The main purpose of this research study is to find out if the combination of acalabrutinib
and high frequency low dose subcutaneous rituximab is safe and effective in patients who have
previously untreated chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL).
Despite an array of available therapies, CLL remains an incurable disease. Furthermore, the
presence of certain cytogenetic abnormalities and high-risk mutational features predicts for
a reduced response to treatment, and as a result, a shorter period of progression-free
survival. The development of a well-tolerated more effective, easily administered and limited
duration therapy would be a major contribution to the management of CLL and other B cell
malignancies.
Acalabrutinib is an imidazopyrazine analogue and a potent inhibitor of BTK in vitro and in
vivo. Acalabrutinib shows improved selectivity for BTK compared with ibrutinib. Functional
inhibition of non-target cells (eg, T cells, NK cells, platelets) was not observed for
acalabrutinib at clinically relevant concentrations. Rituximab is a chimeric monoclonal
antibody targeting CD20 FDA approved for the treatment of CLL/SLL using intravenous or
subcutaneous formulations.
Antibody dependent cellular phagocytosis may be optimized using high frequency subcutaneous
administration of anti-CD20 monoclonal antibodies. Unlike ibrutinib, acalabrutinib does not
cause significant in vitro inhibition of rituximab induced antibody dependent cellular
phagocytosis in vitro. The investigator thus proposes that acalabrutinib would be an ideal
partner drug with high frequency low dose SQ rituximab in the treatment of CLL and that the
combination will increase the efficacy of therapy for CLL patients by decreasing the time to
achievement of complete response and allowing for shorter and less toxic therapy.
Inclusion Criteria:
1. Diagnosis of B-cell CLL or SLL, with diagnosis established according to IWCLL criteria
and documented within medical records. Patients must not have received previous
therapy for CLL/SLL
2. CLL/SLL that warrants treatment consistent with accepted IWCLL criteria for initiation
of therapy. Any one of the following conditions constitutes CLL/SLL that warrants
treatment:
1. Evidence of progressive marrow failure as manifested by the onset or worsening of
anemia and/or thrombocytopenia, or
2. Massive (i.e., lower edge of spleen ≥6 cm below the left costal margin),
progressive, or symptomatic splenomegaly, or
3. Massive (i.e., ≥10 cm in the longest diameter), progressive, or symptomatic
lymphadenopathy, or
4. Progressive lymphocytosis in the absence of infection, with an increase in blood
absolute lymphocyte count (ALC) ≥50% over a 2-month period or lymphocyte doubling
time of <6 months (as long as initial ALC was ≥30,000/L), or
5. Autoimmune anemia and/or thrombocytopenia that is poorly responsive to
corticosteroids or other standard therapy, or
6. Constitutional symptoms, defined as any one or more of the following
disease-related symptoms or signs occurring in the absence of evidence of
infection:
i. Unintentional weight loss of ≥10% within the previous 6 months, or
ii. Significant fatigue (≥Grade 2), or
iii. Fevers >100.5°F or 38.0°C for ≥2 weeks, or
iv. Drenching night sweats for >1 month.
3. Adequate organ system function, defined as follows:
1. Absolute neutrophil count (ANC) ≥ 0.5x109/L and platelet count ≥ 30x109/L
2. Total bilirubin ≤2.5 times the upper limit of normal (ULN) unless due to
Gilbert's disease
3. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤2.5 x ULN if
no liver involvement or ≤5 x the ULN if known liver involvement
4. Calculated creatinine clearance >30 mL/min (as calculated by the Cockcroft-Gault
formula)
5. Patients with PT/INR or aPTT ≤2xULN.
4. ECOG performance status ≤ 2 unless related to CLL.
5. Male or female ≥ 18 years of age.
6. Ability to swallow and retain oral medication.
7. Woman of childbearing potential (WOCBP) who are sexually active must use highly
effective methods of contraception during treatment and for 2 days after the last dose
of acalabrutinib and for 12 months following last dose of rituximab. (see Appendix 3
for examples)
8. Willingness and ability to comply with study and follow-up procedures, and give
written informed consent.
Exclusion Criteria:
1. Patients receiving cancer therapy (i.e., chemotherapy, radiation therapy,
immunotherapy, biologic therapy, hormonal therapy, surgery).
a. Systemic corticosteroid therapy started prior to study entry is allowed as
clinically warranted. Topical or inhaled corticosteroids are permitted.
2. Serologic status reflecting active hepatitis B or C infection. Patients 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.
3. Known history of HIV.
4. Known histological transformation from CLL to an aggressive lymphoma.
5. Evidence of ongoing systemic bacterial, fungal or viral infection, except localized
fungal infections of skin or nails. NOTE: Patients may be receiving prophylactic
antiviral or antibacterial therapies at investigator discretion.
6. Live virus vaccines within 4 weeks prior to C1D1 or during rituximab therapy.
7. History of anaphylaxis (excluding infusion related reactions) in association with
previous anti-CD20 administration or acalabrutinib.
8. Any severe and/or uncontrolled medical conditions or other conditions that could
affect their participation in the study such as:
1. Symptomatic, or history of documented congestive heart failure (NY Heart
Association functional classification III-IV)
2. Uncontrolled cardiac arrhythmia (Patients with controlled atrial
fibrillation/flutter are eligible)
3. Myocardial infarction within 3 months of enrollment
4. Angina not well-controlled by medication
5. Poorly controlled or clinically significant atherosclerotic vascular disease
including cerebrovascular accident (CVA), transient ischemic attack (TIA),
angioplasty, cardiac/vascular stenting within 3 months of enrollment.
6. Active bleeding or history of bleeding diathesis (eg, hemophilia or von
Willebrand disease).
7. Any history of intracranial bleed or stroke within 6 months of first dose of
study drug
8. Patients with suspected or confirmed PML
9. Patients with malabsorption syndrome or gastrointestinal disease that limits
absorption of oral medication
9. Malignancy within 2 years of study enrollment except for adequately treated basal,
squamous cell carcinoma or non-melanomatous skin cancer, carcinoma in situ of the
cervix, superficial bladder cancer not treated with intravesical chemotherapy or BCG
within 6 months, localized prostate cancer and PSA <1.0 mg/dL on 2 consecutive
measurements at least 3 months apart with the most recent one being within 4 weeks of
study entry.
10. Patients with active uncontrolled autoimmune hemolytic anemia or ITP.
11. Inability to discontinue use of strong CYP3A inhibitors. Patients taking moderate
CYP3A inhibitors or strong CYP3A inducers are eligible.
12. Requires or receiving anticoagulation with warfarin or equivalent vitamin K
antagonists (eg, phenprocoumon) within 7 days of first dose of study drug.
13. Requires treatment with proton pump inhibitors (eg, omeprazole, esomeprazole,
lansoprazole, dexlansoprazole, rabeprazole, or pantoprazole) at study entry. Subjects
receiving proton pump inhibitors who switch to H2-receptor antagonists or antacids are
eligible for enrollment to this study.
