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Ruxolitinib in the Treatment of Chronic Lymphocytic Leukemia

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT02015208
Recruitment Status : Completed
First Posted : December 19, 2013
Last Update Posted : September 26, 2016
Sponsor:
Collaborator:
Novartis
Information provided by (Responsible Party):
Sunnybrook Health Sciences Centre

Brief Summary:
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.

Condition or disease Intervention/treatment Phase
Chronic Lymphocytic Leukemia Drug: Ruxolitinib Phase 1 Phase 2

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.

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 13 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: 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
Study Start Date : April 2014
Actual Primary Completion Date : July 2015
Actual Study Completion Date : July 2015


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 Name: jakafi




Primary Outcome Measures :
  1. Clinical response rate [ Time Frame: at 7 months ]

Secondary Outcome Measures :
  1. number of patients with adverse events [ Time Frame: participants will be followed for an average of 8 months ]

Other Outcome Measures:
  1. Effects of ruxolitinib on immune and leukemia cell numbers, JAK signaling, and circulating cytokine levels [ Time Frame: within 6 months of completing enrollment ]


Information from the National Library of Medicine

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Ages Eligible for Study:   65 Years and older   (Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02015208


Locations
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Canada, Ontario
Sunnybrook Odette Cancer Center
Toronto, Ontario, Canada, M4N3M5
Sponsors and Collaborators
Sunnybrook Health Sciences Centre
Novartis
Investigators
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Principal Investigator: David E Spaner, MD, PhD Sunnybrook Health Sciences Center
Publications:
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Responsible Party: Sunnybrook Health Sciences Centre
ClinicalTrials.gov Identifier: NCT02015208    
Other Study ID Numbers: CINC424XCA03T
First Posted: December 19, 2013    Key Record Dates
Last Update Posted: September 26, 2016
Last Verified: September 2016
Keywords provided by Sunnybrook Health Sciences Centre:
CLL
cytokine signaling
signal transduction inhibitors
elderly
p53
Additional relevant MeSH terms:
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Leukemia
Leukemia, Lymphoid
Leukemia, Lymphocytic, Chronic, B-Cell
Neoplasms by Histologic Type
Neoplasms
Lymphoproliferative Disorders
Lymphatic Diseases
Immunoproliferative Disorders
Immune System Diseases
Leukemia, B-Cell