early intervention with acalabrutinib in patients with high risk cll

Conditions: Chronic Lymphocytic Leukemia; CLL/SLL

Summary: this study evaluates the effectiveness of acalabrutinib treatment in patients with chronic lymphocytic leukemia (cll) deemed at high risk for richter's transformation (rt). this is a single arm study. enrolled patients will initiate therapy with acalabrutinib and will dose continuously. while on study, subjects will be monitored monthly for the first 3 months, then every three months thereafter until disease progression, discontinuation due to toxicity, death, or study completion.

this is a multi-center, single arm, phase ii clinical trial to investigate the effectiveness of acalabrutinib treatment within 6 months of chronic lymphocytic leukemia (cll) diagnosis for patients with cll deemed at high risk for richter's transformation (rt).

Eligibility criteria:
inclusion criteria: * subject must be able to voluntarily sign and date an informed consent, approved by an independent ethics committee (iec)/institutional review board (irb), prior to the initiation of any screening or study specific procedures. * the time from diagnosis to consent should be ≤6 months. * subject must be ≥ 18 years of age. * subject must have diagnosis of cll/sll based upon 2018 iwcll guidelines. * rai stage 0-2 disease without indication for treatment as defined by the 2018 iwcll guidelines * subject must have high risk cll as defined by any one of the following: * notch1 mutated (classic frameshift mutation only) * unmutated v4-39 b cell receptor usage * pathogenic c-myc mutations * complex karyotype, (by cpg/oligodeoxynucleotide stimulation) * deletion 17p, or presence of tp53 mutation * subject has an eastern cooperative oncology group (ecog) performance score of ≤ 2. * pt/ptt/inr within 1.5 x the uln * adequate renal function defined by serum creatinine less than 2 x uln * adequate hepatic function: * alt/ast less than 2x uln * tbili less than 1.5 x uln unless bilirubin elevation is due to gilbert's syndrome (total bilirubin \<3) * subject must have adequate bone marrow function. * absolute neutrophil count ≥1.0 x103/μl * hemoglobin ≥ 11.0 g/dl * platelets ≥ 100 x 103/μl exclusion criteria: * previous exposure to any systemic anti-cancer therapy as a treatment for cll, including but not limited to chemotherapy, immunotherapy, radiotherapy, or investigational therapy. note, patients treated with chemotherapy for a prior non-hematologic malignancy if more than 5 years earlier are eligible. * subject with a history of malignancy except for non-melanoma skin cancers. subjects treated with curative intent via methods of local resection and or locally targeted anticancer treatment and are free of malignancy for at least 5 years from treatment end will be allowed to enroll. * subject requires chronic immunosuppressive therapy for any reason or was treated with immunosuppressive therapy within 6 months of study entry. * subjects with a history of autoimmune hemolytic anemia or immune thrombocytopenia purpura. * subject has prolymphocytic leukemia. * active bleeding, or history of bleeding diathesis (e.g., hemophilia or von willebrand disease) * subject requires warfarin or equivalent vitamin k antagonist * uncontrolled or active significant infection, * history of or suspected or confirmed pml * 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 disease as defined by the new york heart association functional classification. subjects with controlled, asymptomatic atrial fibrillation during screening can enroll on study. * patients with stroke or cns hemorrhage within 6 months * pregnant or breastfeeding * women of childbearing potential (wcbp) who are sexually active with heterosexual partners must agree to use highly effective methods of contraception during treatment and for 2 days after the last dose of acalabrutinib. * major surgical procedure within 28 days of first dose of study drug. if a subject had surgery, they must have recovered adequately from any toxicity or complications before the first dose of study drug. * has difficulty with or is unable to swallow oral medication or has significant gastrointestinal disease that would limit absorption of oral medication. * subject is known to be positive for human immunodeficiency virus (hiv) * active hepatitis c, as confirmed by being positive for hep c rna by pcr * active hepatitis b infection documented by a positive pcr for hep b dna. if hepatitis b serology is positive for hepatitis b core antibody, but hep b dna pcr is negative, patient is eligible to enroll. * subject requires strong cyp 3a4/5 inhibitors or inducers (appendix b). * subject requires proton pump inhibitors. (subjects that can transition to an h2 antagonist are allowed to enroll.)

Keywords: cll untreated