PRIMARY OBJECTIVES:
I. To evaluate the efficacy of ibrutinib combined with rituximab and lenalidomide in patients
with previously untreated follicular lymphoma (FL) and marginal zone lymphoma (determined by
progression-free survival at 2 years).
SECONDARY OBJECTIVES:
I. To evaluate the efficacy of ibrutinib combined with rituximab and lenalidomide in subjects
with FL as assessed by complete response rate (CR) at 120 weeks, overall response rate (ORR),
duration of response (DOR), event free survival (EFS), time to next anti-lymphoma treatment
(TTNT), and overall survival (OS).
II. To evaluate the safety and tolerability of ibrutinib combined with rituximab and
lenalidomide in previously untreated subjects with FL and marginal zone lymphoma.
EXPLORATORY OBJECTIVES:
I. To evaluate prognostic and mechanistic biomarkers relative to treatment outcomes.
OUTLINE:
Patients receive lenalidomide orally (PO) on days 1-21, rituximab intravenously (IV) over 4-6
hours on days 1, 8, 15, and 22 of cycle 1 and day 1 of all subsequent cycles, and ibrutinib
PO once daily (QD) on days 1-28. Treatment repeats every 28 days for up to 12 cycles in the
absence of disease progression or unacceptable toxicity.
After completion of study treatment, patients are followed up every 12 weeks for 1 year and
then every 24 weeks for 2 years.
Inclusion Criteria:
- Histologically confirmed CD20+ follicular lymphoma, grade 1, 2, or 3a or marginal zone
lymphoma
- Have had no prior systemic treatment for lymphoma
- Bi-dimensionally measurable disease, with at least one mass lesion >= 2 cm in longest
diameter by computed tomography (CT), positron emission tomography (PET)/CT, and/or
magnetic resonance imaging (MRI)
- In the opinion of the investigator would benefit from systemic therapy
- Stage II, III, or IV disease
- Eastern Cooperative Oncology Group (ECOG) performance status =< 2
- Absolute neutrophil count (ANC) >= 1,000/mm^3, independent of growth factor support
(within 28 days prior to signing informed consent).
- Platelet counts >= 100,000/mm^3 or >= 50,000/mm^3 if bone marrow involvement with
lymphoma, independent of transfusion support in either situation (within 28 days prior
to signing informed consent).
- Serum aspartate transaminase (AST) or alanine transaminase (ALT) < 3 x upper limit of
normal (ULN)
- Creatinine clearance > 30 ml/min calculated by modified Cockcroft-Gault formula
- Bilirubin < 1.5 x ULN unless bilirubin is due to Gilbert's syndrome, documented liver
involvement with lymphoma, or of non-hepatic origin, in which case bilirubin should
not exceed 3 g/dL
- Prothrombin time (PT)/international normalized ratio (INR) < 1.5 x ULN and partial
thromboplastin time (PTT) < 1.5 x ULN
- Must be able to adhere to the study visit schedule and other protocol requirements
- 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; females of
childbearing potential: must either completely abstain from heterosexual sexual
conduct or must use 2 methods of reliable contraception, 1 highly effective
(intrauterine device, birth control pills, hormonal patches, injections, vaginal
rings, or implants) and at least 1 additional method (condom, diaphragm, cervical cap)
of birth control; reliable contraceptive methods must be started at least 4 weeks
before lenalidomide; males who are sexually active must be practicing complete
abstinence or agree to a condom during sexual contact with a pregnant female or female
of child bearing potential; men must agree to not donate sperm during and after the
study; for females, these restrictions apply at least 4 weeks before study treatment,
during the period of therapy and for 1 month after the last dose of study drug; for
males, these restrictions apply during the period of therapy and 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]) pregnancy test at screening; women who are pregnant or
breastfeeding are ineligible for this study; females of reproductive potential must
adhere to the scheduled pregnancy testing as required in the Revlimid Risk Evaluation
and Mitigation Strategy (REMS) program
- 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
- All study participants must be registered into the mandatory Revlimid REMS program,
and be willing and able to comply with the requirements of the REMS program
Exclusion Criteria:
- Known central nervous system lymphoma or leptomeningeal disease, except subjects with
a history of central nervous system lymphoma treated and in remission > 6 months
- Evidence of diffuse large B-cell transformation
- Grade 3b FL
- Any prior history of other malignancy besides FL or marginal zone lymphoma, unless the
patient has been free of disease for >= 5 years and felt to be at low risk for
recurrence by the treating physician, except:
- Adequately treated non-melanoma skin cancer or lentigo maligna without evidence
of disease
- Adequately treated cervical carcinoma in situ without evidence of disease
- 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, including but not limited to:
- Moderate to severe hepatic impairment (Child-Pugh classes B and C)
- Known history of human immunodeficiency virus (HIV) or active hepatitis C virus or
active hepatitis B virus infection, or any uncontrolled active systemic infection
- Patients with inactive hepatitis B infection must adhere to hepatitis B
reactivation prophylaxis unless contraindicated
- Prior use of ibrutinib or other BTK inhibitors, rituximab or lenalidomide
- Concurrent systemic immunosuppressant therapy (e.g., cyclosporine, tacrolimus, etc.,
or chronic administration glucocorticoid equivalent of > 10 mg/day of prednisone)
within 28 days of the first dose of study drug
- Known anaphylaxis or immunoglobulin E (IgE)-mediated hypersensitivity to murine
proteins or to any component of rituximab
- Requires anticoagulation with warfarin or equivalent vitamin K antagonists (e.g.,
phenprocoumon); if patients have been on warfarin or equivalent vitamin K antagonists
in the past, they will not be eligible if administered within 30 days of the first
dose of study drug
- Requires chronic treatment with strong CYP3A inhibitors; if patients have been on a
strong CYP3A inhibitor in the past, they will not be eligible if the CYP3A inhibitor
was administered within 7 days of the first dose of study drug
- Requires chronic treatment with strong CYP3A inducers, for a list of strong CYP3A
inducers, see the protocol. If patients have been on a strong CYP3A inducer in the
past, they will not be eligible if the CYP3A inducer was administered within 7 days of
the first dose of study drug
- 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
- Significant screening electrocardiogram (ECG) abnormalities including left bundle
branch block, 2nd degree atrioventricular (AV) block, type II AV block, or 3rd degree
block
- Known bleeding diathesis (e.g., von Willebrand's disease) or hemophilia
- History of stroke or intracranial hemorrhage within 6 months prior to study entry
- Vaccinated with live, attenuated vaccines within 4 weeks of study entry
- Lactating or pregnant subjects
- Administration of any investigational agent within 28 days of first dose of study drug
- Patients who have undergone major surgery within 7 days or minor surgery within 3 days
of first dose of study drug
