Testing Early Treatment for Patients With High-Risk Chronic Lymphocytic Leukemia (CLL) or Small Lymphocytic Leukemia (SLL), EVOLVE CLL/SLL Study

Study Overview
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Brief Summary
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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 body's 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.

Detailed Description
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PRIMARY OBJECTIVE: I. To evaluate whether early treatment with venetoclax and obinutuzumab (V-O) extends overall survival (OS) compared with delayed treatment with V-O in high-risk (Chronic Lymphocytic Leukemia [CLL] International Prognostic Indicator [CLL-IPI] >= 4 or complex cytogenetics), newly diagnosed asymptomatic CLL/small lymphocytic lymphoma (SLL) patients. SECONDARY OBJECTIVES: I. To compare overall response rates (complete response [CR] + partial response [PR]), CR rates, progression-free survival (PFS), and event-free survival (EFS) between arms. II. To evaluate safety and tolerability of each arm. III. To compare time to second CLL-directed treatment (from randomization and from response) between arms. IV. To compare relapse-free survival (RFS) and time to second objective disease progression (PFS2) between arms. V. To compare the rates of Richter's transformation between arms. VI. To describe distribution of Cumulative Illness Rating Scale across the study, in each treatment arm, and to estimate the interaction between the scale and treatment arm and OS. PATIENT-REPORTED OUTCOMES OBJECTIVES: I. To assess the impact of early intervention with V-O versus delayed therapy with V-O in CLL patients in relation to Health-Related Quality of Life (HRQoL) using the Functional Assessment of Cancer Therapy (FACT)-Leukemia scale. II. To assess the impact of the two treatment arms on the specific domains of the FACT-Leukemia, including physical, social, emotional, and functional well-being and leukemia-specific HRQoL. TRANSLATIONAL MEDICINE OBJECTIVES (INTEGRATED): I. To evaluate the prognostic association between OS and measurable residual disease (MRD) undetectable disease state at 15 months after treatment initiation, across and between treatment arms. (Primary) II. To describe the prognostic association between the endpoints RFS and OS and MRD undetectable disease state at all measured time points (cycle [C]7 day[D]1, C9D1, C12D1, and 15, 21, 27, 33, 39, 45, 51, 57, 63, 69, 75, 81, 87, 93, and 99 months after treatment initiation) using landmark analyses, across and between treatment arms. (Secondary) III. To evaluate the prognostic association of MRD undetectable disease state over time in each treatment arm with respect to OS and RFS using time-dependent covariate analyses. (Secondary) IV. To describe the proportion of variation in OS and RFS explained by MRD sampling schemes with the goal of providing information on how much additional variation in OS and RFS is explained by additional MRD sampling for future trial designs. (Secondary) V. To compare the rate of MRD undetectable disease state at 15 months after initiation of treatment between treatment arms. (Secondary) VI. To compare duration of MRD undetectable disease state between treatment arms. (Secondary) VII. To describe associations between pretreatment stimulated karyotype risk, p53 mutation, IGHV mutational analysis, fluorescence in situ hybridization (FISH) for del(13q), del(11q), trisomy 12, and del(17p), and beta-2-microglobulin levels and other biomarkers with OS, PFS, overall and complete response rates, achievement of MRD undetectable disease state, and Richter's transformation. (Secondary) VIII. To describe associations between clinical complete or partial response (by International Workshop on Chronic Lymphocytic Leukemia [IWCLL] 2018 criteria) and response as assessed by MRD status and CT scans at 15 months after treatment initiation. (Secondary) OUTLINE: Patients are randomized to 1 of 2 arms. ARM I (DELAYED V-O): Treatment begins once 2018 IWCLL indications are met. Patients receive obinutuzumab intravenously (IV) over 4 hours on days 1, 2, 8, and 15 of cycle 1 and on day 1 of cycles 2-6. Patients also receive venetoclax orally (PO) once daily (QD) on days 22-28 of cycle 1 and on days 1-28 of cycles 2-12. Treatment repeats every 28 days for 12 cycles in the absence of disease progression or unacceptable toxicity. Patients also undergo CT, collection of blood samples, and bone marrow aspiration throughout the trial. ARM II (EARLY V-O): Treatment begins as soon as eligibility criteria are met. Patients receive obinutuzumab IV over 4 hours on days 1, 2, 8, and 15 of cycle 1 and on day 1 of cycles 2-6. Patients also receive venetoclax PO QD on days 22-28 of cycle 1 and on days 1-28 of cycles 2-12. Treatment repeats every 28 days for 12 cycles in the absence of disease progression or unacceptable toxicity. Patients also undergo CT, collection of blood samples, and bone marrow aspiration throughout the trial. After completion of study treatment, patients are followed up for 10 years after registration.

Official Title
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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

Conditions
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Chronic Lymphocytic Leukemia, Small Lymphocytic Lymphoma

Intervention / Treatment
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* Procedure: Biospecimen Collection
* Procedure: Bone Marrow Aspiration
* Procedure: Computed Tomography
* Biological: Obinutuzumab
* Other: Quality-of-Life Assessment
* Other: Questionnaire Administration
* Drug: Venetoclax


Participation Criteria
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Eligibility Criteria
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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 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 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 =< 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 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 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 Exclusion Criteria: Participants 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 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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Arm I (delayed V-O)<br>Treatment begins once 2018 IWCLL indications are met. Patients receive obinutuzumab IV over 4 hours on days 1, 2, 8, and 15 of cycle 1 and on day 1 of cycles 2-6. Patients also receive venetoclax PO QD on days 22-28 of cycle 1 and on days 1-28 of cycles 2-12. Treatment repeats every 28 days for 12 cycles in the absence of disease progression or unacceptable toxicity. Patients also undergo CT, collection of blood samples, and bone marrow aspiration throughout the trial. | Procedure: Biospecimen Collection<br>* Undergo collection of blood samples<br>* Other names: Specimen Collection;Procedure: Bone Marrow Aspiration<br>* Undergo bone marrow aspiration<br>Procedure: Computed Tomography<br>* Undergo CT<br>* Other names: tomography;Biological: Obinutuzumab<br>* Given IV<br>* Other names: RO5072759;Other: Quality-of-Life Assessment<br>* Ancillary studies<br>* Other names: Quality of Life Assessment;Other: Questionnaire Administration<br>* Ancillary studies<br>Drug: Venetoclax<br>* Given PO<br>* Other names: Venclyxto;|
| Experimental: Arm II (early V-O)<br>Treatment begins as soon as eligibility criteria are met. Patients receive obinutuzumab IV over 4 hours on days 1, 2, 8, and 15 of cycle 1 and on day 1 of cycles 2-6. Patients also receive venetoclax PO QD on days 22-28 of cycle 1 and on days 1-28 of cycles 2-12. Treatment repeats every 28 days for 12 cycles in the absence of disease progression or unacceptable toxicity. Patients also undergo CT, collection of blood samples, and bone marrow aspiration throughout the trial. | Procedure: Biospecimen Collection<br>* Undergo collection of blood samples<br>* Other names: Specimen Collection;Procedure: Bone Marrow Aspiration<br>* Undergo bone marrow aspiration<br>Procedure: Computed Tomography<br>* Undergo CT<br>* Other names: tomography;Biological: Obinutuzumab<br>* Given IV<br>* Other names: RO5072759;Other: Quality-of-Life Assessment<br>* Ancillary studies<br>* Other names: Quality of Life Assessment;Other: Questionnaire Administration<br>* Ancillary studies<br>Drug: Venetoclax<br>* Given PO<br>* Other names: Venclyxto;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall survival | The final analysis will use stratified Cox proportional hazards regression stratified by Chronic Lymphocytic Leukemia [CLL] International Prognostic Indicator [CLL-IPI] Risk score status (high risk versus very high risk) with a two-sided alpha of 0.042. The final analysis will occur after 58 OS events have been observed, or at 4 years after accrual completes, whichever occurs first. Under the alternative hypothesis, the final analysis is expected to occur at approximately 7.9 years after study activation (about 3.8 years after accrual completes). | From the day of registration on study until death from any cause with observations censored on the day of last contact for patients not known to have died, assessed up to 10 years | 
| Functional Assessment of Cancer Therapy (FACT)-Leukemia total score | A single comparison in the FACT-Leukemia total scores between patients randomized to early V-O versus delayed V-O will be conducted at the alpha=.05 level. The analysis of the 2-year FACT-Leukemia Total score will be conducted using multiple linear regression analysis, adjusting for stratification factor and the baseline FACT-Leukemia Total score as covariates. Will also conduct longitudinal modeling of the outcome measures over time. | At 2 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of adverse events | Will utilize the CTCAE (National Cancer Institute [NCI] Common Terminology Criteria for Adverse Events) version 5.0 for toxicity and adverse event reporting. | Up to 10 years | 
| Overall Response rate | Will be compared using Fisher's exact test. | Up to 10 years | 
| Progression free survival | Will be estimated using the Kaplan-Meier method and will be compared using log-rank tests and Cox regression models. | From the day of registration on study until the first of: relapse from complete response, progression, or death from any cause, assessed up to 10 years | 
| Event free survival | Will be estimated using the Kaplan-Meier method and will be compared using log-rank tests and Cox regression models. | From the day of registration on study until the first of: relapse from complete response, death from any cause, start of new (non-protocol) therapy, or completion of protocol therapy without documentation of complete response, assessed up to 10 years | 
| Relapse free survival | Will be estimated using the Kaplan-Meier method and will be compared using log-rank tests and Cox regression models. | From the date the patient first achieves complete response until relapse from complete response or death from any cause, assessed up to 10 years | 
| Time to second treatment | Will be defined as the next chronic lymphocytic leukemia (CLL) treatment the patient receives after removal from protocol therapy. Will be estimated using the Kaplan-Meier method and will be compared using log-rank tests and Cox regression models. | Up to 10 years | 
| Patient compliance | Will be reported descriptively by arm. | Up to 10 years |