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

Inclusion Criteria:

• Diagnosis of CLL or SLL according to WHO criteria

• Participants must require therapy according to iwCLL 2018 guidelines

• Participants must have ≥ 2 points (high or intermediate risk disease) according tothe CLL

BALL Risk Model:

• Beta-2 microglobulin If ≥ 5 mg/L, assign 1 point

• Lactate dehydrogenase If >institutional upper limit of normal, assign 1 point

• Hemoglobin If <11 g/dL (female) or <12 g/dL (male), assign 1 point

• Time from start of last therapy If <24 months, assign 1 point, If 4 points, patientis high risk, If 2-3 points, patient is intermediate risk, If 0-1 points, patient islow risk

• Participants must have received prior systemic therapy for CLL

• Age over 18 years

• ECOG performance status ≤2 (Karnofsky ≥60%, see Appendix A)

• Participants must have adequate organ function as defined below:

• total bilirubin ≤2 × institutional upper limit of normal unless considered secondaryto Gilbert's syndrome, in which case ≤3 x ULN

• AST(SGOT)/ALT(SGPT) ≤2 × institutional upper limit of normal

• creatinine within normal institutional limits OR

• creatinine clearance ≥30 mL/min according to the Cockcroft-Gault Equation forparticipants with creatinine levels above institutional normal.

• Participants must have adequate marrow function as defined below (unlessclearly due to disease under study per investigator discretion)

• absolute neutrophil count ≥1,000/mcL

• platelets ≥75,000/mcL OR

• > 20,000/mcL if thrombocytopenia is clearly due to disease under study (perinvestigator discretion).

• For females of childbearing potential, a negative serum pregnancy test within 7days of study treatment

• For female patients of childbearing potential and male patients with partnersof childbearing potential, agreement (by patient and/or partner) to use highlyeffective form(s) of contraception (i.e., one that results in a low failurerate [<1% per year] when used consistently and correctly) and to continue itsuse for 90 days after the last dose of acalabrutinib or venetoclax AND for 18months after the last dose of obinutuzumab (whichever date is later)

• The reliability of sexual abstinence should be evaluated in relation to theduration of the clinical trial and the preferred and usual lifestyle of thepatient. Periodic abstinence (e.g., calendar, ovulation, symptothermal, orpostovulation methods) and withdrawal are not acceptable methods ofcontraception.

• Willingness to not donate sperm or oocytes during the entire study treatmentperiod and after treatment discontinuation

• Ability to understand and the willingness to sign a written informed consentdocument.

Exclusion Criteria:

• Prior therapy with a BTK inhibitor (e.g. acalabrutinib) or BCL2 inhibitor (e.g.venetoclax), with the following exception:

• Patients with undetectable MRD by flow cytometry at 10 (peripheral blood or bonemarrow) or CR from prior treatment with BCL2 inhibitor (with or without BTKinhibitor) are eligible. Note: Patients who received prior BTK inhibitor therapyalone are not eligible.

• Known hypersensitivity (IgE-mediated) reaction to obinutuzumab or to any of itsexcipients

• Participants who are receiving any other investigational agents unless authorized bythe overall study principal investigator

• Known active histological transformation from CLL to an aggressive lymphoma (i.e.,Richter's transformation)

• Active malignancy or systemic therapy for another malignancy within 3 years;local/regional therapy with curative intent such as surgical resection or localizedradiation within 3 years of treatment is permitted; active prostate cancer that isconsidered low-risk and appropriate for continued active surveillance strategy ispermitted.

• Uncontrolled intercurrent illness including, but not limited to, ongoing or activeinfection, symptomatic congestive heart failure, unstable angina pectoris, cardiacarrhythmia, or psychiatric illness/social situations that would limit compliancewith study requirements

• Known active bacterial, viral, fungal, mycobacterial, parasitic, or other infection (excluding fungal infections of nail beds) at study enrollment, or any major episodeof infection requiring treatment with IV antibiotics or hospitalization (relating tothe completion of the course of antibiotics) within 2 weeks prior to Cycle 1, Day 1

• Known bleeding diathesis

• Pregnant women are excluded from this study because the study agents have potentialfor teratogenic or abortifacient effects. Because there is an unknown but potentialrisk for adverse events in nursing infants secondary to treatment of the mother withthe study agents, breastfeeding should be discontinued if the mother is treated withstudy therapy.

• Prior major surgical procedure within 4 weeks of study, or anticipation of need fora major surgical procedure during the course of the study

• Known CNS hemorrhage or stroke within 6 months of the study

• History of progressive multifocal leukoencephalopathy (PML)

• History of HIV infection or active hepatitis B (chronic or acute) or hepatitis Cinfection

• Patients with occult or prior HBV infection (defined as positive totalhepatitis B core antibody [HBcAb] and negative HBsAg) may be included if HBVDNA is undetectable. These patients must be willing to take appropriateanti-viral prophylaxis as indicated and undergo monthly DNA testing.

• Patients positive for hepatitis C virus (HCV) antibody are eligible only ifpolymerase chain reaction (PCR) is negative for HCV RNA

• Congestive heart failure, New York Heart Association classification III/IV

• Clinically significant history of liver disease, including viral or other hepatitis,current alcohol abuse, or cirrhosis

• Receipt of live-virus vaccines within 28 days prior to the initiation of studytreatment or need for live-virus vaccines at any time during study treatment

• Known condition or other clinical situation that would affect oral absorption

• Psychiatric illness/social situations that would interfere with study compliance

• Receipt of therapy with strong inhibitors or inducers of CYP3A, CYP2C8, CYP2C9 andCYP2C19, within 7 days prior to the first dose of study drug administration

• Consumption of grapefruit, grapefruit products, Seville oranges (including marmaladecontaining Seville oranges), or star fruit within 3 days prior to the first dose ofstudy drug administration.

• Requires dual antiplatelet therapy or anticoagulation with warfarin