Acalabrutinib and Venetoclax With or Without Early Obinutuzumab for the Treatment of High Risk, Recurrent, or Refractory Chronic Lymphocytic Leukemia or Small Lymphocytic Lymphoma
brief summary
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.
detailed description
PRIMARY OBJECTIVES:
I. Demonstrate improvement in bone marrow (BM) undetectable-minimal residual disease,10-4 sensitivity (MRD4) from 40% to 70% after 7 courses of combined acalabrutinib (ACA) and venetoclax (VEN) (end of C9 overall) with addition of early obinutuzumab (OBIN). (Treatment-naive \[TN\] cohort) II. Demonstrate improvement in BM undetectable-MRD4 from 40% to 70% after 12 courses of combined acalabrutinib (ACA) and venetoclax (VEN) (end of cycle \[C\]14 overall) with addition of early obinutuzumab (OBIN). (Relapsed/refractory \[R/R\] cohort)
SECONDARY AND EXPLORATORY OBJECTIVES:
I. Determine the safety of combined acalabrutinib, venetoclax obinutuzumab. II. Determine the overall best response rates (complete response \[CR\], partial response \[PR\], overall response \[OR\]) for each cohort and each treatment arm by International Workshop on Chronic Lymphocytic Leukemia (iwCLL) 2018 criteria.
III. Estimate the time to best response for each cohort and each treatment arm with this combination.
IV. Estimate the progression-free (PFS) for each cohort and each treatment arm. V. Estimate proportion of patients with blood/BM undetectable-MRD4, blood/BM undetectable-MRD6 (10-6 sensitivity), CR after 12 and 24 courses combination with VEN (end of C14 and C26 overall) (by cohort and OBIN status).
VI. Determine the proportion of patients who receive late OBIN (C15-C20 overall) and conversion rate for blood/BM undetectable-MRD4 and blood/BM undetectable-MRD6 and CR in those who receive late OBIN.
VII. Correlate plasma cell-free deoxyribonucleic acid (DNA) (cfDNA) with cell-based blood/BM undetectable-MRD4, blood/BM undetectable-MRD6 status at all response assessment time points.
VIII. Determine proportion of patients who discontinue treatment early based on undetectable-MRD results.
IX. Determine time-to-blood MRD6 relapse for those who achieve undetectable-MRD6.
X. Determine response to re-treatment upon relapse. XI. Assess clonal evolution at relapse and correlate with plasma cell-free DNA (cfDNA).
XII. Determine OBIN pharmacokinetics - free drug level assessments to optimize dosing.
official title
A Randomized Phase II Study of Acalabrutinib (ACA) + Venetoclax (VEN) +/- Early Obinutuzumab (OBIN) for Patients With Chronic Lymphocytic Leukemia (CLL)