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:

Active, not recruiting

Phase:

Phase 1/Phase 2

Trial Eligibility

Document

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

  • ORG STUDY ID: OSU-14266
  • SECONDARY ID: NCI-2015-00252
  • NCT ID: NCT02427451

Conditions

  • Chronic Lymphocytic Leukemia
  • Refractory Chronic Lymphocytic Leukemia

Interventions

DrugSynonymsArms
Bcl-2 Inhibitor GDC-0199ABT-0199, ABT-199, GDC-0199, RG7601Treatment (obinutuzumab, ibrutinib, Bcl-2 inhibitor GDC-0199)
ObinutuzumabAnti-CD20 Monoclonal Antibody R7159, GA101, Gazyva, R7159, RO 5072759Treatment (obinutuzumab, ibrutinib, Bcl-2 inhibitor GDC-0199)
IbrutinibBTK Inhibitor PCI-32765, CRA-032765, Imbruvica, PCI-32765Treatment (obinutuzumab, ibrutinib, Bcl-2 inhibitor GDC-0199)

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

NameTypeDescriptionInterventions
Treatment (obinutuzumab, ibrutinib, Bcl-2 inhibitor GDC-0199)ExperimentalPatients 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
  • Obinutuzumab
  • 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-naïve 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.)
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Maximum tolerated dose of Bcl-2 inhibitor GDC-0199 in combination with obinutuzumab and ibrutinib (Phase Ib)
Time Frame:28 days (course 3)
Safety Issue:
Description:Assessments of MRD will be used in patients classified as CR to further evaluate their status as disease-free and if this further impacts their ability to remain progression-free and alive. MRD will be determined by high sensitivity 4 color flow cytometric analysis of the bone marrow using validated panels.

Secondary Outcome Measures

Measure:Incidence of adverse events graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0
Time Frame:Up to 4 years
Safety Issue:
Description:For all patients who receive at least one day of treatment, toxicities will be tabulated by type and grade and displayed in summary form.
Measure:Number of courses started/completed
Time Frame:Up to 14 months
Safety Issue:
Description:May be summarized.
Measure:Number of patients who reach the target dose of Bcl-2 inhibitor GDC-0199
Time Frame:Up to 14 months
Safety Issue:
Description:May be summarized.
Measure:Number of patients requiring dose reductions
Time Frame:Up to 14 months
Safety Issue:
Description:May be summarized.
Measure:Reason for going off treatment
Time Frame:Up to 14 months
Safety Issue:
Description:May be summarized.
Measure:Overall response rate
Time Frame:Up to 4 years
Safety Issue:
Description:Overall response rate with a 95% confidence interval will be reported for all evaluable patients in the phase II setting, within and potentially across cohorts, assuming a binomial distribution.
Measure:Progression-free survival
Time Frame:Time from first treatment date until the date of progression or death, whichever occurs first, assessed up to 4 years
Safety Issue:
Description:Will be summarized by the Kaplan-Meier method for each of the phase II cohorts.
Measure:Baseline prognostic factors
Time Frame:Baseline
Safety Issue:
Description:Relationships between baseline prognostic factors and response may be screened and analyzed quantitatively using logistic regression and adjusting for disease cohort, particularly if a sufficient number of patients respond to this combination therapy.
Measure:Health related quality of life
Time Frame:Up to 2 years
Safety Issue:
Description:Validated instruments will be administered serially to assess longitudinal changes in measures of health related quality of life (SF-12, BIPQ)
Measure:Serial assessment of immune effector cell number and function.
Time Frame:Up to day 1 of course 2
Safety Issue:
Description:Peripheral blood immunophenotyping will be used to enumerate immune effector cells (counts and percentages of B-, T-, and NK-cell subsets).
Measure:Emotional distress assessment
Time Frame:Up to 2 years
Safety Issue:
Description:Validated instruments will be administered serially to assess changes in emotional distress.

Details

Phase:Phase 1/Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Kerry Rogers

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