A Sequential Two-Stage Dose Escalation Study to Evaluate the Safety and Efficacy of Ruxolitinib for the treatment of Chronic Myelomonocytic Leukemia (CMML) and Cataloging the Molecular Consequences of JAK2 Inhibition in Chronic Myelomonocytic Leukemia: A Correlative Study
Primary Objectives:1. To determine the safety and tolerability of ruxolitinib in CMML subjects at diagnosis or relapse. (phase I)2. To determine overall best response rates as measured by the international working group criteria (2006). (phaseII)Secondary Objectives:1. To determine the time to AML transformation of subjects on Ruxolitinib. 2. To determine the median overallsurvival.3. To determine the duration of response.4. To determine the change in symptom score from baseline to best response.5. To determine the change in spleen length at 16 weeks6. To determine the change in downstream targets of JAK2 on ruxolitinib. 7. To determine if the in vitro activity ofruxolitinib correlates to response rates.8. To determine if a correlation exist between the presence of the known recurrent mutations (JAK2, c-CBL, N-RAS,K-RAS, RUNX-1, TET2, SRSF2, EZH2, ASXL1, and DNMT3a) and response to ruxolitinib.9. To determine non-V617F JAK2 mutations at end of study or progression and their clinical relevance in the contextof ruxolitinib.This is a phase 1/2, two-stage, sequential cohort dose escalation study. In phase 1, subjects will be allocated to BIDdoses of 10 mg/d up to 40mg/d. The starting dose will be 10 mg/d (5mg BID). Each cohort will include up to 6subjects. Once MTD is reached, 10 additional subjects will be treated during the first stage of phase 2 (stage 1) at theMTD. The trial will be terminated if 1 or fewer respond. If the trial goes on to the second stage, a total of 29 patientswill be studied to determine efficacy in phase 2.
Inclusion Criteria: •Confirmed diagnosis of CMML using the World Health Organization (WHO) classification •Age greater than 18 years at the time of obtaining informed consent •Must be able to adhere to the study visit schedule and other protocol requirements •Must be able to provide adequate bone marrow (BM) aspirate and biopsy specimens for histopathological analysis and standard cytogenetic analysis during the screening procedure •An Eastern Cooperative Oncology Group (ECOG) performance status score of 0,1, or 2 •Women of childbearing potential must have a negative pregnancy test at time of screening and baseline visits and agree to use two reliable forms of contraception simultaneously or to practice complete abstinence from heterosexual intercourse 1) for at least 28 days before starting study drug; 2) while participating in the study; and 3) for at least 28 days after discontinuation from the study. •Must understand and voluntarily sign an informed consent form •Must have a life expectancy of greater than 3 months at time of screening Exclusion Criteria: •Platelet count of less than 35,000/uL •Absolute Neutrophil Count (ANC) of less than 250 cells/uL •Estimated creatinine clearance of less than 60 mL/min •Serum total bilirubin greater than 1.5 x upper limit of normal (ULN) •Use of cytotoxic chemotherapeutic agents, or experimental agents (agents that are not commercially available) for the treatment of CMML within 28 days of the first day of study drug treatment •Any serious medical condition or psychiatric illness that will prevent the subject from signing the informed consent form or will place the subject at unacceptable risk if he/she participates in the study •Concurrent use of Granulocyte/macrophage colony stimulating factor (GM-CSF). Granulocyte colony-stimulating factor (G-CSF) could be used for the short-term management of neutropenic infection. Stable doses of erythropoietin stimulating agents that were started greater than 8 weeks from first ruxolitinib dose or corticosteroids that were being administered prior to screening are allowed. •Uncontrolled current 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 because ruxolitinib has not been studied in pregnant subjects. Because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with ruxolitinib, breastfeeding should be discontinued if the mother is treated with ruxolitinib. •Patients who have participated in other interventional (treatment-related) clinical trials within 30 days of enrollment are excluded.
This is a phase 1/2, two-stage, sequential cohort dose escalation study. If dose escalation is completed as planned, no more than 53 subjects are expected to enroll onto this study at a rate of approximately 3 subjects every month. For the Phase 2 study the Simon's optimal two-stage design will be employed to test the null hypothesis that response rate (RR) equals to 10% versus the alternative that RR equals to 30%.Plan to accrue patients through September 2017.
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