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Combination of Ibrutinib and As2O3 in the Treatment of CLL

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ClinicalTrials.gov 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
Sponsor:
Collaborator:
Beijing Hospital
Information provided by (Responsible Party):
Peking University People's Hospital

Brief Summary:
The purpose of this study is to determine whether the combination of As2O3 and ibrutinib is synergistic in chronic lymphocytic leukemia

Condition or disease Intervention/treatment Phase
Leukemia, Lymphocytic, Chronic, B-Cell Drug: Ibrutinib combined with As2O3 Drug: ibrutinib Phase 3

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 : Interventional  (Clinical Trial)
Estimated Enrollment : 70 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Combination of Ibrutinib and As2O3 in the Treatment of CLL
Study Start Date : December 2016
Estimated Primary Completion Date : December 2017
Estimated Study Completion Date : December 2018


Arm Intervention/treatment
Experimental: Ibrutinib combined with As2O3
Ibrutinib combined with As2O3
Drug: Ibrutinib combined with As2O3
arsenic trioxide combined with ibrutinib in CLL
Other Name: Ibrutinib combined with arsenic trioxide

Active Comparator: Ibrutinib
Ibrutinib only
Drug: ibrutinib
ibrutinib
Other Name: BTK inhibitor




Primary Outcome Measures :
  1. overall response rate [ Time Frame: 2 years ]


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Ages Eligible for Study:   18 Years to 90 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes
Criteria

Inclusion Criteria:

  • patients fulfilling clinical and immune-phenotypic criteria for CLL

Exclusion Criteria:


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): NCT02757040


Contacts
Contact: Xiao-Hui Zhang, Doctor 861088324677 zhangxh100@sina.com
Contact: Ru Feng, Doctor 861085136381 frbld@sina.com

Sponsors and Collaborators
Peking University People's Hospital
Beijing Hospital
Investigators
Principal Investigator: Xiao-Jun Huang, Doctor Peking University People's Hospital

Responsible Party: Peking University People's Hospital
ClinicalTrials.gov Identifier: NCT02757040     History of Changes
Other Study ID Numbers: ibrutinib combined study
First Posted: April 29, 2016    Key Record Dates
Last Update Posted: April 29, 2016
Last Verified: April 2016
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided

Keywords provided by Peking University People's Hospital:
chronic lymphocytic leukemia
ibrutinib
arsenic trioxide
phosphatidylinositol 3-kinase

Additional relevant MeSH terms:
Leukemia, Lymphoid
Leukemia, Lymphocytic, Chronic, B-Cell
Leukemia
Neoplasms by Histologic Type
Neoplasms
Lymphoproliferative Disorders
Lymphatic Diseases
Immunoproliferative Disorders
Immune System Diseases
Leukemia, B-Cell
Arsenic trioxide
Antineoplastic Agents