PRIMARY OBJECTIVE:
I. To determine if treatment acalabrutinib and obinutuzumab is effective in patients with
untreated, low tumor burden follicular lymphoma and other indolent non-Hodgkin lymphomas
(NHLs).
SECONDARY OBJECTIVES:
I. Determine the complete response (CR) rate for single agent acalabrutinib at the end of a
single-agent run-in for patients with untreated low tumor burden follicular lymphoma (FL).
II. Determine tolerability of acalabrutinib and obinutuzumab via assessment of
patient-reported outcomes and conventional assessments.
III. Assess duration of response and long-term outcomes including progression-free survival.
IV. Assess the impact of early treatment with this regimen on health-related quality of life.
TERTIARY/EXPLORATORY OBJECTIVES:
I. Evaluate the impact of treatment discontinuation in patients who have achieved a complete
response at the end of the induction phase.
II. To assess the safety and efficacy of acalabrutinib and obinutuzumab in other subtypes of
indolent NHL.
OUTLINE:
INDUCTION PHASE: Patients receive acalabrutinib orally (PO) twice daily (BID) on days 1-28.
Patients also receive obinutuzumab intravenously (IV) on days 1, 8, and 15 of cycle 3, then
on day 1 of cycles 4-8. Treatments repeat every 28 days for up to 12 cycles in the absence of
disease progression or unacceptable toxicity.
FOLLOW-UP PHASE: After cycle 12, patients who are in CR are randomized to either discontinue
acalabrutinib or to continue acalabrutinib monotherapy in the absence of disease progression
or unacceptable toxicity. Patients with partial response (PR) or stable disease (SD) after
cycle 12 continue acalabrutinib monotherapy in the absence of disease progression or
unacceptable toxicity. Patients with disease progression after cycle 12 discontinue study
treatment. Patients with disease progression at any time prior to the conclusion of cycle 12
may continue study therapy if they are felt to be benefiting by the treating physician, but
not past cycle 12.
After completion of study treatment, patients are followed up at 30 days, every 12 weeks for
1 year, then every 6 months until disease progression or next anti-lymphoma treatment.
Inclusion Criteria:
- Men and women >= 18 years of age
- Patients will need to have one of the following clinical scenarios:
- Previously untreated follicular lymphoma grade 1-3a with low tumor burden by
Groupe d'Etude des Lymphomes Folliculaires (GELF) criteria
- Previously untreated follicular lymphoma grade 1-3a with high tumor burden by
GELF criteria but who are unable or unwilling to receive standard front-line
treatment approaches
- Previously untreated marginal zone lymphoma, lymphoplasmacytic lymphoma, or any
other indolent B-cell lymphoproliferative disorder with low tumor burden by GELF
criteria or who are unable/unwilling to receive more intensive front-line
treatment
- Previously untreated mantle cell lymphoma who would otherwise be appropriate
candidates for watchful waiting OR who have symptomatic disease but are not
candidates for or decline standard induction approaches
- Patients with previously untreated low tumor burden FL (criterion above) must have
measurable and/or assessable disease defined as at least one involved lymph node or
extranodal disease site that measures >= 1.5cm in greatest diameter
- Patients who meet inclusion criteria above are eligible as long as they meet one of
the following criteria for measurable/assessable disease:
- At least one involved lymph node or extranodal disease site measuring > 1.5cm in
greatest diameter
- Pathologically-confirmed bone marrow or peripheral blood involvement that can be
reassessed for response
- Pathologically confirmed splenic or extranodal involvement with at least one
known site of disease remaining after diagnostic biopsy that can be reassessed
(i.e., patients with splenic marginal zone lymphoma who complete splenectomy and
have no other detectable disease would not be eligible)
- Eastern Cooperative Oncology Group (ECOG) performance status of 0-2
- Woman of childbearing potential (WOCBP) and men enrolled on this protocol must agree
to use adequate contraception (hormonal or barrier method of birth control;
abstinence) prior to study entry for the duration of study participation, and for at
least 2 days after the last dose of acalabrutinib or 18 months after the last dose of
obinutuzumab, whichever is longer. Should a woman become pregnant or suspect she is
pregnant while she or her partner is participating in this study, she should inform
her treating physician immediately
- Women of childbearing potential must have a negative serum or urine pregnancy test
prior to starting therapy
- Willing and able to participate in all required evaluations and procedures in this
study protocol
