Back to resultsIbrutinib, Obinutuzumab and Venetoclax for Patients With Chronic Lymphocytic Leukemia
Primary Purpose
B-Cell Chronic Lymphocytic Leukemia, B-Cell Chronic Lymphocytic Leukemia in Relapse (Diagnosis)
Status
Completed
Phase
Phase 2
Locations
Mexico
Study Type
Interventional
Intervention
Ibrutinib
Obinutuzumab
Venetoclax
Sponsored by
About this trial
This is an interventional treatment trial for B-Cell Chronic Lymphocytic Leukemia
Eligibility Criteria
Inclusion Criteria:
- Patients diagnosed with B cell chronic lymphocytic leukemia according to 2017 WHO criteria by immunophenotype/immunohistochemistry with active disease according to the 2018 International Workshop on Chronic Lymphocytic Leukemia (iwCLL) criteria and do not present TP53 mutation and/or del(17)p. (Cohort 1).
- Patients diagnosed with relapsed/refractory chronic lymphocytic leukemia that have previously received at least one line of treatment that does not include the drugs in the study scheme. (Cohort 2).
- Functional stage of 0 - 2 measured by the Eastern Cooperative Oncology Group (ECOG) scale.
- Creatinine depuration ≥ 30 ml/min measured in a 24-hour urine recollection or utilizing the CKD-EPI formula.
- Proper liver function: total bilirubin ≤ 1.5 x upper limit of normal (ULN) or ≤ 3 x ULN in patients with Gilbert syndrome, alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 3.0 x ULN.
- Capacity and willingness to provide a written informed consent.
Exclusion Criteria:
- T cell lymphocytic leukemia diagnosis.
- TP53 mutation and/or del(17)p presence.
- Non-controlled systematic active infection (viral, bacterial and/or fungic).
- Patients with known infection by human immunodeficiency virus (HIV).
- Active infection by hepatitis B (defined as the presence of detectable HBV's DNA, HBe antigen or HBs antigen). Patients with serological evidence of previous vaccination (HBsAg negative, anti-HBs positive antibodies, anti-HBc negative antibodies) are eligible. The patients that are HBsAg negative/ anti-Hbs positive antibodies but anti-HBc positive antibodies are eligible, if the HBV DNA is negative, and the HBV-DNA PCR is realized every 12 months after the last cycle of treatment.
- Active infection by hepatitis C, defined by the ribonucleic acid (RNA) of hepatitis C is detectable in plasma by polymerase chain reaction (PCR).
- Significant cardiovascular diseases such as uncontrolled or symptomatic arrhythmias, congestive heart failure or acute myocardial infarction within 2 months prior to screening, or any class 3 or 4 heart disease according to the functional classification of the NYHA.
- Diagnosis of previous malignancies for 2 years, with exception of patients with basal or squamous cell carcinoma or "in situ" carcinoma of cervix or breast.
- Requiring therapy with inhibitors or potent inducers of CYP3A4 and CYP3A5 inhibitors.
- Anticoagulant therapy with acenocoumarol or warfarin.
- History of cerebrovascular accident or intracranial hemorrhage within 6 months prior to screening.
- History of allergic reaction or severe anaphylaxis to humanized or murine monoclonal antibodies.
- Pregnant or lactating women.
Sites / Locations
- Grupo Cooperativo de Hemopatías Malignas
Arms of the Study
Arm 1
Arm Type
Experimental
Arm Label
IGV
Arm Description
Cytoreduction 3 cycles (I) Ibrutinib, [Imbruvica, Janssen] Induction 6 cycles (G) Obinutuzumab, [Gazyva, Roche] Consolidation 12 cycles (V) Venetoclax, [Venclexta, Abbvie].
Outcomes
Primary Outcome Measures
Best response obtained
The best response obtained will be defined as CR with negative MRD by the iwCLL response criteria measured subsequent a cytoreduction treatment, induction and consolidation with the triple sequencing therapy with Ibrutinib, Obinutuzumab and Venetoclax in patients with chronic lymphocytic leukemia.
Secondary Outcome Measures
Overall Survival
Defined as the time since the end of treatment to time of death in the patients diagnosed with chronic lymphocytic leukemia in treatment with a triple sequencing therapy with Ibrutinib, Obinutuzumab and Venetoclax
Relapse-Free Survival
Defined as the time since the end of treatment to time to relapse in the patients diagnosed with chronic lymphocytic leukemia in treatment with a triple sequencing therapy with Ibrutinib, Obinutuzumab and Venetoclax
Rate of AcuteToxicity
Adverse effects associated to triple sequencing therapy with Ibrutinib, Obinutuzumab and Venetoclax
Rate of Late Toxicity
Adverse effects associated to triple sequencing therapy with Ibrutinib, Obinutuzumab and Venetoclax on long term follow up.
