This is a phase I/II study in which patients will be enrolled in a standard 3+3 design. Once the maximum tolerated dose (MTD) is determined amongst patients with relapsed or refractory grade 1-3a follicular lymphoma, there will be a 17-patient phase II study.

In vitro studies of ibrutinib and venetoclax have noted significant cytotoxicity and synergy in mantle cell lymphoma and chronic lymphocytic leukemia cell lines.Data have demonstrated synergy between the two agents in various other B-cell Non-Hodgkin Lymphoma (NHL) cell lines. The investigators theorize that the combination of ibrutinib and venetoclax will provide dual, yet unique, targeted inhibition for patients with follicular lymphoma, resulting in both significant efficacy and less nonspecific toxicity.

Inclusion Criteria:

1. 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

2. 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

3. All risk by FLIPI 0-5 factors (Appendix I)

4. 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)

5. 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.

6. 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)

7. Prothrombin time (PT)/International normalized ratio (INR) <1.5 x ULN and PTT (aPTT) <1.5 x ULN.

8. Men and women ≥ 18 years of age.

9. Eastern Cooperative Oncology Group (ECOG) performance status of ≤ 2. (Appendix II)

10. Female subjects who are of non-reproductive potential (i.e., post-menopausal by history - no menses for ≥1 year; OR history of hysterectomy; OR history of bilateral tubal ligation; OR history of bilateral oophorectomy). Female subjects of childbearing potential must have a negative serum pregnancy test upon study entry.

11. Male and female subjects who agree to use highly effective methods of birth control (e.g., condoms, implants, injectables, combined oral contraceptives, some intrauterine devices (IUDs), sexual abstinence, or sterilized partner) during the period of therapy and for 30 days after the last dose of study drug

Exclusion Criteria:

1. Chemotherapy, monoclonal antibody, or small molecule kinase inhibitor less than or equal 21 days prior to first administration of study treatment

2. Prior exposure to a Bruton's tyrosine kinase (BTK) or B-cell lymphoma 2 (BCL-2) inhibitor.

3. History of allergic reactions attributed to compounds of similar chemical or biologic composition to ibrutinib or venetoclax.

4. Known allergy to xanthine oxidase inhibitors and/or rasburicase for subjects at risk for tumor lysis syndrome.

5. History of other malignancies, except:

   • Malignancy treated with curative intent and with no known active disease present for ≥ 3 years before the first dose of study drug and felt to be at low risk for recurrence by treating physician.
   • Adequately treated non-melanoma skin cancer or lentigo maligna without evidence of disease.
   • Adequately treated carcinoma in situ without evidence of disease.

6. Concurrent systemic immunosuppressant therapy (e.g., cyclosporine A, tacrolimus, etc., or chronic administration [>14 days] of > 20 mg/day of prednisone) within 28 days of the first dose of study drug.

7. Undergone an allogeneic stem cell transplant within the past 1 year.

8. Current or history of graft versus host disease

9. Vaccinated with live, attenuated vaccines within 4 weeks of first dose of study drug.

10. Recent infection requiring systemic treatment that was completed ≤14 days before the first dose of study drug.

11. 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.

12. Known bleeding disorders (e.g., von Willebrand's disease) or hemophilia.

13. History of stroke or intracranial hemorrhage within 6 months prior to enrollment.

14. Known HIV infection

15. 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.

16. Any uncontrolled active systemic infection.

17. Major surgery within 4 weeks of first dose of study drug.

18. 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.

19. 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.

20. 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 ulcerative colitis, or partial or complete bowel obstruction.

21. Concomitant use of warfarin or other Vitamin K antagonists.

22. Requires treatment with a strong cytochrome P450 CYP3A4/5 inhibitor. (Appendix V)

23. Richter's transformation confirmed by biopsy.

24. Malabsorption syndrome or other condition precluding enteral route of administration.

25. Known Central nervous system (CNS) involvement by lymphoma

26. Erythema multiforme, toxic epidermal necrolysis, or Stevens-Johnson syndrome

27. Lactating or pregnant.

28. Unwilling or unable to participate in all required study evaluations and procedures.

29. Unable to understand the purpose and risks of the study and to provide a signed and dated informed consent form (ICF) and authorization to use protected health information (in accordance with national and local subject privacy regulations).

30. Currently active, clinically significant hepatic impairment (greater than or equal moderate hepatic impairment according to the Child Pugh classification (see Appendix IX)

From the time of consent to 30 days after discontinuation of treatment (3.5 years)