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
Overview
- Phase
- Phase 2
- Intervention
- IBRUTINIB
- Conditions
- Mantle Cell Lymphoma
- Sponsor
- Grupo Español de Linfomas y Transplante Autólogo de Médula Ósea
- Enrollment
- 50
- Locations
- 15
- Primary Endpoint
- Rate of complete remission
- Status
- Active, not recruiting
- Last Updated
- 2 years ago
Overview
Brief Summary
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.
Investigators
Eligibility Criteria
Inclusion Criteria
- •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.
- •Age 18 years or older.
- •Subjects must not have received any prior therapies (excluding diagnostic splenectomy).
- •Asymptomatic patients.
- •Ann Arbor clinical stages I-IV.
- •Eastern Cooperative Oncology Group (ECOG) performance status \<2 (0-1).
- •Subjects with a non-nodal MCL presentation with mainly bone marrow or peripheral blood involvement.
- •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%).
- •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 m
- •Stable disease without evidence of clinical progression criteria for at least 3 months. Patients in prolonged therapeutic abstention may be included.
Exclusion Criteria
- •Aggressive histological variants: blastic and pleomorphic variants (blastoid).
- •Proliferation index measured by Ki-67 \> 30%.
- •B-cell monoclonal lymphocytosis with MCL phenotype
- •Eastern Cooperative Oncology Group (ECOG) performance status ≥
- •Presence of B symptoms or any relevant symptoms related to the MCL.
- •Nodal clinical forms with lymph node enlargement \>3 cm (maximum diameter).
- •Cytopenias attributable to MCL: Neutrophil count \< 1×10e9/L, Hemoglobin level \< 100 g/L or platelet count \< 100×10e9/L.
- •Organ dysfunction related to MCL including creatinine level \> 2 x ULN or altered liver biochemistry (\> 3x ULN).
- •Gradual increase in different determinations of serum LDH attributable to MCL that exceeds 20% of the ULN.
- •Known CNS infiltration.
Arms & Interventions
IBRUTINIB + RITUXIMAB
Subjects 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.
Intervention: IBRUTINIB
IBRUTINIB + RITUXIMAB
Subjects 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.
Intervention: Rituximab
Outcomes
Primary Outcomes
Rate of complete remission
Time Frame: 12 months
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 Outcomes
- Response Duration(7 years)
- Score of the EORTC quality of life questionnaire QLQ-30(12 months)
- Adverse Events (AEs), Serious Adverse Events (SAES) and Suspected Unexpected Serious Adverse Reactions (SUSARs)(7 years)
- Secore of the FACT-LYM(12 months)
- Progression Free Survival(7 years)
- Minimal residual disease (MRD)(within 12 months after initiation of study treatment)
- Overall survival(7 years)
- Overall Response Rate (OR)(12 months)