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

Study Overview
=================
Brief Summary
-----------------
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.

Official Title
-----------------
Obinutuzumab, Ibrutinib, and Venetoclax for Relapsed and Previously Untreated Chronic Lymphocytic Leukemia (CLL)

Conditions
-----------------
Chronic Lymphocytic Leukemia, Refractory Chronic Lymphocytic Leukemia

Intervention / Treatment
-----------------
* Drug: Bcl-2 Inhibitor GDC-0199
* Biological: Obinutuzumab
* Drug: Ibrutinib
* Other: Pharmacological Study
* Other: Laboratory Biomarker Analysis
* Other: Quality-of-Life Assessment


Participation Criteria
=================
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.)

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment (obinutuzumab, ibrutinib, Bcl-2 inhibitor GDC-0199)<br>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. | Drug: Bcl-2 Inhibitor GDC-0199<br>* Given PO<br>* Other names: RG7601;Biological: Obinutuzumab<br>* Given IV<br>* Other names: RO 5072759;Drug: Ibrutinib<br>* Given PO<br>* Other names: PCI-32765;Other: Pharmacological Study<br>* Correlative studies<br>* Other names: pharmacological studies;Other: Laboratory Biomarker Analysis<br>* Correlative studies<br>Other: Quality-of-Life Assessment<br>* Ancillary studies<br>* Other names: Quality of Life Assessment;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum tolerated dose of Bcl-2 inhibitor GDC-0199 in combination with obinutuzumab and ibrutinib (Phase Ib) |  | 28 days (course 3) | 
| MRD-complete response (CR) defined by the IWCLL 2008 criteria (Phase II) | 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. | Up to 8 weeks post-treatment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of adverse events graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0 | For all patients who receive at least one day of treatment, toxicities will be tabulated by type and grade and displayed in summary form. | Up to 4 years | 
| Number of courses started/completed | May be summarized. | Up to 14 months | 
| Number of patients who reach the target dose of Bcl-2 inhibitor GDC-0199 | May be summarized. | Up to 14 months | 
| Number of patients requiring dose reductions | May be summarized. | Up to 14 months | 
| Reason for going off treatment | May be summarized. | Up to 14 months | 
| Overall response rate | 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. | Up to 4 years | 
| Progression-free survival | Will be summarized by the Kaplan-Meier method for each of the phase II cohorts. | Time from first treatment date until the date of progression or death, whichever occurs first, assessed up to 4 years | 
| Baseline prognostic factors | 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. | Baseline | 
| Health related quality of life | Validated instruments will be administered serially to assess longitudinal changes in measures of health related quality of life (SF-12, BIPQ) | Up to 2 years | 
| Serial assessment of immune effector cell number and function. | Peripheral blood immunophenotyping will be used to enumerate immune effector cells (counts and percentages of B-, T-, and NK-cell subsets). | Up to day 1 of course 2 | 
| Emotional distress assessment | Validated instruments will be administered serially to assess changes in emotional distress. | Up to 2 years |