Acalabrutinib With R-CHOP in Previously Untreated Mantle Cell Lymphoma

Cohort A:

Inclusion Criteria Eligible subjects will be considered for inclusion in Cohort A of this study if they meet all of the following criteria:

1. Men and women greater than or equal to 18 years of age deemed eligible for treatmentwith Full dose RCHOP and ASCT by the qualified investigator.

2. Histologic diagnosis of MCL according to the World Health Organizationclassification [Swerdlow, Blood 2016].

3. Previously untreated MCL with the following exceptions: (a) prior radiotherapy forlocalized disease, (b) up to 7 days of corticosteroids (prednisone 100mg/dayequivalent), (c) up to one dose of single-agent chemotherapy (for example,cyclophosphamide), (d) up to one cycle of R-CHOP if last R-CHOP is between 21 daysand 2 months from start of RCHOP+acalabrutinib or up to one cycleofbendamustine-rituximab (BR) if BR is between 28 days and 2 months from start ofRCHOP+acalabrutinib. Patients with exceptions (c) and (d) are eligible as long asall other eligibility criteria are met AND at least a CT scan and bone marrow biopsywere performed prior to chemotherapy.

4. Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2.

5. Presence of at least one radiologically measurable nodal or extranodal mass. Ameasurable nodal mass must have a longest diameter ≥1.5 cm. A measurable extranodalmass should have a longest diameter ≥1.0 cm.[Cheson, JCO 2014]

6. Women of childbearing potential (WOCBP) who are sexually active must use highlyeffective methods of contraception during treatment and up to 12 months after thelast dose of rituximab or R-CHOP, or 2 days after the last dose of acalabrutinib,whichever is last administered. Examples of highly effective contraceptive methodsinclude an agreement to remain abstinent (ie, refrain from heterosexualintercourse), bilateral tubal ligation, male sterilization, established proper useof hormonal contraceptives that inhibit ovulation, hormone-releasing intrauterinedevices, and copper intrauterine devices. Men who are sexually active must usehighly effective methods of contraception during treatment and up to 6 months afterthe last dose of rituximab or R-CHOP, or 2 days after the last dose ofacalabrutinib, whichever is last administered. Men require an agreement to remainabstinent (ie, refrain from heterosexual intercourse) or use a condom, and anagreement to refrain from donating sperm. Periodic abstinence and withdrawal are notacceptable methods of contraception. Fertility preservation options should bediscussed.

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

8. Ability to understand the purpose and risks of the study and provide signed anddated informed consent and authorization to use protected health information.

Exclusion Criteria:

Subjects will be ineligible for Cohort A of this study if they meet any of the following criteria:

1. Secondary central nervous system involvement.

2. Prior exposure to a BCR inhibitor (eg, BTK inhibitors, phosphoinositide-3 kinase (PI3K), or Syk inhibitors) or BCL-2 inhibitor.

3. Prior malignancy (or any other malignancy requiring active treatment), except foradequately treated basal cell or squamous cell skin cancer, in situ cervical orprostate cancer, or other cancer from which the subject has been disease free for ≥ 3 years or which will not limit survival to < 5 years. Subjects receiving adjuvanthormonal therapy for early breast or prostate cancer are eligible.

4. Clinically significant cardiovascular disease such as uncontrolled or symptomaticarrhythmias, congestive heart failure, or myocardial infarction within 6 months ofscreening, or any Class 3 or 4 cardiac disease as defined by the New York HeartAssociation Functional Classification. Subjects with controlled, asymptomatic atrialfibrillation during screening can enroll on study.

5. Difficulty with or unable to swallow oral medication, or conditions significantlyaffecting gastrointestinal function that would limit absorption of oral medication.

6. Known history of infection with HIV or any significant active infection (eg,bacterial, viral or fungal), including suspected or confirmed progressive multifocalleukoencephalopathy.

7. Known history of drug-specific hypersensitivity or anaphylaxis to study drugs (acalabrutinib and individual components of R-CHOP), including active product orexcipient components.

8. Active bleeding or history of bleeding diathesis (eg, hemophilia or von Willebranddisease).

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

10. Requires treatment with a strong cytochrome P450 3A4 (CYP3A4) inhibitor/inducerwhich cannot be modified as described in Sections 3.8.2 and 3.9.2, and/or the doseof acalabrutinib cannot be modified as described in these sections.

11. Requires or receiving anticoagulation with warfarin or equivalent vitamin Kantagonists (eg, warfarin).

12. Requires treatment with proton pump inhibitors (eg, omeprazole, esomeprazole,lansoprazole, dexlansoprazole, rabeprazole, or pantoprazole). Subjects receivingproton pump inhibitors who switch to H2-receptor antagonists or antacids areeligible for enrollment to this study.

