Venetoclax and Combination Chemotherapy in Treating Patients with Relapsed or Refractory Diffuse Large B-Cell Lymphoma

Inclusion Criteria

• Relapsed/refractory diffuse large B-cell lymphoma after prior rituximab and anthracycline-containing systemic treatment regimen such as rituximab-cyclophosphamide, hydroxydaunorubicin hydrochloride (doxorubicin hydrochloride), vincristine (Oncovin), and prednisone (R-CHOP), rituximab-etoposide, vincristine, and doxorubicin (R-EPOCH), rituximab-hyperfractionated cyclophosphamide, vincristine, Adriamycin, and dexamethasone (R-HyperCVAD), etc; a biopsy immediately before enrollment is not required
• Subjects must have received no more than 2 prior systemic therapies for lymphoma; prior therapy with systemic rituximab monotherapy or conventional chemotherapy (i.e. bendamustine, cyclophosphamide, vincristine, and prednisone [CVP] or other) +/- rituximab for indolent non-Hodgkin lymphoma (NHL) +/- maintenance/extended-use rituximab will count as 1 line of systemic therapy
• Eastern Cooperative Oncology Group (ECOG) performance status =< 2
• Hemoglobin >= 8.0 g/dl
• Absolute neutrophil count >= 1,000/mcL
• Platelet count >= 75,000/mcL
• Total bilirubin =< 1.5 X the upper limit of normal (ULN) unless a known history of impaired bilirubin conjugation such as Gilbert’s, for whom the maximum will be 2.5 ULN
• Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT]) =< 2.5 X institutional ULN
• Alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2.5 X institutional ULN
• International normalized ratio (INR) =< 1.5 x ULN
• Patients must have a calculated serum creatinine clearance >= 50 mL/min using Cockcroft-Gault calculation or based on 24-hour urine collection performed within 7 days prior to treatment
• Specific guidelines will be followed regarding inclusion of relapsed/refractory DLBCL based on hepatitis B serological testing as follow: * Hepatitis B surface antigen (HBsAg) negative, hepatitis B virus core antibody (HBcAb) negative, hepatitis B virus surface antibody (HBsAb) negative patients are eligible * HBsAg negative, HBcAb negative, HBsAb positive patients are eligible * Patients who test positive for HBsAg are ineligible * Patients with HBsAg negative, but HBcAb positive (regardless of HBsAb status) should have a hepatitis B virus (HBV) deoxyribonucleic acid (DNA) testing performed and protocol eligibility determined as follow: ** If HBV DNA is positive, the subject is ineligible ** If HBV DNA is negative, the subject may be included but must undergo HBV DNA polymerase chain reaction (PCR) testing monthly x 3 months beginning from the start of treatment
• Subjects must have the ability to understand and the willingness to sign a written informed consent document
• For women of childbearing potential: agreement to remain abstinent (refrain from heterosexual intercourse) or use a contraceptive method with a failure rate of < 1% per year during the treatment period and for at least 30 days after the last dose of venetoclax or 12 months after the last dose of rituximab, whichever is longer * A woman is considered to be of childbearing potential if she is postmenarcheal, has not reached a postmenopausal state (< 12 continuous months of amenorrhea with no identified cause other than menopause), and has not undergone surgical sterilization (removal of ovaries and/or uterus); examples of contraceptive methods with a failure rate of < 1% per year include bilateral tubal ligation, male sterilization, hormonal contraceptives that inhibit ovulation, hormone-releasing intrauterine devices, and copper intrauterine devices * The reliability of sexual abstinence should be evaluated in relation to the duration of the clinical trial and the preferred and usual lifestyle of the patient; periodic abstinence (e.g., calendar, ovulation, symptothermal, or postovulation methods) and withdrawal are not acceptable methods of contraception
• For men: agreement to remain abstinent (refrain from heterosexual intercourse) or use contraceptive measures, and agreement to refrain from donating sperm, as defined below: * With female partners of childbearing potential, men must remain abstinent or use a condom plus an additional contraceptive method that together result in a failure rate of < 1% per year during the treatment period and for at least 6 months after the last dose of rituximab; men must refrain from donating sperm during this same period * With pregnant female partners, men must remain abstinent or use a condom during the treatment period and for at least 6 months after the last dose of rituximab to avoid exposing the embryo * The reliability of sexual abstinence should be evaluated in relation to the duration of the clinical trial and the preferred and usual lifestyle of the patient; periodic abstinence (e.g., calendar, ovulation, symptothermal, or postovulation methods) and withdrawal are not acceptable methods of contraception

Exclusion Criteria

• Prior treatment toxicities have not resolved to =< grade 2 according to National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 (except clinically insignificant toxicities such as alopecia)
• Subjects receiving any other investigational agents
• Patients with active tumor lysis syndrome (TLS)
• Patients with active central nervous system (CNS) disease defined as symptomatic meningeal lymphoma or known CNS parenchymal lymphoma
• History of severe allergic reactions attributed to compounds of similar chemical or biologic composition to rituximab or other agents used in this study
• Subjects with uncontrolled intercurrent illness including, but not limited to ongoing or active infection, symptomatic congestive heart failure (New York Heart Association [NYHA] class II or greater), unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements
• Human immunodeficiency virus (HIV)-positive subjects on combination antiretroviral therapy are ineligible because of the potential for pharmacokinetic interactions with venetoclax; In addition, these subjects are at increased risk of lethal infections when treated with marrow suppressive therapy; appropriate studies will be undertaken in subjects receiving combination antiretroviral therapy when indicated; HIV testing prior to enrollment is not required for screening but strongly encouraged for patients with no documented prior HIV assessment
• Presence of positive test results for hepatitis B virus (HBV), hepatitis B surface antigen (HBsAg), or hepatitis C (HCV) antibody * Patients who are positive for HCV antibody must be negative for HCV by polymerase chain reaction (PCR) to be eligible for study participation * Patients with occult or prior HBV infection (defined as positive total hepatitis B core antibody [HBcAb] and negative HBsAg) may be included if HBV DNA is undetectable; these patients must be willing to undergo monthly DNA testing
• Women who are pregnant or lactating
• Malabsorption syndrome or other condition that precludes enteral route of administration
• Chemotherapy or radiation within 3 weeks of the first scheduled study treatment
• Less than 2-year disease free from another primary malignancy (other than squamous or basal cell carcinoma of the skin, “in-situ” carcinoma of the cervix or breast, superficial bladder carcinoma, or previously treated localized prostate cancer with normal PSA levels); patients who have had completed all anti-cancer treatment for another primary malignancy more than 2 years prior to screening are eligible if they are not considered to have a “currently active” malignancy based on having less than a 30% risk of relapse
• Major surgery, other than diagnostic surgery, within 2 weeks
• Medical conditions requiring chronic use of high dose systemic corticosteroids (i.e., doses of prednisone higher than 10 mg/day or equivalent); brief (=< 7 days) treatment with glucocorticoids (prednisone 100 mg by mouth daily, or equivalent) prior to initiation of study therapy is acceptable
• Known allergy to both xanthine oxidase inhibitors and rasburicase; allergy to only one of these agents does not constitute an exclusion criterion
• Use of warfarin is prohibited; anticoagulation with low-molecular weight heparin (i.e. enoxaparin) or direct thrombin inhibitors is permitted
• The following concomitant medications are not allowed from 7 days prior to the first dose of study drug and during venetoclax administration: strong CYP3A4 inhibitors including but not limited to fluconazole, ketoconazole, and clarithromycin or strong CYP3A4 inducers included but not limited to rifampin, carbamazepine
• Receipt of live-virus vaccines within 28 days prior to the initiation of study