This is the study to test combination regimen of Nilotinib and Ruxolitinib therapy for the treatment of patients with Philadelphia positive chronic myeloid leukemia (CML) or acute lymphoblastic leukemia (ALL) who is resistant to multiple tyrosine kinase inhibitor therapies with BCR-ABL kinase inhibition activity. Ruxolitinib is a tyrosine kinase inhibitor blocking alternative pathway independent of BCR-ABL mediated pathway, thus having a potential to overcome tyrosine kinase inhibitor resistance in Philadelphia positive CML or ALL patients. Phase I study will be conducted to define a recommended phase II dose (RPTD) and phase II study will examine the hypothesis that combinational approach will increase response rate of resistant CML/ALL patients, thus evaluating efficacy of the combination regimen.
Name: Nilotinib
Name: Ruxolitinib
Description: Maximum Tolerated Dose (MTD) of Ruxolitinib with fixed dose of Nilotinib. Dose escalation will follow a 3+3 study design. The CTCAE v4.03 criteria will be used. Grade 4 toxicity will be accounted as dose limiting toxicity (DLT).
Measure: Phase I: Maximum Tolerated Dose (MTD) Time: Average of 6 monthsDescription: Major cytogenetic response defined by 35% or less of Philadelphia chromosomes by metaphase cytogenetics in marrow from CML and ALL patients
Measure: Phase II: Major cytogenetic response Time: Average of 6 monthsDescription: Complete hematologic response defined by CBC differential without any evidence of leukemia. It will be evaluated in CML patients in AP or BP, and patients with Ph+ ALL.
Measure: Phase I: complete hematologic response Time: Average of 3 monthsDescription: Major cytogenetic response defined by 35% or less of Philadelphia chromosomes by metaphase cytogenetics in marrow taken at 6 months.
Measure: Phase I: major cytogenetic response Time: Average of 6 monthsDescription: It will be defined by NCI Common Terminology Criteria for Adverse Events (CTCAE)version 4.03 for adverse event reporting.
Measure: Phase I: Safety and tolerability Time: Average of 6 monthsDescription: Complete hematologic response defined by CBC differential without any evidence of leukemia. It will be evaluated in the CML patients in AP or BP and in patients with Ph+ ALL.
Measure: Phase II: complete hematologic response Time: Average of 3 monthsDescription: Cmax will be measured for the maximum plasma concentration of nilotinib after oral administration.
Measure: Phase II (exploratory): pharmacokinetic profile of combination of Nilotinib with Ruxolitinib Time: During first 24 hours of first doseAllocation: N/A
Single Group Assignment
There are 5 SNPs
Developed the T315I, T315A Y253H, E255K/V or F359C/V mutation after any TKI therapy. --- T315I --- --- T315A --- --- Y253H --- --- E255K ---
Developed the T315I, T315A Y253H, E255K/V or F359C/V mutation after any TKI therapy. --- T315I --- --- T315A --- --- Y253H --- --- E255K --- --- F359C ---
Developed the T315I, T315A Y253H, E255K/V or F359C/V mutation after any TKI therapy. --- T315I --- --- T315A ---
Developed the T315I, T315A Y253H, E255K/V or F359C/V mutation after any TKI therapy. --- T315I ---
Developed the T315I, T315A Y253H, E255K/V or F359C/V mutation after any TKI therapy. --- T315I --- --- T315A --- --- Y253H ---