Acalabrutinib plus Rituximab followed by Brexucabtagene Autoleucel for the Treatment of High-Risk Mantle Cell Lymphoma

Inclusion Criteria

• Confirmed diagnosis of mantle cell lymphoma with CD20 positivity (by flow or immunohistochemistry [IHC] in tissue or in BM) and presence of chromosome translocation t(11;14), (q13;q32) and/or overexpression of cyclin D1 in tissue biopsy
• Newly diagnosed high risk patient without any prior therapy for MCL and are eligible to receive AR and CAR T cell therapy
• High risk MCL (blastoid/pleomorphic histology, high Ki-67 [>= 50%], TP53/NOTCH1/2, NSD2, UBR5, FAT1, POT1, SMARCA4, KMT2D, BIRC3 mutated or any of these mutations or more than 2 mutations with some evidence of prognostic impact, complex karyotype and/or bulky disease > 5 cm, fluorescence in situ hybridization [FISH] positive for TP53 or MYC from involved tissues or TP53 and MYC positive intensity in lymphoma cells in involved tissues [positive by hem-path criteria at MD Anderson Cancer Center (MDACC)]), high risk Mantle Cell Lymphoma International Prognostic Index (MIPI) score (with Ki-67%). Presence of any or all of these features would qualify as high risk but will need to be reviewed and approved by the study PI
• Patients who are eligible to receive CAR T therapy
• Patients who are willing and able to participate in all required evaluations and procedures in this study protocol, including swallowing capsules and tablets without difficulty
• Understand and voluntarily sign an Institutional Review Board (IRB)-approved informed consent form
• Age >= 18 years at the time of signing the informed consent
• Bi-dimensional measurable disease using the 2014 Cheson criteria (measurable disease by positron emission tomography-computed tomography (PET-CT) scan defined as at least 1 lesion that measures >= 1.5 cm in single dimension.) Spleen only involved (>=20 cm), these patients are allowed if they meet other high-risk features, determined by the study PI
• Eastern Cooperative Oncology Group (ECOG) performance status of 1 or less
• An absolute neutrophil count (ANC) > 1,000/mm^3 (Patients who have > 50% bone marrow or spleen infiltration by MCL are eligible if their ANC is >= 500/mm^3 [growth factor allowed]. These patients should be discussed with the PI of the study for final approval)
• Platelet count > 100,000/mm^3 (Patients who have > 50% bone marrow or spleen infiltration by MCL are eligible if their platelet level is equal to or >= than 30,000/mm^3. These patients should be discussed with either the PI or Co-PI of the study for final approval)
• Serum bilirubin < 1.5 mg/dl
• Creatinine (Cr) clearance >= 50 mL/min by Cockroft-Gault Formula
• Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT]) and alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) < 2.5 x upper limit of normal or < 5 x upper limit of normal if hepatic metastases are present. Gilbert’s disease is allowed
• Women of childbearing potential (WOBP) must have a negative serum or urine pregnancy test. WOBP and males must be willing to use highly effective methods of birth control. Woman of childbearing potential (WOCBP) who are sexually active must use highly effective methods of contraception during treatment and for 2 days after the last dose of acalabrutinib and for 12 months following the last dose of rituximab and 6 months after the completion of CAR T infusion. For male patients with a pregnant or non-pregnant WOCBP partner, should use barrier contraception, during treatment and for 2 days after the last dose of acalabrutinib and for 1 month following the last dose of rituximab and 6 months after the completion of CAR T infusion even if they have had a successful vasectomy
• LEUKAPHERESIS:
• Absolute neutrophil count (ANC >= 1,000/uL) * If the ANC is 500-1000 (due to marrow/splenic infiltration), then growth factors can be administered to improve the ANC up to > 1000. If the patients develop PR while on AR along with grade 3-4 toxicities, then we will hold up on CAR T until the cytopenias recover up to grade 1. This delay can be up to 1 month or until the patient is in PR
• Platelet count >= 75,000/uL
• Absolute lymphocyte count >= 100/uL
• Creatinine clearance (as estimated by Cockcroft Gault formula) >= 60 cc/min
• Serum alanine aminotransferase/aspartate aminotransferase (ALT)/(AST) =< 2.5 x upper limit of normal (ULN)
• Total bilirubin =< 1.5 mg/dl, except in patients with Gilbert’s syndrome
• Cardiac ejection fraction >= 50%, no evidence of pericardial effusion (except trace or physiological) as determined by an echocardiogram (ECHO), and no clinically significant electrocardiogram (ECG) findings
• No clinically significant pleural effusion
• Baseline oxygen saturation > 92% on room air

