A Phase II Study of Rituximab, Lenalidomide, and Ibrutinib Combined With Chemotherapy For Patients With High Risk Diffuse Large B-Cell Lymphoma
Jason R. Westin
The goal of this clinical research study is to learn if the combination of rituximab, lenalidomide, and ibrutinib, when given alone and with standard chemotherapy (called either "EPOCH" - Etoposide, Prednisone, Oncovin [vincristine], Cyclophosphamide, and Hydrodaunorubicin [doxorubicin] or "R-CHOP" - Rituximab, Cyclophosphamide, Hydrodaunorubicin [doxorubicin], Oncovin [vincristine], and Prednisone), can help to control diffuse large B cell lymphoma. The safety of this drug combination will also be studied.
Disease Group: Lymphoma
Treatment Agent: Cyclophosphamide,Doxorubicin,Etoposide,Ibrutinib,Lenalidomide,Prednisone,Rituximab,Vincristine
Treatment Location: Only at MDACC
Sponsor: Celgene (Supporter),Janssen Scientific Affairs, LLC (Supporter)
Primary Endpoint 1: To determine the overall response rate at the end of 2 cycles of therapy with rituximab, lenalidomide, and ibrutinib in patients with high risk newly diagnosed non-GCB DLBCL Primary Endpoint 2: To determine the complete response rate at the end of 6 cycles of therapy with rituximab, lenalidomide, and ibrutinib combined with chemotherapy (CHOP or EPOCH) in patients with high risk newly diagnosed non-GCB DLBCL Secondary Endpoint 1: To determine the overall response rate, landmark survival outcomes (progression free and overall survival), and safety of lenalidomide and ibrutinib with chemotherapy (CHOP or EPOCH) in patients with high risk newly diagnosed non-GCB DLBCL. Secondary Endpoint 2: To evaluate descriptively the complete response rate in RLI-CHOP and in RLI-EPOCH. Exploratory objectives: To evaluate the baseline and therapy induced changes in the profile of mutations, gene expression, minimal residual disease clonotype levels, immune cell subsets, and tumor protein expression in tumor biopsy and blood samples in patients with high risk newly diagnosed non-GCB DLBCL.
IRB Review and Approval Date: 03/29/2016
Recruitment Status: Open
Projected Accrual: N/A
1) Histopathologially confirmed diagnosis of previously untreated DLBCL
of the non-GCB DLBCL subtype.
2) No prior treatment except a prior limited-field radiotherapy, a short course of glucocorticoids </= 25mg daily of prednisone equivalent which must cease prior to day 1 of cycle 1, and/or cyclophosphamide for an urgent lymphoma related problem at diagnosis (e.g. epidural cord compression, superior vena cava syndrome).
3) Patient or durable power of attorney (DPA) for healthcare must be able to understand and voluntarily sign an IRB-approved informed consent form.
4) Age >/=18 years at the time of signing the informed consent.
5) Patients must have bi-dimensional measurable disease, as defined as radiographically apparent disease with the longest dimension of >/= 1.5cm.
6) Patients with performance status of </=3 (3 only allowed if decline in status is deemed related to lymphoma and felt potentially reversible by the treating physician)
7) Serum bilirubin <1.5x ULN except in patients with Gilbert’s syndrome as defined by > 80% unconjugated bilirubin; AST (SGOT) and ALT (SGPT) </= 3x ULN or < 5x ULN if hepatic metastases are present; ANC >1000/mm^3 and platelets >100,000/mm^3 unless deemed related to lymphoma involvement in the bone marrow and felt potentially reversible by the treating physician.
8) Renal function assessed by calculated creatinine clearance: a. Calculated creatinine clearance >/=30ml/min by Cockcroft-Gault formula. See section below, Dosing Regimen, regarding lenalidomide dose adjustment for calculated creatinine clearance >/=30ml/min and < 60ml/min.
9) Patients must be willing to receive transfusions of blood products.
10) All study participants must be registered into the mandatory Revlimid REMS® program, and be willing and able to comply with the requirements of the REMS® program.
11) Women of childbearing potential must have a negative serum (Beta-human chorionic gonadotropin [Beta-hCG]) or urine pregnancy test at screening and must adhere to the scheduled pregnancy testing as required in the Revlimid REMS® program.
12) Women of childbearing potential and men who are sexually active with a woman of childbearing potential must be practicing a highly effective method of birth control during and after the study (12 months for women and 3 months for men), consistent with local regulations regarding the use of birth control methods for subjects participating in this clinical study. Men must agree to not donate sperm during and for up to 3 months after their conclusion of therapy on study.
13) Able to take aspirin (81mg) daily or alternative therapy as prophylactic anticoagulation.
1) 1. Any serious medical condition including but not limited to
uncontrolled hypertension, uncontrolled congestive heart failure within
past 6 months prior to screening (Class 3 (moderate) or Class 4 (severe)
cardiac disease as defined by the New York Heart Association Functional
Classification), uncontrolled diabetes mellitus, active/symptomatic
coronary artery disease, COPD, LVEF less than 40%, renal failure, active
infection, history of invasive fungal infection, moderate to severe
hepatic disease (Child Pugh Class B or C), active hemorrhage, laboratory
abnormality, or psychiatric illness that, in the investigators opinion
places the patient at unacceptable risk and would prevent the subject
from signing the informed consent form. Patients with history of cardiac
arrhythmias should have cardiac evaluation and clearance.
2) Pregnant or lactating females.
3) Known hypersensitivity to lenalidomide or thalidomide, ibrutinib, rituximab, etoposide, vincristine, doxorubicin, cyclophosphamide, or prednisone.
4) Known HIV infection. Patients with active hepatitis B infection (not including patients with prior hepatitis B vaccination; or positive serum Hepatitis B antibody). Known hepatitis C infection is allowed as long as there is no active disease and is cleared by GI consultation.
5) All patients with central nervous system involvement with lymphoma.
6) Diagnosis of prior malignancy within the past 2 years with the exception of successfully treated basal cell carcinoma, squamous cell carcinoma of the skin, carcinoma "in situ" of the cervix or breast. History of other malignancies are allowed if in remission (including prostate cancer patients in remission from radiation therapy, surgery or brachytherapy), not actively being treated, with a life expectancy > 3 years.
7) Significant neuropathy (Grades 2 or Grade 1 with pain) within 14 days prior to enrollment
8) Contraindication to any of the required concomitant drugs or supportive treatments or intolerance to hydration due to preexisting pulmonary or cardiac impairment including pleural effusion requiring thoracentesis or ascites requiring paracentesis not due to lymphoma.
9) Patients with active pulmonary embolism or deep vein thrombosis (diagnosed within 30 days of study enrollment).
10) Patients with severe bradycardia (heart rate <40 bpm, hypotension, light-headedness, syncope).
11) Major surgery within 4 weeks of study entry, or wound that is not healed from prior surgery or trauma.
12) History of stroke or intracranial hemorrhage within 6 months prior to study entry.
13) Requires anticoagulation with warfarin or equivalent vitamin K antagonists.
14) Requires chronic treatment with strong CYP3A inhibitors
15) Vaccinated with live, attenuated vaccines within 4 weeks of study entry
Information and next steps
Jason R. Westin
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