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Assessing the Ability of Combination Treatment With Venetoclax to Permit Time Limited Therapy in Chronic Lymphocytic Leukemia

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT03701282
Recruitment Status : Active, not recruiting
First Posted : October 10, 2018
Last Update Posted : May 16, 2023
Sponsor:
Information provided by (Responsible Party):
National Cancer Institute (NCI)

Study Description
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Brief Summary:
This phase III trial studies how well ibrutinib and obinutuzumab with or without venetoclax work in treating patients with chronic lymphocytic leukemia. Ibrutinib may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Obinutuzumab is a monoclonal antibody. It binds to a protein called CD20, which is found on B cells (a type of white blood cell) and some types of cancer cells. This may help the immune system kill cancer cells. 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. Giving ibrutinib, obinutuzumab, and venetoclax may work better than giving ibrutinib and obinutuzumab in treating patients with chronic lymphocytic leukemia.

Condition or disease Intervention/treatment Phase
Chronic Lymphocytic Leukemia Small Lymphocytic Lymphoma Procedure: Biospecimen Collection Procedure: Bone Marrow Biopsy Procedure: Computed Tomography Drug: Ibrutinib Biological: Obinutuzumab Other: Quality-of-Life Assessment Drug: Venetoclax Phase 3

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Study Design
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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 720 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Randomized Phase III Study of the Addition of Venetoclax to Ibrutinib and Obinutuzumab Versus Ibrutinib and Obinutuzumab in Untreated Younger Patients With Chronic Lymphocytic Leukemia (CLL)
Actual Study Start Date : January 3, 2019
Estimated Primary Completion Date : May 7, 2028
Estimated Study Completion Date : May 7, 2028

Resource links provided by the National Library of Medicine


Arms and Interventions
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Arm Intervention/treatment
Experimental: Arm A (ibrutinib, obinutuzumab, venetoclax)
Patients receive ibrutinib PO daily on days 1-28 and 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 1-28 of cycles 3-14. Treatment repeats every 28 days for up to 19 cycles in the absence of disease progression or unacceptable toxicity. Patients undergo biopsy and CT scans before and after treatment and collection of blood throughout the study.
 Procedure: Biospecimen Collection
Undergo collection of blood
Other Names:
  • Biological Sample Collection
  • Biospecimen Collected
  • Specimen Collection

Procedure: Bone Marrow Biopsy
Undergo biopsy
Other Names:
  • Biopsy of Bone Marrow
  • Biopsy, Bone Marrow

Procedure: Computed Tomography
Undergo CT
Other Names:
  • CAT
  • CAT Scan
  • Computed Axial Tomography
  • Computerized Axial Tomography
  • Computerized axial tomography (procedure)
  • Computerized Tomography
  • CT
  • CT Scan
  • tomography

Drug: Ibrutinib
Given PO
Other Names:
  • BTK Inhibitor PCI-32765
  • CRA-032765
  • Imbruvica
  • PCI-32765

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

Drug: Venetoclax
Given PO
Other Names:
  • ABT-0199
  • ABT-199
  • ABT199
  • GDC-0199
  • RG7601
  • Venclexta
  • Venclyxto
Active Comparator: Arm B (ibrutinib, obinutuzumab)
Patients receive ibrutinib PO and obinutuzumab as in arm A. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients undergo biopsy and CT scans before and after treatment and collection of blood throughout the study.
 Procedure: Biospecimen Collection
Undergo collection of blood
Other Names:
  • Biological Sample Collection
  • Biospecimen Collected
  • Specimen Collection

Procedure: Bone Marrow Biopsy
Undergo biopsy
Other Names:
  • Biopsy of Bone Marrow
  • Biopsy, Bone Marrow

Procedure: Computed Tomography
Undergo CT
Other Names:
  • CAT
  • CAT Scan
  • Computed Axial Tomography
  • Computerized Axial Tomography
  • Computerized axial tomography (procedure)
  • Computerized Tomography
  • CT
  • CT Scan
  • tomography

Drug: Ibrutinib
Given PO
Other Names:
  • BTK Inhibitor PCI-32765
  • CRA-032765
  • Imbruvica
  • PCI-32765

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


Outcome Measures
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Primary Outcome Measures :
  1. Progression-free survival [ Time Frame: Time from randomization to progression or death without documented progression, assessed up to 10 years ]
    The analysis will be performed using the repeated confidence intervals methodology. At each interim or final analysis, two-sided repeated confidence interval will be constructed using the partial likelihood estimate from stratified Cox proportional hazards model and the critical value based on the Lan-DeMets error-spending function that corresponds to the truncated O'brien-Fleming boundaries.


