Clinical Trials /

Bcl-2 Inhibitor GDC-0199 in Combination With Obinutuzumab and Ibrutinib in Treating Patients With Relapsed, Refractory, or Previously Untreated Chronic Lymphocytic Leukemia

NCT02427451

Description:

This phase Ib/II trial studies the best dose and safety of Bcl-2 inhibitor GDC-0199 in combination with obinutuzumab and ibrutinib and to see how well they work in treating patients with chronic lymphocytic leukemia that has returned (relapsed), does not respond to treatment (refractory), or is previously untreated. Bcl-2 inhibitor GDC-0199 and ibrutinib may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Monoclonal antibodies, such as obinutuzumab, may block cancer growth in different ways by targeting certain cells. Giving Bcl-2 inhibitor GDC-0199 together with obinutuzumab and ibrutinib may be a better treatment for chronic lymphocytic leukemia.

Related Conditions:
  • Chronic Lymphocytic Leukemia
Recruiting Status:

Recruiting

Phase:

Phase 1/Phase 2

Trial Eligibility

Document

<span class="go-doc-concept go-doc-intervention">Bcl-2 Inhibitor GDC-0199</span> in Combination With Obinutuzumab and <span class="go-doc-concept go-doc-intervention">Ibrutinib</span> in Treating Patients With Relapsed, Refractory, or Previously Untreated <span class="go-doc-concept go-doc-disease">Chronic Lymphocytic Leukemia</span>

Title

  • Brief Title: Bcl-2 Inhibitor GDC-0199 in Combination With Obinutuzumab and Ibrutinib in Treating Patients With Relapsed, Refractory, or Previously Untreated Chronic Lymphocytic Leukemia
  • Official Title: Obinutuzumab, Ibrutinib, and Venetoclax for Relapsed and Previously Untreated Chronic Lymphocytic Leukemia (CLL)
  • Clinical Trial IDs

    NCT ID: NCT02427451

    ORG ID: OSU-14266

    NCI ID: NCI-2015-00252

    Trial Conditions

    Chronic Lymphocytic Leukemia

    Refractory Chronic Lymphocytic Leukemia

    Trial Interventions

    Drug Synonyms Arms
    Bcl-2 Inhibitor GDC-0199 ABT-0199, ABT-199, GDC-0199, RG7601 Treatment (obinutuzumab, ibrutinib, Bcl-2 inhibitor GDC-0199)
    Ibrutinib BTK Inhibitor PCI-32765, CRA-032765, Imbruvica, PCI-32765 Treatment (obinutuzumab, ibrutinib, Bcl-2 inhibitor GDC-0199)

    Trial Purpose

    This phase Ib/II trial studies the best dose and safety of Bcl-2 inhibitor GDC-0199 in
    combination with obinutuzumab and ibrutinib and to see how well they work in treating
    patients with chronic lymphocytic leukemia that has returned (relapsed), does not respond to
    treatment (refractory), or is previously untreated. Bcl-2 inhibitor GDC-0199 and ibrutinib
    may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth.
    Monoclonal antibodies, such as obinutuzumab, may block cancer growth in different ways by
    targeting certain cells. Giving Bcl-2 inhibitor GDC-0199 together with obinutuzumab and
    ibrutinib may be a better treatment for chronic lymphocytic leukemia.

    Detailed Description

    PRIMARY OBJECTIVES:

    I. To identify the dose of venetoclax (Bcl-2 inhibitor GDC-0199) that can be safely
    administered in combination with obinutuzumab and ibrutinib for the treatment of
    relapsed/refractory or previously untreated chronic lymphocytic leukemia (CLL).

    II. To evaluate the feasibility, safety, and tolerability of venetoclax in combination with
    obinutuzumab and ibrutinib in patients with relapsed/refractory or previously untreated CLL.

    III. To determine the minimal residual disease (MRD)-negative complete response (CR) rate
    after 12 cycles of treatment with venetoclax in combination with obinutuzumab and ibrutinib
    in patients with relapsed/refractory or previously untreated CLL.

    SECONDARY OBJECTIVES:

    I. To determine the overall response rate (ORR) and complete response rate (CR) of
    venetoclax in combination with obinutuzumab and ibrutinib in patients with
    relapsed/refractory or previously untreated patients with CLL.

    II. To estimate progression free survival (PFS) after treatment with venetoclax in
    combination with obinutuzumab and ibrutinib in patients with relapsed/refractory or
    previously untreated patients with CLL.

    III. To conduct pharmacokinetic and pharmacodynamic studies of venetoclax in combination
    with obinutuzumab and ibrutinib in patients with relapsed/refractory or previously untreated
    patients with CLL.

