PRIMARY OBJECTIVE:
I. To evaluate the efficacy of acalabrutinib combined with rituximab and lenalidomide in
patients with previously untreated follicular lymphoma (FL) (determined by complete remission
[CR] rate by the end of treatment).
SECONDARY OBJECTIVES:
I. To evaluate the efficacy of acalabrutinib combined with rituximab and lenalidomide in
subjects with FL as assessed by objective response rate (ORR) at the end of treatment,
duration of response (DOR), progression rate within 24 months from treatment initiation
(progression-free survival [PFS] 24), PFS and overall survival (OS).
II. To evaluate the safety and tolerability of acalabrutinib combined with rituximab and
lenalidomide in previously untreated subjects with FL.
EXPLORATORY OBJECTIVE:
I. To determine the pharmacodynamic effects and investigate biomarkers of response and
resistance of the 3-drug combination.
OUTLINE:
Patients receive acalabrutinib orally (PO) twice daily (BID) on days 1-28. Beginning cycle 2,
patients receive lenalidomide PO once daily (QD) on days 1-21 and rituximab intravenously
(IV) on days 1, 8, 15, and 22 of cycle 2 and day 1 of subsequent cycles. Treatment repeats
every 28 days for 13 cycles 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 for 2 years.
Inclusion Criteria:
- Histologically confirmed CD20 positive (+) follicular lymphoma, grade 1, 2, or 3a
- 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)
- Meeting Groupe d'Etude des Lymphomes Folliculaires (GELF) criteria for initiation of
treatment
- Stage 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)
- Hemoglobin > 8 g/dL, independent of transfusion support (within 28 days prior to
signing informed consent)
- Serum aspartate transaminase (AST) or alanine transaminase (ALT) < 2 x upper limit of
normal (ULN) (within 28 days prior to signing informed consent)
- Creatinine clearance > 30 ml/min calculated by modified Cockcroft-Gault formula
(within 28 days prior to signing informed consent)
- 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 (within 28 days prior to signing informed consent)
- Prothrombin time (PT)/international normalized ratio (INR) < 1.5 x ULN and partial
thromboplastin time (PTT) < 1.5 x ULN (within 28 days prior to signing informed
consent)
- 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, and continued for at least 4 weeks after last dose of
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 Strategies (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 active 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 acalabrutinib or lenalidomide capsules, or put the study
outcomes at undue risk
- Known history of human immunodeficiency virus (HIV), or active hepatitis C Virus, or
active hepatitis B Virus infection, or any uncontrolled active significant infection,
including suspected or confirmed John Cunningham (JC) virus infection
- Patients with inactive hepatitis B infection must adhere to hepatitis B
reactivation prophylaxis unless contraindicated. Hepatitis B or C serologic
status: subjects who are hepatitis B core antibody (anti-HBc) positive and who
are surface antigen negative will need to have a negative polymerase chain
reaction (PCR). Those who are hepatitis B surface antigen (HbsAg) positive or
hepatitis B PCR positive will be excluded. Subjects who are hepatitis C antibody
positive will need to have a negative PCR result. Those who are hepatitis C PCR
positive will be excluded. Subjects with a history of Hepatitis C who received
antiviral treatment are eligible as long as PCR is negative
- 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 (Ig) E-mediated hypersensitivity to murine
proteins or to any component of acalabrutinib, lenalidomide and/or 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, for a list of 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. 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. Subjects with controlled,
asymptomatic atrial fibrillation during screening can enroll on study
- Significant screening electrocardiogram (ECG) abnormalities including left bundle
branch block, 2nd degree atrioventricular (AV) block, type II AV block, or 3rd degree
block
- Active bleeding or 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 28 days or minor surgery within 3
days of first dose of study drug
- Patients taking corticosteroids during the last 4 weeks, unless administered at a dose
equivalent to < 10 mg/day prednisone (over these 4 weeks)
- Life expectancy < 6 months
- Neuropathy > grade 1
- Prior exposure to lenalidomide or to a BCR inhibitor, independently from indication
- Patient who require treatment with proton pump inhibitors (e.g., omeprazole,
esomeprazole, lansoprazole, dexlansoprazole, rabeprazole, or pantoprazole), and are
unable to switch to H2-receptor antagonists
- Patients who have difficulty with or are unable to swallow oral medication, or have
disease significantly affecting gastrointestinal function that would limit absorption
of oral medication
- Uncontrolled autoimmune hemolytic anemia (AIHA) or idiopathic thrombocytopenic purpura
(ITP)
- Known history of deep vein thrombosis or pulmonary embolism
- Known history of Stevens-Johnson syndrome (SJS) or toxic epidermal necrolysis (TEN) or
drug rash with eosinophilia and systemic symptoms (DRESS)
