A Phase II Study of Ibrutinib plus Rituximab with Hyper-CVAD Consolidation in Newly Diagnosed Young Patients with Mantle Cell Lymphoma: A Window Period for Bioimmunotherapy before Chemotherapy
The goal of this clinical research study is to learn if a combination of ibrutinib and rituximab plus the combination of 2 different intensive chemotherapy regimens can help to control MCL. The safety of this drug combination will also be studied.
Disease Group: Lymphoma
Treatment Agent: Cytarabine,Hyper-CVAD,Ibrutinib,Methotrexate,Rituximab
Treatment Location: Only at MDACC
Primary Objectives · To evaluate the response rate of ibrutinib plus rituximab in young newly diagnosed mantle cell lymphoma (MCL) patients. Secondary Objectives · To evaluate the Progression Free Survival of ibrutinib plus rituximab with rituximab – cyclophosphamide, vincristine, doxorubicin, and dexamethasone (Hyper-CVAD) consolidation in newly diagnosed MCL patients. · To further evaluate the toxicity profile of the ibrutinib/rituximab combination and consolidation therapy · To estimate the rate of complete response (CR) prior to and following consolidation therapy. · To estimate the response duration and overall survival.
IRB Review and Approval Date: 06/03/2015
Recruitment Status: Open
Projected Accrual: N/A
1) Patient has a confirmed diagnosis of mantle cell lymphoma with
B-lymphocyte antigen CD20 (CD20) positivity in tissue biopsy.
2) Patients with MCL must be symptomatic and need immediate therapy. Symptoms and nature of MCL include any of the following: a) blastoid variant; b) pleomorphic variant; c) B symptoms, d) MIPI > 3, e) Ki 67 >/= 30%, f) bulky tumors > 7 cm or in case of >/=2 tumors, each >/=5 cm in diameter, g) disease threatening organ function, h) elevated LDH, i) PB WBC > 50,000, j) pancytopenia due to bone marrow MCL, k) patient’s choice due to anxiety; l) pain due to lymphoma; m) somatic mutations in the TP53, c-MYC or NOTCH genes; n) size of spleen >/=20 cm
3) Patient has newly diagnosed disease with no prior therapy.
4) Understand and voluntarily sign an IRB-approved informed consent form.
5) Age </= 65 years at the time of signing the informed consent.
6) Patients should have bi-dimensional measurable disease using the Cheson criteria (Measureable disease by CT scan defined as at least 1 lesion that measures =/>1.5 cm in single dimension.) Gastrointestinal or bone marrow or spleen only patients are allowable.
7) Eastern Cooperative Oncology Group (ECOG) performance status of 2 or less
8) An absolute neutrophil count (ANC) > 1,000/mm^3 and platelet count >100,000/mm^3 (Patients who have bone marrow infiltration by MCL are eligible if their ANC is >/= 500/mm^3 [growth factor allowed] or their platelet level is equal to or > than 20,000/mm^3. These patients should be discussed with either the principal investigator (PI) or Co-PI of the study for final approval).
9) Serum bilirubin <1.5 mg/dl and Cr Clearance >/= 30 mL/min, Aspartate transaminase (AST)/ serum glutamic oxaloacetic transaminase (SGOT) and Alanine transaminase (ALT)/ serum glutamic-pyruvic transaminase (SGPT) < 2 x upper limit of normal or < 5 x upper limit of normal if hepatic metastases are present. Gilbert’s disease is allowed.
10) Cardiac ejection fraction >/= 50% by Echocardiogram (ECHO) or multiple gated acquisition scan (MUGA).
11) Disease free of prior malignancies with exception of currently treated basal cell, squamous cell carcinoma of the skin, carcinoma "in situ" of the cervix or breast, or other malignancies in remission (including prostate cancer patients in remission from radiation therapy, surgery or brachytherapy), not actively being treated.
12) Females of childbearing potential (FCBP)* must have a negative serum or urine pregnancy test (within 30 days of initiation of protocol therapy) and must be willing to use acceptable methods of birth control. Men must agree to use a latex condom during sexual contact with a female of childbearing potential even if they have had a successful vasectomy. *A female of childbearing potential is a sexually mature woman who: 1) has not undergone a hysterectomy or bilateral oophorectomy; or 2) has not been naturally postmenopausal for at least 24 consecutive months (i.e., has had menses at any time in the preceding 24 consecutive months).
1) Any serious medical condition including but not limited to,
uncontrolled hypertension, uncontrolled diabetes mellitus,
active/symptomatic coronary artery disease, chronic obstructive
pulmonary disease (COPD), renal failure, active hemorrhage, 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.
2) Pregnant or breast feeding females.
3) Known human immunodeficiency virus (HIV) infection.
4) Patients with active Hepatitis B or C infection (not including patients with prior Hepatitis B vaccination.) These patients should be cleared by gastrointestinal (GI) consultation for Hepatitis B and Infectious Disease consult for Hepatitis C.
5) All patients with central nervous system lymphoma.
6) Significant neuropathy (Grades 3 - 4, or Grade 2 with pain) within 14 days prior to enrollment.
7) 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 unless due to lymphoma.
8) Malabsorption syndrome, disease significantly affecting gastrointestinal function, or resection of the stomach or small bowel or ulcerative colitis, symptomatic inflammatory bowel disease, or partial or complete bowel obstruction, or any other gastrointestinal condition that could interfere with the absorption and metabolism of ibrutinib.
9) Major surgery within 4 weeks of initiation of therapy. Clearance letter from primary physician required.
10) Requires anticoagulation with warfarin or equivalent vitamin K antagonist.
11) Requires treatment with strong Cytochrome P4503A (CYP3A) inhibitors
12) Patients with New York Heart Association (NYHA) Class III and IV heart failure, myocardial infarction in the preceding 6 months, and significant conduction abnormalities, including but not limited to 2nd degree atrioventricular block (AV block) type II, 3rd degree block, QT prolongation (QTc > 500 msec), sick sinus syndrome, ventricular tachycardia, symptomatic bradycardia (heart rate < 50 bpm), hypotension, light headedness and syncope. Patients with persistent and uncontrolled atrial fibrillation will be excluded. The protocol excludes patients who have recently had a stent and by recommendation of their cardiologist need to stay on anticoagulants such as warfarin or equivalent vitamin K antagonist.
13) Acute infection requiring treatment (IV antibiotics, antivirals, or antifungals) within 14 days prior to initiation of study.
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