Ruxolitinib or Dasatinib With Chemotherapy in Patients With Philadelphia Chromosome (Ph)-Like Acute Lymphoblastic Leukemia (ALL)

Condition(s) targeted: Leukemia

Intervention: Ruxolitinib (Drug); Dasatinib (Drug); Rituximab (Drug); G-CSF (Drug); Pegfilgrastim (Drug); Methotrexate (Drug); Cytarabine (Drug); Cyclophosphamide (Drug); Mesna (Drug); Doxorubicin (Drug); Vincristine (Drug); Dexamethasone (Drug); Solumedrol (Drug); 6-mercaptopurine (Drug); Prednisone (Drug); Leucovorin (Drug)

Phase: Phase 2

Status: Recruiting

Sponsored by: M.D. Anderson Cancer Center

Official(s) and/or principal investigator(s):
Nitin Jain, MBBS, Principal Investigator, Affiliation: M.D. Anderson Cancer Center

Overall contact:
Nitin Jain, MBBS, Phone: 713-745-6080

The goal of this clinical research study is to learn if ruxolitinib or dasatinib in combination with chemotherapy can help to control Ph-like ALL. The safety of these drug combinations will also be studied.

Official title: A Phase II Study of the Combination of Ruxolitinib or Dasatinib With Chemotherapy in Patients With Philadelphia Chromosome (Ph)-Like Acute Lymphoblastic Leukemia (ALL)

Study design: Allocation: Non-Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment

Primary outcome: Response Rate (CR/CRi) of Ruxolitinib or Dasatinib in Combination With Philadelphia Chromosome (Ph)-Like Acute Lymphoblastic Leukemia (ALL)

Detailed description: Study Groups: If you are found to be eligible to take part in this study, you will be assigned to 1 of 2 study groups, based on the molecular type of the disease. You and the study staff will know which study drug you will receive:

- Participants in Group A will receive ruxolitinib.

- Participants in Group B will receive dasatinib.

Study Drug Administration: Each study cycle is 21 days. Participants in Group A will take ruxolitinib tablets by mouth 2 times a day (about 12 hours apart), with or without food. Participants in Group B will take dasatinib tablets by mouth 1 time each day, with or without food. You should take the study drug at the same time each day. If your doctor thinks it is needed, you may receive steroids and/or hydroxyurea if your white blood cell counts are too high. If the disease does not respond to treatment by the end of Cycle 1, you will also receive up to 2½ years of chemotherapy treatment. You will receive 8 cycles of intensive chemotherapy, using 2 different chemotherapy schedules. Once you complete intensive chemotherapy, you will receive up to 2 years of maintenance chemotherapy. During intensive chemotherapy and maintenance chemotherapy, you may continue taking ruxolitinib or dasatinib every day, for as long as you are receiving benefit and you are not having intolerable side effects. Chemotherapy is given several different ways:

- By mouth

- By vein, through a central venous catheter (CVC): 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.

- Intrathecal administration, through a lumbar puncture (spinal tap): 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. Occasionally, a sample of the fluid obtained from the spinal taps may be tested for leukemia. Your chemotherapy doses may be raised or lowered, depending on side effects. You will receive other drugs during chemotherapy to help prevent or lower the risk of certain side effects, including tumor lysis syndrome (breakdown products of the cancer cells entering the blood stream, which may cause possible weakness, low blood pressure, muscle cramps, kidney damage, and/or other organ damage). Intensive Chemotherapy: You will receive several drugs (listed below) as part of your chemotherapy. Each cycle of intensive chemotherapy is 21 days. You may receive up to 8 cycles of intensive chemotherapy in the hospital. You will need to stay in the hospital for the first 4-5 days of each cycle. Hyper-CVAD: Cycles 1, 3, 5, and 7:

- On Days 1-3 of these cycles, you will receive cyclophosphamide by vein over about 3

hours, 2 times a day (about every 12 hours).

- On Days 1-3 of these cycles, starting about 1 hour before your cyclophosphamide

infusion, you will receive MESNA by vein over about 16 hours. MESNA is given to lower the risk of side effects.

- On Day 4 of these cycles, you will receive doxorubicin by vein over 24-48 hours. On

Days 4 and 11 (+/- 2 days) of these cycles, you will receive vincristine by vein over about 30 minutes.