    IV. To examine pre-treatment and serial biomarkers associated with response and mechanisms
    of resistance to venetoclax, obinutuzumab and ibrutinib when given in combination for
    relapsed/refractory or previously untreated patients with CLL.

    OUTLINE: This is a phase Ib, dose-escalation study of Bcl-2 inhibitor GDC-0199 followed by a
    phase II study.

    Patients receive obinutuzumab intravenously (IV) on day 1 (days 1, 2, 8, and 15 for course 1
    only) every 28 days for up to 8 courses. Beginning in course 2, patients receive ibrutinib
    orally (PO) once daily (QD) on days 1-28. Beginning in course 3, patients receive Bcl-2
    inhibitor GDC-0199 PO QD on days 1-28. Treatment repeats every 28 days for up to 14 courses
    in the absence of disease progression or unacceptable toxicity.

    After completion of study treatment, patients are followed up at 4 and 8 weeks, every 3
    months for 2 years, and then every 6 months thereafter.

    Trial Arms

    Name Type Description Interventions
    Treatment (obinutuzumab, ibrutinib, Bcl-2 inhibitor GDC-0199) Experimental Patients receive obinutuzumab IV on day 1 (days 1, 2, 8, and 15 for course 1 only) every 28 days for up to 8 courses. Beginning in course 2, patients receive ibrutinib PO QD on days 1-28. Beginning in course 3, patients receive Bcl-2 inhibitor GDC-0199 PO QD on days 1-28. Treatment repeats every 28 days for up to 14 courses in the absence of disease progression or unacceptable toxicity. Bcl-2 Inhibitor GDC-0199, Ibrutinib

    Eligibility Criteria

    Inclusion Criteria:

    - Diagnosis of CLL meeting criteria established in the World Health Organization (WHO)
    classification of hematologic disorders

    - Eastern Cooperative Oncology Group (ECOG) performance status =< 1

    - Relapsed or refractory CLL patients must meet the following requirements:

    - Received at least 1 prior therapy

    - Require treatment in the opinion of the investigator

    - Relapsed patients must have developed progressive disease following a response
    to a prior therapy

    - Refractory patients must have failed to respond or relapsed within 6 months to
    the last prior therapy

    - Treatment-nave CLL patients must meet the following requirements (Phase II only):

    - Symptomatic disease as defined by International Workshop on Chronic Lymphocytic
    Leukemia (IWCLL) 2008 criteria

    - Received no prior chemotherapy, immunotherapy, or targeted therapy for the
    treatment of CLL with the exceptions of palliative loco-regional radiotherapy
    and corticosteroids for symptom control

    - Hemoglobin >= 8 g/dL

    - Absolute neutrophil count (ANC) >= 1000/mm^3

    - Platelets >= 40,000/mm^3

    - Prothrombin time (PT)/partial thromboplastin time (PTT) =< 1.5 x upper limit of
    normal (ULN)

    - Total bilirubin =< 1.5 x ULN (excepting Gilbert's syndrome)

    - Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =< 2.5 ULN

    - Serum creatinine < 2.0 mg/dL or creatinine clearance (Cockcroft) >= 50 mL/min/1.73
    m^2 for patients with creatinine levels above institutional normal

    - Female patients must be surgically sterile, post-menopausal (for at least 1 year), or
    have negative results from a pregnancy test performed as follows:

    - At screening, on a serum sample obtained within 14 days prior to the first study
    drug administration, and

    - Prior to dosing, on a urine sample obtained on day 1 of treatment if it has been
    > 7 days since obtaining the serum pregnancy test result

    - All female patients not surgically sterile or post-menopausal (for at least 1 year)
    and non-vasectomized male patients must practice at least one of the following
    methods of birth control:

    - Total abstinence from sexual intercourse (minimum one complete menstrual cycle)

    - A vasectomized partner

    - Hormonal contraceptives for at least 2 months prior to day 1 of treatment

    - Double-barrier method

    - Non-vasectomized male patients must practice at least one of the following methods of
    birth control throughout the duration of study participation and for at least 3
    months after study treatment:

    - A partner who is surgically sterile or postmenopausal (for at least 1 year) or
    who is taking hormonal contraceptives (oral, parenteral, vaginal ring, or
    transdermal) for at least 3 months prior to study drug administration

    - Total abstinence from sexual intercourse

    - Double-barrier method (condom, diaphragm or cervical cup with spermicidal,
    contraceptive sponge, jellies, or cream)

    - Ability to understand and the willingness to sign a written informed consent document

    Exclusion Criteria:

    - Patients who have had chemotherapy, immunotherapy, radiotherapy, or investigational
    therapy within 28 days prior to entering the study or those who have not recovered
    from adverse events due to agents administered more than 28 days earlier; steroids
    for control of disease related symptoms are permitted

