Identification of Biomarkers That Are Predictive of Early Ibrutinib Treatment Failure in High Risk TP53 Mutated Chronic Lymphocytic Leukemia

Chronic Lymphocytic Leukemia Clinical Trial

Official title:

Prospective, Observational, Multi-centred, Non-interventional Study on the Identification of Biomarkers That Are Predictive of Early Ibrutinib Treatment Failure in High Risk TP53 Mutated Chronic Lymphocytic Leukemia

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT02827617
• Other study ID #: IOSI-EMA-001
• Status: Active, not recruiting
• Start date: June 1, 2016
• Est. completion date: December 31, 2024

Study information

• Verified date: April 2024
• Source: Oncology Institute of Southern Switzerland
• Contact: n/a
• Is FDA regulated: No
• Study type: Observational

Clinical Trial Summary

The general aim of the project is the identification of dynamic molecular markers that can help the early and real time prediction of sustained benefit or no benefit from ibrutinib treatment in CLL harboring TP53 mutations. Specific aims of the project include: 1) Assess whether clearance of TP53 mutated clones translates into a predictive biomarker of long term benefit from ibrutinib treatment in CLL. 2) Assess whether plasma cell free DNA represents a sensitive tool that can early and dynamically inform on the development of ibrutinib resistant mutations in CLL.

Description:

In the chemoimmunotherapy era, TP53 mutations defined a subgroup of high risk chronic lymphocytic leukemia (CLL) patients in whom allogeneic stem cell transplantation had to be strongly considered. As a result of the accumulating favorable outcome data reported for new biological drugs, including ibrutinib, in high risk CLL harboring TP53 mutations, there is concern about whether these patients should continue to be offered allogeneic stem cell transplantation. Despite their improved outcome, a proportion of high risk CLL harboring TP53 mutations is going to develop ibrutinib resistance, which in turns translate in a very poor survival. On these bases, in the setting of ibrutinib treatment, novel biomarkers are required to re-define high risk CLL patients candidate for consolidation strategies including allogeneic stem cell transplantation. Our working hypotheses are that: i) clearance of high risk TP53 mutated clones upon treatment with ibrutinib may associate with long progression free survival (PFS), while conversely, the persistence or increase of high risk TP53 mutated subclones under ibrutinib may associate with acquisition of resistance and disease progression; and ii) plasma cell free DNA represents an accessible source of tumor DNA for the early and sensitive identification of mutations causing resistance to ibrutinib. By using highly sensitive ultra-deep next generation sequencing strategies to monitor molecular biomarkers potentially relevant for ibrutinib in DNA coming from both cellular and the plasma fractions of peripheral blood, the project has the chance of identifying new dynamic molecular markers that can help the early and real time prediction of sustained benefit from ibrutinib treatment vs imminent progression in TP53 mutated CLL patients. In the end, the results of this study will provide the bases to refine the current approach for treatment tailoring in TP53 mutated patients by allowing the identification of cases who, though being in clinical response under ibrutinib, will conceivably benefit from immediate switch to alternative options (i.e. novel drugs, allogeneic stem cell transplantation, or CART).

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 56
• Est. completion date: December 31, 2024
• Est. primary completion date: August 31, 2021
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

• Male or female adults 18 years or older

• Documented diagnosis of CLL, according to iwCLL 2008 criteria

• Presence of TP53 mutation as demonstrated by sequencing at the local laboratory and/or presence of 17p deletion as demonstrated by fluorescence in situ hybridization (FISH) testing performed at the local laboratory

• CLL that warrants treatment

• Planned treatment with ibrutinib 420 mg quaque die

• Willing and able to comply with scheduled visits, laboratory tests, and study procedures

• Evidence of a signed informed consent

Exclusion Criteria:

• Current or prior histological transformation from CLL to an aggressive lymphoma (ie, Richter transformation).

