Defining ctDNA Metrics in Posttransplant Lymphoproliferative Disorder (PTLD)

Official title

Defining the Role of ctDNA Monitoring in a Risk Stratified Clinical Trial for Posttransplant Lymphoproliferative Disorder (PTLD)

Overview

The purpose of this study is to find out if there is a benefit to giving rituximab with etoposide, prednisone, vincristine, cyclophosphamide and doxorubicin (R-EPOCH) in participants who have high-risk B-cell PTLD in their 2nd phase of treatment (consolidation) while those with low-risk disease will be spared of chemotherapy and treated with rituximab consolidation alone. This study is also being done to find out about the usefulness of circulating tumor DNA (ctDNA), a novel blood test which, has been shown to help guide treatment decisions in other types of lymphoma. The goal is to answer the question if ctDNA is a viable and informative tool in treating PTLD with the hope that in the future it may be used to individualize study treatment for participants with PTLD in a way that limits study treatment toxicity without losing the effectiveness of the treatment plan.

Detailed description

This is a multi-center, phase 2, open-label clinical trial to evaluate the efficacy of dose modified R-EPOCH in high-risk, treatment naïve CD20+ posttransplant lymphoproliferative disorder (PTLD) patients. The purpose of this study is to define the benefit of rituximab with etoposide, prednisone, vincristine, cyclophosphamide and doxorubicin (R-EPOCH) in patients who have high-risk B cell PTLD while those with low-risk disease will be spared of chemotherapy and treated with rituximab alone. Concurrently this study also seeks to evaluate the usefulness of circulating tumor DNA (ctDNA), a novel blood test which has been shown to improve a physician's ability to prognosticate and guide treatment decisions in other types of lymphoma. The goal is to demonstrate that ctDNA is a viable and informative tool in treating PTLD with the hope that in the future it may be used to individualize treatment for patients with PTLD in a way that limits treatment toxicity without losing the effectiveness of the treatment plan.

Interventions

• Drug Rituximab
  Rituximab is a genetically engineered chimeric murine/human monoclonal IgG1 kappa antibody directed against the CD20 antigen. The Fab domain of rituximab binds to the CD20 antigen on B lymphocytes, and the Fc domain recruits immune effector functions to mediate B cell lysis. 375 mg/m2 Rituximab will be administered to participants by IV.
• Drug Etoposide
  Etoposide is a topoisomerase II inhibitor and appears to cause DNA strand breaks. It has been shown to delay transit of cells through S phase and arrest cells in late S or early G2 phase. 50 mg/m2 Etoposide will be administered to participants by IV.
• Drug Prednisone
  Prednisone can prevent or suppress inflammation and immune responses. Prednisone's action may include the inhibition of leukocyte infiltration at the site of inflammation, interference in the function of mediators of inflammatory response, and suppression of humoral immune responses. 60 mg/m2 Prednisone will be administered to participants by PO.
• Drug Vincristine
  Vincristine is a vinca alkaloid. The mechanism of action of vincristine is thought to be due to inhibition of microtubule formation in the mitotic spindle. This leads to arrest of dividing cells during the metaphase stage. 0.4 mg/m2 Vincristine will be administered to participants by IV.
• Drug Cyclophosphamide
  The mechanism of action is thought to involve cross-linking of tumor cell DNA. Cyclophosphamide is biotransformed principally in the liver to active alkylating metabolites which are thought to cross-link to tumor cell DNA. These metabolites interfere with the growth of rapidly proliferating susceptible malignant cells. 375 mg/m2 Cyclophosphamide will be administered to participants by IV.
• Drug Doxorubicin
  Doxorubicin is an anthracycline, topoisomerase II inhibitor. It is isolated from cultures of Streptomyces peucetius var. caesius. The cytotoxic effect of doxorubicin is related to nucleotide base intercalation and cell membrane lipid binding activities. It blocks nucleotide replication and the action of DNA and RNA polymerases. The interaction between doxorubicin and topoisomerase II to form DNA-cleavable complexes appears to be an important mechanism of its cytocidal activity. 10 mg/m2 Doxorubi
• Device CAPP-seq
  Next generation sequencing (NGS) tool used to detect tiny amounts of cancer DNA in the blood, allowing for early diagnosis and monitoring of cancer in a non-invasive way.

