the same dose level of the rest of the study drugs.
  Study Drug Administration:
  Participant will receive up to 8 cycles of induction and consolidation therapy and possibly 4 cycles of blinatumomab treatment. Each induction/consolidation cycle is about 3-4 weeks. Blinatumomab cycles are about 42 days.
  Hyper-CVD: Cycles 1, 3, 7, and 9:
  On Days 1-3 of Cycles 1, 3, 7, and 9, participant will receive cyclophosphamide every 12 hours by vein over about 3 hours.
  On Days 1-3 of Cycles 1, 3, 7, and 9, participant will receive mesna as a continuous infusion starting about 1 hour before participant receives cyclophosphamide and ending about 12 hours after the last dose of cyclophosphamide. Mesna is given to lower the risk of side effects.
  On Days 1 and 8 of Cycles 1, 3, 7, and 9 (+/- 2 days), participant will receive vincristine by vein over about 30 minutes.
  On Days 1-4 and 11-14 of Cycles 1, 3, 7, and 9 (+/- 2 days), participant will take dexamethasone by vein or by mouth 1 time a day.
  On Days 2 and 8 of Cycles 1 and 3 (+/- 2 days), participant will receive inotuzumab ozogamycin by vein over about 60 minutes (+/- 15 minutes). The dose participant receives will depend on when participant starts treatment. If participant's doctor thinks it is needed to lower the risk of side effects, participant will take acetaminophen, diphenhydramine, and hydrocortisone before participant's doses of inotuzumab ozogamycin. Acetaminophen will be given by mouth. Diphenhydramine will be given by mouth or by vein over 15-30 minutes. Hydrocortisone will be given by vein over 15-30 minutes.
  On Days 1 and 8 of Cycles 1 and 3 (+/- 2 days), if participant's doctor feels it is in participant's best interest, participant may receive rituximab. The study doctor will decide how long the infusion will last.
  Participant 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 participant's 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.
  On Day 2 of Cycles 1 and 3 (+/- 2 days) and on Day 8 of Cycles 2 and 4, participant will receive intrathecal methotrexate.
  On Day 8 of Cycles 1 and 3 (+/- 2 days) and on Day 5 of Cycles 2 and 4, participant will receive intrathecal cytarabine.
  On Day 4 of Cycles 1, 3, 7, and 9 (+/- 2 days) participant will receive pegfilgrastim as an injection under the skin.
  Methotrexate alternating with cytarabine by vein: Cycles 2, 4, 8, and 10 On Day 1 of Cycles 2, 4, 6 and 8, participant will receive methotrexate by vein over about 24 hours (+/- 3 hours).
  On Days 2 and 3 of Cycles 2, 4, 8, and 10 participant will receive cytarabine by vein 2 times a day over about 3 hours each time.
  On Days 1 and 8 of Cycles 2 and 4 (+/- 2 days), if participant's doctor feels it is in participant's best interest, participant may receive rituximab by vein over about 2-6 hours.
  On Days 2 and 8 of Cycles 2 and 4 (+/- 2 days), participant will receive inotuzumab ozogamycin by vein over about 60 minutes (+/- 15 minutes). If participant's doctor thinks it is in participant's best interest, participant may receive inotuzumab ozogamycin more often.
  On Day 4 of Cycles 2, 4, 8, and 10 (+/- 2 days), participant will receive pegfilgrastim as an injection under the skin.
  On Days 2-5 of Cycles 2, 4, 8, and 10 participant will receive leucovorin by vein over about 1 hour or by mouth every 6 hours for 8 doses beginning about 12 hours (+/- 2 hours) after participant finishes receiving methotrexate. Leucovorin is given to lower the risk of side effects.
  On Days 1-29 of Cycles 5-6 and 11-12, if participant's doctor thinks it is in participant's best interest, participant may receive blinatumomab by vein as a continuous infusion followed by 2 weeks of rest without treatment. During Cycle 5, participant will receive a lower dose on Days 1-4, then the dose will be increased on Days 5-29. During Cycles 6, 11, and 12, the dose will be the same each day. Participant may be asked to remain in the hospital on Days 1-6 of Cycle 5 and Days 1-2 of Cycle 6. If participant is tolerating the treatment well, participant may receive the remaining treatment as an outpatient. Participant will be asked to return to MD Anderson at specific times, or allow a home health care provider to visit participant at home, so the infusion bag can be properly changed.
  On Day 1 of Cycles 5, 6, 11 and 12 participant will receive dexamethasone by vein over 15 - 30 minutes about 1 hour before beginning the treatment with blinatumomab to lower the risk of side effects.
  Participant's dose of the study drugs may change depending on any side effects participant may have.