    - Patients who are receiving any other investigational agents

    - Uncontrolled autoimmune hemolytic anemia or thrombocytopenia

    - Active Richter's transformation

    - Known active involvement of the central nervous system by lymphoma or leukemia

    - Patients who require warfarin anticoagulation or who have received warfarin or
    equivalent vitamin K antagonists =< 7 days prior to treatment day 1; patients may be
    eligible if able to be taken off warfarin and started on an alternative anticoagulant

    - Received potent cytochrome P450 3A4 (CYP3A4) inhibitors (such as fluconazole,
    ketoconazole, and clarithromycin) within 7 days prior to the first dose of study
    treatment

    - Received potent CYP3A4 inducers (such as rifampin, carbamazepine, phenytoin, St.
    John's wort) within 7 days prior to the first dose of study treatment

    - Consumed grapefruit or grapefruit products, Seville oranges (including marmalade
    containing Seville oranges), or star fruit within 3 days prior to the first dose of
    study treatment

    - History of a prior significant toxicity, other than thrombocytopenia, from another
    Bcl-2 family protein inhibitor

    - Known cysteine-481 Bruton's tyrosine kinase (BTK) mutation or CLL refractory to or
    progressed during ibrutinib or other Cys-481 binding BTK inhibitor treatment

    - Known infection with the human immunodeficiency virus (HIV) virus

    - A cardiovascular disability status of New York Heart Association class >= 2, defined
    as cardiac disease in which patients are comfortable at rest but ordinary physical
    activity results in fatigue, palpitations, dyspnea, or angina pain

    - Positive hepatitis serology:

    - Hepatitis B virus (HBV): patients with positive serology for hepatitis B defined
    as positivity for hepatitis B surface antigen (HBsAg) or hepatitis B core
    antibody (anti-HBc); patients who are positive for anti-HBc may be considered
    for inclusion in the study on a case-by-case basis if they are hepatitis B viral
    deoxyribonucleic acid (DNA) negative and are willing to undergo ongoing HBV DNA
    testing by real-time polymerase chain reaction (PCR); patients with positive
    serology may be referred to a hepatologist or gastroenterologist for appropriate
    monitoring and management

    - Patients with positive HBSAg consistent with prior vaccination to HBV
    (i.e., anti-HBs+, anti-HBc-) may participate

    - Patients suspected to have false positive serologic studies because of IV
    immunoglobulin administration are potentially eligible after negative PCR
    studies for viral DNA/ribonucleic acid (RNA) and discussion with the
    principal investigator

    - Hepatitis C (HCV): patients with positive hepatitis C serology unless HCV RNA is
    confirmed negative and may be considered for inclusion in the study on a
    case-by-case basis (e.g., patients with negative viral load after HCV-specific
    treatment)

    - History of severe (defined as grade 4 and/or requiring permanent discontinuation of
    prior antibody therapy) allergic or anaphylactic reactions to human, humanized,
    chimeric, or murine monoclonal antibodies

    - Patients who received a live viral vaccination within 6 months prior to the first
    dose of study drug

    - A female patient who is pregnant or breast-feeding

    - Uncontrolled intercurrent illness including, but not limited to, ongoing or active
    infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac
    arrhythmia, or psychiatric illness/social situations that would limit compliance with
    study requirements

    - History of other active malignancies other than CLL within the past 3 years prior to
    study entry, with the exception of:

    - Adequately treated in situ carcinoma or the cervix uteri or breast

    - Basal cell or localized squamous cell carcinoma of the skin

    - Previous malignancy confirmed and surgically resected (or treated with other
    modalities) with curative intent or without relapse for >= 2 years

    - Vaccination with a live vaccine < 28 days prior to the start of treatment

    - Inability to swallow capsules or tablets, or disease significantly affecting
    gastrointestinal function and/or inhibiting small intestine absorption (malabsorption
    syndrome, resection of the small bowel, poorly controlled inflammatory bowel disease,
    etc.)

    Minimum Eligible Age: 18 Years

    Maximum Eligible Age: N/A

    Eligible Gender: Both

    Primary Outcome Measures

    Maximum tolerated dose of Bcl-2 inhibitor GDC-0199 in combination with obinutuzumab and ibrutinib (Phase Ib)

    MRD-complete response (CR) defined by the IWCLL 2008 criteria (Phase II)

    Secondary Outcome Measures

    Incidence of adverse events graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0

    Number of courses started/completed

    Number of patients who reach the target dose of Bcl-2 inhibitor GDC-0199

    Number of patients requiring dose reductions

    Reason for going off treatment

    Overall response rate

    Progression-free survival

    Baseline prognostic factors

    Health related quality of life

    Serial assessment of immune effector cell number and function.

    Emotional distress assessment

    Trial Keywords