Clinical trial NCT04138875: 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
Overall status: WITHDRAWN
Phase: PHASE2
Conditions: PTLD
Lymphoid Tumor
Hematopoietic/Lymphoid Cancer
Plasmacytic Hyperplasia PTLD
Infectious Mononucleosis
Florid Follicular Hyperplasia PTLD
Polymorphic PTLD
Monomorphic PTLD
Classical Hodgkin Lymphoma Type PTLD
Lead sponsor: Yale University
Sponsor class: OTHER
First posted: 2019-10-25
Enrollment: 0
Sex: ALL
Minimum age (years): 18
Maximum age (years): 70
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SEQUENTIAL
Intervention model description: This is an open label, sequential, risk stratified study.
Primary purpose: TREATMENT

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.

Eligibility criteria: 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.

Primary outcomes:
measure: Overall response rate (ORR) (complete + partial response rate)
timeFrame: Up to 84 days of treatment (4 cycles of treatment)
measure: Progression free survival (PFS) rate
timeFrame: Up to 84 days of treatment (4 cycles of treatment)
Secondary outcomes:
measure: ORR at the end of the induction phase
timeFrame: Up to 126 days of treatment (6 cycles of treatment)
measure: Duration of response (DOR)
timeFrame: Up to 84 days of treatment (4 cycles of treatment)
measure: Overall survival (OS)
timeFrame: 3 years
Other outcomes:
Locations:
city: New Haven
country: United States
facility: Yale University
state: Connecticut
city: Rochester
country: United States
facility: Mayo Clinic
state: Minnesota
Study officials:
affiliation: Yale University
name: Francesa Montanari, MD
role: PRINCIPAL_INVESTIGATOR
References: