Acalabrutinib and Rituximab, Ifosfamide, Carboplatin and Etoposide for the Treatment of Patients with Relapsed/Refractory Non-Germinal Center Diffuse Large B Cell Lymphoma, Transformed Chronic Lymphocytic Leukemia//Small Lymphocytic Leukemia or Transformed Marginal Zone Lymphoma

Inclusion Criteria

• Patients must have histologic confirmation of relapsed or refractory lymphoma
• Baseline fluorodeoxygalactose F-18 (FDG)-positron emission tomography (PET) scans must demonstrate positive lesions compatible with computed tomography (CT) defined anatomical tumor sites. * CT scan showing at least: ** 2 or more clearly demarcated lesions/nodes with a long axis > 1.5 cm and short axis >= 1.0 cm, or ** 1 clearly demarcated lesion/node with a long axis > 2.0 cm and short axis >= 1.0 cm
• Patient must have been previously treated for B cell non-Hodgkin lymphoma with any of the allowable below: * First-line treatment with rituximab and an anthracycline-based chemotherapy * Monotherapy rituximab, dosed prior to first-line rituximab combined with anthracycline containing chemotherapy, or as maintenance therapy * Radiotherapy as part of the first-line treatment plan including anthracycline and rituximab
• Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2
• Life expectancy of greater than 6 weeks
• Absolute neutrophil count >= 1000/mcL (unless due to lymphoma involvement of the bone marrow)
• Platelets >= 75,000/mcL (unless due to lymphoma involvement of the bone marrow)
• Total bilirubin < 1.5 x within normal institutional limits (unless due to lymphoma involvement of liver or a known history of Gilbert’s disease)
• Aspartate aminotransferase (AST)(serum glutamic-oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT)(serum glutamate pyruvate transaminase [SGPT]) =< 2.5 x institutional upper limit of normal (unless due to lymphoma involvement of liver)
• Creatinine within normal institutional limits, or
• Creatinine clearance >= 40 mL/min/1.73 m^2 for patients with creatinine levels above institutional normal (unless due to lymphoma)
• Major surgical procedure within 28 days of first dose of study drug. 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
• Women who are sexually active and can bear children must agree to use highly effective forms of contraception during the study and for 90 days after the last dose of acalabrutinib + R-ICE
• Men who are sexually active and can beget children must agree to use highly effective forms of contraception during the study and for 90 days after the last dose of acalabrutinib + R-ICE
• Men must agree to refrain from sperm donation during the study and for 90 days after the last dose of study drug
• Willing and able to participate in all required evaluations and procedures in this study protocol including swallowing capsules without difficulty
• Ability to understand the purpose and risks of the study and provide signed and dated informed consent and authorization to use protected health information (in accordance with national and local subject privacy regulations)
• History of prior malignancy, with the exception of the following: * Malignancy treated with curative intent felt to be at low risk for recurrence by treating physician * Adequately treated non-melanomatous skin cancer or lentigo maligna melanoma without current evidence of disease * Adequately treated cervical carcinoma in situ without current evidence of disease

Exclusion Criteria

• Germinal-center cell-of-origin DLBCL
• Patients who have had chemotherapy or radiotherapy < 21 days prior to first administration of study treatment or those who have not recovered from adverse events due to agents administered more than 4 weeks earlier
• Patients who are receiving any other investigational agents
• Patients with known central nervous system involvement of lymphoma
• History of allergic reactions attributed to compounds of similar chemical or biologic composition to acalabrutinib or R-ICE with the exception of first-infusion reaction to rituximab
• Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements. Recent infections requiring systemic treatment need to have completed therapy > 7 days before the first dose of study drug
• Pregnant women are excluded from this study because an acalabrutinib R-ICE is a chemotherapy program with the potential for teratogenic or abortifacient effects. Because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with acalabrutinib R-ICE, breastfeeding should be discontinued if the mother is treated with acalabrutinib R-ICE
• Human immunodeficiency virus (HIV)-positive patients on combination antiretroviral therapy are eligible, unless the patient’s CD4 count is below the institutional lower limit of normal, or the patient is taking prohibited CYP3A4/5 strong inhibitors or inducers
• Patients may not have received any anti-cancer therapy for their primary rel/ref DLBCL with the exception of palliative radiation therapy (RT)
• Uncontrolled autoimmune hemolytic anemia or immune thrombocytopenic purpura (ITP) resulting in (or as evidenced by) declining platelet or hemoglobin (Hgb) levels within the 4 weeks prior to first dose of study drug
• Presence of transfusion-dependent thrombocytopenia
• Prior exposure to a BTK inhibitor
• Currently active clinically significant cardiovascular disease such as uncontrolled arrhythmia, congestive heart failure, or class 3 or 4 congestive heart failure as defined by the New York Heart Association Functional Classification, or history of myocardial infarction, unstable angina, or acute coronary syndrome within 6 months prior to first dose with study drug
• Unable to swallow capsules, or disease significantly affecting gastrointestinal function or, resection of the stomach or small bowel, or symptomatic inflammatory bowel disease or ulcerative colitis, or partial or complete bowel obstruction
• Serologic status reflecting active hepatitis B or C infection. Patients that are positive for hepatitis B core antibody, hepatitis B surface antigen (HBsAg), or hepatitis C antibody will need a negative polymerase chain reaction (PCR) prior to enrollment. (PCR positive patients will be excluded). Hepatitis C antibody positive patients are eligible if PCR is negative. Hepatitis B core antibody (+) patients without evidence of HBsAg or Hep B PCR (+) are eligible with appropriate Hepatitis B reactivation prophylaxis
• History of stroke or intracranial hemorrhage within 6 months prior to enrollment
• Current life-threatening illness, medical condition, or organ system dysfunction which, in the investigator’s opinion, could compromise the patient’s safety, or put the study at risk
• Received anticoagulation therapy with Coumadin or equivalent vitamin K antagonists within the last 28 days
• Vaccinated with live, attenuated vaccines with 4 weeks of first does of study drug
• Unresolved toxicities from prior anti-cancer therapy, defined as having not resolved to Common Terminology Criteria for Adverse Event (CTCAE, version 5), grade =< 1, or to the levels dictated in the inclusion/exclusion criteria with the exception of alopecia
• Known bleeding disorders (e.g., von Willebrand’s disease) or hemophilia
• Unwilling or unable to participate in all required study evaluations and procedures
• Currently active, clinically significant hepatic impairment (>= moderate hepatic impairment according to the National Cancer Institute (NCI)/Child Pugh classification
• Breastfeeding or pregnant
• Concurrent participation in another therapeutic clinical trial
• Patients who require proton pump inhibitors at baseline (prior to first dose of study drug) or strong CYP3A4 inhibitor or inducer and are not able to switch to another medication