Acalabrutinib, Venetoclax, and Obinutuzumab for Initial Therapy of CLL

Inclusion Criteria:

* Subjects must have CLL or SLL
* In cohort 2, subjects must have TP53-aberrant disease defined as:

  * Del(17p) detected on karyotype and/or FISH; OR
  * TP53 mutation
* Participants must have measurable disease (lymphocytosis \> 5,000 / µl, or palpable or CT measurable lymphadenopathy ≥ 1.5 cm, or bone marrow involvement ≥30%).
* Subjects must not have received any prior systemic therapy for CLL or SLL due to meeting IWCLL 2018 guidelines and must currently have an indication for treatment as defined by the IWCLL 2018 guidelines:

  * Massive or progressive or symptomatic splenomegaly; OR
  * Massive lymph nodes, nodal clusters, or progressive lymphadenopathy; OR
  * Significant fatigue (i.e. ECOG PS 2 or worse; cannot work or unable to perform usual activities); OR
  * Fever ≥ 100.5°F for 2 or more weeks without evidence of infection; OR
  * Night sweats for ≥ 1 months without evidence of infection; OR
  * Presence of weight loss ≥ 10% over the preceding 6 months; OR
  * Progressive lymphocytosis with an increase of ≥ 50% over a 2-month period or lymphocyte doubling time of less than 6 months; OR
  * Evidence of progressive marrow failure as manifested by the development of or worsening of anemia and/or thrombocytopenia; OR
  * Autoimmune anemia and/or thrombocytopenia that is poorly responsive to corticosteroids and another standard therapy such as rituximab; OR
  * Symptomatic or functional extranodal involvement
* Age greater than or equal to 18 years.
* ECOG performance status ≤2
* Participants must have adequate organ and marrow function as defined below:

  * total bilirubin ≤1.5 times upper limit of normal, unless there is disease involvement of the liver, hemolysis, or a known history of Gilbert's disease, in which case direct bilirubin must be ≤3 times the upper limit of normal
  * AST and ALT ≤ 2.5 times the upper limit of normal. If there is hemolysis or documented disease involvement of the liver, then patients with any AST or ALT abnormalities remain eligible.
  * creatinine clearance (CrCl) ≥ 50 mL/min using 24-hour urine collection for creatinine clearance or calculated CrCl
  * PT/INR ≤2 times the upper limit of normal and PTT ≤2 times the upper limit of normal
  * Absolute neutrophil count ≥750 cells/mm3 or ≥500 cells/mm3 in subjects with documented bone marrow involvement
  * Platelet count without transfusional support must be ≥50,000 cells/mm3 or ≥ 30,000 cells/mm3 in subjects with documented bone marrow involvement
* Pregnant or lactating

Exclusion Criteria:

* Participants who have a history of other malignancies except:

  * Malignancy treated with curative intent and with no known active disease present and felt to be at low risk for recurrence by treating physician. Current adjuvant hormonal therapy for disease treated with curative intent is permissible.
  * Adequately treated non-melanoma skin cancer or lentigo maligna without evidence of disease.
  * Adequately treated carcinoma in situ without evidence of disease.
  * Low-risk prostate cancer on active surveillance
* Participants who are receiving any other investigational agents.
* History of severe allergic reactions attributed to compounds of similar chemical or biologic composition to obinutuzumab, venetoclax, or acalabrutinib. Patients with reactions to other CD20 monoclonal antibodies (e.g. rituximab, ofatumumab) are not excluded.
* Unable to receive prophylactic treatment for pneumocystis, herpes simplex virus (HSV), and herpes zoster (VZV) at start of treatment
* Known or suspected Richter's transformation or known CNS involvement
* Concurrent systemic immunosuppressant therapy (e.g., cyclosporine A, tacrolimus, etc., within 28 days of the first dose of study drug or chronic administration of \>20 mg/day of prednisone within 7 days of the first dose)
* Vaccinated with live, attenuated vaccines within 4 weeks of first dose of study drug.
* Ongoing or recent infection requiring intravenous antimicrobials at time of screening.
* Known bleeding disorders (e.g. von Willebrand's disease) or hemophilia.
* Presence of a gastrointestinal ulcer diagnosed by endoscopy within 3 months before screening.
* History of stroke or intracranial hemorrhage within 6 months prior to enrollment.
* Major surgery within 4 weeks of first dose of study drug. If a subject had major surgery greater than 4 weeks prior to the first dose, they must have recovered adequately from any toxicity and/or complications from the intervention before the first dose of study drug.
* 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.
* Baseline QTcF \>480 ms. NOTE: This criterion does not apply to patients with a left bundle branch block.
* Patients who require warfarin or other vitamin K antagonists for anticoagulation (other anticoagulants are allowed).
* Patients who require treatment with proton pump inhibitors (see Appendix F). Subjects receiving proton pump inhibitors who switch to H2-receptor antagonists or antacids are eligible for enrollment on this study.
* Patients who require concurrent treatment with strong CYP3A inhibitors or strong CYP3A inducers are excluded from the study. If patients are receiving strong CYP3A inhibitors/inducers at time of screening but do not require continuous administration of these agents, these patients are eligible if there is a 3-day washout period between discontinuation of the strong CYP3A inhibitor/inducer and initiation of the first study drug, acalabrutinib.
* Patients who require concurrent treatment with P-gp inhibitors or narrow therapeutic index P-gp substrates are excluded from the study. If patients are receiving P-gp inhibitors or narrow therapeutic index P-gp substrates at time of screening but do not require continuous administration of these agents, these patients are eligible if there is a 3-day washout period between discontinuation of the P-gp inhibitor and initiation of acalabrutinib.
* Unable to swallow capsules or malabsorption syndrome, disease significantly affecting gastrointestinal function, or resection of the stomach or small bowel if thought by the investigator to compromise systemic absorption, active, symptomatic inflammatory bowel disease or ulcerative colitis, or partial or complete bowel obstruction.
* Patients with human immunodeficiency virus (HIV) or active hepatitis C virus (HCV) or hepatitis B virus (HBV) infection.
* Significant co-morbid condition or disease which in the judgment of the Principal Investigator would place the patient at undue risk or interfere with the study
* Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements, compromise the subject's safety, or put the study outcomes at undue risk.