R-EPOCH in Combination With Ibrutinib for Patients With Classical RT of CLL

Study Overview
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Brief Summary
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This is an investigator-initiated Phase 2 study, which combines R-EDOCH with Ibrutinib to treat patients with Ritcher Transformation in consideration of DLBCL and CLL components both could being targeted at the same time. The investigator will observe the 2-year overall survival rate of this regimen for RT and explore the new regimen for RT in the novel drugs era, which aims to improve the efficacy and prolong survival.

Official Title
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A Multicenter Phase 2 Study of R-EPOCH in Combination With Ibrutinib for Patients With Classical Richter Transformation of Chronic Lymphocytic Leukemia

Conditions
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Richter Transformation

Intervention / Treatment
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* Drug: R-EPOCH in Combination With Ibrutinib


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age 18-65 years ECOG 0-2 Confirmed Richter transformation, whether or not previously treated Unexposed to BTKi, or discontinue BTKi more than 1 year (due not to toxicity or ineffectiveness) No serious liver, kidney, heart and other complications; including: a. alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 3 times the upper limit of normal (ULN); b. total bilirubin (TBIL) ≤ 1.5 times the ULN; c. serum creatinine (Cr) ≤ 2 times the ULN, or glomerular filtration rate ≥ 40ml/min; d. LVEF > 50% determined by echocardiography; e. no arrhythmia and active heart disease, such as coronary heart disease, myocardial infarction, etc The patient agreed to participate and signed the informed consent form Exclusion Criteria: Major surgery within 4 weeks prior to first dose of ibrutinib Require receiving anticoagulation with warfarin or equivalent Vitamin K antagonists; Requires treatment with a strong CYP3A4/5 inhibitor Require corticosteroid , anti-cancer drugs, immunomodulatory or Chinese medicine for other medical conditions Pregnant or lactating women History of prior malignancy Currently active clinically significant cardiovascular disease Uncontrolled active systemic fungal, bacterial, viral, or other infection Known history of human immunodeficiency virus (HIV) or active infection with Hepatitis B or Hepatitis C History of stroke or intracranial hemorrhage prior to randomization Other conditions that is unfit for the clinical trial in the investigator' opinion

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 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
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: R-EPOCH plus IBR for RT<br> | Drug: R-EPOCH in Combination With Ibrutinib<br>* Induction: (21-day per cycle) Ibrutinib:420mg given orally , once daily. Details of R-DA-EPOCH are as follows: Rituximab: 375 mg/m2 given intravenously (IV) on day 0 Etoposide: 50 mg/m2 given CIV from day 1-4 Doxorubicin: 10 mg/m2 given CIV from day 1-4 Vincristine: 0.4 mg/m2 given CIV from day 1-4 Cyclophosphamide: 750 mg/m2/day IV on day 5 Prednisone: 60 mg/m2 given orally bid on days 1-5. Patients who achieve CR after 4 cycles enter the consolidation treatment ; Patients with PR after 4 cycles would receive another 2 cycles of R-EPOCH + ibrutinib induction therapy, they could enter the consolidation treatment if they achieve CR ,withdrawn from the study if they achieve ≤ PR; Patients with SD/PD after 4 cycles of treatment are withdrawn from the study. Consolidation: 2 cycles of R-EPOCH + Ibrutinib (dose as before) treatment Maintenance: Ibrutinib 420 mg/day for 24 months or until disease progression or intolerable toxicity<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 2-year overall survival rate (OS) | Defined as the time interval from enrollment to death of patients in the intent-to-treat population (ITT). If the patient is alive or death of the patient is unknown, the date of death will be the latest time point at which the patient was known to be alive. | 2 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Complete response rate (CRR) | Defined as the percentage of subjects who achieved CR after treatment in the per-protocol population as well as in the intent-to-treat population. | 1 month after completion of consolidation therapy | 
| Overall response rate (ORR) | Defined as the percentage of subjects who achieved CR + PR after treatment in the per-protocol population and the intention-to-treat population. | 1 month after completion of consolidation therapy | 
| Progression-free survival (PFS) | Defined as the time interval from enrollment to disease progression or death, whichever occurred first, for patients in the intent-to-treat (ITT) population. If there is no progression or time of disease progression is not recorded at the time of withdrawal from the trial, the date of the last examination will be used as the endpoint date. | 2 years | 
| Minimal residual disease (MRD) negative rate | For patients with bone marrow invasion, on the basis of CR, multicolor flow cytometry detects that tumor cells account for the proportion of nuclear cells, and < 0.01% are MRD negative. | 1 month after completion of consolidation therapy | 
| Toxic side effects | Non-hematologic toxicity was evaluated according to NCI CTCAE 5.0 criteria; hematologic toxicity was evaluated according to NCI CLL 2018 criteria | 3 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Richter transformation, chronic lymphocytic leukemia, R-EPOCH, Ibrutinib, Therapeutics