13. History of significant cerebrovascular disease/event, including stroke orintracranial hemorrhage, within 6 months before the first dose of study drug.

14. Major surgical procedure within 4 weeks of first dose of study drug. Note: If asubject had major surgery, they must have recovered adequately from any toxicityand/or complications from the intervention before the first dose of study drug.

15. Received a live virus vaccination within 28 days of first dose of R-CHOP +acalabrutinib.

16. Hepatitis B or C serologic status: subjects who are hepatitis B core antibody (antiHBc) positive and who are surface antigen negative will need to have a negativepolymerase chain reaction (PCR) result before enrolment and must be willing toundergo PCR testing during the study. Those who are hepatitis B surface antigen (HbsAg) positive or hepatitis B PCR positive will be excluded.Subjects who arehepatitis C antibody positive will need to have a negative PCR result. Those who arehepatitis C PCR positive will be excluded. Subjects with a history of Hepatitis Cwho received antiviral treatment are eligible as long as PCR is negative.

17. ANC <1.0 x109/L (subjects with bone marrow involvement by lymphoma are eligibleregardless of ANC)

18. Platelets <50 x109/L (subjects with bone marrow involvement by lymphoma are eligibleregardless of platelet count)

19. Total serum bilirubin ≥1.5 times the upper limit of normal, unless directlyattributable to Gilbert's syndrome (or >3 times for documented hepatic involvementby lymphoma), AST and ALT >3 times the upper limit of normal (or >5 times fordocumented hepatic involvement by lymphoma)

20. Creatinine clearance <30 mL/min.

21. PT/INR >2 times the upper limit of normal in the absence of anticoagulants and/orPTT >2 times the upper limit of normal in the absence of anticoagulants.

22. Breastfeeding or pregnant. WOCBP must have a serum and/or urine pregnancy test donea maximum of 7 days prior to treatment initiation and a negative result must bedocumented prior to recruitment.

23. Concurrent participation in another therapeutic clinical trial.

24. Evidence of disease (such as severe or uncontrolled systemic diseases, includinguncontrolled hypertension and renal transplant) that, in the investigator's opinion,make it undesirable for the patient to participate in the study or that wouldjeopardize compliance with the protocol.

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

26. Current life-threatening illness, medical condition, or organ system dysfunctionwhich, in the Investigator's opinion, could compromise the subject's safety or putthe study at risk.

Cohort B:

Inclusion Criteria:

Eligible subjects will be considered for inclusion in Cohort B of this study if they meet all of the following criteria:

1. Men and women 18-70 years of age deemed eligible for treatment with full dose RCHOPby the qualified investigator.

2. Histologic diagnosis of MCL according to the World Health Organizationclassification [Swerdlow, Blood 2016].

3. Previously untreated MCL with the following exceptions: (a) prior radiotherapy forlocalized disease, (b) up to 7 days of corticosteroids (prednisone 100mg/dayequivalent), (c) up to one dose of single-agent chemotherapy (for example,cyclophosphamide), (d) up to one cycle of R-CHOP if last R-CHOP is between 21 daysand 2 months from start of R-CHOP+acalabrutinib. Other chemotherapy regimens (forexample, bendamustine and rituximab) are not allowed. Patients with exceptions (c)and (d) are eligible as long as all other eligibility criteria are met AND at leasta CT scan and bone marrow biopsy were performed prior to chemotherapy.

4. Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2.

5. Presence of at least one radiologically measurable nodal or extranodal mass. Ameasurable nodal mass must have a longest diameter ≥1.5 cm. A measurable extranodalmass should have a longest diameter ≥1.0 cm.[Cheson, JCO 2014]

6. Women of childbearing potential (WOCBP) who are sexually active must use highlyeffective methods of contraception during treatment and up to 12 months after thelast dose of rituximab or R-CHOP, or 2 days after the last dose of acalabrutinib,whichever is last administered. Examples of highly effective contraceptive methodsinclude an agreement to remain abstinent (ie, refrain from heterosexualintercourse), bilateral tubal ligation, male sterilization, established proper useof hormonal contraceptives that inhibit ovulation, hormone-releasing intrauterinedevices, and copper intrauterine devices. Men who are sexually active must usehighly effective methods of contraception during treatment and up to 6 months afterthe last dose of rituximab or R-CHOP, or 2 days after the last dose ofacalabrutinib, whichever is last administered. Men require an agreement to remainabstinent (ie, refrain from heterosexual intercourse) or use a condom, and anagreement to refrain from donating sperm. Periodic abstinence and withdrawal are notacceptable methods of contraception. Fertility preservation options should bediscussed.