- Ability to understand the purpose and risks of the study and provide signed and dated
informed consent and authorization to use protected health information Ability to
understand the purpose and risks of the study and provide signed and dated informed
consent and authorization to use protected health information
Exclusion Criteria:
- The presence or history of histologically transformed or co-existing high-grade or
aggressive non-Hodgkin lymphoma
- Confirmed active or prior central nervous system disease
- Prior receipt of lymphoma-directed therapy or prior antibody-based therapy (except for
anti-microbial therapy for infection-associated marginal zone lymphoma such as
hepatitis C or H pylori)
- A short course of steroids is permitted for patients aside from those in the low
tumor burden FL cohort. This course may be no more than 14 days and steroids must
be discontinued (or tapered to =< 10mg prednisone or equivalent) no later than 3
days after initiation of study treatment. Patients in the low tumor burden FL
cohort may not receive corticosteroids as an anti-lymphoma therapy at any time
before starting treatment
- Prior malignancy (or any other malignancy requiring active treatment), except for
adequately treated basal cell or squamous cell skin cancer, in situ cervical cancer,
or other cancer from which the subject has been disease free for >= 2 years or which
will not limit survival to < 5 years
- Clinically significant cardiovascular disease such as symptomatic ventricular
arrhythmias, congestive heart failure, or myocardial infarction within 6 months of
screening, or any class 3 or 4 cardiac disease as defined by the New York Heart
Association Functional Classification. Note: Subjects with controlled, asymptomatic
atrial fibrillation can enroll on study if deemed appropriate by the investigator
- Has difficulty with or is unable to swallow oral medication, or has significant
gastrointestinal disease that would limit absorption of oral medication
- Known history of human immunodeficiency (HIV) or any active significant infection
(e.g., bacterial, viral, or fungal) within 14 days of cycle 1. Patients with
uncomplicated viral or bacterial infections that are being managed with oral
antibiotics and/or supportive care alone are eligible
- Known history of hypersensitivity or anaphylaxis to study drug(s) including active
product or excipient components
- Active bleeding or history of bleeding diathesis (e.g., hemophilia or von Willebrand
disease)
- Uncontrolled AIHA (autoimmune hemolytic anemia) or ITP (idiopathic thrombocytopenic
purpura)
- Presence of a gastrointestinal ulcer diagnosed by endoscopy within 3 months before
screening
- Requires treatment with a strong cytochrome P450 3A4 (CYP3A4) inhibitor/inducer
- Requires or receiving anticoagulation with warfarin or equivalent vitamin K
antagonists
- Requires treatment with proton pump inhibitors (e.g, omeprazole, esomeprazole,
lansoprazole, dexlansoprazole, rabeprazole, or pantoprazole). Note: Subjects receiving
proton pump inhibitors who switch to H2-receptor antagonists or antacids are eligible
for enrollment to this study
- History of significant cerebrovascular disease/event, including stroke or intracranial
hemorrhage, within 6 months before the first dose of study drug. Patients with a
transient ischemic attack which has resolved and for which there are no ongoing
symptoms are eligible
- Major surgical procedure within 28 days of first dose of study drug (not including a
diagnostic procedure to make the lymphoma diagnosis). Note: If a subject had major
surgery, they must have recovered adequately from any toxicity and/or complications
from the intervention before the first dose of study drug
- Hepatitis B or C serologic status: subjects who are hepatitis B core antibody
(anti-HBc) positive and who are hepatitis B surface antigen (HBsAg) negative will need
to have a negative polymerase chain reaction (PCR) and must be willing to undergo
deoxyribonucleic acid (DNA) PCR testing during the study to be eligible. Those who are
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 to be eligible
and have completed appropriate anti-viral treatment. Those who are hepatitis C PCR
positive will be excluded. Anti-viral therapy for patients with hepatitis-C associated
marginal zone lymphoma will not be considered a prior anti-lymphoma treatment
- Absolute neutrophil count (ANC) < 1,000/mcL
- Platelet count < 50,000/mcL (Unless felt to be related to underlying disease)
- Total bilirubin >= 1.5 x the upper limit of normal (ULN). Isolated bilirubin > 1.5 x
ULN is permitted if the direct proportion is < 35%
- Aspartate aminotransferase (AST)/alanine aminotransferase (ALT) > 2.5 x ULN
- Creatinine clearance =< 40 mL/min/1.73m^2
- Breastfeeding or pregnant
- Concurrent participation in another therapeutic clinical trial
