An Early Phase Study of Venetoclax, Lenalidomide, and Rituximab/Hyaluronidase in Slow-Growing Lymphomas That Have Come Back After Treatment or Have Not Responded to Treatment

This phase I trial studies the side effects and best dose of venetoclax when given together with lenalidomide and rituximab hyaluronidase in treating patients with follicular lymphoma and marginal zone lymphoma that has come back after treatment (relapsed) or has not responded to treatment (refractory). Venetoclax may stop the growth of cancer cells by blocking the action of a protein called Bcl-2, that helps cancer cells survive. Immunotherapy with lenalidomide, may induce changes in body's immune system and may interfere with the ability of tumor cells to grow and spread. Immunotherapy with monoclonal antibodies, such as rituximab and rituximab hyaluronidase, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. The purpose of this research is to determine if the combination of three drugs, venetoclax, lenalidomide, and rituximab hyaluronidase are safe to administer in patients whose low-grade lymphoma (follicular or marginal zone) has come back after initial therapy or was not responsive to initial therapy.

PRIMARY OBJECTIVE: I. To determine the safety (and the recommended phase 2 dose \[RP2D\]), of the combination of venetoclax, lenalidomide, and rituximab hyaluronidase in patients with relapsed/refractory (R/R) follicular lymphoma (FL) and marginal zone lymphoma (MZL). SECONDARY OBJECTIVES: I. To determine the overall response rate (ORR) with rituximab hyaluronidase, venetoclax, and lenalidomide. II. To determine the 2-year progression-free survival (PFS) with rituximab hyaluronidase, venetoclax, and lenalidomide. III. To determine the overall survival (OS) following therapy with rituximab hyaluronidase, venetoclax, and lenalidomide. CORRELATIVE STUDY OBJECTIVES: I. Describe changes in the level of expression and expression ratio between anti-apoptotic and pro-apoptotic BCL-2 family members before and after therapy with venetoclax/lenalidomide/rituximab hyaluronidase for each patient. II. Examine the metabolic landscape before and after venetoclax/lenalidomide/rituximab hyaluronidase and their effects on mitochondrial metabolism. III. Describe the immune effects of venetoclax and its effects on serum cytokines and different immune cell subsets (e.g. B-cells, T-cells, dendritic cells, etc.) in addition to T-cell activation markers and expression of immune checkpoint proteins. OUTLINE: This is a dose-escalation study of venetoclax. Patient receive venetoclax orally (PO) once daily (QD) on days 1-28. Beginning cycle 2, patients receive lenalidomide PO QD on days 1-21. Patients also receive rituximab intravenously (IV) on days 1, 8, 15, and 22 of cycle 2 and rituximab hyaluronidase (if no significant infusion reaction to rituximab) subcutaneously (SC) on day 1 of cycles 4, 6, 8, 10, and 12. Patients may receive rituximab IV (instead of rituximab hyaluronidase) on days 1, 8, 15, and 22 of cycles 4, 6, 8, 10, and 12 if the patient requires rituximab IV in the opinion of the treating physician. Treatment repeats every 28 days for up to 12 cycles in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed up at 30 days, and then for up to 5 years.