Overview

This phase II trial studies how well acalabrutinib and venetoclax with or without early obinutuzumab work for the treatment of chronic lymphocytic leukemia or small lymphocytic lymphoma that is high risk, has come back (recurrent), or does not respond to treatment (refractory). Acalabrutinib may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Venetoclax may stop the growth cancer cells by blocking BCL-2 protein needed for cell growth. Immunotherapy with monoclonal antibodies, such as obinutuzumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Giving acalabrutinib and venetoclax together with early obinutuzumab may improve clinical outcomes and control the disease.

Eligibility

Inclusion Criteria:

1. Patients with a diagnosis of CLL/SLL and indication for treatment by 2018 iwCLL

   criteria

             Cohort 1: Untreated patients with at least 1 high-risk feature (del(17p) or mutated
             TP53 or del(11q) or unmutated IGHV or complex karyotype) OR ≥65 years of age Cohort 2:
             Relapsed after and/or refractory to at least one prior therapy
          2. Age 18 years or older
          3. Eastern Cooperative Oncology Group (ECOG) Performance Status ≤2
          4. Adequate renal and hepatic function:
               -  Total bilirubin ≤1.5 x upper limit of normal (ULN) or ≤3 x ULN for patients with
                  Gilbert's disease
               -  Creatinine clearance >50 mL/min (calculated according to institutional standards
                  or using Cockcroft-Gault, MDRD, or CKD-EPI formula)
               -  ALT and AST ≤3.0 x ULN, unless clearly due to disease involvement
          5. Absolute neutrophil count greater than 750 neutrophils/L, unless thought to be due to
             marrow infiltration with CLL. Platelet count of greater than 30,000/µl, with no
             platelet transfusion in 2 weeks prior to registration , unless thought to be due to
             marrow infiltration with CLL.
          6. Women of childbearing potential must have a negative serum or urine beta human
             chorionic gonadotropin (β-hCG) pregnancy test result within 7 days prior to the first
             dose of study drugs and must agree to use an effective contraception method during the
             study and for 2 days after the last dose of acalabrutinib, 30 days after the last dose
             of venetoclax, or 18 months after the last dose of obinutuzumab, whichever is longer.
             Women of non-childbearing potential are those who are postmenopausal greater than 1
             year or who have had a bilateral tubal ligation or hysterectomy. Men who are sexually
             active must agree to use highly effective forms of contraception with the addition of
             a barrier method (condom) during the study and for 30 days after the last dose of
             venetoclax and for 18 months after the last dose obinutuzumab, whichever is longer.
          7. Free of prior malignancies for 2 years with exception of patients diagnosed with basal
             cell or squamous cell carcinoma of the skin, or carcinoma "in situ" of the cervix or
             breast, who are eligible even if they are currently treated or have been treated
             and/or diagnosed in the past 2 years prior to study enrolment. If patients have
             another malignancy that was treated within the last 2 years, such patients may be
             enrolled, if the likelihood of requiring systemic therapy for this other malignancy
             within 2 years is less than 10%, as determined by an expert in that particular
             malignancy at MD Anderson Cancer Center, and after consultation with the Principal
             Investigator.
          8. Patients must provide written informed consent.
        Exclusion Criteria:
          1. Prior treatment with combined BTKi and BCL2i where patients do not achieve at least
             partial response or progress and need new treatment within 2 years of completing
             fixed-duration combined treatment.
          2. Major surgery, radiotherapy, chemotherapy, biologic therapy, immunotherapy,
             investigational therapy or live virus vaccination within 3 weeks prior to the first
             dose of the study drugs, unless patients have rapidly progressive disease, in which
             case, washout will be 3 drug half-lives
          3. History of severe allergic or anaphylactic reactions to humanized or murine monoclonal
             antibodies or known sensitivity or allergy to murine products
          4. Uncontrolled clinically significant active infection (viral, bacterial, and fungal)
          5. Known positive serology for human immunodeficiency virus (HIV), due to potential
             drug-drug interactions between anti-retroviral medications and the study drugs
          6. Active hepatitis B infection (defined as the presence of detectable HBV DNA, HBe
             antigen or HBs antigen). Subjects with serologic evidence of prior vaccination (HBsAg
             negative, anti-HBs antibody positive, anti-HBc antibody negative) are eligible.
             Patients who are HBsAg negative/HBsAb positive but HBcAb positive are eligible,
             provided HBV DNA is negative.
          7. Active hepatitis C, defined by the detectable hepatitis C RNA in plasma by PCR
          8. Active, uncontrolled autoimmune phenomenon (autoimmune hemolytic anemia or immune
             thrombocytopenia) requiring steroid therapy with >20mg daily of prednisone dose or
             equivalent
          9. 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.
         10. Patient is pregnant or breast-feeding
         11. Concurrent use of warfarin
         12. Received strong CYP3A inhibitors or strong CYP3A inducers within 7 days of starting
             study drugs and throughout venetoclax administration
         13. Consumed grapefruit, grapefruit products, Seville oranges, or star fruit within 7 days
             of starting venetoclax
         14. Known bleeding disorder or history of stroke or intracranial hemorrhage within past 6
             months
         15. Malabsorption syndrome or other condition that precludes enteral route of
             administration
         16. Other severe acute or chronic medical or psychiatric condition or laboratory
             abnormality that in the opinion of the investigator may increase the risk associated
             with study participation or investigational product administration or may interfere
             with the interpretation of study results and/or would make the patient inappropriate
             for enrollment into this study.