Ruxolitinib in the Treatment of Chronic Lymphocytic Leukemia

September 23, 2016 updated by: Sunnybrook Health Sciences Centre

A Phase I/II Trial of Ruxolitinib (Jakafi) in Patients With Chronic Lymphocytic Leukemia Who Are Unfit for Conventional First-line Therapy Due to Age or 17p Deletions

The purpose of this study is to determine if Ruxolitinib, an inhibitor of cytokine-signaling, is effective in the treatment of patients with Chronic Lymphocytic Leukemia for whom conventional chemotherapy is either too toxic or ineffective.

Study Overview

Status

Completed

Conditions

Intervention / Treatment

Detailed Description

Chronic lymphocytic leukemia (CLL) is the commonest leukemia in adults and, until recently, had limited treatment options. However, the combination of fludarabine, cyclophosphamide, and rituximab (FCR) produces impressive clinical responses and prolongs survival of many CLL patients with symptomatic disease. Unfortunately, FCR is a toxic regimen that cannot generally be tolerated by patients over the age of 65 years who constitute more than 70% of the CLL patient population. In addition, FCR is contraindicated in patients whose leukemia cells harbor deletions of chromosome 17, where the tumor suppressor p53 is located, because such cells are intrinsically resistant to genotoxic drugs. This group constitutes 10-15% of patients of all ages who require first-line therapy. Better therapies for these two large groups of patients are needed.

The initiating event in CLL is thought to be genetic damage to a class of B lymphocytes that prevents proper functioning of apoptotic pathways. However, disease progression is driven by signals from the proliferation centers in tumor microenvironments where circulating CLL cells originate. Signals that cause CLL cells to proliferate include antigens that activate B-cell receptors (BCRs), Toll-like receptor ligands, chemokines, and cytokines. CLL cells that respond strongly to these microenvironmental signals exhibit more aggressive clinical behavior and resistance to cytotoxic drugs. These observations have motivated the use of signal transduction inhibitors to treat CLL and initial results of targeting kinases in the BCR-signaling cascade, such as Bruton's Tyrosine Kinase (BTK), suggest this strategy is effective and likely to change the treatment paradigm for CLL.

BCR signaling is not the only driver of CLL proliferation in vivo. Cytokines and chemokines in the tumor microenvironment activate Janus Kinases (JAKs) and mediate many of the pathological features of CLL cells. Cytokine signaling pathways have been shown to be rewired in aggressive tumor cells to support rapid growth and will eventually overcome the effects of inhibiting BCR-signaling. Preclinical findings suggest that JAK inhibitors will also have a place in the treatment of CLL.

Based on this strong theoretical rationale and pre-clinical evidence, along with its known toxicity profile, Ruxolitinib is expected to have significant activity with limited toxicity as a single agent in CLL. This trial is designed to investigate the efficacy and toxicity of Ruxolitinib in patients who are otherwise unfit for first-line therapy with FCR.

Study Type

Interventional

Enrollment (Actual)

13

Phase

  • Phase 2
  • Phase 1

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • Canada
    • Ontario
      • Toronto, Ontario, Canada, M4N3M5
        • Sunnybrook Odette Cancer Center

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

65 years and older (Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

Inclusion Criteria:

  1. Age greater than 65 years unless a 17p deletion is present in more than 20% of circulating tumor cells, in which case age can be younger than 65 years.
  2. Diagnosis of CLL meeting published diagnostic criteria.
  3. CLL requiring treatment on the basis of National Cancer Institute (NCI) working group criteria.
  4. Not previously treated with cytotoxic drugs or antibodies but may have received glucocorticoid monotherapy, local radiation, or splenectomy.
  5. Unfit for full dose FCR chemotherapy.
  6. Platelets >50x10**9/L. Neutrophils>.75x10**9/L.
  7. At least 1 lymph node >1.5 cm or splenomegaly as detected by CT scan.

Exclusion Criteria:

  1. Fit for full-dose FCR as initial treatment.
  2. Progressive multifocal leukoencephalopathy (PML).
  3. Clinically significant bacterial, fungal, parasitic or viral infection, which require therapy.
  4. Richter's transformation or prolymphocytic leukemia.
  5. Uncontrolled autoimmune hemolytic anemia or idiopathic thrombocytopenia purpura.
  6. Prior exposure to chemotherapy for CLL with the exception of glucocorticoids, local radiation, or splenectomy.
  7. History of prior malignancy, with the exception of the following: i. Malignancy treated with curative intent and with no evidence of active disease for more than 2 years. ii. Adequately treated skin cancer. iii. Adequately treated cervical carcinoma in situ.
  8. Currently active clinically significant cardiovascular disease.
  9. History of stroke or intracranial hemorrhage within 6 months prior to enrollment.
  10. Renal failure requiring dialysis and patients with moderate and severe renal impairment with platelet counts less than 100,000/ml.
  11. Hepatic impairment.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: N/A
  • Interventional Model: Single Group Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: Ruxolitinib
Ruxolitinib will be administered over a 28-day cycle, which will be repeated 6 more times in the absence of intolerable toxicity, disease progression, patient withdrawal of consent, or investigator decision to end therapy. The dose and schedule have been adapted from the product monograph for myelofibrosis. The starting dose will be 20 mg orally twice a day with normal .platelet and absolute neutrophil counts and no hepatic and renal impairment.
Drug: Ruxolitinib
20 mg orally on day 1 to 21 of each 28 day cycle. Number of Cycles: 7 or until progression or unacceptable toxicity develops.
Other Names:
  • jakafi

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Time Frame
Clinical response rate
Time Frame: at 7 months
at 7 months

Secondary Outcome Measures

Outcome Measure
Time Frame
number of patients with adverse events
Time Frame: participants will be followed for an average of 8 months
participants will be followed for an average of 8 months

Other Outcome Measures

Outcome Measure
Time Frame
Effects of ruxolitinib on immune and leukemia cell numbers, JAK signaling, and circulating cytokine levels
Time Frame: within 6 months of completing enrollment
within 6 months of completing enrollment

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Sunnybrook Health Sciences Centre

Collaborators

Novartis

Investigators

  • Principal Investigator: David E Spaner, MD, PhD, Sunnybrook Health Sciences Center

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start

April 1, 2014

Primary Completion (Actual)

July 1, 2015

Study Completion (Actual)

July 1, 2015

Study Registration Dates

First Submitted

December 3, 2013

First Submitted That Met QC Criteria

December 12, 2013

First Posted (Estimate)

December 19, 2013

Study Record Updates

Last Update Posted (Estimate)

September 26, 2016

Last Update Submitted That Met QC Criteria

September 23, 2016

Last Verified

September 1, 2016

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • CINC424XCA03T

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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