- On Days 1-4 and 11-14 (+/- 2 days) of these cycles, you will take dexamethasone by

mouth 1 time a day or by vein over 30 minutes.

- If the doctor thinks it is needed, on Days 1 and 11 of Cycles 1 and 3 only, you may

also receive rituximab by vein over several hours. Methotrexate alternating with cytarabine by vein: Cycles 2, 4, 6, and 8:

- On Day 1 of these cycles, you will receive methotrexate by vein over about 24 hours

(+/- 3 hours).

- On Days 2-5 of these cycles, you will receive leucovorin by vein over or by mouth every

6 hours, beginning about 12 hours (+/- 2 hours) after you finish receiving methotrexate. Each infusion will last about 1 hour. Leucovorin is given to lower the risk of side effects such as mouth sores and kidney damage.

- On Days 1-3 of these cycles, you will receive Solu-Medrol (methylprednisolone) by vein

about every 12 hours. Each infusion will last about 2 hours.

- On Days 2 and 3 of these cycles, you will receive cytarabine by vein about every 12

hours. Each infusion will last about 2 hours.

- If the doctor thinks it is needed, on Days 1 and 8 for Cycles 2 and 4 only, you may

also receive rituximab by vein over several hours. Additional Treatment during Intensive Chemotherapy:

- If your doctor thinks it is needed, on Day 2 of Cycles 1, 2, 3, and 4 only (+/- 2

days), you will receive intrathecal methotrexate to help lower the risk of the disease coming back in the fluid surrounding your brain.

- If your doctor thinks it is needed, on Day 7 of Cycles 1, 2, 3, and 4 only (+/- 2

days), you will receive intrathecal cytarabine to help lower the risk of the disease coming back in the fluid surrounding your brain.

- You will also receive either filgrastim every day or pegfilgrastim once after each

cycle. The drug will be given as injection just under your skin, until your white blood cell counts have recovered. Your study doctor will tell you when this happens. As long as 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. At that point, you will go on to the maintenance therapy phase. Maintenance Chemotherapy: Each maintenance cycle will be 28 days. Maintenance chemotherapy will last for up to 2 years after you complete all 8 courses of intensive chemotherapy. During maintenance chemotherapy:

- You will take mercaptopurine tablets by mouth 3 times a day.

- You will take methotrexate tablets by mouth once a week.

- On Day 1 of each cycle, you will receive vincristine by vein over about 30 minutes.

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

Study Visits: On Day 1 of Cycle 1:

- You will have a physical exam.

- Blood (about 1 tablespoon) will be drawn for routine tests. For the Day 1 tests, if you

have had any of these tests or procedures in the last 3 days, they may not need to be repeated. On Days 8 and 15 of Cycle 1, you will have a physical exam. Every week during Cycle 1, blood (about 1 tablespoon each time) will be drawn for routine tests 3 times a week. On Day 21 of every cycle, you will have a bone marrow aspiration and/or biopsy, to check the status of the disease. Once your doctor believes the disease has shown enough response, this will be done every 2-3 cycles at that point. On Day 1 of Cycle 2 and every cycle after that, you will have a physical exam. During the Intensive Chemotherapy cycles, blood (about 1 tablespoon each time) will be drawn for routine tests every week. During Maintenance Chemotherapy cycles, these routine blood samples will be drawn 1 time every month. On Day 1 of every even-numbered cycle (Cycles 2, 4, 6, and so on), you will have an x-ray of your chest Length of Treatment: You may receive the intensive chemotherapy for up to 8 cycles (up to 8 months) and then maintenance therapy for up to 2 years. You may continue to take ruxolitinib or dasatinib every day for as long as the doctor thinks it is in your best interest. 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 after the follow-up visit. 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. Ruxolitinib is FDA approved and commercially available for the treatment of myelofibrosis. Its use in this study is investigational. The study doctor can explain how ruxolitinib is designed to work. Dasatinib is FDA approved and commercially available for the treatment of CML and Philadelphia chromosome-positive ALL. All other drugs used in this study are FDA approved and commercially available. Their use together in this study is investigational. The study doctor can explain how the study drug(s) are designed to work. You will be given standard drugs to help decrease the risk of side effects. You may ask the study staff for information about how the drugs are given and their risks. Up to 92 participants will take part in this study. All will be enrolled at MD Anderson Cancer Center.

