A Pilot "Window-3" Study of Acalabrutinib Plus Rituximab Followed by Brexucabtagene Autoleucel Therapy in Patients With Previously Untreated High-risk Mantle Cell Lymphoma

1. Isolated bone marrow or GI only disease MCL patients and/or lack of measurable disease.

2. Pregnant or breast-feeding females.

3. Patients who are primary refractory to AR (No response/progressive disease within first 4 months of AR)

4. Received any investigational drug within 30 days or 5 half-lives (whichever is shorter) before first dose of study drug.

5. Current life-threatening illness, medical condition, or organ system dysfunction which, in the Investigator's opinion, could compromise the subject's safety or put the study at risk.

6. Known HIV infection.

7. Patients who do not meet high risk features as indicated above. Hepatitis B or C serologic status: subjects who are hepatitis B core antibody (anti-HBc) positive and who are hepatitis B surface antigen (HBsAg) negative will need to have a negative polymerase chain reaction (PCR) and must be willing to undergo DNA PCR testing during the study to be eligible. Those who are HBsAg positive or hepatitis B PCR positive will be excluded. Subjects who are hepatitis C antibody positive will need to have a negative PCR result to be eligible. Those who are hepatitis C PCR positive will be excluded.

8. Prior malignancy (or any other malignancy requiring active treatment), except for adequately treated basal cell or squamous cell skin cancer, in situ cervical cancer, in situ ca prostate, in situ melanoma (\> 5 mm margins) or other cancer from which the subject has been disease free for ≥ 3 years or which will not limit survival to \< 3 years.

9. Central nervous system involvement with mantle cell lymphoma or with suspected or confirmed progressive multifocal leukoencephalopathy (PML). Magnetic resonance imaging (MRI) of the brain, if performed, showing evidence of central nervous system (CNS) lymphoma or Lumbar puncture with flow cytometry, if performed, with CSF involvement.

10. History or presence of CNS disorder, such as seizure disorder, cerebrovascular ischemia/hemorrhage, dementia, cerebellar disease, cerebral edema, posterior reversible encephalopathy syndrome, or any autoimmune disease with CNS involvement.

11. Active bleeding, history of bleeding diathesis (such as Hemophilia or Von-Willebrand disease), Any history of intracranial bleed or stroke within 6 months of first dose of study drug.

12. Uncontrolled AIHA (autoimmune hemolytic anemia) or ITP (idiopathic thrombocytopenic purpura).

13. Malabsorption syndrome, disease significantly affecting gastrointestinal function, or resection of the stomach or small bowel or ulcerative colitis, symptomatic inflammatory bowel disease, or partial or complete bowel obstruction, or any other gastrointestinal condition that could interfere with the absorption and metabolism of acalabrutinib.

14. Presence of a clinically significant gastrointestinal ulcer diagnosed by endoscopy within 3 months before first dose of study drug.

15. Requires anticoagulation with warfarin or equivalent vitamin K antagonist, active treatment for pulmonary embolism (PE)/ deep vein thrombosis (DVT) and persons with mechanical cardiac valves.

16. History of symptomatic deep vein thrombosis (DVT) or pulmonary embolism requiring systemic anticoagulation within the last 6 months of enrollment

17. Concomitant use of corticosteroids at \> 20 mg prednisone or equivalent per day longer than 2 weeks.

18. Primary immunodeficiency

19. History of confirmed autoimmune disease (e.g. Crohn's disease, rheumatoid arthritis, systemic lupus) resulting in end organ injury or requiring systemic immunosuppression/systemic disease modifying agents within the last 2 years. Rheumatology clearance required for pts with remote history of auto-immune disease.

20. History of severe, immediate hypersensitivity reaction attributed to aminoglycosides

21. The use of strong CYP3A inhibitors within 1 week or strong CYP3A inducers within 3 weeks of the first dose of study drug is prohibited.

22. Requires treatment with strong CYP3A inhibitors or inducers (refer to list in Appendix VI).

23. Any of the following cardiac related conditions:

* NYHA Class III and IV heart failure (Appendix IX),

* Active/symptomatic coronary artery disease,

* Myocardial infarction in the preceding 6 months,

* Significant conduction abnormalities, including but not limited to:

* Left bundle branch block,

* 2nd degree AV block type II,

* 3rd degree block,

* QT prolongation (QTc \> 500 msec),

* Sick sinus syndrome,

* Ventricular tachycardia,

* Symptomatic bradycardia (heart rate \< 50 bpm),

* Persistent and uncontrolled atrial fibrillation.

* Uncontrolled hypertension

* Uncontrolled Hypotension

* Light headedness and syncope,

24. Acute infection requiring systemic anti-infective treatment systemic antibiotics, antivirals, or antifungals, or including subjects with positive cytomegalovirus \[CMV\] DNA polymerase chain reaction \[PCR\] within 14 days prior to initiation of therapy. Patient who exhibit active uncontrolled infection on AR alone will not be excluded but would await adequate infection control and then get CAR T, as long as they have evidence of disease.

25. Vaccinated with live, attenuated vaccines within 6 weeks of first dose of study drug.

26. Any other serious medical condition including, but not limited to, uncontrolled diabetes mellitus, COPD, renal failure, psychiatric illness or social circumstances that, in the investigator's opinion places the patient at unacceptable risk and would prevent the patient from signing the informed consent form or complying with study procedures.

27. Known history of hypersensitivity or anaphylaxis to study drug(s) including active product or excipient components.

28. Prothrombin time (PT)/INR or aPTT (in the absence of lupus anticoagulant) \>2x ULN.

29. Concurrent participation in another therapeutic clinical trial.

30. Has difficulty with or is unable to swallow oral medication or has significant gastrointestinal disease that would limit absorption of oral medication.

31. Known history of hypersensitivity or anaphylaxis to study drug(s) including active product or excipient components.

32. Major surgical procedure within 28 days of first dose of study drug. Note: If a subject had major surgery, they must have recovered adequately from any toxicity and/or complications from the intervention before the first dose of study drug.

What this study is about