Description:
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.
Title
- 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
Clinical Trial IDs
- ORG STUDY ID:
HAL 306/2018
- NCT ID:
NCT03755947
Conditions
- B-Cell Chronic Lymphocytic Leukemia
- B-Cell Chronic Lymphocytic Leukemia in Relapse (Diagnosis)
Interventions
| Drug | Synonyms | Arms |
|---|
| Ibrutinib | Imbruvica | IGV |
| Obinutuzumab | Gazyva | IGV |
| Venetoclax | Venclexta | IGV |
Purpose
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.
Trial Arms
| Name | Type | Description | Interventions |
|---|
| IGV | Experimental | Cytoreduction 3 cycles (I) Ibrutinib, [Imbruvica, Janssen]
Induction 6 cycles (G) Obinutuzumab, [Gazyva, Roche]
Consolidation 12 cycles (V) Venetoclax, [Venclexta, Abbvie]. | - Ibrutinib
- Obinutuzumab
- Venetoclax
|
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.
| Maximum Eligible Age: | N/A |
| Minimum Eligible Age: | 18 Years |
| Eligible Gender: | All |
| Healthy Volunteers: | No |
Primary Outcome Measures
| Measure: | Best response obtained |
| Time Frame: | Two months after finishing the triple sequencing therapy |
| Safety Issue: | |
| 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. |
Secondary Outcome Measures
| Measure: | Overall Survival |
| Time Frame: | Three years |
| Safety Issue: | |
| 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 |
| Measure: | Relapse-Free Survival |
| Time Frame: | Three years |
| Safety Issue: | |
| 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 |
| Measure: | Rate of AcuteToxicity |
| Time Frame: | Two years |
| Safety Issue: | |
| Description: | Adverse effects associated to triple sequencing therapy with Ibrutinib, Obinutuzumab and Venetoclax |
| Measure: | Rate of Late Toxicity |
| Time Frame: | Three years |
| Safety Issue: | |
| Description: | Adverse effects associated to triple sequencing therapy with Ibrutinib, Obinutuzumab and Venetoclax on long term follow up. |
Details
| Phase: | Phase 2 |
| Primary Purpose: | Interventional |
| Overall Status: | Completed |
| Lead Sponsor: | Grupo Cooperativo de Hemopatías Malignas |
Last Updated
February 2, 2021
