Venetoclax and Acalabrutinib in Treating Patients With Relapsed or Refractory Mantle Cell Lymphoma

Inclusion Criteria:

• Confirmed diagnosis of MCL in previously treated relapsed/refractory patientswith/without chromosome translocation t(11;14), (q13;q32) by FISH and/or overexpresscyclin D1 in tissue biopsy (blastoid/pleomorphic morphology, complex karyotype isacceptable), cyclin D1 negative mantle cell lymphoma is allowed. MCL diagnosisconfirmation is needed by pathologist.

• Disease had relapsed after or been refractory to >= 1 prior therapy for MCL and nowrequires further treatment.

• Ability to understand the purpose and risks of the study and provide signed anddated Institutional Review Board (IRB) approved informed consent and authorizationto use protected health information (in accordance with national and local patientprivacy regulations).

• Willing and able to participate in all required evaluations and procedures in thisstudy protocol, including swallowing capsules and tablets without difficulty.

• Age ≥ 18 years at the time of signing the ICF.

• Bi-dimensional measurable disease using the Cheson criteria (measurable disease bycomputed tomography [CT] scan defined as at least 1 lesion that measures >= 1.5 cmin single dimension). Gastrointestinal (GI), bone marrow or spleen only patients areallowable.

• Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2 with nodeterioration over the previous 2 weeks prior to baseline or day of first dosing.The following laboratory criteria must be met

• Absolute neutrophil count (ANC) > 1,000/mm^3 independent of growth factor support.

• Platelet count >= 100,000/mm^3 or >= 50,000/mm^3 if bone marrow involved withlymphoma, independent of transfusion support in either situation.

• Creatinine (Cr) =< 2 or Cr clearance >= 30 mL/min.

• Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) < 3 x upperlimit of normal (ULN), serum bilirubin < 1.5 mg/dl, unless due to Gilbert'ssyndrome, documented liver involvement with lymphoma, or of non-hepatic origin.

• Prothrombin time (PT)/international normalized ratio (INR) =< 1.5 x ULN and partialthromboplastin time (PTT) =< 1.5 x ULN.

• Disease free of prior malignancies other than MCL with exception of currentlytreated basal cell, squamous cell carcinoma of the skin, carcinoma "in situ" of thecervix or breast, or other malignancies in remission (including prostate cancerpatients in remission from radiation therapy, surgery or brachytherapy), notactively being treated with life expectancy of > 3 years. Principal investigator (PI) can use clinical judgement in the best interest of patients.

• Females of childbearing potential (FCBP) must have a negative serum or urinepregnancy test and willing to use highly effective methods of birth control.

• Male subjects must agree to refrain from sperm donation during the study.

• A female of childbearing potential is a sexually mature woman who:

• Has not undergone a hysterectomy or bilateral oophorectomy; or

• 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).

Exclusion Criteria:

• Prior treatment with acalabrutinib or any investigational drug within 30 days or 5half-lives (whichever is shorter) before first dose of study drug.

• History of prior malignancy that could affect compliance with the protocol orinterpretation of results, except for the following:

1. Curatively treated basal cell carcinoma or squamous cell carcinoma of the skinor carcinoma in situ of the cervix or carcinoma in situ of the prostate at anytime prior to study.

2. Other cancers not specified above that have been curatively treated by surgeryand/or radiation therapy from which subject is disease-free for ≥3 yearswithout further treatment.

• Any serious medical condition including but not limited to, uncontrolledhypertension, uncontrolled diabetes mellitus, active/symptomatic coronary arterydisease, chronic obstructive pulmonary disease, renal failure, active hemorrhage, orpsychiatric illness that, in the investigator's opinion places the patient atunacceptable risk and would prevent the subject from signing the ICF.

• Pregnant or breast-feeding females.

• Known human immunodeficiency virus (HIV) infection.

• Uncontrolled autoimmune hemolytic anemia (AIHA) or idiopathic thrombocytopenicpurpura (ITP). History of or ongoing confirmed progressive multifocalleukoencephalopathy (PML)

• Any active significant infection (e.g., bacterial, viral or fungal, includingsubjects with positive cytomegalovirus [CMV] DNA polymerase chain reaction [PCR]).

• Serologic status reflecting active hepatitis B or C infection.

• a. Subjects who are hepatitis B core antibody (anti-HBc) positive and who arehepatitis B surface antigen (HBsAg) negative will need to have a negative PCR resultbefore randomization and must be willing to undergo DNA PCR testing during thestudy. Those who are HbsAg-positive or hepatitis B PCR positive will be excluded. b.Subjects who are hepatitis C antibody positive will need to have a negative PCRresult before randomization. Those who are hepatitis C PCR positive will beexcluded.

• Central nervous system (CNS) disease with serious significance.

• Refractory nausea and vomiting, inability to swallow the formulated product, orMalabsorption syndrome, disease significantly affecting GI function, or resection ofthe stomach or small bowel or ulcerative colitis, symptomatic inflammatory boweldisease, or partial or complete bowel obstruction, or any other GI condition thatcould interfere with the absorption metabolism, and excretion of acalabrutinib orvenetoclax.

• Major surgical procedure within 30 days before the first dose of study drug. Note:If a subject had major surgery, they must have recovered adequately from anytoxicity and/or complications from the intervention before the first dose of studydrug.

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

• History of stroke or intracranial hemorrhage within 6 months prior to study entry

• Requires anticoagulation with warfarin or equivalent vitamin K antagonist

• Vaccinated with live, attenuated vaccines within 4 weeks of study entry

• Concurrent systemic immunosuppressant therapy (e.g., cyclosporine, tacrolimus, etc.,or chronic administration of >10mg/day of prednisone or equivalent) within 28 daysof the first dose of study drug.

• Requires treatment with strong CYP3A inhibitors or inducers or strong CYP1A2inhibitors (refer to list in Appendix V and Sections 8.2.1 and 8.2.2).

• Refractory to prior ibrutinib or BTK mutation or previous exposure to other BTKinhibitors