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Testing the Effects of Early Treatment with Venetoclax and Obinutuzumab versus Delayed Treatment with Venetoclax and Obinutuzumab for Newly Diagnosed Patients with High-Risk Chronic Lymphocytic Leukemia or Small Lymphocytic Lymphoma Who Do Not Have Symptoms, the EVOLVE CLL / SLL Study

This phase III trial compares early treatment with venetoclax and obinutuzumab versus delayed treatment with venetoclax and obinutuzumab in patients with newly diagnosed high-risk chronic lymphocytic leukemia or small lymphocytic lymphoma. Venetoclax is in a class of medications called B-cell lymphoma-2 (BCL-2) inhibitors. It may stop the growth of cancer cells by blocking Bcl-2, a protein needed for cancer cell survival. Immunotherapy with monoclonal antibodies, such as obinutuzumab, may help the bodys immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Starting treatment with the venetoclax and obinutuzumab early (before patients have symptoms) may have better outcomes for patients with chronic lymphocytic leukemia or small lymphocytic lymphoma compared to starting treatment with the venetoclax and obinutuzumab after patients show symptoms.
Leukemia, Lymphoma
Phase III
Adults
Mol. targeted/Immunotherapy/Biologics
Obinutuzumab, Venetoclax
Morgan, David
National
Vanderbilt University
01-18-2022
Treatment
SWOGPCLS1925
NCT04269902

Eligibility

18 Years
BOTH
NO
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 12 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 fluorescence in situ hybridization (FISH) analyses must be completed at a Clinical Laboratory Improvement Act (CLIA)-approved laboratory within 12 months prior to registration. FISH panel should use probes to detect for abnormalities in chromosomes 13q, 12, 11q, and 17p

TP53 mutation status (if completed) must be obtained within 12 months prior to registration

Immunoglobulin heavy chain locus variable (IgVH) mutational status 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

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 be >= 18 years of age

Participants must have Eastern Cooperative Oncology Group (ECOG) performance status =
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)
Total bilirubin =
Participants must be able to take oral medications

Human immunodeficiency virus (HIV)-infected patients 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

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 agree to have specimens submitted for translational medicine (MRD) and specimens must be submitted

Participants must be offered participation in banking for future research. With patients consent, specimens must be submitted

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



Exclusion Criteria:

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

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 not have current, clinically significant gastrointestinal malabsorption, in the opinion of treating doctor

Participants must not have cirrhosis

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 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 Willebrands 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

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