Prospective Randomized Phase 2 Study of Acalabrutinib + Obinutuzumab or Venetoclax in Previously Untreated CLL

Background and Significance:

Combination regimens that include Bruton-Tyrosine Kinase inhibitors (BTKi), anti-CD20 monoclonal antibodies (MOAB), and/or BCL2 inhibitors (BCL2i) are increasingly studied for the initial treatment of chronic lymphocytic leukemia (CLL). Currently, all studies combining these agents start them in the first 3 cycles when disease bulk is typically highest. There is rationale for adding a second drug in a delayed manner when disease burden is less to improve efficacy and safety. The addition of venetoclax (Thompson Leukemia 2023) and obinutuzumab (Rawstron ASH 2018) in patients already receiving ibrutinib led to deep responses in two separate studies. Furthermore, there is no current study comparing the efficacy of BTKi plus anti-CD20 MOAB versus BTKi plus BCL2i. Therefore, we designed a randomized phase 2 study of the BTKi acalabrutinib (A) for 12 cycles followed by randomization to A plus obinutuzumab (AO) or the BCL2i venetoclax (AV) for a fixed-duration of 6 additional cycles with a primary endpoint of rate of bone marrow undetectable measurable residual disease (MRD) after treatment to test both a delayed approach to combination therapy and choice of agent added to BTKi.

Study Design and Methods:

This single center phase 2 study, NCT05336812, is currently enrolling patients at The Ohio State University in Columbus, OH. Eligible patients must have untreated CLL or small lymphocytic lymphoma that is not high-risk defined as having del(17p) on FISH, TP53 mutation, or complex karyotype (≥3 abnormalities). Patients will receive 12 cycles of A monotherapy, and then will be randomized to either AO or AV for 6 cycles (cycle = 28 days). At randomization, patients will be stratified based on presence of MRD in the bone marrow. After 18 cycles, all patients discontinue therapy and are followed. The primary endpoint assessment is 2 cycles after end of treatment. Bone marrow undetectable MRD (uMRD) is defined as <1x10⁴ CLL cells by flow cytometry.

The primary endpoint will be analyzed using a two-stage flexible screening design with historical control comparison. This design allows factors other than uMRD rates (e.g. response, safety, survival) to be reviewed if uMRD rates in both arms are similar (within 15%). This ensures a high probability of selecting the better arm, if it exists, while controlling the probability of selecting either arm when neither is better than the historical control. The historical control is the A arm of the ELEVATE-TN which had 7% peripheral blood uMRD (Sharman Lancet 2020), which likely over-estimates uMRD in the bone marrow. The goal uMRD rate is based on a phase 2 study (Thompson Leukemia 2023) in which uMRD was achieved in 40% of patients with high-risk CLL who received 6 cycles of venetoclax after continuous ibrutinib. To have an 88% power to select the more promising arm if it exists, assuming true uMRD rates of 20% and 45%, while constraining the global one-sided type I error to 10% when the true uMRD rate for historical control is 5%, <7% due to the presumed overestimation, a total of 23 evaluable patients are required per arm. This calculation assumes a 50:50 chance of selecting the better arm based on other factors when uMRD rates are within 15%. If ≤2 patients in each arm have uMRD, neither arm will be considered promising. If only 1 arm has ≥3 patients with uMRD, that arm will be selected for further study. If both arms have ≥3 patients with uMRD and the uMRD rate for one arm is >15% higher than the other arm, the arm with the higher uMRD rate will be selected as best. If the difference in uMRD is within 15% between arms, factors other than uMRD will be used to decide which treatment strategy to further study. There will not be a direct comparison of uMRD rates between arms as the study is not designed or powered to do this.

Secondary endpoints include progression-free survival, time to next treatment, overall response rate, and duration of response. Safety will be characterized by the type, frequency, severity, timing of onset, duration, and relationship to study drug of any treatment emergent adverse events. The study will enroll 52 patients to target 46 evaluable patients randomized.

This single center phase 2 study will determine the rate of bone marrow uMRD after 6 cycles of delayed treatment with AO or AV started after 12 cycles of A monotherapy. The results are expected to add information on the delayed combination approach as well as choice of combination agent.