Avo In R/R And Previously Untreated MCL

Inclusion Criteria:

• Participants must meet the following criteria on screening examination to beeligible to participate in the study:

• Participants must have histologically determined mantle cell lymphoma withpathologic review at the participating institutions, that has either:

• Relapsed or primary refractory after at least one line of therapy includinganti-CD20 monoclonal antibody treatment (part A) or; Had no previousanti-lymphoma therapy other than corticosteroids or radiotherapy (parts B andC).

• Participants in part A, relapsed or refractory following prior therapy, mayhave had a prior autologous or allogeneic stem cell transplant and may havebeen treated with chimeric antigen receptor T-cells (CAR T-cells).

• Participants in parts B and C, without prior anti-lymphoma therapy, must requiretreatment as defined by any of the following criteria:

• Symptomatic adenopathy or splenomegaly

• Local symptoms due to extranodal disease

• Organ function impairment due to disease involvement, including cytopenias dueto marrow involvement (WBC <1.5x109/L; absolute neutrophil count [ANC] <1.0x109/L, Hgb <10g/dL; platelets <100x109/L)

• Presence of systemic B symptoms (fever, drenching night sweats, orunintentional weight loss ≥ 10% body weight over previous 6 months) orfunctionally significant fatigue

• Participants in part B without prior anti-lymphoma therapy should be deemed to beineligible for autologous stem cell transplant by the treating physician and/or havea TP53 mutation detected by next generation sequencing at a variant (mutant) allelefraction above the validated threshold for calling a new variant or high TP53expression on immunohistochemistry (>50% positive lymphoma cells)

• Participants in part C without prior anti-lymphoma therapy should be deemed to beeligible for autologous stem cell transplant by the treatment physician and have noevidence of TP53 mutation (TP53 wild type) detected by next generation sequencingand no evidence of high TP53 expression on immunohistochemisty

• Participants in parts B and C must have an archived formalin-fixed paraffin-embedded (FFPE) tumor tissue specimen from the original diagnostic biopsy and peripheralblood available for submission to Adaptive Biotechnologies for ClonoSEQ®ID molecularmarker identification of a unique clonal immunoglobulin DNA sequence. Only thoseparticipants in parts B and C who have a molecular marker identified from theperipheral blood will be eligible for minimal residual disease (MRD) driventreatment interruptions.

• Participants in parts B and C who do not have a molecular marker identified byClonoSEQ from the peripheral blood will be deemed to be MRD indeterminate and arenot eligible for peripheral blood MRD driven treatment interruptions. Theseparticipants will be able to enroll in the study assuming all other eligibilitycriteria are met but will receive 7 cycles of AVO combination therapy followed by 17cycles of acalabrutinib and venetoclax therapy (24 total cycles of AV) and 2 yearsof maintenance obinutuzumab for a total of 31 cycles of therapy.

• Measurable disease with a lymph node or tumor mass ≥ 1.5 cm in at least onedimension by CT, PET/CT, or MRI. Patients without measurable disease will beeligible if they have marrow involvement and cytopenias related to their lymphoma (hemoglobin <10 g/dL, absolute neutrophil count < 1.0 x 109/L, or platelets < 100 x 109/L) OR symptomatic splenomegaly > 15cm in craniocaudal diameter.

• Age ≥ 18 years.

• ECOG performance status ≤2 (Karnofsky ≥60%)

• Participants must have adequate organ and marrow function as defined below:

• Absolute neutrophil count ≥ 750 cells/mm3 (0.75 x109/L) unless due to marrowinvolvement by lymphoma in which case ANC must be ≥ 500 cells/mm3 (0.5x109/L)

• Platelet count without transfusional support must be ≥ 75,000 cells/mm3 (75x109/L), unless due to marrow involvement by lymphoma, in which case plateletsmust be ≥ 50,000 cells/mm3 (50 x109/L)

• Hemoglobin without transfusional support must be ≥ 8.0 g/dL (80 g/L) unless dueto marrow involvement by lymphoma, in which case hemoglobin must be ≥ 7.0 g/dL (70 g/L)

• Creatinine clearance (CrCl) ≥ 50 ml/min using 24-hour urine collection forcreatinine clearance or calculated CrCl or calculated glomerular filtrationrate (GFR) ≥ 50 ml/min/1.73 m2 using the CKD-EPI equation

• Total bilirubin ≤ 2 times the upper limit of normal, unless there is diseaseinvolvement of the liver, hemolysis, or a known history of Gilbert's disease,in which case direct bilirubin must be ≤ 3 times the upper limit of normal

• AST and ALT ≤ 2.5 times the upper limit of normal, unless documented liverinvolvement by lymphoma, in which case AST and ALT must be ≤ 5 times the upperlimit of normal

• PT/INR ≤ 2 times the upper limit of normal and PTT ≤ 2 times the upper limit ofnormal

• Willingness to provide pre-treatment bone marrow (or recent archival w/o interveningtherapy) and on-treatment bone marrow and peripheral blood samples

• The effects of the study drugs on the developing human fetus are unknown. Women ofchild-bearing potential must agree to remain abstinent or use highly effectivecontraception (defined as contraceptive measures that result in a failure rate of <1% per year) during the treatment period and for at least 2 days after the lastdose of acalabrutinib, 90 days after the last dose of venetoclax or 18 months afterthe last dose of obinutuzumab, whichever is longer. Men with female sexual partnersof childbearing potential should agree to remain abstinent or use contraceptivemeasures which include a condom plus an additional contraceptive method thattogether result in a failure rate of <1% per year during the treatment period andfor at least 90 days after the last dose of venetoclax or 6 months after the lastdose of obinutuzumab, whichever is longer. Men should refrain from donating spermduring the same period. Should a woman become pregnant or suspect she is pregnantwhile she or her partner is participating in this study, she should inform hertreating physician immediately.

