Clinical Trials /

Ibrutinib in Combination With Rituximab in Patients With Indolent Clinical Forms of MCL

NCT02682641

Description:

Phase II study with a two-stage design to evaluate efficacy and safety of ibrutinib in combination with rituximab (I+R) in untreated patients with indolent clinical forms of MCL. An extensive biological study will be conducted in order to further characterize this population of MCL patients and evaluate the response obtained with the mutational profile of the tumor.

Related Conditions:
  • Mantle Cell Lymphoma
Recruiting Status:

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Ibrutinib in Combination With Rituximab in Patients With Indolent Clinical Forms of MCL
  • Official Title: Multicentric Phase II Trial to Evaluate the Efficacy and Safety of Ibrutinib in Combination With Rituximab in Patients With Indolent Clinical Forms of Mantle Cell Lymphoma

Clinical Trial IDs

  • ORG STUDY ID: GELTAMO-IMCL-2015
  • SECONDARY ID: 2015-004158-17
  • NCT ID: NCT02682641

Conditions

  • Mantle Cell Lymphoma

Interventions

DrugSynonymsArms
IBRUTINIBImbruvicaIBRUTINIB + RITUXIMAB
RituximabIBRUTINIB + RITUXIMAB

Purpose

Phase II study with a two-stage design to evaluate efficacy and safety of ibrutinib in combination with rituximab (I+R) in untreated patients with indolent clinical forms of MCL. An extensive biological study will be conducted in order to further characterize this population of MCL patients and evaluate the response obtained with the mutational profile of the tumor.

Detailed Description

      Patients with mantle cell lymphoma (MCL) have a median survival of 3-5 years despite
      treatment. Indeed, the best therapeutic approach for different patients with MCL remains to
      be established, coexisting different options of immunochemotherapy regimes which may include
      autologous transplantation in first-line treatment or rituximab maintenance.

      Moreover, last years MCL starts to be recognized as a heterogeneous disease both from
      biological and clinical stand points. For instance, MCL cases with a non-nodal clinical
      presentation, usually have distinctive biological features such as SOX-11 negativity,
      hypermutated IGHV genes and a low number of genetic lesions associated. The outcome of these
      cases is much more favourable compared to conventional MCL, reaching median survivals over 7
      to 10 years even receiving less intensive treatments. In addition to that, up to 30% of the
      patients with newly diagnosed MCL can be safely deferred from initial therapy until
      progression . Therapeutic abstention may be prolonged for more than one year in 50% of cases.
      These patients usually show longer survivals from the start of treatment compared to patients
      immediately treated after diagnosis. Therefore, all these observations indicate that there
      are indolent clinical forms in MCL, so its clinico-biological identification is crucial to
      tailor treatment appropriately. However, at present there is no consensus on the diagnostic
      criteria or treatment recommendations in cases of indolent MCL. This results in difficulties
      for the identification of these forms in the clinical practice as well as with a certain
      therapeutic in definition, as indolent forms of MCL can be treated either with therapeutic
      abstention until progression or receive immediate treatment with conventional or more
      intensive immuno-chemotherapy regimes, which may even include an autologous hematopoietic
      stem cell transplantation. With the emergence of new biological agents in the therapeutic
      arsenal of MCL arises the question whether a completely different approach with new drugs and
      chemotherapy-free could be more appropriate in selected subsets of patients such as indolent
      MCL forms.
    

Trial Arms

NameTypeDescriptionInterventions
IBRUTINIB + RITUXIMABExperimentalSubjects will receive the ibrutinib in combination with rituximab according to the following schedule: Ibrutinib 560 mg daily po until disease progression or unacceptable toxicity. In case of sustained negative MRD (at least for 6 months) after 2 years of continuous therapy, ibrutinib will be discontinued. Rituximab 375 mg/m2 iv day 1,8, 15 and 22 (cycle 1). Rituximab 375 mg/m2 iv, day one of every cycle 3, 5, 7 and 9.
  • IBRUTINIB
  • Rituximab

Eligibility Criteria

        Inclusion Criteria:

          1. Subjects with confirmed diagnosis of Mantle Cell Lymphoma (World Health Organization
             Classification, WHO 2008). Classical, small-cell variants and marginal-zone variants
             can be included.

          2. Age 18 years or older.

          3. Subjects must not have received any prior therapies (excluding diagnostic
             splenectomy).

          4. Asymptomatic patients.

          5. Ann Arbor clinical stages I-IV.

          6. Eastern Cooperative Oncology Group (ECOG) performance status <2 (0-1).

          7. Subjects with a non-nodal MCL presentation with mainly bone marrow or peripheral blood
             involvement.

          8. Other asymptomatic clinical presentations are acceptable in case of low tumor burden,
             including nodal MCL with lymph node enlargement ≤3 cm in the maximum diameter and with
             low proliferation index (Ki-67 ≤ 30%).

          9. The following laboratory values at screening: a) Neutrophil count ≥ 1×10e9/L,
             Hemoglobin level ≥ 100 g/L or platelet count ≥100×10e9/L; b) Transaminases (AST and
             ALT) ≤ 3 x ULN. c)Total bilirubin ≤1.5 x ULN unless bilirubin rise is due to Gilbert's
             syndrome or of non-hepatic origin; d) Creatinine ≤ 2 x ULN or calculated creatinine
             clearance ≥ 40 mL/min/1.73 m2.

         10. Stable disease without evidence of clinical progression criteria for at least 3
             months. Patients in prolonged therapeutic abstention may be included.