Secondary Outcome Measures :
  1. Overall survival [ Time Frame: Time from randomization to death due to any cause, assessed up to 10 years ]
    A hierarchical testing strategy will be used. The analysis will be performed using the repeated confidence intervals methodology. At each interim or final analysis, two-sided repeated confidence interval will be constructed using the partial likelihood estimate from stratified Cox proportional hazards model and the critical value based on the Lan-DeMets error-spending function that corresponds to the truncated O'brien-Fleming boundaries.

  2. Incidence of adverse events [ Time Frame: Up to 10 years ]
    Graded according to Common Terminology Criteria for Adverse Events version 5.0.


Other Outcome Measures:
  1. Quality of life (QOL) [ Time Frame: Baseline up to 10 years ]
    Assessed using Functional Assessment of Cancer Therapy-General (FACT-G) and the leukemia sub-scale. FACT-G and the leukemia subscale will be analyzed at randomization, on day 1 of cycles 3, 7, 15, at the end of cycle 19, every 6 months for 2 years post response evaluation, at 48 months after randomization and at the time of disease progression. Linear mixed effects models will be used to perform repeated measures regression analysis. Will compare treatment toxicity-related QOL between the two arms. The entire FACT-Leukemia instrument (FACT-G and the leukemia subscale) at baseline will be analyzed using descriptive statistics to assess the impact of CLL on QOL independent of treatment.

  2. FACT-Leu Trial Outcome Index (TOI) score over time [ Time Frame: Baseline up to 10 years ]
    Will use linear mixed effects models will be used to perform repeated measures regression analysis to examine the treatment effect and time effect on FACT-Leu TOI score.

  3. Adherence [ Time Frame: Baseline up to 10 years ]
    Defined as patients taking 80% or more of their prescribed doses. The ASK-12 Survey will be used to measure the likelihood that a patient will take prescribed medications for patients on both arms at baseline and on day 1 +/- 4 days of the following cycles 3, 7, 15, at the time of response evaluation (end of cycle 19), every 6 months for 2 years post response evaluation, at 48 months after randomization, and at time of disease progression. Descriptive statistics will be used to summarize trend in adherence to prescription.

  4. Minimal residual disease (MRD) analysis [ Time Frame: Up to 10 years ]

Eligibility Criteria
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Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years to 69 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Diagnosis of CLL according to the National Cancer Institute (NCI)/International Workshop on Chronic Lymphocytic Leukemia (IWCLL) criteria or small lymphocytic lymphoma (SLL) according to the World Health Organization (WHO) criteria. This includes previous documentation of:

    • Biopsy-proven small lymphocytic lymphoma OR

    • Diagnosis of CLL according to the NCI/IWCLL criteria as evidenced by all of the following:

      • Peripheral blood lymphocyte count of greater than 5 x10^9/L

      • Immunophenotype consistent with CLL defined as:

        • The predominant population of lymphocytes share both B-cell antigens (CD19, CD20 [typically dim expression], or CD23) as well as CD5 in the absence of other pan-T-cell markers (CD3, CD2, etc).
        • Clonality as evidenced by kappa or lambda light chain restriction (typically dim immunoglobulin expression)
    • Negative fluorescent in situ hybridization (FISH) analysis for t(11;14)(IgH/CCND1) on peripheral blood or tissue biopsy (e.g. marrow aspirate) or negative immunohistochemical stains for cyclin D1 staining on involved tissue biopsy (e.g. marrow aspirate or lymph node biopsy)
  • No prior chemotherapy, BTK inhibitor therapy, venetoclax, small molecule signaling inhibitor, or monoclonal anti-body therapy for treatment of CLL or SLL

  • Has met at least one of the following indications for treatment:

