Bortezomib and Ibrutinib in Treating Patients with Relapse Mantle Cell Lymphoma

Inclusion Criteria

• Adult patients with history of MCL that has relapsed (documented disease progression after previously responding for at least 6 months to therapy (complete response [CR]/partial response [PR]) on single agent ibrutinib as the last treatment prior to enrollment
• Total bilirubin < 1.5 mg/dl
• Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =< 2.5 x upper limit of normal (ULN)
• Creatinine clearance (CrCL) > 30 mL/minute
• Absolute neutrophil count (ANC) > 1000 (750 if known bone morrow [BM] involvement)
• Platelet > 75 K (or 50 K if known BM involvement)
• Hemoglobin (Hgb) > 8.0 g/dL
• Prothrombin time (PT)/international normalized ratio (INR) < 1.5 x ULN and partial thromboplastin time (PTT) (activated partial thromboplastin time [aPTT]) < 1.5 x ULN (unless abnormalities are unrelated to coagulopathy or bleeding disorder)
• Female subjects who are of non-reproductive potential (i.e., post-menopausal by history - no menses for >= 1 year; OR history of hysterectomy; OR history of bilateral tubal ligation; OR history of bilateral oophorectomy). Female subjects of childbearing potential must have a negative urine/serum pregnancy test upon study entry. Women as well are not advised to breastfeed during treatment with bortezomib and for 2 months after treatment
• Male and female subjects of reproductive potential who agree to use both a highly effective method of birth control (e.g., implants, injectables, combined oral contraceptives, some intrauterine devices [IUDs], complete abstinence, or sterilized partner) and a barrier method (e.g., condoms, vaginal ring, sponge, etc.) during the period of therapy and for 30 days after the last dose of study drug for females and 90 days for males * Complete abstinence is a highly effective method only if defined as refraining from heterosexual intercourse during the entire period of risk associated with the study treatments. The reliability of sexual abstinence needs to be evaluated in relation to the duration of the clinical trial and the preferred and usual lifestyle of the subject
• Diagnosis of mantle cell lymphoma established by histologic assessment by a hemato-pathologist with additional assessment of the histologic diagnosis by either one of the following: * Immunohistochemistry of the biopsy * Flow cytometry of the biopsy
• Eastern Cooperative Oncology Group (ECOG) performance status of < 2

Exclusion Criteria

• Concurrent diagnosis of another malignancy unless treated with curative intent more than 2 years from study start * Basal/squamous cell carcinoma of the skin is not included
• Previous treatment with bortezomib
• Patients who are eligible for autologous stem cell transplantation unless they refuse this procedure
• History of allogeneic stem cell transplant
• Vaccinated with live, attenuated vaccines within 4 weeks of first dose of study drug
• Recent infection requiring systemic treatment that was completed =< 14 days before the first dose of study drug
• Unresolved toxicities from prior anti-cancer therapy, defined as having not resolved to Common Terminology Criteria for Adverse Event (CTCAE, version 4.03), grade 0 or 1, or to the levels dictated in the inclusion/exclusion criteria with the exception of alopecia
• Known bleeding disorders (e.g., von Willebrand’s disease or hemophilia)
• History of stroke or intracranial hemorrhage within 6 months prior to enrollment
• Known history of human immunodeficiency virus (HIV) or active with hepatitis C virus (HCV) or hepatitis B virus (HBV). Subjects who are positive for hepatitis B core antibody, hepatitis B surface antigen, or hepatitis C antibody must have a negative polymerase chain reaction (PCR) result before enrollment. Those who are PCR positive will be excluded
• Any uncontrolled active systemic infection
• Major surgery within 4 weeks of first dose of study drug
• Any life-threatening illness, medical condition, or organ system dysfunction that, in the investigator’s opinion, could compromise the subject’s safety or put the study outcomes at undue risk
• Currently active, clinically significant cardiovascular disease, such as uncontrolled arrhythmia or class 3 or 4 congestive heart failure as defined by the New York Heart Association Functional Classification; or a history of myocardial infarction, unstable angina, or acute coronary syndrome within 6 months prior to randomization
• Fridericia's correction formula (QTCf) > 470 ms
• Concomitant use of warfarin or other vitamin K antagonists
• Use of a strong cytochrome P450 (CYP) 3A inhibitor/Inducer within 14 days of study start
• Currently active, clinically significant hepatic impairment Child-Pugh class B or C according to the Child Pugh classification
• Pregnant or breastfeeding women
• Grade 2 or higher peripheral neuropathy
• Concomitant therapy in the last 2 weeks of any of the following: cytotoxic chemotherapy, immunosuppressive agents, other investigational therapies
• Intolerance to ibrutinib
• Prior treatment with a proteasome inhibitor
• Patients with hypersensitivity (not including local reactions) to bortezomib, boron, or mannitol, including anaphylactic reactions
• Patients in need of immediate cytoreductive therapy