Pacritinib in Combination With a BTK Inhibitor for the Treatment of Patients With Relapsed or Refractory Mantle Cell Lymphoma

Inclusion Criteria:

* Documented informed consent of the participant and/or legally authorized representative
* Be willing to provide tissue from a fresh core or excisional biopsy (performed as standard of care) of a tumor lesion prior to starting study therapy or from diagnostic tumor biopsies

  * If unavailable, exceptions may be granted with study principal investigator (PI) approval
* Age: ≥ 18 years
* Eastern Cooperative Oncology Group (ECOG) ≤ 2
* Histologically confirmed diagnosis of mantle cell lymphoma according to the World Health Organization (WHO) classification with a characteristic immunophenotypic profile with CD5+, CD20+, and with either cyclin D1 expression by immunohistochemistry (IHC), or positive by fluorescence in situ hybridization (FISH) or cytogenetics for the t(11,14) translocation, or both. Patients whose tumor is negative for cyclin D1 expression are allowed providing hemato-pathology confirmation of the diagnosis of MCL

  * Relapsed or refractory disease after at least 1 prior line of systemic therapy
  * Relapse must have been confirmed histologically with hematopathology review. Exceptions may be granted with study PI approval
* Patient must be receiving treatment with single agent ibrutinib or another covalent BTK inhibitor (e.g., acalabrutinib, zanubrutinib), and must have previously achieved complete response (CR) or partial response (PR) to the BTK inhibitor, and must show evidence of progressive MCL at the time of enrollment
* Radiographically measurable disease by Lugano criteria (e.g., one or more nodal sites of disease ≥ 1.5 cm and/or extranodal sites of disease ≥ 1.0 cm in longest dimension)

  * If measurable bone marrow involvement or circulating disease has been confirmed in the absence of radiographically measurable disease, exceptions may be granted with study PI approval
* Fully recovered from the acute toxic effects (except alopecia) to ≤ grade 1 to prior anti-cancer therapy
* WITHOUT BONE MARROW INVOLVEMENT: Absolute neutrophil count (ANC) ≥ 1,000/mm\^3

  * NOTE: Growth factor is not permitted within 7 days of ANC assessment unless cytopenia is secondary to disease involvement
* WITH BONE MARROW INVOLVEMENT: ANC ≥ 500/mm\^3

  * NOTE: Growth factor is not permitted within 7 days of ANC assessment unless cytopenia is secondary to disease involvement
* WITHOUT BONE MARROW INVOLVEMENT: Platelets ≥ 75,000/mm\^3

  * NOTE: Platelet transfusions are not permitted within 7 days of platelet assessment unless cytopenia is secondary to disease involvement
* WITH BONE MARROW INVOLVEMENT: Platelets ≥ 25,000/mm\^3

  * NOTE: Platelet transfusions are not permitted within 7 days of platelet assessment unless cytopenia is secondary to disease involvement
* Total bilirubin ≤ 4 x upper limit of normal (ULN) (If hepatic involvement by lymphoma, or Gilbert's disease: ≤ 3 x ULN)
* Aspartate aminotransferase (AST) ≤ 3 x ULN (If hepatic involvement by lymphoma: AST ≤ 5 x ULN)
* Alanine aminotransferase (ALT) ≤ 3 x ULN (If hepatic involvement by lymphoma: ALT ≤ 5 x ULN)
* Creatinine clearance of ≥ 30 mL/min per 24 hour urine test or the Cockcroft-Gault formula
* IF NOT RECEIVING ANTICOAGULANTS: International normalized ratio (INR) OR prothrombin (PT) ≤ 1.5 x ULN
* IF ON ANTICOAGULANT THERAPY: PT must be within therapeutic range of intended use of anticoagulants
* IF NOT RECEIVING ANTICOAGULANTS: Activated partial thromboplastin time (aPTT) ≤ 1.5 x ULN
* Left ventricular ejection fraction (LVEF) ≥ 50%
* Mean corrected QT interval (QTc) (calculated from 3 electrocardiograms using Fridericia formula) ≤ 480 ms
* WOMEN OF CHILDBEARING POTENTIAL: (WOCBP): Negative urine or serum pregnancy test

  * If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required
* Agreement by females and males of childbearing potential to abstain from heterosexual intercourse or use a highly effective method of birth control (defined as those resulting in a failure rate of \< 1% per year) during the treatment period until at least 90 days after the last dose of pacritinib and until at least 30 days after the last dose of BTK inhibitor

  * Childbearing potential defined as not being surgically sterilized (men and women) or have not been free from menses for \> 1 year (women only) with no identified cause other than menopause
  * Examples of contraceptive methods with a failure rate of \< 1% per year include bilateral tubal ligation, male sterilization, hormone releasing intrauterine devices, and copper intrauterine devices. Note that oral contraceptives or progestin injection (e.g., Depo-Provera) alone are not considered highly effective methods of contraception on their own in combination with pacritinib; an additional barrier method (diaphragm with spermicidal gel or condoms with spermicide), double-barrier methods (diaphragm with spermicidal gel and condoms with spermicide), partner vasectomy, or total abstinence are required

