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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.
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.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| IBER treatment arm | Experimental | This is the only arm in a single-arm phase II study. |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| IBER salvage chemotherapy followed by ibrutinib maintenance therapy | Drug | 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 |
| 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 |
| 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 |
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Inclusion Criteria:
Exclusion Criteria:
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| Name | Role | Phone | Extension | |
|---|---|---|---|---|
| Deok-Hwan Yang, M.D., Ph.D. | Contact | +82-61-379-7636 | drydh1685@hotmail.com | |
| Yoon Seok Choi, M.D., Ph.D. | Contact | +82-42-280-7107 | wyfran@gmail.com |
| Name | Affiliation | Role |
|---|---|---|
| Deok-Hwan Yang | Chonnam National University Hospital | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Chonnam National University Hwasun Hospital | Hwasun | Jeollanam-do | 519-809 | South Korea |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
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| 20054396 | Background | Davis RE, Ngo VN, Lenz G, Tolar P, Young RM, Romesser PB, Kohlhammer H, Lamy L, Zhao H, Yang Y, Xu W, Shaffer AL, Wright G, Xiao W, Powell J, Jiang JK, Thomas CJ, Rosenwald A, Ott G, Muller-Hermelink HK, Gascoyne RD, Connors JM, Johnson NA, Rimsza LM, Campo E, Jaffe ES, Wilson WH, Delabie J, Smeland EB, Fisher RI, Braziel RM, Tubbs RR, Cook JR, Weisenburger DD, Chan WC, Pierce SK, Staudt LM. Chronic active B-cell-receptor signalling in diffuse large B-cell lymphoma. Nature. 2010 Jan 7;463(7277):88-92. doi: 10.1038/nature08638. |
| 28619981 | Background | Grommes C, Pastore A, Palaskas N, Tang SS, Campos C, Schartz D, Codega P, Nichol D, Clark O, Hsieh WY, Rohle D, Rosenblum M, Viale A, Tabar VS, Brennan CW, Gavrilovic IT, Kaley TJ, Nolan CP, Omuro A, Pentsova E, Thomas AA, Tsyvkin E, Noy A, Palomba ML, Hamlin P, Sauter CS, Moskowitz CH, Wolfe J, Dogan A, Won M, Glass J, Peak S, Lallana EC, Hatzoglou V, Reiner AS, Gutin PH, Huse JT, Panageas KS, Graeber TG, Schultz N, DeAngelis LM, Mellinghoff IK. Ibrutinib Unmasks Critical Role of Bruton Tyrosine Kinase in Primary CNS Lymphoma. Cancer Discov. 2017 Sep;7(9):1018-1029. doi: 10.1158/2159-8290.CD-17-0613. Epub 2017 Jun 15. |
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