    • Evidence of progressive marrow failure as manifested by the development of worsening anemia (hemoglobin [Hg] < 11 g/dl) and/or thrombocytopenia (platelets < 100 x 10^9/L)
    • Symptomatic or progressive lymphadenopathy, splenomegaly, or hepatomegaly

    • One or more of the following disease-related symptoms:

      • Weight loss >= 10% within the previous 6 months
      • Grade 2 or 3 fatigue attributed to CLL
      • Fevers > 100.5 degree Fahrenheit (F) for 2 weeks without evidence of infection
      • Clinically significant night sweats without evidence of infection
    • Progressive lymphocytosis (not due to the effects of corticosteroids) with an increase of > 50% over a two-month period or an anticipated doubling time of less than six months
  • Age >= 18 years and < 70
  • Eastern Cooperative Oncology Group (ECOG) performance status between 0-2
  • Life expectancy of >= 12 months
  • No deletion of 17p13 on cytogenetic analysis by FISH
  • Glomerular filtration rate (GFR) > 40 mL/minute as calculated by the Cockcroft-Gault Formula (obtained =< 14 days prior to registration)
  • Total bilirubin =< 1.5 x upper limit of normal (ULN) unless due to Gilbert's disease. For those with a total bilirubin > 1.5 x ULN, a direct bilirubin should be performed and must be < 1.5 mg/dL for Gilbert's to be diagnosed (obtained =< 14 days prior to registration)

  • Serum glutamic-oxaloacetic transaminase (SGOT) (aspartate aminotransferase [AST])/serum glutamate pyruvate transaminase (SGPT) (alanine aminotransferase [ALT]) =< 3.0 x the institutional ULN (obtained =< 14 days prior to registration)

    • NOTE: If value is higher due to hepatic involvement by CLL, patient is eligible
  • Prothrombin time (PT)/international normalized ratio (INR) < 1.5 ULN and partial thromboplastin time (PTT) (activated partial thromboplastin time [aPTT]) < 1.5 x ULN (obtained =< 14 days prior to registration)
  • No active hemolytic anemia requiring immunosuppressive therapy or other pharmacologic treatment. Patients who have a positive Coombs test but no evidence of hemolysis are NOT excluded from participation
  • No current use of corticosteroids. EXCEPTION: Low doses of steroids (< 10 mg of prednisone or equivalent dose of other steroid; inhaled steroids) used for treatment of non-hematologic medical condition (e.g. chronic adrenal insufficiency) is permitted
  • No previous autoimmune complications (e.g. autoimmune hemolytic anemia or immune thrombocytopenia) that have developed since the initial diagnosis of CLL and have required treatment with high dose corticosteroids (e.g. equivalent of > 20 mg/day of prednisone), monoclonal antibody based therapy, or chemotherapy. Prior use of corticosteroids for reasons other than treatment of autoimmune complications is allowed

  • No other active primary malignancy (other than non-melanomatous skin cancer or carcinoma in situ of the cervix) requiring treatment or limiting expected survival to =< 2 years

    • NOTE: If there is a history of prior malignancy, the patient must not currently be receiving other specific treatment (other than hormonal therapy for their cancer)
  • Able to adhere to the study visit schedule and other protocol requirements
  • No major surgery within 4 weeks (28 days) of first dose of study drug or minor surgery within 3 days of first dose of study drug
  • No radiation therapy =< 4 weeks prior to registration to Step 1
  • Patients who are human immunodeficiency virus positive (HIV+) with undetectable HIV viral load are eligible provided they meet all other protocol criteria for participation and are not being treated with protease inhibitors or any non-nucleoside reverse transcriptase inhibitors (NNRTI) that are CYP3A4 inducers; if being treated for HIV, patients should be receiving an alternative antiretroviral therapy (ART) that is not a CYP3A inhibitor

  • Women of childbearing potential and sexually active males must be strongly advised to use accepted and highly effective method(s) of contraception or to abstain from sexual intercourse for the duration of their participation in the study and for:

    • 18 months after the last dose of obinutuzumab
    • 90 days after the last dose of ibrutinib, and
    • 30 days after the last dose of venetoclax Male subjects must also agree to refrain from sperm donation until 90 days after the last dose of protocol treatment

  • Patient must be able to swallow capsules and not have the following conditions:

