Venetoclax, Lenalidomide, and Rituximab in Treating Patients with Mantle Cell Lymphoma

Inclusion Criteria

• PHASE I: Age 18-80 years
• PAHSE I: Diagnosis of mantle cell lymphoma established by histologic assessment including one of the following: * Immunohistochemistry of the biopsy * Flow cytometry of the biopsy * Note: all patients should have evidence of cyclin D1 (11;14) translocation, and/or cyclin D1 expression by immunohistochemistry (IHC) unless disease is morphologically consistent with MCL and has IHC expression of SOX11
• PAHSE I: Laboratory, radiographic, physical exam findings and/or symptoms attributable to MCL
• PHASE I: Eastern Cooperative Oncology Group (ECOG) performance status 0, 1, or 2
• PHASE I: All study participants must be registered into the mandatory Revlimid Risk Evaluation and Mitigation Strategy (REMS) program, and be willing and able to comply with the requirements of the REMS program (including use of aspirin [ASA]/Food and Drug Administration [FDA] approved blood thinner)
• PHASE I: Females of reproductive potential must adhere to the scheduled pregnancy testing as required in the Revlimid REMS program
• PHASE I: Men and women of childbearing potential on appropriate contraception
• PHASE I: Total bilirubin =< x 1.5 upper limit of normal (ULN)
• PHASE I: Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =< 3.0 x ULN (unless due to disease related complications)
• PHASE I: Creatinine clearance (CrCL) (by either Cockcroft-Gault or direct measurement) > 60 mL/minute
• PHASE I: Absolute neutrophil count (ANC) >= 1000 (unless known bone marrow [BM] involvement); If bone marrow involvement noted then ANC >= 500
• PHASE I: Platelet >= 75K (unless known BM involvement); If bone marrow involvement noted then platelet >= 25k. Transfusion support is allowed to reach Hgb and platelet parameters
• PHASE I: Hemoglobin (Hgb) >= 7 g/dl; If bone marrow involvement noted then Hgb >= 6 g/dL. Transfusion support is allowed to reach Hgb and platelet parameters
• PHASE I: Ability to understand and the willingness to sign a written informed consent
• PHASE I: Ability to swallow oral capsules/tablets
• PHASE II: Age: 18-80 years
• PHASE II: Diagnosis of mantle cell lymphoma established by histologic assessment including one of the following: * Immunohistochemistry of the biopsy * Flow cytometry of the biopsy Note: all patients should have evidence of cyclin D1 (11;14) translocation, and/or cyclin D1 expression by IHC unless disease is morphologically consistent with MCL and has IHC expression of SOX11
• PHASE II: Laboratory, radiographic, physical exam findings and/or symptoms attributable to MCL
• PHASE II: ECOG performance status ≤ 2
• PHASE II: 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 (including use of ASA/FDA approved blood thinner)
• PHASE II: Females of reproductive potential must adhere to the scheduled pregnancy testing as required in the Revlimid REMS® program
• PHASE II: Agreement by females of childbearing potential* to use two reliable methods of birth control** or abstain from heterosexual activity for the course of the study treatment period through at least 12 months after the last dose of rituximab, and at least 30 days after the last dose of venetoclax and lenalidomide. Agreement by males of childbearing potential to use a condom for the course of the study treatment period through at least 3 months after the last dose of rituximab, and at least 30 days after the last dose of venetoclax and lenalidomide. Lenalidomide is present in the semen of patients receiving the drug so male patients should use a condom even if they have undergone a successful vasectomy. * Childbearing potential defined as not being surgically sterilized or have not been free from menses for > 1 year. ** Reliable birth control methods are defined as: one highly effective form of contraception – hysterectomy, tubal ligation, IUD, hormonal (birth control pills, injections, hormonal patches, vaginal rings, or implants), or partner’s vasectomy, and 1 additional effective contraceptive method – male latex or synthetic condom, diaphragm, or cervical cap. *** 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 (including use of aspirin (ASA)/FDA approved blood thinner). *** Females of reproductive potential must adhere to the scheduled pregnancy testing as required in the Revlimid REMS® program. *** Advise females of reproductive potential that they must avoid pregnancy 4 weeks before starting protocol therapy
• PHASE II: Total bilirubin ≤ 1.5 x ULN
• PHASE II: AST ≤ 3.0 x ULN (unless due to disease related complications)
• PHASE II: ALT ≤ 3.0 x ULN (unless due to disease related complications)
• PHASE II: CrCL (creatinine clearance) by either Crockroft-Gault or direct measurement) > 60 mL/minute
• PHASE II: * Without known bone marrow involvement by lymphoma: ANC ≥ 1,000/mm^3 * With known bone marrow involvement by lymphoma: ANC ≥ 500/mm^3
• PHASE II: * Without known bone marrow involvement by lymphoma: Platelets ≥ 75,000/mm^3 * With known bone marrow involvement by lymphoma: Platelets ≥ 25,000/mm^3 Note: Transfusion support is allowed to reach platelet parameters if cytopenia is related to disease involvement. If cytopenia is not related to disease involvement, a 7-day washout is required.
• PHASE II: * Without known bone marrow involvement by lymphoma: Hemoglobin ≥ 7 g/dl * With known bone marrow involvement by lymphoma: Hemoglobin ≥ 6 g/dl Note: Transfusion support is allowed to reach Hgb parameters if cytopenia is related to disease involvement. If cytopenia is not related to disease involvement, a 7-day washout is required.
• PHASE II: Ability to understand and the willingness to sign a written informed consent
• PHASE II: Ability to swallow oral capsules/tablets
• PHASE II: Prior treatment for MCL with any systemic therapy

