The main purpose of this study to find the ideal dose for the combination treatment of Zanubrutinib and Tafasitamab in patients with mantle cell lymphoma. Another purpose is to assess how well the combination treatment works in patients with the study disease.

Inclusion Criteria:

1. Men and women ≥ 18 years of age

2. Patients must have histologic confirmation of mantle cell lymphoma (MCL) defined by the World Health Organization (WHO) classification

3. Baseline PET/CT scans must demonstrate fluorodeoxyglucose (FDG) avid lesions compatible with CT defined anatomical tumor sites. Patients should have at least one measurable site of disease per Lugano classification

4. Patient should have indication according to primary investigator for treatment initiation

5. Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2

6. Life expectancy of greater than 4 months.

7. Willingness to avoid pregnancy or fathering children during the study and for at least 90 days after the last dose of the study drug.

8. Patients must have normal organ and marrow function as defined below:

   1. Absolute neutrophil count >1,000/mm3 independent of growth factor support within 7 days of study entry (>700/mm3 if lymphoma involvement of the bone marrow or spleen)
   2. Platelets >70,000/mm3 independent of transfusion support within 7 days of study entry (>50,000/mm3 independent of transfusion support within 7 days of study entry if lymphoma involvement of the bone marrow or spleen)
   3. Hemoglobin >9 g/dL or >8 g/dL in case of bone marrow involvement by lymphoma independent of transfusion support within 7 days of study entry.
   4. Total bilirubin < 1.5 x within normal institutional limits (unless known history of Gilbert's disease or up to 3 x upper limit of normal (ULN) if due to lymphoma involvement of liver)
   5. Gamma-Glutamyl Transpeptidase (GGT)/Aspartate transaminase (AST, SGOT)/Alanine transaminase (ALT, SGPT) ≤ 2.5 x institutional upper limit of normal
   6. Creatinine within normal institutional limits, or creatinine clearance ≥ 40 mL/min (as estimated by the Cockcroft-Gault equation) for patients with creatinine levels above institutional normal (creatinine clearance ≥ 30 mL/min as estimated by the Cockcroft-Gault equation if due to lymphoma).

Inclusion Criteria, Phase 1 Only:

1. Relapsed MCL patients with at least 1 but no more than 3 lines of therapy, regardless of previous Bruton Tyrosine Kinase (BTK) inhibitor exposure

Inclusion Criteria, Phase 2 Only:

1. Untreated symptomatic MCL deemed by the primary investigator not to be eligible for intensive combination immunochemotherapy.

Exclusion Criteria, Phase 1 and 2:

1. Patients receiving any other investigational agents
2. Patients with known central nervous system involvement of lymphoma
3. Uncontrolled intercurrent illness such as: clinically significant active cardiovascular disease such as uncontrolled or symptomatic arrhythmia, uncontrolled hypertension, congestive heart failure New York Heart Association (NYHA) Class III-IV, history of myocardial infarction within 6 months of screening, stroke in last 6 months, liver cirrhosis, autoimmune disorder requiring immunosuppression or long-term corticosteroids (>10 mg daily prednisone equivalent), or any other serious medical condition, laboratory abnormality, or psychiatric illness that would prevent the subject from signing the informed consent form
4. QT interval corrected with Fridericia's formula (QTcF) > 450 msec or other significant ECG abnormalities including second-degree atrioventricular block Type II, or third-degree atrioventricular block
5. Prior or concurrent malignancies with exception of surgically cured carcinoma in situ (CIS) of the uterus, carcinoma of the skin without evidence of disease for ≥5 years
6. Concurrent malignancy requiring active therapy
7. Known seropositive and requiring anti-viral therapy for human immunodeficiency virus
8. Breastfeeding or pregnant women
9. Serologic status reflecting active hepatitis B or C infection. Patients that are positive for hepatitis B core antibody, hepatitis B surface antigen (HBsAg), or hepatitis C antibody will need a polymerase chain reaction (PCR) below cutoff value prior to enrollment. (PCR positive patients will be excluded). Hepatitis C antibody positive patients are eligible if PCR is negative. Hepatitis B core antibody (+) patients without evidence of HBsAg or Hep B PCR (+) are eligible with appropriate Hepatitis B reactivation prophylaxis
10. Ongoing treatment with medications that are moderate or strong cytochrome P (CYP) 450, family 3, subfamily A (CYP3A) inhibitors, or strong CYP3A inducers that cannot be safely substituted. For patients with ongoing treatment with these medications that can be safely substituted, minimum washout period should be 7 days or five half-lives, whichever is shorter.
11. History of allogenic hematopoietic stem cell transplantation prior to enrollment
12. Active systemic infection (including severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) positive test) or other Active infection including infections requiring oral or intravenous antimicrobial therapy.
13. Administration of live vaccine within 28 days prior to start of study treatment
14. Any life-threatening illness, medical condition, or organ system dysfunction that, in the investigator's opinion, could compromise the patient's safety or put the study at risk.
15. Toxicity must have recovered to ≤ Grade 1 from prior chemotherapy (except for alopecia, absolute neutrophil count, and platelet count). (Please refer to Inclusion Criteria 7 and 8 for absolute neutrophil count and platelet count, respectively.)
16. Unable to swallow capsules, or disease significantly affecting gastrointestinal function such as malabsorption syndrome, resection of the stomach or small bowel, symptomatic inflammatory bowel disease, or partial or complete bowel obstruction.
17. Prior corticosteroids in excess of prednisone 10 mg/day or its equivalent with antineoplastic intent within 7 days of the start of study drug. Prior chemotherapy, targeted therapy, or radiation therapy within 3 weeks, antineoplastic therapy with Chinese herbal medication or antibody-based therapies within 4 weeks of the start of study drug.
18. History of severe bleeding disorder such as hemophilia A, hemophilia B, von Willebrand disease, or history of spontaneous bleeding requiring blood transfusion or other medical intervention
19. History of stroke or intracranial hemorrhage within 180 days before first dose of study drug
20. Major surgery within 4 weeks of the first dose of study drug
21. Patient requires treatment with warfarin or other vitamin K antagonists
22. Any contraindication per Tafasitamab United States Prescribing Information (USPI).
23. Patients with impaired decision-making capacity.