PRIMARY OBJECTIVE:
I. Evaluate the anti-tumor activity of acalabrutinib, umbralisib and ublituximab (AU2)
regimen as induction therapy in patients with treatment-naïve mantle cell lymphoma (MCL), as
assessed by the complete response (CR) rate.
SECONDARY OBJECTIVES:
I. Evaluate the overall response rate (ORR) to AU2 in treatment-naive MCL. II. Evaluate the
progression-free survival (PFS), overall survival (OS) and duration of response (DOR) in
patients with treatment-naïve MCL who received AU2.
III. Evaluate the safety and tolerability of AU2 in patients with treatment-naive MCL.
EXPLORATORY OBJECTIVES:
I. Examine the T-cell populations and functionality in patients treated with AU2.
II. Explore the predictive value of minimal residual disease (MRD) in MCL. III. Explore the
mechanisms of resistance to AU2 therapy.
OUTLINE:
INDUCTION: Patients receive ublituximab intravenously (IV) over 90 minutes-4 hours on days 1,
8, and 15 of cycle 1 and days 1 of cycles 2-6. Patients also receive acalabrutinib orally
(PO) twice daily (BID) and umbralisib PO once daily (QD) on days 1-28. Treatment repeats
every 28 days for 6 cycles in the absence of disease progression or unacceptable toxicity.
MAINTENANCE: Patients receive ublituximab IV on day 1 on cycles 8, 10, 12, 14, 16, 18, 20,
22, 24, 26, 28, 30. Patients also receive acalabrutinib Po BID and umbralisib PO QD on day
1-28. Treatment repeats every 28 days for 24 cycles in the absence of disease progression of
unacceptable toxicity.
After completion of study treatment, patients are followed up for 30 days and then every 6
months for 2 years.
Inclusion Criteria:
- Documented informed consent of the participant and/or legally authorized
representative
- Assent, when appropriate, will be obtained per institutional guidelines
- Histologically confirmed mantle cell lymphoma with documentation of monoclonal CD20+ B
cells that have a chromosome translocation t(11;14)(q13;q32) and/or overexpress cyclin
D1
- Age >= 65 years; or >= 50 years and deemed ineligible for aggressive induction therapy
or autologous stem cell transplant by the investigator, or unwilling to undergo
aggressive induction; or >= 18 years with documented del(17p), or TP53 mutation, or
complex karyotype (CK) by cytogenetics and/or fluorescence in situ hybridization
(FISH) studies
- Requiring treatment for MCL, and for which no prior systemic anticancer therapies have
been received (local radiotherapy not exceeding a total dose of 20 Gy at least 2 weeks
prior the first dose of study therapy is allowed)
- Measurable disease by computed tomography (CT) or positron emission tomography
(PET)/CT scan with one or more sites of disease >= 1.5 cm in longest dimension
(including splenomegaly), or bone marrow involvement with or without malignant
lymphocytosis
- Without bone marrow involvement: Absolute neutrophil count (ANC) >= 1000/mm^3
- NOTE: Growth factor is not permitted within 7 days of ANC assessment unless
cytopenia is secondary to disease involvement
- With bone marrow involvement: ANC >= 500/mm^3
- NOTE: Growth factor is not permitted within 7 days of ANC assessment unless
cytopenia is secondary to disease involvement
- Without bone marrow involvement: Platelets >= 75,000/mm^3
- NOTE: Platelet transfusions are not permitted within 7 days of platelet
assessment unless cytopenia is secondary to disease involvement
- With bone marrow involvement: Platelets >= 30,000/mm^3
- NOTE: Platelet transfusions are not permitted within 7 days of platelet
assessment unless cytopenia is secondary to disease involvement
- Total bilirubin =< 1.5 X upper limit of normal (ULN) or =< 3X ULN for Gilbert's
disease
- Aspartate aminotransferase (AST) =< 2.5 x ULN
- Alanine aminotransferase (ALT) =< 2.5 x ULN
- Creatinine clearance of >= 30 mL/min per 24 hour urine test or the Cockcroft-Gault
formula
- If not receiving anticoagulants: International normalized ratio (INR) OR prothrombin
(PT) =< 1.5 x ULN. If on anticoagulant therapy: PT must be within therapeutic range of
intended use of anticoagulants
- If not receiving anticoagulants: Activated partial thromboplastin time (aPTT) =< 1.5 x
ULN. If on anticoagulant therapy: aPTT must be within therapeutic range of intended
use of anticoagulants
- Left ventricular ejection fraction (LVEF) >= 40%
- Women of childbearing potential (WOCBP): negative serum pregnancy test
- Agreement by females and males of childbearing potential to use an highly effective
method of birth control or abstain from heterosexual activity for the course of the
study through at least 2 days after the last dose of acalabrutinib for females, and at
least 4 months after the last dose of ublituximab or umbralisib, whichever comes
later, for both men and women
- Childbearing potential defined as not being surgically sterilized (men and women)
or have not been free from menses for > 1 year (women only)
Exclusion Criteria:
- Chronic use of corticosteroids >= 20 mg/day (short-term use of steroids < 14 days is
allowed)
- Major surgical procedure within 28 days of start of protocol therapy. 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
- Known history of hypersensitivity or anaphylaxis to study drug(s) including active
product or excipient components
- Concurrent participation in another therapeutic clinical trial
- Subjects for whom the goal of therapy is tumor debulking before stem cell transplant
- History of prior malignancy. Exceptions include malignancy treated with curative
intent and no known active disease present for >= 2 years prior to initiation of
protocol therapy; adequately treated non-melanoma skin cancer or lentigo maligna
(melanoma in situ) without evidence of disease; adequately treated in situ carcinomas
(e.g., cervical, esophageal, etc.) without evidence of disease; asymptomatic prostate
cancer managed with "watch and wait" strategy
- Uncontrolled AIHA (autoimmune hemolytic anemia) or ITP (idiopathic thrombocytopenic
purpura)
- Requires treatment with proton pump inhibitors (e.g., omeprazole, esomeprazole,
lansoprazole, dexlansoprazole, rabeprazole, or pantoprazole). Subjects receiving
proton pump inhibitors who switch to H2-receptor antagonists or antacids are eligible
for enrollment to this study
- Requires treatment with a strong cytochrome P450 3A4 (CYP3A4) inhibitor/inducer
- Requires or receiving anticoagulation with warfarin or equivalent vitamin K
antagonists
- Malabsorption syndrome, disease significantly affecting gastrointestinal function, or
resection of the stomach or small bowel that is likely to affect absorption,
symptomatic inflammatory bowel disease, partial or complete bowel obstruction, or
gastric restrictions and bariatric surgery, such as gastric bypass
- Presence of a gastrointestinal ulcer diagnosed by endoscopy within 3 months before
screening
- Known bleeding disorders (e.g., von Willebrand's disease or hemophilia)
- History of significant cerebrovascular disease/event, including stroke, myocardial
infarction or intracranial hemorrhage, within 6 months prior to start of protocol
therapy
- Known active central nervous system (CNS) involvement by lymphoma, including
leptomeningeal involvement
- Clinically significant cardiovascular disease such as symptomatic arrhythmias,
congestive heart failure, or myocardial infarction within 6 months of screening, or
any class III or IV cardiac disease as defined by the New York Heart Association
Functional Classification. Note: Subjects with controlled, asymptomatic atrial
fibrillation can enroll on study
- Unstable angina (angina symptoms at rest), new-onset angina (begun within the last 6
months)
- History of or current progressive multifocal leukoencephalopathy (PML)
- Inability to swallow and retain an oral medication
- Clinically significant uncontrolled illness, including active infection requiring
antibiotics
- Live virus vaccines within 4 weeks of start of protocol therapy or planned
administration of live virus vaccines during ublituximab therapy
- Evidence of chronic active hepatitis B (HBV, not including patients with prior
hepatitis B vaccination; or positive serum Hepatitis B antibody) or chronic active
hepatitis C infection (HCV), or active cytomegalovirus (CMV). If hepatitis B virus
core (HBc) antibody is positive, the subject must be evaluated for the presence of HBV
deoxyribonucleic acid (DNA) by polymerase chain reaction (PCR). If HCV antibody is
positive, the subject must be evaluated for the presence of HCV RNA by PCR. If the
subject is CMV IgG or CMV IgM positive, the subject must be evaluated for the presence
of CMV DNA by PCR. Subjects with positive HBc antibody and negative HBV DNA by PCR are
eligible. Subjects with positive HCV antibody and negative HCV RNA by PCR are
eligible. Subjects who are CMV IgG or CMV IgM positive but who are CMV DNA negative by
PCR are eligible. Patients with a prior known history of hepatitis B and those with a
positive anti-HBc with negative hepatitis B surface antigen (HBsAg) at screening must
be able to receive antiviral agents effective against hepatitis B
- Known history of human immunodeficiency virus (HIV) infection
- Females only: Pregnant or breastfeeding
- Any other condition that would, in the Investigator's judgment, contraindicate the
patient's participation in the clinical study due to safety concerns with clinical
study procedures
- Prospective participants who, in the opinion of the investigator, may not be able to
comply with all study procedures (including compliance issues related to
feasibility/logistics)
