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

Study Status: Active, not recruiting
Recruit Status: Active, not recruiting
Study Type: Interventional

Official Title: 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

Brief Summary: 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 Summary:

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.

Current Primary Outcome:

• The Maximum Tolerated Dose (MTD) of Ruxolitinib for the Treatment of Myelomonocytic Leukemia (CMML) [ Time Frame: 17 weeks ]
  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.
• Occurrence of Clinical Response [ Time Frame: Up to 2 years ]
  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.

Original Primary Outcome:

• The Maximum Tolerated Dose (MTD) of Ruxolitinib for the Treatment of Myelomonocytic Leukemia (CMML) [ Time Frame: 17 weeks ]
  Phase I - The MTD is defined as the highest dose where less than 33% of subjects experience a drug related predefined dose limited toxicity (DLT).
• Occurrence of Clinical Response [ Time Frame: 2 years ]
  Phase II - Proportion of subjects 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.

Current Secondary Outcome:

• Time to Acute Myeloid Leukemia (AML) Transformation [ Time Frame: Up to 2 years ]
  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.
• Number of Participants with Overall Survival (OS) [ Time Frame: Up to 2 years ]
  Phase II - To determine the median overall survival. Off study data on AML transformation and overall survival will be updated every 6 months or until death, whichever occurs first.
• Duration of Response in Months [ Time Frame: Up to 2 years ]
  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.

Original Secondary Outcome:

• Time to AML Transformation [ Time Frame: 2 years ]
  Phase II - To determine the time to AML transformation of subjects 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.
• Number of Participants with Overall Survival (OS) [ Time Frame: 2 years ]
  Phase II - To determine the median overall survival. Off study data on AML transformation and overall survival will be updated every 6 months or until death, whichever occurs first.
• Duration of Response in Months [ Time Frame: 2 years ]
  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.

Dates:
Date Received: January 24, 2013
Date Started: February 2013
Date Completion: September 2017
Last Updated: December 9, 2016
Last Verified: September 2016