Exclusion Criteria

• EXCLUSION CRITERIA PART 1:
• Isolated bone marrow or GI only disease MCL patients and/or lack of measurable disease
• Pregnant or breast-feeding females
• Patients who are primary refractory to AR (No response/progressive disease within first 4 months of AR)
• Received any investigational drug within 30 days or 5 half-lives (whichever is shorter) before first dose of study drug
• 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
• Known human immunodeficiency virus (HIV) infection
• 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
• 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
• 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 cerebrospinal fluid (CSF) involvement
• 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
• 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
• Uncontrolled AIHA (autoimmune hemolytic anemia) or ITP (idiopathic thrombocytopenic purpura)
• 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
• Presence of a gastrointestinal ulcer diagnosed by endoscopy within 3 months before first dose of study drug
• 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
• History of symptomatic deep vein thrombosis (DVT) or pulmonary embolism requiring systemic anticoagulation within the last 6 months of enrollment
• Concomitant use of corticosteroids at > 20 mg prednisone or equivalent per day longer than 2 weeks
• Primary immunodeficiency
• 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
• History of severe, immediate hypersensitivity reaction attributed to aminoglycosides
• 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
• Requires treatment with strong CYP3A inhibitors or inducers
• Any of the following cardiac related conditions: * New York Heart Association (NYHA) class III and IV heart failure, * 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 atrioventricular (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
• 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
• Vaccinated with live, attenuated vaccines within 6 weeks of first dose of study drug
• Requires treatment with proton-pump inhibitors (eg, omeprazole, esomeprazole, lansoprazole, dexlansoprazole, rabeprazole or pantoprazole). Patients receiving proton-pump inhibitors who switch to H2-receptor antagonists (2 hours after acalabrutinib/placebo) or antacid (2 hours before or 2 hours after acalabrutinib/placebo). Avoid co-administration with proton pump inhibitors
• Any other serious medical condition including, but not limited to, uncontrolled diabetes mellitus, chronic obstructive pulmonary disease (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
• Known history of hypersensitivity or anaphylaxis to study drug(s) including active product or excipient components
• Prothrombin time (PT)/international normalized ratio (INR) or activated partial thromboplastin time (aPTT) (in the absence of lupus anticoagulant) > 2 x ULN
• Concurrent participation in another therapeutic clinical trial
• Has difficulty with or is unable to swallow oral medication or has significant gastrointestinal disease that would limit absorption of oral medication
• 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
• EXCLUSION CRITERIA: LEUKAPHERESIS:
• Temperature > 38°C within 72 hours of leukapheresis or patients with active infection and requiring IV antibiotics
• C-reactive protein (CRP) > 100 mg/L anytime from completion of acalabrutinib/rituximab therapy and start of leukapheresis
• White blood cell (WBC) count, or WBC differential, that is suggestive of infectious process and is observed between completion of acalabrutinib /rituximab therapy and the initiation of leukapheresis, (e.g. WBC > 20,000/uL, rapidly increasing WBC, or differential with high percentage of segs/bands)
• Presence or suspicion of fungal, bacterial, viral, or other infection that is uncontrolled or requiring intravenous (IV) antimicrobials for management. Simple urinary tract infection (UTI) and uncomplicated bacterial pharyngitis are permitted if responding to active treatment and after consultation with the PI
• Corticosteroid therapy at a pharmacologic dose (≥5 mg/day of prednisone or equivalent doses of other corticosteroids) and other immunosuppressive drugs within 7 days prior to leukapheresis
• In-dwelling line or drain (e.g., percutaneous nephrostomy tube, in-dwelling Foley catheter, biliary drain, or pleural/peritoneal/pericardial catheter). Ommaya reservoirs (if inserted for indication other than active CNS disease treatment). Dedicated central venous access catheters, such as a Port-a-Cath or Hickman catheter, are permitted. In-dwelling stents (e.g., ureteral stents or hepatic stents) inserted to relieve obstruction from lymphadenopathy from underlying MCL are permitted