Exclusion Criteria:

* Autologous hematopoietic stem cell transplant within 3 months of day 1 of protocol therapy
* Prior allogeneic stem cell transplant
* Prior treatment with pacritinib or a janus kinase 2 (JAK2) inhibitor
* Concomitant treatment with pirtobrutinib
* Strong CYP3A4 inducers/ inhibitors within 14 days prior to day 1 of protocol therapy

  * Note: Shorter washout periods may be permitted with approval of the study PI, provided that the washout period is at least five half-lives of the drug prior to day 1 of protocol therapy
* Systemic treatment with medications that increase the risk of bleeding, including anticoagulants, antiplatelet agents (except for aspirin dosages of ≤ 100 mg per day), anti-vascular endothelial growth factor (anti-VEGF) agents, and daily use of cytochrome C oxidase subunit 1 (COX-1) inhibiting non-steroidal anti-inflammatory drugs (NSAIDs) within 14 days prior to day 1 of protocol therapy
* Systemic treatment with medications with arrhythmogenic potential within 14 days prior to day 1 of protocol therapy. Shorter washout periods may be permitted with approval of the study PI, provided that the washout period is at least five half-lives of the drug prior to day 1 of protocol therapy
* Systemic steroid therapy for any cause must be tapered down to ≤ 20 mg/day prednisone or equivalent. Exceptions are:

  * Use of brief (≤ 7 days) course of high dose corticosteroids (100 mg/day prednisone or equivalent) prior to initiation of study therapy for control of lymphoma-related symptoms
  * Inhaled or topical steroids
  * Use of mineralocorticoids for management of orthostatic hypotension
  * Use of physiologic doses of corticosteroids for management of adrenal insufficiency
* Significant recent bleeding history defined as National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) grade ≥ 2 within 3 months prior to day 1 of protocol therapy, unless precipitated by an inciting event (e.g., surgery, trauma, or injury)
* Known bleeding disorders (e.g., von Willebrand's disease or hemophilia)
* Factors that increase the risk for QT interval prolongation (eg, hypokalemia \[defined as serum potassium \< 3.0 mEq/L that is persistent and refractory to correction\], or history of long QT interval syndrome)
* Clinically significant cardiovascular disease such as symptomatic arrhythmias, congestive heart failure, or myocardial infarction within 3 months of screening, any class III or IV cardiac disease as defined by the New York Heart Association (NYHA) Functional Classification, or any class C or D cardiac disease as defined by the NYHA Objective Assessment

  * Note: Subjects with controlled, asymptomatic atrial fibrillation/flutter can enroll on study
* Inability to swallow and retain an oral medication
* Any active gastro-intestinal or metabolic condition that could significantly interfere with absorption of oral medication
* Active or uncontrolled inflammatory or chronic functional bowel disorder such as Crohn's disease, inflammatory bowel disease, chronic diarrhea, or chronic constipation
* Known hypersensitivity to compounds of similar chemical composition to study agent or any of the following inactive ingredients: microcrystalline cellulose, polyethylene glycol, and magnesium stearate, or to loperamide or equivalent antidiarrheal medication
* Known active central nervous system (CNS) involvement by lymphoma, including leptomeningeal involvement
* Known history of progressive multifocal leukoencephalopathy (PML)
* Prior or concurrent malignancy whose natural history or treatment could interfere with the safety or efficacy assessment of the protocol therapy
* Known active bacterial, viral, fungal, mycobacterial, parasitic, or other infection (excluding fungal infections of nail beds) at study enrollment or any major episode of infection (as evaluated by the investigator) within 4 weeks prior to day 1 of protocol therapy
* Known active hepatitis B virus (HBV) or hepatitis C virus (HCV) infection. Testing to be done only in patients suspected of having infections or exposures. Patients with history of HBV infection (defined as negative hepatitis B surface antigen \[HBsAg\] and positive hepatitis B core antibody \[HBcAb\]) are eligible if HBV deoxyribonucleic acid (DNA) is undetectable, if they are willing to undergo DNA testing on day 1 of every cycle and every three months for at least 12 months after the last cycle of study treatment and appropriate antiviral therapy. Patients who are positive for HCV antibody are eligible if polymerase chain reaction (PCR) is negative for HCV RNA (PCR testing only required if HCV antibody testing is positive).
* Known active human immunodeficiency virus (HIV) infection. Subjects who have an undetectable or unquantifiable HIV viral load with CD4 \> 200 and are on highly active antiretroviral therapy (HAART) medication are allowed. Testing to be done only in patients suspected of having infections or exposures
* FEMALES ONLY: Pregnant or breastfeeding
* Any other condition that would, in the Investigator's judgment, contraindicate the patient's participation in the clinical study due to safety concerns with clinical study procedures
* Prospective participants who, in the opinion of the investigator, may not be able to comply with all study procedures (including compliance issues related to feasibility/logistics)