Ibrutinib and Obinutuzumab in Treating Patients with Relapsed or Refractory Chronic Lymphocytic Leukemia
This randomized phase Ib trial studies the side effects and best dose of obinutuzumab when given together with ibrutinib in treating patients with chronic lymphocytic leukemia that has returned after a period of improvement (relapsed) or has not responded to previous treatment (refractory). 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. Ibrutinib may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Giving obinutuzumab with ibrutinib may work better in treating chronic lymphocytic leukemia.
Inclusion Criteria
- Must have a confirmed diagnosis of chronic lymphocytic leukemia or small lymphocytic lymphoma as per International Workshop on Chronic Lymphocytic Leukemia (IW-CLL) 2008 criteria; specifically, patients must also require therapy for that diagnosis, based on meeting at least one of the following criteria: * Evidence of progressive marrow failure as manifested by the development of, or worsening of, anemia (hemoglobin < 11.0 g/L) and/or thrombocytopenia (platelets < 100 x 10^9/L) * Massive (>= 6 cm below the left costal margin), progressive, or symptomatic splenomegaly * Massive nodes (at least 10 cm longest diameter), progressive, or symptomatic lymphadenopathy * Progressive lymphocytosis with an increase of more than 50% over a 2-month period or lymphocyte doubling time (LDT) of < 6 months; lymphocyte doubling time may be obtained by linear regression extrapolation of absolute lymphocyte counts obtained at intervals of 2 weeks over an observation period of 2 to 3 months; in subjects with initial blood lymphocyte counts of < 30 x 10^9/L, LDT should not be used as a single parameter to define indication for treatment; in addition, factors contributing to lymphocytosis or lymphadenopathy other than CLL (e.g., infections) should be excluded * Autoimmune anemia and/or thrombocytopenia that is poorly responsive to corticosteroids or other standard therapy * Documented constitutional symptoms, defined as 1 or more of the following disease-related symptoms or signs: ** Unintentional weight loss > 10% within 6 months prior to screening ** Significant fatigue (inability to work or perform usual activities) *** Fevers > 100.5 degrees Fahrenheit (F) or 38.0 degrees Celsius (C) for 2 or more weeks prior to screening without evidence of infection ** Night sweats for more than 1 month prior to screening without evidence of infection
- Relapsed after or refractory to at least one prior CLL-directed therapy that was instituted due to patient previously meeting IWCLL 2008 criteria for treatment
- Age greater than or equal to 18 years. Because CLL is extremely rare in persons <18 years of age, children are excluded from this study
- Eastern Cooperative Oncology Group (ECOG) performance status =< 2
- Absolute neutrophil count >= 500 cells/mm^3 (0.5 x 10^9/L); growth factor allowed to achieve
- Platelet count >= 25,000 cells/mm^3 (25 x 10^9/L) independent of transfusion within 7 days of screening
- Serum aspartate transaminase (AST) and alanine transaminase (ALT) =< 4.0 x upper limit of normal (ULN)
- Bilirubin =< 2.0 x ULN (unless bilirubin rise is due to Gilbert’s syndrome or of non-hepatic origin)
- Serum creatinine < 2.0 x ULN unless due to biopsy proven CLL kidney infiltration
- The effects of ibrutinib and obinutuzumab on the developing human fetus are unknown; for this reason, women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation; should a woman become pregnant or suspect she is pregnant while participating in this study, she should inform her treating physician immediately
- Patients who have undergone prior allogeneic transplantation are eligible provided that their transplant day 0 is > 6 months from their first dose of study drug
- Ability to understand and the willingness to sign a written informed consent document
Exclusion Criteria
- Patients receiving cancer therapy (i.e., chemotherapy, radiation therapy, immunotherapy, biologic therapy, hormonal therapy, surgery and/or tumor embolization) within 2 weeks of cycle 1/day 1 with the following exceptions: * Corticosteroid therapy (prednisone or equivalent =< 20 mg daily) is allowed as clinically warranted as long as the dose is stabilized at least for 7 days prior to initial dosing; topical or inhaled corticosteroids are permitted * Patients who may experience clinical deterioration may start therapy after a shorter washout period with prior approval by the principal investigator (PI)
- Post allo patients must not have active graft versus-host disease and be off all immune suppression (other than steroids, as above)
- History of severe allergic or anaphylactic reactions to monoclonal antibody therapy
- Prior treatment with either obinutuzumab or ibrutinib
- History of other malignancies, except: * Malignancy treated with curative intent and with no known active disease present for >= 3 years before the first dose of study drug and felt to be at low risk for recurrence by treating physician * Adequately treated non-melanoma skin cancer or lentigo maligna without evidence of disease * Adequately treated carcinoma in situ without evidence of disease * Low-risk prostate cancer on active surveillance
- Concurrent systemic immunosuppressant therapy (e.g., cyclosporine A, tacrolimus, etc., or chronic administration of > 20 mg/day of prednisone) within 28 days of the first dose of study drug
- Vaccinated with live, attenuated vaccines within 4 weeks of first dose of study drug
- Recent infection requiring systemic treatment that was completed =< 7 days before the first dose of study drug
- Known bleeding disorders (e.g., von Willebrand’s disease) or hemophilia
- History of stroke or intracranial hemorrhage within 6 months prior to enrollment
- Known history of human immunodeficiency virus (HIV) or active hepatitis C virus (HCV) or hepatitis B virus (HBV); patients who are positive for hepatitis B core antibody or hepatitis B surface antigen must have a negative polymerase chain reaction (PCR) result before enrollment; those who are PCR positive will be excluded
- Any uncontrolled active systemic infection
- Major surgery within 4 weeks of first dose of study drug
- Any life-threatening illness, medical condition, or organ system dysfunction that, in the investigator’s opinion, could compromise the subject’s safety or put the study outcomes at undue risk
- Currently active, clinically significant cardiovascular disease, such as uncontrolled arrhythmia or class 3 or 4 congestive heart failure as defined by the New York Heart Association Functional Classification; or a history of myocardial infarction, unstable angina, or acute coronary syndrome within 6 months prior to randomization
- Unable to swallow capsules or malabsorption syndrome, disease significantly affecting gastrointestinal function, or resection of the stomach or small bowel, symptomatic inflammatory bowel disease or ulcerative colitis, or partial or complete bowel obstruction
- Lactating or pregnant
- Unwilling or unable to participate in all required study evaluations and procedures
- Unable to understand the purpose and risks of the study and to provide a signed and dated informed consent form (ICF) and authorization to use protected health information (in accordance with national and local subject privacy regulations)
- Patients receiving any other study agents
- Patients with known central nervous system (CNS) involvement
- Baseline Fridericia corrected QT (QTcF) > 480 ms; NOTE: this criterion does not apply to patients with a left bundle branch block
- Patients who require warfarin or other vitamin K antagonists for anticoagulation (other anticoagulants are allowed after consultation with the principal investigator)
- Concurrent administration of medications or foods that are strong inhibitors or inducers of cytochrome P450, family 3, subfamily A (CYP3A)
- Patients with ongoing use of prophylactic antibiotics are eligible as long as there is no evidence of active infection and the antibiotic is not included on the list of prohibited medications
- Significant co-morbid condition or disease which in the judgment of the principal investigator would place the patient at undue risk or interfere with the study
Study sponsor and potential other locations can be found on ClinicalTrials.gov for NCT02537613.
PRIMARY OBJECTIVE:
I. To assess the safety of 3 different dosing regimens of ibrutinib plus obinutuzumab in patients with relapsed or refractory chronic lymphocytic leukemia (CLL).
SECONDARY OBJECTIVES:
I. To assess the efficacy of ibrutinib plus obinutuzumab in patients with relapsed/refractory CLL as measured by:
Ia. Overall response rate (ORR), partial response (PR), complete response (CR).
Ib. Minimal residual disease (MRD) status in the bone marrow and blood.
Ic. Duration of response (DOR), 2-year progression free survival (PFS), 2-year overall survival (OS).
II. To further characterize the safety of ibrutinib plus obinutuzumab in relapsed/refractory CLL.
III. To evaluate the association of established CLL prognostic factors such as fluorescence in situ hybridization (FISH) cytogenetics, immunoglobulin heavy chain variable (IGHV) mutation status, ZAP-70, and TP53 mutation status with clinical response.
EXPLORATORY OBJECTIVES:
I. To assess BH3 profiling as a predictive biomarker for this therapy.
II. To assess the association of genomic markers such as SF3B1, NOTCH1, and BCR/NFKB pathway somatic mutation with clinical response.
III. To evaluate for resistance mechanisms such as BTK mutation or changes in CD20 expression in patients who progress on treatment.
IV. To determine whether the rates of developing such resistance mechanisms differ depending on the sequence of therapy administration.
OUTLINE: This is a dose-escalation study of obinutuzumab. Patients are randomized to 1 of 3 arms.
ARM I (CLOSED TO ACCRUAL): Patients receive obinutuzumab intravenously (IV) over 4 hours on days 1, 2, 8 and 15 of cycle 1. Patients then receive ibrutinib orally (PO) once daily (QD) on days 1-28 and obinutuzumab IV over 4 hours on day 1. Treatment with ibrutinib repeats every 28 days in the absence of disease progression or unacceptable toxicity and treatment with obinutuzumab repeats every 28 days for up to 6 cycles in the absence of disease progression or unacceptable toxicity.
ARM II: Patients receive ibrutinib PO QD on days 1-28 for 1 cycle. Patients then receive ibrutinib PO QD on days 1-28 and obinutuzumab IV over 4 hours on day 1, 2, 8 and 15 of cycle 2 and day 1 of subsequent cycles. Treatment with ibrutinib repeats every 28 days in the absence of disease progression or unacceptable toxicity and treatment with obinutuzumab repeats every 28 days for up to 6 cycles in the absence of disease progression or unacceptable toxicity.
ARM III: Patients receive ibrutinib PO QD on days 1-28 and obinutuzumab IV over 4 hours on days 1, 2, 8 and 15 of cycle 1 and day 1 of subsequent cycles. Treatment with ibrutinib repeats every 28 days in the absence of disease progression or unacceptable toxicity and treatment with obinutuzumab repeats every 28 days for up to 6 cycles in the absence of disease progression or unacceptable toxicity.
After completion of study treatment, patients are followed up periodically.
Trial PhasePhase I
Trial Typetreatment
Lead OrganizationDana-Farber Harvard Cancer Center
Principal InvestigatorMatthew Steven Davids
- Primary ID15-283
- Secondary IDsNCI-2015-02275, ML29416
- ClinicalTrials.gov IDNCT02537613