Rituximab, Idelalisib, and Venetoclax in Treating Participants with Relapsed or Refractory Chronic Lymphocytic Leukemia or Small Lymphocytic Lymphoma

Inclusion Criteria

• Relapsed or refractory B-cell CLL or biopsy-proven small lymphocytic lymphoma (SLL). Treatment required in the opinion of the investigator
• Must have had at least one standard treatment with a regimen containing at least one of the following agents/classes of agents; and where specified, must also meet the treatment duration, progression, and/or relapse criteria for that class of agent: * Fludarabine * An alkylator (eg, chlorambucil, bendamustine) * A BTK inhibitor (eg, ibrutinib, acalabrutinib); and must have progressed or relapsed > 6 months after last BTK inhibitor treatment * An anti-CD20 monoclonal antibody (eg, rituximab, obinutuzumab) * A BCL-2-family protein inhibitor (eg, venetoclax, navitoclax); and ** If best response is < complete response (CR) with BCL-2-family protein inhibitor treatment *** Must have had >= 1 year of BCL-2-family protein inhibitor treatment; and *** Must have progressed > 6 months after last BCL-2-family protein inhibitor treatment ** If best response is CR with BCL-2-family protein inhibitor treatment *** Must have relapsed >= 1 year after last BCL-2-family protein inhibitor treatment * A PI3K inhibitor (eg, idelalisib, duvelisib, TGR-1202, copanlisib, buparlisib); and must have progressed or relapsed > 6 months after last treatment with the PI3K inhibitor. * (NOTE THAT THIS CRITERION IS NOT APPLICABLE TO 2ND-STEP REGISTRATION)
• Prior allogeneic stem cell transplant allowed provided the following criteria are met: * >= 12 months have elapsed since allogeneic transplant * No current or prior evidence of graft-versus-host disease * No current requirement for immunosuppressive therapy
• Prior autologous stem cell transplant allowed provided ≥ 6 months have elapsed since autologous transplant
• Eastern Cooperative Oncology Group performance status of 0, 1, or 2
• Absolute neutrophil count (ANC) >= 1,000/mm^3 (without support of granulocyte colony stimulating factors)
• Platelets >= 50,000/mm^3 (untransfused)
• Hemoglobin >= 9.0 g/dL
• Activated partial thromboplastin time (aPTT) and prothrombin time (PT) =< 1.2 x upper limit of normal (ULN) for the laboratory
• Calculated creatinine clearance >= 50 mL/min as calculated by the standard Cockcroft-Gault equation using age, actual weight, creatinine, and gender
• Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =< 1.5 x ULN for the laboratory
• Bilirubin =< 1.5 x ULN for the laboratory
• For a woman of childbearing potential (WCBP), a negative serum pregnancy test performed within 7 days prior to initiation of study treatment. Note: Postmenopausal is defined as any of the following: * Age >= 60 years * Age < 60 years and amenorrheic for at least 1 year with follicle-stimulating hormone (FSH) and plasma estradiol levels in the postmenopausal range * Bilateral oophorectomy
• WCBP and male patients must agree to use a medically accepted form of birth control for the duration of study treatment and for at least 1 month following completion of venetoclax and/or idelalisib or 12 months following rituximab, whichever occurs later
• Ability to understand and the willingness to sign a written informed consent document

Exclusion Criteria

• Known histologic transformation from CLL/SLL to an aggressive lymphoma (i.e., Richter’s transformation)
• Known history of drug-induced pneumonitis
• History of inflammatory bowel disease
• Central nervous system involvement
• Clinically significant infection including active hepatitis B or hepatitis C requiring active treatment, or active cytomegalovirus (CMV) infection
• Known human immunodeficiency virus (HIV) seropositivity. Note: HIV testing is not required
• Vaccination within 4 weeks prior to initiation of rituximab. * Note: Review vaccination status. Patients should, if possible, be brought up-to-date with all immunizations in agreement with current immunization guidelines at least 4 weeks prior to initiating rituximab
• Ongoing requirement for warfarin (due to potential drug-drug interactions that may increase the exposure of warfarin and ensuing complications)
• Has received any of the following within 14 days prior to initiation of study treatment: * Anti-cancer therapy * Investigational therapy (NOTE THAT THIS CRITERION IS NOT APPLICABLE TO 2ND-STEP REGISTRATION)
• Has not recovered to = < grade 1 toxicity(s) from prior therapy, except for chronic residual toxicities that in the opinion of the investigator are not clinically relevant given the known safety/toxicity profiles of the study regimen (eg, alopecia). (NOTE THAT THIS CRITERION IS NOT APPLICABLE TO 2ND-STEP REGISTRATION)
• Has not recovered to =< grade 1 toxicity(s) from idelalisib and rituximab, except for chronic residual toxicities that in the opinion of the investigator are not clinically relevant given the known safety/toxicity profiles of the study regimen (eg, alopecia). (NOTE THAT THIS CRITERION IS NOT APPLICABLE TO 1ST-STEP REGISTRATION)
• Ongoing or planned treatment with any of the following: * Steroid therapy for anti-neoplastic intent * Strong or moderate CYP3A inhibitor or inducer, and/or a narrow-therapeutic sensitive substrate * P-glycoprotein (gp) inhibitor or narrow-therapeutic sensitive P-gp substrate If any of these agents have been used, patients must be off them for >= 1 week before initiation of study treatment
• Prior intolerance to any component of study regimen that, in the opinion of the investigator would preclude study treatment
• A cardiovascular disability status of New York Heart Association class >= II
• Diagnosis or treatment for another malignancy within 1 year of study registration, with the exception of complete resection of basal cell carcinoma or squamous cell carcinoma of the skin, any in situ malignancy, or low-risk prostate cancer after curative therapy
• Active liver disease other than lymphoid involvement, inflammatory bowel disease, or Crohn’s disease
• Malabsorption syndrome or other condition that precludes enteral route of administration
• Exhibits evidence of other clinically significant uncontrolled condition(s) including, but not limited to: * Uncontrolled infection (viral, bacterial, or fungal) * Grade 3 or greater neutropenic fever within 1 week prior to initiation of study treatment
• Active autoimmune cytopenias (for 2 or more weeks), including autoimmune hemolytic anemia (AIHA) and idiopathic thrombocytopenic purpura
• Pregnancy or breastfeeding
• Medical, psychological, or social condition that, in the opinion of the investigator, may increase the patient’s risk, interfere with the patient’s participation in the study or hinder evaluation of study results