Randomized, Phase III Study of Early Intervention with Venetoclax and Obinutuzumab Versus Delayed Therapy with Venetoclax and Obinutuzumab in Newly Diagnosed Asymptomatic High-Risk Patients with Chronic Lymphocytic Leukemia / Small Lymphocytic Lymphoma (CLL/SLL): EVOLVE CLL/SLL Study.

Inclusion Criteria

- Participants must have a confirmed diagnosis of chronic lymphocytic leukemia (CLL) or

small lymphocytic lymphoma (SLL) (collectively referred to as CLL throughout)

according to the 2018 International Workshop on CLL. Participants must have been

diagnosed within 18 months prior to registration

- Participants must have CLL-International Prognostic Index (CLL-IPI) score >= 4 and/or

complex cytogenetics (defined as 3+ chromosomal abnormalities)

- Cytogenetic AND/OR FISH analyses must be completed at a Clinical Laboratory

Improvement Act (CLIA)-approved (or laboratories accredited under Accreditation Canada

Diagnostics to conduct FISH analyses) laboratory within 18 months prior to

registration. FISH panel should use probes to detect for abnormalities in chromosomes

13q, 12, 11q, and 17p

- TP53 mutation status from an next generation sequencing (NGS) test performed at any

CLIA-approved (or laboratories accredited under Accreditation Canada Diagnostics) lab

(if completed) must be obtained within 18 months prior to registration. This

sequencing test is distinct from FISH studies for del(17p)

- Immunoglobulin heavy chain locus variable (IgVH) mutational status from an NGS test

performed at any CLIA-approved lab (or laboratories accredited under Accreditation

Canada Diagnostics) must be obtained prior to registration (at any time prior to

registration)

- Serum beta-2 microglobulin level must be obtained within 28 days prior to registration

- Participants must not meet any of the IWCLL specified criteria for active CLL therapy

- Treatment with high dose corticosteroids and/or intravenous immunoglobulin for

autoimmune complications of CLL must be complete at least 4 weeks prior to enrollment

- Steroids used for treatment of conditions other than CLL/SLL must be at a dose of at

most 20 mg/day of prednisone or equivalent corticosteroid at the time of registration

- Prior therapy with anti CD20 monoclonal antibodies is not allowed

- Participants must not have received or be currently receiving any prior CLL-directed

therapy, including non-protocol-related therapy, anti-cancer immunotherapy,

experimental therapy (with exception of agents approved for emergency access use for

the prevention or treatment of COVID-19), or radiotherapy

- Participants must not be receiving or planning to receive any other investigational

agents before completing protocol therapy

- Participants must be >= 18 years of age

- Participants must have Eastern Cooperative Oncology Group (ECOG) performance status =<

2

- Platelet count >= 100,000/mm^3 within 28 days prior to registration

- Absolute neutrophil count (ANC) >= 1,000/mm^3 within 28 days prior to registration

- Creatinine clearance >= 30mL/min (by Cockcroft Gault) within 28 days prior to

registration

- Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) < 3.0 x upper

limit of normal (ULN) within 28 days prior to registration

- Total bilirubin =< 2.0 x ULN (or 5.0 x ULN if the participant has a history of

Gilbert's disease), within 28 days prior to registration

- Participants must be able to take oral medications

- Human immunodeficiency virus (HIV)-infected participants on effective anti-retroviral

therapy with undetectable viral load within 6 months are eligible for this trial

- Participants with history of malignancy are allowed providing the cancer has not

required active treatment within 2 years prior to registration (hormonal therapy is

permissible). The following exceptions are permissible: basal cell, squamous cell

skin, or non-melanomatous skin cancer, in situ cervical cancer, superficial bladder

cancer not treated with intravesical chemotherapy or Bacillus Calmette-Guerin (BCG)

within 6 months, localized prostate cancer requiring no more than chronic hormonal

therapy, or localized breast cancer requiring no more than chronic hormonal therapy

- Participants must not have current, clinically significant gastrointestinal

malabsorption, in the opinion of treating doctor

- Participants must not have cirrhosis

- Obinutuzumab has been associated with hepatitis reactivation. Participants must not

have uncontrolled active infection with hepatitis B or C. Participants with latent

hepatitis B infection must agree to take prophylaxis during and for 6 months following

active protocol therapy with V-O.

