PRIMARY OBJECTIVES:
I. To evaluate the response rate of ibrutinib plus rituximab in patients with relapsed and/or
refractory mantle cell lymphoma (MCL).
II. To evaluate the safety and response rate of ibrutinib plus rituximab in elderly patients
(> 65) with newly-diagnosed, untreated MCL.
SECONDARY OBJECTIVES:
I. To further evaluate the toxicity profile of the combination of ibrutinib and rituximab in
patients with relapsed and/or refractory MCL.
II. To estimate the overall response rate (ORR); (partial response [PR] or better), the
response duration (DOR), progression-free survival (PFS), time to progression (TTP) and
overall survival (OS) in patients with relapsed and/or refractory MCL; clinical benefit
response (CBR) = (minimal response [MR] + ORR) will also be evaluated.
III. To estimate the response duration, PFS, time to progression (TTP), and OS in elderly
patients (> 65) with newly-diagnosed, untreated MCL.
EXPLORATORY OBJECTIVES:
I. To correlate detected gene mutations and changes in gene and/or protein expression with
response to treatment.
OUTLINE:
Patients receive ibrutinib orally (PO) daily on days 1-28 and rituximab intravenously (IV)
over 4-8 hours on days 1, 8, 15, and 22 of course 1; on day 1 of courses 3-8; and on day 1 of
every other course for all subsequent courses. Treatment with rituximab repeats every 28 days
for up to 2 years in the absence of disease progression or unacceptable toxicity. Courses
with ibrutinib repeat every 28 days in the absence of disease progression or unacceptable
toxicity.
After completion of study treatment, patients are followed up every 3 months for 1 year and
then every 6 months thereafter.
Inclusion Criteria:
- Relapsed/refractory MCL: Confirmed diagnosis of mantle cell lymphoma with cluster of
differentiation (CD)20 and cyclin D1 through cyclin D3 positivity in tissue biopsy
- Relapsed/refractory MCL: Patient has relapsed and or refractory MCL and must have
received at least one prior treatment regimen for their disease; patient with leukemia
phase (peripheral blood involvement), leptomeningeal disease, cerebral spinal fluid
(CSF) MCL, central nervous system (CNS) MCL, non-measurable disease, gastrointestinal
(GI) MCL, or bone marrow (BM) MCL are also eligible
- Relapsed/refractory MCL: Understand and voluntarily sign an Institutional Review Board
(IRB)-approved informed consent form
- Relapsed/refractory MCL: Patients with bone marrow or gastrointestinal (GI) only
involvement are acceptable
- Relapsed/refractory MCL: Eastern Cooperative Oncology Group (ECOG) performance status
of 2 or less
- Relapsed/refractory MCL: Absolute neutrophil count (ANC) >= 500/mm^3; (patients who
have bone marrow infiltration by MCL are eligible if their ANC is >= 500/mm^3 [growth
factor allowed]; these patients should be discussed with either the principal
investigator [PI] or Co-PI of the study for final approval)
- Relapsed/refractory MCL: Platelet count >= 30,000/mm^3 (transfusion to reach platelet
count allowed); (patients who have bone marrow infiltration by MCL are eligible if
their platelet level is equal to or > than 15,000/mm^3; these patients should be
discussed with either the PI or Co-PI of the study for final approval)
- Relapsed/refractory MCL: Aspartate transaminase (AST) (serum glutamic oxaloacetic
transaminase [SGOT]) and alanine transaminase (ALT) (serum glutamate pyruvate
transaminase [SGPT]) < 2 x upper limit of normal or < 5 x upper limit of normal if
hepatic metastases are present
- Relapsed/refractory MCL: Serum bilirubin < 1.5 mg/dl
- Relapsed/refractory MCL: Creatinine (Cr) clearance >= 30 mL/min
- Relapsed/refractory MCL: Patients must be willing to receive transfusions of blood
products
- Relapsed/refractory MCL: Willing and able to participate in all study related
procedures and therapy including swallowing capsules without difficulty
- Newly diagnosed MCL: Confirmed diagnosis of MCL with CD20 and cyclin D1 positivity in
tissue biopsy; patients must have never received any prior therapy for their disease
- Newly diagnosed MCL: Understand and voluntarily sign an IRB-approved informed consent
form
- Newly diagnosed MCL: Age > 65 years at the time of signing the informed consent
- Newly diagnosed MCL: Patients should in general have bi-dimensional measurable disease
with their biggest tumor less than 10 cm; (bone marrow or gastrointestinal [GI] only
involvement is acceptable)
- Newly diagnosed MCL: Eastern Cooperative Oncology Group (ECOG) performance status of 2
or less
- Newly diagnosed MCL: Absolute neutrophil count (ANC) > 750/mm^3; patients who have
bone marrow infiltration by MCL are eligible if their ANC is equal to or > than 500
- Newly diagnosed MCL: Platelet count > 50,000/mm^3; patients who have bone marrow
infiltration by MCL are eligible if their platelet level is equal to or > than 15,000
/mm^3; (platelet transfusions are allowed; these patients should be discussed with
either the PI or Co-PI of the study for final approval)
- Newly diagnosed MCL: AST (SGOT) and ALT (SGPT) < 2 x upper limit of normal or < 5 x
upper limit of normal if hepatic metastases are present
- Newly diagnosed MCL: Uric acid within normal limits (allopurinol is allowed to bring
abnormal level to within normal limits)
- Newly diagnosed MCL: Serum bilirubin < 1.5 mg/dl
- Newly diagnosed MCL: Creatinine (Cr) Clearance >= 30 mL/min
- Newly diagnosed MCL: Ki67 protein (Ki67) < 50%
- Newly diagnosed MCL: Disease free of prior malignancies of equal to or greater than 6
months with exception of currently treated basal cell, squamous cell carcinoma of the
skin, carcinoma "in situ" of the cervix or breast, or other malignancies in remission
(including prostate cancer patients in remission from radiation therapy, surgery or
brachytherapy), not actively being treated, with a life expectancy > 3 years
- Newly diagnosed MCL: Patients must be willing to receive transfusions of blood
products
- Newly diagnosed MCL: Willing and able to participate in all study related procedures
and therapy including swallowing capsules without difficulty
Exclusion Criteria:
- Relapsed/refractory MCL: Any serious medical condition that places the patient at
unacceptable risk and/or would prevent the subject from signing the informed consent
form; examples include but are not limited to, uncontrolled hypertension, uncontrolled
diabetes mellitus, active/symptomatic coronary artery disease, active infection,
active hemorrhage, or psychiatric illness
- Relapsed/refractory MCL: Pregnant or breast feeding females
- Relapsed/refractory MCL: Known human immunodeficiency virus (HIV) infection; patients
with active hepatitis B infection (not including patients with prior hepatitis B
vaccination; or positive serum hepatitis B antibody); known hepatitis C infection is
allowed as long as there is no active disease and is cleared by gastrointestinal (GI)
consultation
- Relapsed/refractory MCL: The patient has a prior or concurrent malignancy that in the
opinion of the investigator, presents a greater risk to the patient's health and
survival, than of the MCL, within the subsequent 6 months at the time of consent
- Relapsed/refractory MCL: History of stroke or intracranial hemorrhage within 6 months
prior to signing the consent
- Relapsed/refractory MCL: Clinically significant cardiovascular disease such as
uncontrolled or symptomatic arrhythmias, congestive heart failure or myocardial
infarction within 6 months at the time of consent or any class 3 (moderate) or 4
(severe) cardiac disease defined by the New York Heart Association classification
- Relapsed/refractory MCL: Significant screening electrocardiogram (ECG) abnormalities
including left bundle branch block, 2nd degree atrioventricular (AV) block type II,
3rd degree block, bradycardia (< 50 beats per minute [bpm]), or corrected QT (QTc) >
500 msec
- Relapsed/refractory MCL: Malabsorption syndrome, disease significantly affecting
gastrointestinal function, or resection of the stomach or small bowel or ulcerative
colitis, symptomatic inflammatory bowel disease, or partial or complete bowel
obstruction
- Relapsed/refractory MCL: Prior chemotherapy within 3 weeks, nitrosoureas within 6
weeks, therapeutic anticancer antibodies within 4 weeks, radio- or
toxin-immunoconjugates within 10 weeks, radiation therapy or other investigational
agents within 3 weeks, major surgery within 4 weeks or vaccination with live
attenuated vaccines within 4 weeks of the first dose of study drug
- Relapsed/refractory MCL: Prior treatment with ibrutinib
- Relapsed/refractory MCL: Requires anticoagulation with warfarin or equivalent vitamin
K antagonist
- Relapsed/refractory MCL: Requires treatment with strong cytochrome P450, family 3,
subfamily A, polypeptide 4/5 (CYP3A4/5) inhibitors
- Newly Diagnosed MCL: Any serious medical condition that places the patient at
unacceptable risk and/or would prevent the subject from signing the informed consent
form; examples include but are not limited to, uncontrolled hypertension, uncontrolled
diabetes mellitus, active/symptomatic coronary artery disease, active infection
requiring treatment with systemic antibiotics, antiviral or antifungal agents, active
hemorrhage, or psychiatric illness
- Newly diagnosed MCL: Known HIV infection; patients with active hepatitis B infection
(not including patients with prior hepatitis B vaccination; or positive serum
Hepatitis B antibody); known hepatitis C infection is allowed as long as there is no
active disease and is cleared by GI consultation
- Newly diagnosed MCL: The patient has a prior or concurrent malignancy that in the
opinion of the investigator, presents a greater risk to the patient's health and
survival, than of the MCL, within the subsequent 6 months at the time of consent
- Newly diagnosed MCL: History of stroke or intracranial hemorrhage within 6 months
prior to signing the consent
- Newly diagnosed MCL: Clinically significant cardiovascular disease such as
uncontrolled or symptomatic arrhythmias, congestive heart failure or myocardial
infarction within 6 months at the time of consent or any class 3 (moderate) or 4
(severe) cardiac disease defined by the New York Heart Association Classification
- Newly diagnosed MCL: Significant screening electrocardiogram (ECG) abnormalities
including left bundle branch block, 2nd degree AV block type II, 3rd degree block,
bradycardia (< 50 bpm), or QTc > 500 msec
- Newly diagnosed MCL: Malabsorption syndrome, disease significantly affecting
gastrointestinal function, or resection of the stomach or small bowel or ulcerative
colitis, symptomatic inflammatory bowel disease, or partial or complete bowel
obstruction
- Newly diagnosed MCL: Major surgery within 4 weeks or vaccination with live attenuated
vaccines within 4 weeks of the first dose of study drug
- Newly diagnosed MCL: Prior treatment with ibrutinib
- Newly diagnosed MCL: Requires concomitant anticoagulation with warfarin or equivalent
vitamin K antagonist
- Newly diagnosed MCL: Requires treatment with strong CYP3A4/5 inhibitors
- Newly diagnosed MCL: Patients with blastoid and pleomorphic variants
- Newly diagnosed MCL: Ki-67 to be equal or more than 50%
- Newly diagnosed MCL: Central nervous system lymphoma
- Newly diagnosed MCL: Patients with bi-dimensional measurable disease with a tumor >=
10 cm
