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

June 21, 2022 updated by: FRANCESCA MONTANARI, Yale University

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

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).

Study Overview

Status

Withdrawn

Conditions

Intervention / Treatment

Detailed Description

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.

Study Type

Interventional

Phase

  • Phase 2

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • United States
    • Connecticut
      • New Haven, Connecticut, United States, 06519
        • Yale University
    • Minnesota
      • Rochester, Minnesota, United States, 55902
        • Mayo Clinic

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years to 70 years (Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

Inclusion Criteria:

  1. Age ≥ 18 and ≤ 70 at the time of signing informed consent
  2. Patient must have histologically confirmed newly diagnosed polymorphic or monomorphic PTLD defined according to the 2016 World Health Organization (WHO) classification criteria.
  3. Diagnostic archival tissue available for review and correlative studies
  4. Previous solid organ or allogeneic hematopoietic stem cell transplant
  5. Measurable disease
  6. Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2
  7. Patients must have adequate organ and marrow function
  8. Negative urine or serum pregnancy test for women of childbearing potential
  9. Patients must be able to understand and to sign a written consent document.

Exclusion Criteria:

  1. Previous treatment for PTLD with the exception of immunosuppression reduction
  2. Known involvement of the central nervous system by the PTLD
  3. Known allergic reactions against foreign proteins
  4. Uncontrolled inter-current illness including active infection, acute graft versus host disease and/or transplant organ rejection
  5. Active concurrent malignancy with the exception of non-melanoma skin cancer, carcinoma in situ of the cervix or localized prostate cancer
  6. Severe non-compensated diabetes mellitus
  7. Pre-existing neuropathy grade 2 or greater
  8. Pregnant or lactating
  9. Psychiatric illness / social situations that would limit compliance with study requirements
  10. Patients with previous hypersensitivity to Rituximab
  11. Known HIV positive.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Non-Randomized
  • Interventional Model: Sequential Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Active Comparator: Low Risk
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
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.
Other Names:
  • Rituxan
Drug: Brentuximab Vedotin
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.
Other Names:
  • Adcetris
Active Comparator: High Risk
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
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.
Other Names:
  • Rituxan
Drug: Brentuximab Vedotin
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.
Other Names:
  • Adcetris
Drug: Bendamustine
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.
Other Names:
  • Bendamustine hydrochloride

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Overall response rate (ORR) (complete + partial response rate)
Time Frame: Up to 84 days of treatment (4 cycles of treatment)
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
Time Frame: Up to 84 days of treatment (4 cycles of treatment)
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
Time Frame: Up to 126 days of treatment (6 cycles of treatment)
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)
Time Frame: Up to 84 days of treatment (4 cycles of treatment)
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)
Time Frame: 3 years
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

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Yale University

Investigators

  • Principal Investigator: Francesa Montanari, MD, Yale University

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Anticipated)

January 1, 2022

Primary Completion (Anticipated)

September 1, 2023

Study Completion (Anticipated)

December 1, 2023

Study Registration Dates

First Submitted

October 23, 2019

First Submitted That Met QC Criteria

October 23, 2019

First Posted (Actual)

October 25, 2019

Study Record Updates

Last Update Posted (Actual)

June 23, 2022

Last Update Submitted That Met QC Criteria

June 21, 2022

Last Verified

June 1, 2022

More Information

Terms related to this study

Additional Relevant MeSH Terms

Other Study ID Numbers

  • 2000029609

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

Yes

Studies a U.S. FDA-regulated device product

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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