OUTLINE:
Patients receive acalabrutinib orally (PO) twice a day (BID) and venetoclax PO once daily
(QD) on days 1-28. Patients receive acalabrutinib alone for the first three 28 day cycles.
Venetoclax is added beginning with Cycle 4. Treatment repeats every 28 days for up to 26
cycles in the absence of disease progression or unacceptable toxicity.
After completion of study treatment, patients are followed-up every 12 weeks and annually for
10 years.
Inclusion Criteria:
- Men and women >= 18 years of age.
- Diagnosis of CLL or small lymphocytic lymphoma (SLL) that meets the published
diagnostic criteria.
- Active disease per IWCLL 2018 criteria that require treatment. At least one of the
following:
- Evidence of progressive marrow failure as manifested by the development of, or
worsening of, anemia and/or thrombocytopenia
- Massive (> 6 cm below left costal margin), progressive, or symptomatic
splenomegaly
- Massive nodes (> 10 cm in longest diameter), or progressive or symptomatic
lymphadenopathy
- Progressive lymphocytosis with an increase of > 50% over a 2-month period or
lymphocyte-doubling time of < 6 months. Lymphocyte-doubling time may be obtained
by linear regression extrapolation of absolute lymphocyte counts obtained at
intervals of 2 weeks over an observation period of 2 to 3 months. In patients
with initial blood lymphocyte counts of < 30 x 109/L lymphocyte-doubling time
should not be used as a single parameter to define treatment indication. In
addition, factors contributing to lymphocytosis or lymphadenopathy other than
CLL/SLL (e.g., infection) should be excluded.
- Constitutional symptoms, defined as any 1 or more of the following
disease-related symptoms or signs
- Unintentional weight loss of > 10% within the previous 6 months
- Significant fatigue
- Fevers > 100.5 degrees Fahrenheit (F) or 38 degrees Celsius (C) for 2 weeks
without other evidence of infection
- Night sweats for > 1 month without evidence of infection
- Relapsed or refractory to at least 1 prior systemic therapy for CLL/SLL. A line of
therapy is defined as completing at least 2 cycles of treatment of standard regimen
according to current National Comprehensive Cancer Network (NCCN) guidelines, or of an
investigational regimen on a clinical trial.
- Absolute neutrophil count (ANC) >= 750 cells/microliter (0.75 x 10^9/L); ANC >= 500
cells/microliter (0.50 x 10^9/L) in subjects with documented bone marrow involvement
of CLL (independent of growth factor or transfusion support within 1 week of
screening).
- Hemoglobin >= 10 g/dL (independent of growth factor or transfusion support within 1
week of screening).
- Platelet count >= 50,000 cells/microliter (50 x 10^9/L); platelet count >= 25,000
cells/microliter (25 x 10^9/L) in subjects with documented bone marrow involvement of
CLL (independent of growth factor or transfusion support within 1 week of screening).
- Serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =< 2.5 x
upper limit of normal (ULN)
- Total bilirubin =< 2 x ULN, unless directly attributable to Gilbert's syndrome
- Estimated creatinine clearance of >= 50 mL/min
- Eastern Cooperative Oncology Group (ECOG) performance status of 0-2
- Women of childbearing potential (WOCBP) who are sexually active must use highly
effective methods of contraception during treatment and for 30 days after the last
dose of acalabrutinib or venetoclax, whichever occurs later
- Wiling and able to participate in all required evaluations and procedures in this
study protocol, including swallowing capsules without difficulty
- Able to understand the purpose and the risks of the study and provide signed and dated
informed consent and authorization to use protected health information
Exclusion Criteria:
- Known prolymphocytic leukemia or history of, or currently suspected, Richter's
transformation (biopsy based on clinical suspicion may be needed to rule out
transformation)
- Prior disease progression while on a BTK inhibitor
- Prior disease progression while on venetoclax
- Prior intolerance to acalabrutinib or venetoclax
- Prior malignancy (or any other malignancy requiring active treatment), except for
adequately treated basal cell or squamous cell skin cancer, in situ cervical cancer,
low-grade prostate carcinoma (Gleason grade =< 6) or other cancer from which the
subject has been disease free for >= 2 years or which will not limit survival to < 3
years
- 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 or 4 cardiac diseases as defined by the New York Heart
Association Functional Classification, or corrected QT interval (QTc) > 480 msec at
screening. Subjects with controlled, asymptomatic atrial fibrillation during screening
can enroll on study.
- 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. Patients with
history of such operations are eligible if in treating physician's opinion they have
no absorption issues.
- Known history of drug-specific hypersensitivity or anaphylaxis to acalabrutinib or
venetoclax
- Active bleeding or history of bleeding diathesis (e.g. hemophilia or von Willebrand
disease), or requires/is receiving anticoagulation with warfarin or equivalent vitamin
K antagonists
- Prothrombin time (PT)/international normalized ratio (INR) or activated partial
thromboplastic time (aPTT) (in the absence of lupus anticoagulant) > 2 x ULN
- Uncontrolled autoimmune hemolytic anemia (AIHA) or idiopathic thrombocytopenic purpura
(ITP)
- Presence of a gastrointestinal ulcer diagnosed by endoscopy within 3 months before
screening
- Requires treatment with a strong cytochrome P450 3A4 (CYP3A4) inhibitor or inducers.
The use of strong or moderate CYP3A inhibitors or inducers within 7 days of the first
dose of study drug is prohibited.
- Requires treatment with proton pump inhibitors (eg, omeprazole, esomeprazole,
lansoprazole, dexlansoprazole, rabeprazole, or pantoprazole) at the time of
enrollment. 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
- Major surgical procedure within 7 days of first dose of study drug. 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 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.
- Breastfeeding or pregnant
- Concurrent participation in another therapeutic clinical trial
- Known history of infection with human immunodeficiency virus (HIV) or any active
significant infection (eg. bacterial, viral, or fungal)
- History of confirmed progressive multifocal leukoencephalopathy (PML)