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

8. Ability to understand the purpose and risks of the study and provide signed anddated informed consent and authorization to use protected health information

Exclusion Criteria:

Subjects will be ineligible for Cohort B of this study if they meet any of the following criteria:

1. Secondary central nervous system involvement.

2. Prior exposure to a BCR inhibitor (eg, BTK inhibitors, phosphoinositide-3 kinase (PI3K), or Syk inhibitors) or BCL-2 inhibitor.

3. Prior malignancy (or any other malignancy requiring active treatment), except foradequately treated basal cell or squamous cell skin cancer, in situ cervical orprostate cancer, or other cancer from which the subject has been disease free for ≥ 3 years or which will not limit survival to < 5 years. Subjects receiving adjuvanthormonal therapy for early breast or prostate cancer are eligible.

4. Clinically significant cardiovascular disease such as uncontrolled or symptomaticarrhythmias, congestive heart failure, or myocardial infarction within 6 months ofscreening, or any Class 3 or 4 cardiac disease as defined by the New York HeartAssociation Functional Classification. Subjects with controlled, asymptomatic atrialfibrillation during screening can enroll on study.

5. Difficulty with or unable to swallow oral medication, or conditions significantlyaffecting gastrointestinal function that would limit absorption of oral medication.

6. Known history of infection with HIV or any significant active infection (eg,bacterial, viral or fungal), including suspected or confirmed progressive multifocalleukoencephalopathy.

7. Known history of drug-specific hypersensitivity or anaphylaxis to study drugs (acalabrutinib and individual components of R-CHOP), including active product orexcipient components.

8. Active bleeding or history of bleeding diathesis (eg, hemophilia or von Willebranddisease).

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

10. Requires treatment with a strong cytochrome P450 3A4 (CYP3A4) inhibitor/inducerwhich cannot be modified as described in Sections 3.8.2 and 3.9.2, and/or the doseof acalabrutinib cannot be modified as described in these sections.

11. Requires or receiving anticoagulation with warfarin or equivalent vitamin Kantagonists (eg, warfarin).

12. History of significant cerebrovascular disease/event, including stroke orintracranial hemorrhage, within 6 months before the first dose of study drug.

13. Major surgical procedure within 4 weeks of first dose of study drug. Note: If asubject had major surgery, they must have recovered adequately from any toxicityand/or complications from the intervention before the first dose of study drug.

14. Received a live virus vaccination within 28 days of first dose of R-CHOP +acalabrutinib.

15. Hepatitis B or C serologic status: subjects who are hepatitis B core antibody (anti-HBc) positive and who are surface antigen negative will need to have anegative polymerase chain reaction (PCR) result before enrolment and must be willingto undergo PCR testing during the study. Those who are hepatitis B surface antigen (HbsAg) positive or hepatitis B PCR positive will be excluded. Subjects who arehepatitis C antibody positive will need to have a negative PCR result. Those who arehepatitis C PCR positive will be excluded. Subjects with a history of Hepatitis Cwho received antiviral treatment are eligible as long as PCR is negative.

16. ANC <1.0 x109/L (subjects with bone marrow involvement by lymphoma are eligibleregardless of ANC)

17. Platelets <50 x109/L (subjects with bone marrow involvement by lymphoma are eligibleregardless of platelet count)

18. Total serum bilirubin ≥1.5 times the upper limit of normal, unless directlyattributable to Gilbert's syndrome (or >3 times for documented hepatic involvementby lymphoma), AST and ALT >3 times the upper limit of normal (or >5 times fordocumented hepatic involvement by lymphoma)

19. Creatinine clearance <30 mL/min.

20. PT/INR >2 times the upper limit of normal in the absence of anticoagulants and/orPTT >2 times the upper limit of normal in the absence of anticoagulants.

21. Breastfeeding or pregnant. WOCBP must have a serum and/or urine pregnancy test donea maximum of 7 days prior to treatment initiation and a negative result must bedocumented prior to recruitment.

22. Concurrent participation in another therapeutic clinical trial.

23. Evidence of disease (such as severe or uncontrolled systemic diseases, includinguncontrolled hypertension and renal transplant) that, in the investigator's opinion,make it undesirable for the patient to participate in the study or that wouldjeopardize compliance with the protocol.

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

25. Current life-threatening illness, medical condition, or organ system dysfunctionwhich, in the Investigator's opinion, could compromise the subject's safety or putthe study at risk.