Full Information
NCT ID
NCT03755947
First Posted
November 20, 2018
Last Updated
February 1, 2021
Sponsor
Grupo Cooperativo de Hemopatías Malignas
1. Study Identification
Unique Protocol Identification Number
NCT03755947
Brief Title
Ibrutinib, Obinutuzumab and Venetoclax for Patients With Chronic Lymphocytic Leukemia
Official Title
Sequential Triple Therapy With Ibrutinib, Obinutuzumab and Venetoclax in First and Second Line for Patients With Chronic Lymphocytic Leukemia
Study Type
Interventional
2. Study Status
Record Verification Date
February 2021
Overall Recruitment Status
Completed
Study Start Date
December 1, 2018 (Actual)
Primary Completion Date
December 31, 2020 (Actual)
Study Completion Date
February 1, 2021 (Actual)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Grupo Cooperativo de Hemopatías Malignas
4. Oversight
Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No
5. Study Description
Brief Summary
Background: Chronic Lymphocytic Leukemia (CLL) is the most common leukemia in the occidental countries. Until now, it is considered a chronic disease without a cure. The development of new molecular therapies have showed that the cure may be an option. This protocol propose a triple sequential therapy with three direct therapies for the leukemic cell: an inhibitor of Bruton´s tyrosine kinase (ibrutinib), a second generation monoclonal antibody versus CD20 (obinutuzumab) and a BCL-2 inhibitor (venetoclax) as treatment of first or second line in CLL.
Objective: Negativize the minimal residual disease and by this way obtain longer survivals (overall survival and relapse free survival).
Design: This is a multicenter, longitudinal, experimental, open, non-randomized and non-comparable study coordinated by the "Grupo Cooperativo de Hemopatías Malignas" situated on Hospital Angeles Lomas in Huixquilucan, México. The study, is a phase II clinical study that will employ three target therapy drugs in sequencing phases. It will start with a BTK inhibitor as induction, later an anti-CD20 will be used for consolidation and it will end with a BH3 analog as maintenance for one year. The primary outcome is the negativization of minimal residual disease.
Detailed Description
The international recommendations indicate that the first line of treatment for patients <65 years old and with no significant comorbidities (fit patients) the known regime of FCR with recommendation of category 1 and later bendamustine with antiCD20 or ibrutinib. For patients >65 years old or not fit for intensive treatment it is recommended chlorambucil with obinutuzumab, monotherapy with ibrutinib, bendamustine with antiCD20 or chlorambucil with another antiCD20 like rituximab or ofatumumab. In case of patients with high-risk alterations of relapse due to positive MRD at the end of the treatment it is recommended a maintenance schedule with lenalidomide.
The antibodies against CD20 have shown through the years its activity in diverse alterations of B-cells. Rituximab was approved in 1998 for B-cells Non-Hodgkin lymphomas including CLL. Currently there are new anti-CD20 with more activity than rituximab. One of them is obinutuzumab which, by the monoclonal antibody engineering shows a greater affinity to the union of the epitope CD20 generating increased cellular cytotoxicity.
Bruton's tyrosine kinase (BTK), generates signaling cascades for the cell survival by the NF-KB and MAP kinases way, which leads to the transduction of the B cell receptor (BCR). Ibrutinib is a molecule that inhibits BTK inducing apoptosis in the B cells being currently used in the diverse mature B cell neoplasms.
Another therapeutic target is the BCL-2 protein (B-cell lymphoma 2) which is a key regulator in the apoptotic and it's compromised in the B cell neoplasms. Venetoclax is a mimetic drug to BH3 that blocks the function of BCL-2.
Based in the old and new drugs described in CLL, there is a great number of combinations that can be applied in the different phases of the disease as well as by risk stages and physical state of the patient. Before this scenario diverse CLL study groups proposes the strategy of sequencing in three phases (triple T) trying to prevent the development of leukemic subclones, minimize the use of chemotherapy that generates secondary mutations in CLL and other neoplasms. These type of treatment counts with the advantage of: 1) being available for patients physically fit or not due to the a limited toxicity of the drugs, 2) applying in an out-of-hospital environment and 3) adjusting the treatment according to the response to generate an effective cost in the new drugs. Thus, it is proposed the cytoreduction sequencing for 1 to 2 cycles, induction for 6 to 12 months and the MRD maintenance that could go from one year up to undefined with ibrutinib, obinutuzumab and venetoclax in that order.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
B-Cell Chronic Lymphocytic Leukemia, B-Cell Chronic Lymphocytic Leukemia in Relapse (Diagnosis)
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Single Group Assignment
Model Description
This is a multicenter, longitudinal, experimental, open, non-randomized and non-comparable study
Masking
None (Open Label)
Allocation
N/A
Enrollment
3 (Actual)
8. Arms, Groups, and Interventions
Arm Title
IGV
Arm Type
Experimental
Arm Description
Cytoreduction 3 cycles (I) Ibrutinib, [Imbruvica, Janssen]
Induction 6 cycles (G) Obinutuzumab, [Gazyva, Roche]
Consolidation 12 cycles (V) Venetoclax, [Venclexta, Abbvie].
Intervention Type
Drug
Intervention Name(s)
Ibrutinib
Other Intervention Name(s)
Imbruvica
Intervention Description
Ibrutinib Oral Capsule [Imbruvica] Tablets 120 mg. Oral. 420mg/day, day 1 to 28, every 28 days. 3 cycles.
