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Combination of Ibrutinib and As2O3 in the Treatment of CLL

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. Identifier: NCT02757040
Recruitment Status : Unknown
Verified April 2016 by Peking University People's Hospital.
Recruitment status was:  Not yet recruiting
First Posted : April 29, 2016
Last Update Posted : April 29, 2016
Beijing Hospital
Information provided by (Responsible Party):
Peking University People's Hospital

Tracking Information
First Submitted Date  ICMJE April 17, 2016
First Posted Date  ICMJE April 29, 2016
Last Update Posted Date April 29, 2016
Study Start Date  ICMJE December 2016
Estimated Primary Completion Date December 2017   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: April 27, 2016)
overall response rate [ Time Frame: 2 years ]
Original Primary Outcome Measures  ICMJE Same as current
Change History No Changes Posted
Current Secondary Outcome Measures  ICMJE Not Provided
Original Secondary Outcome Measures  ICMJE Not Provided
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
Descriptive Information
Brief Title  ICMJE Combination of Ibrutinib and As2O3 in the Treatment of CLL
Official Title  ICMJE Combination of Ibrutinib and As2O3 in the Treatment of CLL
Brief Summary The purpose of this study is to determine whether the combination of As2O3 and ibrutinib is synergistic in chronic lymphocytic leukemia
Detailed Description

Chronic lymphocytic leukemia (CLL) is a common adult leukemia characterized by the extensive accumulation of monoclonal, relatively mature , positives of cluster of differentiation antigen 5 and cluster of differentiation antigen 23 B lymphocytes in lymphoid organs, bone marrow, and peripheral blood. CLL cells accumulate because of defective apoptosis, which extends survival. CLL is a heterogeneous disease. Chemoimmunotherapy is the standard front-line approach for patients younger than 65 years with CLL, with the combination of fludarabine, cyclophosphamide, and rituximab used most commonly. Some CLL patients do not respond well to routine chemoimmunotherapy. Despite recent advances in the treatment of CLL by use of modern chemoimmunotherapy, the disease remains incurable for most patients with the exception of those who have the option of an allogeneic transplantation. However, treatments with chemoimmunotherapy are associated with significant toxicities and sustained immunosuppression, and the rates of myelosuppression and infection are high. Such complications are more frequent and more severe in patients older than 65 years because of reduced marrow reserve, and presence of comorbidities. Because CLL is a disease of the elderly, identifying effective therapies with better toxicity profiles is thus a high priority, and targeted therapies may allow attainment of this goal.

Ibrutinib is an irreversible inhibitor of Bruton tyrosine kinase (BTK) that binds covalently to the cysteine residue (C481) in the kinase domain. This inhibition has been shown in vitro to induce modest CLL cell apoptosis and to abolish proliferation and B-cell receptor (BCR) signaling. Clinical trial results with this agent have been outstanding, including an estimated 26-month progression-free survival (PFS) of 75% for patients with relapsed and refractory disease. Although PFS with ibrutinib is excellent, the overall response rate for this group of relapsed patients is only 71%, lagging behind the clinical benefit seen in 88% of patients because of lymphocytosis induced by this agent and all agents targeting the BCR pathway.

Nevertheless, the long-term safety for ibrutinib has not been established. Caution must be exercised for the development of resistant clones due to the persistence of the disease, because most patients treated with ibrutinib often have prolonged partial remissions. Moreover, about 2-5% of CLL patients will develop Richter's syndrome or transformation during the disease course and treatment. The rate of serious adverse events in patients who continued treatment for 1 year or longer was 43% in the first year of treatment and 32% after the first year. Within the first year of treatment, 8% patients discontinued therapy, while 6% discontinued therapy after the first year. Besides, considering that genetic mutations cause resistance to ibrutinib in CLL patients and altered signaling pathways are common mechanisms of resistance to single agents. It's expected to combine other agent with ibrutinib to obtain higher response in those CLL patients who have not obtained perfect effect and to relieve the toxicity from treatment of ibrutinib.

However, arsenic trioxide (As2O3) has attracted worldwide interest in the field of oncology because of its substantial anticancer activity in patients with acute promyelocytic leukemia (APL). Interestingly, a number of studies have revealed that As2O3 can induce apoptosis, not only in APL, but also in a wide variety of hematologic malignancies, including CLL, either as monotherapy or combined therapy. Investigators previous study has also suggested that As2O3 could induce CLL cells apoptosis, and could be an efficient therapeutic agent for CLL.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 3
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE Leukemia, Lymphocytic, Chronic, B-Cell
Intervention  ICMJE
  • Drug: Ibrutinib combined with As2O3
    arsenic trioxide combined with ibrutinib in CLL
    Other Name: Ibrutinib combined with arsenic trioxide
  • Drug: ibrutinib
    Other Name: BTK inhibitor
Study Arms  ICMJE
  • Experimental: Ibrutinib combined with As2O3
    Ibrutinib combined with As2O3
    Intervention: Drug: Ibrutinib combined with As2O3
  • Active Comparator: Ibrutinib
    Ibrutinib only
    Intervention: Drug: ibrutinib
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by Identifier (NCT Number) in Medline.
Recruitment Information
Recruitment Status  ICMJE Unknown status
Estimated Enrollment  ICMJE
 (submitted: April 27, 2016)
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE December 2018
Estimated Primary Completion Date December 2017   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  • patients fulfilling clinical and immune-phenotypic criteria for CLL

Exclusion Criteria:

  • none
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years to 90 Years   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE Yes
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Not Provided
Removed Location Countries  
Administrative Information
NCT Number  ICMJE NCT02757040
Other Study ID Numbers  ICMJE ibrutinib combined study
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE
Plan to Share IPD: Undecided
Responsible Party Peking University People's Hospital
Study Sponsor  ICMJE Peking University People's Hospital
Collaborators  ICMJE Beijing Hospital
Investigators  ICMJE
Principal Investigator: Xiao-Jun Huang, Doctor Peking University People's Hospital
PRS Account Peking University People's Hospital
Verification Date April 2016

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP