Status and phase
Conditions
Treatments
Study type
Funder types
Identifiers
About
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.
Full 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.
Enrollment
Sex
Ages
Volunteers
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:
Treatment-naïve CLL patients must meet the following requirements (Phase II only):
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:
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:
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:
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
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:
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.)
Primary purpose
Allocation
Interventional model
Masking
87 participants in 1 patient group
Loading...
Data sourced from clinicaltrials.gov
Clinical trials
Research sites
Resources
Legal