Ibrutinib, Rituximab, Venetoclax, and Combination Chemotherapy in Treating Patients With Newly Diagnosed Mantle Cell Lymphoma

PRIMARY OBJECTIVES:

I. To determine the complete response rate of the ibrutinib plus rituximab combination
followed by venetoclax in newly diagnosed young mantle cell lymphoma (MCL) patients.

SECONDARY OBJECTIVES:

I. To determine the safety profile of the ibrutinib plus rituximab combination followed by
venetoclax in newly diagnosed young MCL patients.

II. To evaluate the progression-free survival and overall survival time of the ibrutinib plus
rituximab combination followed by venetoclax and hyper-fractionated cyclophosphamide,
vincristine, doxorubicin hydrochloride, and dexamethasone (hyper-CVAD) in newly diagnosed
young MCL patients.

EXPLORATORY OBJECTIVES:

I. Developing a novel minimal residual disease (MRD) assay using circulating tumor
deoxyribonucleic acid (DNA) (ctDNA) from patients' plasma samples collected in this trial.

OUTLINE:

PART I: Patients receive ibrutinib orally (PO) once daily (QD) on days 1-28 and receive
rituximab intravenously (IV) over 4-8 hours on days 1, 8, 15, and 22 of course 1 and on day 1
of courses 3-12. Patients also receive venetoclax PO QD on days 1-28 of courses 5-12.
Treatment repeats every 28 days for up to 12 courses in the absence of disease progression or
unacceptable toxicity.

PART II: Patients are assigned to 1 of 3 groups depending on risk status.

GROUP I:

COMBINATION CHEMOTHERAPY: Patients receive rituximab IV over 6 hours on day 1, dexamethasone
PO or IV on days 1-4, cyclophosphamide IV over 3 hours twice daily (BID) on days 2-4, and
doxorubicin hydrochloride IV over 24 hours and vincristine IV over 15-30 minutes on day 5 of
odd-numbered courses (1, 3, 5, and 7). Patients also receive rituximab IV over 6 hours on day
1, methotrexate IV over 24 hours on day 2, and cytarabine IV over 2 hours BID on days 3-4 of
even-numbered courses (2, 4, 6, and 8). Treatment repeats every 28 days for up to 8 courses
in the absence of disease progression or unacceptable toxicity.

MAINTENANCE THERAPY: Patients receive ibrutinib and venetoclax PO QD on days 1-28, and
rituximab IV over 4-8 hours on day 1 of every other month. Courses repeat every 28 days for
up to 24 months in the absence of disease progression or unacceptable toxicity.

GROUP II: Patients receive combination chemotherapy as in group I. Treatment repeats every 28
days for up to 4 courses in the absence of disease progression or unacceptable toxicity.
Patience also receive maintenance therapy as in group I.

GROUP III: Patients receive maintenance therapy as in group I.

After completion of study treatment, patients are followed up at 30 days, every 4 months for
2 years, every 6 months for 2 years, and then annually for up to 5 years.

Inclusion Criteria:

- Confirmed diagnosis of mantle cell lymphoma with CD20 positivity in tissue biopsy

- MCL must be symptomatic and need immediate therapy. Symptoms and nature of MCL include
any of the following: a) B-symptoms, b) Mantle Cell Lymphoma International Prognostic
Index (MIPI) larger than 3, c) Ki 67 larger than or equal to 30%, d) bulky tumors
larger than 10cm or in case of larger than or equal to 2 tumors, each larger than or
equal to 5cm in diameter, e) disease threatening organ function, f) elevated lactate
dehydrogenase (LDH), g) peripheral blood (PB) white blood cell (WBC) larger than
50,000, h) pancytopenia due to bone marrow MCL, i) patient's choice due to anxiety; j)
pain due to lymphoma; k) somatic mutations in the TP53, c-MYC or NOTCH genes; l) size
of spleen larger than or equal to 20 cm

- Newly diagnosed MCL with no prior therapy and consent to provide a new baseline
(pretreatment) tumor biopsy (bone marrow biopsy and/or surgical biopsy)

- Sign (or their legally-acceptable representatives must sign) an informed consent
document indicating that they understand the purpose of and procedures required for
the study, including biomarkers, and are willing to participate in the study

- Bi-dimensional measurable disease using both computed tomography (CT) scan and/or
positron emission tomography (PET)-CT gastrointestinal, bone marrow or spleen only
patients are allowable

- Eastern Cooperative Oncology Group (ECOG) performance status of 2 or less

- Absolute neutrophil count (ANC) larger than or equal to 1000/mm^3 independent of
growth factor support

