Phase I/II Study of Nilotinib/Ruxolitinb Therapy for TKI Resistant Ph-Leukemia

Exclusion Criteria

• •1. Received Tyrosine Kinase Inhibitor therapy within 7 days prior to receiving the first dose of Ruxolitinib+Nilotinib, with the exception of patients who have previously received Nilotinib who must have stopped Nilotinib 4 weeks prior to receiving the first dose of Ruxolitinib+Nilotinib.
• •Patients who have not recovered (\> grade 1 by NCI CTCAE, v. 4.03) from AEs (except alopecia) due to agents previously administered.
• •2. Patients who received other therapies as follows:
• •* For CP and AP patients:
• •Received any of the following within 2 weeks prior to receiving first dose of Ruxolitinib + Nilotinib:
• •* Hydroxyurea (within 7 days of first dose)
• •* anagrelide
• •* interferon
• •* cytarabine
• •* immunotherapy
• •* any other cytotoxic chemotherapy, radiotherapy, or investigational therapy
• •* For BP patients:
• •Received any of the following within 2 weeks prior to receiving first dose of Ruxolitinib + Nilotinib:
• •* chemotherapy other than hydroxyurea
• •* anagrelide
• •* interferon
• •* cytarabine
• •* immunotherapy
• •* any other cytotoxic chemotherapy, radiotherapy, or investigational therapy
• •* For Ph+ ALL patients:
• •Received any of the following within 2 weeks prior to the first dose of Ruxolitinib+Nilotinib:
• •* corticosteroids
• •* vincristine
• •* Hydroxyurea (within 7 days of first dose)
• •* anagrelide
• •* interferon
• •* cytarabine
• •* immunotherapy
• •* any other cytotoxic chemotherapy, radiotherapy, or investigational therapy
• •3. Underwent autologous or allogeneic stem cell transplant within 60 days prior to receiving the first dose of Ruxolitinib+Nilotinib; any evidence of on-going graft versus-host disease (GVHD), or GVHD requiring immunosuppressive therapy.
• •4. Patients with any of the following:
• •Have prolonged QT (QTc \>450 ms) or take medications that are known to be associated with Torsades de Pointes, or potentially prolonging QT.
• •Long QT syndrome or familiar history of long QT syndrome Persistent significant bradicardia (\<50bpm) Experienced a myocardial infarction within 12 months of registration
• •5. Require concurrent treatment with immunosuppressive agents, other than corticosteroids prescribed for a short course of therapy.
• •6. Have previously been treated with Ruxolitinib.
• •7. Patients with CML CP are excluded if they are in MCyR.
• •8. Patients with CML AP, CML BP, or Ph+ ALL are excluded if they are in MCyR.
• •9. Have active central nervous system (CNS) disease as evidenced by cytology or pathology. History itself of CNS involvement is not exclusionary if CNS has been cleared with a documented negative lumbar puncture. In the absence of clinical CNS disease, lumbar puncture is not required.
• •10. Have significant or active cardiovascular disease or significant bleeding disorder unrelated to CML or Ph+ ALL.
• •11. Have a history of pancreatitis or alcohol abuse.
• •12. Have uncontrolled hypertriglyceridemia (triglycerides \>450 mg/dL).
• •13. Have malabsorption syndrome or other gastrointestinal illness that could affect the absorption of the study drug.
• •14. Patients with inadequate bone marrow reserve within 2 weeks prior to start study drug as demonstrated by:
• •* Absolute neutrophil count (ANC) that is ≤ 1000/µL.
• •* Platelet count that is \< 125,000/µL without the assistance of growth factors, thrombopoietic factors or platelet transfusions.
• •15. Patients with any history of platelet counts \< 50,000/µL or ANC \< 500/µL except during treatment for a myeloproliferative disorder or treatment with cytotoxic therapy for any other reason.
• •16. Patients with coagulation parameters (PT, PTT, INR) ≥ 1.5 ULN within 2 weeks prior to starting study drug.
• •17. Developed the T315I, T315A Y253H, E255K/V or F359C/V mutation after any TKI therapy.
• •18. Patients with HLA matched donor and eligible for allogeneic transplantation for CML treatment.
• •19. Patient being treated concurrently with any of the following prohibited medications:
• •* JAK inhibitor
• •* Any investigational medication other than the study drugs. Use of such medications within 14 days or 6 half-lives, whichever is longer, prior to the first dose of study drug is prohibited
• •* Potent inducers and inhibitors of CYP3A4• Use of HU, interferon, thalidomide, busulfan, lenalidomide, anagrelide, is not permitted at any time beginning 28 days prior to the first Baseline assessment.
• •* Hematopoietic growth factor receptor agonists (eg, erythropoietin (Epo), granulocyte colony stimulating factor (GCSF), romiplostim, eltrombopag) must not be used as they may be associated with spleen size increases. Growth factors must not have been used for at least one month prior to receiving the first dose of study drug.