A Sequential Two-Stage Dose Escalation Study to Evaluate the Safety and Efficacy of Ruxolitinib

Study Overview
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Brief Summary
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The purpose of this study is to find out if treating Chronic Myelomonocytic Leukemia (CMML) with a study drug [ruxolitinib] can improve outcomes of patients with CMML. The first step of the study is to learn the dose of ruxolitinib that is tolerable (bearable). It has already been studied in a number of patients with different bone marrow diseases and is approved for the treatment of a disease called Myelofibrosis; however, it is not approved for treatment of CMML. It is given orally (by mouth). Most people tolerate it well but the tolerability has not been determined in patients with CMML. We will be testing different doses to determine how much of the medication people can tolerate (bear) before they develop side effects.

Detailed Description
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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%. Demographic and clinical variables for the study patients will be summarized using descriptive statistics (mean, standard deviation, median, inter-quartile range, range, and frequency counts and percentages). Safety and efficacy data will be analyzed overall as well as separately for each dose cohort when appropriate.

Official Title
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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 Identifying Targetable CMML Sub-Clones by Leveraging GM-CSF Dependent pSTAT Hypersensitivity

Conditions
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Myelomonocytic Leukemia

Intervention / Treatment
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* Drug: Ruxolitinib


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Confirmed diagnosis of CMML using the World Health Organization (WHO) classification Age >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/uL Serum Creatinine >2.0 Serum total bilirubin >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 >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.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: I: Dose Escalation - Ruxolitinib<br>Phase I: Dose Escalation. In Phase I, participants will be allocated to dose levels starting at 10 mg/d (twice a day [BID] dosing) according to the rolling six Phase I design. | Drug: Ruxolitinib<br>* In Phase I, participants will be allocated to twice a day (BID) doses of 10 mg/d up to 40mg/d. The starting dose will be 10 mg/d (5mg BID). Each cohort will include up to 6 subjects. Once MTD is reached, 10 additional participants will be treated during the first stage of Phase II (stage 1) at the MTD.<br>* Other names: Kinase Inhibitor;|
| Experimental: II: Maximum Tolerated Dose - Ruxolitinib<br>Phase II: Treatment at Maximum Tolerated Dose (MTD). | Drug: Ruxolitinib<br>* In Phase I, participants will be allocated to twice a day (BID) doses of 10 mg/d up to 40mg/d. The starting dose will be 10 mg/d (5mg BID). Each cohort will include up to 6 subjects. Once MTD is reached, 10 additional participants will be treated during the first stage of Phase II (stage 1) at the MTD.<br>* Other names: Kinase Inhibitor;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The Maximum Tolerated Dose (MTD) of Ruxolitinib for the Treatment of Myelomonocytic Leukemia (CMML) | Phase I - The MTD is defined as the highest dose where less than 33% of participants experience a drug related predefined dose limited toxicity (DLT). Dose-limiting toxicity (DLT) is defined as any grade 4 hematologic toxicity and any grade 3 or greater non-hematologic toxicity except nausea that is controlled by antiemetic therapy based on the NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4.0. Grade 3 metabolic/electrolyte abnormalities that are not clinically significant, and are adequately controlled within 72 hours are not to be considered a DLT. | 17 weeks | 
| Occurrence of Clinical Response | Phase II - Proportion of participants achieving clinical benefit defined as hematologic improvement, complete remission (CR), partial remission (PR), marrow complete remission (Marrow CR) or stable disease (SD) by the International Working Group (IWG) 2006 criteria. Erythroid Response for pretreatment hemoglobin < 11 g/dl; Platelet response for subjects with a pre-treatment platelet count < 50 x 10^9/L; Neutrophil response with pretreatment absolute neutrophil count (ANC) < 1 x 10^9/L. | Up to 2 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With Acute Myeloid Leukemia (AML) Transformation | Phase II - To determine the time to AML transformation of participants on Ruxolitinib. Acute myeloid leukemia (AML) transformation according to World Health Organization (WHO) criteria. CMML-1: peripheral blood <5% blasts, bone marrow <10% myeloblast. CMML-2: peripheral blood <19 percent blasts persistent monocytosis >1000/ul +/- cytopenias Leukocytosis frequent, bone marrow <19 percent blasts >10% dysplasia in affected lineage, Auer Rods. | Up to 2 years | 
| Median Overall Survival (OS) | Phase II - To determine the median overall survival. | Up to 2 years | 
| Duration of Response in Days | Phase II - To determine the duration of response achieved as in secondary endpoint one. The duration of response is measured from the time measurement criteria are met for major or complete platelet response (which ever is first recorded) until the first date that disease progression defined by the bone marrow response outlined above, progression/relapse following a CR, marrow CR or PR, or progressions/relapse following hematological improvement (HI) as outlined above. | 3.5 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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CMML, Chronic Myelomonocytic Leukemia, Leukemia