    • Disease significantly affecting gastrointestinal function
    • Resection of the stomach or small bowel
    • Symptomatic inflammatory bowel disease
    • Ulcerative colitis
    • Partial or complete bowel obstruction
  • Patient must undergo assessment with Timed Up and Go (TUG) test and comorbidity index
  • Patient must be able to receive xanthine oxidase inhibitor or rasburicase for tumor lysis syndrome (TLS) prophylaxis

Exclusion Criteria:

  • Patients must not have any of the following conditions:

    • Congestive heart failure or New York Heart Association Functional Classification III or IV congestive heart failure
    • History of myocardial infarction, unstable angina, or acute coronary syndrome within 6 months prior to registration
    • Recent infections requiring systemic treatment; need to have completed anti-biotic therapy > 14 days before the first dose of study drug
    • Cerebral vascular accident or intracranial bleed within the last 6 months
    • Infection with known chronic, active hepatitis C
    • Positive serology for hepatitis B defined as a positive test for hepatitis B surface antigen (HBsAg); in addition, if negative for HBsAg but hepatitis B core antibody (HBcAb) positive (regardless of hepatitis B surface antibody [HBsAb] status), a hepatitis B deoxyribonucleic acid (DNA) test will be performed and, if positive the subject will be ineligible; if the hepatitis (Hep) B DNA test is negative (i.e. viral load undetectable) then the individual is eligible; if a patient who is HBsAg negative, HBsAb negative, HBcAb positive, and Hep B DNA negative is enrolled, they should be considered for either prophylactic anti-viral therapy (J Clin Oncol. 2013 Aug 1;31(22):2765-72) or careful monitoring for Hep B reactivation (J Clin Oncol. 2014 Nov 20;32(33):3736-43)
  • Patients are not eligible if they require treatment with a strong cytochrome P450 (CYP) 3A inhibitor

  • Patients may not have received the following within 7 days prior to the first dose of study drug:

    • Steroid therapy for anti-neoplastic intent
    • Strong and moderate CYP3A inhibitors
    • Strong and moderate CYP3A inducers
  • Patients may not be on any other investigational agents
  • Patients may not have received warfarin or another vitamin K antagonist in the preceding 30 days
  • Women must not be pregnant or breast-feeding since this study involves investigational agents whose genotoxic, mutagenic, and teratogenic effects on the developing fetus and newborn are unknown; all females of childbearing potential must have a blood test within 2 weeks prior to registration to Step 1 to rule out pregnancy; a female of childbearing potential is defined as any woman, regardless of sexual orientation or whether they have undergone tubal ligation, who meets the following criteria: 1) has achieved menarche at some point, 2) has not undergone a hysterectomy or bilateral oophorectomy; or 3) has not been naturally postmenopausal (amenorrhea following cancer therapy does not rule out childbearing potential) for at least 24 consecutive months (i.e., has had menses at any time in the preceding 24 consecutive months)
  • Patient must not be on any other systemic immunosuppressant therapy other than corticosteroids within 28 days of the first dose of study drug
  • Patient must not be vaccinated with live, attenuated vaccines within 4 weeks of first dose of study drug
  • Patient must not have any known bleeding disorders (e.g., von Willebrand's disease) or hemophilia
  • Patient must not have currently active, clinically significant hepatic impairment (>= moderate hepatic impairment according to the NCI/Child Pugh classification)
Contacts and Locations
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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): NCT03701282


Locations
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Sponsors and Collaborators
National Cancer Institute (NCI)
Investigators
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Principal Investigator: Tait D Shanafelt ECOG-ACRIN Cancer Research Group
More Information
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Responsible Party: National Cancer Institute (NCI)
ClinicalTrials.gov Identifier: NCT03701282    
Other Study ID Numbers: NCI-2018-02127
NCI-2018-02127 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
EA9161 ( Other Identifier: ECOG-ACRIN Cancer Research Group )
EA9161 ( Other Identifier: CTEP )
U10CA180820 ( U.S. NIH Grant/Contract )
First Posted: October 10, 2018    Key Record Dates
Last Update Posted: May 16, 2023
Last Verified: March 2023
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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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
Chronic Disease
Disease Attributes
Pathologic Processes
Venetoclax
Obinutuzumab
Antineoplastic Agents
Antineoplastic Agents, Immunological