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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

NCT04269902

Description:

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.

Related Conditions:
  • Chronic Lymphocytic Leukemia
  • Small Lymphocytic Lymphoma
Recruiting Status:

Not yet recruiting

Phase:

Phase 3

Trial Eligibility

Document

Title

  • Brief Title: 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: 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

Clinical Trial IDs

  • ORG STUDY ID: NCI-2020-00752
  • SECONDARY ID: NCI-2020-00752
  • SECONDARY ID: S1925
  • SECONDARY ID: S1925
  • SECONDARY ID: U10CA180888
  • NCT ID: NCT04269902

Conditions

  • Chronic Lymphocytic Leukemia
  • Small Lymphocytic Lymphoma

Interventions

DrugSynonymsArms
ObinutuzumabAnti-CD20 Monoclonal Antibody R7159, GA-101, GA101, Gazyva, huMAB(CD20), R7159, RO 5072759, RO-5072759, RO5072759Arm I (delayed V-O)
VenetoclaxABT-0199, ABT-199, ABT199, GDC-0199, RG7601, Venclexta, VenclyxtoArm I (delayed V-O)

Purpose

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.
    

Trial Arms

NameTypeDescriptionInterventions
Arm I (delayed V-O)Active ComparatorTreatment 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.
  • Obinutuzumab
  • Venetoclax
Arm II (early V-O)ExperimentalTreatment 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.
  • Obinutuzumab
  • Venetoclax

Eligibility Criteria

        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
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure: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
Safety Issue:
Description: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.

Secondary Outcome Measures

Measure:Incidence of adverse events
Time Frame:Up to 10 years
Safety Issue:
Description:Will utilize the CTCAE (National Cancer Institute [NCI] Common Terminology Criteria for Adverse Events) version 5.0 for toxicity and adverse event reporting.
Measure:Response rate
Time Frame:Up to 10 years
Safety Issue:
Description:Will be compared using Fisher's exact test.
Measure: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
Safety Issue:
Description:Will be estimated using the Kaplan-Meier method and will be compared using log-rank tests and Cox regression models.
Measure: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
Safety Issue:
Description:Will be estimated using the Kaplan-Meier method and will be compared using log-rank tests and Cox regression models.
Measure: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
Safety Issue:
Description:Will be estimated using the Kaplan-Meier method and will be compared using log-rank tests and Cox regression models.
Measure:Time to second treatment
Time Frame:Up to 10 years
Safety Issue:
Description: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.
Measure:Patient compliance
Time Frame:Up to 10 years
Safety Issue:
Description:Will be reported descriptively by arm.

Details

Phase:Phase 3
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:National Cancer Institute (NCI)

Last Updated

February 20, 2020