A Risk Stratified Sequential Treatment With Rituximab, Brentuximab Vedotin and Bendamustine (RBvB)

Study Overview
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Brief Summary
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This is an open label, risk-stratified, sequential treatment, phase 2 study of newly diagnosed post-transplant lymphoproliferative disorders with positive CD20 and CD30 expression. It includes an induction phase with rituximab and brentuximab vedotin (RBv), followed by a treatment phase with RBv or RBv in combination with bendamustine (RBvB) based on response to induction. The primary end point is treatment efficacy measured as the overall response rate (ORR) and progression free survival (PFS).

Detailed Description
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Post-Transplant Lymphoproliferative Disorders (PTLD) are defined by the revised 2017 edition of the WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues as lymphoid or plasmacytic proliferations that develop as a consequence of immunosuppression in a recipient of a solid organ, bone marrow or stem cell allograft. Within this definition 4 distinct categories exist, including: (1) Non-destructive PTLDs (plasmacytic hyperplasia, infectious mononucleosis, and florid follicular hyperplasia) (2) Polymorphic PTLD; (3) Monomorphic PTLD and (4) Classical Hodgkin Lymphoma type PTLD. The incidence of PTLD varies between different transplanted organs. Across all transplants monomorphic PTLD is the most common accounting for 75% of all cases. Lymphoma derived of B- cell origin account for the majority of cases (70%), while T-cell neoplasms represent a small minority (5%). Within monomorphic PTLD 50% of cases demonstrate association with the Epstein Barr Virus (EBV). Polymorphic PTLD accounts for 15-20% of all PTLD cases with the majority demonstrating EBV involvement. Early lesions account for 5% of PTLD and are all uniformly associated with EBV as are all the cases of Classic Hodgkin Lymphoma type PTLD. The current understanding of the pathogenesis of PTLD is incomplete. Despite concerted efforts, the investigators are unable to predict who will develop PTLD and do not understand why only 1 - 2% of all transplant recipients develop these disorders.

Official Title
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A Phase II Multicenter Open Label Risk Stratified Sequential Treatment With Rituximab, Brentuximab Vedotin and Bendamustine (RBvB) in Patients Newly Diagnosed.

Conditions
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PTLD, Lymphoid Tumor, Hematopoietic/Lymphoid Cancer, Plasmacytic Hyperplasia PTLD, Infectious Mononucleosis, Florid Follicular Hyperplasia PTLD, Polymorphic PTLD, Monomorphic PTLD, Classical Hodgkin Lymphoma Type PTLD

Intervention / Treatment
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* Drug: Rituximab
* Drug: Brentuximab Vedotin
* Drug: Bendamustine


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age ≥ 18 and ≤ 70 at the time of signing informed consent Patient must have histologically confirmed newly diagnosed polymorphic or monomorphic PTLD defined according to the 2016 World Health Organization (WHO) classification criteria. Diagnostic archival tissue available for review and correlative studies Previous solid organ or allogeneic hematopoietic stem cell transplant Measurable disease Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2 Patients must have adequate organ and marrow function Negative urine or serum pregnancy test for women of childbearing potential Patients must be able to understand and to sign a written consent document. Exclusion Criteria: Previous treatment for PTLD with the exception of immunosuppression reduction Known involvement of the central nervous system by the PTLD Known allergic reactions against foreign proteins Uncontrolled inter-current illness including active infection, acute graft versus host disease and/or transplant organ rejection Active concurrent malignancy with the exception of non-melanoma skin cancer, carcinoma in situ of the cervix or localized prostate cancer Severe non-compensated diabetes mellitus Pre-existing neuropathy grade 2 or greater Pregnant or lactating Psychiatric illness / social situations that would limit compliance with study requirements Patients with previous hypersensitivity to Rituximab Known HIV positive.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 70 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
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Interventional Model Description: This is an open label, sequential, risk stratified study.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Low Risk<br>Low risk patients (those in complete response (CR) after induction) will receive rituximab (375mg/m2) and brentuximab vedotin (1.8mg/m2) on day 1 of 21 day cycles, for 4 cycles. | Drug: Rituximab<br>* Rituximab is dosed at 375mg/m2 as an intravenous infusion. No adjustments are necessary for hepatic or renal impairment. Dosing will be done on baseline weight and height, however in patients who experience a >10% change in weight dosing will be readjusted.<br>* Other names: Rituxan;Drug: Brentuximab Vedotin<br>* Brentuximab vedotin is to be given as intravenous infusion at a dose of 1.2mg/kg during induction and 1.8mg/kg with each cycle. Dose reductions to 1.2mg/kg are allowed at investigator discretion.<br>* Other names: Adcetris;|
| Active Comparator: High Risk<br>High risk patients (those who do not achieve a CR after induction), will receive rituximab (375mg/m2) and brentuximab vedotin (1.8mg/m2) on day 1 and bendamustine (90mg/m2) on day 1-2 of 21 day cycles for up to 8 cycles. Interim imaging will be performed in cycle 4 (days 14-21) and patients achieving CR will receive additional 2 cycles for a total of 6, patients achieving partial response (PR) will receive 4 additional cycles. | Drug: Rituximab<br>* Rituximab is dosed at 375mg/m2 as an intravenous infusion. No adjustments are necessary for hepatic or renal impairment. Dosing will be done on baseline weight and height, however in patients who experience a >10% change in weight dosing will be readjusted.<br>* Other names: Rituxan;Drug: Brentuximab Vedotin<br>* Brentuximab vedotin is to be given as intravenous infusion at a dose of 1.2mg/kg during induction and 1.8mg/kg with each cycle. Dose reductions to 1.2mg/kg are allowed at investigator discretion.<br>* Other names: Adcetris;Drug: Bendamustine<br>* Bendamustine is to be given intravenously at a dose of 90mg/m2 on day 1 and day 2 of each high risk cycle. Dose reductions to 60mg/m2 are allowed at investigator discretion.<br>* Other names: Bendamustine hydrochloride;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall response rate (ORR) (complete + partial response rate) | Overall response rate (ORR) (complete + partial response rate) of the combination of rituximab, brentuximab vedotin +/-bendamustine in patients. | Up to 84 days of treatment (4 cycles of treatment) | 
| Progression free survival (PFS) rate | Progression free survival (PFS) of the combination of rituximab, brentuximab vedotin +/-bendamustine in patients. | Up to 84 days of treatment (4 cycles of treatment) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| ORR at the end of the induction phase | ORR at the end of the induction phase with rituximab and brentuximab vedotin (RBv) in patients | Up to 126 days of treatment (6 cycles of treatment) | 
| Duration of response (DOR) | duration of response (DOR) of the combination of rituximab, brentuximab vedotin +/-bendamustine in patients with newly diagnosed polymorphic and monomorphic CD20+ and CD 30+ PTLD. | Up to 84 days of treatment (4 cycles of treatment) | 
| Overall survival (OS) | Overall survival (OS) of the combination of rituximab, brentuximab vedotin +/-bendamustine in patients with newly diagnosed polymorphic and monomorphic CD20+ and CD 30+ PTLD | 3 years |