- Active infection with hepatitis B or C:

- Active infection is defined as detectable hepatitis B deoxyribonucleic acid

(DNA) or hepatitis C ribonucleic acid (RNA) by quantitative polymerase chain

reaction (PCR).

- Latent infection with hepatitis B:

- Latent infection is defined as meeting all of the following criteria:

- Hepatitis B surface antigen positive

- Anti-hepatitis B total core antibody positive

- Anti-hepatitis IgM core antibody undetectable

- Hepatitis B PCR undetectable

- Participants with latent hepatitis B infection must agree to take

prophylaxis with anti-hepatitis agents during and for 6 months following

active protocol therapy with V-O.

- Participants who have received intravenous immunoglobulin (IVIG) therapy

within 6 months who are hepatitis B core total antibody positive but PCR

undetectable are not mandated to take prophylaxis

- Participants must not have had major surgery within 30 days prior registration or

minor surgery within 7 days prior to registration. Examples of major surgery include

neurosurgical procedures, joint replacements, and surgeries that occur inside the

thoracic or abdomino-pelvic cavities. Examples of minor surgery include dental

surgery, insertion of a venous access device, skin biopsy, or aspiration of a joint.

If a participant has had a bone marrow biopsy for diagnosis or evaluation of CLL, this

will not exclude the patient from registration to the study. If there is a question

about whether a surgery is major or minor, this should be discussed with the Study

Chair

- Participants must not have known bleeding disorders (e.g., von Willebrand's disease or

hemophilia)

- Participants must not have a history of stroke or intracranial hemorrhage within 6

months prior to enrollment

- Participants must not require continued therapy with a strong inhibitor or inducer of

CYP3A4/5, as venetoclax is extensively metabolized by CYP3A4/5

- Participants must not have uncontrolled autoimmune hemolytic anemia or idiopathic

thrombocytopenia purpura

- Participants must not have any 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

- Participants must not have a history of myocardial infarction, unstable angina, or

acute coronary syndrome within 6 months prior to enrollment

- Participants must not be pregnant or nursing, as there are no safety data available

for these drug regimens during pregnancy. Women/men of reproductive potential must

have agreed to use an effective contraceptive method. A woman is considered to be of

"reproductive potential" if she has had menses at any time in the preceding 12

consecutive months. In addition to routine contraceptive methods, "effective

contraception" also includes heterosexual celibacy and surgery intended to prevent

pregnancy (or with a side-effect of pregnancy prevention) defined as a hysterectomy,

bilateral oophorectomy or bilateral tubal ligation. However, if at any point a

previously celibate patient chooses to become heterosexually active during the time

period for use of contraceptive measures outlined in the protocol, he/she is

responsible for beginning contraceptive measures

- Participants must agree to have specimens submitted for translational medicine (MRD)

and specimens must be submitted as outlined

- Participants must be offered participation in banking for future research. With

patient's consent, specimens must be submitted as outlined

- Participants who are able to complete patient reported outcome (PRO) forms in English,

Spanish, French, German, Russian or Mandarin must agree to participate in the quality

of life assessments. (Those participants who are unable to read and write in English,

Spanish, French, German, Russian or Mandarin may be registered to S1925 without

contributing to the quality of life portion of the study.)

- Participants must be informed of the investigational nature of this study and must

sign and give written informed consent in accordance with institutional and federal

guidelines

- NOTE: As a part of the Oncology Patient Enrollment Network (OPEN) registration process

the treating institution's identity is provided in order to ensure that the current

(within 365 days) date of institutional review board approval for this study has been

entered in the system