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Nilotinib

Tyrosine Kinase Inhibitors

Janus Kinase Inhibitors

Imatinib Mesylate

Protein Kinase Inhibitors

Enzyme Inhibitors

Tyrosine

Nilotinib: Given that recommended dose of Nilotinib for imatinib failed CML patients is 400mg twice daily, Nilotinib dose will remain fixed at 400mg bid throughout the cycles.

Ruxolitinib: In the phase I part of the study, dose escalation will follow a 3+3 study design. Dose modifications will not occur, as the purpose of this study is to determine the maximum tolerated dose. Ruxolitinib will be given at one of 3 fixed dose levels for the duration of their treatment, either 10mg twice daily, 15mg twice daily or 20mg twice daily.

Nilotinib dose will remain fixed at 400mg bid throughout the cycles. BCR-ABL kinase inhibitor

In the phase I part of the study, dose escalation will follow a 3+3 study design at either of 3 fixed dose levels (10 mg bid, 15 mg bid or 20 mg bid).

No intra-patient dose-escalation will occur. JAK inhibitor

Ruxolitinib

Dennis Kim, MD/PhD

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.

The purpose of this study is to find out if multiple tyrosine kinase inhibitor resistant chronic myeloid leukemia (CML) or acute lymphoblastic leukemia (ALL) can be treated with combination approach of Nilotinib with Ruxolitinib which may block alternative pathway besides BCR-ABL kinase inhibition in Ph positive leukemia, esp against JAK2-STAT5 pathway. First step is to define the dose of Ruxolitinib with fixed dose of Nilotinib which had been approved at the dose of 400mg bid for imatinib failed CML.

During phase I part of the study,dose escalations will be decided on the basis of DLTs observed hence the exact sample size could not be predicted with certainty but will range between 9-12 patients. Three patients will be enrolled per dose level. Accordingly 9 patients are expected to be enrolled. If a DLT is observed, 3 more patients will be enrolled at the dose level in which the DLT occurred.

The study will be conducted at multiple sites across Canada and enrollment will be competitive. Once 3 patients are enrolled in a cohort, that dose level will be closed to enrollment until safety assessment of the 3 subjects is performed at the end of cycle 1. This procedure will be performed for each dosing cohort. Patients will be assigned to a dose level based on authorization from the sponsor in collaboration with Ozmosis Research Inc.

For the phase II part of the study, once the RPTD has been established in the phase I portion of this trial, the phase II will begin. The phase II portion will be a two-stage, single arm, unblinded study investigating the potential efficacy of the combination of Ruxolitinib and Nilotinib.

A maximum of 20 patients will be accrued in the phase II portion. Those patients treated in the phase I portion of this trial at the RPTD will be included in the analysis of the Phase II study.

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

A PHASE I/II, MULTI-CENTRE, TRIAL OF RUXOLITINIB THERAPY IN COMBINATION WITH NILOTINIB IN PATIENTS WITH PHILADELPHIA POSITIVE CHRONIC MYELOID LEUKEMIA OR ACUTE LYMPHOBLASTIC LEUKEMIA WHO HAVE FAILED TYROSINE KINASE INHIBITOR THERAPY

Cmax will be measured for the maximum plasma concentration of nilotinib after oral administration.

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).

Major cytogenetic response defined by 35% or less of Philadelphia chromosomes by metaphase cytogenetics in marrow from CML and ALL patients

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.

Major cytogenetic response defined by 35% or less of Philadelphia chromosomes by metaphase cytogenetics in marrow taken at 6 months.

It will be defined by NCI Common Terminology Criteria for Adverse Events (CTCAE)version 4.03 for adverse event reporting.

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.

Novartis

University Health Network, Toronto

Spots Global Cancer Trial Database for blastic phase chronic myeloid leukemia