Exclusion Criteria

• PHASE I: Prior treatment with chemotherapy for MCL
• PHASE I: Pregnant or breastfeeding women
• PHASE I: Grade 2 or higher peripheral neuropathy
• PHASE I: Known history of central nervous system (CNS) or leptomeningeal involvement by MCL prior to study enrollment
• PHASE I: Significant cardiovascular disease such as uncontrolled or symptomatic arrhythmias, congestive heart failure, or myocardial infarction within 6 months of screening, or any class 3 or 4 cardiac disease as defined by the New York Heart Association Functional Classification, or corrected QT (QTc) > 480 msec at screening
• PHASE I: Any condition that might significantly impair drug absorption as determined by the investigator such as malabsorption syndrome, disease significantly affecting gastrointestinal function, or resection of the stomach or small bowel, symptomatic inflammatory bowel disease, partial or complete bowel obstruction, or gastric restrictions and bariatric surgery, such as gastric bypass
• PHASE I: Uncontrolled infection (defined as exhibiting ongoing signs/symptoms related to the infection and without improvement, despite appropriate antibiotics or other treatment), or intravenous anti-infective treatment within 2 weeks before first dose of study drug
• PHASE I: History of stroke or intracranial hemorrhage within 6 months of 1st dose of study drug
• PHASE I: Concurrent participation in another clinical trial that necessitates pharmacological intervention
• PHASE I: Subject has received a moderate or strong CYP3A inhibitor or inducer within 1 week prior to treatment initiation
• PHASE I: Psychiatric illness or social situations that would limit compliance with study requirements
• PHASE I: Subject has known positivity to human immunodeficiency virus (HIV) (due to potential drug-drug interactions between anti-retroviral medications and venetoclax as well as anticipated venetoclax mechanism based lymphopenia that may potentially increase the risk of opportunistic infections and potential drug-drug interactions with certain antiinfective agents
• PHASE I: Active infection with hepatitis B or C virus as determined by a detectable viral load on polymerase chain reaction (PCR)
• PHASE I: Prior malignancy except for adequately treated basal cell or squamous cell skin cancer, in situ cervical cancer, or any other cancer from which the subject has been disease free for >= 2 years or which will not limit survival to < 2 years
• PHASE II: Pregnant or breastfeeding women
• PHASE II: Known history of CNS or leptomeningeal involvement by MCL prior to study enrollment
• PHASE II: Significant cardiovascular disease such as uncontrolled or symptomatic arrhythmias, congestive heart failure, or myocardial infarction within 6 months of screening, or any Class 3 or 4 cardiac disease as defined by the New York Heart Association Functional Classification, or corrected QT interval by Fridericia (QTcF) > 480 msec at screening
• PHASE II: Any condition that might significantly impair drug absorption as determined by the investigator such as malabsorption syndrome, disease significantly affecting gastrointestinal function, or resection of the stomach or small bowel, symptomatic inflammatory bowel disease, partial or complete bowel obstruction, or gastric restrictions and bariatric surgery, such as gastric bypass
• PHASE II: Uncontrolled infection (defined as exhibiting ongoing signs/symptoms related to the infection and without improvement, despite appropriate antibiotics or other treatment), or intravenous anti-infective treatment within 2 weeks before first dose of study drug
• PHASE II: History of stroke or intracranial hemorrhage within 6 months of 1st dose of study drug
• PHASE II: Concurrent participation in another clinical trial that necessitates pharmacological intervention
• PHASE II: Subject has received a moderate or strong CYP3A inhibitor or inducer within 1 week prior to treatment initiation
• PHASE II: Psychiatric illness or social situations that would limit compliance with study requirements
• PHASE II: Subject has known positivity to HIV (due to potential drug-drug interactions between anti-retroviral medications and venetoclax as well as anticipated venetoclax mechanism based lymphopenia that may potentially increase the risk of opportunistic infections and potential drug-drug interactions with certain anti-infective agents
• PHASE II: Active Infection with hepatitis B or C virus as determined by a detectable viral load on PCR
• PHASE II: Prior malignancy except for adequately treated non-invasive basal cell or squamous cell skin cancer, in situ cervical cancer, or any other cancer from which the subject has been disease free for ≥ 2 years or which will not limit survival to < 2 years
• PHASE II: Presence of p53 mutation as noted by WES or exon testing