Acalabrutinib, Venetoclax, and Obinutuzumab for Initial Therapy of CLL

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 FDA (the U.S.
Food and Drug Administration) has not approved acalabrutinib for CLL, although it is
FDA-approved for patients with relapsed mantle cell lymphoma. The FDA has approved venetoclax
and obinutuzumab separately for the treatment of patients with CLL. However, the FDA has not
approved the combination of these three drugs together (acalabrutinb, venetoclax, and
obinutuzumab) as a treatment for any disease. This combination is investigational. In this
research study, the investigators are trying to learn if giving the three drugs together can
safely and effectively treat CLL.

Acalabrutinib is a type of drug called a kinase inhibitor. It blocks a type of protein called
Bruton Tyrosine Kinase (BTK) that helps CLL cells live and grow. By blocking BTK,
acalabrutinib may kill cancer cells or stop them from growing. As of September 2017,
acalabrutinib has been administered to more than 2,000 people including healthy volunteers,
patients with cancers, and patients with rheumatoid arthritis. A few hundred patients with
CLL have been treated with acalabrutinib as a single drug, and some of these patients had
improvement of their cancer with this treatment.

Obinutuzumab is a type of drug called a monoclonal antibody. It targets a protein on the
surface of the CLL cell, causing it to die. Obintuzumab has already been shown to be safe and
effective at treating CLL, and is FDA-approved when given together with chemotherapy.

Venetoclax is an oral drug that blocks the function of a protein called BCL-2. CLL cancer
cells are thought to depend on the BCL-2 protein for their survival. By blocking BCL-2,
venetoclax may kill cancer cells or stop them from growing. Venetoclax has been shown to be
safe and effective when given alone to treat patients with CLL and is FDA-approved for
patients with CLL after their disease has worsened after at least 1 prior therapy.

If, after 15 or 24 cycles of this investigational therapy, participants have a complete
response to the drugs in this trial -- meaning that the investigators cannot detect any CLL
using CT scans, bone marrow biopsy and a sensitive test called minimal residual disease (MRD)
testing -- participants will stop therapy with acalabrutinib and venetoclax. The
investigators will continue to monitor participants while they are off of therapy, and if the
CLL comes back participants will be able to restart acalabrutinib and venetoclax. The use of
MRD testing to identify small amounts of CLL is investigational, meaning that it has not been
FDA-approved. The use of results from this test to guide the decision to stop and re-start
therapy, as is done in the trial here, is also investigational.

Inclusion Criteria:

- Subjects must have CLL or SLL

- 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.