Intervention Type
Drug
Intervention Name(s)
Obinutuzumab
Other Intervention Name(s)
Gazyva
Intervention Description
Obinutuzumab Injection. Intravenous Solution [Gazyva] Parenteral. 1000 mg, day 1 of every cycle, every 28 days. 6 cycles.
Intervention Type
Drug
Intervention Name(s)
Venetoclax
Other Intervention Name(s)
Venclexta
Intervention Description
Venetoclax Oral Tablets [Venclexta] Tablets 100 mg. Oral. 400 mg/day. Day 1 to 28, every 28 days. 12 cycles.
Primary Outcome Measure Information:
Title
Best response obtained
Description
The best response obtained will be defined as CR with negative MRD by the iwCLL response criteria measured subsequent a cytoreduction treatment, induction and consolidation with the triple sequencing therapy with Ibrutinib, Obinutuzumab and Venetoclax in patients with chronic lymphocytic leukemia.
Time Frame
Two months after finishing the triple sequencing therapy
Secondary Outcome Measure Information:
Title
Overall Survival
Description
Defined as the time since the end of treatment to time of death in the patients diagnosed with chronic lymphocytic leukemia in treatment with a triple sequencing therapy with Ibrutinib, Obinutuzumab and Venetoclax
Time Frame
Three years
Title
Relapse-Free Survival
Description
Defined as the time since the end of treatment to time to relapse in the patients diagnosed with chronic lymphocytic leukemia in treatment with a triple sequencing therapy with Ibrutinib, Obinutuzumab and Venetoclax
Time Frame
Three years
Title
Rate of AcuteToxicity
Description
Adverse effects associated to triple sequencing therapy with Ibrutinib, Obinutuzumab and Venetoclax
Time Frame
Two years
Title
Rate of Late Toxicity
Description
Adverse effects associated to triple sequencing therapy with Ibrutinib, Obinutuzumab and Venetoclax on long term follow up.
Time Frame
Three years
10. Eligibility
Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria:
Patients diagnosed with B cell chronic lymphocytic leukemia according to 2017 WHO criteria by immunophenotype/immunohistochemistry with active disease according to the 2018 International Workshop on Chronic Lymphocytic Leukemia (iwCLL) criteria and do not present TP53 mutation and/or del(17)p. (Cohort 1).
Patients diagnosed with relapsed/refractory chronic lymphocytic leukemia that have previously received at least one line of treatment that does not include the drugs in the study scheme. (Cohort 2).
Functional stage of 0 - 2 measured by the Eastern Cooperative Oncology Group (ECOG) scale.
Creatinine depuration ≥ 30 ml/min measured in a 24-hour urine recollection or utilizing the CKD-EPI formula.
Proper liver function: total bilirubin ≤ 1.5 x upper limit of normal (ULN) or ≤ 3 x ULN in patients with Gilbert syndrome, alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 3.0 x ULN.
Capacity and willingness to provide a written informed consent.
Exclusion Criteria:
T cell lymphocytic leukemia diagnosis.
TP53 mutation and/or del(17)p presence.
Non-controlled systematic active infection (viral, bacterial and/or fungic).
Patients with known infection by human immunodeficiency virus (HIV).
Active infection by hepatitis B (defined as the presence of detectable HBV's DNA, HBe antigen or HBs antigen). Patients with serological evidence of previous vaccination (HBsAg negative, anti-HBs positive antibodies, anti-HBc negative antibodies) are eligible. The patients that are HBsAg negative/ anti-Hbs positive antibodies but anti-HBc positive antibodies are eligible, if the HBV DNA is negative, and the HBV-DNA PCR is realized every 12 months after the last cycle of treatment.
Active infection by hepatitis C, defined by the ribonucleic acid (RNA) of hepatitis C is detectable in plasma by polymerase chain reaction (PCR).
Significant cardiovascular diseases such as uncontrolled or symptomatic arrhythmias, congestive heart failure or acute myocardial infarction within 2 months prior to screening, or any class 3 or 4 heart disease according to the functional classification of the NYHA.
Diagnosis of previous malignancies for 2 years, with exception of patients with basal or squamous cell carcinoma or "in situ" carcinoma of cervix or breast.
Requiring therapy with inhibitors or potent inducers of CYP3A4 and CYP3A5 inhibitors.
Anticoagulant therapy with acenocoumarol or warfarin.
History of cerebrovascular accident or intracranial hemorrhage within 6 months prior to screening.
History of allergic reaction or severe anaphylaxis to humanized or murine monoclonal antibodies.
Pregnant or lactating women.
Facility Information:
Facility Name
Grupo Cooperativo de Hemopatías Malignas
City
Huixquilucan
State/Province
Estado De México
ZIP/Postal Code
52763
Country
Mexico
12. IPD Sharing Statement
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Ibrutinib, Obinutuzumab and Venetoclax for Patients With Chronic Lymphocytic Leukemia
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