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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 : July 28, 2021
Sponsor:
Information provided by (Responsible Party):
National Cancer Institute (NCI)

Tracking Information
First Submitted Date  ICMJE February 13, 2020
First Posted Date  ICMJE February 17, 2020
Last Update Posted Date July 28, 2021
Actual Study Start Date  ICMJE December 14, 2020
Estimated Primary Completion Date October 1, 2028   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: April 23, 2020)
  • 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).
  • 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.
Original Primary Outcome Measures  ICMJE
 (submitted: February 13, 2020)
  • 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.
  • 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.
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: April 23, 2020)
  • 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.
  • Overall Response rate [ Time Frame: Up to 10 years ]
    Will be compared using Fisher's exact test.
  • 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.
  • 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.
  • 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.
  • 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.
  • Patient compliance [ Time Frame: Up to 10 years ]
    Will be reported descriptively by arm.
Original Secondary Outcome Measures  ICMJE
 (submitted: February 13, 2020)
  • 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.
  • Response rate [ Time Frame: Up to 10 years ]
    Will be compared using Fisher's exact test.
  • 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.
  • 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.
  • 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.
  • 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.
  • Patient compliance [ Time Frame: Up to 10 years ]
    Will be reported descriptively by arm.
Current Other Pre-specified Outcome Measures
 (submitted: February 13, 2020)
  • 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.
  • 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.
  • 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.
Original Other Pre-specified Outcome Measures Same as current
 
Descriptive Information
Brief Title  ICMJE 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
Official Title  ICMJE 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
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.
Detailed Description

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.

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.

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.

After completion of study treatment, patients are followed up for 10 years after registration.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 3
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE
  • Chronic Lymphocytic Leukemia
  • Small Lymphocytic Lymphoma
Intervention  ICMJE
  • 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
Study Arms  ICMJE
  • 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.
    Interventions:
    • Biological: Obinutuzumab
    • Other: Quality-of-Life Assessment
    • Other: Questionnaire Administration
    • Drug: Venetoclax
  • 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.
    Interventions:
    • Biological: Obinutuzumab
    • Other: Quality-of-Life Assessment
    • Other: Questionnaire Administration
    • Drug: Venetoclax
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: February 13, 2020)
247
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE October 1, 2028
Estimated Primary Completion Date October 1, 2028   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  • Patients 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. Patients must have been diagnosed within 12 months prior to registration
  • Patients must not meet any of the International Workshop on Chronic Lymphocytic Leukemia (IWCLL) specified criteria for active CLL therapy
  • Patients 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 the site's 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
  • Patients 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
  • The treating physician must have the intent of using V-O as initial therapy when the patient requires initial treatment
  • Treatment with high dose corticosteroids and/or intravenous immunoglobulin for autoimmune complications of CLL must be complete at least 4 weeks prior to enrollment. Palliative steroids must be at a dose not higher than 20 mg/day of prednisone or equivalent corticosteroid at the time of registration. Prior therapy with anti CD20 monoclonal antibodies is not allowed
  • Patients must not be receiving or planning to receive any other investigational agents before completing protocol therapy
  • Patients must be >= 18 years of age
  • Patients 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
  • Patients must not have current, clinically significant gastrointestinal malabsorption, in the opinion of treating doctor
  • Patients must be able to take oral medications
  • 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
  • Human immunodeficiency virus (HIV)-infected patients on effective anti-retroviral therapy with undetectable viral load within 6 months are eligible for this trial
  • Patients may 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
  • Patients must not have known bleeding disorders (e.g., von Willebrand's disease or hemophilia)
  • Patients must not have a history of stroke or intracranial hemorrhage within 6 months prior to enrollment
  • Patients must not require continued therapy with a strong inhibitor or inducer of CYP3A4/5, as venetoclax is extensively metabolized by CYP3A4/5
  • Patients must not have uncontrolled autoimmune hemolytic anemia or idiopathic thrombocytopenia purpura
  • Patients 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; or a history of myocardial infarction, unstable angina, or acute coronary syndrome within 6 months prior to enrollment
  • Patients 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
  • Patients 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
  • Patients must be offered participation in banking for future research. With patient's consent, specimens must be submitted
  • Patients 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 patients 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.)
  • Patients 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.
  • 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
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT04269902
Other Study ID Numbers  ICMJE 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 )
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE
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
Responsible Party National Cancer Institute (NCI)
Study Sponsor  ICMJE National Cancer Institute (NCI)
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Principal Investigator: Deborah M Stephens Southwest Oncology Group
PRS Account National Cancer Institute (NCI)
Verification Date July 2021

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP