PRIMARY OBJECTIVES:
I. To characterize the safety of treatment with daratumumab and ibrutinib for previously
untreated chronic lymphocytic leukemia (CLL).
II. To determine the complete response rate (CR) at the post cycle 12 response assessment
following treatment with daratumumab and ibrutinib for previously untreated chronic
lymphocytic leukemia (CLL).
SECONDARY OBJECTIVES:
I. To characterize the activity of daratumumab and ibrutinib as measured by overall response
rate (ORR), duration of response (DOR), progression-free survival (PFS), overall survival
(OS), and time-to-next treatment.
TERTIARY OBJECTIVES:
I. To measure pharmacodynamic parameters in B cells including drug occupancy of BTK and B
cell receptor signaling during treatment.
II. To determine the influence of this combination on T cell and natural killer (NK) cell
number and function.
III. To assess for development of mutations that may confer resistance to this combination.
IV. To assess the ability of daratumumab to clear CLL in the peripheral blood and association
of CD38 expression on CLL cells with response.
OUTLINE:
Patients receive daratumumab intravenously (IV) on days 1, 8, 15, and 22 of courses 1-2, days
1 and 15 of courses 3-6, and day 1 of subsequent courses. Treatment repeats every 28 days for
up to 12 courses in the absence of disease progression or unacceptable toxicity. Beginning
course 2, patients also receive ibrutinib orally (PO) once daily (QD) on days 1-28. Courses
repeat every 28 days in the absence of disease progression or unacceptable toxicity.
After completion of study treatment, patients are followed up every 12 weeks for up to 2
years.
Inclusion Criteria:
- Diagnosis of chronic lymphocytic leukemia (CLL) meeting criteria established in the
International Workshop on Chronic Lymphocytic Leukemia (IWCLL) 2008 criteria for the
diagnosis and treatment of CLL
- Requires therapy for symptomatic CLL in the opinion of the treating physician as
defined by:
- Evidence of marrow failure as manifested by the development or worsening of
anemia or thrombocytopenia (not attributable to autoimmune hemolytic anemia or
thrombocytopenia)
- Massive (>= 6 cm below the costal margin), progressive or symptomatic
splenomegaly
- Massive nodes (>= 10 cm) or progressive or symptomatic lymphadenopathy
- Constitutional symptoms, which include any of the following:
- Unintentional weight loss of 10% or more within 6 months
- Significant fatigue limiting activity
- Fevers >= 100.5 degrees Fahrenheit (F) for 2 weeks or more without evidence
of infection
- Night sweats > 1 month without evidence of infection
- No prior chemotherapy, immunotherapy, or targeted therapy for the treatment of CLL
with the exception of palliative loco-regional radiotherapy and corticosteroids for
symptom control
- Eastern Cooperative Oncology Group (ECOG) performance status =< 2
- Hemoglobin >= 8 g/dL
- Absolute neutrophil count (ANC) >= 1000/mm^3
- Platelets >= 30,000/mm^3
- Prothrombin time (PT)/partial thromboplastin time (PTT) =< 1.5 x ULN
- Total bilirubin =<1.5 x ULN (excepting Gilbert?s syndrome)
- Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =< 3 x ULN (unless
due to liver involvement)
- Serum creatinine < 2.0 mg/dL OR creatinine clearance (Cockcroft) >= 40 mL/min/1.73 m^2
- Women of childbearing potential and men who are sexually active must be practicing a
highly effective method of birth control during and after the study consistent with
local regulations regarding the use of birth control methods for subjects
participating in clinical trials; men must agree to not donate sperm during and after
the study; for females, these restrictions apply for 1 month after the last dose of
study drug; for males, these restrictions apply for 3 months after the last dose of
study drug
- Women of childbearing potential must have a negative serum (beta-human chorionic
gonadotropin [beta-hCG]) or urine pregnancy test at screening; women who are pregnant
or breastfeeding are ineligible for this study
- Sign (or their legally-acceptable representatives must sign) an informed consent
document indicating that they understand the purpose of and procedures required for
the study, including biomarkers, and are willing to participate in the study
- 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 virus 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 hepatitis B surface antigen (HBSAg) consistent with
prior vaccination to HBV (i.e., hepatitis B virus surface antibody
[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 virus (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)
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
- History of stroke or intracranial hemorrhage within 6 months prior to randomization
- Uncontrolled autoimmune hemolytic anemia or thrombocytopenia
- Active Richter's transformation
- Known active involvement of the central nervous system by lymphoma or leukemia
- Requires anticoagulation with warfarin or equivalent vitamin K antagonists (eg,
phenprocoumon); patients may be eligible if able to be taken off warfarin and started
on an alternative anticoagulant
- Requires chronic treatment with strong CYP3A inhibitors
- Known infection with the human immunodeficiency virus (HIV) virus
- Clinically significant cardiovascular disease such as uncontrolled or symptomatic
arrhythmias, congestive heart failure, or myocardial infarction within 6 months of
screening, or any class 3 (moderate) or class 4 (severe) cardiac disease as defined by
the New York Heart Association functional classification
- 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
- 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
- Known chronic obstructive pulmonary disease (COPD) (defined as a forced expiratory
volume in 1 second [FEV1] < 50% of predicted normal), persistent asthma, or a history
of poorly controlled asthma within the last 2 years (controlled intermittent asthma or
controlled mild persistent asthma is allowed)
- 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
- Any life-threatening illness, medical condition, or organ system dysfunction which, in
the investigator?s opinion, could compromise the subject?s safety, interfere with the
absorption or metabolism of ibrutinib capsules, or put the study outcomes at undue
risk
