GATE1: A Multicenter Phase II Study of Pirtobrutinib, Rituximab and Venetoclax Combination Therapy for Patients With Previously Untreated Mantle Cell Lymphoma

Inclusion Criteria:

1. Age ≥ 18 years old.

2. Confirmed pathology diagnosis of MCL with t(11;14)(q13;q32) translocation and/orcyclin D1 overexpression (e.g., positive immunohistochemistry staining).

3. MCL cells are CD20 positive (e.g., positive staining on immunohistochemistry or flowcytometry).

4. No prior MCL-directed systemic treatment (such as chemotherapy, immunotherapy,targeted therapy, and cellular therapy) or radiotherapy. NOTE: A short course of corticosteroids (e.g., ≤ 1 week of intravenous or ≤ 2 weeksof oral) given for acute MCL-related symptoms or impending severe organ dysfunctionis allowed, but a washout period of 3 days is required before registration.

5. Have a clinical indication to treat (e.g., B symptoms, or symptomatic or progressivelymphadenopathy or hepatosplenomegaly, or cytopenia caused by MCL, etc.).

6. ECOG performance status (PS) 0-2 (Appendix I).

7. Evaluable disease, i.e., ANY of the following:

• Measurable lymph node or extranodal lesion with at least one dimeson > 1.5 cm

• Spleen size > 15 cm if spleen is involved by MCL (based on imaging or biopsy)

• WBC > 15,000/µL if peripheral blood is involved by MCL (based on flowcytometry)

• Bone marrow involvement by MCL (> 10% of cellularity)

• Endoscopically visible lesion that is biopsy-proven to be involved by MCL

8. Meet ALL following criteria in lab values obtained ≤ 14 days prior to registration:

• Absolute neutrophil count (ANC) ≥ 1000/µL without growth factor support

• Platelet count ≥ 75,000/µL without transfusion support (≥ 50,000/µL if there isevidence of bone marrow involvement by MCL or splenomegaly due to MCL)

• Hemoglobin ≥ 8.0 g/dL without transfusion support

• Prothrombin (PT) or international normalized ratio (INR) ≤ 1.5 × upper normallimit (ULN)

• Activated partial thromboplastin time (aPTT) or partial thromboplastin time (PTT) ≤ 1.5 × ULN

• Total bilirubin ≤ 1.5 × ULN, or ≤ 3 × ULN if there is evidence of parenchymalliver involvement by MCL; patients with Gilbert's syndrome or hemolysis areeligible if direct bilirubin is ≤ 1.5 × ULN

• Alanine aminotransferase (ALT) and aspartate transaminase (AST) ≤ 3 × ULN, or ≤ 5 × ULN if there is evidence of parenchymal liver involvement by MCL

• Creatinine clearance > 50 mL/min using the Cockcroft-Gault formula (AppendixII)

9. Left ventricular ejection fraction by ECHO or MUGA ≥ 50% (must be within 12 monthsprior to registration).

10. Able to understand and voluntarily sign an IRB-approved informed consent form.

11. Willing to provide mandatory research blood, bone marrow, lymphoma biopsy tissue,and saliva specimens for correlative research.

12. Willing to return to enrolling institution for follow-up.

13. Negative serum pregnancy test done ≤ 7 days prior to registration, for persons ofchildbearing potential, defined as post menarche and not postmenopausal (i.e., ≥ 2years of non-therapy-induced amenorrhea) or surgically sterile (e.g.,post-hysterectomy, bilateral salpingectomy, or oophorectomy).

14. Persons of reproductive potential and their partners must agree to use highlyeffective birth control methods for the duration of study treatment and for 1 month (30 days) following the last dose of pirtobrutinib and/or venetoclax and for 12months following the last dose of rituximab (Appendix III).

15. Males must agree to not donate sperms for the duration of study treatment and for 3months following the last dose of any study drug.

Exclusion Criteria:

1. CNS involvement by MCL (e.g., any parenchymal, leptomeningeal, CSF, cranial nerve,or spinal cord or nerve root involvement).

2. Pregnant or plan to become pregnant during study treatment or within 1 monthfollowing the last dose of pirtobrutinib and/or venetoclax or within 12 monthsfollowing the last dose of rituximab; or breast-feeding or plan to breastfeed duringstudy treatment or within 1 week following the last dose of pirtobrutinib and/orvenetoclax or within 6 months following the last dose of rituximab.

