Venetoclax-Obinutuzumab +/- Acalabrutinib in R/R CLL

This research study is studying a combination of drugs as a possible treatment for chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL). The names of the study drugs involved in this study are: * obinutuzumab * venetoclax * acalabrutinib

This research study is a Phase II clinical trial. Phase II clinical trials test the safety and effectiveness of investigational drugs to learn whether the drugs work in treating a specific disease. "Investigational" means that the drugs are being studied. The U.S. Food and Drug Administration (FDA) has approved \[1\] venetoclax- obinutuzumab and \[2\] acalabrutinib individually as treatment options for chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL). However, the combination of all 3 drugs has not yet been approved by the FDA. * Venetoclax is a targeted therapy drug that works by blocking a protein called Bcl-2 in cancer cells. Bcl-2 helps cancer cells survive and resist the effects of cancer treatments. By blocking Bcl-2, venetoclax may kill cancer cells and/or make them more open to the effects of other cancer treatments. * Obinutuzumab is a drug that targets a protein called CD20, which is found on the surface of B cells, the white blood cells that are affected by CLL. When obinutuzumab attaches to CD20, it directly both destroys the B cells and makes them more "visible" to the immune system. The immune system then attacks and destroys the cancerous B cells. * Acalabrutinib is a small-molecule inhibitor of Bruton's tyrosine kinase (BTK). BTK is a protein inside of the cell that may be over-expressed in malignant B cells. It is involved in the signaling pathway from the B-cell receptor. BTK inhibition caused by taking acalabrutinib results in decreased malignant B-cell growth and survival. On this study, participants will receive obinutuzumab and venetoclax. We will monitor for minimal residual disease (MRD) using a test called "Adaptive ClonoSEQ" after treatment with obinutuzumab and venetoclax. MRD is a molecular test, which can detect whether there is any evidence of CLL/SLL in the blood or bone marrow. For participants with detectable MRD despite treatment with obinutuzumab and venetoclax, acalabrutinib will be added with the goal of achieving undetectable MRD. Additionally, for participants who have progressive CLL/SLL despite venetoclax and obinutuzumab, acalabrutinib will be added. The research study procedures include screening for eligibility, study treatment, end of treatment visit, follow-up visits and an off-study visit. * Participants will receive study treatment for 2 or 3 years. * Participants will be followed for 2 years after completion of the study. * It is expected that 40 people will take part in this research study * Genentech is supporting this research study by providing venetoclax and obinutuzumab.