Minimum age: 10 Years. Maximum age: N/A. Gender(s): Both.

Criteria:

Inclusion Criteria: 1. Patients with previously treated Philadelphia-chromosome-negative B-cell ALL (relapsed and/or refractory after prior therapy) 2. Bone marrow involvement with >/= 5% lymphoblasts 3. Age >/= 10 years 4. Documented genetic lesion(s) known to confer susceptibility to inhibition by either ruxolitinib or dasatinib or CRLF2 positivity by flow cytometry (for the Ruxolitinib cohort) 5. Eastern Cooperative Oncology Group (ECOG) performance status control include the following: - - Any 2 of the following methods used together:

- -Birth control implants, injections, or pills (except for progesterone only pills),

- -Intrauterine device (IUD), --Vasectomy, --Tubal Ligation, --Barrier method (female

or male condom with spermicide, cervical cap with spermicide, diaphragm with

spermicide); - -Male condom with spermicide and diaphragm; Male condom with spermicide

and cervical cap 8. (Continuation of #7) Unacceptable methods of birth control include using no birth control, withdrawal, rhythm method, vaginal sponge, any barrier method that does not use spermicide, progesterone only pills, and using male and female condoms at the same time. 9. Males who have partners of childbearing potential must agree to use an effective contraceptive method during the study and for 30 days following the last dose of study drug 10. Patients or their legally authorized representative must provide written informed consent Exclusion Criteria: 1. Ph-positive ALL, Burkitt's Leukemia or Lymphoma, T-cell ALL or lymphoblastic lymphoma 2. Patients having undergone prior allogeneic stem cell transplant within 3 months or having active graft versus host disease 3. Patient is pregnant or breastfeeding 4. Patients with uncontrolled active infections (Fever >/= 38 degree C, Septic shock) 5. Isolated extramedullary relapse (i. e. testicular, central nervous system) 6. Current or chronic hepatitis B or C infection, or known seropositivity for HIV 7. Concurrent chemotherapy (except intrathecal chemotherapy) 8. Major surgery within 4 weeks prior to first study dose 9. Systemic chemotherapy/radiotherapy/investigational therapy within 14 days (with the exception of hydroxyurea and steroids) prior to starting therapy. For patients receiving ALL maintenance with 6-mercaptopurine, methotrexate, vincristine, and

steroids - these agents should be discontinued at least 48 hours prior to start of

study drugs. 10. Patients must have recovered from acute non hematologic toxicity (to /= 2 consecutive spinal fluid assessments with no evidence of disease) at the time of registration. Prophylactic intrathecal chemotherapy is not a criterion for exclusion. 12. Patients with active heart disease (NYHA class 3-4 as assessed by history and physical examination, unstable angina/stroke/myocardial infarction within the last 6 months) 13. Patients with a cardiac ejection fraction (as measured by either Multi-gated Acquisition (MUGA) scan or echocardiogram) < 40%. (Note: Patients who have had prior anthracycline exposure of >250 mg/m2 may be eligible after discussion with the PI). 14. Second malignancy other than basal cell or squamous cell carcinoma of the skin or in situ carcinoma of the cervix or the breast, unless they are successfully treated with curative intent for more than 2 years before entering the study 15. Malabsorption syndrome or other conditions that preclude enteral route of administration 16. Patients requiring strong CYP3A4 inhibitors. (Complete list of inhibitors can be found at: http://medicine. iupui. edu/clinpharm/ddis/table. aspx) 17. Other severe acute or chronic medical or psychiatric condition or laboratory abnormality that in the opinion of the investigator may increase the risk associated with study participation or investigational product administration or may interfere with the interpretation of study results and/or would make the patient inappropriate for enrollment into this study.

Nitin Jain, MBBS, Phone: 713-745-6080

University of Texas MD Anderson Cancer Center, Houston, Texas 77030, United States; Recruiting

University of Texas MD Anderson Cancer Center Website

Starting date: July 2015
Last updated: July 15, 2015