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

This study is currently recruiting participants. (see Contacts and Locations)
Verified June 2014 by H. Lee Moffitt Cancer Center and Research Institute
Sponsor:
Collaborator:
Incyte Corporation
Information provided by (Responsible Party):
H. Lee Moffitt Cancer Center and Research Institute
ClinicalTrials.gov Identifier:
NCT01776723
First received: January 24, 2013
Last updated: June 11, 2014
Last verified: June 2014
  Purpose

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.


Condition Intervention Phase
Myelomonocytic Leukemia
Drug: Ruxolitinib
Phase 1
Phase 2

Study Type: Interventional
Study Design: Allocation: Non-Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
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

Resource links provided by NLM:


Further study details as provided by H. Lee Moffitt Cancer Center and Research Institute:

Primary Outcome Measures:
  • The maximum tolerated dose (MTD) of ruxolitinib for the treatment of Myelomonocytic Leukemia (CMML) [ Time Frame: 17 weeks ] [ Designated as safety issue: Yes ]
    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 ] [ Designated as safety issue: No ]
    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.


Secondary Outcome Measures:
  • Time to AML Transformation [ Time Frame: 2 years ] [ Designated as safety issue: No ]
    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 ] [ Designated as safety issue: No ]
    Phase II - To determine the median overall survival. Off study data on AML transformation and overall survival will be updated every 6 month or until death, whichever occurs first.

  • Duration of Response in Months [ Time Frame: 2 years ] [ Designated as safety issue: No ]
    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.


Estimated Enrollment: 53
Study Start Date: February 2013
Estimated Study Completion Date: September 2017
Estimated Primary Completion Date: September 2017 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: I: Dose Escalation - Ruxolitinib
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
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.
Other Names:
  • Jakafi®
  • INCB-018424
  • Kinase Inhibitor
Experimental: II: Maximum Tolerated Dose - Ruxolitinib
Phase II: Treatment at Maximum Tolerated Dose (MTD).
Drug: Ruxolitinib
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.
Other Names:
  • Jakafi®
  • INCB-018424
  • Kinase Inhibitor

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

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
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 cells/uL
  • Estimated creatinine clearance of <60 mL/min
  • 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.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01776723

Locations
United States, Florida
H. Lee Moffitt Cancer Center and Research Institute Recruiting
Tampa, Florida, United States, 33612
Contact: Nancy Hillgruber    813-745-2071    nancy.hillgruber@moffitt.org   
Sub-Investigator: Rami Komrokji, M.D.         
Sub-Investigator: Jeffrey Lancet, M.D.         
Sub-Investigator: Alan List, M.D.         
Sub-Investigator: Bijal Shah, M.D.         
Principal Investigator: Eric Padron, M.D.         
Sub-Investigator: Pearlie Burnette, Pharm.D., Ph.D.         
United States, Ohio
Cleveland Clinic Recruiting
Cleveland, Ohio, United States, 44106
Contact: Cassie Zimmerman    216-636-5646    zimmerc@ccf.org   
Principal Investigator: Mikkael Sekeres, M.D.         
Sponsors and Collaborators
H. Lee Moffitt Cancer Center and Research Institute
Incyte Corporation
Investigators
Principal Investigator: Eric Padron, M.D. H. Lee Moffitt Cancer Center and Research Institute
  More Information

Additional Information:
No publications provided

Responsible Party: H. Lee Moffitt Cancer Center and Research Institute
ClinicalTrials.gov Identifier: NCT01776723     History of Changes
Other Study ID Numbers: MCC-17259
Study First Received: January 24, 2013
Last Updated: June 11, 2014
Health Authority: United States: Food and Drug Administration

Keywords provided by H. Lee Moffitt Cancer Center and Research Institute:
Chronic Myelomonocytic Leukemia
CMML
Leukemia

Additional relevant MeSH terms:
Leukemia
Leukemia, Myelomonocytic, Chronic
Leukemia, Myelomonocytic, Acute
Neoplasms by Histologic Type
Neoplasms
Leukemia, Myeloid
Myelodysplastic-Myeloproliferative Diseases
Bone Marrow Diseases
Hematologic Diseases

ClinicalTrials.gov processed this record on August 21, 2014