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Trial record 1 of 1 for:    EA9161
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Ibrutinib and Obinutuzumab With or Without Venetoclax in Treating Patients With Chronic Lymphocytic Leukemia

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ClinicalTrials.gov Identifier: NCT03701282
Recruitment Status : Recruiting
First Posted : October 10, 2018
Last Update Posted : March 21, 2019
Sponsor:
Information provided by (Responsible Party):
National Cancer Institute (NCI)

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. 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. Drugs used in chemotherapy, such as venetoclax, work in different ways to stop the growth of cancer cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Giving ibrutinib, obinutuzumab and venetoclax may work better in treating patients with chronic lymphocytic leukemia.

Condition or disease Intervention/treatment Phase
CCND1/IGHG1 Fusion Negative Chronic Lymphocytic Leukemia Small Lymphocytic Lymphoma t(11;14) Negative Drug: Ibrutinib Biological: Obinutuzumab Other: Quality-of-Life Assessment Drug: Venetoclax Phase 3

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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 : October 31, 2025
Estimated Study Completion Date : October 31, 2025


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 course 1 and on day 1 of courses 2-6. Patients also receive venetoclax PO QD on days 1-28 of courses 3-14. Treatment repeats every 28 days for up to 19 courses in the absence of disease progression or unacceptable toxicity.
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

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

Active Comparator: Arm B (ibrutinib, obinutuzumab)
Patients receive ibrutinib PO and obinutuzumab as in arm A. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.
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

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




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 graded according to Common Terminology Criteria for Adverse Events version 5.0 [ Time Frame: Up to 10 years ]

Other Outcome Measures:
  1. Quality of life (QOL) assessed using Functional Assessment of Cancer Therapy-General (FACT-G) and the leukemia sub-scale [ Time Frame: Baseline up to 10 years ]
    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 defined as patients taking 80% or more of their prescribed doses [ Time Frame: Baseline up to 10 years ]
    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.



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
  • 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)
  • 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)

    • NOTE: If value is higher due to hepatic involvement by CLL, patient is eligible
  • 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) 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
  • 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
  • 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
    • Serologic status reflecting active hepatitis B or C infection. Patients with hepatitis B or C infection may be eligible if viral loads are undetectable. Patients may be on suppressive therapy
  • 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 rule out pregnancy. A female of childbearing potential is any woman, regardless of sexual orientation or whether they have undergone tubal ligation, who meets the following criteria: 1) has not undergone a hysterectomy or bilateral oophorectomy; or 2) has not been naturally postmenopausal for at least 24 consecutive months (i.e., has had menses at any time in the preceding 24 consecutive months
  • 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 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
  • Patient must undergo assessment with Timed Up and Go (TUG) test
  • Patient must be able to receive xanthine oxidase inhibitor or rasburicase for tumor lysis syndrome (TLS) prophylaxis

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


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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

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Responsible Party: National Cancer Institute (NCI)
ClinicalTrials.gov Identifier: NCT03701282     History of Changes
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: March 21, 2019
Last Verified: January 2019

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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
Venetoclax
Obinutuzumab
Rituximab
Antineoplastic Agents
Antineoplastic Agents, Immunological
Immunologic Factors
Physiological Effects of Drugs
Antirheumatic Agents