Bendamustine-based Combination Therapy for PCNSL

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

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).

Study Overview

• Status: Unknown
• Conditions: PCNSL
• Intervention / Treatment: Drug: R-B(O)AD

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.

• Study Type: Interventional
• Enrollment (Anticipated): 15
• Phase: Phase 2

Contacts and Locations

Study Locations

• Korea, Republic of
  • Jeollanam-do
    • Hwasun-gun, Jeollanam-do, Korea, Republic of, 519-809
      • Chonnam National University Hwasun Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 19 years and older (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. PCNSL of diffuse large B-cell lymphoma (DLBCL) with a CNS lesion by tissue biopsy
2. Age ≥ 19 years old
3. Relapsed or refractory PCNSL after frontline combined chemotherapy or radiation
4. ECOG performance status 0-2
5. Absolute neutrophil count ≥ 1000/uL
6. Platelets ≥ 100,000/uL
7. Total bilirubin ≤ 1.5 x ULN (upper limit of normal)
8. Aspartate aminotransferase (AST) ≤ 3 x ULN
9. Creatinine ≤ 2.0 x ULN

Exclusion Criteria:

1. PCNSL of other than DLBCL or T-cell lymphoma with a CNS lesion by tissue biopsy
2. Any of the following: pregnant women, nursing women, men or women of childbearing potential who are unwilling to employ adequate contraception
3. Uncontrolled infection
4. Therapy with myelosuppressive chemotherapy or biologic therapy < 21 days prior to registration
5. Persistent toxicities ≥ grade 3 from prior chemotherapy or biologic therapy regardless of interval since last treatment
6. History of thromboembolic episodes ≤ 3 months prior to registration
7. Active hepatitis B or C with uncontrolled disease
8. Active other malignancy requiring treatment that would interfere with the assessments of response of the lymphoma to protocol treatment
9. Any severe and/or uncontrolled medical conditions or other conditions that could adversely impact their ability to participate in the study
10. Major surgery ≤ 4 weeks prior to registration or have not recovered from side effects of such therapy

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: NA
• Interventional Model: SINGLE_GROUP
• Masking: NONE

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: R-B(O)AD; Intravenous R-B(O)AD every 4 weeks for up to 4 cycles	Drug: R-B(O)AD; 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

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

Collaborators and Investigators

• Sponsor: Chonnam National University Hospital
• Investigators: Principal Investigator: Deok-Hwan Yang, MD, Chonnam National University Hwasun Hospital, Department of Hematology-Oncology

Publications and helpful links

General Publications

• Kim T, Choi HY, Lee HS, Jung SH, Ahn JS, Kim HJ, Lee JJ, Yoo HD, Yang DH. Clinical response and pharmacokinetics of bendamustine as a component of salvage R-B(O)AD therapy for the treatment of primary central nervous system lymphoma (PCNSL). BMC Cancer. 2018 Jul 9;18(1):729. doi: 10.1186/s12885-018-4632-y.

Study record dates

Study Major Dates

• Study Start (ACTUAL): January 20, 2016
• Primary Completion (ANTICIPATED): January 20, 2018
• Study Completion (ANTICIPATED): January 20, 2019

Study Registration Dates

• First Submitted: December 6, 2017
• First Submitted That Met QC Criteria: January 2, 2018
• First Posted (ACTUAL): January 8, 2018

Study Record Updates

• Last Update Posted (ACTUAL): January 8, 2018
• Last Update Submitted That Met QC Criteria: January 2, 2018
• Last Verified: January 1, 2018

More Information

Terms related to this study

• Keywords: Pharmacokinetics; Salvage therapy; Bendamustine; CSF; PCNSL
• Other Study ID Numbers: CNUHH-2016-145

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No