Ruxolitinib in Combination With Nilotinib in Chronic Myeloid Leukemia (CML) Patients

Sponsor

H. Lee Moffitt Cancer Center and Research Institute (Other)

Overall Status

Completed

CT.gov ID

NCT01702064

Collaborator

Incyte Corporation (Industry)

Enrollment

Location

Arm

70.6

Actual Duration (Months)

0.2

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

This study is designed to determine the maximal tolerated dose of Ruxolitinib in combination with nilotinib in patients with chronic myeloid leukemia (CML).

Condition or Disease	Intervention/Treatment	Phase
Chronic Phase Chronic Myeloid Leukemia	Drug: Nilotinib Drug: Ruxolitinib	Phase 1

Study Design

Study Type:

Interventional

Actual Enrollment :

11 participants

Allocation:

N/A

Intervention Model:

Single Group Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

A Phase I Study of Ruxolitinib in Combination With Nilotinib in CML Patients With Evidence of Molecular Disease

Actual Study Start Date :

Feb 21, 2013

Actual Primary Completion Date :

Oct 17, 2016

Actual Study Completion Date :

Jan 9, 2019

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Nilotinib with Ruxolitinib The starting dose of ruxolitinib will be 5mg by mouth (PO) twice a day (BID) and will increase by 5 mg increments in each cohort, to a maximum dose of 15 mg PO BID. Nilotinib will be given at a dose ranging from 300 mg PO BID to 400 mg PO BID, depending on the participant's dose prior to enrollment on the trial. Dose Level 1: Ruxolitinib 5 mg twice a day (BID); Nilotinib 300 mg or 400 mg BID. Dose Level 2: Ruxolitinib 10 mg BID; Nilotinib 300 mg or 400 mg BID. Dose Level 3: Ruxolitinib 15 mg BID; Nilotinib 300 mg or 400 mg BID.	Drug: Nilotinib Participants will remain on the same dose of nilotinib they have been receiving prior to enrollment on the trial. This will range from 300 mg PO BID to 400 mg PO BID. Dose modifications will not occur, as the purpose of this study is to determine the maximum tolerated dose of ruxolitinib, based on the number of dose. Other Names: Tasigna BCR-ABL kinase inhibitor Drug: Ruxolitinib 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, based on the number of dose limiting toxicities seen at a specific dose. Other Names: INCB018424

Arm

Intervention/Treatment

Experimental: Nilotinib with Ruxolitinib

The starting dose of ruxolitinib will be 5mg by mouth (PO) twice a day (BID) and will increase by 5 mg increments in each cohort, to a maximum dose of 15 mg PO BID. Nilotinib will be given at a dose ranging from 300 mg PO BID to 400 mg PO BID, depending on the participant's dose prior to enrollment on the trial. Dose Level 1: Ruxolitinib 5 mg twice a day (BID); Nilotinib 300 mg or 400 mg BID. Dose Level 2: Ruxolitinib 10 mg BID; Nilotinib 300 mg or 400 mg BID. Dose Level 3: Ruxolitinib 15 mg BID; Nilotinib 300 mg or 400 mg BID.

Drug: Nilotinib

Participants will remain on the same dose of nilotinib they have been receiving prior to enrollment on the trial. This will range from 300 mg PO BID to 400 mg PO BID. Dose modifications will not occur, as the purpose of this study is to determine the maximum tolerated dose of ruxolitinib, based on the number of dose.

Other Names:

Tasigna

BCR-ABL kinase inhibitor

Drug: Ruxolitinib

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, based on the number of dose limiting toxicities seen at a specific dose.

Other Names:

INCB018424

Outcome Measures

Primary Outcome Measures

Phase I: Maximum Tolerated Dose (MTD) [Average of 6 months]
Maximum tolerated dose (MTD) of ruxolitinib with nilotinib. Dose escalation will follow a 3+3 study design. If 2 or more participants within a cohort experience a dose limiting toxicity (DLT), then the MTD will have been exceeded and the preceding dose level will be evaluated as the MTD. A minimum of 6 participants must be evaluated at the dose level in order for it to be declared as the MTD. Dose limiting toxicity is defined as: Any non-hematological toxicity ≥ grade three, excluding any untreated nausea, vomiting, diarrhea or fatigue that occurs during the first 56 days of therapy. Grade three thrombocytopenia with active bleeding or grade four thrombocytopenia or febrile neutropenia (ANC <500 cells/µL and fever > 101.0 F (38.5C)). Any treatment related grade five toxicity (i.e., death).

Other Outcome Measures

Complete Molecular Response Rate [Up to 36 months]
Complete molecular response rate (CMR >4.5 log reduction) after the treatment combination.

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

Must have chronic phase chronic myeloid leukemia (CML). They must also be under treatment with nilotinib as either first, second, or third-line therapy.
Must have a complete cytogenetic response (CCyR) OR must have been on nilotinib for a minimum of 6 months.
Must not have undergone treatment for any other form of cancer (aside from non-melanoma skin cancer) in the past 5 years.
18 years of age or older and must be able to speak and read English or Spanish.
Able to provide informed consent.
Prior therapy with a tyrosine kinase inhibitor (TKI) other than nilotinib is allowable, however, nilotinib must be the current therapy. All participants must be under the care of a Moffitt Cancer Center physician, and enrollment is expected to be complete within 6 months.
Eastern Cooperative Oncology Group (ECOG) performance status ≤2 (Karnofsky ≥60%.
Must have normal organ and marrow function as defined in study protocol.
Women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation. Should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately. Men treated or enrolled on this protocol must also agree to use adequate contraception prior to the study, for the duration of study participation, and 4 months after completion of Ruxolitinib and nilotinib administration. Women of child-bearing age will be required to have a negative pregnancy test within 14 days of enrolling in this study.
Ability to understand and the willingness to sign a written informed consent document
B-HCG will be performed on all women of child-bearing potential as screening prior to enrollment on this trial. STAT3 levels in the bone marrow will also be measured prior to enrollment.

Exclusion Criteria:

Patients who are in accelerated phase or blast phase CML.
May not be receiving any other investigational agents.
History of allergic reactions attributed to compounds of similar chemical or biologic composition to ruxolitinib or other agents used in the study.
Known history of a prolonged QT interval (QTc >480).
Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements.
Pregnant women are excluded from this study. Women who are breast feeding their infants should discontinue this practice if the mother is treated with ruxolitinib.
Currently receiving any drugs considered to be strong CYP3A4 inducers or inhibitors which cannot be discontinued or changed to an alternative drug prior to enrolling on the trial.
HIV-positive patients receiving combination anti-retroviral therapy are excluded from the study.
Patients receiving nilotinib 200 mg by mouth, twice a day (PO BID) or a lower dose are not eligible.