         11. Women of childbearing potential and men who are sexually active must be practising a
             highly effective method of birth control during and after the study consistent with
             local regulations regarding the use of birth control methods for subjects
             participating in clinical trials. Men must agree to not donate sperm during and after
             the study. For females, these restrictions apply for 1 month after the last dose of
             study drug. For males, these restrictions apply for 3 months after the last dose of
             study drug.

         12. Women of childbearing potential must have a negative serum (beta-human chorionic
             gonadotropin [-hCG]) or urine pregnancy test at Screening. Women who are pregnant or
             breastfeeding are ineligible for this study.

         13. Sign (or their legally-acceptable representatives must sign) an informed consent
             document indicating that they understand the purpose of and procedures required for
             the study, including biomarkers, and are willing to participate in the study.

        Exclusion Criteria:

          1. Aggressive histological variants: blastic and pleomorphic variants (blastoid).

          2. Proliferation index measured by Ki-67 > 30%.

          3. B-cell monoclonal lymphocytosis with MCL phenotype

          4. Eastern Cooperative Oncology Group (ECOG) performance status ≥2. Presence of B
             symptoms or any relevant symptoms related to the MCL.

        6. Nodal clinical forms with lymph node enlargement >3 cm (maximum diameter). 7. Cytopenias
        attributable to MCL: Neutrophil count < 1×10e9/L, Hemoglobin level < 100 g/L or platelet
        count < 100×10e9/L.

        8. Organ dysfunction related to MCL including creatinine level > 2 x ULN or altered liver
        biochemistry (> 3x ULN).

        9. Gradual increase in different determinations of serum LDH attributable to MCL that
        exceeds 20% of the ULN.

        10. Known CNS infiltration. 11. Subjects with expected therapy requirement for MCL in a
        short time (< 3 months) 12. Patients with active hepatitis B or C infection or HIV
        infection. Positive test results for chronic HBV infection (defined as positive HBsAg
        serology) or positive test results for hepatitis C (hepatitis C virus [HCV] antibody
        serology testing) will be excluded with the following exceptions. Patients with occult or
        prior HBV infection (defined as negative HBsAg and positive total HBcAb) may be included if
        HBV DNA is undetectable, provided that they are willing to undergo monthly DNA testing or
        antiviral prophylaxis. Patients who have protective titers of hepatitis B surface antibody
        (HBsAb) after vaccination or prior but cured hepatitis B are eligible. Patients positive
        for HCV antibody are eligible only if PCR is negative for HCV RNA.

        13. Anticoagulation requirement with vitamin K antagonists. 14. Past medical history of
        stroke or intracranial haemorrhage within 6 months prior to inclusion.

        15. Required medication with strong CYP3A4/5 inhibitors 16. Any serious comorbidity that
        makes the patient unacceptable for receiving the treatment.

        17. Concomitant or previous malignancies the last 2 years other than basal skin cancer or
        in situ uterine cervix cancer.

        18. Pregnancy or lactation. 19. Major surgery within 4 weeks of inclusion. 20. Clinically
        significant cardiovascular disease such as uncontrolled or symptomatic arrhythmias,
        congestive heart failure, or myocardial infarction within 6 months of Screening, or any
        Class 3 (moderate) or Class 4 (severe) cardiac disease as defined by the New York Heart
        Association Functional Classification.

        21. Vaccinated with live, attenuated vaccines within 4 weeks of randomization. 22.
        Uncontrolled systemic infection requiring intravenous (IV) antibiotics. 23. Any
        life-threatening illness, medical condition, or organ system dysfunction which, in the
        investigator's opinion, could compromise the subject's safety, interfere with the
        absorption or metabolism of ibrutinib capsules, or put the study outcomes at undue risk.
      
Maximum Eligible Age:99 Years
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Rate of complete remission
Time Frame:12 months
Safety Issue:
Description:Percentage of patients who are alive and in complete response at 12 months from the date of treatment initiation. All patients will be evaluated with PET- CT and bone marrow biopsy at that time.

Secondary Outcome Measures

Measure:Overall Response Rate (OR)
Time Frame:12 months
Safety Issue:
Description:Including complete response and partial response according to the International Response Criteria for Non- Hodgkin Lymphoma
Measure:Progression Free Survival
Time Frame:7 years
Safety Issue:
Description:Percentage of patients without progression of disease
Measure:Response Duration
Time Frame:7 years
Safety Issue:
Description:Length of time between
Measure:Minimal residual disease (MRD)
Time Frame:within 12 months after initiation of study treatment
Safety Issue:
Description:Proportion of subjects who are MRD negative (ie, less than the lower limit of detection for the MRD assay).
Measure:Overall survival
Time Frame:7 years
Safety Issue:
Description:Percentage of patients alive from first dose of treatment to end of follow-up.
Measure:Adverse Events (AEs), Serious Adverse Events (SAES) and Suspected Unexpected Serious Adverse Reactions (SUSARs)
Time Frame:7 years
Safety Issue:
Description:Number of events classified according to the Common Toxicity Criteria of the National Cancer Institute (CTC AE V 4.03).
Measure:Score of the EORTC quality of life questionnaire QLQ-30
Time Frame:12 months
Safety Issue:
Description:Health related quality of life questionnaire
Measure:Secore of the FACT-LYM
Time Frame:12 months
Safety Issue:
Description:Health related quality of life questionnaire

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Grupo Español de Linfomas y Transplante Autólogo de Médula Ósea

Last Updated

January 24, 2020