Ibrutinib and Venetoclax in Relapsed and Refractory Follicular Lymphoma

Inclusion Criteria

• Relapsed or refractory, histologically confirmed follicular lymphoma, grade I, II, or IIIa which requires therapy defined by at least one of the following:
• Constitutional symptoms
• Cytopenias
• High tumor burden (single mass > 7 cm, three masses > 3 cm, symptomatic splenomegaly, organ compression or compromise, ascites, pleural effusion)Must have received at least two prior systemic therapies
• All risk by FLIPI 0-5 factors (Appendix I)
• Measurable disease Measurable disease must be present either on physical examination or imaging studies; non-measurable disease alone is not acceptable. Any tumor mass > 1.5 cm is acceptable.

Lesions that are considered non-measurable include the following:

• Bone lesions (lesions if present should be noted)
• Ascites
• Pleural/pericardial effusion
• Lymphangitis cutis/pulmonis
• Bone marrow (involvement by lymphoma should be noted)
• Adequate hematologic function independent of transfusion and growth factor support for at least 3 weeks prior to screening unless attributable to disease. Defined as:
• Absolute neutrophil count (ANC) >1000 cells/mm3 (1.0 x 109/L). ANC > 500 cells/mm3 is permissible if due to disease.
• Platelet count >50, 000 cells/mm3 (50 x 109/L) unless attributable to disease. Platelet count > 20,000 cells/mm3 is permissible if due to disease.
• Hemoglobin >8.0 g/dL.
• Adequate hepatic and renal function defined as:
• Serum aspartate transaminase (AST) or alanine transaminase (ALT) ≤ 2.5 x upper limit of normal (ULN) Serum aspartate transaminase (AST) or alanine transaminase (ALT) ≤ 5 is permissible if due to disease.
• Bilirubin ≤1.5 x ULN (unless bilirubin rise is due to Gilbert's syndrome or of non-hepatic origin) Bilirubin ≤3 x ULN is permissible if due to disease.
• Estimated Creatinine Clearance ≥50 ml/min (Cockcroft-Gault based on actual weight)
• Prothrombin time (PT)/International normalized ratio (INR) 14 days] of > 20 mg/day of prednisone) within 28 days of the first dose of study drug.
• Undergone an allogeneic stem cell transplant within the past 1 year.
• Current or history of graft versus host disease
• Vaccinated with live, attenuated vaccines within 4 weeks of first dose of study drug.
• Recent infection requiring systemic treatment that was completed ≤14 days before the first dose of study drug.
• Unresolved toxicities from prior anti-cancer therapy, defined as having not resolved to Common Terminology Criteria for Adverse Event (CTCAE, version 4.03), 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.
• History of stroke or intracranial hemorrhage within 6 months prior to enrollment.
• Known HIV infection
• Active infection with hepatitis C virus (HCV) or hepatitis B virus (HBV).
• Subjects who are positive for hepatitis B core antibody, hepatitis B surface antigen, hepatitis C antibody, must have a negative polymerase chain reaction (PCR) result for the respective disease before enrollment. Those who are PCR positive will be excluded.
• Any uncontrolled active systemic infection.
• Major surgery within 4 weeks of first dose of study drug.
• Any life-threatening illness, medical condition, or organ system dysfunction that, in the investigator's opinion, could compromise the subject's safety or put the study outcomes at undue risk.
• Currently active, clinically significant cardiovascular disease, such as uncontrolled arrhythmia or Class 3 or 4 congestive heart failure as defined by the New York Heart Association Functional Classification; or a history of myocardial infarction, unstable angina, or acute coronary syndrome within 6 months prior to randomization.
• Unable to swallow capsules or tablets or malabsorption syndrome, disease significantly affecting gastrointestinal function, or resection of the stomach or small bowel, symptomatic inflammatory bowel disease or ulc