Clinical Trial Details
— Status: Not yet recruiting
Administrative data
NCT number |
NCT05360758 |
Other study ID # |
GATLA 11-LLC-21 |
Secondary ID |
|
Status |
Not yet recruiting |
Phase |
|
First received |
|
Last updated |
|
Start date |
June 1, 2023 |
Est. completion date |
December 1, 2025 |
Study information
Verified date |
December 2022 |
Source |
Grupo Argentino de Tratamiento de la Leucemia Aguda |
Contact |
Astrid Pavlovsky, Dr. |
Phone |
5491150613683 |
Email |
astridp[@]intramed.net |
Is FDA regulated |
No |
Health authority |
|
Study type |
Observational [Patient Registry]
|
Clinical Trial Summary
As everyone knows in clinical practice, Ibrutinib dose reduction in patients with CLL with
good response does not alter disease-free survival (DFS) or increase the risk of
transformation.
Supported by the evidence of retrospective studies that have shown parity in DFS and OS
between a group with standard treatment and another in which the dose of ibrutinib was
reduced and others in which no significant differences were observed in the saturation point
of the BTK receptor with good clinical response, even comparing plasma and intracellular
pharmacokinetics and BTK occupancy together with the pharmacodynamic response, we propose to
carry out a prospective response-adapted study with the aim of potentially reducing the rate
of adverse events and improving the cost/benefit ratio of this therapy. Evaluating the
efficacy and safety of Ibrutinib dose appropriate to the response in patients diagnosed with
CLL.
Description:
Chronic lymphatic leukemia is the most common form of leukemia in adults, most often arising
from a malignant clone of B cells with a characteristic phenotype. It is far from uniform in
presentation and clinical course. About a third of patients never require treatment and have
a long survival; in another third, an initial indolent phase is followed by disease
progression; the remaining third of patients have aggressive disease at onset and require
immediate treatment.
The development of the Rai and Binet staging systems has allowed the division of patients
with chronic lymphocytic leukemia into three prognostic groups: good, intermediate and poor
prognosis.
The two staging systems have improved the identification of patients who need immediate
treatment.
In recent years, a variety of new kinase inhibitors have been designed that target various
components of the BCR signaling pathway. Targets primarily include phosphatidylinositol
3'kinase (PI3K) and Bruton's tyrosine kinase (BTK). All of these new drugs share a response
pattern that results in nodal reduction and increased lymphocytosis, reflecting modulation of
the microenvironment, which could prevent these cells from receiving survival signals emitted
by the microenvironment. More importantly, these drugs appear to be able to bypass p53
deletion, raising the possibility that they may target existing proliferative pools in the
bone marrow and lymph nodes, thus bringing therapy closer to curing p53. disease.
The treatment of chronic lymphatic leukemia (CLL) represents the paradigm of advances in the
therapy of hematological neoplasms. In its beginnings, CLL therapy used monodrugs that
gradually led to their combination in duplets and triplets with which results never before
obtained were achieved. The development of Ibrutinib was probably the milestone that marked
the importance of the signaling pathways of leukemic cells in the progression of the disease,
opening the investigation of new target drugs that constitute the basis of current treatment
in CLL.
The treatment paradigm changes with the approval of BTK (Bruton tyrosine kinase) (iBTK)
inhibitors in patients with del17p and/or TP53 (MTP53) mutations, which have achieved overall
survival results that have never been achieved before. Quickly after the randomized study of
the first-generation iBKT Ibrutinib (I) vs Cl (Resonate 2), this iBTK achieved approval for
first-line treatment in all patients. Shortly thereafter, the second generation iBTK
acalabrutinib (A) is approved. In June 2020, the National Cancer Center Net (NCCN) guidelines
place these agents as preferred in the initial treatment of CLL and make them the agents of
choice among North American experts.
According to the study by Mato based on 197 patients, parity in DFS and OS between one group
and another has been shown when the ibrutinib dose is reduced. In more than half of the
cases, the dose reduction was by medical decision even in the absence of adverse effects.
No significant differences in the saturation point of the BTK receptor with good clinical
response with reduced dose are observed in a pharmacokinetic and pharmacodynamic study
carried out by Advani et al.
Chen et al carried out a pilot study on 11 patients reducing the dose in 3 phases starting
with the standard, a second phase with 280mg/day and a third at 140mg/day, comparing
plasmatic and intracellular pharmacokinetics and the occupation of BTK together with the
response pharmacodynamics, showing that the lowest dose was sufficient to occupy >95% of the
BTK receptor and inhibit the downstream BTK signal.
Despite the improvements in outcomes for patients with poor-prognosis Chronic Lymphocytic
Leukemia seen with ibrutinib, these patients are rarely cured. To further improve the results
obtained, reduce the toxicity generated from prolonged treatment and reduce the costs of
therapy, this protocol is proposed based on a dose adapted to the response to personalized
treatment in each patient who meets the initial criteria. of treatment.
This is a prospective, open-label, multicenter, uncontrolled phase II study to evaluate the
response to reduced doses of ibrutinib after achieving complete hematologic response or
persistent partial response (for 3 or more months), in patients diagnosed with CLL with
criteria treatment, first line or relapsed / refractory.
The study design consists of 2 phases:
PHASE I: Treatment with Ibrutinib 420mg/day (3 capsules). Laboratory controls, physical
examination with cardiological evaluation will be performed every 14 days during the first 3
months, then every 3 months.
PHASE II: Upon achieving complete hematologic or sustained partial remission for more than 3
months, the Ibrutinib dose is reduced to 280 mg per day (2 capsules). Controls will be
carried out every 2 months for 6 months. If complete/partial response is sustained, continue
with checkups every 3 months.
Patients who reach phase II, at 6 months, CFM will be performed in peripheral blood. If MRD
is negative, CFM should be performed on the bone marrow.