• Prior treatment with ibrutinib or idelalisib

Related Conditions & MeSH terms

• Chronic Lymphocytic Leukemia
• Leukemia
• Leukemia, Lymphocytic, Chronic, B-Cell
• Leukemia, Lymphoid

Intervention

Drug:
• Ibrutinib
Treatment with ibrutinib 420 mg quaque die in the clinical practice

Locations

Country	Name	City	State
Italy	Onco Ematologia Clinico Sperimentale, I.R.C.C.S. Centro di Riferimento Oncologico	Aviano
Italy	Dipartimento di Ematologia, Niguarda Cancer Center, Ospedale Niguarda	Milano
Italy	Ospedale San Raffaele	Milano
Italy	Department of Medical and Surgical Sciences, section of Hematology	Modena
Italy	Divisione di Ematologia, Universita' del Piemonte Orientale	Novara
Italy	Institute of Hematology, Catholic University S. Cuore	Roma
Italy	Department of Haematology, Tor Vergata Hospital	Rome
Italy	Clinica Ematologica, Centro Trapianti e Terapie Cellulari "Carlo Melzi"	Udine
Italy	Ematologia, Ospedale di Circolo e Fondazione Macchi	Varese
Switzerland	Division of Hematology, Department of Internal Medicine, Basel University Hospital	Basel
Switzerland	Oncology Institute of Southern Switzerland	Bellinzona
Switzerland	Clinica Luganese Moncucco	Lugano
Switzerland	Hematology, Luzern Kantonsspital	Luzern

Sponsors (1)

Lead Sponsor	Collaborator
Oncology Institute of Southern Switzerland

Countries where clinical trial is conducted

Italy,  Switzerland, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Impact of clonal response on PFS	To evaluate the impact of clonal response (namely clearance of TP53 mutated alleles in the peripheral blood (PB) CLL cells at Week 24 after treatment start) on PFS measured according to iwCLL guidelines (Hallek 2008) as the interval from ibrutinib treatment start to progression (event), death (event) or last follow-up (censoring). Progression will be defined as per investigator assessment.	2/2016-2/2021
Secondary	Proportion of clonal response at Week 24 after treatment start	To evaluate the proportion of clonal response, defined as clearance (100% reduction compared to baseline) of TP53 mutated alleles in the PB CLL cells at Week 24 after treatment start	2/2016-2/2021
Secondary	Cumulative proportion of clonal response	To evaluate the cumulative proportion of clonal response, defined as clearance (100% reduction compared to baseline) of TP53 mutated alleles in the PB CLL cells at any time from treatment start	2/2016-2/2021
Secondary	Impact of clonal response on overall survival	To evaluate the impact of clonal response on overall survival (OS) measured according to iwCLL guidelines (Hallek 2008) as the interval from ibrutinib treatment start to death (event) or last follow-up (censoring)	2/2016-2/2021
Secondary	Effect of clonal response on the cumulative incidence of acquisition of resistance-mutations	To evaluate the effect of clonal response on the cumulative incidence of acquisition of resistance-mutations	2/2016-2/2021
Secondary	Effect clonal response on the cumulative incidence of transformation to Richter syndrome	To evaluate the effect of clonal response on the cumulative incidence of transformation to Richter syndrome defined as the interval between ibrutinib treatment start to histologically documented development of an aggressive lymphoma	2/2016-2/2021
Secondary	Impact of treatment-emergent BTK and PLC?2 resistance mutations on PFS	To evaluate the impact of treatment-emergent BTK and PLC?2 resistance mutations on PFS	2/2016-2/2021
Secondary	Impact of treatment-emergent BTK and PLC?2 resistance mutations on OS	To evaluate the impact of treatment-emergent BTK and PLC?2 resistance mutations on OS	2/2016-2/2021
Secondary	Impact of treatment-emergent BTK and PLC?2 resistance mutations on the cumulative incidence of transformation to Richter syndrome	To evaluate the impact of treatment-emergent BTK and PLC?2 resistance mutations on the cumulative incidence of transformation to Richter syndrome	2/2016-2/2021
Secondary	Accuracy of plasma cell free DNA for the identification of BTK and PLC?2 resistance mutations	To evaluate the sensitivity, specificity, positive predictive value, negative predictive value and accuracy of plasma cell free DNA vs tumor genomic DNA genotyping for the identification of BTK and PLC?2 resistance mutations	2/2016-2/2021