  Participant may be given other drugs to help prevent side effects. Participant's doctor will tell participant about these drugs, how they will be given, and the possible risks.
  Maintenance Therapy:
  After participant completes the cycles described above, participant will receive POMP maintenance therapy for up to 1 year if participant received all 4 blinatumomab cycles, or otherwise up to 3 years.
  Participant will take mercaptopurine by mouth 2 times a day for 3 years.
  Participant will take methotrexate by mouth 1 time a week for 3 years.
  Participant will receive vincristine by vein over about 30 minutes 1 time a month for 1 year.
  Participant will take prednisone by mouth 1 time a day for 5 days every month for 1 year.
  If bone marrow samples drawn during consolidation and maintenance therapy show that the disease is not gone, participant's doctor may recommend that participant receives additional doses of inotuzumab ozogamycin. Participant would receive it at a lower dose 1 time every 3-4 weeks for up to 6 doses instead of receiving the POMP maintenance therapy.
  Study Visits:
  Within 1 week before Day 1 of each cycle:
  -  Participant will have a physical exam, including measurement of participant's vital signs.
  -  Participant will be asked how participant is feeling and about any drugs participant may be taking.
  -  If the doctor thinks it is needed, blood (about 1 tablespoon) will be drawn to test how the study drugs may affect cancer cells.
  -  If participant is receiving rituximab and if participant has a history of irregular heartbeat or chest pain due to heart trouble, participant will have ECGs performed before the rituximab infusion, 1 time during the infusion, and within 2 hours after the infusion. The rituximab infusion will be stopped if participant has any serious episodes of irregular heartbeat.
  Blood (about 1 tablespoon) will be drawn for routine tests 1-3 times each week during Cycles 1 and 2, at least every 1-2 weeks during consolidation, and every 2-4 weeks during maintenance cycles.
  Participant will have a bone marrow aspiration and/or biopsy (about 1 teaspoon) to check the status of the disease between Days 14-21 (+/- 3 days) of Cycle 1, and then every 2-4 cycles during consolidation.
  Within 1 week before Day 1 of Cycles 2, 4, 6, and 8, participant will have a chest x-ray to check participant's lungs.
  Every 3 months during maintenance:
  -  Participant will be asked how participant is feeling and about any drugs participant may be taking.
  -  Participant will have a bone marrow aspiration and/or biopsy (about 1 teaspoon). Bone marrow aspirations and/or biopsies may be done every 3-6 months beginning in the 2nd year of 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:
  Participant may receive the study drugs for up to 12 cycles and then maintenance therapy for up to 3 years. Participant will no longer be able to take the study drugs if the disease gets worse, if intolerable side effects occur, or if participant is unable to follow study directions.
  Participation on the study will be over once participant has completed the follow-up.
  Follow-up:
  Participant will have a follow-up visit 30 days after participant's last dose of the study drugs. At this visit, participant will be asked about any side effects participant may be having. If participant 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. Rituximab, Hyper-CVD, methotrexate, cytarabine, blinatumomab, and POMP maintenance drugs are FDA approved and commercially available for the treatment of leukemia. Combining inotuzumab ozogamycin with rituximab is investigational. Giving inotuzumab ozogamycin to patients with leukemia is investigational.
  Up to 206 participants will take part in this study. All will be enrolled at MD Anderson.

Eligibility: Inclusion Criteria:
  1. Patients age 60 years or older with previously untreated ALL of pre-B, Philadelphia chromosome (Ph-) negative ALL. Minimal prior therapy (less than 1 week of steroids, vincristine, and/or 1 dose of anthracycline or alkylating agents) are allowed.
  2. Zubrod performance status 0-3.
  3. Adequate liver function (bilirubin </= 1.95 mg/dL and SGPT or SGOT </= 3 x upper limit of normal [ULN], unless considered due to tumor), and renal function (creatinine </= 2 mg/dL). Even if organ function abnormalities are considered due to tumor, the upper limit for bilirubin is </= 2.6 mg/dL and creatinine </= 3 mg/dL.
  4. Provision of written informed consent.
  5. Patients in first remission are eligible.
  6. Patients with refractory-relapsed ALL of any age are eligible, provided they are not eligible for regimens of higher priority.
  Exclusion Criteria:
  1. Ph-positive ALL, Burkitt's Leukemia or Lymphoma, T-cell ALL or lymphoblastic lymphoma.
  2. Patient with active heart disease (NYHA class >/= 3 as assessed by history and physical examination).
  3. Patients with a cardiac ejection fraction (as measured by either MUGA or echocardiogram) < 40% are excluded.
  4. Patients with active hepatitis are excluded.
  5. Pregnant or breast-feeding women are excluded.

Relevance to patient case: not relevant