• Ability to understand and the willingness to sign a written informed consentdocument.

Exclusion Criteria:

• Participants who exhibit any of the following conditions at screening will noteligible for admission into the study:

• Participants who have progressed or relapsed after receiving either a BTK inhibitoror BCL2 inhibitor.

• Participants who are receiving any other investigational agents, or have receivedinvestigational agents within 4 weeks (or 3 half-lives, whichever is longer) ofbeginning treatment.

• Concurrent systemic immunosuppressant therapy (e.g., cyclosporine A, tacrolimus,etc., within 28 days of the first dose of study drug or chronic administration of >20 mg/day of prednisone equivalent corticosteroid within 7 days of the first dose)

-- Note: Glucocorticoids for lymphoma symptom palliation are allowed but must bediscontinued at time of initiation of protocol therapy.

• History of severe allergic reactions attributed to compounds of similar chemical orbiologic composition to obinutuzumab, venetoclax, or acalabrutinib. Patients withreactions to other CD20 monoclonal antibodies (e.g. rituximab, ofatumumab) are notexcluded if they were able to eventually tolerate treatment in an outpatient settingwithout grade 2 or higher infusion reactions.

• Participants who have a history of other malignancies except:

• Malignancy treated with curative intent and with no known active diseasepresent and felt to be at low risk for recurrence by treating physician.Current adjuvant hormonal therapy for disease treated with curative intent ispermissible.

• Adequately treated non-melanoma skin cancer or lentigo maligna without evidenceof disease.

• Adequately treated carcinoma in situ without evidence of disease.

• Low-risk prostate cancer on active surveillance

• Other exceptions may be made after consultation with the study chair

• Participants with known leptomeningeal or brain metastases. Imaging or spinal fluidanalysis to exclude CNS involvement is not required, unless there is clinicalsuspicion by the treating investigator.

• Participants who have had a major surgery or significant traumatic injury within 4weeks of start of study drug, participants who have not adequately recovered fromthe side effects of any major surgery (defined as requiring general anesthesia), orparticipants that may require major surgery during the course of the study.

• Vaccinated with live, attenuated vaccines within 28 days of study entry or need forlive virus vaccines at any time during study period.

• Patients with human immunodeficiency virus (HIV) or active hepatitis C virus (HCV)or hepatitis B virus (HBV) infection. HIV-positive participants are ineligiblebecause of the potential for pharmacokinetic interactions between certain componentsof anti-retroviral therapy and venetoclax. Patients who are positive for hepatitis Bcore antibody or hepatitis B surface antigen must have a negative polymerase chainreaction (PCR) result before enrollment. Those who are PCR positive will beexcluded. Those who are positive for either hepatitis B surface antigen and/orhepatitis B core antibody but negative for HBV DNA will be managed. Patients who arepositive for HCV antibody must be negative for HCV by polymerase chain reaction (PCR) to be eligible for study participation.

• Ongoing or recent infection requiring intravenous antimicrobials at time ofscreening. Patients with ongoing use of prophylactic antibiotics are eligible aslong as there is no evidence of active infection and the antibiotic is not includedon the list of prohibited medications.

• Uncontrolled intercurrent illness or psychiatric illness/social situations thatwould limit compliance with study requirements, compromise the subject's safety, orput the study outcomes at undue risk.

• Lactating or pregnant women are excluded from this study because venetoclax has beenshown to decrease implantation, litter size, live fetuses, and fetal body weight inanimal models. Because there is an unknown but potential risk for adverse events innursing infants secondary to treatment of the mother with venetoclax, breastfeedingshould be discontinued if the mother is treated with venetoclax. These potentialrisks may also apply to other agents used in this study.

• Known bleeding disorders (e.g. von Willebrand's disease) or hemophilia.

• Presence of a bleeding gastrointestinal ulcer diagnosed by endoscopy within 3 monthsprior to enrollment.

• History of stroke or intracranial hemorrhage within 6 months prior to enrollment.

• Participants who require warfarin or other vitamin K antagonists for anticoagulation (other anticoagulants are allowed).

• Currently active, clinically significant cardiovascular disease, such asuncontrolled arrhythmia or Class 3 or 4 congestive heart failure as defined by theNew York Heart Association Functional Classification; or a history of myocardialinfarction, unstable angina, or acute coronary syndrome within 6 months prior torandomization. Patients with atrial fibrillation are allowed as long as they areadequately rate controlled.

• Participants who require concurrent treatment with strong CYP3A inhibitors or strongCYP3A inducers are excluded from the study. If patients are receiving strong CYP3Ainhibitors/inducers at time of screening but do not require continuousadministration of these agents, these patients are eligible if there is a 7-daywashout period between discontinuation of the strong CYP3A inhibitor/inducer andinitiation of the first study drug, acalabrutinib.

• Participants who require concurrent treatment with P-gp inhibitors or narrowtherapeutic index P-gp substrates are excluded from the study. If patients arereceiving P-gp inhibitors or narrow therapeutic index P-gp substrates at time ofscreening but do not require continuous administration of these agents, thesepatients are eligible if there is a 7-day washout period between discontinuation ofthe P-gp inhibitor and initiation of venetoclax.

• Unable to swallow capsules, a large number of tablets, or malabsorption syndrome,disease significantly affecting gastrointestinal function, or resection of thestomach or small bowel if thought by the investigator to compromise systemicabsorption, active, symptomatic inflammatory bowel disease or ulcerative colitis, orpartial or complete bowel obstruction.

• Significant co-morbid condition or disease which in the judgment of the PrincipalInvestigator would place the participant at undue risk or interfere with the study.

• History of or ongoing confirmed progressive multifocal leukoencephalopathy (PML).