- Platelets larger than or equal to 100,000/mm^3 or larger than or equal to 50,000/mm^3
if bone marrow involvement without necessitating transfusion

- Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) less than or equal
to 3 x upper limit of normal (ULN)

- Total bilirubin less than or equal to 1.5 x ULN unless bilirubin rise is due to
Gilbert's syndrome or of non-hepatic origin

- Creatinine clearance (CLcr) larger than 50 mL/min

- Cardiac ejection fraction larger than or equal to 50% by echocardiogram (ECHO) or
multigated acquisition (MUGA)

- 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, or
other malignancies in remission (including prostate cancer patients in remission from
radiation therapy, surgery or brachytherapy), not actively being treated with life
expectancy of larger than 3 years. Principal investigator (PI) can use clinical
judgement in the best interest of patients

- Females of childbearing potential (FCBP) must have a negative serum or urine pregnancy
test (within 30 days of initiation of protocol therapy) and must be willing to use
acceptable methods of birth control during and after the study consistent with local
regulations regarding the use of birth control methods for subjects participating in
clinical trials. Men must agree to use a latex condom during sexual contact with a
female of childbearing potential even if they have had a successful vasectomy. Men
must agree to not donate sperm during and after the study. For females, these
restrictions apply for 1 month after the last dose of study drug. For males, these
restrictions apply for 3 months after the last dose of study drug

Exclusion Criteria:

- Any serious medical condition including but not limited to, uncontrolled hypertension,
uncontrolled diabetes mellitus, active/symptomatic coronary artery disease, chronic
obstructive pulmonary disease (COPD), renal failure, active hemorrhage, laboratory
abnormality, or psychiatric illness that, in the investigators opinion, places the
patient at unacceptable risk or would prevent the subject from signing the informed
consent form.

- Pregnant or breast-feeding females

- Known human immunodeficiency virus (HIV) infection (HIV testing is not required)

- Evidence of other clinically significant uncontrolled condition(s) including, but not
limited to: a. Uncontrolled and/or active systemic infection (viral, bacterial or
fungal) b. Chronic hepatitis B virus (HBV) or hepatitis C (HCV) requiring treatment.
Note: subjects with serologic evidence of prior vaccination to HBV (i.e. hepatitis B
surface (HBs) antigen negative-, anti-HBs antibody positive and anti-hepatitis B core
(HBc) antibody negative) or positive anti-HBc antibody from intravenous
immunoglobulins (IVIG) may participate

- Treatment with any of the following within 7 days prior to the first dose of study
drug:

- Steroid therapy for anti-neoplastic intent

- Moderate or strong cytochrome P450 3A (CYP3A) inhibitors

- Moderate or strong CYP3A inducers

- Administration or consumption of any of the following within 3 days prior to the first
dose of study drug:

- Grapefruit or grapefruit products

- Seville oranges (including marmalade containing Seville oranges)

- Star fruit

- Patients with active hepatitis B infection (not including patients with prior
hepatitis B vaccination; or positive serum hepatitis B antibody). Known hepatitis C
infection is allowed as long as there is no active disease and is cleared by
gastrointestinal (GI) consultation

- Central nervous system with mantle cell lymphoma

- Significant neuropathy (grades 3 to 4, or grade 2 with pain) within 14 days prior to
enrollment

- Contraindication to any of the required concomitant drugs or supportive treatments or
intolerance to hydration due to preexisting pulmonary or cardiac impairment including
pleural effusion requiring thoracentesis or ascites requiring paracentesis unless due
to lymphoma

- 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
ibrutinib

- Major surgery within 4 weeks of initiation of therapy or a wound that has not fully
healed within 4 weeks of randomization. Clearance letter from primary physician
required

- Requires anticoagulation with warfarin or equivalent vitamin K antagonist

- Requires chronic treatment with strong CYP3A inhibitors

- Patients with New York Health Association (NYHA) Class III and IV heart failure,
myocardial infarction in the preceding 6 months, and significant conduction
abnormalities, including but not limited to left bundle branch block, 2nd degree
atrioventricular (AV) block type II, 3rd degree block, QT prolongation (corrected QT
[QTc] larger than 500 msec), sick sinus syndrome, ventricular tachycardia, symptomatic
bradycardia (heart rate less than 50 bpm), hypotension, light headedness and syncope,
persistent and uncontrolled atrial fibrillation

- Recent placement of a stent and by recommendation of their cardiologist need to stay
on anticoagulants such as warfarin or equivalent vitamin K antagonist

- Acute infection requiring treatment (IV antibiotics, antivirals, or antifungals)
within 14 days prior to initiation of therapy

- Child-Pugh class B or C are excluded

- Vaccinated with live, attenuated vaccines within 4 weeks of randomization