PRIMARY OBJECTIVE:
I. To assess the overall response rate (ORR) at the end of 3 cycles of acalabrutinib.
SECONDARY OBJECTIVES:
I. To assess the proportion of patients that are progression free without any of the
following toxicities at the end of 3 cycles:
Ia. Recurrence of intolerable toxicities previously noted on ibrutinib. Ib. The occurrence of
intolerable toxicities related to acalabrutinib defined as: grade 4 neutropenia or
thrombocytopenia lasting greater than 7 days or any grade >= 3 non-hematologic toxicity as
assessed by the investigator to be related to study drug).
II. To determine the efficacy of acalabrutinib, progression free survival (PFS) and duration
of response (DOR) in patients.
III. To assess the safety profile of acalabrutinib in patient's intolerant to ibrutinib.
EXPLORATORY OBJECTIVE:
I. Sequential peripheral blood (PB)/plasma/tissue fine-needle aspiration (FNA) will be stored
for evaluation of:
Ia. Clonal evolution with targeted sequencing (seq) and/or whole exome sequencing (WES) in
sequential samples.
Ib. Pattern of mutation changes with acalabrutinib. Ic. Response predictors - mutations,
cytokine-chemokines. Id. Minimal residual disease (MRD) assay using flow cytometry (FC) and
circulating tumor-derived deoxyribonucleic acid (ctDNA) analysis.
Ie. Sequential immunologic studies with cytokines/chemokines, T cells and immunoglobulins.
OUTLINE:
Patients receive acalabrutinib orally (PO) twice daily (BID) on days 1-28. Treatment repeats
every 28 days for up to 36 cycles in the absence of disease progression or unacceptable
toxicity.
After completion of study treatment, patients are followed up every 4 months for 2 years,
every 6 months for 1 years, then annually for up to 3 years.
Inclusion Criteria:
- Confirmed diagnosis of mantle cell lymphoma with CD20 positivity and chromosome
translocation t(11;14), (q13;q32) and/or overexpress cyclin D1 in tissue biopsy
- Include patients who require treatment (versus watch/wait)
- Prior treatment with ibrutinib discontinued for reasons other than progression
- Ibrutinib intolerance is defined as unacceptable toxicity where, in the opinion of the
investigator, treatment should be discontinued in spite of optimal supportive care as
a result of one of the following:
- 2 or more grade >= 2 non-hematological toxicities; OR
- 1 or more grade 3 >= 3 non-hematological toxicity; OR
- 1 or more grade 3 neutropenia with infection or fever; OR,
- Grade 4 hematologic toxicity which persists to the point that the investigator
chose to stop therapy due to toxicity NOT progression
- Toxicity must have resolved to =< grade 1 prior to acalabrutinib dosing
- Understand and voluntarily sign an Institutional Review Board (IRB)-approved informed
consent form
- Bi-dimensional measurable disease using the Cheson criteria (measurable disease by
positron emission tomography [PET]-computed tomography [CT] scan defined as at least 1
lesion that measures >= 1.5 cm in single dimension). Gastrointestinal, bone marrow or
spleen only patients are allowable
- Eastern Cooperative Oncology Group (ECOG) performance status of 2 or less
- Absolute neutrophil count (ANC) > 1,000/mm^3
- Patients who have bone marrow infiltration by mantle cell lymphoma (MCL) are
eligible if their ANC is >= 500/mm^3 (growth factor allowed) or their platelet
level is equal to or > 20,000/mm^3. These patients should be discussed with
either the principal investigator (PI) or co-PI of the study for final approval
- Platelet count > 75,000/mm^3
- Patients who have bone marrow infiltration by MCL are eligible if their ANC is >=
500/mm^3 (growth factor allowed) or their platelet level is equal to or >
20,000/mm^3. These patients should be discussed with either the PI or co-PI of
the study for final approval
- Serum bilirubin < 1.5 mg/dl
- Creatinine (Cr) clearance minimum to 30 mL/min per the Cockcroft-Gault formula as
acalabrutinib pharmacokinetic (PK) has not been evaluated in patients with severe
renal impairment (estimated glomerular filtration rate [eGFR] < 29 mL/min/1.7 3^m2,
MDRD) or renal impairment requiring dialysis
- Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT]) and
alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) < 2.5 x
upper limit of normal or < 5 x upper limit of normal if hepatic metastases are
present. Gilbert's disease is allowed
- Disease free of prior malignancies 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 life
expectancy of > 3 years. PI can use clinical judgement in the best interest of
patients
- Women of childbearing potential (WOBP) must have a negative serum or urine pregnancy
test. WOBP and males must be willing to use highly effective methods of birth control
prior to starting therapy. Woman of childbearing potential (WOCBP) who are sexually
active must use highly effective methods of contraception during treatment and for one
week after the last dose of acalabrutinib. For male subjects with a pregnant or
non-pregnant WOCBP partner, should use barrier contraception even if they have had a
successful vasectomy
- Patients who were not placed originally on ibrutinib by the providers due to concerns
for worsening of comorbidities due to ibrutinib, such as atrial fibrillation can be
included after cardiology clearance
- Patients with well-controlled human immunodeficiency virus (HIV)/acquired
immunodeficiency syndrome (AIDS) would be eligible
Exclusion Criteria:
- Prior treatment with acalabrutinib
- History of BTK mutations conferring resistance to BTK inhibitors. Known mutations in
the BTK gene that confer resistance to ibrutinib in mantle cell lymphoma include (e.g.
