IBER Salvage Treatment Followed by Ibrutinib Maintenance for Relapsed or Refractory PCNSL

Study Overview
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Brief Summary
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This is a multicenter, single-arm, prospective phase II study to evaluate the efficacy and safety of a novel combination regimen for relapsed/refractory PCNSL. Specifically, ibrutinib will be administered in combination with ifosfamide, etoposide and rituximab (IBER) as a salvage chemotherapy, which is followed by maintenance ibrutinib monotherapy of fixed duration.

Detailed Description
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Given the limited activity of salvage therapy with high-dose methotrexate re-treatment and/or alkylator-based treatment in patients with relapse or refractory PCNSL, the development of novel salvage chemotherapy regimen remains an area of clinical unmet need. Ibrutinib, an oral inhibitor of bruton tyrosine kinase (BTK), is known to induce death of diffuse large B-cell lymphoma (DLBCL) cells with dysregulated B-cell receptor (BCR) signaling and has shown promising activity in patients with a variety of B-cell malignancies. Recently, several studies reported that ibrutinib may have an excellent single-agent clinical activity against relapsed or refractory PCNSL. Furthermore, proven pharmacokinetic data suggested that ibrutinib successfully penetrated the BBB and reached the achievable concentration in cerebrospinal fluid. When ibrutinib is administered in combination with BBB-destructing chemotherapeutic agents (such as, temozolomide or etoposide) for salvage treatment of PCNSL, therefore, anti-lymphoma activity of ibrutinib could be maximized. In this context, this phase II study is designed to evaluate the efficacy and safety of IBER salvage chemotherapy followed by ibrutinib maintenance for transplant ineligible patients with relapsed or refractory PCNSL.

Official Title
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Clinical Efficacy and Safety of IBER Salvage Treatment Followed by Ibrutinib Maintenance for Transplant-ineligible Patients With Relapsed or Refractory Primary Central Nervous System Lymphoma (PCNSL): a Multicenter, Single-arm, Prospective Phase II Study

Conditions
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Primary Central Nervous System Lymphoma

Intervention / Treatment
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* Drug: IBER salvage chemotherapy followed by ibrutinib maintenance therapy


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histologically confirmed PCNSL of CD20+ diffuse large B cell lymphoma (DLBCL) PCNSL relapsed or refractory after frontline methotrexate-based chemotherapy (with or without radiation therapy) At least one measurable lesion, which is defined as longest diameter of lesion > 0.5 cm, by contrast-enhanced MRI ECOG performance status 0-2 Normal function of major organs Exclusion Criteria: PCNSL other than DLBCL Primary ocular lymphoma PCNSL accompanied by systemic involvement Active infection with hepatitis B or C virus Known history of human immunodeficiency virus (HIV) infection Therapy with myelosuppressive chemotherapy or biologic therapy < 21 days prior to registration

Ages Eligible for Study
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Minimum Age: 20 Years
Maximum Age: 79 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: IBER treatment arm<br>This is the only arm in a single-arm phase II study. | Drug: IBER salvage chemotherapy followed by ibrutinib maintenance therapy<br>* Induction therapy with IBER (up to 6 cycles) [ Ibrutinib 560 mg/d on D1-21 + Rituximab 375 mg/m2 on D1 (on D1/8/15 in C1) + Ifosfamide 3.75 g/m2 on D2 + Etoposide 100 mg/m2 on D2-4 ], followed by ibrutinib 560 mg/d maintenance therapy for up to 6 months<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall response rate | The percentage of patients with a complete response (CR) or a partial response (PR) | From date of starting the study treatment until the date of finishing the study treatment for any reason, assessed up to 10 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety and tolerability of the study treatment | Treatment-emergent adverse events graded according to the NCI-CTCAC version 4.0 | From the first day of the first cycle of IBER induction chemotherapy to 30 days after the last dose of study drug, assessed up to 12 months |