A Risk Stratified Sequential Treatment With Rituximab, Brentuximab Vedotin and Bendamustine (RBvB)
Primary Purpose
PTLD, Lymphoid Tumor, Hematopoietic/Lymphoid Cancer
Status
Withdrawn
Phase
Phase 2
Locations
United States
Study Type
Interventional
Intervention
Rituximab
Brentuximab Vedotin
Bendamustine
Sponsored by
About this trial
This is an interventional treatment trial for PTLD
Eligibility Criteria
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.
Sites / Locations
- Yale University
- Mayo Clinic
Arms of the Study
Arm 1
Arm 2
Arm Type
Active Comparator
Active Comparator
Arm Label
Low Risk
High Risk
Arm Description
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.
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.
Outcomes
Primary Outcome Measures
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.
Progression free survival (PFS) rate
Progression free survival (PFS) of the combination of rituximab, brentuximab vedotin +/-bendamustine in patients.
Secondary Outcome Measures
ORR at the end of the induction phase
ORR at the end of the induction phase with rituximab and brentuximab vedotin (RBv) in patients
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.
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
Full Information
1. Study Identification
Unique Protocol Identification Number
NCT04138875
Brief Title
A Risk Stratified Sequential Treatment With Rituximab, Brentuximab Vedotin and Bendamustine (RBvB)
Official Title
A Phase II Multicenter Open Label Risk Stratified Sequential Treatment With Rituximab, Brentuximab Vedotin and Bendamustine (RBvB) in Patients Newly Diagnosed.
Study Type
Interventional
2. Study Status
Record Verification Date
June 2022
Overall Recruitment Status
Withdrawn
Why Stopped
Lack of funding
Study Start Date
January 2022 (Anticipated)
Primary Completion Date
September 2023 (Anticipated)
Study Completion Date
December 2023 (Anticipated)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
Yale University
4. Oversight
Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
Yes
5. Study Description
Brief Summary
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
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.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
PTLD, Lymphoid Tumor, Hematopoietic/Lymphoid Cancer, Plasmacytic Hyperplasia PTLD, Infectious Mononucleosis, Florid Follicular Hyperplasia PTLD, Polymorphic PTLD, Monomorphic PTLD, Classical Hodgkin Lymphoma Type PTLD
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Sequential Assignment
Model Description
This is an open label, sequential, risk stratified study.
Masking
None (Open Label)
Allocation
Non-Randomized
Enrollment
0 (Actual)
8. Arms, Groups, and Interventions
Arm Title
Low Risk
Arm Type
Active Comparator
Arm Description
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.
Arm Title
High Risk
Arm Type
Active Comparator
Arm Description
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.
Intervention Type
Drug
Intervention Name(s)
Rituximab
Other Intervention Name(s)
Rituxan
Intervention Description
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.
Intervention Type
Drug
Intervention Name(s)
Brentuximab Vedotin
Other Intervention Name(s)
Adcetris
Intervention Description
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.
Intervention Type
Drug
Intervention Name(s)
Bendamustine
Other Intervention Name(s)
Bendamustine hydrochloride
Intervention Description
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.
Primary Outcome Measure Information:
Title
Overall response rate (ORR) (complete + partial response rate)
Description
Overall response rate (ORR) (complete + partial response rate) of the combination of rituximab, brentuximab vedotin +/-bendamustine in patients.
Time Frame
Up to 84 days of treatment (4 cycles of treatment)
Title
Progression free survival (PFS) rate
Description
Progression free survival (PFS) of the combination of rituximab, brentuximab vedotin +/-bendamustine in patients.
Time Frame
Up to 84 days of treatment (4 cycles of treatment)
Secondary Outcome Measure Information:
Title
ORR at the end of the induction phase
Description
ORR at the end of the induction phase with rituximab and brentuximab vedotin (RBv) in patients
Time Frame
Up to 126 days of treatment (6 cycles of treatment)
Title
Duration of response (DOR)
Description
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.
Time Frame
Up to 84 days of treatment (4 cycles of treatment)
Title
Overall survival (OS)
Description
Overall survival (OS) of the combination of rituximab, brentuximab vedotin +/-bendamustine in patients with newly diagnosed polymorphic and monomorphic CD20+ and CD 30+ PTLD
Time Frame
3 years
10. Eligibility
Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
70 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
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.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Francesa Montanari, MD
Organizational Affiliation
Yale University
Official's Role
Principal Investigator
Facility Information:
Facility Name
Yale University
City
New Haven
State/Province
Connecticut
ZIP/Postal Code
06519
Country
United States
Facility Name
Mayo Clinic
City
Rochester
State/Province
Minnesota
ZIP/Postal Code
55902
Country
United States
12. IPD Sharing Statement
Plan to Share IPD
No
Learn more about this trial
A Risk Stratified Sequential Treatment With Rituximab, Brentuximab Vedotin and Bendamustine (RBvB)
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