3. Malabsorption syndrome or other condition that precludes enteral route ofadministration.

4. Any of the following medication requirement or recent use:

• Use of a strong or moderate cytochrome P450 (CYP) 3A inhibitor or inducer ≤ 7days prior to registration

• Anticipated requirement of a strong CYP3A inhibitor or inducer during the studythat cannot be substituted

• Use of grapefruit or grapefruit products, Seville oranges or products fromSeville oranges, or star fruit ≤ 3 days prior to registration, or planned useduring the study

• Anticipated requirement of a strong P-gp inhibitor during the study

• Anticoagulation with a vitamin K antagonist ≤ 7 days prior to registration oranticipated use during the study

5. Co-morbid systemic illnesses or other severe concurrent disease which, in thejudgment of the investigator, would make the patient inappropriate for entry intothis study or interfere significantly with the proper assessment of safety andtoxicity of the prescribed regimens.

6. History of a bleeding disorder (e.g., hemophilia, von Willebrand disease, etc.) oractive bleeding.

7. Active or recent infections, including but not limited to:

• Active infections requiring treatment (such as systemic antibiotics,antivirals, or antifungals) ≤ 7 days prior to registration

• History of a positive COVID-19 (SARS-CoV-2) test (nucleic acid or antigen)within 4 weeks prior to registration, or presence of continued COVID-19-relatedclinically relevant symptoms or COVID-19-related significant pulmonaryinfiltrates in patients with a history of COVID-19 disease

• Human Immunodeficiency Virus (HIV) positive NOTE: Patients who have testedpositive for Human Immunodeficiency Virus (HIV) are excluded due to potentialdrug-drug interactions between anti-retroviral medications and pirtobrutiniband risk of opportunistic infections with both HIV and irreversible BTKinhibitors. For patients with unknown HIV status, HIV testing will be performedat Screening and result should be negative for the patient to be eligible.

• Known active Cytomegalovirus (CMV) infection

• Hepatitis B virus (HBV): Patients with positive hepatitis B surface antigen (HBsAg) are excluded. Patients with positive hepatitis B core antibody (anti-HBc) and negative HBsAg require HBV polymerase chain reaction (PCR)evaluation. Patients who are HBV PCR positive will be excluded. Due torituximab's black box warning for Hepatitis B reactivation, patients withpositive hepatitis B core antibody (anti-HBc) should have prophylactic therapywith an approved nucleos(t)ide analogue to prevent reactivation.

• Hepatitis C virus (HCV): If hepatitis C antibody result is positive, patientwill need to have a negative result for hepatitis C ribonucleic acid (RNA).Patients who are hepatitis C RNA positive will be excluded.

8. Uncontrolled cardiovascular disease including but not limited to: Uncontrolled hypertension (SBP > 160 mmHg or DBP > 110 mmHg despite of 3 differentclasses of full dose anti-hypertensives medications) History of myocardialinfarction ≤ 3 months prior to registration Unstable angina or acute coronarysyndrome ≤ 2 months prior to registration New York Heart Association (NYHA) ClassIII or IV or symptomatic congestive heart failure or dilated cardiomyopathyUncontrolled or symptomatic arrhythmias NOTE: Patients with pacemakers are eligibleif they have no history of fainting or clinically relevant arrhythmias while usingthe pacemaker

9. Prolongation of QT interval corrected for heart rate (QTcF, calculated usingFridericia's Formula: QTcF=QT/∛RR) > 470 msec. NOTE: Correction for widened QRS complex (e.g., with pacing, or underlying bundlebranch block, etc) allowed (e.g., "Adjusted QTcF" = measured QTcF - [measured QRS - 90 ms]). Correction of suspected drug induced QTcF prolongation can be attempted atthe investigator's discretion and only if clinically safe to do so with eitherdiscontinuation of the offending drug or switch to another drug not known to beassociated with QTcF prolongation.

10. History of cerebral vascular accident ≤ 6 months prior to registration.

11. Oxygen dependent lung disease (such as interstitial lung disease or COPD).

12. Ongoing inflammatory bowel disease (such as ulcerative colitis) requiring activetreatment.

13. Psychiatric illness/social situations that would limit compliance with studyrequirements.

14. Major surgery ≤ 28 days prior to registration.

15. Vaccination with a live vaccine ≤ 28 days prior to registration.

16. Another primary malignancy (other than localized non-melanotic skin cancer orcarcinoma in situ of the cervix or breast) that is not in remission or requiresongoing treatment (except for adjuvant hormonal therapy for adequately treatednonmetastatic breast or prostate cancer), or limits expected survival to ≤ 3 years.