Clinical Trial Details
— Status: Active, not recruiting
Administrative data
| NCT number |
NCT03734198 |
| Other study ID # |
IDA53-FILOCLL09 |
| Secondary ID |
|
| Status |
Active, not recruiting |
| Phase |
Phase 2
|
| First received |
|
| Last updated |
|
| Start date |
December 19, 2018 |
| Est. completion date |
June 2026 |
Study information
| Verified date |
June 2022 |
| Source |
French Innovative Leukemia Organisation |
| Contact |
n/a |
| Is FDA regulated |
No |
| Health authority |
|
| Study type |
Interventional
|
Clinical Trial Summary
Ibrutinib, a first-in-class Bruton Tyrosine kinase (BTK) inhibitor, has become an established
treatment in relapsed/refractory chronic lymphocytic leukemia (CLL). However, despite a
considerable improvement of Progression Free Survival (PFS) and Overall Survival (OS) in
comparison with historical controls, the prognosis of patients with 17p deletion (del17p)
remains a concern, as it is clearly much less favourable than that of patient without del17p.
Again, TP53 mutations correlated to poorer prognostic in Relapsed/Refractory (R/R) CLL
patients treated with ibrutinib (Brown JR et al,2018). Despite these therapeutic advances,
the treatment of CLL with TP53 disruption thus remains a difficult issue that warrants
evaluation of alternative treatment strategies, in particular the use of ibrutinib in
combination with other agents. A body of evidence suggests that targeting the extracellular
molecule CD38 might be an interesting option. CD38 is a transmembrane glycoprotein with
multiple receptor and enzymatic functions. The interaction of CD38 with its ligand CD31 (also
known as Platelet Endothelial Cell Adhesion Molecule (PECAM-1)) not only plays a role in the
binding and the migration of leucocytes through the endothelial cells wall but also triggers
the activation of intracellular pathways involved in the differentiation and activation of B
cells. Previous results strongly suggest that CD38 favours the expansion of CLL clones not
only directly by transducing a proliferation signal but also by directing them to anatomic
sites where they find favourable conditions for proliferation and survival.
Daratumumab is a first-in-class human IgG1ĸ monoclonal antibody (mAb) that binds
CD38-expressing malignant cells with high affinity. Daratumumab induces tumor cell death
through multiple mechanisms such as antibody-dependent cell-mediated cytotoxicity (ADCC),
complement dependent cytotoxicity (CDC), antibody-dependent cellular phagocytosis (ADCP) and
induction of apoptosis (de Weers et al, 2011). Recent data show that daratumumab may also
display an immunomodulatory effect through depletion of a subset of immunosuppressive CD38+
Tregs (Krejcik et al, 2016). Early-stage clinical trials found daratumumab to be safe and to
display encouraging clinical activity as a single agent in relapsed/refractory multiple
myeloma (MM) patients (Lockhorst et al 2016, Lonial et al, 2016). Overall response rate was
31%, with rapid (median 1 month) and durable responses in this heavily pretreated MM
population. Interestingly, no patient discontinued the treatment because of drug-related
adverse events. These results led to approval of daratumumab in relapsed/refractory MM in
December 2015. The clinical efficacy of daratumumab along with its very favourable safety
profile supports its investigation in other lymphoproliferative malignancies. In particular,
the expression of CD38 in poor prognosis CLL and the key role of CD38 in CLL biology provide
a basis for examining the potential of daratumumab in this disease.
In preclinical studies, (Matas-Céspedes et al, 2016; Manna et al, 2017) Daratumumab
efficiently kills CLL cell lines and patient-derived CLL cells by ADCC and ADCP in vitro.
Daratumumab modulates CLL-T reg levels and increase cytotoxic effector T cells.
Rationale for combining ibrutinib with daratumumab:
These data suggest that combining ibrutinib with daratumumab might have a synergistic or
additive effect. Both drugs inhibit B cell receptor (BCR) signalling via two different
converging pathways, i.e. BTK and CD38/ZAP70/ERK (Deaglio et al, 2007). In vitro, Manna et al
have shown that daratumumab is able to modulate BCR signaling.
Interestingly, the ibrutinib /daratumumab combination significantly enhanced
mitochondrial-mediated apoptosis bth in CD38 high and CD38 low CLL cells (Manna et al, 2017).
Altogether, this provides a rationale for evaluating the safety and efficacy of the
association of daratumumab with ibrutinib in high-risk relapsed/refractory patients for whom
the standard-of-care using ibrutinib as a single agent has demonstrated limitations in terms
of long-term disease control.
Primary objective of the study: to determine the efficacy of a treatment combining
daratumumab and ibrutinib in a poor risk population of relapsed CLL patients with TP53
dysfunction.
Secondary objectives of the study : to determine the safety profile of daratumumab in
combination with ibrutinib in CLL patients.
Inclusion period: 24 months Treatment duration (ibrutinib + daratumumab): continuous, until
disease progression or unacceptable toxicity.
Follow-up period: will begin once the subject discontinues study treatment, during 2 years.
Description:
This study will take place in several periods and phases of treatment:
- Observational period of selection of 28 days maximum
- Treatment period constituted:
- a first phase of treatment with ibrutinib alone (28 days): pre-phase,
- a formal protocol phase during which the two study drugs (ibrutinib and
daratumumab) will be used together until progression of the disease or intolerance
to treatment.
- 2-year follow-up period that will begin after protocol processing has been stopped.
Selection period (before starting treatment): exams performing to verify patients'
eligibility.
- Collection of the medical history,
- Clinical examination with measurement of height and weight, vital signs (temperature,
pulse / heart rate, blood pressure),
- Conventional blood tests to check all the functions of the body such as kidney, liver,
etc
- Viral serologies (Human Immunodeficiency Virus (HIV) and hepatitis B and C) (10 ml).
- Blood Pregnancy Test for women who may have children,
- Specific blood tests to evaluate the disease and in particular to characterize the cells
of LLC (mutational profile, search for chromosomal abnormalities and analysis of
residual disease rate to have a reference point before the start of treatment will be
made on leukemic cells),
- CT scan (thorax, abdomen and pelvis) to accurately search for and evaluate a deep tumor
syndrome (lymph nodes, spleen in particular),
- Urine examination,
- Cardiological examination with an electrocardiogram (ECG)..
Treatment period: the treatment period is divided into successive cycles of 28 days.
Before starting ibrutinib and before each daratumumab cycle, a complete clinical examination
and blood work will be performed.
After 12 months of treatment, an evaluation report will be made with a complete clinical
examination, a complete blood test, an urinalysis if necessary, a Computed Tomography (CT)
scan, a myelogram and if necessary a marrow biopsy. Regularly after this assessment (every 6
months until the end of the study), a report will be made with clinical examination, complete
blood test, ECG, CT scan and if necessary, myelogram possibly associated with a marrow biopsy
if justified and not previously carried out.
After the end of the protocol treatment (progression of the disease, intolerance of the
protocol treatment), a last evaluation will be carried out within 30 days after the last
taking of the protocol treatment. This evaluation includes a complete clinical examination,
biological tests (complete blood test) and a CT scan.
Follow-up period the completed treatment you will then be followed in consultation every 6
months for 2 years to evaluate the duration of the response to treatment and thus meet the
objectives of the study.
