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

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ClinicalTrials.gov Identifier: NCT02827617
Recruitment Status : Active, not recruiting
First Posted : July 11, 2016
Last Update Posted : April 3, 2023
Sponsor:
Information provided by (Responsible Party):
Davide Rossi, Oncology Institute of Southern Switzerland

Study Description
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Brief 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.

Condition or disease Intervention/treatment
Chronic Lymphocytic Leukemia Drug: Ibrutinib

Detailed 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).
Study Design
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Study Type : Observational
Estimated Enrollment : 56 participants
Observational Model: Cohort
Time Perspective: Prospective
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
Actual Study Start Date : June 1, 2016
Actual Primary Completion Date : August 31, 2021
Estimated Study Completion Date : October 31, 2023

Resource links provided by the National Library of Medicine

Drug Information available for: Ibrutinib

Groups and Cohorts
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Group/Cohort Intervention/treatment
TP53 mutated CLL Drug: Ibrutinib
Treatment with ibrutinib 420 mg quaque die in the clinical practice
Other Name: PCI-32765


Outcome Measures
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Primary Outcome Measures :
  1. Impact of clonal response on PFS [ Time Frame: 2/2016-2/2021 ]
    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.


Secondary Outcome Measures :
  1. Proportion of clonal response at Week 24 after treatment start [ Time Frame: 2/2016-2/2021 ]
    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. Cumulative proportion of clonal response [ Time Frame: 2/2016-2/2021 ]
    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

  3. Impact of clonal response on overall survival [ Time Frame: 2/2016-2/2021 ]
    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)

  4. Effect of clonal response on the cumulative incidence of acquisition of resistance-mutations [ Time Frame: 2/2016-2/2021 ]
    To evaluate the effect of clonal response on the cumulative incidence of acquisition of resistance-mutations

  5. Effect clonal response on the cumulative incidence of transformation to Richter syndrome [ Time Frame: 2/2016-2/2021 ]
    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

  6. Impact of treatment-emergent BTK and PLCγ2 resistance mutations on PFS [ Time Frame: 2/2016-2/2021 ]
    To evaluate the impact of treatment-emergent BTK and PLCγ2 resistance mutations on PFS

  7. Impact of treatment-emergent BTK and PLCγ2 resistance mutations on OS [ Time Frame: 2/2016-2/2021 ]
    To evaluate the impact of treatment-emergent BTK and PLCγ2 resistance mutations on OS

  8. Impact of treatment-emergent BTK and PLCγ2 resistance mutations on the cumulative incidence of transformation to Richter syndrome [ Time Frame: 2/2016-2/2021 ]
    To evaluate the impact of treatment-emergent BTK and PLCγ2 resistance mutations on the cumulative incidence of transformation to Richter syndrome

  9. Accuracy of plasma cell free DNA for the identification of BTK and PLCγ2 resistance mutations [ Time Frame: 2/2016-2/2021 ]
    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 PLCγ2 resistance mutations


Biospecimen Retention:   Samples With DNA
Tumor periphral blood cells, Plasma, Tumor genomic DNA, Plasma cell free DNA

Eligibility Criteria
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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Sampling Method:   Probability Sample
Study Population
Adult CLL patients harboring TP53 genetic abnormalities, independent of whether treatment naïve or previously treated, who warrants treatment according to iwCLL 2008 criteria, and who is planned to receive ibrutinib at standard dose as per clinical practice
Criteria

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
Contacts and Locations
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Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02827617


Locations
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Italy
Onco Ematologia Clinico Sperimentale, I.R.C.C.S. Centro di Riferimento Oncologico
Aviano, Italy, 33081
Ospedale San Raffaele
Milano, Italy, 20132
Dipartimento di Ematologia, Niguarda Cancer Center, Ospedale Niguarda
Milano, Italy, 20133
Department of Medical and Surgical Sciences, section of Hematology
Modena, Italy, 41124
Divisione di Ematologia, Universita' del Piemonte Orientale
Novara, Italy, 28100
Institute of Hematology, Catholic University S. Cuore
Roma, Italy, 00168
Department of Haematology, Tor Vergata Hospital
Rome, Italy, 00133
Clinica Ematologica, Centro Trapianti e Terapie Cellulari "Carlo Melzi"
Udine, Italy, 33100
Ematologia, Ospedale di Circolo e Fondazione Macchi
Varese, Italy, 21100
Switzerland
Division of Hematology, Department of Internal Medicine, Basel University Hospital
Basel, Switzerland, 4031
Oncology Institute of Southern Switzerland
Bellinzona, Switzerland, 6500
Clinica Luganese Moncucco
Lugano, Switzerland, 6903
Hematology, Luzern Kantonsspital
Luzern, Switzerland, 6000
Sponsors and Collaborators
Oncology Institute of Southern Switzerland
Investigators
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Principal Investigator: Davide Rossi, MD, PhD Oncology Institute of Southern Switzerland
More Information
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Responsible Party: Davide Rossi, Sponsor, Project Leader and Coordinating researcher, Oncology Institute of Southern Switzerland
ClinicalTrials.gov Identifier: NCT02827617    
Other Study ID Numbers: IOSI-EMA-001
First Posted: July 11, 2016    Key Record Dates
Last Update Posted: April 3, 2023
Last Verified: March 2023
Keywords provided by Davide Rossi, Oncology Institute of Southern Switzerland:
Ibrutinib
TP53
Chronic lymphocytic leukemia
Additional relevant MeSH terms:
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Leukemia
Leukemia, Lymphoid
Leukemia, Lymphocytic, Chronic, B-Cell
Neoplasms by Histologic Type
Neoplasms
Lymphoproliferative Disorders
Lymphatic Diseases
 Immunoproliferative Disorders
Immune System Diseases
Leukemia, B-Cell
Chronic Disease
Disease Attributes
Pathologic Processes