Clinical trial NCT01776723: A Sequential Two-Stage Dose Escalation Study to Evaluate the Safety and Efficacy of Ruxolitinib
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 JAK2 Inhibition in Chronic Myelomonocytic Leukemia: A Correlative Study Identifying Targetable CMML Sub-Clones by Leveraging GM-CSF Dependent pSTAT Hypersensitivity
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
PHASE2
Conditions: Myelomonocytic Leukemia
Keywords: Chronic Myelomonocytic Leukemia
CMML
Leukemia
Lead sponsor: H. Lee Moffitt Cancer Center and Research Institute
Sponsor class: OTHER
Collaborators: name: Incyte Corporation
First posted: 2013-01-28
Enrollment: 50
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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 description: 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.

Eligibility criteria: 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.

Primary outcomes:
measure: The Maximum Tolerated Dose (MTD) of Ruxolitinib for the Treatment of Myelomonocytic Leukemia (CMML)
timeFrame: 17 weeks
measure: Occurrence of Clinical Response
timeFrame: Up to 2 years
Secondary outcomes:
measure: Percentage of Participants With Acute Myeloid Leukemia (AML) Transformation
timeFrame: Up to 2 years
measure: Median Overall Survival (OS)
timeFrame: Up to 2 years
measure: Duration of Response in Days
timeFrame: 3.5 years
Other outcomes:
Locations:
city: Tampa
country: United States
facility: H. Lee Moffitt Cancer Center and Research Institute
state: Florida
city: Baltimore
country: United States
facility: Johns Hopkins Sidney Kimmel Comprehensive Cancer Center
state: Maryland
city: Boston
country: United States
facility: Brigham and Women's Hospital
state: Massachusetts
city: Boston
country: United States
facility: Dana-Farber Cancer Institute
state: Massachusetts
city: New York
country: United States
facility: Weill Medical College of Cornell
state: New York
city: Cleveland
country: United States
facility: Cleveland Clinic
state: Ohio
Study officials:
affiliation: H. Lee Moffitt Cancer Center and Research Institute
name: Eric Padron, M.D.
role: PRINCIPAL_INVESTIGATOR
References: