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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

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ClinicalTrials.gov Identifier: NCT04269902
Recruitment Status : Recruiting
First Posted : February 17, 2020
Last Update Posted : November 29, 2021
Sponsor:
Information provided by (Responsible Party):
National Cancer Institute (NCI)

Brief Summary:
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 may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. 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.

Condition or disease Intervention/treatment Phase
Chronic Lymphocytic Leukemia Small Lymphocytic Lymphoma Biological: Obinutuzumab Other: Quality-of-Life Assessment Other: Questionnaire Administration Drug: Venetoclax Phase 3

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 247 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: 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
Actual Study Start Date : December 14, 2020
Estimated Primary Completion Date : October 1, 2028
Estimated Study Completion Date : October 1, 2028


Arm Intervention/treatment
Active Comparator: Arm I (delayed V-O)
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.
Biological: Obinutuzumab
Given IV
Other Names:
  • Anti-CD20 Monoclonal Antibody R7159
  • GA-101
  • GA101
  • Gazyva
  • huMAB(CD20)
  • R7159
  • RO 5072759
  • RO-5072759
  • RO5072759

Other: Quality-of-Life Assessment
Ancillary studies
Other Name: Quality of Life Assessment

Other: Questionnaire Administration
Ancillary studies

Drug: Venetoclax
Given PO
Other Names:
  • ABT-0199
  • ABT-199
  • ABT199
  • GDC-0199
  • RG7601
  • Venclexta
  • Venclyxto

Experimental: 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.
Biological: Obinutuzumab
Given IV
Other Names:
  • Anti-CD20 Monoclonal Antibody R7159
  • GA-101
  • GA101
  • Gazyva
  • huMAB(CD20)
  • R7159
  • RO 5072759
  • RO-5072759
  • RO5072759

Other: Quality-of-Life Assessment
Ancillary studies
Other Name: Quality of Life Assessment

Other: Questionnaire Administration
Ancillary studies

Drug: Venetoclax
Given PO
Other Names:
  • ABT-0199
  • ABT-199
  • ABT199
  • GDC-0199
  • RG7601
  • Venclexta
  • Venclyxto




Primary Outcome Measures :
  1. Overall survival [ Time Frame: 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 ]
    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).

  2. Functional Assessment of Cancer Therapy (FACT)-Leukemia total score [ Time Frame: At 2 years ]
    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.


Secondary Outcome Measures :
  1. Incidence of adverse events [ Time Frame: Up to 10 years ]
    Will utilize the CTCAE (National Cancer Institute [NCI] Common Terminology Criteria for Adverse Events) version 5.0 for toxicity and adverse event reporting.

  2. Overall Response rate [ Time Frame: Up to 10 years ]
    Will be compared using Fisher's exact test.

  3. Progression free survival [ Time Frame: 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 ]
    Will be estimated using the Kaplan-Meier method and will be compared using log-rank tests and Cox regression models.

  4. Event free survival [ Time Frame: 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 ]
    Will be estimated using the Kaplan-Meier method and will be compared using log-rank tests and Cox regression models.

  5. Relapse free survival [ Time Frame: From the date the patient first achieves complete response until relapse from complete response or death from any cause, assessed up to 10 years ]
    Will be estimated using the Kaplan-Meier method and will be compared using log-rank tests and Cox regression models.

  6. Time to second treatment [ Time Frame: Up to 10 years ]
    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.

  7. Patient compliance [ Time Frame: Up to 10 years ]
    Will be reported descriptively by arm.


Other Outcome Measures:
  1. FACT-Leukemia total score [ Time Frame: At randomization and at months 3, 6, 9, 12, 15, 18, 24, 30, and 36 ]
    Will include linear regression analyses by arm.

  2. The individual components of the FACT-Leukemia [ Time Frame: At randomization and at months 3, 6, 9, 12, 15, 18, 24, 30, and 36 ]
    Will include physical, social, emotional, and functional well-being. Will include linear regression analyses by arm.

  3. Patient-reported health-related quality of life (HRQoL) [ Time Frame: Up to 36 months ]
    Will use simple descriptive statistics (means, medians, standard deviations, ranges) to describe patient-reported health related quality of life using the FACT-Leukemia and its individual domains between randomized arms. To assess potential trends, P-values using t-tests will be provided.



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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 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 =< 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 patient 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 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 patient's 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, 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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04269902


Locations
Show Show 461 study locations
Sponsors and Collaborators
National Cancer Institute (NCI)
Investigators
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Principal Investigator: Deborah M Stephens Southwest Oncology Group
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Responsible Party: National Cancer Institute (NCI)
ClinicalTrials.gov Identifier: NCT04269902    
Other Study ID Numbers: NCI-2020-00752
NCI-2020-00752 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
S1925 ( Other Identifier: SWOG )
S1925 ( Other Identifier: CTEP )
U10CA180888 ( U.S. NIH Grant/Contract )
First Posted: February 17, 2020    Key Record Dates
Last Update Posted: November 29, 2021
Last Verified: October 2021
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description: NCI is committed to sharing data in accordance with NIH policy. For more details on how clinical trial data is shared, access the link to the NIH data sharing policy page.
URL: https://grants.nih.gov/policy/sharing.htm

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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Lymphoma
Leukemia
Leukemia, Lymphoid
Leukemia, Lymphocytic, Chronic, B-Cell
Neoplasms by Histologic Type
Neoplasms
Lymphoproliferative Disorders
Lymphatic Diseases
Immunoproliferative Disorders
Immune System Diseases
Leukemia, B-Cell
Venetoclax
Obinutuzumab
Antineoplastic Agents
Antineoplastic Agents, Immunological