Primary outcome measures

• Number of participants with Complete Response (CR) rate of 60% or higher [Time frame: Up to 3 years]

Secondary outcome measures (7)

• Circulating tumor DNA (ctDNA) rate [Time frame: Up to 3 years]
• Event Free Survival rate [Time frame: Up to 3 years]
• Duration of Overall Response (OR) [Time frame: Up to 3 years]
• Duration of stable disease [Time frame: Up to 3 years]
• Progression-Free Survival (PFS) rate [Time frame: Up to 3 years]
• Early Molecular Response (EMR) rate [Time frame: Up to 3 years]
• Measurable Residual Disease (MRD) rate [Time frame: 8 weeks]

Eligibility criteria

Inclusion criteria

• Histologically confirmed CD20+ PTLD including the below subtypes:

• Polymorphic
• Monomorphic
• Age ≥ 15.
• Participants must have measurable disease, defined as lymph node ≥ 1.5 cm in greatest diameter per Lugano Classification
• Patients must have a PET-CT scan (preferred; alternatively CT chest, abdomen and pelvis with IV contrast) performed within 28 days prior to the start of the study.
• All participants must be screened for chronic hepatitis B virus (HBV) within 28 days prior to registration. Participants with known HBV infection (positive serology) must also have a HBV viral load performed within 28 days prior to registration, and participants must have an undetectable HBV viral load on suppressive therapy within 28 days prior to start of treatment. Participants found to be HBV carriers during screening are eligible and must receive standard of care prophylaxis. Participants with active Hepatitis B (HBV viral load > 500 IU/mL) within 28 days prior to registration are not eligible.
• Participants with a history of hepatitis C virus (HCV) infection must have been treated and cured. Participants with an active HCV infection who are currently on treatment must have an undetectable HCV viral load within 28 days prior to registration.
• Participants with known human immunodeficiency virus (HIV)-infection are eligible providing they are on effective anti-retroviral therapy and have undetectable viral load at their most recent viral load test (must be within 26 weeks prior to registration). Participants with known HIV must have a CD4 count checked within 28 days prior to registration, but may proceed with therapy regardless of CD4 count.
• Organ function as assessed by laboratory testing is in appropriate range for receipt of rituximab and R-EPOCH per individual treating physician discretion.
• Cardiac function testing is in appropriate range for receipt of rituximab and R-EPOCH per individual treating physician discretion.
• Eastern Cooperate Oncology Group (ECOG) performance status is in appropriate range for receipt of rituximab and R-EPOCH per individual treating physician discretion.
• Ability to understand and the willingness to sign a written informed consent document. In cases of partial impairment, impairment that fluctuates over time, or complete impairment due to dementia, stroke, traumatic brain injury, developmental disorders (including mentally disabled persons), serious mental illness, and delirium, a subject may be enrolled if the subject's legally authorized representative consents on the subject's behalf.
• Due to the potential teratogenic effects of chemotherapy, women of childbearing age must have a documented negative serum β-hCG measured within 2 weeks of starting treatment.
• Both women of childbearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence).
• Women must agree to not breastfeed during the entirety of the study period.
• Participants must not have had chemotherapy for other indications within 4 weeks (6 weeks for nitrosoureas or mitomycin C) prior to entering the study and must have recovered from adverse events due to agents administered more than 4 weeks earlier.
• Participants must not have received more than a cumulative of dose 250 mg/m 2 of prior doxorubicin (or equivalent dose of another anthracycline, such as epirubicin) therapy (at any time prior to registration).
• Intrathecal chemotherapy administered for CNS prophylaxis is allowed in addition to protocol therapy per institution practice.

Exclusion criteria

• Patients who have received systemic chemotherapy for PTLD.
• Patients who have known lymphomatous involvement of the central nervous system (CNS).

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Non-randomized

Model

Parallel assignment

Masking

Open label

Primary purpose

Treatment

Study locations

United States · 2 centers

• Stanford Medical Center — Stanford
• Columbia University Irving Medical Center — New York

Identifiers

NCT: NCT06954805 · AAAV2404

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