Bendamustine-based Combination Therapy for PCNSL

Study Overview
=================
Brief Summary
-----------------
This pilot study will i) evaluate the efficacy and the safety of bendamustine-based combination chemotherapy and ii) investigate the pharmacokinetics (PK)of bendamustine in plasma and CSF when given as salvage treatment for patients with relapsed or refractory primary central nervous system lymphoma (PCNSL).

Detailed Description
-----------------
A relatively high proportion of patients diagnosed with primary CNS lymphoma will experience recurrent disease, yet therapy options are limited in salvage therapy. Based on the demonstrated activity and proposed additive mechanisms of the chemotherapeutic agents included in the bendamustine-based combination regimen, the efficacy and safety of R-B(O)AD will be evaluated for treatment of relapsed/refractory (R/R) primary CNS lymphoma. Evidence from previous preclinical tissue distribution studies and single agent intravenous drug therapy trials in CNS malignancies suggests that bendamustine penetrates brain and tumor tissue, however there are no clinical data available on the PK of bendamustine in the CSF. This study will evaluate the PK of plasma and CSF drug levels through a population based nonlinear mixed-effects model approach in a R/R PCNSL cohort with the goals to define the currently unknown PK profile of bendamustine in the CSF and to further characterize the relationship between plasma and CSF drug levels, and the influence of exposure on response to therapy.

Official Title
-----------------
Plasma and Cerebrospinal Fluid (CSF) Pharmacokinetics of Bendamustine as a Component of Salvage Therapy for Primary Central Nervous System Lymphoma (PCNSL)

Conditions
-----------------
PCNSL

Intervention / Treatment
-----------------
* Drug: R-B(O)AD


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: PCNSL of diffuse large B-cell lymphoma (DLBCL) with a CNS lesion by tissue biopsy Age ≥ 19 years old Relapsed or refractory PCNSL after frontline combined chemotherapy or radiation ECOG performance status 0-2 Absolute neutrophil count ≥ 1000/uL Platelets ≥ 100,000/uL Total bilirubin ≤ 1.5 x ULN (upper limit of normal) Aspartate aminotransferase (AST) ≤ 3 x ULN Creatinine ≤ 2.0 x ULN Exclusion Criteria: PCNSL of other than DLBCL or T-cell lymphoma with a CNS lesion by tissue biopsy Any of the following: pregnant women, nursing women, men or women of childbearing potential who are unwilling to employ adequate contraception Uncontrolled infection Therapy with myelosuppressive chemotherapy or biologic therapy < 21 days prior to registration Persistent toxicities ≥ grade 3 from prior chemotherapy or biologic therapy regardless of interval since last treatment History of thromboembolic episodes ≤ 3 months prior to registration Active hepatitis B or C with uncontrolled disease Active other malignancy requiring treatment that would interfere with the assessments of response of the lymphoma to protocol treatment Any severe and/or uncontrolled medical conditions or other conditions that could adversely impact their ability to participate in the study Major surgery ≤ 4 weeks prior to registration or have not recovered from side effects of such therapy

Ages Eligible for Study
-----------------
Minimum Age: 19 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: R-B(O)AD<br>Intravenous R-B(O)AD every 4 weeks for up to 4 cycles | Drug: R-B(O)AD<br>* rituximab 375 mg/m2 on day 1; vincristine 1.4 mg/m2 on day 1, omitted in patients ≥70 years of age due to risk of neurotoxicity; bendamustine 75 mg/m2 over 1 h on days 2 and 3; cytarabine 1000 mg/m2 over 3 h on days 2-4; dexamethasone 20 mg on days 1-4, administered intravenously<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall response rate (ORR) | rate of complete or partial response (CR/PR) | 2 year | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Toxicity based on NCI Common Terminology Criteria version 4.0 | adverse event incidence of combination regimen | 2 year | 
| Progression-free survival (PFS) | calculated from the time of study entry until progression, relapse, or death | 2 years | 
| Overall survival (OS) | calculated from the time of study entry until death | 2 years | 
| Maximum concentration [Cmax] of bendamustine in plasma and CSF | peak concentration of bendamustine after 1 hour IV infusion | 6 months | 
| Area under the curve [AUC] of bendamustine in plasma and CSF | overall exposure of bendamustine after IV infusion | 6 months | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Bendamustine, CSF, Pharmacokinetics, PCNSL, Salvage therapy