BTK C481S, C481R mutations)
- Progressive disease while on ibrutinib therapy. Patients who progressed while on
ibrutinib therapy will be excluded from the study, patients who discontinue ibrutinib
due to anaphylaxis or hypersensitivity reaction related to ibrutinib will be excluded
from participation in the study
- Known history of drug-specific hypersensitivity or anaphylaxis to ibrutinib (including
active product or excipient components)
- Pregnant or breast-feeding females
- Patients with active hepatitis B infection. Those with prior hepatitis (hep)-B
vaccination (i.e., anti-HBs antibody positive) or natural immunity as evidenced by the
presence of anti-HBs and anti-HBc positivity are eligible to enroll. (Known hepatitis
C infection is allowed as long as there is no active disease and is cleared by
gastrointestinal [GI] consultation)
- Patients with central nervous system involvement with mantle cell lymphoma or with
suspected or confirmed progressive multifocal leukoencephalopathy (PML) are excluded
since those patients have very poor prognosis, need aggressive intensive
chemoimmunotherapy and intrathecal chemotherapy along with BTK inhibitors and these
patients would not be eligible for single agent acalabrutinib as proposed in this
study
- Active bleeding, history of bleeding diathesis (such as hemophilia or Von-Willebrand
disease), Any history of intracranial bleed or stroke within 6 months of first dose of
study drug
- Uncontrolled AIHA (autoimmune hemolytic anemia) or ITP (idiopathic thrombocytopenic
purpura)
- Ongoing adverse events from prior ibrutinib therapy (except persistent hematologic
toxicity if meeting entry criteria). The PI should determine if AEs are an ongoing
sequel of prior BTK therapy such as fungal infections, skin rash, diarrhea, fatigue,
cramps and colitis or if the patient has resolved AE and is free of these adverse
events >= 2 months after stopping ibrutinib)
- 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, or any other
gastrointestinal condition that could interfere with the absorption and metabolism of
acalabrutinib
- Presence of a gastrointestinal ulcer diagnosed by endoscopy within 3 months before
first dose of study drug
- Major surgery within 4 weeks of initiation of therapy
- Requires anticoagulation with warfarin or equivalent vitamin K antagonist
- Concomitant use of corticosteroids at > 10 mg prednisone or equivalent per day
- Requires treatment with strong CYP3A inhibitors or inducers
- Any of the following cardiac related conditions:
- New York Heart Association (NYHA) class III and IV heart failure,
- Active/symptomatic coronary artery disease,
- Myocardial infarction in the preceding 6 months,
- Significant conduction abnormalities, including but not limited to:
- Left bundle branch block,
- 2nd degree atrioventricular (AV) block type II,
- 3rd degree block,
- QT prolongation (corrected QT interval [QTc] > 500 msec),
- Sick sinus syndrome,
- Ventricular tachycardia,
- Symptomatic bradycardia (heart rate < 50 bpm),
- Persistent and uncontrolled atrial fibrillation.
- Uncontrolled hypertension,
- Hypotension,
- Light headedness and syncope
- Acute infection requiring systemic anti-microbial treatment (systemic antibiotics,
antivirals, or antifungals) within 14 days prior to initiation of therapy
- 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
- Any other serious medical condition including, but not limited to, uncontrolled
diabetes mellitus, chronic obstructive pulmonary disease (COPD), renal failure,
psychiatric illness or social circumstances that, in the investigator's opinion places
the patient at unacceptable risk and would prevent the subject from signing the
informed consent form or complying with study procedures
