Acalabrutinib and Rituximab for the Treatment of Previously Untreated Mantle Cell Lymphoma

Inclusion Criteria:

The study will enroll 50 elderly (≥65 years) previously untreated patient with newly diagnosed MCL.

1. Pathology confirmed diagnosis of mantle cell lymphoma with CD20 positivity andchromosome translocation t (11;14), (q13;q32) and/or positive cyclin D1 in tissuebiopsy (See Appendix I, footnote 10). Cyclin D1 negative MCL are allowed afterconfirming the diagnosis of MCL from hem-path at MDACC.

2. Newly diagnosed elderly MCL (age ≥65 years) with no prior therapy under all riskcategories

3. Patients with preexisting well-controlled cardio-vascular comorbidities - patientson anticoagulants (excluding warfarin and vitamin K antagonists), antiplatelet,anti-hypertensive, prior ablation, anti-arrhythmia, prior arrhythmias, baseline EKGabnormalities and cardiology clearance are allowed. Ejection fraction >=50% andcardiology clearance are required. (Echo and EKG and cardiology consultation within 2 months prior to C1D1 are allowed).

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

5. Ability to understand the purpose and risks of the study and provide signed anddated informed consent and authorization to use protected health information (inaccordance with national and local patient privacy regulations).

6. Bi-dimensional measurable disease using the Cheson criteria (Measurable disease byPET-CT scan defined as at least 1 lesion that measures ≥ 1.5 cm in singledimension.) Gastrointestinal, bone marrow or spleen only patients are allowable.

7. 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.

8. An absolute neutrophil count (ANC) > 1,000/mm3 and platelet count >100,000/mm3 (Patients who have bone marrow and spleen infiltration by MCL are eligible, the ANCand platelets counts will not be limited).

9. Serum bilirubin <1.5 mg/dl and creatinine clearance minimum to 50 mL/min per theCockcroft-Gault formula (Appendix VII)

10. AST (SGOT) and ALT (SGPT) < 2. x upper limit of normal or < 5 x upper limit ofnormal if hepatic metastases are present. Gilbert's disease is allowed.

11. Disease free of prior malignancies with exception of currently treated basal cell,squamous cell carcinoma of the skin, carcinoma "in situ" of the cervix or breast, orother malignancies in remission (including prostate cancer patients in remissionfrom radiation therapy, surgery or brachytherapy), not actively being treated withlife expectancy of > 3 years. PI can use clinical judgement in the best interest ofpatients.

12. WOBP and males must be willing to use highly effective methods of birth control.therapy. Woman of childbearing potential (WOCBP) who are sexually active must usehighly effective methods of contraception during treatment and for 2 days after thelast dose of acalabrutinib tablet and for 12 months following the last dose ofrituximab. For male subjects with a pregnant or non-pregnant WOCBP partner, shoulduse barrier contraception, during treatment and for 2 days after the last dose ofacalabrutinib and for 1 month following the last dose of rituximab even if they havehad a successful vasectomy. Male subjects must agree to refrain from sperm donationduring the study. (See Appendix VI)

Exclusion Criteria:

1. Prior treatment with acalabrutinib or any treatment for MCL.

2. History of prior malignancy that could affect compliance with the protocol orinterpretation of results, except for the following: a. Curatively treated basal cell carcinoma or squamous cell carcinoma of the skin orcarcinoma in situ of the cervix or carcinoma in situ of the prostate at any timeprior to study. b. Other cancers not specified above that have been curatively treated by surgeryand/or radiation therapy from which subject is disease-free for ≥3 years withoutfurther treatment.

3. Patients with central nervous system involvement with mantle cell lymphoma or withsuspected or confirmed progressive multifocal leukoencephalopathy (PML) are excludedsince those patients have very poor prognosis, need aggressive intensivechemoimmunotherapy and intrathecal chemotherapy along with BTK inhibitors and thesepatients would not be eligible for this study.

4. Pregnant or breast-feeding females.

5. Refractory nausea and vomiting, inability to swallow the formulated product, ormalabsorption syndrome; chronic gastrointestinal disease, gastric restrictions, orbariatric surgery such as gastric bypass; partial or complete bowel obstruction, orprevious significant bowel resection that would preclude adequate absorption,distribution, metabolism, or excretion of study treatment

6. Known history of hypersensitivity or anaphylaxis to study drug(s) including activeproduct or excipient components.

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

8. Concurrent participation in another therapeutic clinical trial.

9. Immunization with live vaccine within 4 weeks of and during therapy with Rituximab.

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

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

12. Serologic status reflecting active hepatitis B or C infection.

13. Subjects who are hepatitis B core antibody (anti-HBc) positive and who arehepatitis B surface antigen (HBsAg) negative will need to have a negative PCRresult before randomization and must be willing to undergo DNA PCR testingduring the study. Those who are HbsAg-positive or hepatitis B PCR positive willbe excluded.

14. 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.13. Major surgical procedure within 30 days before the first dose ofstudy drug. Note: If a subject had major surgery, they must have recoveredadequately from any toxicity and/or complications from the intervention beforethe first dose of study drug.

15. Patients with HIV/AIDS

16. Active bleeding, history of bleeding diathesis (such as Hemophilia or Von-Willebranddisease), Any history of intracranial bleed or stroke within 6 months of first doseof study drug.

17. Uncontrolled AIHA (autoimmune hemolytic anemia) or ITP (idiopathic thrombocytopenicpurpura).

18. Presence of a gastrointestinal ulcer diagnosed by endoscopy within 3 months beforefirst dose of study drug.

19. 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.

20. Requires anticoagulation with warfarin or equivalent vitamin K antagonist.

21. Concomitant use of corticosteroids at > 20 mg prednisone or equivalent per day > 2weeks.

22. Requires treatment with strong CYP3A inhibitors or inducers (refer to section 8.6.1and list in Appendix V).

23. Patients who have had a stroke within 6 months.

24. Any of the following conditions considered clinically significant cardiovasculardiseases as determined after cardiology consultation: Note: Subjects withcontrolled, asymptomatic atrial fibrillation can enroll on study.

• Diagnosed Congestive heart failure,

• Active/symptomatic coronary artery disease

• Congestive heart failure

• Myocardial infarction in the preceding 6 months,

• Significant conduction abnormalities, including but not limited to: o Left bundle branch block, o 2nd degree AV block type II, o 3rd degree block, o QT prolongation (QTc > 480 msec), o Sick sinus syndrome o Ventricular tachycardia

• Symptomatic bradycardia (heart rate < 50 bpm),

• Persistent, controlled and uncontrolled atrial fibrillation.

• Uncontrolled hypertension

• Hypotension,

• light headedness and syncope,

24. Active infection

25. Acute infection requiring systemic anti-microbial treatment (systemicantibiotics, antivirals, or antifungals) within 14 days prior to initiation oftherapy.

26. Active infection including systemic fungal or CMV infection who werehospitalized in past 6 months.

27. Any other serious medical condition including, but not limited to, uncontrolleddiabetes mellitus, uncontrolled thyroid disorder, uncontrolled hypertensioni.e. Uncontrolled BP - >160/110 despite 3 different classes of full doseanti-hypertensives medications and in spite of cardiology evaluation.Documentation from cardiology is required to say that the BP isuncontrollable.), COPD, renal failure, psychiatric illness or socialcircumstances that, in the investigator's opinion places the patient atunacceptable risk and would prevent the subject from signing the informedconsent form or complying with study procedures.